Primary Outcomes

Description: The change from baseline in number of airway submucosal inflammatory cells/mm2 of bronchoscopic biopsies.

Measure: The change from baseline in number of airway submucosal inflammatory cells/mm2 of bronchoscopic biopsies.

Time: Baseline, End of Treatment (EoT). The EoT will be performed at Week 28 for the majority of subjects but may be performed at later timepoints for some subjects (Week 32, etc.) due to up to 6 additional doses added during the Covid-19 pandemic.

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Secondary Outcomes

Description: The change in reticular basement membrane (RBM) thickness from baseline, determined by microscopic evaluation of bronchoscopic biopsies

Measure: The change in reticular basement membrane (RBM) thickness from baseline, determined by microscopic evaluation of bronchoscopic biopsies

Time: Baseline, End of Treatment (EoT). The EoT will be performed at Week 28 for the majority of subjects but may be performed at later timepoints for some subjects (Week 32, etc.) due to up to 6 additional doses added during the Covid-19 pandemic.

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Description: The change in % airway epithelial integrity from baseline determined by microscopic evaluation of bronchoscopic biopsies

Measure: The change in % airway epithelial integrity from baseline determined by microscopic evaluation of bronchoscopic biopsies

Time: Baseline, End of Treatment (EoT). The EoT will be performed at Week 28 for the majority of subjects but may be performed at later timepoints for some subjects (Week 32, etc.) due to up to 6 additional doses added during the Covid-19 pandemic.

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Description: The change in number of airway submucosal inflammatory cells per mm2 from baseline, across the spectrum of T2 status, determined by microscopic evaluation of bronchoscopic biopsies

Measure: The change in number of airway submucosal inflammatory cells per mm2 from baseline, across the spectrum of T2 status, determined by microscopic evaluation of bronchoscopic biopsies

Time: Baseline, End of Treatment (EoT). The EoT will be performed at Week 28 for the majority of subjects but may be performed at later timepoints for some subjects (Week 32, etc.) due to up to 6 additional doses added during the Covid-19 pandemic.

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Primary Outcomes

Description: A well-established, supervised, self-completion health status questionnaire. This consists of eight sections for which a score of 0 to 100 is created, with 0 being maximum disability and 100 equivalent to no disability.

Measure: Change from Baseline in Short Form 36 tool (SF-36)

Time: At baseline, then repeated after 12 weeks.

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Secondary Outcomes

Description: a disease specific health status measure. This includes 8 items, scored 0-5 with a possible score from 0 (best) to 40 (worst).

Measure: Changes in COPD assessment test (CAT)

Time: At baseline, then repeated after 12 weeks.

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Description: Self-administered questionnaire to assess for symptoms, and severity, of anxiety. Includes seven questions scored from 0 to 3, giving a total score out of 21. Lower scores indicate less symptoms of anxiety.

Measure: Changes in Generalised Anxiety Disorder Assessment (GAD-7)

Time: At baseline, then repeated after 12 weeks.

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Description: Self-administered questionnaire to assess for symptoms, and severity, of depression. Includes nine questions scored from 0 to 3, giving a total score out of 27. Lower scores indicate less symptoms of depression.

Measure: Changes in Patient Health Questionnaire 9 (PHQ-9)

Time: At baseline, then repeated after 12 weeks.

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Description: Assessment of dyspnoea. Includes 12 descriptors scored from 0 to 3, giving a total score of 36. Lower scores indicate less severe dyspnoea.

Measure: Changes in Dyspnoea-12 questionnaire

Time: At baseline, then repeated after 12 weeks.

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Description: Distance walked in 6 minutes. Tests exercise capacity. To be performed in accordance with ATS/ERS guidelines including a practice walk.

Measure: Changes in Six-minute walk test

Time: At baseline, then repeated after 12 weeks.

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Description: This involves a one week recall questionnaire and McRoberts MoveMonitor device physical activity monitor.

Measure: Changes in PROactive physical activity in COPD tool (cPPAC)

Time: At baseline, then repeated after 12 weeks.

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Description: Balance confidence during activities of daily living, assessed using self-reported questionnaire. 16 item scale which gives a total balance confidence score of 0 to 100. Lower scores indicate less confidence.

Measure: Changes in Activities-specific Balance Confidence scale

Time: At baseline, then repeated after 12 weeks.

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Description: Physical performance evaluated using the SPPB (instrumented with the McRoberts fixed-body sensor MoveTest device). Consists of 4 performance tasks (balance, walk speed and sit-to-stand) scored from 0 to 4, giving a total score out of 12 for SPPB.

Measure: Changes in Short Physical Performance Battery (SPPB)

Time: At baseline, then repeated after 12 weeks.

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Primary Outcomes

Description: The exacerbation rate is based on exacerbations reported by the investigator over 52 weeks.

