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---|---|---|
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drug591 | Hydroxychloroquine Wiki | 0.23 |
drug1016 | Placebo Wiki | 0.20 |
drug1148 | Remestemcel-L Wiki | 0.17 |
drug1213 | Saliva collection Wiki | 0.17 |
drug136 | Azithromycin Tablets Wiki | 0.17 |
drug421 | Dexamethasone Wiki | 0.17 |
drug163 | Baricitinib Wiki | 0.16 |
drug820 | Mesenchymal Stromal Cells Wiki | 0.14 |
drug763 | Losartan Wiki | 0.14 |
drug1305 | Standard-of-care treatment Wiki | 0.12 |
drug950 | Organicell Flow Wiki | 0.12 |
drug57 | Aerosolized All trans retinoic acid Wiki | 0.12 |
drug1030 | Placebo of excipient(s) will be administered Wiki | 0.12 |
drug87 | Anti-SARS-CoV2 Serology Wiki | 0.12 |
drug192 | Biospecimen collection Wiki | 0.12 |
drug1442 | Umbilical Cord Mesenchymal Stem Cells Wiki | 0.12 |
drug130 | Azithromycin (Azithro) Wiki | 0.12 |
drug754 | Lopinavir 200Mg/Ritonavir 50Mg Tab Wiki | 0.12 |
drug448 | ECCO2R Wiki | 0.12 |
drug972 | PROTECTIVE VENTILATION Wiki | 0.12 |
drug414 | DeltaRex-G Wiki | 0.12 |
drug1461 | Valsartan (Diovan) Wiki | 0.12 |
drug1259 | Sodium Nitrite Wiki | 0.12 |
drug1407 | Tocilizumab Prefilled Syringe Wiki | 0.12 |
drug183 | Biological test Wiki | 0.12 |
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drug1018 | Placebo (Plasma-Lyte 148) Wiki | 0.12 |
drug1449 | Urine Test Wiki | 0.12 |
drug1662 | standard procedure Wiki | 0.12 |
drug559 | HLCM051 Wiki | 0.12 |
drug1098 | Qualitative interviews (in 40 patients : 20 with COVID-19 and 20 without COVID-19) Wiki | 0.12 |
drug229 | CAStem Wiki | 0.12 |
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drug1453 | Usual Care Wiki | 0.12 |
drug134 | Azithromycin 500Mg Oral Tablet Wiki | 0.12 |
drug139 | Açaí palm berry extract - natural product Wiki | 0.12 |
drug436 | Dociparastat sodium Wiki | 0.12 |
drug68 | Alteplase 50 MG [Activase] Wiki | 0.12 |
drug1541 | consultation Wiki | 0.12 |
drug1289 | Standard of care therapies Wiki | 0.12 |
drug125 | Ayurveda Wiki | 0.12 |
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drug1021 | Placebo Administration Wiki | 0.12 |
drug916 | Normal Saline Infusion + standard of care Wiki | 0.12 |
drug128 | Azinc Wiki | 0.12 |
drug1079 | Prone Positioning (PP) Wiki | 0.12 |
drug709 | Invasive mechanical ventilation Wiki | 0.12 |
drug54 | Additional biological samples Wiki | 0.12 |
drug1495 | XCEL-UMC-BETA Wiki | 0.12 |
drug1460 | Vaccine Wiki | 0.12 |
drug200 | Blood donation from convalescent donor Wiki | 0.12 |
drug56 | Aerosolized 13 cis retinoic acid Wiki | 0.12 |
drug1491 | Wharton's jelly derived Mesenchymal stem cells. Wiki | 0.12 |
drug71 | Amiodarone Wiki | 0.12 |
drug638 | Hydroxychloroquine, lopinavir/ritonavir or azithromycin and placebo (standard therapy) Wiki | 0.12 |
drug1648 | risk factors Wiki | 0.12 |
drug198 | Blood collection on admission and longitudinally Wiki | 0.12 |
drug74 | Anakinra Prefilled Syringe Wiki | 0.12 |
drug186 | Biological: mRNA-1273: 100 mcg Wiki | 0.12 |
drug36 | APL-9 Wiki | 0.12 |
drug867 | NaCl 0.9% Wiki | 0.12 |
drug1342 | TD-0903 Wiki | 0.12 |
drug18 | 2: Placebo Comparator Wiki | 0.12 |
drug294 | Cell therapy protocol 2 Wiki | 0.12 |
drug750 | Lopinavir / Ritonavir Pill Wiki | 0.12 |
drug1272 | Standard Mask Wiki | 0.12 |
drug197 | Blood collection Wiki | 0.12 |
drug966 | PEEP trial Wiki | 0.12 |
drug692 | Interleukin-1 receptor antagonist Wiki | 0.12 |
drug63 | Allogeneic NK transfer Wiki | 0.12 |
drug681 | Inhaled sedation Wiki | 0.12 |
drug1314 | Streptokinase Wiki | 0.12 |
drug1467 | Veru-111 Wiki | 0.12 |
drug33 | ACEIs Wiki | 0.12 |
drug1026 | Placebo for Azithromycin Wiki | 0.12 |
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drug1250 | Simvastatin Wiki | 0.12 |
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drug1463 | Vehicle Control Wiki | 0.12 |
drug1435 | ULTRAPROTECTIVE VENTILATION Wiki | 0.12 |
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drug100 | Ascorbic Acid Wiki | 0.12 |
drug1027 | Placebo for Hydroxychloroquine Wiki | 0.12 |
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drug1446 | Unfractionated heparin Wiki | 0.08 |
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drug1367 | Telmisartan Wiki | 0.08 |
drug1080 | Prone position Wiki | 0.08 |
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drug440 | Dornase Alfa Inhalation Solution [Pulmozyme] Wiki | 0.08 |
drug153 | BNT162a1 Wiki | 0.08 |
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drug622 | Hydroxychloroquine and Azithromycin Wiki | 0.08 |
drug1402 | Tocilizumab Wiki | 0.08 |
drug1280 | Standard of Care Wiki | 0.07 |
drug144 | BCG Vaccine Wiki | 0.07 |
drug893 | Nitric Oxide Wiki | 0.07 |
drug592 | Hydroxychloroquine (HCQ) Wiki | 0.07 |
drug442 | Doxycycline Wiki | 0.07 |
drug1302 | Standard treatment Wiki | 0.07 |
drug252 | COVID-19 RT-PCR Wiki | 0.07 |
drug1146 | Remdesivir Wiki | 0.06 |
drug1207 | Saline Wiki | 0.06 |
drug1530 | blood sampling Wiki | 0.06 |
drug952 | Oseltamivir Wiki | 0.05 |
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drug1104 | Questionnaire Wiki | 0.04 |
drug1042 | Placebos Wiki | 0.03 |
Name (Synonyms) | Correlation | |
---|---|---|
D012127 | Respiratory Distress Syndrome, Newborn NIH | 0.92 |
D012128 | Respiratory Distress Syndrome, Adult NIH | 0.87 |
D013577 | Syndrome NIH | 0.51 |
D055370 | Lung Injury NIH | 0.38 |
D014947 | Wounds and Injuries NIH | 0.17 |
D045169 | Severe Acute Respiratory Syndrome NIH | 0.17 |
D018352 | Coronavirus Infections NIH | 0.15 |
D012818 | Signs and Symptoms, Respiratory NIH | 0.12 |
D000071257 | Emergence Delirium NIH | 0.12 |
D018754 | Ventricular Dysfunction NIH | 0.08 |
D003693 | Delirium NIH | 0.08 |
D018487 | Ventricular Dysfunction, Left NIH | 0.08 |
D011024 | Pneumonia, Viral NIH | 0.08 |
D018746 | Systemic Inflammatory Response Syndrome NIH | 0.07 |
D009102 | Multiple Organ Failure NIH | 0.07 |
D011014 | Pneumonia NIH | 0.06 |
D012769 | Shock, NIH | 0.06 |
D011665 | Pulmonary Valve Insufficiency NIH | 0.05 |
D004417 | Dyspnea NIH | 0.05 |
D016638 | Critical Illness NIH | 0.05 |
D003141 | Communicable Diseases NIH | 0.05 |
D007239 | Infection NIH | 0.04 |
D058186 | Acute Kidney Injury NIH | 0.04 |
D007249 | Inflammation NIH | 0.04 |
D009369 | Neoplasms, NIH | 0.03 |
D014777 | Virus Diseases NIH | 0.02 |
Name (Synonyms) | Correlation | |
---|---|---|
HP:0010444 | Pulmonary insufficiency HPO | 0.06 |
HP:0002090 | Pneumonia HPO | 0.05 |
HP:0002098 | Respiratory distress HPO | 0.05 |
HP:0001919 | Acute kidney injury HPO | 0.05 |
HP:0002664 | Neoplasm HPO | 0.04 |
There are 70 clinical trials
Acute Respiratory Distress Syndrome (ARDS) causes the lungs to fail due to the collection of fluid in the lungs (pulmonary oedema). ARDS is common in severely ill patients in Intensive Care Units and is associated with a high mortality and a high morbidity in those who survive. ARDS occurs in approximately 20% case of COVID-19 and respiratory failure is the leading cause of mortality. There is a large economic burden with direct healthcare costs, but also indirectly due to the impact on the carer and patient through the patients inability to return to full time employment. There is little evidence for effective drug (pharmacological) treatment for ARDS. There is increasing information that mesenchymal stem cells (MSCs) might be important in treating ARDS. REALIST will investigate if a single infusion of MSCs will help in the treatment of ARDS. The first step will be to first of all determine what dose of MSCs is safe and then divide patients suffering from ARDS into two groups, one of which will get MSCs and the other a harmless dummy (or placebo) infusion, who will then be followed up to determine if lung function improves. If effective this may lead to further research to determine if MSCs are effective in patients with ARDS.
Description: OI is a physiological index of the severity of ARDS and measures both impaired oxygenation and the amount of mechanical ventilation delivered
Measure: Oxygenation index (OI) Time: Day 7Description: Incidence of SAEs
Measure: Incidence of Serious Adverse Events (SAEs) Time: 28 daysDescription: SOFA score is a measure of organ failure
Measure: Sequential Organ Failure Assessment (SOFA) score Time: Days 4, 7 and 14Description: Crs is a physiological measure of pulmonary function in ARDS
Measure: Respiratory compliance (Crs) Time: Days 4, 7 and 14Description: P/F ratio is a physiological measure of pulmonary function in ARDS
Measure: Partial pressure of arterial oxygen to the fraction of inspired oxygen ratio (P/F ratio) Time: Days 4, 7 and 14This is a quality improvement study with the purpose of observing and measuring the effects of implementation of a proven standardized lung protective ventilation protocol in the new electronic medical record system iCentra across all Intermountain Healthcare hospitals. Approximately 14,000 records will be accessed for this study from a database of mechanically ventilated patients established for quality improvement purposes. The investigators hypothesize that implementation of a standardized computerized lung protective ventilation protocol across all Intermountain Healthcare hospitals will be feasible, will decrease initial tidal volumes to the target 6 ml/kg PBW, and will improve outcomes. The objectives of this study are to: - Determine if the implementation of lung protective ventilation (with a 6 ml/kg PBW tidal volume ventilation protocol on initiation of mechanical ventilation) improves outcomes in patients with acute respiratory failure requiring mechanical ventilation - Determine if the implementation of lung protective ventilation (with a 6 ml/kg PBW tidal volume ventilation protocol on initiation of mechanical ventilation) improves outcomes in the sub-group of patients with the acute respiratory distress syndrome (ARDS) - Measure compliance with the implementation of a computerized lung protective ventilation protocol at 12 Intermountain Healthcare hospitals
Background: Intra-alveolar clotting and alveolar collapse in ARDS is due to alveolar capillaries epithelial and leakage. Subsequently, collapse induces hypoxemia that is resistant to recruitment (RM). Heparin and Streptokinase may prevent or dissolve intra-alveolar fibrin clot respectively helping alveolar re-expansion. We examined and compared the effect of nebulizing Heparin versus Streptokinase on reversing this pathology. Methods: Sixty severe ARDS (PaO2/FiO2<100) patients and failure of RM, prone position (PP) and neuromuscular block (NMB) were partially randomised into Group (I): (n=20) received nebulized Heparin 10000 IU/4h. Group (II): (n=20) received nebulized Streptokinase 250,000 IU/4h. Group (III): (n=20) received conservative management. Randomization to either Heparin or Streptokinase groups was applied to patients whom guardian accepted participation, while those who declined participation were followed-up as a control. The primary outcome was the change in PaO2/FiO2; the secondary outcomes included the change in compliance, plateau pressure, ventilation-off days, coagulation and ICU mortality.
Description: Change in the ratio of arterial oxygen tension to fraction of inspired oxygen from the baseline (day 0, before randomization and or the start of intervention) to day 1 to day 8 after the randomization and or start of intervention.
Measure: Change in PaO2/FiO2 ratio Time: daily over eight daysDescription: Change in the plateau airway pressure during ventilation from the baseline (day 0, before randomization and or the start of intervention) to day 1 to day 8 after the randomization and or start of intervention.
Measure: Change in the plateau pressure Time: daily over eight daysDescription: change in volume of the lungs per change in pressure during ventilation from the baseline (day 0, before randomization and or the start of intervention) to day 1 to day 8 after the randomization and or start of intervention.
Measure: Change in the pulmonary compliance Time: daily over eight daysDescription: Number of patients who are discharged alive
Measure: ICU survival rate Time: At the end of ICU stay up to one year after the start of recruitmentDescription: the total duration the patient stays in ICU
Measure: ICU length of stay Time: At the end of ICU stay up to one year after the start of recruitmentDescription: number of patients who required tracheostomy
Measure: Tracheostomy rate Time: During ICU stay up to one month after the start of recruitmentThe primary object of this clinical study is to investigate the efficacy of HLCM051 in patients with ARDS caused by pneumonitis.
Description: VFD for 28 days after administration of the investigational product
Measure: Ventilator-free days (VFD)(ARDS caused by pneumonia cohort) Time: 28 days after administration of the investigational productDescription: The number and rate of adverse events
Measure: Adverse events(ARDS caused by COVID-19 cohort) Time: From informed consent to 180 days after administration of the investigational productDescription: Change from baseline in systolic blood pressure(mmHg)
Measure: Change from baseline in systolic blood pressure(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in diastolic blood pressure(mmHg)
Measure: Change from baseline in diastolic blood pressure(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in pulse rate(beats/min)
Measure: Change from baseline in pulse rate(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in respiration(breath/min)
Measure: Change from baseline in respiration(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in oxygen saturation(%)
Measure: Change from baseline in oxygen saturation(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in body temperature(C)
Measure: Change from baseline in body temperature(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in red blood cell count(/uL)
Measure: Change from baseline in red blood cell count(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in hemoglobin(g/dL)
Measure: Change from baseline in hemoglobin(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in hematocrit(%)
Measure: Change from baseline in hematocrit(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in leukocyte count(/uL)
Measure: Change from baseline in leukocyte count(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in neutrophils(%)
Measure: Change from baseline in neutrophils(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in eosinophils(%)
Measure: Change from baseline in eosinophils(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in basophils(%)
Measure: Change from baseline in basophils(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in lymphocytes(%)
Measure: Change from baseline in lymphocytes(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in monocytes(%)
Measure: Change from baseline in monocytes(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in platelet count(/uL)
Measure: Change from baseline in platelet count(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in asparate aminotransferase(AST)(IU/L)
Measure: Change from baseline in asparate aminotransferase(AST)(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in alanine aminotransferase(ALT)(IU/L)
Measure: Change from baseline in alanine aminotransferase(ALT)(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in alkaline phosphatase(ALP)(IU/L)
Measure: Change from baseline in alkaline phosphatase(ALP)(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in total bilirubin(mg/dL)
Measure: Change from baseline in total bilirubin(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in blood urea nitrogen(BUN)(mg/dL)
Measure: Change from baseline in blood urea nitrogen(BUN)(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in creatinine(mg/dL)
Measure: Change from baseline in creatinine(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in sodium(Na)(mmol/L)
Measure: Change from baseline in sodium(Na)(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in potassium(K)(mmol/L)
Measure: Change from baseline in potassium(K)(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in chloride(Cl)(mmol/L)
Measure: Change from baseline in chloride(Cl)(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in calcium(Ca)(mg/dL)
Measure: Change from baseline in calcium(Ca)(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in blood sugar(mg/dL)
Measure: Change from baseline in blood sugar(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in urinary protein(- to >= 4+)
Measure: Change from baseline in urinary protein(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in urinary sugar(- to >= 4+)
Measure: Change from baseline in urinary sugar(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in uric blood(- to >= 4+)
Measure: Change from baseline in uric blood(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in urinary sediment(RBC)(/HPF)
Measure: Change from baseline in urinary sediment(RBC)(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in urinary sediment(WBC)(/HPF)
Measure: Change from baseline in urinary sediment(WBC)(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productDescription: Change from baseline in urinary sediment(Other)(/HPF)
Measure: Change from baseline in urinary sediment(Other)(ARDS caused by COVID-19 cohort) Time: From screening to 180 days after administration of the investigational productThe scientific community is in search for novel therapies that can help to face the ongoing epidemics of novel Coronavirus (SARS-Cov-2) originated in China in December 2019. At present, there are no proven interventions to prevent progression of the disease. Some preliminary data on SARS pneumonia suggest that inhaled Nitric Oxide (NO) could have beneficial effects on SARS-CoV-2 due to the genomic similarities between this two coronaviruses. In this study we will test whether inhaled NO therapy prevents progression in patients with mild to moderate COVID-19 disease.
Description: The primary outcome will be the reduction in the incidence of patients requiring intubation and mechanical ventilation, as a marker of deterioration from a mild to a severe form of COVID-19. Patients with indication to intubation and mechanical ventilation but concomitant DNI (Do Not Intubate) or not intubated for any other reason external to the clinical judgment of the attending physician will be considered as meeting the criteria for the primary endpoint.
Measure: Reduction in the incidence of patients with mild/moderate COVID-19 requiring intubation and mechanical ventilation Time: 28 daysDescription: Proportion of deaths from all causes
Measure: Mortality Time: 28 daysDescription: Time from initiation of the study to discharge or to normalization of fever (defined as <36.6°C from axillary site, or < 37.2°C from oral site or < 37.8°C from rectal or tympanic site), respiratory rate (< 24 bpm while breathing room air), alleviation of cough (defined as mild or absent in a patient reported scale of severe >>moderate>>mild>>absent) and resolution of hypoxia (defined as SpO2 ≥ 93% in room air or P/F ≥ 300 mmHg). All these improvements must be sustained for 72 hours.
Measure: Time to clinical recovery Time: 28 daysDescription: Proportion of patients with a negative conversion of RT-PCR from an oropharyngeal or oropharyngeal swab.
Measure: Negative conversion of COVID-19 RT-PCR from upper respiratory tract Time: 7 daysStudy Objective: 1. To test if post-exposure prophylaxis with hydroxychloroquine can prevent symptomatic COVID-19 disease after known exposure to the SARS-CoV-2 coronavirus. 2. To test if early preemptive hydroxychloroquine therapy can prevent disease progression in persons with known symptomatic COVID-19 disease, decreasing hospitalizations and symptom severity.
Description: Number of participants at 14 days post enrollment with active COVID19 disease.
Measure: Incidence of COVID19 Disease among those who are asymptomatic at baseline Time: 14 daysDescription: Repeated Measure mixed regression model of change in: Visual Analog Scale 0-10 score of rating overall symptom severity (0 = no symptoms; 10 = most severe)
Measure: Overall change in disease severity over 14 days among those who are symptomatic at baseline Time: 14 daysDescription: Outcome reported as the number of participants in each arm who require hospitalization for COVID19-related disease.
Measure: Incidence of Hospitalization Time: 14 daysDescription: Outcome reported as the number of participants in each arm who expire due to COVID-19-related disease.
Measure: Incidence of Death Time: 90 daysDescription: Outcome reported as the number of participants in each arm who have confirmed SARS-CoV-2 infection.
Measure: Incidence of Confirmed SARS-CoV-2 Detection Time: 14 daysDescription: Outcome reported as the number of participants in each arm who self-report symptoms compatible with COVID19 infection.
Measure: Incidence of Symptoms Compatible with COVID19 (possible disease) Time: 90 daysDescription: Outcome reported as the number of participants in each arm who discontinue or withdraw medication use for any reason.
Measure: Incidence of All-Cause Study Medicine Discontinuation or Withdrawal Time: 14 daysDescription: Visual Analog Scale 0-10 score of rating overall symptom severity (0 = no symptoms; 10 = most severe)
Measure: Overall symptom severity at 5 and 14 days Time: 5 and 14 daysDescription: Participants will self-report disease severity status as one of the following 3 options; no COVID19 illness (score of 1), COVID19 illness with no hospitalization (score of 2), or COVID19 illness with hospitalization or death (score of 3). Increased scale score indicates greater disease severity. Outcome is reported as the percent of participants who fall into each category per arm.
Measure: Ordinal Scale of COVID19 Disease Severity at 14 days among those who are symptomatic at trial entry Time: 14 daysThis is a multi-center, double-blinded study of COVID-19 infected patients randomized 1:1 to daily losartan or placebo for 10 days or treatment failure (hospital admission).
Description: Outcome reported as the number of participants per arm admitted to inpatient hospital care due to COVID-19-related disease within 15 days of randomization. Currently, there is a pre-planned pooled analysis with a national trial network under development.
Measure: Hospital Admission Time: 15 daysDescription: The PROMIS Dyspnea (shortness of breath) item banks and pools assess self-reported Functional Limitations, Severity, Activity Motivation, Activity Requirements, Airborne Exposure, Assistant Devices Resources, Characteristics, Emotional Response, Task Avoidance and Time Extension as they related to dyspnea. In the 33-item Functional Limitations bank, 33 daily activities are rated in terms of degree of difficulty while engaging in the activity over the past 7 days (0 = no difficulty, 1 = a little difficulty, 2 = some difficulty, 3 = much difficulty). Total scores range from 0 to 99, with higher scores reflecting greater functional limitations.
Measure: Change in PROMIS Dyspnea Functional Limitations Time: baseline, 10 daysDescription: The PROMIS Dyspnea (shortness of breath) item banks and pools assess self-reported Functional Limitations, Severity, Activity Motivation, Activity Requirements, Airborne Exposure, Assistant Devices Resources, Characteristics, Emotional Response, Task Avoidance and Time Extension as they related to dyspnea. The 33-item Severity bank assesses the severity of difficulty breathing during various specific activities (the same 33 activities assessed in Dyspnea Functional Limitations). Each activity is rated in terms of degree of dyspnea (0 = no shortness of breath, 1 = mildly short of breath, 2 = moderately short of breath, 3 = severely short of breath) while engaging in the activity over the past 7 days. Total scores range from 0 to 99 with higher scores reflecting greater levels of dyspnea during daily activity.
Measure: Change in PROMIS Dyspnea Severity Time: baseline, 10 daysDescription: Participants will report their maximum daily oral temperature to the study team. Outcome is reported as the mean maximum daily body temperature (in degrees Celsius) over 10 days.
Measure: Daily Maximum Temperature Time: 10 daysDescription: Outcome is reported as the mean number of emergency department and clinic presentations combined per participant in each arm.
Measure: Emergency Department/Clinic Presentations Time: 28 daysDescription: Outcome reported as the number of participants in each arm who fall into each of 7 categories. Lower scores indicate greater condition severity. The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities.
Measure: Disease Severity Rating Day 7 Time: 7 daysDescription: Outcome reported as the number of participants in each arm who fall into each of 7 categories. Lower scores indicate greater condition severity. The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities.
Measure: Disease Severity Rating Day 15 Time: 15 daysDescription: Outcome reported as the number of participants in each arm who fall into each of 7 categories. Lower scores indicate greater condition severity. The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities.
Measure: Disease Severity Rating Day 28 Time: 28 daysDescription: Participants will collect oropharyngeal swabs every third day for the duration of study participation. Viral load is measured as number of viral genetic copies per mL.
Measure: Viral Load by Oropharyngeal Swab Day 9 Time: 9 daysDescription: Participants will collect oropharyngeal swabs every third day for the duration of study participation. Viral load is measured as number of viral genetic copies per mL.
Measure: Viral Load by Oropharyngeal Swab Day 15 Time: 15 daysDescription: Outcome reported as the mean number of days participants in each arm did not require ventilator use.
Measure: Ventilator-Free Days Time: 28 daysDescription: Outcome reported as the mean number of days participants in each arm did not require therapeutic oxygen use.
Measure: Therapeutic Oxygen-Free Days Time: 28 daysDescription: Outcome reported as the percent of participants in each arm who require hospital admission by day 15 following randomization.
Measure: Need for Hospital Admission at 15 Days Time: 15 daysDescription: Outcome reported as the percent of participants in each arm who require oxygen therapy by day 15 following randomization.
Measure: Need for Oxygen Therapy at 15 Days Time: 15 daysNovel Corona Virus (SARS-CoV-2) is known to cause Respiratory Failure, which is the hallmark of Acute COVID-19, as defined by the new NIH/FDA classification. Approximately 50% of those who develop Critical COVID-19 die, despite intensive care and mechanical ventilation. Patients with Critical COVID-19 and respiratory failure, currently treated with high flow nasal oxygen, non-invasive ventilation or mechanical ventilation will be treated with Aviptadil, a synthetic form of Human Vasoactive Intestinal Polypeptide (VIP) plus maximal intensive care vs. placebo + maximal intensive care. Patients will be randomized to intravenous Aviptadil will receive escalating doses from 50 -150 pmol/kg/hr over 12 hours.
Description: Mortality
Measure: Mortality Time: 5 Days with followup through 30 daysDescription: Index of Respiratory Distress
Measure: PaO2:FiO2 ratio Time: 5 Days with followup through the end of telemetry monitoringDescription: TNF alpha levels as measured in hospital laboratory
Measure: TNF alpha Time: 5 DaysDescription: Multi-system organ failure free days
Measure: Multi-system organ failure free days Time: 5 days with followup through 30 daysThis is a multi-center, double-blinded study of COVID-19 infected patients requiring inpatient hospital admission randomized 1:1 to daily Losartan or placebo for 7 days or hospital discharge.
Description: Outcome calculated from the partial pressure of oxygen or peripheral saturation of oxygen by pulse oximetry divided by the fraction of inspired oxygen (PaO2 or SaO2 : FiO2 ratio). PaO2 is preferentially used if available. A correction is applied for endotracheal intubation and/or positive end-expiratory pressure. Patients discharged prior to day 7 will have a home pulse oximeter send home for measurement of the day 7 value, and will be adjusted for home O2 use, if applicable. Patients who died will be applied a penalty with a P/F ratio of 0.
Measure: Difference in Estimated (PEEP adjusted) P/F Ratio at 7 days Time: 7 daysDescription: Outcome reported as the mean number of daily hypotensive episodes (MAP < 65 mmHg) prompting intervention (indicated by a fluid bolus >=500 mL) per participant in each arm.
Measure: Daily Hypotensive Episodes Time: 10 daysDescription: Outcome reported as the number of participants in each arm requiring the use of vasopressors for hypotension.
Measure: Hypotension Requiring Vasopressors Time: 10 daysDescription: Outcome reported as the number of participants in each arm who experience acute kidney injury as defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines: Increase in serum creatinine by 0.3mg/dL or more within 48 hours OR Increase in serum creatinine to 1.5 times baseline or more within the last 7 days OR Urine output less than 0.5 mL/kg/h for 6 hours.
Measure: Acute Kidney Injury Time: 10 daysDescription: The SOFA assessment is used to track a person's risk status during stay in the Intensive Care Unit (ICU). The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal, and neurological systems. Each organ system is assigned a point value from 0 (normal) to 4 (high degree of dysfunction/failure). Total score is calculated by entering patient data into a SOFA calculator, a widely-available software. Total scores range from 0-24, with higher scores indicating greater chance of mortality.
Measure: Sequential Organ Failure Assessment (SOFA) Total Score Time: 10 daysDescription: Oxygen saturation (percent) is measured by pulse oximeter. Fraction of inspired oxygen (FiO2) (unitless) is the volumetric fraction of oxygen to other gases in respiratory support. The F/S ratio is unitless.
Measure: Oxygen Saturation / Fractional Inhaled Oxygen (F/S) Time: 10 daysDescription: Outcome reported as the number of participants who have expired at 28 days post enrollment.
Measure: 28-Day Mortality Time: 28 daysDescription: Outcome reported as the number of participants who have expired at 90 days post enrollment.
Measure: 90-Day Mortality Time: 90 daysDescription: Outcome reported as the number of participants in each arm who require admission to the Intensive Care Unit (ICU).
Measure: ICU Admission Time: 10 daysDescription: Outcome reported as the mean number of days participants in each arm did not require mechanical ventilation during an in-patient hospital admission.
Measure: Number of Ventilator-Free Days Time: 10 daysDescription: Outcome reported as the mean number of days participants in each arm did not require therapeutic oxygen usage during an in-patient hospital admission.
Measure: Number of Therapeutic Oxygen-Free Days Time: 10 daysDescription: Outcome reported as the mean number of days participants in each arm did not require vasopressor usage during an in-patient hospital admission.
Measure: Number of Vasopressor-Free Days Time: 10 daysDescription: Outcome reported as the mean length of stay (in days) in the Intensive Care Unit (ICU) for participants in each arm.
Measure: Length of ICU Stay Time: 10 daysDescription: Outcome reported as the mean length of in-patient hospital stay (in days) for participants in each arm.
Measure: Length of Hospital Stay Time: 10 daysDescription: Outcome reported as the number of participants requiring BiPAP OR high flow nasal cannula OR mechanical ventilation OR extracorporeal membranous oxygenation (ECMO) utilization during in-patient hospital care in each arm.
Measure: Incidence of Respiratory Failure Time: 10 daysDescription: The PROMIS Dyspnea (shortness of breath) item banks and pools assess self-reported Functional Limitations, Severity, Activity Motivation, Activity Requirements, Airborne Exposure, Assistant Devices Resources, Characteristics, Emotional Response, Task Avoidance and Time Extension as they related to dyspnea. In the 33-item Functional Limitations bank, 33 daily activities are rated in terms of degree of difficulty while engaging in the activity over the past 7 days (0 = no difficulty, 1 = a little difficulty, 2 = some difficulty, 3 = much difficulty). Total scores range from 0 to 99, with higher scores reflecting greater functional limitations.
Measure: Change in PROMIS Dyspnea Functional Limitations Time: 10 daysDescription: The PROMIS Dyspnea (shortness of breath) item banks and pools assess self-reported Functional Limitations, Severity, Activity Motivation, Activity Requirements, Airborne Exposure, Assistant Devices Resources, Characteristics, Emotional Response, Task Avoidance and Time Extension as they related to dyspnea. The 33-item Severity bank assesses the severity of difficulty breathing during various specific activities (the same 33 activities assessed in Dyspnea Functional Limitations). Each activity is rated in terms of degree of dyspnea (0 = no shortness of breath, 1 = mildly short of breath, 2 = moderately short of breath, 3 = severely short of breath) while engaging in the activity over the past 7 days. Total scores range from 0 to 99 with higher scores reflecting greater levels of dyspnea during daily activity.
Measure: Change in PROMIS Dyspnea Severity Time: 10 daysDescription: Outcome reported as the number of participants in each arm who fall into each of 7 categories. Lower scores indicate greater condition severity. The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities.
Measure: Disease Severity Rating Time: 10 daysDescription: Nasopharyngeal swabs will be collected every third day for the duration of study participation. Viral load is measured as number of viral genetic copies per mL.
Measure: Viral Load by Nasopharyngeal Swab Day 9 Time: 9 daysDescription: Nasopharyngeal swabs will be collected every third day for the duration of study participation. Viral load is measured as number of viral genetic copies per mL.
Measure: Viral Load by Nasopharyngeal Swab Day 15 Time: 15 daysDescription: Blood will be collected every third day for viral load assessment for the duration of study participation. Viral load is measured as number of viral genetic copies per mL.
Measure: Viral Load by Blood Day 9 Time: 9 daysDescription: Blood will be collected every third day for viral load assessment for the duration of study participation. Viral load is measured as number of viral genetic copies per mL.
Measure: Viral Load by Blood Day 15 Time: 15 daysThe study aims to investigate organ dysfunction and biomarkers in patients with suspected or verified COVID-19 during intensive care at Uppsala University Hospital.
Description: KDIGO AKI score
Measure: Acute Kidney Injury Time: During Intensive Care, an estimated average of 10 days.Description: Acute Respiratory Distress Syndrome yes/no
Measure: ARDS Time: During intensive care, an estimated average of 10 days.Description: Death within 30 days of ICU admission
Measure: 30 day mortality Time: 30 daysDescription: Death within 1 year of ICU admission
Measure: 1 year mortality Time: 1 yearDescription: Development of Chronic Kidney Disease
Measure: Chronic Kidney Disease Time: 60 days and 1 year after ICU admissionDescription: Sequential Organ Failure Score as a continuous variable
Measure: SOFA-score Time: During Intensive Care, an estimated average of 10 days.The (World Health Organization) WHO NOR- (Coronavirus infectious disease) COVID 19 study is a multi-centre, adaptive, randomized, open clinical trial to evaluate the safety and efficacy of hydroxychloroquine, remdesivir and standard of care in hospitalized adult patients diagnosed with COVID-19. This trial will follow the core WHO protocol but has additional efficacy, safety and explorative endpoints.
Description: All cause in-hospital mortality
Measure: In-hospital mortality Time: 3 weeksCoronavirus disease 2019 (COVID-19) is an emerging infectious disease that was first reported in Wuhan, China, and had subsequently spread worldwide. Twenty-nine percent of COVID-19 patients may develop ARDS. Based on the potential beneficial mechanisms of HFNC and PP, whether early use of prone positioning combined with HFNC can avoid the need for intubation in COVID-19 induced moderate to severe ARDS patients needs to be further investigated.
Description: the treatment failure rate of HFNC/HFNC+PP support and clinical requirement for advanced respiratory support
Measure: Treatment failure Time: 28 daysDescription: the improvement of SpO2/FIO2 or PaO2/FiO2 from HFNC alone to HFNC+PP
Measure: Efficacy of PP Time: 28 daysThe Severe Acute Respiratory Syndrome COronaVirus 2 (SARS-CoV2) is a new and recognized infectious disease of the respiratory tract. Most cases are mild or asymptomatic. However, around 5% of all patients develop Acute Respiratory Distress Syndrome (ARDS), which is the leading mortality cause in these patients. Corticosteroids have been tested in deferent scenarios of ARDS, including viral pneumonia, and the early use of dexamethasone is safe and appears to reduce the duration of mechanical ventilation in ARDS patients. Nevertheless, no large, randomized, controlled trial was performed evaluating the role of corticosteroids in patients with ARDS due SARS-CoV2 virus. Therefore, the present study will evaluate the effectiveness of dexamethasone compared to control (no corticosteroids) in patients with moderate and severe ARDS due to SARS-CoV2 virus.
Description: Ventilator-free days, defined as alive and free from mechanical ventilation, at 28 days after randomization.
Measure: Ventilator-free days Time: 28 days after randomizationDescription: Evaluation of the clinical status of patients on the 15th day after randomization defined by the 6-point Ordinal Scale, this scale ranges from 1 (Not hospitalized) to 6 (Death) with higher scores meaning worse outcomes.
Measure: Evaluation of the clinical status Time: 15 days after randomizationDescription: All-cause mortality rates at 28 days after randomization.
Measure: All-cause mortality Time: 28 days after randomizationDescription: Number of days of mechanical ventilation from randomization to day 28.
Measure: Mechanical ventilation duration Time: 28 days after randomizationDescription: Sequential Organ Failure Assessment (SOFA) Score 48 hours, 72 hours and 7 days after randomization
Measure: Sequential Organ Failure Assessment (SOFA) Score Time: Score at 48 hours, 72 hours and 7 days after randomizationDescription: Intensive Care Unit free days, defined as alive and discharged from the intensive care unit, at 28 days after randomization.
Measure: Intensive Care Unit free days Time: 28 days after randomizationObjective: To determine if pre-exposure prophylaxis with hydroxychloroquine is effective for the prevention of COVID-19 disease.
Description: Outcome reported as the percent of participants in each arm who are COVID-19-free at the end of study treatment.
Measure: COVID-19-free survival Time: up to 12 weeksDescription: Outcome reported as the percent of participants in each arm who have a confirmed SARS-CoV-2 infection during study treatment.
Measure: Incidence of confirmed SARS-CoV-2 detection Time: up to 12 weeksDescription: Outcome reported as the percent of participants in each arm who report COVID-19-related symptoms during study treatment.
Measure: Incidence of possible COVID-19 symptoms Time: up to 12 weeksDescription: Outcome reported as the percent of participants in each arm who discontinue study medication use for any reason during treatment.
Measure: Incidence of all-cause study medicine discontinuation Time: up to 12 weeksDescription: Participants will self-report COVID-19 status on an ordinal scale as follows: No illness (score=1), Illness with outpatient observation (score=2), Hospitalization (or post-hospital discharge) (score=3), or Hospitalization with ICU stay or death (score=4). Possible scores range from 1-4 with higher scores indicating greater disease severity.
Measure: Ordinal Scale of COVID-19 Disease maximum severity if COVID-19 diagnosed at study end Time: up to 12 weeksDescription: Outcome reported as the percent of participants in each arm who are hospitalized or expire due to COVID-19 during study treatment.
Measure: Incidence of Hospitalization for COVID-19 or death Time: up to 12 weeksDescription: Outcome reported as the percent of participants in each arm who experience medication-related side effects during study treatment.
Measure: Incidence of study medication-related side effects Time: up to 12 weeksA phase1/2, open label, dose escalation, safety and early efficacy study of CAStem for the treatment of severe COVID-19 associated with or without ARDS.