Measure: Moderate or severe COPD exacerbation rate ratio (tezepelumab vs placebo)

Time: Over 52 Weeks

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Secondary Outcomes

Description: Time to first occurrence of moderate/severe exacerbation post randomization. Outcome measures: Hazard ratio

Measure: Time to first moderate or severe COPD exacerbation

Time: By Week 52

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Description: Proportion of subjects with at least one moderate/severe exacerbation reported by the Investigator over 52 weeks Outcome measure: Odds Ratio

Measure: Proportion with at least one moderate/severe COPD exacerbation

Time: Over 52 Weeks

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Description: The severe exacerbation rate is based on severe exacerbations reported by the Investigator over 52 weeks.

Measure: Severe COPD exacerbation rate ratio (tezepelumab vs. placebo)

Time: Over 52 Weeks

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Description: Difference in change from baseline in pre-BD forced expiratory volume in 1 second (FEV1) in tezepelumab arm as compared to placebo at Week 52. FEV1 is defined as the volume of air exhaled from the lungs in the first second of forced expiration.

Measure: Change from baseline in pre-bronchodilator (pre-BD) forced expiratory volume in 1 second (FEV1)

Time: Baseline, Week 52

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Description: Proportion of subjects achieving a decrease of 4 units or more in the St. George's Respiratory Questionnaire (SGRQ) total score at Week 52, i.e. minimum clinically important difference (MCID). Outcome measure: odds ratio

Measure: Change in respiratory health status/health-related quality of life

Time: Baseline, Week 52

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Description: Difference (tezepelumab vs. placebo) in SGRQ from baseline at Week 52. SGRQ is a 50-item patient reported outcome questionnaire. The SGRQ total score is expressed as a percentage of overall impairment, in which 100% means the worst possible health status and 0% indicates the best possible health status. Likewise, the domain scores range from 0 to 100, with higher scores indicative of greater impairment. Decrease of 4 units is associated with a minimum clinically important difference (MCID).

Measure: Change from baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score

Time: Baseline, Week 52

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Description: Difference (tezepelumab vs. placebo) in COPD assessment tool (CAT) from baseline at Week 52. CAT is an 8-item patient reported outcome questionnaire developed to measure the impact of COPD on health status. The instrument uses semantic differential six-point response scales. A CAT total score is the sum of item responses. The score ranges from 0 to 40, with higher scores indicating greater COPD impact on health status.

Measure: Change from baseline in the COPD Assessment Test (CAT) Total Score

Time: Baseline, Week 52

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Description: Serum trough concentration of tezepelumab

Measure: Evaluate pharmacokinetics of tezepelumab

Time: Weeks 0, 4, 12, 24, 36, 52, 64

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Description: Incidence of anti-drug antibodies (ADA)

Measure: Evaluate immunogenicity of tezepelumab

Time: Over 52 weeks

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Primary Outcomes

Description: The newly developed survey that is being validated consists of 42 items that assess the impact that Hypersensitivity Pneumonitis has on daily life for those who have the disease.

Measure: Validation of a health-related quality of life instrument for patients with Chronic Hypersensitivity Pneumonitis

Time: Day 0

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Description: This survey will be used to assess the validity of the newly developed health-related quality of life instrument. This survey consists of 12 items. The average score for this survey has been calibrated to 50 with scores below 50 indicating a below average score and scores above 50 indicating an above average score.

Measure: Validation of a health-related quality of life instrument for patients with Chronic Hypersensitivity Pneumonitis by administering the Short Form (SF-12) Survey

Time: Day 0

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Description: This survey will be used to assess the validity of the newly developed health-related quality of life instrument. This survey consists of 15 items and is scored from 0-100 with 100 indicating good health.

Measure: Validation of a health-related quality of life instrument for patients with Chronic Hypersensitivity Pneumonitis by administering the King's Brief Interstitial Lung Disease Questionnaire

Time: Day 0

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Description: The newly developed survey will be administered again in 2 weeks following the first assessment.

Measure: Change in Health-related Quality of Life Assessment Score

Time: 2 weeks following Day 0

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Primary Outcomes

Description: The primary outcome is the proportion of patients who have a goals-of-care (GOC) discussion that has been documented in the EHR in the period between randomization and 30 days following randomization The proportion is the number of patients with GOC documentation over the number of patients in each study arm. Documentation of goals-of-care discussions will be evaluated using our NLP/ML methods. Study staff will manually review and compare findings using a randomly-selected sample of charts using our standard EHR abstraction methods; manual chart abstraction will be the gold standard.

Measure: EHR documentation of Goals of Care discussions

Time: Assessed for the period between randomization and 30 days following randomization

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Secondary Outcomes

Description: Secondary outcomes include measures of intensity of care, including utilization metrics: Number of ICU admissions during the patient's (index) hospital stay will be collected from the EHR using our automated and validated methods.

Measure: Intensity of care/ICU use: ICU admissions

Time: Assessed for the period between randomization and 30 days following randomization

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Description: Secondary outcomes include measures of intensity of care, including utilization metrics: Number of days the patient spent in the ICU during their (index) hospital stay will be collected from the EHR using our automated and validated methods.