Description: Frequency of adverse reaction (AE) and severe adverse reaction (SAE) within 28 days after treatment
Measure: Adverse reaction (AE) and severe adverse reaction (SAE) Time: Within 28 days after treatmentDescription: Evaluation by chest CT
Measure: Changes of lung imaging examinations Time: Within 28 days after treatmentDescription: Marker for SARS-CoV-2
Measure: Time to SARS-CoV-2 RT-PCR negative Time: Within 28 days after treatmentDescription: The duration of a fever above 37.3 degrees Celsius
Measure: Duration of fever (Celsius) Time: Within 28 days after treatmentDescription: Marker for efficacy
Measure: Changes of blood oxygen (%) Time: Within 28 days after treatmentDescription: Marker for efficacy
Measure: Rate of all-cause mortality within 28 days Time: Within 28 days after treatmentDescription: Counts of lymphocyte in a litre (L) of blood
Measure: Lymphocyte count (*10^9/L) Time: Within 28 days after treatmentDescription: Alanine aminotransferase in unit (U)/litre(L)
Measure: Alanine aminotransferase (U/L) Time: Within 28 days after treatmentDescription: Creatinine in micromole (umol)/litre(L)
Measure: Creatinine (umol/L) Time: Within 28 days after treatmentDescription: Creatine kinase in U/L
Measure: Creatine kinase (U/L) Time: Within 28 days after treatmentDescription: C-reactive in microgram (mg)/litre(L)
Measure: C-reactive protein (mg/L) Time: Within 28 days after treatmentDescription: Procalcitonin in nanogram (ng)/litre(L)
Measure: Procalcitonin (ng/L) Time: Within 28 days after treatmentDescription: Lactate in millimole(mmol)/litre(L)
Measure: Lactate (mmol/L) Time: Within 28 days after treatmentDescription: IL-1beta in picogram(pg)/millilitre(mL)
Measure: IL-1beta (pg/mL) Time: Within 28 days after treatmentDescription: IL-2 in pg/mL
Measure: IL-2 (pg/mL) Time: Within 28 days after treatmentDescription: IL-6 in pg/mL
Measure: IL-6 (pg/mL) Time: Within 28 days after treatmentDescription: IL-8 in pg/mL
Measure: IL-8 (pg/mL) Time: Within 28 days after treatmentWhereas the pandemic due do Covid-19 continues to spread, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Severe Acute Respiratory Distress Syndrome in 30% of patients with a 30%-60% mortality rate for those requiring hospitalization in an intensive care unit. The main physio-pathological hallmark is an acute pulmonary inflammation. Currently, there is no treatment. Mesenchymal stem cells (MSC) feature several attractive characteristics: ease of procurement, high proliferation potential, capacity to home to inflammatory sites, anti-inflammatory, anti-fibrotic and immunomodulatory properties. If all MSC share several characteristics regardless of the tissue source, the highest productions of bioactive molecules and the strongest immunomodulatory properties are yielded by those from the Wharton's jelly of the umbilical cord. An additional advantage is that they can be scaled-up to generate banks of cryofrozen and thus readily available products. These cells have already been tested in several clinical trials with an excellent safety record. The objective of this project is to treat intubated-ventilated patients presenting with a SARS-CoV2-related Acute Respiratory Distress Syndrome (ARDS) of less than 96 hours by three intravenous infusions of umbilical cord Wharton's jelly-derived mesenchymal stromal cells (UC-MSC) one every other day (duration of the treatment: one week). The primary endpoint is the PaO2/FiO2 ratio at day 7. The evolution of several inflammatory markers, T regulatory lymphocytes and donor-specific antibodies will also be monitored. The trial will include 40 patients, of whom 20 will be cell-treated while the remaining 20 patients will be injected with a placebo solution in addition to the standard of care. Given the pathophysiology of SARS-CoV2, it is thus sound to hypothesize that the intravenous administration of UC-MSC during the initial phase of ARDS could control inflammation, accelerate its recovery with improved oxygenation, reduced mechanical ventilation and ventilation weaning time and therefore reduced length of stay in intensive care. The feasibility of the project is supported by the expertise of the Meary Cell and Gene Therapy Center, which is approved for the production of Advanced Therapy Medicinal Products and has already successfully prepared the first batches of cells, as well as by the involvement of a cardiac surgery team which will leverage its experience with stem cells for the treatment of heart failure to make it relevant to the Stroma-Cov-2 project.
Rationale: The current SARS-CoV-2 pandemic has a high burden of morbidity and mortality due to development of the so-called acute respiratory distress syndrome (ARDS). The renin-angiotensin-system (RAS) plays an important role in the development of ARDS. ACE2 is one of the enzymes involved in the RAS cascade. Virus spike protein binds to ACE2 to form a complex suitable for cellular internalization. The downregulation of ACE2 results in the excessive accumulation of angiotensin II, and it has been demonstrated that the stimulation of the angiotensin II type 1a receptor (AT1R) increases pulmonary vascular permeability, explaining the increased lung pathology when activity of ACE2 is decreased. Currently available AT1R blockers (ARBs) such as valsartan, have the potential to block this pathological process mediated by angiotensin II. There are presently two complementary mechanisms suggested: 1) ARBs block the excessive angiotensin-mediated AT1R activation, and 2) they upregulate ACE2, which reduces angiotensin II concentrations and increases the production of the protective vasodilator angiotensin 1-7. In light of the above, ARBs may prevent the development of ARDS and avert morbidity (admission to intensive care unit (ICU) and mechanical ventilation) and mortality. Objective: To investigate the effect of the ARB valsartan in comparison to placebo on the occurrence of one of the following items, within 14 days of randomization:1) ICU admission; 2) Mechanical ventilation; 3) Death. Study design: A double-blind, placebo-controlled 1:1 randomized clinical trial Study population: Adult hospitalized SARS-CoV-2-infected patients (n=651). Intervention: The active-treatment arm will receive valsartan in a dosage titrated to blood pressure up to a maximum of 160mg b.i.d. and the placebo arm will receive a matching placebo also titrated to blood pressure. Treatment duration will be 14 days or up to hospital discharge < 14 days or occurrence of the primary endpoint if < 14 days. Main study endpoint: The primary study endpoint is the occurrence within 14 days of randomization of either: 1) ICU admission; 2) Mechanical ventilation; 3) Death.
Description: Death is defined as all-cause mortality
Measure: first occurrence of intensive care unit admission, mechanical ventilation or death Time: within 14 daysDescription: All-cause mortality; and time to all-cause mortality
Measure: Death Time: Within 14 days, 30 days, 90 days and at 1 yearDescription: Occurrence of mechanical ventilation and time to ventilation
Measure: Mechanical ventilation Time: within 14 daysDescription: Occurrence of ICU admission and time to admission
Measure: Intensive care unit admission Time: within 14 daysDescription: Defined as a 50% decline in estimated glomerular filtration rate relative to baseline, or decrease of >30 ml/min/1.73m2 and to a value below 60 ml/min/1.73m2
Measure: Occurrence of acute kidney injury Time: Within 14 daysThe actual pandemic infection related to SARS-CoV2 results in viral pneumonitis (COVID-19), that may, in the more severe cases, lead the patients to the intensive care unit (ICU). The more frequent presentation is acute respiratory distress syndrome (ARDS). To penetrate cells, SARS-CoV2 uses Angioconvertase type 2 (ACE2) as a cellular entry receptor. ACE2 belong to the renin-angiotensin-aldosteron system (SRAA), and ACE2 levels are directly modified when SRAA inhibitors are administred to patients, and ACE2 level increases particularely with Angiotensin II Receptor blockers (ARA2) use. The aim of our study is to determine ACE2 level and activity in patients with SARSCoV2 infection admitted to the intensive care unit (ICU). COVID ARA2 is a propsective cohort of patient with blood sampling at the day of admission, day 3 and day 7.
Description: ELISA test (Higher the ACE2 level, higher the virus penetrate cells)
Measure: ACE2 level change over time Time: at the day of admission, day 3 and day 7Description: Ratio angiotensin (1-7)/angiotensin(1/10) (Higher Ratio angiotensin (1-7)/angiotensin(1/10), higher is ACE2 activity)
Measure: ACE2 activity over time Time: at the day of admission, day 3 and day 7Description: Mortality at day 28
Measure: Mortality at day 28 Time: day 28Description: PaO2/FiO2 ratio (ARDS is severe when <100, moderate when between 100 and 200, mild when >200)
Measure: ARDS severity Time: from the day of admission to day 7Description: Day under mechanical ventilation
Measure: Duration of mechanical ventilation Time: from the day of admission to day 28Description: Need for prone positionning
Measure: Need for prone positionning Time: from the day of admission to day 28Description: Need for extracorporeal membran oxygenation
Measure: Need for extracorporeal membran oxygenation Time: from the day of admission to day 28Description: Need for use of paralytic agents
Measure: Use of paralytic agents Time: from the day of admission to day 28Description: Need for renal replacement therapy
Measure: Need for renal replacement therapy Time: from the day of admission to day 28Description: Need for vasoactive drugs
Measure: Need for vasoactive drugs (norepinephrine, dobutamine,epinephrine) Time: from the day of admission to day 28Description: The SOFA score evaluates the severity of patients through 6 items: respiration (PaO2/FiO2 ratio); coagulation (platelets count); liver (bilirubin); Cardiovascular (hypotension); Central nervous system (coma glasgow score) and Renal (creatinine serum level). Score ranges from 0 to 24, a higher score indicates higher severity and probability of death
Measure: Sequential Organ Failure Assessment (SOFA) score Time: from the day of admission to day 7Description: Number of session(s) of prone positionning
Measure: Number of session(s) of prone positionning Time: from the day of admission to day 28Description: Duration of extracorporeal membran oxygenation treatment
Measure: Duration of extracorporeal membran oxygenation treatment Time: from the day of admission to day 28Description: Several vasoactive agents may be used: norepinephrine, dobutamine, epinephrine, vasopressin analogues...
Measure: Type of vasoactive drugs Time: from the day of admission to day 28Description: Duration of vasoactive treatment
Measure: Duration of vasoactive treatment Time: from the day of admission to day 28The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared a public health emergency of international concern. Hospitalized COVID-19-positive patients requiring ICU care is increasing along with the course of epidemic. A large number of these patients developed acute respiratory distress syndrome (ARDS) according to current data. However, the related hemodynamic characteristic has so far been rarely described.
Description: Body temperature(°C)
Measure: Body temperature Time: Through study completion, an estimation of 6 monthsDescription: Blood pressure in mmHg
Measure: Blood pressure Time: Through study completion, an estimation of 6 monthsDescription: Pulse (heart rate) in times/minute
Measure: Pulse (heart rate) Time: Through study completion, an estimation of 6 monthsDescription: Respiratory rate in times/minute
Measure: Respiratory rate Time: Through study completion, an estimation of 6 monthsDescription: Cardiac index (L/min/m2)
Measure: Data provided by transpulmonary thermodilution-CI Time: Through study completion, an estimation of 6 monthsDescription: Global end-diastolic volume(mL/m2)
Measure: Data provided by transpulmonary thermodilution-GEDV Time: Through study completion, an estimation of 6 monthsDescription: Extravascular lung water (mL/kg)
Measure: Data provided by transpulmonary thermodilution-EVLW Time: Through study completion, an estimation of 6 monthsDescription: Pulmonary vascular permeability index
Measure: Data provided by transpulmonary thermodilution-PVPI Time: Through study completion, an estimation of 6 monthsDescription: Left ventricle ejection fraction, Segmental left ventricle contractility, Speckle tracking data of the left and right ventricles, Dimensions of right and left cavities and Diastolic function of left ventricle
Measure: Incidence of new-onset or reversible systolic left ventricular dysfunction Time: Through study completion, an estimation of 6 monthsDescription: The worst extravascular lung water
Measure: Changes of extravascular lung water measured by transpulmonary thermodilution Time: Change from baseline extravascular lung water at 6 monthsDescription: The worst pulmonary vascular permeability index
Measure: Changes of pulmonary vascular permeability index measured by transpulmonary thermodilution Time: Change from baseline extravascular lung water at 6 monthsThis study will test to see if a 72-hour intravenous vitamin C infusion protocol (100 mg/kg every 8 hours) in patients with hypoxemia and suspected COVID-19 will reduce the lung injury caused by the SARS-Cov-2.
Description: Documented days free off mechanical ventilation the first 28 days post enrollment
Measure: Number of ventilator-free days Time: Up to 28 daysDescription: Mortality at 28-days by all causes
Measure: All-cause-mortality Time: Up to 28 daysDescription: Number of days free of acute inflammation (defined as CRP >= 10 mg/L)
Measure: Acute-inflammation-free days Time: Up to 28 daysDescription: Number of days that the participant is free of organ failure in ALL of the following organ systems: Cardiovascular, Respiratory, Neurological, Liver, Bone marrow organ, Renal
Measure: Organ-failure-free days Time: Up to 1 yearThis is a study for patients who have respiratory infection caused by SARS-CoV-2 that have not gotten better. Because there is no standard treatment for this infection, patients are being asked to volunteer for a gene transfer research study using mesenchymal stem cells (MSCs). Stem cells are cells that do not yet have a specific function in the body. Mesenchymal stem cells (MSCs) are a type of stem cell that can be grown from bone marrow (the spongy tissue inside of bones). Stem cells can develop into other types of more mature (specific) cells, such as blood and muscle cells. The purpose of this study is to see if MSCs can help to treat respiratory infections caused by SARS-CoV-2.
Description: Incidence of unexpected adverse events within 28 days following infusion of MSCs. Adverse events are graded by CTCAE version 5.
Measure: Incidence of unexpected adverse events Time: 28 days post cell infusionDescription: Proportion of patients with improved oxygenation, defined as oxygen saturation >=93% on room air or no more than 5L of supplemental oxygen.
Measure: Improved oxygen saturations ≥93% Time: Within 7 days of cell infusionDescription: Decrease in oxygen supplementation assessed by FiO2 % by non-invasive or invasive interventions from baseline to day 7.
Measure: Decrease in oxygen supplementation by non-invasive or invasive interventions Time: Within 7 days of cell infusionDescription: Frequency of patients who progress using mechanical ventilation or ECMO
Measure: Frequency of progression to mechanical ventilation or ECMO Time: 28 days post cell infusionDescription: Days on mechanical ventilation
Measure: Duration of mechanical ventilation Time: Days from time of intubation to extubation or date of death, whichever occurs first, assessed up to 28 days post-infusionDescription: Days of ICU stay
Measure: Duration of ICU stay Time: Days from admission to ICU to discharge from ICU or date of death, whichever occurs first, assessed up to 28 days post-infusionDescription: Days of hospital stay
Measure: Duration of hospital stay Time: Days from admission to hospital to discharge from hospital or date of death, whichever occurs first, assessed up to 28 days post-infusionDescription: Mortality rate from all causes at day 28
Measure: All-cause mortality at day 28 Time: 28 days post cell infusionSingle blind randomized clinical trial designed to evaluate the efficacy of the combination of hydroxychloroquine and dexamethasone as treatment for severe Acute Respiratory Distress Syndrome (ARDS) related to coronavirus disease 19 (COVID-19). We hypothesize that dexamethasone (20 mg for 5 days followed by 10 mg for 5 days) combined with 600 mg per day dose of hydroxychloroquine for 10 days will reduce the 28-day mortality compared to hydroxychloroquine alone in patients with severe ARDS related COVID-19.
Description: Mortality rate evaluated 28 days after randomization
Measure: Day-28 mortality Time: 28 days after randomizationDescription: Ventilator-free days (VFDs) at 28 days are one of several organ failure-free outcome measures to quantify the efficacy of therapies and interventions. VFDs are typically defined as follows: VFDs = 0 if subject dies within 28 days of mechanical ventilation. VFDs = 28 − x if successfully liberated from ventilation x days after initiation. VFDs = 0 if the subject is mechanically ventilated for >28 days.
Measure: Ventilator-free days Time: 28 days after randomizationDescription: Mortality rate evaluated during Intensive care unit stay
Measure: Intensive Care Unit mortality Time: Up to 60 days after randomizationDescription: Mortality rate evaluated 60 days after randomization
Measure: Day-60 mortality Time: 60 days after randomizationDescription: Number of patients with pneumonia diagnosed during intensive care unit stay
Measure: Nosocomial pneumonia Time: Up to 60 days after randomizationDescription: Number of patients with bacteremia diagnosed during intensive care unit
Measure: Bacteremia Time: Up to 60 days after randomizationDescription: Placement of ECMO during intensive care unit stay
Measure: Extra corporeal membrane oxygenation (ECMO) Time: Up to 60days after randomizationDescription: Number of patients who underwent tracheostomy during intensive care unit stay
Measure: Tracheostomy Time: Up to 60 days after randomizationDescription: Number of Prone position session
Measure: Prone Position Time: Up to 60 days after randomizationMortality of COVID-19 pneumonia with acute respiratory distress syndrome (ARDS) is extremely high in preliminary reports amounting to 50-60%. Duration of mechanical ventilation in these patients appears to exceed standard duration of mechanical ventilation in non-COVID-19 ARDS patients, suggesting that COVID-19 patients may be particularly at risk for ventilator-induced lung injury. Treatment of COVID-19 ARDS patients is to date mainly supportive with protective mechanical ventilation (ventilation with low tidal volume (VT) i.e. 6 ml/kg of predicted body weight (PBW) and plateau pressure control below 30 cm H2O). Mechanical ventilation with VT reduction below 6 ml/kg PBW in ARDS may reduce alveolar strain, driving pressure and hence ventilator-induced lung injury. Investigators recently performed a multicenter pilot study on 34 moderately severe to severe ARDS patients. This study demonstrated that ultraprotective ventilation with ultra-low VT (≤4.2 ml/kg PBW) without extracorporeal circulation may be applied in approximately 2/3 of the patients, with a 4 cmH2O median reduction in driving pressure, at the price of transient episodes of severe acidosis in approximately 1/3 of the patients. Investigators hypothesized that ultraprotective ventilation without extracorporeal circulation may reduce the mortality at day-90 and increase the number of days free from mechanical ventilation (VFD) at day-60, as compared to protective ventilation.
Description: For an alive patient at day 90, the score will be built as follow: a value +1 will be given for comparisons to dead patients and alive patients with a lower number of VFD. For comparisons to alive patients with a higher number of VFD a value -1 will be given and in case of identical number of VFD a value 0 will be given. For a dead patient a value -1 will be given for comparisons to alive patients and 0 for comparisons to dead patients. For a given patients the score will correspond to the sum of values resulting to the comparison to all patients of the other group. A higher score indicates a more favorable result.
Measure: A composite score based on all-cause mortality and the number of ventilator free-days (VFD) Time: Day 90Description: All-cause mortality with analysis in intention to treat, i.e. each patient will be analyzed in his initial randomization group regardless of whether the allocated strategy was effectively applied or not.
Measure: All-cause mortality (intention to treat) Time: 90-day after inclusionDescription: VFD will be computed as follows from the day of inclusion: VFD= 0 if the patient dies between inclusion and day 60 VFD = 60-x if the patient is successfully weaned from invasive mechanical ventilation x days after inclusion. Successful weaning from mechanical ventilation is defined by extubation without reintubation within at least 48 hours (or weaning from mechanical ventilation for at least 48 hours in patients with tracheostomy) VFD= 0 if the patient is mechanically ventilated for more than 60 days after inclusion
Measure: Ventilator-free days (VFD) Time: day 60 after inclusionDescription: Per protocol analysis will be carried out by comparing the group of patients in whom median daily tidal volume from inclusion to weaning of deep sedation will be lower of equal to 4.2 ml/kg of predicted body weight to the group of patients in whom median tidal volume from inclusion to weaning of deep sedation will be greater than 4.2 ml/kg of predicted body weight, whatever the patients' initial randomization group. Weaning of deep sedation is defined by a Richmond Agitation Sedation (RASS) score greater than -3 for at least 48 hours.
Measure: All-cause mortality with per protocol analysis Time: 90-dayDescription: Successful extubation is defined by extubation without reintubation within at least 48 hours (or weaning from mechanical ventilation for at least 48 hours in patients with tracheostomy) Data will be right censored at 60 days and death will be taken into account as a competing risk.
Measure: Time to successful extubation Time: 60 daysDescription: Data will be right censored at 90 days and death will be taken into account as a competing risk.
Measure: Length of hospital stay Time: 90 daysDescription: Weaning of deep sedation is defined by a Richmond Agitation Sedation (RASS) score greater than -3 for at least 48 hours.
Measure: Respiratory parameters assessed daily from inclusion to weaning of deep sedation or 14 days whichever comes first Time: 14 daysDescription: Doses of the following drugs used for deep sedation will be assessed daily: midazolam, propofol and opioid. Opioid dose will be expressed as morphine equivalent with the following conversion factor: 1µg of sufentanil = 10 µg of fentanyl = 1 mg of morphine
Measure: Daily sedation dose during the first 14 days of the study Time: 14 daysDescription: Rescue therapies are any therapy among the following ones: neuromuscular blocking agents, prone position, nitric oxide, recruitment maneuvers, ECMO
Measure: Rate of use of rescue therapies Time: 14 daysDescription: Severe mixed acidosis is defined by the association of pH<7.15 and PaCO2>45 mm Hg.
Measure: Incidence density rate of severe mixed acidosis Time: ICU stayDescription: Ventilator associated pneumonia will be defined as any pneumonia acquired under mechanical ventilation after inclusion.
Measure: Incidence density rate of ventilator associated pneumonia Time: ICU stayDescription: Acute cor pulmonale is defined by the association of right ventricle dilatation (right ventricle surface / left ventricle surface >0,6) and septal dyskinesia assessed by echocardiography
Measure: Incidence density rate of acute cor pulmonale Time: ICU stayDescription: Barotrauma is defined by any pneumothorax OR pneumomediastinum OR subcutaneous emphysema, OR pneumatocele of more than 2 cm detected on image examinations.