Measure: Intensity of care/ICU use: ICU length of stay

Time: Assessed for the period between randomization and 30 days following randomization

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Description: Secondary outcomes include measures of intensity of care, including utilization metrics: Number of days the patient spent in the hospital during that (index) hospital stay will be collected from the EHR using our automated and validated methods.

Measure: Intensity of care/Hospital use: Hospital length of stay

Time: Assessed for the period between randomization and 30 days following randomization

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Description: Secondary outcomes include measures of intensity of care, including utilization metrics: Number of hospital readmissions between randomization and 30 days following randomization will be collected from the EHR using our automated and validated methods.

Measure: Intensity of care: Hospital Readmissions 30 days

Time: Assessed for the period between randomization and 30 days following randomization

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Description: Secondary outcomes include measures of intensity of care, including utilization metrics: Number of ICU readmissions between randomization and 30 days following randomization will be collected from the EHR using our automated and validated methods.

Measure: Intensity of care: ICU Readmissions 30 days

Time: Assessed for the period between randomization and 30 days following randomization

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Description: Costs for intervention vs. control will be reported in US dollars and identified from UW Medicine administrative financial databases. Costs will be reported for total hospital costs and disaggregated costs (direct-variable, direct fixed, indirect costs). Direct-variable costs will include supply and drug costs. Direct-fixed costs will include labor, clinical department administration, and overhead fees. Indirect costs represent services provided by cost centers not directly linked to patient care such as information technology and environmental services. Costs for ED (emergency department) days and ICU days will be similarly assessed.

Measure: Intensity of care: Healthcare costs

Time: 1 and 3 months after randomization

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Description: From Washington State death certificates.

Measure: All-cause mortality at 1 year (safety outcome)

Time: 1 year after randomization

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Other Outcomes

Description: Qualitative interviews after individual participation. Interviews will be guided by the RE-AIM and Consolidated Framework for Implementation Research (CFIR) to explore the factors associated with implementation (e.g., reach, maintenance, feasibility, inner and outer settings, individuals, and processes of care.) Individual constructs within these domains were chosen to fit this specific intervention and context.

Measure: Key Implementation Factors

Time: 3 months after randomization

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Primary Outcomes

Description: mean rate of recovery in patients with diagnosis of Covid-19 pneumonia, who present with complications at the time of hospital admission (such as diabetes, obesity, cardiovascular disease, hypertension or respiratory failure), with the mean recovery rate in patients without any of the above-mentioned complications.

Measure: rate of recovery

Time: 3 weeks

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Secondary Outcomes

Description: comparison of the survival curves (times to improvement) in the two groups (patients with and without complications) and among patients presenting with different types of complications

Measure: time to improvement

Time: 3 weeks

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Description: the efficacy of different pharmaceutical treatment against Covid-19

Measure: efficacy of treatments

Time: 3 weeks

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Description: liver, kidney or multiorgan failure, cardiac failure

Measure: organ failure

Time: 3 weeks

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Primary Outcomes

Description: Reporting of Adverse Events or Severe Adverse Events Assessed by CTCAE v4.0

Measure: Incidence of Treatment-Emergent Adverse Events

Time: 1 month

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Secondary Outcomes

Description: High Resolution Computerized Tomography of Lung (HRCT Lung) for Fluidda Analysis comparative at baseline and 3 and 6 months post-treatment comparative analytics

Measure: Pulmonary Function Analysis

Time: baseline, 3 Month, 6 months

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Description: Finger Pulse Oximetry taken before and after 6 minute walk on level ground, compare desaturation tendency

Measure: Digital Oximetry

Time: 3 months, 6 months

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Primary Outcomes

Description: Collection of conjunctival cell samples from eyes of COVID-19 patients. Analysis of conjunctival cells by real-time PCR to document presence of COVID-19. Binary outcome: yes, no. To evaluate the result in relation to nasopharyngeal swab (binary outcome yes, no) and to correlate conjunctival with nasopharyngeal swab positivity

Measure: Conjunctival swab results based on RT-PCR

Time: 2 months

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Secondary Outcomes

Description: To evaluate the agreement between conjunctival swab positivity and the degree of systemic impairment. The latter will be measured on the basis of pulmonary disease severity as assessed by a standardized scale (Occhipinti et al 2019) for interstitial lung involvement in systemic sclerosis; the blood measurements of d-dimer, LDH and reactive CP.

Measure: Conjunctival swab positivity in relation to Pulmonary and blood abnormalities

Time: 2 months

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Primary Outcomes

Description: Number and severity of adverse events

Measure: Phase 1: Frequency and Severity of Adverse Events (AE)

Time: Up to 6 months

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Description: Proportion of subjects with "negative" measurement of COVID-19 by rRT-PCR

Measure: Phase 1: Rate of clearance of SARS-CoV-2

Time: Up to 6 months

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Description: Proportion of subjects who improved clinical symptoms related to lower respiratory tract infection, as measured by National Early Warning Score 2 (NEWS2) score.

Measure: Phase 1: Rate of clinical improvement

Time: Up to 6 months

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Description: Time from the date of randomization to the clearance of SARS-CoV-2 by rRT-PCR. Negative results will need to be confirmed by a second negative result in the same sample type at least 24 hours after the first negative result.

Measure: Phase 2: Time to Clearance of SARS-CoV-2

Time: Up to 28 days

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Description: Time from the date of randomization to the first date of improved clinical symptoms related to lower respiratory tract infection. Improvement as measured by National Early Warning Score 2 (NEWS2) Score.

Measure: Phase 2: Time to Clinical Improvement by NEWS2 Score

Time: Up to 28 days

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Secondary Outcomes

Description: Proportion of subjects with "negative" measurement of COVID-19 by rRT-PCR

Measure: Rate of Clearance of SARS-CoV-2

Time: Up to 6 months

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Description: Number and severity of adverse events

Measure: Phase 2: Frequency and Severity of Adverse Events (AE)

Time: up to 6 months

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Description: Time to medical discharge as an assessment of overall clinical benefit

Measure: Overall Clinical Benefit by time to medical discharge

Time: up to 6 months

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Description: Hospital utilization will be measured as an assessment of overall clinical benefit

Measure: Overall Clinical Benefit by hospital utilization

Time: up to 6 months

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Description: Mortality rate will be measured as an assessment of overall clinical benefit

Measure: Overall Clinical Benefit by measuring mortality rate

Time: up to 6 months

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Description: Assess the impact of CYNK-001 on changes in sequential organ failure assessment (SOFA) score.

Measure: Impact of CYNK-001 on sequential organ failure assessment (SOFA) score

Time: Up to 28 days

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Description: Time from randomization to the date of disappearance of virus from lower respiratory tract infection (LRTI) specimen where it has previously been found (induced sputum, endotracheal aspirate).

Measure: Time to Pulmonary Clearance

Time: Up to 28 days

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Description: For ventilatory support subjects, the days with supplemental oxygen-free.

Measure: Supplemental oxygen-free days

Time: Up to 28 days

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Description: Proportion of subjects who need invasive or non-invasive ventilation

Measure: Proportion of subjects requiring ventilation

Time: Up to 28 days

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Primary Outcomes

Description: assess if inpatients who presented with pneumonia but had a negative test for Covid-19 are positive at the serology for SARS-CoV-2.

Measure: Serology

Time: 3 weeks

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Secondary Outcomes

Description: to find if the combination of CT scan and serology could help us in the identification of those patients who were initially negative at laboratory testing alone.

Measure: Efficacy of CT scan and Serology

Time: 3 weeks

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Description: the efficacy of different pharmaceutical treatments against Covid-19

Measure: Efficacy of different pharmaceutical treatments

Time: 3 weeks

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Primary Outcomes

Description: ICU on vent, ICU not requiring ventilation, Discharge to Rehab requiring assistance, Discharge to Home unable to perform ADL's, Discharge to Home able to perform ADL's

Measure: Patient Disposition Post treatment

Time: 7 days

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Description: Patients oxygen requirements pulse oximetry will be evaluated for change from pre and post individual treatment as well as end of protocol

Measure: oxygenation

Time: Daily for 4 days

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Description: The change in pre treatment levels and 24 hours post final treatment

Measure: IL-6 levels

Time: First four days of trial

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Description: Pre treatment CXR will be compared to post treatment CXR using the RALE CXR evaluation scale

Measure: Chest Xray radiographic results

Time: 7 Days

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Description: The change in pretreatment and post treatment BCRSS will be evaluated

Measure: Brescia-COVID Respiratory Severity Scale

Time: 7 days

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Description: The change in pretreatment and post treatment scores will be evaluated

Measure: SMART-COP Score

Time: 7 days

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Description: The change in pretreatment and post treatment scores will be evaluated

Measure: PSI Score

Time: 7 days

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Description: The change in pretreatment and post treatment levels will be evaluated The change in pretreatment and post treatment levels will be evalutated

Measure: CRP levels

Time: 7 days

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Primary Outcomes

Measure: Rate of Therapeutic failure, defined as a combined outcome of rate of intubation or death

Time: Up to 28 days after randomization

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Secondary Outcomes

Measure: Intubation rate

Time: Up to 28 days after randomization

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Measure: Mortality

Time: Up to 28 days after randomization

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Measure: Days spent on mechanical ventilation

Time: Until discharge, up to 24 weeks after randomization

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Measure: Days spent in the ICU

Time: Until discharge, up to 24 weeks after randomization

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Measure: Hospital stay (in days)

Time: From admission to discharge, up to 24 weeks after randomization

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Other Outcomes

Description: Total time spent in prone position, as recorded by nursing or respiratory therapists

Measure: Time in prone position

Time: Up to 28 days post randomization

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Description: Daily evolution of oxygenation

Measure: Oxygenation (SpO2/FiO2 ratio)

Time: Until HFNC weaning, or up to 14 days after randomization, whichever is first

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Primary Outcomes

Description: Define the frequency of ILD and pulmonary vascular disease in SARS-CoV-2 infected patients with a severe/prolonged Course (inhospital stay, either on the normal ward or ICU), with and without oxygen supplementation, non-invasive or invasive ventilation) at 1 month after discharge or diagnosis of COVID-19 disease by the use of HR-CT.