Measure: Incidence density rate of barotrauma Time: ICU stayDescription: Serious adverse event is any life threatening event OR any event resulting in death.
Measure: Incidence density rate of any serious adverse events Time: ICU stayDescription: The Telephone Montreal Cognitive Assessment score will be assessed by phone call. The total score ranges from 0 to 30; higher scores being associated to a better outcome.
Measure: Cognitive impairment assessed by phone call using the Telephone Montreal Cognitive Assessment (T-MoCA) test Time: Day 365 after inclusionDescription: The RAND 36-Item Health Survey (SF-36) score will be assessed by phone call. The score ranges from 0 to 100; higher scores being associated to a better outcome.
Measure: Quality of life assessed by the RAND 36-Item Health Survey (SF-36) score Time: Day 365 after inclusionDescription: The Impact of Event Scale - revised (IES-R) score will be assessed by phone call. The total score ranges from 0 to 88; higher scores being associated to a worse outcome.
Measure: Post-traumatic stress disorder assessed by the Impact of Event Scale - revised (IES-R) score by phone call Time: Day 365 after inclusionDescription: The cost-efficacy ratio will be computed as the ratio of cost difference on efficacy difference between the intervention arm and the reference arm. The costs taken into account will be the direct hospitalized costs. The efficacy will be assessed as the number of days alive free from mechanical ventilation.
Measure: Cost-efficacy ratio of the innovative strategy compared to the reference strategy Time: Day 90 after inclusionAs of 30/03/2020, 715600 people have been infected with COVID-19 worldwide and 35500 people died, essentially due to respiratory distress syndrome (ARDS) complicated in 25% of the with acute renal failure. No specific pharmacological treatment is available yet. The lung lesions are related to both the viral infection and to an intense inflammatory reaction. Because of it's action, as an immunomodulatory agent that can attenuate the inflammatory reaction and also strengthen the antiviral response, it is proposed to evaluate the effectiveness and safety of intravenous immunoglobulin administration (IGIV) in patients developing ARDS post-SARS-CoV2. IGIV modulates immunity, and this effect results in a decrease of pro-inflammatory activity, key factor in the ARDS related to the COVID-19. It should be noted that IGIV is part of the treatments in various diseases such as autoimmune and inflammatory diffuse interstitial lung diseases. In addition, they have been beneficial in the post-influenza ARDS but also have been in 3 cases of post-SARS-CoV2 ARDS. IGIV is a treatment option because it is well tolerated, especially concerning the kidney. These elements encourage a placebo-controlled trial testing the benefit of IGIV in ARDS post-SARS-CoV2.
Description: Sum of the days the patient did not receive VM, but if death occurs before D28, the score is zero
Measure: Ventilator-free days Time: 28 daysDescription: Used to determine the extent of a person's organ function or rate of failure, from 0 to 24, with severity increasing the higher the score
Measure: Sequential Organ Failure Assessment Score Time: Days 1, 3, 7, 14, 21 and 28Description: Ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2 expressed as a fraction, not a percentage)
Measure: P/F ratio Time: Days 1, 3, 7, 14, 21 and 28Description: Severity scoring of lung oedema on the chest radiograph
Measure: Radiological score Time: Days 1, 3, 7, 14, 21 and 28Description: Concentration in mg/L
Measure: Biological efficacy endpoints - C-reactive protein Time: Days 1, 3, 7, 14, 21 and 28Description: Concentration in microgram/L
Measure: Biological efficacy endpoints - Procalcitonin Time: Days 1, 3, 7, 14, 21 and 28Description: Number of CD4 HLA-DR+ and CD38+, CD8 lymphocytes
Measure: Immunological profile Time: Up to 28 daysDescription: Use of corticosteroids, antiretroviral, chloroquine
Measure: Number of patients using other treatments for COVID-19 related ARDS Time: Up to 28 daysDescription: Divided in 3 stages, with higher severity of kidney injury in higher stages
Measure: Kidney Disease: Improving Global Outcomes (KDIGO) score and need for dialysis Time: 28 daysDescription: Kidney failure, hypersensitivity with cutaneous or hemodynamic manifestations, aseptic meningitis, hemolytic anemia, leuko-neutropenia, transfusion related acute lung injury (TRALI)
Measure: Occurrence of adverse event related to immunoglobulins Time: 28 daysDescription: Medical research council sum score on awakening
Measure: Occurrence of critical illness neuromyopathy Time: Up to 28 daysDescription: Radiological and clinical context associated with a bacteriological sampling in culture of tracheal secretions, bronchiolar-alveolar lavage or a protected distal sampling
Measure: Occurrence of ventilator-acquired pneumonia Time: Up to 28 daysThe aim of this observationnal study is to describe respiratory mechanics and lung recruitement in patients with SARS-CoV-2 Associated Acute Respiratory Distress Syndrome who underwent invasive ventilation on endotracheal tube, admitted to the medical ICU of Angers university hospital . Statics measurements of respiratory system compliance were performed at 2 differents levels of PEEP (15 cmH2O and 5 cmH2O). The recruited volume is computed as the difference between the volume expired from PEEP 15 to 5 cmH2O and the volume predicted by compliance at PEEP 5 cmH2O . The recruitment-to-Inflation (R/I) ratio (i.e. the ratio between the recruited lung compliance and CRS at PEEP 5 cmH2O) is used to assess lung recruitability. A R/I ratio value higher than or equal to 0.5 was used to define highly recruiter patients.
Description: no unit
Measure: Recruitment-to Inflation ratio (R/I ratio) Time: Day 1Description: no unit
Measure: Recruitment-to Inflation ratio (R/I ratio) Time: Day 5Description: no unit
Measure: Recruitment-to Inflation ratio (R/I ratio) Time: Day 10Description: Arterial blood gases
Measure: PaO2/FiO2 (mmHg) Time: Day 1Description: Arterial blood gases
Measure: PaO2/FiO2 (mmHg) Time: Day 5Description: Arterial blood gases
Measure: PaO2/FiO2 (mmHg) Time: Day 10Description: mL
Measure: Lung volume recruited (VRec) Time: Day 1Description: mL
Measure: Lung volume recruited (VRec) Time: Day 5Description: mL
Measure: Lung volume recruited (VRec) Time: Day 10Description: Obtained by inspiratory pause of 5 seconds
Measure: Plateau pressure (cm H2O) Time: Day 1Description: Obtained by inspiratory pause of 5 seconds
Measure: Plateau pressure (cm H2O) Time: Day 5Description: Obtained by inspiratory pause of 5 seconds
Measure: Plateau pressure (cm H2O) Time: Day 10Description: Obtained by expiratory pause of 5 seconds
Measure: PEEP total (cm H2O) Time: Day 1Description: Obtained by expiratory pause of 5 seconds
Measure: PEEP total (cm H2O) Time: Day 5Description: Obtained by expiratory pause of 5 seconds
Measure: PEEP total (cm H2O) Time: Day 10Description: respiratory rate decreased to 10 /min, expired tidal volume displayed by the ventilator is noted
Measure: Expired volume in PEEP setted at 15 cmH2O (mL) Time: Day 1Description: respiratory rate decreased to 10 /min, expired tidal volume displayed by the ventilator is noted
Measure: Expired volume in PEEP setted at 15 cmH2O (mL) Time: Day 5Description: respiratory rate decreased to 10 /min, expired tidal volume displayed by the ventilator is noted
Measure: Expired volume in PEEP setted at 15 cmH2O (mL) Time: Day 10Description: respiratory rate decreased to 10 /min, expired tidal volume displayed by the ventilator is noted
Measure: Expired volume in PEEP setted at 5 cmH2O (mL) Time: Day 1Description: respiratory rate decreased to 10 /min, expired tidal volume displayed by the ventilator is noted
Measure: Expired volume in PEEP setted at 5 cmH2O (mL) Time: Day 5Description: respiratory rate decreased to 10 /min, expired tidal volume displayed by the ventilator is noted
Measure: Expired volume in PEEP setted at 5 cmH2O (mL) Time: Day 10This is a phase 1 study in healthy subjects to evaluate the safety, tolerability and pharmacokinetics of single (Part A and B) and multiple (Part B) doses of inhaled TD-0903.
Description: Number and severity of treatment emergent adverse events
Measure: Safety and Tolerability of SAD of TD-0903: Adverse Events Time: Day 1 to Day 8Description: Number and severity of treatment emergent adverse events
Measure: Safety and Tolerability of MAD of TD-0903: Adverse Events Time: Day 1 to Day 14Description: Multiple PK variables of TD-0903 will be assessed during SAD and may include, but are not limited to: Area under the plasma concentration-time curve (AUC)
Measure: Pharmacokinetics (PK) of TD-0903 when given as a Single Ascending Dose (SAD): AUC Time: Day 1 through Day 4Description: Multiple PK variables of TD-0903 will be assessed during SAD and may include, but are not limited to: Maximum observed concentration (Cmax)
Measure: Pharmacokinetics (PK) of TD-0903 when given as a Single Ascending Dose (SAD): Cmax Time: Day 1 through Day 4Description: Multiple PK variables of TD-0903 will be assessed during SAD and may include, but are not limited to: Time to reach maximum observed concentration (Tmax)
Measure: Pharmacokinetics (PK) of TD-0903 when given as a Single Ascending Dose (SAD): Tmax Time: Day 1 through Day 4Description: Multiple PK variables of TD-0903 will be assessed during MAD and may include, but are not limited to: Area under the plasma concentration-time curve (AUC)
Measure: Pharmacokinetics (PK) of TD-0903 when given as a Multiple Ascending Dose (MAD): AUC Time: Day 1 through Day 9Description: Multiple PK variables of TD-0903 will be assessed during MAD and may include, but are not limited to: Maximum observed concentration (Cmax)
Measure: Pharmacokinetics (PK) of TD-0903 when given as a Multiple Ascending Dose (MAD): Cmax Time: Day 1 through Day 9Description: Multiple PK variables of TD-0903 will be assessed during MAD and may include, but are not limited to: Time to reach maximum observed concentration (Tmax)
Measure: Pharmacokinetics (PK) of TD-0903 when given as a Multiple Ascending Dose (MAD): Tmax Time: Day 1 through Day 9Study KIN-1901-2001 is a multi-center, adaptive, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of gimsilumab in subjects with lung injury or acute respiratory distress syndrome (ARDS) secondary to COVID-19.
Description: Mortality at Day 43
Measure: Primary endpoint Time: 43 daysDescription: Subjects who die will be assigned "0" ventilator-free days
Measure: Number of ventilator-free days. Time: Day 43The study aims to investigate the efficacy of extracorporeal CO2 removal for correction of hypercapnia in coronavirus disease 19 (COVID-19)-associated acute respiratory distress syndrome
Description: Delta partial pressure of carbon dioxide change during ECCO2R treatment
Measure: Delta change in arterial partial pressure of carbon dioxide during ECCO2R treatment Time: Up to 72 hoursDescription: Epinephrine and norepinephrine dose, mcg/kg/min
Measure: Change in vasopressor use during ECCO2R Time: Up to 72 hoursDescription: Assessment of changes in tidal volume
Measure: Assessment of changes in tidal volume during ECCO2R Time: Up to 72 hoursDescription: Assessment of changes in pH
Measure: Assessment of changes in pH during ECCO2R Time: Up to 72 hoursDescription: Assessment of changes in Positive End-Expiratory Pressure
Measure: Assessment of changes in Positive End-Expiratory Pressure during ECCO2R Time: Up to 72 hoursDescription: Adverse events directly related to ECCO2R are infection at the catheter site, hemorrhage at the cannulation site, air entry in the circuit.
Measure: Number of participants with adverse events directly related to ECCO2R Time: Up to 72 hoursDescription: Adverse events directly related to ECCO2R are clotting of the circuit.
Measure: Rate of technical adverse events related to ECCO2R Time: Up to 72 hoursDescription: Delta change in delta venous partial pressure of carbon dioxide before and after ECCO2R membrane
Measure: Delta change in venous partial pressure of carbon dioxide before and after ECCO2R membrane Time: Up to 72 hoursThis study plans to learn more about the effects of Dornase Alfa in COVID19 (coronavirus disease of 2019) patients, the medical condition caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Dornase Alfa is a FDA-approved drug for the treatment of cystic fibrosis, which facilitates mucus clearance by cutting apart neutrophil-derived extracellular double-stranded DNA. This study intends to define the impact of aerosolized intra-tracheal Dornase Alfa administration on the severity and progression of acute respiratory distress syndrome (ARDS) in COVID-19 patients. This drug might make lung mucus thinner and looser, promoting improved clearance of secretions and reduce extracellular double-stranded DNA-induced hyperinflammation in alveoli, preventing further damage to the lungs. The study will recruit mechanically ventilated patients hospitalized in ICU who have been diagnosed with COVID-19 and meet ARDS criteria. It is a prospective, randomized, controlled, multicentric, open-label clinical trial. The goal is to recruit 100 patients.
Description: The primary endpoint is the occurrence of at least one grade improvement between D0 (inclusion) and D7 in the ARDS scale severity (Berlin criteria). For instance from severe to moderate or from moderate to mild
Measure: Efficacy of intratracheal administration: occurrence of at least one grade improvement Time: Day 7This protocol provides access to eculizumab treatment for participants with severe COVID-19.
The purpose of this research study is to learn about the safety and efficacy of human umbilical cord derived Mesenchymal Stem Cells (UC-MSC) for treatment of COVID-19 Patients with Severe Complications of Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS).
Description: Safety will be defined by the incidence of pre-specified infusion associated adverse events as assessed by treating physician
Measure: Incidence of pre-specified infusion associated adverse events Time: Day 5Description: Safety will be defined by the incidence of severe adverse events as assessed by treating physician
Measure: Incidence of Severe Adverse Events Time: 90 daysDescription: Number of participants that are alive at 90 days post first infusion follow up.
Measure: Survival rate after 90 days post first infusion Time: 90 daysDescription: Number of days participants were off ventilators within up to 28 days of hospitalization
Measure: Ventilator-Free Days Time: 28 days or hospital discharge, whichever is earlierDescription: Measure the fraction of inspired oxygen (FiO2) and its usage within the body during intensive care, measured using fNIRS (Functional Near Infrared Spectroscopy).
Measure: Change in Oxygenation Index (OI) Time: 28 daysDescription: Measuring respiratory mechanics in ventilated patients [plateau pressure (Pplat)-positive end-expiratory pressure]
Measure: Plat-PEEP Time: 28 daysDescription: The SOFA assessment is used to track a person's risk status during stay in the Intensive Care Unit (ICU). The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal, and neurological systems. Each organ system is assigned a point value from 0 (normal) to 4 (high degree of dysfunction/failure)
Measure: Sequential Organ Failure Assessment (SOFA) Scores Time: 28 daysDescription: The SIT is a self-administered 40-item test involving microencapsulated (scratch-and-sniff) odors with a forced-choice design. The test has a total score ranging from 0-40 Follows scoring key for evaluation. The higher score indicates better outcome.
Measure: Small Identification Test (SIT) scores Time: At baseline, day 18 and day 28.Description: As assessed via serum blood samples.
Measure: Troponin I levels Time: Baseline, 28 daysDescription: As assessed via serum blood samples.
Measure: C-Reactive Protein levels Time: Baseline, 28 daysDescription: As assessed via serum blood samples.
Measure: Arachidonic Acid (AA)/Eicosapentaenoic Acid (EPA) Ratio Time: Baseline, 28 daysDescription: As assessed via serum blood samples.
Measure: D-dimer levels Time: Baseline, 28 daysDescription: As assessed via serum blood samples.
Measure: 25-Hydroxy Vitamin D levels Time: Baseline, 28 daysDescription: As assessed via serum blood samples.
Measure: Alloantibodies levels Time: Baseline, 28 daysDescription: As assessed via serum blood samples.
Measure: Blood white cell count Time: Baseline, 28 daysDescription: As assessed via serum blood samples.
Measure: Platelets count Time: Baseline, 28 daysThe purpose is to demonstrate the efficacy of low-dose interleukin 2 (Ld-IL2) administration in improving clinical course and oxygenation parameters in patients with SARS-CoV2-related ARDS.
Description: To evaluate selected immune and inflammatory markers: Serum concentrations of cytokines and soluble factors related to the immune response and inflammatory processes will be evaluated and compare to baseline by multiplex immunoprofiling to analyse a larger number of molecules including at least IFNα2, IFNγ, IL-1α, IL-1β, IL-1RA, IL-2, IL-6, IL-8, IL-10, IL-17, TNFα, TNFβ, VEGF-A, TGF-beta, S-RAGE, SP-A, SP-D, Angiopoétine 1 and KGF.
Measure: Cytokines analysis on plasma samples at Day 0, 7 and 14 Time: at Day 0, 7 and 14Description: Cellular components will be analysed by flow cytometry covering (i) most of the innate and adaptive immune cells including Tregs, T helper cell subsets including follicular helper cells, B cell subsets, NK cell subsets, (ii) the associated relevant markers of activation/function/differentiation, tissue migration, as well as (iii) unconventional lymphoid cells (NKT/MAIT, innate lymphoid cells), myeloid-derived suppressor cells, classical and non-classical monocytes and dendritic cells (mDC1/2, pDC).
Measure: Deep Immunophenotyping of Cellular components in blood samples at Day 0, 7, and 14 Time: at Day0, 7 and Day14The global pandemic COVID-19 has overwhelmed the medical capacity to accommodate a large surge of patients with acute respiratory distress syndrome (ARDS). In the United States, the number of cases of COVID-19 ARDS is projected to exceed the number of available ventilators. Reports from China and Italy indicate that 22-64% of critically ill COVID-19 patients with ARDS will die. ARDS currently has no evidence-based treatments other than low tidal ventilation to limit mechanical stress on the lung and prone positioning. A new therapeutic approach capable of rapidly treating and attenuating ARDS secondary to COVID-19 is urgently needed. The dominant pathologic feature of viral-induced ARDS is fibrin accumulation in the microvasculature and airspaces. Substantial preclinical work suggests antifibrinolytic therapy attenuates infection provoked ARDS. In 2001, a phase I trial 7 demonstrated the urokinase and streptokinase were effective in patients with terminal ARDS, markedly improving oxygen delivery and reducing an expected mortality in that specific patient cohort from 100% to 70%. A more contemporary approach to thrombolytic therapy is tissue plasminogen activator (tPA) due to its higher efficacy of clot lysis with comparable bleeding risk 8. We therefore propose a phase IIa clinical trial with two intravenous (IV) tPA treatment arms and a control arm to test the efficacy and safety of IV tPA in improving respiratory function and oxygenation, and consequently, successful extubation, duration of mechanical ventilation and survival.
Description: Ideally, the PaO2/FiO2 will be measured with the patient in the same prone/supine position as in baseline, as change in positions may artificially reduce the improvement attributable to the study drug. However, given the pragmatic nature of the trial, the prone/supine position will be determined by the attending physician, in which case, we will use as an outcome the PaO2/FiO2 closest to the 48 hours obtained prior to the change in position as the outcome.
Measure: PaO2/FiO2 improvement from pre-to-post intervention Time: at 48 hours post randomizationDescription: Achievement of PaO2/FiO2 ≥ 200 or 50% increase in PaO2/FiO2 (whatever is lower)
Measure: Achievement of PaO2/FiO2 ≥ 200 or 50% increase in PaO2/FiO2 Time: at 48 hours post randomizationDescription: This score is based on seven clinical features (respiration rate, hypercapnic respiratory failure, any supplemental oxygen, temperature, systolic blood pressure, heart rate and level of consciousness) and determines the degree of illness of a patient and prompts critical care intervention.
Measure: National Early Warning Score 2 (NEWS2) Time: at 48 hours post randomizationDescription: The ordinal scale is an assessment of the clinical status as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities. (combined items 7 and 8 as our study is limited to hospital).