Measure: Pattern of pulmonary abnormalities in SARS-CoV2 infected patients after 1 month

Time: 1 month

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Description: Define the frequency of ILD and pulmonary vascular disease in SARS-CoV-2 infected patients with a severe/prolonged Course (inhospital stay, either on the normal ward or ICU), with and without oxygen supplementation, non-invasive or invasive ventilation) at 3 months after discharge or diagnosis of COVID-19 disease by the use of HR-CT

Measure: Pattern of pulmonary abnormalities in SARS-CoV2 infected patients after 3 months

Time: 3 months

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Description: Define the frequency of ILD and pulmonary vascular disease in SARS-CoV-2 infected patients with a severe/prolonged Course (inhospital stay, either on the normal ward or ICU), with and without oxygen supplementation, non-invasive or invasive ventilation) at 6 months after discharge or diagnosis of COVID-19 disease by the use of HR-CT

Measure: Pattern of pulmonary abnormalities in SARS-CoV2 infected patients after 6 months

Time: 6 months

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Primary Outcomes

Description: Reduction below 80% of predicted values of DLCO

Measure: Reduction of Diffusion of Lung CO (DLCO, single breath technique)

Time: T1 at 6 months from discharge

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Description: Reduction below 80% of predicted values of DLCO

Measure: Reduction of Diffusion of Lung CO (DLCO, single breath technique)

Time: T2 at 12 months from discharge

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Secondary Outcomes

Description: reduction in maximum distance walked

Measure: Alterations in 6 minute walking test (6MWT)

Time: T1 at 6 months from discharge

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Description: reduction in maximum distance walked

Measure: Alterations in 6 minute walking test (6MWT)

Time: T2 at 12 months from discharge

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Description: reduction in oxygen saturation nadir

Measure: Alterations in 6 minute walking test (6MWT)

Time: T1 at 6 months from discharge

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Description: reduction in oxygen saturation nadir

Measure: Alterations in 6 minute walking test (6MWT)

Time: T2 at 12 months from discharge

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Description: reduction of Forced Vital Capacity (FVC, %)

Measure: Alterations of pletismography

Time: T1 at 6 months from discharge

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Description: reduction of Forced Vital Capacity (FVC, %)

Measure: Alterations of pletismography

Time: T2 at 12 months from discharge

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Description: reduction of Forced Vital Capacity (FVC, L)

Measure: Alterations of pletismography

Time: T1 at 6 months from discharge

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Description: reduction of Forced Vital Capacity (FVC, L)

Measure: Alterations of pletismography

Time: T2 at 12 months from discharge

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Description: reduction of Vital Capacity (VC, %)

Measure: Alterations of pletismography

Time: T1 at 6 months from discharge

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Description: reduction of Vital Capacity (VC, %)

Measure: Alterations of pletismography

Time: T2 at 12 months from discharge

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Description: reduction of Vital Capacity (VC, L)

Measure: Alterations of pletismography

Time: T1 at 6 months from discharge

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Description: reduction of Vital Capacity (VC, L)

Measure: Alterations of pletismography

Time: T2 at 12 months from discharge

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Description: reduction of Forced Expiratory Volume in the 1st second (FEV1, L)

Measure: Alterations of pletismography

Time: T1 at 6 months from discharge

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Description: reduction of Forced Expiratory Volume in the 1st second (FEV1, %)

Measure: Alterations of pletismography

Time: T1 at 6 months from discharge

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Description: reduction of Forced Expiratory Volume in the 1st second (FEV1, L)

Measure: Alterations of pletismography

Time: T2 at 12 months from discharge

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Description: reduction of Forced Expiratory Volume in the 1st second (FEV1, L%)

Measure: Alterations of pletismography

Time: T2 at 12 months from discharge

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Description: reduction of Total Lung Capacity (TLC, L)

Measure: Alterations of pletismography

Time: T1 at 6 months from discharge

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Description: reduction of Total Lung Capacity (TLC, %)

Measure: Alterations of pletismography

Time: T1 at 6 months from discharge

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Description: reduction of Total Lung Capacity (TLC, L)

Measure: Alterations of pletismography

Time: T2 at 12 months from discharge

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Description: reduction of Total Lung Capacity (TLC, %)

Measure: Alterations of pletismography

Time: T2 at 12 months from discharge

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Description: alterations of Residual Volume (RV,%)

Measure: Alterations of pletismography

Time: T1 at 6 months from discharge

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Description: alterations of Residual Volume (RV, L)