Measure: National Institute of Allergy and Infectious Diseases (NIAID) ordinal scale Time: at 48 hours post randomizationDescription: 48 hour mortality for hospitalized patients
Measure: 48 hour in-hospital mortality Time: at 48 hours post randomizationDescription: 14 days mortality for hospitalized patients
Measure: 14 days in-hospital mortality Time: 14 days post randomizationDescription: 28 days mortality for hospitalized patients
Measure: 28 days in-hospital mortality Time: 28 days post randomizationDescription: ICU-free days will be calculated based on (28 - number of days spent in the ICU) formula
Measure: ICU-free days Time: 28 days of hospital stay or until hospital discharge (whichever comes first)Description: In-hospital coagulation-related events include bleeding, stroke, myocardial infarction and venous thromboembolism (VTE). In-hospital coagulation-related event-free (arterial and venous) days will be calculated based on (28 - number of days without coagulation-related event) formula.
Measure: In-hospital coagulation-related event-free (arterial and venous) days Time: 28 days of hospital stay or until hospital discharge (whichever comes first)Description: Ventilator-free days will be calculated based on (28 - number of days on mechanical ventilation) formula.
Measure: Ventilator-free days Time: 28 days of hospital stay or until hospital discharge (whichever comes first)Description: Calculated for patients who was on a mechanical ventilation any period of time during hospitalization. The extubation will be considered successful if no re-intubation occurred for more than 3 days have passed after the initial extubation.
Measure: Successful extubation Time: Day 4 after initial extubationDescription: Calculated for patients who was on paralytics at the time of randomization. The weaning will be considered successful if no paralytics were used for more than 3 days have passed after termination of paralytics.
Measure: Successful weaning from paralysis Time: Day 4 after initial termination of paralyticsDescription: Is counted for the patients who was alive at the time of discharge.
Measure: Survival to discharge Time: 28 days of hospital stay or until hospital discharge (whichever comes first)A continuous infusion of Dexmedetomidine (DEX) will be administered to 80 patients admitted to Critical Care because of signs of Respiratory Insufficiency requiring non-invasive ventilation. Measurements of respiratory performance and quantification of cellular and molecular inflammatory mediators. The primary outcome will be the avoidance of mechanical ventilation with secondary outcomes duration of mechanical ventilation, avoidance of delirium after sedation and association of mediators of inflammation to outcomes. Outcomes will be compared to a matched historical control (no DEX) series
Description: (Presence/Absence) requirement of mechanical ventilation
Measure: Mechanical ventilation Time: expected within first three days (non conclusive due to lack of evidence yet)Description: Duration of mechanical ventilation if it is required (hours from the start)
Measure: Duration of mechanical ventilation Time: expected within first seven days (non conclusive due to lack of evidence yet)Description: Delirium criteria as defined in DSM-4
Measure: Delirium on recovery from sedation Time: First 24 hours after retiring dexmedetomidine sedationBrief Summary: SARS-CoV-2 virus infection is known to cause Lung Injury that begins as dyspnea and exercise intolerance, but may rapidly progress to Acute Respiratory Distress Syndrome and the need for mechanical ventilation. Mortality rates as high as 80% have been reported among those who develop ARDS, despite intensive care and mechanical ventilation. Patients with COVID-19 induced non-Acute Lung Injury who have demonstrated reduction in blood oxygenation, dyspnea, and exercise intolerance but do not require endotracheal intubation and mechanical ventilation will be treated with Aviptadil, a synthetic version of Vasoactive Intestinal Polypeptide (VIP) plus Standard of Care vs. placebo + Standard of Care. Patients will be randomized to intravenous Aviptadil will receive inhaled Aviptadil, 100 μg 3x daily vs. placebo 3x daily. The primary outcome will be progression to ARDS over 28 days. Secondary outcomes will include blood oxygenation as measured by pulse oximetry, dyspnea, exercise tolerance, and levels of TNFα IL-6 and other cytokines.
Description: Progression to ARDS is defined as the need for mechanical ventilation
Measure: Progression to ARDS Time: 28 daysDescription: Blood PO2 as measured by pulse oximetry
Measure: Blood oxygenation Time: 28 daysDescription: 0 = no shortness of breath at all 0.5 = very, very slight shortness of breath = very mild shortness of breath = mild shortness of breath = moderate shortness of breath or breathing difficulty = somewhat severe shortness of breath = strong or hard breathing 7 = severe shortness of breath or very hard breathing 8 9 = extremely severe shortness of breath 10 = shortness of breath so severe you need to stop the exercise or activity
Measure: RDP Dsypnea Scale Time: 28 daysDescription: Distance walked in six minutes
Measure: Distance walked in six minutes Time: 28 daysBackground: There are no proven therapies for COVID-19 infection. COVID-19 infects the respiratory epithelium of the lower airways, causing widespread damage via cytopathic effects, resulting in severe inflammation and Pneumonitis. High local and circulating levels of cytokines, or cytokine storm, can lead to capillary leak syndrome, progressive lung injury, respiratory failure and acute respiratory distress syndrome (ARDS). Methods: This is a pilot randomized, controlled, uni-center study testing safety and efficacy of cytokine filtration on patients with severe ARDS. Eligible patients will be randomized to 72 hours filtration or no filtration on top of the standard treatment for ARDS. Indications for randomization are patients with moderate or severe ARDS with need of ventilation support (either invasive or non-invasive), with inflammatory markers. The primary outcome will be days on mechanical ventilation (MV) support. Secondary outcomes are 30-day mortality, ICU days, need for extracorporeal membrane oxygenation (ECMO) support, duration of renal replacement therapy (RRT) and catecholamine therapies, hospital length of stay, multi-organ failure. All analysis will be done according to the intention to treat principle.
Description: Number of ventilator-free days (VFDs) at day 28 (defined as days being alive and free from mechanical ventilation at day 28 after enrollment. For patients ventilated 28 days or longer and for ventilated subjects who die, VFD is 0
Measure: Mechanical ventilation-free days Time: up to 28daysIdeal new treatments for Novel Coronavirus-19 (COVID-19) would help halt the progression disease in patients with mild disease prior to the need for artificial respiration (ventilators), and also provide a rescue treatment for patients with severe disease, while also being affordable and available in quantities sufficient to treat large numbers of infected people. Low doses of Naltrexone, a drug approved for treating alcoholism and opiate addiction, as well as Ketamine, a drug approved as an anesthetic, may be able to interrupt the inflammation that causes the worst COVID-19 symptoms and prove an effective new treatment. This study will investigate their effectiveness in a randomized, blinded trial versus standard treatment plus placebo.
Description: Count of participants initially presenting with mild/moderate disease who progress to requiring advanced oxygenation (high flow nasal canula, non-rebreather, continuous positive airway pressure (CPAP), bilevel positive airway pressure (BIPAP), or intubation)
Measure: Progression of oxygenation needs Time: up to 1 monthDescription: Count of participants who develop or experience worsened renal failure as defined by RIFLE criteria, a 5-point scale where the categories are labeled: Risk-Injury-Failure-Loss-End stage renal disease, with Risk being the least severe and End stage renal disease being the most severe. The criteria for determination of stage are factors of serum creatinine and urine output. Numbers of participants worsening one or more RIFLE stages will be reported.
Measure: Renal failure Time: up to 1 monthDescription: Count of participants who develop or experience worsened liver failure as defined by serum transaminases five times normal limits
Measure: Liver failure Time: up to 1 monthDescription: Count of participants who develop cytokine storm as measured by elevated markers of inflammation (elevated D-dimer, hypofibrinogenemia, hyperferritinemia), evidence of acute respiratory distress syndrome (ARDS) measured by imaging findings and mechanical ventilator requirements, and/or continuous fever (≥ 38.1 ° Celsius unremitting)
Measure: Cytokine Storm Time: up to 1 monthDescription: Count of participants who die from COVID-19
Measure: Mortality Time: up to 1 month post hospital dischargeDescription: Length of hospital stay in days
Measure: Length of hospital stay Time: up to 1 monthDescription: Count of patients admitted to the ICU at any time during index hospitalization
Measure: Intensive Care Unit (ICU) admission Time: up to 1 monthDescription: Length of ICU stay in days
Measure: Intensive Care Unit (ICU) duration Time: up to 1 monthDescription: Count of participants requiring intubation
Measure: Intubation Time: up to 1 monthDescription: Length of intubation, measured in days
Measure: Intubation duration Time: up to 1 monthDescription: Time measured in days from hospital admission to determination patient is stable for discharge
Measure: Time until recovery Time: up to 1 monthAcute Respiratory Distress Syndrome (ARDS) is the major cause of death in the COVID-19 pandemic. In this trial, the safety and efficacy of Mesenchymal Stem Cells (MSC) for the treatment of ARDS in COVID-19 patients will be assessed.
Description: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Measure: Adverse events assessment Time: From baseline to day 28Description: Evaluation of Pneumonia Improvement
Measure: Blood oxygen saturation Time: From baseline to day 14Description: Number of days
Measure: Intensive care unit-free days Time: Up to day 8Description: Improvement of clinical symptoms including duration of fever, respiratory distress, pneumonia, cough, sneezing
Measure: Clinical symptoms Time: From baseline to day 14Description: increase in PaO2/FiO2 ratio from baseline to day 7
Measure: Respiratory efficacy Time: From baseline to day 7Description: Biochemical examination
Measure: Biomarkers concentrations in plasma Time: At baseline, 7, 14, 28 days after the first interventionThe objectives of this intermediate-size expanded access protocol are to assess the safety and efficacy of remestemcel-L in participants with ARDS due to coronavirus infection 2019 (COVID-19).
This study will evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of ravulizumab administered in adult patients with Coronavirus Disease 2019 (COVID-19) severe pneumonia, acute lung injury, or acute respiratory distress syndrome. Patients will be randomly assigned to receive ravulizumab in addition to best supportive care (BSC) (2/3 of the patients) or BSC alone (1/3 of the patients). Best supportive care will consist of medical treatment and/or medical interventions per routine hospital practice.
This phase II expanded access trial studies how well tocilizumab works in reducing the serious symptoms including pneumonitis (severe acute respiratory distress), and preventing future complications in patients with cancer and COVID-19. COVID-19 is caused by the SARS-CoV-2 virus. COVID-19 can be associated with a response by the immune system which may also cause symptoms of COVID-19 to worsen. This inflammation may be called "cytokine storm," which can cause widespread problems in the body. Tocilizumab is a medicine designed to block the action of a protein called interleukin-6 (IL-6) that is involved with the immune system and is known to be a key factor for problems with the immune system attacking the body. Tocilizumab is effective in treating "cytokine storm" from a type of cancer immunotherapy and may be effective in reducing the inflammatory response and "cytokine storm" seen in severe COVID-19 disease. Treating the inflammation may help to reduce symptoms, improve the ability to breath without a breathing machine (ventilator), and prevent patients from having more complications.
The mortality rate in SARS-CoV-2-related severe ARDS is high despite treatment with antivirals, glucocorticoids, immunoglobulins, and ventilation. Preclinical and clinical evidence indicate that MSCs migrate to the lung and respond to the pro-inflammatory lung environment by releasing anti-inflammatory factors reducing the proliferation of pro-inflammatory cytokines while modulating regulatory T cells and macrophages to promote resolution of inflammation. Therefore, MSCs may have the potential to increase survival in management of COVID-19 induced ARDS. The primary objective of this phase 3 trial is to evaluate the efficacy and safety of the addition of the mesenchymal stromal cell (MSC) remestemcel-L plus standard of care compared to placebo plus standard of care in patients with acute respiratory distress syndrome (ARDS) due to SARS-CoV-2. The secondary objective is to assess the impact of MSCs on inflammatory biomarkers.
Description: Number of all-cause mortality within 30 days of randomization.
Measure: Number of all-cause mortality Time: 30 daysDescription: Number of days alive off mechanical ventilatory support calculated as the number of days, within the 60 days window, that patients were alive and free of mechanical ventilatory support.
Measure: Number of days alive off mechanical ventilatory support Time: 60 daysDescription: Safety analyses will be assessed by adverse event rates calculated as the ratio of the total number of events over 30 days divided by total patient-time at risk for the specific event from randomization.
Measure: Number of adverse events Time: 30 daysDescription: The number and percent of patients with resolution and/or improvement of ARDS at day 7
Measure: Number of participants with resolution and/or improvement of ARDS Time: 7 daysDescription: The number and percent of patients with resolution and/or improvement of ARDS at day 14
Measure: Number of participants with resolution and/or improvement of ARDS Time: 14 daysDescription: The number and percent of patients with resolution and/or improvement of ARDS at day 21
Measure: Number of participants with resolution and/or improvement of ARDS Time: 21 daysDescription: The number and percent of patients with resolution and/or improvement of ARDS at day 30
Measure: Number of participants with resolution and/or improvement of ARDS Time: 30 daysDescription: Change from baseline of the severity of ARDS according to Berlin Criteria at days 7 post-randomization Change from baseline of the severity of ARDS according to Berlin Criteria at days 7, 14, 21 and 30 post-randomization will be compared between treatment groups using a Cochran-Mantel-Haenszel test stratified by baseline severity.
Measure: Change from baseline of the severity of ARDS Time: baseline and 7 daysDescription: Change from baseline of the severity of ARDS according to Berlin Criteria at days 14 post-randomization Change from baseline of the severity of ARDS according to Berlin Criteria at days 7, 14, 21 and 30 post-randomization will be compared between treatment groups using a Cochran-Mantel-Haenszel test stratified by baseline severity.
Measure: Change from baseline of the severity of ARDS Time: baseline and 14 daysDescription: Change from baseline of the severity of ARDS according to Berlin Criteria at days 21 post-randomization Change from baseline of the severity of ARDS according to Berlin Criteria at days 7, 14, 21 and 30 post-randomization will be compared between treatment groups using a Cochran-Mantel-Haenszel test stratified by baseline severity.
Measure: Change from baseline of the severity of ARDS Time: baseline and 21 daysDescription: Change from baseline of the severity of ARDS according to Berlin Criteria at days 30 post-randomization Change from baseline of the severity of ARDS according to Berlin Criteria at days 7, 14, 21 and 30 post-randomization will be compared between treatment groups using a Cochran-Mantel-Haenszel test stratified by baseline severity.
Measure: Change from baseline of the severity of ARDS Time: baseline and 30 daysDescription: Hospital length of stay
Measure: Length of stay Time: 12 monthsDescription: Change from baseline in Clinical Improvement Scale at day 7. Clinical Improvement Scale full scale from 1 to 7, with higher score indicating more clinical improvement.
Measure: Clinical Improvement Scale Time: 7 daysDescription: Change from baseline in Clinical Improvement Scale at day 14. Full scale from 1 to 7, with higher score indicating more clinical improvement.
Measure: Clinical Improvement Scale Time: 14 daysDescription: Change from baseline in Clinical Improvement Scale at day 21. Clinical Improvement Scale full scale from 1 to 7, with higher score indicating more clinical improvement.
Measure: Clinical Improvement Scale Time: 21 daysDescription: Change from baseline in Clinical Improvement Scale at day 30. Clinical Improvement Scale full scale from 1 to 7, with higher score indicating more clinical improvement.
Measure: Clinical Improvement Scale Time: 30 daysDescription: Changes from baseline in serum hs-CRP concentration at days 7
Measure: Change in serum hs-CRP concentration Time: baseline and 7 daysDescription: Changes from baseline in serum hs-CRP concentration at days 14
Measure: Change in serum hs-CRP concentration Time: baseline and 14 daysDescription: Changes from baseline in serum hs-CRP concentration at days 21
Measure: Change in serum hs-CRP concentration Time: baseline and 21 daysDescription: Changes from baseline in serum hs-CRP concentration at days 30
Measure: Change in serum hs-CRP concentration Time: baseline and 30 daysDescription: Changes from baseline in IL-6 inflammatory marker level at 7 days
Measure: Change in IL-6 inflammatory marker level Time: baseline and 7 daysDescription: Changes from baseline in IL-6 inflammatory marker level at 14 days
Measure: Change in IL-6 inflammatory marker level Time: baseline and 14 daysDescription: Changes from baseline in IL-6 inflammatory marker level at 21 days
Measure: Change in IL-6 inflammatory marker level Time: baseline and 21 daysDescription: Changes from baseline in IL-6 inflammatory marker level at 30 days
Measure: Change in IL-6 inflammatory marker level Time: baseline and 30 daysDescription: Changes from baseline in IL-6 inflammatory marker level at 7 days
Measure: Change in IL-8 inflammatory marker level Time: baseline and 7 daysDescription: Changes from baseline in IL-6 inflammatory marker level at 14 days
Measure: Change in IL-8 inflammatory marker level Time: baseline and 14 daysDescription: Changes from baseline in IL-6 inflammatory marker level at 21 days
Measure: Change in IL-8 inflammatory marker level Time: baseline and 21 daysDescription: Changes from baseline in IL-6 inflammatory marker level at 30 days
Measure: Change in IL-8 inflammatory marker level Time: baseline and 30 daysDescription: Changes from baseline in TNF-alpha inflammatory marker level at 7 days
Measure: Change in TNF-alpha inflammatory marker level Time: baseline and 7 daysDescription: Changes from baseline in TNF-alpha inflammatory marker level at 14 days
Measure: Change in TNF-alpha inflammatory marker level Time: baseline and 14 daysDescription: Changes from baseline in TNF-alpha inflammatory marker level at 21 days
Measure: Change in TNF-alpha inflammatory marker level Time: baseline and 21 daysDescription: Changes from baseline in TNF-alpha inflammatory marker level at 30 days
Measure: Change in TNF-alpha inflammatory marker level Time: baseline and 30 daysProspective, mono centric study on COVID-19 patients with or without acute respiratory distress syndrome (ARDS) to analyse the dynamics of the immune response and to search for biomarkers of evolution
Description: Blood sample
Measure: Number of increased immune population Time: Month 4Description: Blood sample
Measure: Number of decreased immune population Time: Month 4Description: Blood sample
Measure: Number of statically different phenotypes compared to control patients Time: Month 4Description: Qualitative identification of immune subpopulations showing a significant variation compared to controls and quantification of this variation (at D1 and/or D14)
Measure: Gain or loss of functional phenotypic markers between D1 and D14 Time: Day 14Description: Qualitative identification of immune subpopulations showing a significant variation between acute and mild COVID-19 and quantification of this variation (at D1 and/or D14)
Measure: Gain or loss of functional phenotypic markers between between acute and mild infections Time: Day 14Description: Qualitative identification of immune subpopulations showing a significant variation between acute stage and recovery (at 4 months) and quantification of this variation
Measure: Gain or loss of functional phenotypic markers between D1 and month 4 Time: Month 4Description: Blood sample
Measure: Evaluation of V, D, J gene usage alterations in the immunoglobulin and T cell receptor (TCR) repertoires during ARDS linked to COVID-19 Time: Day 14Description: Blood sample
Measure: Identification of the Ig classes and of V, D, J sequences of anti-CoV-2 antibodies Time: Month 4Description: Blood sample
Measure: Characterization of a new set of human antibodies from patients who have recovered of COVID-19 Time: Month 4Acute respiratory distress syndrome (ARDS) is a syndromic definition of an acute lung injury with alteration of biomechanics (lower respiratory system compliance) mostly associated with increased lesional edema. Increase in Pulmonary Vascular Permeability Index (PVPI) accompanied with accumulation of excess Extravascular Lung Water (EVLW) is the hallmark of ARDS. In routine clinical practice, the investigators measure the EVLW and PVPI in ARDS patients, as suggested by expert's recommendations, using a transpulmonary thermodilution (TPTD) technique. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly recognized illness that has spread rapidly throughout Wuhan (Hubei province) to other provinces in China and around the world. Most critically ill patients with SARS-CoV-2 will present the criteria for the definition of ARDS. However, many of these patients have a particular form of ARDS with severe hypoxemia often associated with near normal respiratory system compliance. This combination is almost never seen in severe ARDS. Thus other mechanisms (including probably vascular mechanisms), that are still poorly described, have to be involved in SARS-CoV-2. EVLW and PVPI have never been assessed in SARS-CoV-2 mechanically ventilated patients. The aim of this study is to evaluate these two parameters in order to best characterize and understand the mechanisms related to SARS-CoV-2. Based on observation of several cases in intensive care units (ICU), the investigators hypothesize that there are following different SARS-CoV-2 patterns: 1. Nearly normal compliance, low lung recruitability, normal EVLW and low PVPI. 2. Low compliance due to increased edema, high lung recruitability, high EVLW and high PVPI.
Description: EVLW (ml/kg) measured by a PiCCO device using TPTD thermodilution
Measure: Changes of Extra Vascular Lung Water Time: Since intubation at day 0 and measured repetitively by 6 hours until day 3Description: PVPI measured by a PiCCO device using TPTDventilation, duration of ICU length of stay, ICU mortality
Measure: Changes of Pulmonary Vascular Permeability Index Time: Since intubation at day 0 and measured repetitively by 6 hours until day 3Description: Changes of pulmonary compliance (ml/mmHg)
Measure: Changes of pulmonary compliance Time: Since intubation at day 0 and measured repetitively by 6 hours until day 3COVID-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2. COVID-19 causes life threatening complications known as Cytokine Release Syndrome or Cytokine Storm and Acute Respiratory Distress Syndrome. These complications are the main causes of death in this global pandemic. Over 1000 clinical trials are on-going worldwide to diagnose, treat, and improve the aggressive clinical course of COVID-19. The investigators propose the first, and so far, only gene therapy solution that has the potential to address this urgent unmet medical need. Rationale 1. DeltaRex-G is a safe, non-pathogenic, replication incompetent, RNA virus-based gene vector. DeltaRex-G nanoparticles (~100 nm) can mimic RNA virus SARS-CoV-2 by binding to viral receptors in human cells and may serve as a decoy to prevent SARSCoV-2 cell entry by crowding/neutralizing the SARS-CoV-2 even where the receptors may be different. 2. DeltaRex-G is a disease-seeking retrovector encoding a cytocidal dominant negative human cyclin G1 as genetic payload). When injected intravenously, the DeltaRex-G nanoparticles has a navigational system that targets exposed collagenous proteins (XC proteins) in injured tissues (e.g. inflamed lung, kidney, etc.), thus increasing the effective drug concentration at the sites of injury, in the vicinity of activated/proliferative T cells evoked by COVID-19. The DeltaRex-G then enters the rapidly dividing T cells and kills them by arresting the G1cell division cycle, hence, reducing cytokine release and ARDS; 3. Intravenous DeltaRex-G has minimal systemic toxicity due to its navigational system (targeting properties) that limits the biodistribution of DeltaRex-G only to areas of injury where exposed collagenous (XC) proteins are abnormally found; and 4. DeltaRex-G is currently available in FDA approved "Right to Try" or Expanded Access Program for Stage 4 cancers for an intermediate size population. To gain this approval, FDA requires DeltaRex-G to have demonstrated safety and efficacy in early clinical trials.
Description: The study will employ the standard "cohort of three" design (Storer, 1989). Three patients are treated at each dose level with expansion to six patients per cohort if DLT is observed in one of the three initially-enrolled patients at each dose level. The maximum tolerated dose is defined as the highest safely tolerated dose, where not more than one patient experienced DLT, with the next higher dose level having at least two patients who experienced DLT. No intra-patient escalation will take place.
Measure: Maximum Tolerated Dose Time: 3 weeksDescription: Duration of survival
Measure: Survival Time: 2 monthsDescription: Time of hospital admission to time of discharge
Measure: Hospital Stay Time: 3 weeksDescription: Time from start of mechanical ventilation to extubation or death
Measure: Ventilator Therapy Time: 3 weeksDescription: Time from start of intensive care to discarge to regular room
Measure: Intensive Care Unit Stay Time: 3 weeksDescription: Improvement in serum cytokine IL-6, IL12, TNF alpha
Measure: Cytokine Pattern Time: 3 weeksThis is a case series of patients with COVID-19 admitted to the largest university hospital in Sao Paulo, Brazil, during the 2020 COVID-19 pandemic. Data will be collected prospectively and retrospectively. The main objective is to describe the characteristics of critically ill patients with COVID-19 and their clinical outcomes, and to identify risk factors associated with survival, to inform clinical decision-making and to guide the strategy to mitigate the epidemic, both within each hospital and ICU and in public health management.
Description: the proportion of patients who survive to ICU discharge or for 28 days in the ICU
Measure: ICU survival at 28 days Time: 28 daysDescription: the proportion of patients who survive to hospital discharge or for 60 days in the hospital
Measure: Hospital survival at 60 days Time: 60 daysDescription: Number of days under invasive ventilatory support
Measure: Duration of mechanical ventilation Time: 28 daysDescription: Proportion of patients who received renal replacement therapy during the ICU stay
Measure: Need for renal replacement therapy Time: 28 daysDescription: percentage of patients who developed complications during the ICU stay: thromboembolic events, ventilator associated pneumonia, secondary infections, cardiovascular complications
Measure: Complications during the ICU stay Time: 28 daysCOVID-19 DISEASE Coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by a newly emergent coronavirus, severe acute respiratory syndrome from COVID-19, that was first recognized in Wuhan, China, in December 2019. While most people with COVID-19 develop mild or uncomplicated illness, approximately 14% develop severe disease requiring hospitalization and oxygen support and 5% require admission to an intensive care unit. In severe cases, COVID-19 can be complicated by acute respiratory disease syndrome (ARDS) requiring prolonged mechanical ventilation, sepsis and septic shock, multiorgan failure, including acute kidney, liver and cardiac injury. ARDS REHABILITATION Critically ill people who undergo prolonged mechanical ventilation often develop weakness, with severe symmetrical weakness of and deconditioning of the proximal musculature and of the respiratory muscles (critical illness neuropathy/myopathy).These individuals also develop significant functional impairment and reduced health-related quality of life (HRQL) up to 2 and 5 years after discharge. ARDS survivors may complain of depression, anxiety, memory disturbances, and difficulty with concentration often unchanged at 2 and 5 years. Less than half of all ARDS survivors return to work within the first year following discharge, two-thirds at two years, and more than 70% at five years. Early physiotherapy (PT) of people with ARDS has recently been suggested as a complementary therapeutic tool to improve early and late outcomes. The aims of PT programs should be to reduce complications of immobilization and ventilator-dependency, to improve residual function, to prevent new hospitalisations, and to improve health status and HRQL. Physiotherapy in critical patients is claimed also to prevent and contribute to treat respiratory complications such as secretion retention, atelectasis, and pneumonia. Early mobilization and maintenance of muscle strength may reduce the risk of difficult weaning, limited mobility, and ventilator dependency. Lastly, pulmonary rehabilitation in ICU in mechanically ventilated subjects may reduce length of stay in ICU up to 4.5 day, shorten mechanical ventilation of 2.3 days and weaning by 1.7 days. The aim of this study is to investigate how early pulmonary and motor rehabilitation impacts on length of hospital admission (ICU and acute ward) and early and late outcomes inpatients that develop ARDS due to COVID-19.
Description: days of ICU stay
Measure: Length of ICU stay Time: up to 60 daysDescription: days of hospital stay
Measure: Length of hospital stay Time: up to 90 daysThe study is a prospective, randomized, controlled investigation designed for comparison of two groups for the reduction of respiratory distress in a CoViD-19 population, using gammaCore Sapphire (nVNS) plus standard of care (active) vs. standard of care alone (SoC), the control group. The gammaCore® (nVNS) treatments will be used acutely and prophylactically. The active and control groups will be diseased and severity matched. The primary objective is to reduce initiation of mechanical ventilation in patients with CoViD-19 compared to the control group. Secondary objectives are to evaluate cytokine trends/prevent cytokine storms, evaluate supplemental oxygen requirements, decrease mortality of CoViD-19 patients and to delay the onset of mechanical ventilation.
Description: measure the change (in hours) between the control group and treatment group
Measure: change in initiation of mechanical ventilation in patients with CoViD-19 compared to the control group. Time: From the time of randomization until the time of initiation of mechanical ventilation, assessed up to day of discharge or death, whichever occurs first, assessed up to 3 monthsDescription: measure the changes in the serum/plasma concentrations of TH1 and TH2-type cytokines
Measure: evaluate cytokine trends Time: From the time of initial blood draw until the time of final blood draw, assessed up to date of mechanical ventilation, death, or discharge from hospital, whichever occurs first,assessed up to 3 monthsDescription: compare the difference in oxygen requirements (liters/min) between the control group and active group for patients admitted to the hospital for CoViD-19.
Measure: evaluate supplemental oxygen requirements Time: From the time of randomization, assessed up to time of mechanical ventilation, day of discharge or death, whichever occurs first,assessed up to 3 monthsDescription: measure the change (in hours) to death between control group and treatment group
Measure: decrease mortality of CoViD-19 patients Time: From the time or randomization until the date of death from any cause, assessed up to day of discharge or death,assessed up to 3 monthsDescription: measure the change (in hours) to time of mechanical ventilation between control group and treatment group
Measure: delay onset of ventilation Time: From the time of randomization until the time of initiation of mechanical ventilation, assessed up to day of discharge or death, whichever occurs first,assessed up to 3 monthsThe authors hypothesized that inhaled sedation, either with isoflurane or sevoflurane, might be associated with improved clinical outcomes in patients with COVID-19-related ARDS, compared to intravenous sedation. The authors therefore designed the "Inhaled Sedation for COVID-19-related ARDS" (ISCA) non-interventional, observational, multicenter study of data collected from the patients' medical records in order to: 1. assess the efficacy of inhaled sedation in improving a composite outcome of mortality and time off the ventilator at 28 days in patients with COVID-19-related ARDS, in comparison to a control group receiving intravenous sedation (primary objective), 2. investigate the effects of inhaled sedation, compared to intravenous sedation, on lung function as assessed by gas exchange and physiologic measures in patients with COVID-19-related ARDS (secondary objective), 3. report sedation practice patterns in critically ill patients during the COVID-19 pandemics (secondary objective).
Description: Ventilator-free days to day 28 are defined as the number of days from the time of initiating unassisted breathing to day 28 after intubation, assuming survival for at least two consecutive calendar days after initiating unassisted breathing and continued unassisted breathing to day 28. If a patient returns to assisted breathing and subsequently achieves unassisted breathing to day 28, VFDs will be counted from the end of the last period of assisted breathing to day 28. A period of assisted breathing lasting less than 24 hours and for the purpose of a surgical procedure will not count against the VFD calculation. If a patient was receiving assisted breathing at day 27 or died prior to day 28, VFDs will be zero. Patients transferred to another hospital or other health care facility will be followed to day 28 to assess this endpoint.
Measure: Number of days off the ventilator (VFD28, for ventilator-free days), taking into account death as a competing event Time: Day 28 after inclusionDescription: All-cause mortality
Measure: All-cause mortality Time: Days 7, 14, and 28 after inclusionDescription: Ventilator-free days to days 7 and 14 are defined as the number of days from the time of initiating unassisted breathing to day 7 and 14 after intubation, assuming survival for at least two consecutive calendar days after initiating unassisted breathing and continued unassisted breathing to days 7 and 14 If a patient returns to assisted breathing and subsequently achieves unassisted breathing to days 7 and 14 , VFDs will be counted from the end of the last period of assisted breathing to days 7 and 14. A period of assisted breathing lasting less than 24 hours and for the purpose of a surgical procedure will not count against the VFD calculation. If a patient was receiving assisted breathing at day 6 or 13 or died prior to days 7 and 14, respectively,VFDs to days 7 and 14 will be zero. Patients transferred to another hospital or other health care facility will be followed to days 7 and 14 to assess this endpoint.
Measure: Ventilator-free days Time: Days 7 and 14 after inclusionDescription: Number of days alive and not in the ICU from inclusion to day 28
Measure: ICU-free days Time: Day 28 after inclusionDescription: Total duration of controlled mechanical ventilation to day 28
Measure: Duration of invasive mechanical ventilation Time: Day 28 after inclusionDescription: Total duration of controlled mechanical ventilation to day 28
Measure: Duration of controlled mechanical ventilation Time: Day 28 after inclusionDescription: Arterial hypoxemia, as assessed by the partial pressure of arterial oxygen-to-fraction of inspired oxygen ratio (PaO2/FiO2)
Measure: Physiological measures of lung function Time: Days 1, 2, 3, 4, 5, 6, and 7 from inclusionDescription: Partial pressure of arterial carbon dioxide (PaCO2)
Measure: Physiological measures of lung function Time: Days 1, 2, 3, 4, 5, 6, and 7 from inclusionDescription: Inspiratory plateau pressure
Measure: Physiological measures of lung function Time: Days 1, 2, 3, 4, 5, 6, and 7 from inclusionDescription: Driving pressure
Measure: Physiological measures of lung function Time: Days 1, 2, 3, 4, 5, 6, and 7 from inclusionDescription: Mode of mechanical ventilation (assisted versus controlled)
Measure: Physiological measures of lung function Time: Days 1, 2, 3, 4, 5, 6, and 7 from inclusionDescription: If available, 100 ms occlusion pressure (P0.1), a marker of respiratory drive
Measure: Physiological measures of lung function Time: Days 1, 2, 3, 4, 5, 6, and 7 from inclusionDescription: Development of pneumothorax
Measure: Development of complications Time: Day 7 from inclusionDescription: Supraventricular tachycardia
Measure: Development of complications Time: Day 7 from inclusionDescription: New onset atrial fibrillation
Measure: Development of complications Time: Day 7 from inclusionDescription: Total duration (in days) of vasopressor use
Measure: Duration of vasopressor use Time: Day 28 after inclusionDescription: Total duration (in days)of renal replacement therapy
Measure: Duration of renal replacement therapy Time: Day 28 after inclusionDescription: Adjuvant therapies are defined as: prone position, recruitment maneuvers, inhaled nitric oxide, inhaled epoprostenol sodium, high frequency ventilation, ECMO, neuromuscular blockade
Measure: Duration (in days) of any adjuvant therapies Time: Day 7 from inclusionDescription: Number of days with continuous neuromuscular blockade
Measure: Duration of continuous neuromuscular blockade Time: Day 28 from inclusionDescription: Sedation drug(s) used (name(s))
Measure: Type of sedation practices Time: Day 28 from inclusionDescription: Number of days with sedation
Measure: Duration of sedation practices Time: Day 28 from inclusionDescription: If inhaled sedation, device used to deliver it
Measure: Modalities of sedation practices Time: Day 28 from inclusionThe purpose of this research study is to evaluate the safety and potential efficacy of Intravenous Infusion of Organicell Flow for treatment of moderate to severe Acute Respiratory Syndrome (SARS) related to COVID-19 infection vs Placebo.
Description: Safety will be defined by the incidence of any infusion associated adverse events as assessed by treating physician
Measure: Incidence of any infusion associated adverse events Time: 60 DaysDescription: Safety will be defined by the incidence of severe adverse events as assessed by treating physician
Measure: Incidence of Severe Adverse Events Time: 60 DaysDescription: Measured at day 60 or at hospital discharge, whichever comes first.
Measure: All Cause Mortality Time: 60 DaysDescription: Number of participants that are alive at 60 days post first infusion follow up
Measure: Survival Rate Time: 60 DaysDescription: Measure IL-6, IL-2, TNF-alpha from serum of blood samples
Measure: Cytokine Levels Time: Day 0, Day 4, Day 8, Day14, Day 21, Day 28Description: D-dimer from serum of blood samples methodology using blood samples or nose / throat swab
Measure: D-dimer Levels Time: Day 0, Day 4, Day 8, Day14, Day 21, Day 28Description: CRP from serum of blood samples
Measure: C-reactive protein Levels Time: Day 0, Day 4, Day 8, Day14, Day 21, Day 28Description: Viral load by real time RT methodology using blood samples or nose / throat swab
Measure: Quantification of the COVID-19 Time: Day 0, Day 4, Day 8Description: Improved organ failure within 30 days, including cardiovascular system, coagulation system, liver, kidney and other extra-pulmonary organs using Sequential Organ Failure Assessment (SOFA) score.
Measure: Improved Organ Failure Time: Day 30Description: Chest imaging changes for 30 days compare to placebo: 1) Ground-glass opacity, - 2) Local patchy shadowing, 3) Bilateral patchy shadowing, and 4) Interstitial abnormalities.
Measure: Chest Imaging Changes Time: Day o, Day 30Renal damage in patients hospitalized for ARDS in the ICU can also be related to multiple causes including, but not limited to, the consequences of hemodynamic fluctuations in these patients or the use of nephrotoxic drugs responsible for acute post-ischemic or toxic tubular necrosis. Frequently observed abnormalities of cioagumation may also have a potential impact on renal structures, particularly glomerular capillaries. The researchers wish to characterize and phenotype the renal impairment of patients hospitalized in intensive care with tables of severe Covid19 infections in ARDS: clinical, biological and histological (by performing post-mortem biopsies). Translated with www.DeepL.com/Translator (free version)
Mechanical ventilation in ARDS requires protective ventilation and PEEP. Airway closer has to be overcome to reduce lung heterogeneity, AOP is measured globally with a ventilator PV curve without PEEP. EIT derived PV curve is another method that could determine heterogeneity of AOP between both lung. This study aims to determine whether AOP measured with EIT derived PV curve is similar to AOP on the ventilator PV curve and see if AOP is different between lungs. If airway closer is higher on one lung, global AOP on the ventilator PV curve probably estimates the other lung.
Description: global ventilator method vs regional EIT derived method in all patients
Measure: Comparison of the PV curves Time: At inclusion dayDescription: Global ventilator method vs regional EIT derived method in regional AOP, right and left lungs
Measure: Comparison of regional AOP Time: At inclusion dayDescription: Comparison selected by the EIT-PEEP method
Measure: Comparison of the different AOPs with the level of PEEP Time: At inclusion dayTo demonstrate the efficacy of VERU-111 in the treatment of SARS-Cov-2 Infection by assessing its effect on the proportion of subjects that are alive without respiratory failure at Day 22. Respiratory failure is defined as non-invasive ventilation or high-flow oxygen, intubation and mechanical ventilation, or ventilation with additional organ support (e.g., pressors, RRT, ECMO).
Description: To demonstrate the efficacy of VERU-111 in the treatment of SARS-Cov-2 Infection by assessing its effect on the proportion of subjects that are alive without respiratory failure at Day 29. Respiratory failure is defined as endotracheal intubation and mechanical ventilation, extracorporeal membrane oxygenation, high-flow nasal cannula oxygen delivery, noninvasive positive pressure ventilation, clinical diagnosis of respiratory failure with initiation of none of these measures only when clinical decision making is driven solely by resource limitation
Measure: Proportion of subjects that are alive without respiratory failure at Day 29. Time: Day 29Description: Improvement on the WHO Ordinal Scale for Clinical Improvement (8-point ordinal scale)
Measure: WHO clinical Improvement Time: Day15 Day 22 and Day 29Description: Proportion of subjects with normalization of fever and oxygen saturation through
Measure: Normalization of Fever and Oxygen Time: Day 15, Day 22, and Day 29Description: Percentage of subjects discharged from hospital
Measure: Discharge from Hospital Time: Day 15 and Day 22Description: Proportion of patients alive and free of respiratory failure
Measure: Patients alive and free of respiratory failure Time: Day 15, and Day 22This is a multicenter, single-treatment study. Subjects will consist of adults with COVID-19 associated acute lung injury who are being cared for in a critical care environment.