Measure: Alterations of pletismography

Time: T1 at 6 months from discharge

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Description: alterations of Residual Volume (RV, L)

Measure: Alterations of pletismography

Time: T2 at 12 months from discharge

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Description: alterations of Residual Volume (RV, %)

Measure: Alterations of pletismography

Time: T2 at 12 months from discharge

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Description: increase of Specific Airway Resistance (sRAW) (absolute value)

Measure: Alterations of pletismography

Time: T1 at 6 months from discharge

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Description: increase of Specific Airway Resistance (sRAW) (%)

Measure: Alterations of pletismography

Time: T1 at 6 months from discharge

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Description: increase of Specific Airway Resistance (sRAW) (absolute value)

Measure: Alterations of pletismography

Time: T2 at 12 months from discharge

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Description: increase of Specific Airway Resistance (sRAW) (%)

Measure: Alterations of pletismography

Time: T2 at 12 months from discharge

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Description: alterations of Motley Index (VR/CPT)

Measure: Alterations of pletismography

Time: T1 at 6 months from discharge

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Description: alterations of Motley Index (VR/CPT)

Measure: Alterations of pletismography

Time: T2 at 12 months from discharge

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Description: alterations of Tiffeneau Index (IT)

Measure: Alterations of pletismography

Time: T1 at 6 months from discharge

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Description: alterations of Tiffeneau Index (IT)

Measure: Alterations of pletismography

Time: T2 at 12 months from discharge

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Description: reduction of PaO2 mmHg

Measure: Alterations of Arterial Blood Gas Analysis

Time: T1 at 6 months from discharge

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Description: reduction of PaO2 mmHg

Measure: Alterations of Arterial Blood Gas Analysis

Time: T2 at 12 months from discharge

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Description: alteration of PaCO2 mmHg

Measure: Alterations of Arterial Blood Gas Analysis

Time: T1 at 6 months from discharge

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Description: alteration of PaCO2 mmHg

Measure: Alterations of Arterial Blood Gas Analysis

Time: T2 at 12 months from discharge

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Description: Modified Medical Research Council - mMRC > 0 (minimum 0, maximum 4; higher score means worse outcome)

Measure: Abnormal Dyspnea Score

Time: T1 at 6 months from discharge

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Description: Modified Medical Research Council - mMRC > 0(minimum 0, maximum 4; higher score means worse outcome)

Measure: Abnormal Dyspnea Score

Time: T2 at 12 months from discharge

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Description: Presence and extension of abnormal pulmonary lung sounds at auscultation

Measure: Presence and extension of abnormal pulmonary lung sounds at auscultation

Time: T1 at 6 months from discharge

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Description: Presence and extension of abnormal pulmonary lung sounds at auscultation

Measure: Presence and extension of abnormal pulmonary lung sounds at auscultation

Time: T2 at 12 months from discharge

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Description: Presence and extension of radiological alterations at chest X-ray

Measure: Presence and extension of radiological alterations at chest X-ray

Time: T1 at 6 months from discharge

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Description: Presence and extension of radiological alterations at chest CT scan

Measure: Presence and extension of radiological alterations at chest CT scan

Time: T2 at 12 months from discharge

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Primary Outcomes

Description: Annual rate of the physiologically adjusted lung density change will be measured as the 15th percentile of the lung density measurements (PD15) as assessed by Computed Tomography (CT) densitometry at total lung capacity (TLC). CT lung density at the 15th percentile (PD15) is the threshold below which 15 percentage (%) of the voxels have lower densities and is used as the parameter for estimating the rate of lung density decline. Annual rate of the physiologically adjusted lung density change will be tested in a fixed comparision sequence 1. ARALAST NP 120 mg/kg BW/week group versus (vs) external placebo group, 2. ARALAST NP120 mg/kg BW/week vs 60 mg/kg BW/week, 3. ARALAST NP 60 mg/kg BW/week group vs external placebo group.

Measure: Annual Rate of the Physiologically Adjusted Lung Density Change

Time: Baseline, up to Week 104

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Secondary Outcomes

Description: COPD exacerbations are defined as an acute worsening of respiratory symptoms that results in additional therapy and will be assessed according to the classification in GOLD criteria (2020) as follows: Moderate (treated with short acting bronchodilators [SABDs] plus antibiotics and/or oral corticosteroids) and Severe (required hospitalizations or a visit to the emergency room).

Measure: Number of Moderate or Severe Exacerbations of Chronic Obstructive Pulmonary Disease (COPD)

Time: Baseline, up to Week 104

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Description: Annual rate of change in post-bronchodilator FEV1 will be assessed.

Measure: Annual Rate of Change in Post-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1)

Time: Baseline, up to Week 104

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Description: An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this IP or medicinal product. A TEAE is defined as any event emerging or manifesting at or after the initiation of treatment with an IP or medicinal product or any existing event that worsens in either intensity or frequency following exposure to the IP or medicinal product. TEAE's will include related, serious adverse events (SAEs), suspected adverse reactions plus adverse reactions of interest, temporally-associated adverse events (AEs) with onset during infusion or within 24 hours following the end of IP infusion, and AEs resulting in changes to infusion dose.