Description: The AUC for OI through 12 hours measured using the trapezoidal method, where OI is defined as mean airway pressure (Paw)×fraction of inspired oxygen (FiO2)×100/arterial pressure of oxygen (PaO2)
Measure: Oxygenation index (OI) area under the curve (AUC)0-12 Time: 12 hours post initiation of dosingDescription: FiO2 change from baseline
Measure: FiO2 Time: 24 hours post initiation of dosingDescription: PaO2 change from baseline
Measure: PaO2 Time: 24 hours post initiation of dosingDescription: SpO2 change from baseline
Measure: Oxygenation from pulse oximetry (SpO2) Time: 24 hours post initiation of dosingDescription: Change from baseline in P/F ratio, defined as PaO2/FiO2
Measure: P/F ratio Time: 24 hours post initiation of dosingDescription: Change from baseline in VI, defined as [respiration rate (RR)×(peak inspriatory pressure [PIP] − peak expiratory end pressure [PEEP])× arterial pressure of carbon dioxide (PaCO2)]/1000
Measure: Ventilation Index (VI) Time: 24 hours post initiation of dosingDescription: Change from baseline in lung compliance, as measured by the ventilator
Measure: Lung compliance Time: 24 hours post initiation of dosingA randomized, double-blind, placebo-controlled Phase 2/3 study to evaluate the safety and efficacy of DSTAT in patients with Acute Lung Injury (ALI) due to COVID-19. This study is designed to determine if DSTAT can accelerate recovery and prevent progression to mechanical ventilation in patients severely affected by COVID-19.
Description: Alive and free of invasive mechanical ventilation
Measure: Proportion of participants who are alive and free of invasive mechanical ventilation Time: Through Day 28Description: Time to all-cause mortality
Measure: All-cause mortality Time: Through Day 28Randomized, double-blind, parallel, two-arms clinical trial to assess the efficacy and safety of 2 infusions of Wharton-Jelly mesenchymal stromal cells (day 1 and day 3, endovenously at 1E6cells/Kg per dose) in patients with moderate acute respiratory distress syndrome (ARDS) secondary to SARS-CoV-2 infection. Follow-up will be established on days 3, 5, 7, 14, 21, and 28. Long term follow-up will be performed at 3, 6 and 12 months.
Description: Number of patients who died, by treatment group
Measure: All-cause mortality at day 28 Time: Day 28Description: Number of patients with treatment-emergent adverse events, by treatment group
Measure: Safety of WJ-MSC Time: Day 28Description: Number of patients who, after the start of treatment, required rescue medication, by treatment group
Measure: Need for treatment with rescue medication Time: Day 28Description: Number of days that the patient requires invasive mechanical ventilation from the start of treatment to day +28, by treatment group
Measure: Need and duration of mechanical ventilation Time: Day 28Description: Days after treatment in which the patient remains alive and free of invasive mechanical ventilation, per treatment group.
Measure: Ventilator free days Time: Day 28Description: Variation of the oxygenation index (PaO2 / FiO2) with respect to the baseline value, by treatment group.
Measure: Evolution of PaO2 / FiO2 ratio Time: Day 28Description: Variation of the score of the Sequential Organ Failure Assessment (SOFA) Index with respect to the baseline value, by treatment group.
Measure: Evolution of the SOFA index Time: Day 28Description: Variation of Acute Physiology and Chronic Health disease Classification System II (APACHE II) score, by treatment group.
Measure: Evolution of the APACHE II score Time: Day 28Description: Days of stay in the ICU from the day of admission until discharge to day 28, or date of death if earlier, by treatment group.
Measure: Duration of hospitalization Time: Day 28Description: Variation in the count and percentage of leukocytes and neutrophils, by treatment group.
Measure: Evolution of markers of immune response (leucocyte count, neutrophils) Time: Day 28Description: Feasibility will be evaluated by the time elapsed from the request of the treatment by the hospital center until the delivery date
Measure: Feasibility of WJ-MSC administration Time: Day 28Description: Feasibility will be evaluated by the number of patients treated within 2 days of the request for treatment.
Measure: Feasibility of WJ-MSC administration Time: Day 28Description: Variation in the values of the biomarker, by treatment group.
Measure: Evolution of disease biomarker: polymerase chain reaction (RT-PCR) Time: Day 28Description: Variation in the values of the biomarker, by treatment group.
Measure: Evolution of disease biomarker: lactate dehydrogenase (LDH) Time: Day 28Description: Variation in the values of the biomarker, by treatment group.
Measure: Evolution of disease biomarker: D-dimer Time: Day 28Description: Variation in the values of the biomarker, by treatment group.
Measure: Evolution of disease biomarker: Ferritin Time: Day 28Description: Blood sample analysis
Measure: Analysis of subpopulations of lymphocytes and immunoglobulins Time: Day 28Description: In vitro response will be assessed using commercial viral antigens (Miltenyi Biotech)
Measure: Evaluation of the in vitro response of the receptor lymphocytes Time: Day 28Description: Reactivity will be assessed using ELISPOT
Measure: Study of reactivity against SARS-CoV-2 peptides Time: Day 28Description: Blood sample analysis
Measure: Immunophenotypic study of memory cells in response to SARS-CoV-2 peptides Time: Day 28Description: Blood sample analysis for the patient's genomic sequencing
Measure: Genetic variability of patient's genotype in response to treatment Time: Day 28Description: Genomic sequencing of the SARS-CoV-2 in a nasopharyngeal sample
Measure: Genetic variability of the SARS-CoV-2 genotype in response to treatment Time: Day 28Recent COVID 19 pandemic has overwhelmed health services all around the world, and humanity has yet to find a cure or a vaccine for the treatment of patients, mainly the severe ones, who pose a therapeutic challenge to healthcare professionals given the paucity of information we have regarding SARS-CoV-2 pathogenesis. Recently, reports mainly from China from patients treated with mesenchymal stem cells have shown promise in accelerating recovery, even in the critically ill and the therapy has sustained an increase in research because of it's powerful immunomodulatory effects, making it and interesting alternative in patients with lung and systemic inflammation. These effects could help treat a lot of patients and improve their outcomes, reason why phase I/II studies are needed to show their safety and experimental efficacy.
Description: Evaluation of efficacy of WJ-MSC defined by mortality at 28 days of application.
Measure: Intergroup mortality difference with treatment Time: 28 days.Description: Safety evaluation of WJ-MSC describing and comparing incidence, type and severity of adverse events in both groups.
Measure: Number of patients with treatment related adverse events Time: 6 months.Description: Evaluation of the effect of WJ-MSC in the time of mechanical ventilation compared between the two groups, as prolonged mechanical ventilation days are associated with higher complication risks as pneumonia, tracheostomy and death.
Measure: Difference in days of mechanical ventilation between groups Time: From ICU admission to 180 days.Description: Evaluation of the effect of WJ-MSC in the time of hospitalization between the two groups as a measure of efficacy.
Measure: Median reduction of days of hospitalization Time: From hospital admission to 180 days.Description: Evaluation of the effect of WJ-MSC in the time of oxygen needs compared between the two groups as a measure of efficacy.
Measure: Median reduction of days of oxygen needs Time: From hospital admission to 180 days.Description: "Sequential Organ Failure Assessment" (SOFA) score is a tool used to determine the beginning and evolution of multiorgan failure, ranging from 0 to 24, being 24 the worst scenario. It has been proven useful as an outcome predictor of mortality and ICU stay. The result is the addition of the evaluation of each organ or system. Effect of WJ-MSC in the SOFA score will be compared between the two groups.
Measure: Difference between "Sequential Organ Failure Assessment" score between groups Time: Baseline to 7 daysDescription: Murray score is a tool used to classify lung injury. 0 = no lung injury, 0.1-2.5, mild to moderate lund injury, >2.5 Acute respiratory distress syndrome. The effect of WJ-MSC in the Murray score will be compared between the two groups.
Measure: Difference between median Murray score between groups Time: Baseline and 7 daysDescription: APACHE II is a prognostic score based on 12 different items obtained in the first 24 hours of ICU admission. Its mainly used as a single measure, but some authors have used and described prediction usefulness with repeated measures. It ranges from 0 to 71 points. Higher scores are related to higher ICU mortality. The effect of WJ-MSC in the APACHE II score will compared between the two groups.
Measure: Difference in APACHE II score between groups Time: Baseline and 7 daysDescription: Evaluation of the effect of WJ-MSC in lymphocyte count measured in absolute number/mm3. These laboratory measures have been associated with COVID 19 severity.
Measure: Difference in lymphocyte count between groups Time: baseline and 21 days or dischargeDescription: Evaluation of the effect of WJ-MSC in C reactive protein concentration between the two groups, measured in mg/dl. Highest levels have been associated with COVID 19 severity and inflammation.
Measure: Changes in C reactive protein concentration between groups Time: baseline and 21 days or dischargeDescription: Evaluation of the effect of WJ-MSC in D dimer between the two groups, measured in micrograms Highest levels have been associated with COVID 19 severity and thromboembolic complications.
Measure: Changes in D dimer concentration Time: baseline and 21 days or dischargeDescription: Evaluation of the effect of WJ-MSC in ferritin compared between the two groups, measured in nanograms/ml. These laboratory measures have been associated with COVID 19 infection and severity.
Measure: Changes in ferritin concentration Time: baseline and 21 days or dischargeDescription: Evaluation of the effect of WJ-MSC in LDH compared between the two groups, measured in units/liter. These laboratory measures have been associated with COVID 19 infection and severity.
Measure: Changes in lactate dehydrogenase concentration Time: baseline and 21 days or dischargeDescription: Cytokines are biomarkers of inflammation or inflammatory activity in the human body. Changes in this profile give information about underlying process of inflammation.The effect of WJ-MSC in IL-6 will be compared between the two groups. It will be measured in picograms/ml.
Measure: Impact on interleukin 6 concentrations between groups. Time: Baseline and 7 daysDescription: Cytokines are biomarkers of inflammation or inflammatory activity in the human body. Changes in this profile give information about underlying process of inflammation. The effect of WJ-MSC in IL 8 will be compared between the two groups. It will be measured in picograms/ml.
Measure: Impact on interleukin 8 concentrations between groups. Time: Baseline and 7 daysDescription: Cytokines are biomarkers of inflammation or inflammatory activity in the human body. Changes in this profile give information about underlying process of inflammation. The effect of WJ-MSC in IL 10 will be compared between the two groups. It will be measured in picograms/ml.
Measure: Impact on interleukin 10 concentrations between groups. Time: Baseline and 7 daysDescription: Cytokines are biomarkers of inflammation or inflammatory activity in the human body. Changes in this profile give information about underlying process of inflammation. The effect of WJ-MSC in TNF alpha will be compared between the two groups. It will be measured in nanograms/ml.
Measure: Impact on tumor necrosis factor alpha concentrations between groups. Time: Baseline to 7 days.Description: Evaluation of the effect of WJ-MSC in pulmonary function measured with 6 minute walk. 6 minute walk is a test that gives information about pulmonary, cardiovascular and musculoskeletal functions. It measures the distance walked in 6 minutes in meters.
Measure: Changes in 6 minute walk between groups Time: 6 monthsDescription: Evaluation of the effect of WJ-MSC in pulmonary function with thoracic CT scan. CT scan gives information about lung parenchyma, showing acute and chronic changes related to the underlying condition. Radiologic findings will be compared mainly comparing percentage of patients with pulmonary fibrosis.
Measure: Changes in Pulmonary Computed Tomography Scan between groups Time: 6 monthsDescription: Evaluation of the effect of WJ-MSC in pulmonary function measured with spirometry, compared between the two groups. Spirometry gives information about lung volume and mobilization of air. Main parameters to be measured in spirometry are Forced Vital Capacity, Forced Expiratory Volume in 1 second and relation between these two to define if there is obstruction or restriction of airflow.
Measure: Changes in Spirometry between groups Time: 6 monthsDescription: Evaluation of the effect of WJ-MSC in health related quality of life assessed by 36 Item Short Survey (SF-36). SF 36 is a patient reported tool. Each question is rated from 0 to 100, being 100 the best score possible. The scores are then compared to a population defined median score. Differences in global and specific scoring will be measured between groups.
Measure: Changes in health related quality of life between groups Time: 6 monthsProne position (PP) has been proved to be effective in severe ARDS patients. On the other hand, High flow nasal cannula (HFNC) may prevent intubation in hypoxemic Acute respiratory failure (ARF) patients. Our hypothesis is that the combination of PP and HFNC in patients with COVID19 induced ARDS may decrease the need of mechanical ventilation. Primary outcome: Therapeutic failure within 28 days of randomization (death or intubation). Secondary outcomes: to analyze PP feasibility and safety in HFNC patients and to analyze effectiveness in terms of oxygenation. Methods: multicentric randomized study including patients with COVID19 induced ARDS supported with HFNC. Experimental group will received HFNC and PP whereas observation group will received standard care. Optimization of non-invasive respiratory management of COVID19 induced ARDS patients may decrease the need of invasive mechanical ventilation and subsequently ICU and hospital length of stay.
Description: Therapeutic failure: death or intubation
Measure: Therapeutic failure death or intubation Time: 28 days within randomizationDescription: Comfort measurement using a visual-analog scale. Presence of complications related with prone position and the use of high-flow nasal cannula: Skin ulcers. Intravascular lines displacement HFNC related events (hot air feeling, nasal lesions)
Measure: Feasibility and safety of prone position in HFNC patients Time: 28 days within randomizationDescription: Evolution of the oxygenation (SpO2/FiO2) in prone position. Efficacy Length of HFNC therapy Length of ICU stay Length of mechanical ventilation (in those who require intubation) ICU and hospital mortality
Measure: Efficacy of prone position in HFNC patients Time: 28 days within randomizationThere is compelling data indicating that there is an excessive inflammatory response in some patients with COVID-19 leading them to develop ARDS that can be severe with a very poor prognosis. Many of these patients require very long mechanical ventilation times to survive, which have led to the collapse of the health system in some regions of the world. The current evidence for the treatment of these severe forms is inconsistent and most scientific societies and governmental or international organizations recommend evaluating treatments with randomized clinical trials. Corticosteroids, being non-specific anti-inflammatory drugs, could shorten the duration of respiratory failure and improve the prognosis. Due to the lack of solid data available regarding this serious disease, our objective is to randomly evaluate the efficacy and safety of the use of dexamethasone, a parenteral corticosteroid approved in Argentina, in patients with ARDS with confirmed respiratory infection due to SARS-CoV-2 (COVID-19).
Description: Days without ventilator support in the first 28 days of hospitalization
Measure: Ventilator-free days at 28 days Time: 28 days after starting mechanical ventilationDescription: Dead rate within 28 days of ICU admission
Measure: 28-days mortality Time: 28 days after ICU admissionDescription: Frequency of ventilator associated pneumonia, blood stream infection or candidemia in the first 28 days
Measure: Frequency of nosocomila infections Time: 28 days after ICU admissionDescription: Frequency of positive PCR on nasopharingeal swab
Measure: Viral shedding Time: 10 days after randomizationDescription: Change from baseline CPR
Measure: Serum C-reactive Protein variation Time: 10 days after randomizationDescription: Variation in SOFA over the first 10 days after randomization
Measure: SOFA variation Time: 10 days after randomizationDescription: Cumulative hours spent on prone position
Measure: Use of prone position Time: 10 days after randomizationDescription: Frequency of delirium at ICU discharge
Measure: Delirium Time: 28 days after ICU admissionDescription: mMRC score at ICU discharge
Measure: Muscle weakness Time: 28 days after ICU admissionThe study is a prospective, randomized, placebo-controlled, single-blind phase 2 clinical study of the efficacy and safety of AMY-101, a potent C3 inhibitor, for the management of patients with ARDS caused by SARS-CoV-2 infection. We will assess the efficacy and safety, as well as pharmacokinetics (PK), and pharmacodynamics (PD). The study will assess the impact of AMY-101 in patients with severe COVID19; specifically, it will assess the impact of AMY-101 1) on survival without ARDS and without oxygen requirement at day 21 and 2) on the clinical status of the patients at day 21.
Description: The clinical status is based on the following six-category ordinal scale: 1: not hospitalised; 2: hospitalised, not requiring supplemental oxygen; 3: hospitalised, requiring supplemental oxygen; 4: hospitalised, requiring nasal high-flow oxygen therapy, non-invasive mechanical ventilation, or both; 5: hospitalised, requiring ECMO, invasive mechanical ventilation, or both; and 6: death.
Measure: The proportion of patients assigned to each category, of a six-category ordinal scale. Time: 21 daysDescription: The clinical status is based on the following six-category ordinal scale: 1: not hospitalised; 2: hospitalised, not requiring supplemental oxygen; 3: hospitalised, requiring supplemental oxygen; 4: hospitalised, requiring nasal high-flow oxygen therapy, non-invasive mechanical ventilation, or both; 5: hospitalised, requiring ECMO, invasive mechanical ventilation, or both; and 6: death.
Measure: The proportion of patients assigned to each category, of a six-category ordinal scale. Time: On days 7, 14, and 44Description: With respiratory failure defined as any of the following: Worsening of severe gas transfer deficit, accounting for a shift in ARDS disease category (PaO2/FiO2 ≤200 for patients with PaO2/FiO2 >200 at baseline; PaO2/FiO2 ≤100 for patients with PaO2/FiO2 >100 at baseline), Persistent respiratory distress while receiving oxygen (persistent marked dyspnea,use of accessory respiratory muscles, paradoxical respiratory movements), Transfer to the intensive care unit for intubation, Death.
Measure: Proportion of respiratory failure-free survival Time: Day 44Randomized, placebo controlled study to determine if nebulized heparin may reduce the severity of lung injury caused by the novel coronavirus, also known as COVID-19
The clinical picture of the novel corona virus 2 (SARS-CoV-2) disease (COVID-19) is rapidly evolving. Although infections may be mild, up to 25% of all patients admitted to hospital require admission to the intensive care unit, and as many as 40% will progress to develop severe problems breathing due to the acute respiratory distress syndrome (ARDS). ARDS often requires mechanical ventilation, with a 50% risk of mortality. Researchers at the Ottawa Hospital Research Institute (OHRI) have been studying the potential therapeutic role of mesenchymal stromal/stem cells, or MSCs, for the treatment of ARDS for over a decade. This has led to the world's first clinical trial using MSC therapy for patients with severe infections (sepsis) which is often associated with ARDS (NCT02421484). This trial demonstrated tolerability, and potential signs of efficacy. In addition, the investigators have established expertise in producing clinical-grade MSCs and have received approval from Health Canada for the use of MSCs in three different clinical studies. The investigators propose a Phase 1, open label, dose-escalating and safety trial using a 3+3+3 design to determine the safety, and maximum feasible tolerated dose of repeated delivery of Bone Marrow (BM)-MSCs intravenously. This will take advantage of a limited supply of screened BM-MSCs lines which are available now in the GMP facility and will allow to have product ready to deliver to the first patient within weeks. The investigators will enroll up to 9 patients; each receiving repeated unit doses of BM-MSCs delivered by IV infusion on each of 3 consecutive days (24±4 hours apart) according to the following dose-escalation schedule (3 patients per dose panel): (i) Panel 1: 25 million cells/unit dose (cumulative dose: 75 million MSCs), (ii) Panel 2: 50 million cells/unit dose (cumulative dose: 150 million MSCs), (iii) Panel 3: up to 90 million cells/unit dose (cumulative dose: up to 270 million MSCs).
Description: Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0 to determine the maximum feasible tolerated dose (MFTD) of BM-MSCs given to patients with COVID-19
Measure: Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0 Time: At time of infusion until one year post-infusionDescription: Number of Participants alive by Day 28
Measure: Number of Participants alive by Day 28 Time: Day 28Description: Number of Participants with ventilator-free Days by Day 28
Measure: Number of Participants with ventilator-free Days by Day 28 Time: Day 28This multicenter, randomized, double-blind, placebo-controlled clinical trial will evaluate the efficacy and safety of intravenous Sodium Nitrite Injection for treatment of patients infected with COVID-19 who develop lung injury and require mechanical ventilation.
Description: Proportion of study subjects who are alive and free of respiratory failure at Day 28
Measure: Survival with Unassisted Breathing Time: Day 28Description: Number of days alive without mechanical ventilation from start of study through Day 28
Measure: Survival without Mechanical Ventilation Time: Day 28Description: Number of days alive and not in the intensive care unit from start of study through Day 28.