Measure: Number of Participants with Treatment-Emergent Adverse Events (TEAE's)

Time: From Start of the study drug administration up to End of the study (up to Week 105)

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Description: Number of participants who develop anti- A1PI antibodies following treatment with ARALAST NP will be assessed.

Measure: Number of Participants Who Develop Anti-A1PI Antibodies Following Treatment With ARALAST NP

Time: From Start of the study drug administration up to End of the study (up to Week 105)

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Description: Plasma trough level of antigenic and functional A1PI for ARALAST NP at each dose level (ARALAST NP 60 mg/kg BW/week, ARALAST NP 120 mg/kg BW/week) will be assessed.

Measure: Plasma Trough Level of Antigenic and Functional A1PI for ARALAST NP at each dose Level

Time: Pre-dose, Weeks 4, 13, 28, 52, 78, 91, 104, 105

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Primary Outcomes

Measure: Change From Baseline to the Primary Time Point in Forced Expiratory Volume in 1 Second (FEV1) Compared to Placebo

Time: From Baseline up to average of Weeks 13 and 14

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Secondary Outcomes

Description: The EXACT (E-RS) scale is a participant-reported outcome (PRO) designed to measure the symptoms of participants with COPD. The E-RS utilizes 11 respiratory symptom items from the existing and validated 14-item EXACT, which measures symptoms of exacerbation. The E-RS total score quantifies respiratory symptom severity, and 3 domains assess breathlessness, cough and sputum, and chest symptoms. The E-RS will be collected on the daily e-diary, which will include all 14 items from the EXACT questionnaire.

Measure: Change From Baseline in the EXACT Respiratory Symptoms (E-RS) Daily Symptom Diary to the Primary Time Point

Time: One week prior to first dose through one week after the last dose.

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Description: The CAT is an eight-item questionnaire that will be completed by the participant and is designed to quantify the impact of COPD symptoms on the health status of participants. The CAT provides a score of 0-40 to indicate the impact of the disease.

Measure: Change From Baseline in the COPD Assessment Test (CAT) to the Week 14 Time Point

Time: From Baseline up to Week 14

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Description: The SGRQ is a participant completed, a disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in participants with obstructive airway disease. Scores of the SGRQ-C range from 0 to 100, with higher scores indicating more limitations.

Measure: Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) to the Week 14 Time Point

Time: From Baseline up to Week 14

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Measure: Change from Baseline in Post-Bronchodilator FEV1

Time: From Baseline up to average of Weeks 13 and 14

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Measure: Cmax: Maximum Observed Plasma Concentration for ION-827359

Time: Up to Week 24

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Measure: Tmax: Time to Reach the Maximum Plasma Concentration for ION-827359

Time: Up to Week 24

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Measure: AUC[0-t]: Area Under the Plasma Concentration-Time Curve from Time Zero to t for ION-827359

Time: Up to Week 24

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Measure: Incidence of Participants With at Least One Treatment-Emergent Adverse Event (TEAE), Graded by Severity

Time: Up to Week 24

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Measure: Number of Participants With Abnormal Laboratory Values

Time: Up to Week 24

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Measure: Number of Participants With Abnormal Vital Signs Measurements

Time: Up to Week 24

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Primary Outcomes

Description: Identify organ dysfunction after SARS-CoV-2 infections

Measure: Sequelae after COVID-19

Time: 12 months, extension if required

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Primary Outcomes

Description: Rate of patients with pulmonary embolism diagnosed by thoracic angiography scanner

Measure: Rate of patients with pulmonary embolism

Time: up to Day 12

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Secondary Outcomes

Description: Measure of prothrombin level to assess hemostasis parameters of patients with SARS-COV-2pneumonitis during hospitalization

Measure: Prothrombin level measurement

Time: up to Day 12

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Description: Measure of activated partial thromboplastin time to assess hemostasis parameters of patients with SARS-COV-2pneumonitis during hospitalization

Measure: activated partial thromboplastin time measurement

Time: up to Day 12

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Description: Measure of fibrinogen to assess hemostasis parameters of patients with SARS-COV-2pneumonitis during hospitalization

Measure: Fibrinogen measurement

Time: up to Day 12

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Description: Measure of D-dimers to assess hemostasis parameters of patients with SARS-COV-2pneumonitis during hospitalization

Measure: D-dimers measurement

Time: up to Day 12

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Description: Measure of Protein C to assess hemostasis parameters of patients with SARS-COV-2pneumonitis during hospitalization

Measure: Protein C measurement

Time: up to Day 12

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Description: Measure of Willebrand antigen to assess hemostasis parameters of patients with SARS-COV-2pneumonitis during hospitalization

Measure: Willebrand antigen measurement

Time: up to Day 12

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Description: Measure of Soluble tissue factor to assess hemostasis parameters of patients with SARS-COV-2pneumonitis during hospitalization