Measure: Survival without Intensive Care Time: Day 28Description: Number of days alive and not in hospital from start of study through Day 28.
Measure: Survival without Hospitalization Time: Day 28Description: Alive on Day 28 and no use of ECMO therapy any time between start of study and Day 28.
Measure: Survival without ECMO Time: Day 28Description: Alive on Day 28
Measure: Survival Time: Day 28Description: Oxygenation index (PaO2/FIO2) at Day 14
Measure: Lung Status Time: Day 14Description: Blood urea nitrogen (BUN) at Day 14
Measure: Kidney Status (1) Time: Day 14Description: Creatinine at Day 14
Measure: Kidney Status (2) Time: Day 14Description: Liver function tests (ALT, AST, LDH) at Day 14
Measure: Liver Status Time: Day 14The purpose of this study is to evaluate the safety and effectiveness of APL-9 in adults with mild to moderate ARDS (acute respiratory distress syndrome) caused by COVID-19 who are hospitalized and require supplemental oxygen therapy with or without mechanical ventilation. It is thought that COVID-19 activates the complement system, part of the immune system that responds to infection or tissue damage, and increases inflammation in the lungs. APL-9 has been designed to inhibit or block activation of part of the complement pathway, and potentially reduce inflammation in the lungs. Part 1 of the study is open-label to evaluate safety; all participants will receive APL-9 plus standard of care. Part 2 of the study is double-blind, randomized; participants will receive either APL-9 or the vehicle-control plus standard of care.
The purpose of this trial is to determine whether Prone Positioning (PP) improves outcomes for non-intubated hospitalized patients with hypoxemic respiratory failure due to COVID-19, who are not candidates for mechanical ventilation in the ICU. The investigators hypothesize that PP will reduce in-hospital mortality or discharge to hospice, compared with usual care for non-intubated patients with do-not-intubate goals of care with hypoxemic respiratory failure due to probable COVID-19.
Description: In-hospital mortality or discharge to hospice at Day 60.
Measure: Hospital mortality or discharge to hospice Time: 60 daysDescription: An Adverse Event (AE) is any unfavourable or other finding (including clinically significant laboratory tests), symptom or disease occurring during the during of the study, whether or not it is considered to be related to the medicinal (investigational) product, not explicitly classified elsewhere in this protocol, and whether or not it is expected. A Serious Adverse Event (AE) is any unfavourable medical finding (including clinically significant laboratory tests) at any dose that: Results in death (primary outcome) Is life threatening Results in persistent of significant disability or incapacity Requires in in-patient hospitalisation or prolongation of Hospitalisation
Measure: Adverse Events and Serious Adverse Events Time: 60 daysDescription: Change in SpO2 during each PP session (SpO2 in prone position - SpO2 prior to prone positioning). Clinicians will be asked to record this change for the first proning session per shift (for 12 hour shifts this will result in 2 proning sessions being documented per 24 hour period, and for 8 hour shifts this will result in 3 proning sessions being documented per 24 hour period).
Measure: Change in SpO2 Time: 60 daysDescription: Number of hospital free days in the 60 days after enrolment.
Measure: Hospital free days Time: 60 daysDescription: Admission to the Intensive Care Unit.
Measure: Admission to ICU Time: 60 daysDescription: Patient is intubated and requires mechanical ventilation.
Measure: Intubation and mechanical ventilation Time: 60 daysDescription: Patient requires non-invasive ventilation (NIV) or high-flow nasal oxygen (HFNO).
Measure: Initiation of non-invasive ventilation (NIV) or high-flow nasal oxygen (HFNO). Time: 60 daysDescription: The number of oxygen-free days at Day 60 (censored at discharge).
Measure: Oxygen-free days Time: 60 daysDescription: Time from admission to all-cause in-hospital death.
Measure: In-hospital death (time) Time: 60 daysDescription: Death at 90 days.
Measure: Death at 90 days Time: 90 daysThis study aims to find out whether the use of angiotensin II, which is a drug to raise blood pressure has been approved by European Medical Agency in August 2019, as an add-on medication to increase blood pressure in patients with COVID-19, acute severe lung injury, inflammation and severe shock, compared with standard medication. In addition, the investigators will collect the data of Anakinra, another drug which is frequently used in this condition to reduce inflammation. The investigators will collect clinical data and outcomes from critical care patients. The investigators will analyse for whom these drugs are most beneficial and explore whether there are any patients who don't benefit or have side effects.
Description: Percentage
Measure: Proportions of patients with mean arterial pressure ≥ 65 mmHg or an increase of mean arterial pressure ≥10 mmHg at 3 hours Time: 3 hoursDescription: microgram/kg/min
Measure: Noradrenaline dose Time: 1 hour and 3 hoursDescription: Changes in score, minimum 0, maximum 24, the higher score showing worse prognosis
Measure: Sequential Organ Failure Assessment (SOFA) score Time: baseline, 24, and 48 hoursDescription: Patients who are alive and do not require renal replacement therapy at 28 days
Measure: RRT-free days Time: 28 daysDescription: Proportions of patients who do not require renal replacement therapy
Measure: RRT discontinuation Time: 7 and 28 daysDescription: micromol/L
Measure: Serum creatinine Time: 7 days and 28 daysDescription: Changes in value
Measure: PaO2/FiO2 ratio Time: baseline, 24, and 48 hoursDescription: Mortality rate
Measure: Mortality Time: 7 days and 28 daysDescription: e.g. arrhythmia, thromboembolism, etc.
Measure: Adverse events Time: 28 daysDescription: Change in serum C-reactive protein
Measure: Change in serum C-reactive protein Time: 7 daysDescription: Change in serum ferritin
Measure: Change in serum ferritin Time: 7 daysThis multicentric prospective clinical practice study aims at evaluating clinical factors associated with a prolonged invasive mechanical ventilation and other outcomes such as mortality and ICU length of stay in patients affected from COVID-19 related pneumonia and ARDS.
Description: Ventilator free days (VFDs) will be calculated in a time frame of 28 days, the beginning of observation will coincide with the day of intubation and observation will end after successful disconnection from mechanical ventilation. For intubated patients, post extubation non invasive ventilation (NIV) will not be accounted as a ventilation period, in case of interval reintubation within 28 days, VFDs will be counted from the last successful extubation. For tracheostomized patients, ventilator free days will be counted after successful disconnection from mechanical ventilation and interval reconnections will be considered in the ventilation interval as for intubated patients.
Measure: Duration of mechanical ventilation and 28 days ventilator free days Time: 28 daysDescription: 15D instrument (http://www.15d-instrument.net/15d/) will be administered via telephonic interview Areas assessed: MOBILITY, VISION, HEARING, BREATHING, SLEEPING, EATING, SPEECH, EXCRETION, USUAL ACTIVITIES, MENTAL FUNCTION, DISCOMFORT AND SYMPTOMS, DEPRESSION, DISTRESS, VITALITY, SEXUAL ACTIVITY
Measure: Quality of life at 90 days after ICU discharge measured with 15D instrument Time: 90 daysDescription: First available CT, last CT before ICU admission and intubation, last ICU follow-up CT. First available chest X ray, last chest X ray before ICU admission and intubation, last ICU- follow up chest X ray and 30 days follow-up CT (if available) will be evaluated, if available. Structured description CT scan Date: yyyy/mm/dd Parenchymal alterations: ground glass, crazy paving, parenchymal consolidation Extension: monolateral, bilateral Number of lobes involved: (1-5) Percentage of parenchymal involvement: 0-100% Distribution: subpleural, random, diffuse X-ray scan Date: yyyy/mm/dd Main aspects: normal, focal lesions, monolateral multifocal lesions (right/left), diffuse multifocal lesions Lesion aspects: interstitial, interstitial/alveolar, alveolar, consolidations Pleural effusion presence and entity Pulmonary involvement score: 0 = no involvement =< 25% = 25-50% 3= 50-75% 4 => 75% Total score (0-6): score of the right lung + score of the left lung
Measure: Radiologic aspects - structured description of CT and RX data Time: 90 daysThe study is a prospective, randomized, placebo-controlled, single-blind phase 2 clinical study of the efficacy and safety of CERC-002, a potent inhibitor of LIGHT, for the treatment of patients with COVID-19 pneumonia who have mild to moderate ARDS. LIGHT is a cytokine in the TNF super family (TNFSF14) which drives inflammation and induces many other cytokines including IL-1, IL-6 and GM-CSF. LIGHT levels have been shown to be elevated in COVID-19 infected patients and inhibiting LIGHT is hypothesized to ameliorate the cytokine storm which has shown to be a major factor in progression of ARDS. The study will assess the efficacy and safety of CERC-002 in patients with severe COVID-19 over a 28 day period as single dose on top of standard of care.
Description: Respiratory failure defined based on resource utilization requiring at least one of the following: Endotracheal intubation and mechanical ventilation Oxygen delivered by high-flow nasal cannula (heated, humidified oxygen delivered via reinforced nasal cannula at flow rates >20L/min with fraction of delivered oxygen ≥0.5) Noninvasive positive pressure ventilation, Extracorporeal membrane oxygenation
Measure: Proportion of patient alive and free of respiratory failure Time: Baseline to Day 28Description: 1-month mortality
Measure: Proportion of subjects who are alive Time: Baseline to Day 28The aim of the study is to clinically use bovine Lf as a safe antiviral adjuvant for treatment and to assess the potential in reducing mortality and morbidity rates in COVID-19 patients. The study was approved by the ethical committee of the Egyptian Center for Research and Regenerative Medicine in 11-5-2020.
Description: Comparing the influence of the intervention on the Survival rate.
Measure: Survival rate. Time: up to 8 weeks.Description: For mild/moderate symptoms patients: fever, cough and other symptoms relieved with improved lung CT - For severe symptoms patients: fever, cough and other symptoms relieved with improved lung CT, and oxygen saturation by pulse oximetry (SPO2 )> 93% for nonasthmatic patients, and from 88-92% in asthmatic patients.
Measure: Rate of disease remission. Time: up to 4 weeks.Description: Comparing the influence of the intervention on the PCR negative results.
Measure: The number of patients with PCR negative results. Time: up to 4 weeks.Description: Recording the changes from severe to moderate or mild and the time taken.
Measure: Mean change in the disease severity (clinical assessment). Time: up to 4 weeks.Description: Recording the changes in blood pressure mmHg.
Measure: Mean change in blood pressure. Time: up to 4 weeks.Description: Recording the changes in heart rate in beat/second.
Measure: Mean change in heart beats. Time: up to 4 weeks.Description: Recording the changes in body temperature in Celsius.
Measure: Mean change in body temperature. Time: up to 4 weeks.Description: Recording the changes in the respiratory rate in breath/minute.
Measure: Mean change in body respiratory rate. Time: up to 4 weeks.Description: Recording the changes in arterial oxygen saturation in mmHg.
Measure: Mean change in oxygen saturation. Time: up to 4 weeks.Description: Recording the changes in the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PF ratio).
Measure: Mean change in the ratio in arterial oxygen partial pressure to fractional inspired oxygen (PF ratio). Time: up to 4 weeks.Description: Recording the changes in complete blood picture (CBC) in cells per liter.
Measure: Mean change in complete blood picture (CBC). Time: up to 4 weeks.Description: Recording the changes in C reactive protein (CRP) in mg/L.
Measure: Mean change in C reactive protein (CRP). Time: up to 4 weeks.Description: Recording the changes in erythrocyte sedimentation rate (ESR) in mm/hr.
Measure: Mean change in erythrocyte sedimentation rate (ESR). Time: up to 4 weeks.Description: Recording the changes in D-dimer in ng/mL.
Measure: Mean change in D-dimer. Time: up to 4 weeks.Description: Recording the changes in ferritin in ng/mL.
Measure: Mean change in ferritin. Time: up to 4 weeks.Description: Recording the changes in liver Albumin in g/L.
Measure: Mean change in liver Albumin. Time: up to 4 weeks.Description: Recording the changes in total and direct Bilirubin in mg/dL.
Measure: Mean change in total and direct Bilirubin. Time: up to 4 weeks.Description: Recording the changes in prothrombin time (PT), partial thromboplastin time (PTT ) in seconds and calculating International Normalized Ratio (INR).
Measure: Mean change in prothrombin time (PT) and partial thromboplastin time (PTT ). Time: up to 4 weeks.Description: Recording the changes in aspartate aminotransferase (AST) in IU/L.
Measure: Mean change in aspartate aminotransferase (AST). Time: up to 4 weeks.Description: Recording the changes in Alanine Aminotransferase (ALT) in IU/L.
Measure: Mean change in Alanine Aminotransferase (ALT). Time: up to 4 weeks.Description: Recording the changes in Blood Urea Nitrogen (BUN) in mg/dL.
Measure: Mean change in Blood Urea Nitrogen (BUN). Time: up to 4 weeks.Description: Recording the changes in Serum Creatinine in mg/dL.
Measure: Mean change in Serum Creatinine. Time: up to 4 weeks.Description: Recording the changes in Serum Creatinine in ml/min.
Measure: Mean change in Serum Creatinine clearance. Time: up to 4 weeks.Description: Recording the changes in Glomerular filtration rate (GFR ) ml/min/m2.
Measure: Mean change in Glomerular filtration rate (GFR ). Time: up to 4 weeks.Description: Recording the changes in interleukin-1 (IL-1) in pg/ml.
Measure: The mean change in serum interleukin-1 (IL-1). Time: up to 4 weeks.Description: Recording the changes in interleukin-6 (IL-6) in pg/ml.
Measure: The mean change in serum interleukin-6 (IL-6). Time: up to 4 weeks.Description: Recording the changes in interleukin-10 (IL-10) in pg/ml.
Measure: The mean change in serum interleukin-10 (IL-10). Time: up to 4 weeks.Description: Recording the changes in tumor necrosis factor-alpha (TNF alpha) in ng/ml.
Measure: The mean change in serum tumor necrosis factor-alpha (TNF alpha). Time: up to 4 weeks.Description: Recording the changes in immunoglobulin G (IgG) in ng/ml.
Measure: Mean changes in immunoglobulin G (IgG). Time: up to 4 weeks.Description: Recording the changes in immunoglobulin M (IgM) in ng/ml.
Measure: Mean changes in immunoglobulin M (IgM). Time: up to 4 weeks.Description: Recording the changes in PCR viral load in copies/mL.
Measure: The mean change in PCR viral load. Time: up to 4 weeks.Description: Recording the changes in lung CT.
Measure: Mean change in lung CT manifestation. Time: up to 4 weeks.Description: Recording any unexpected Adverse Events of the intervention.
Measure: Nature and severity of Adverse Events. Time: up to 4 weeks.Description: Recording the changes (the average time of lung imaging recovery), as assessed by lung CT.
Measure: Time for lung recovery. Time: up to 8 weeks.Description: Recording the changes the event of missed drug doses.
Measure: The number of missed drug doses among each treatment group. Time: up to 4 weeks.Acute Respiratory Distress Syndrome (ARDS) is the main cause of death from COVID-19. One of the main mechanisms for ARDS is the violent storm of cytokines and chemokines, which cause uncontrolled fatal systemic inflammation by the immune system on the body, with additional multiple organ failure. Mortality in cases of severe ARDS caused by COVID 19 varies significantly between 50 and 90%, basically depending on the age of the patient and the presence of comorbidities. The plasticity of Mesenchymal Stem Cells (MSC) regulates inflammation and immunity. MSC can promote and inhibit an immune response, depending on the dynamics of inflammation and depending on the activation force of the immune system, the types of inflammatory cytokines present, and the effects of immunosuppressants. Essentially, the state of inflammation determines the immunoregulatory fate of MSC. Thus, IV application of AMSCa has been shown to control the inflammatory response in various diseases, such as the graft-versus-host reaction and the ARDS caused by H5NI. The objective of this study is to describe the clinical changes secondary to IV administration of MSC allogenic, in patients with bilateral COVID-19 pneumonia complicated by severe ARDS, with the evaluation of the PaO2 / FiO2 ratio, heart and respiratory rates, and the fever curve. Five patients, of either sex, over 18 years of age, with bilateral pneumonia caused by COVID-19 and severe SIRA that has not improved with the standard management measures used at that time in the care center, will be included in the study. This treatment will be administered after discussing it with the relatives that it is a procedure considered as rescue and will be carried out with informed consent. 1x10(6) xKg will be applied IV. The follow-up of the patient will be for three weeks. PaO2 / FiO2 data, fever, inflammatory markers and immunity will be evaluated. The results will be compared with the historical controls attended at INCMNSZ.
Description: To describe the clinical changes secondary to IV administration of AMSCa, in patients with bilateral COVID-19 pneumonia complicated by severe SIRA, with the evaluation of the PaO2 / FiO2 ratio.
Measure: Functional Respiratory changes: PaO2 / FiO2 ratio Time: Three weeksDescription: To describe the clinical changes secondary to IV administration of AMSCa, in patients with bilateral COVID-19 pneumonia complicated by severe SIRA, with the evaluation of the heart rate per minute.
Measure: Clinical cardiac changes: Heart rate per minute Time: Three weeksDescription: To describe the clinical changes secondary to IV administration of AMSCa, in patients with bilateral COVID-19 pneumonia complicated by severe SIRA, with the evaluation of the respiratory rate per minute.
Measure: Clinical Respiratory Changes: Respiratory rate per minute Time: Three weeksDescription: To describe the clinical changes secondary to IV administration of AMSCa, in patients with bilateral COVID-19 pneumonia complicated by severe SIRA, with the evaluation of the fever curve in degrees centigrade.
Measure: Changes in body temperature Time: Three weeksDescription: To assess the effect of the proposed treatment on the total Leukocytes
Measure: General biochemical changes in Leukocytes Time: Three weeksDescription: To assess the effect of the proposed treatment on absolute lymphocytes
Measure: General biochemical changes on lymphocytes Time: Three weeksDescription: To assess the effect of the proposed treatment on total platelets
Measure: General biochemical changes on platelets Time: Three weeksDescription: To assess the effect of the proposed treatment on serum fibrinogen
Measure: General biochemical changes on fibrinogen Time: Three weeksDescription: To assess the effect of the proposed treatment on procalcitonin
Measure: General biochemical changes on pocalcitonin Time: Three weeksDescription: To assess the effect of the proposed treatment on ferritin
Measure: General biochemical changes on ferritin Time: Three weeksDescription: To assess the effect of the proposed treatment on D-dimer
Measure: General biochemical changes on D-dimer Time: Three weeksDescription: To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of C-reactive protein
Measure: Changes on inflammatory C-reactive protein Time: Three weeksDescription: To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of TNFa in plasma.
Measure: Cahnges on Inflammatory cytokine TNFa Time: Three weeksDescription: To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of IL10 in plasma.
Measure: Changes on Inflammatory cytokine IL10 Time: Three weeksDescription: To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of IL1 in plasma.
Measure: Changes on Inflammatory cytokine IL1 Time: Three weeksDescription: To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of IL6 in plasma.
Measure: Changes on Inflammatory cytokine IL6 Time: Three weeksDescription: To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of IL17 in plasma
Measure: Changes on Inflammatory cytokine IL 17 Time: Three weeksDescription: To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of VEGF in plasma
Measure: Changes on VEGF Time: Three weeksDescription: Assess the radiological evolution of the proposed treatment through simple chest CT
Measure: Radiological Changes Time: Three weeksDescription: Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: regulatory T cells
Measure: Immunological changes on T cell Time: Three weeksDescription: Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: dendritic cells
Measure: Immunological changes on Dendritic cells Time: Three weeksDescription: Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: CD4 + T
Measure: Immunological changes on CD4+ T Time: Three weeksDescription: Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: CD8 + T
Measure: Immunological changes on CD8+ T Time: Three weeksDescription: Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: NK cells
Measure: Immunological changes on NK cell Time: Three weeksDescription: Evaluate the safety of the proposed treatment (allergic reactions and / or infection)
Measure: Adverse events Time: Three weeksDescription: To assess the negativization of the SARS-Cov2 PCR RNA detection test
Measure: RNA detection by SARS-Cov2 PCR Time: Three weeks