Measure: Soluble tissue factor measurement

Time: up to Day 12

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Description: Measure of soluble thrombomodulin to assess hemostasis parameters of patients with SARS-COV-2pneumonitis during hospitalization

Measure: Soluble thrombomodulin measurement

Time: up to Day 12

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Description: Measure of E-selectin to assess hemostasis parameters of patients with SARS-COV-2pneumonitis during hospitalization

Measure: E-selectin measurement

Time: up to Day 12

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Description: Measure of thrombin-antithrombin complex to assess hemostasis parameters of patients with SARS-COV-2pneumonitis during hospitalization

Measure: Thrombin-antithrombin complex measurement

Time: up to Day 12

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Description: Assessment of clot formation curve by Thrombodynamics® to identify ones predictive of the onset of Pulmonary Embolism or a poor prognosis

Measure: Assessment of clot formation curve

Time: Day 1

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Description: Assessment of thrombin generation by Thrombodynamics® to identify ones predictive of the onset of Pulmonary Embolism or a poor prognosis

Measure: Assessment of thrombin generation

Time: Day 1

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Description: Assessment of fibrinolysis by Thrombodynamics® to identify ones predictive of the onset of Pulmonary Embolism or a poor prognosis

Measure: Assessment of fibrinolysis

Time: Day 1

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Description: Determine patient mortality

Measure: Mortality

Time: Day 30

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Primary Outcomes

Description: The proportion of the total patients contacted, that meet the intieligibility criteria and give consent to take part Data quality: completion of clinical outcomes (questionnaires and other assessments) at each time point and patterns of missing data for the study measures. Intervention: Adherence in delivery and uptake documented in the clinical record.

Measure: Recruitment - contact to consent ratio

Time: through study completion an average of a year

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Description: The proportion of patients consented to the study that do not meet the eligibility criteria

Measure: Recruitment - screen failure rate

Time: through study completion an average of a year

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Description: The number patients recruited over the designated time frame

Measure: Recruitment rate

Time: through study completion an average of a year

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Description: The proportion of consented patients that complete the study

Measure: Recruitment retention

Time: through study completion an average of 16 months

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Secondary Outcomes

Description: The Modified Medical Research Council Dyspnoea Scale is a self rating tool to measure the degree of disability that breathlessness poses on day to day activities on a scale of 0-4; the higher the score the worse the outcome. A comparison of Change in MMRC dyspnoea scale from baseline to post 8 weeks tele rehab within the group and between fast track and wait list group.

Measure: The Modified Medical Research Council (MMRC) Dyspnoea Scale

Time: 8 weeks

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Description: The Numerical Rating Scale is a self rating tool to measure breathlessness on a 0-10 scale; a higher number indicates a worse outcome. A comparison of change in numerical scale from baseline to post 8 weeks tele rehab within the group and between fast track and wait list group

Measure: Numerical Rating Scale (NRS) of breathlessness

Time: 8 weeks

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Description: The Cough Visual Analogue Scale is a self rating assessment of cough on an 0-100mm scale: the higher the number reported the worse the symptom. A comparison of Change in cough visual analogue scale from baseline to post 8 weeks tele rehab within the group and between fast track and wait list group

Measure: Cough Visual analogue Scale (VAS)

Time: 8 weeks

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Description: The EQ-5D-5L questionnaire assesses the patients current health status and consists of two elements: 1. Visual Analogue Scale with a range of 0-100mm- the higher the number the worse the outcome 2. A quality of life questionnaire split into 5 domains which generates a 5 digit code ranging from 11111 to 55555 with the higher number indicating a worse outcome. A comparison of Change in EQ-5D-5L quality of life questionnaire from baseline to post 8 weeks tele rehab within the group and between fast track and wait list group

Measure: EQ-5D-5L questionnaire

Time: 8 weeks

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Description: The Hospital Anxiety and Depression scale consists of two sub scales anxiety and depression with a range of between 0-21, the higher score indicating the worse outcome. A comparison of Change in Hospital anxiety and depression questionnaire from baseline to post 8 weeks tele rehab within the group and between fast track and wait list group

Measure: Hospital Anxiety and Depression scale

Time: 8 weeks

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Description: comparison of sit to stand test from baseline to post 8 weeks tele rehab within the group and between fast track and wait list grou

Measure: Sit to stand test

Time: 8 weeks

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Primary Outcomes

Description: Mean error and root mean square error; measurements for statistical significance using a paired t-test.

Measure: In-Ear vs finger SpO2

Time: 12 months for full participant recruitment (actual head-to head comparison takes 1 minute for baseline reading and 6 minutes for 6-min walk test per patient)

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Primary Outcomes

Description: Change from baseline of Average forced expiratory volume in 1 second (FEV1) area under the curve (AUC)0-12h

Measure: Average forced expiratory volume in 1 second (FEV1) area under the curve (AUC)0-12h

Time: 12 weeks

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Secondary Outcomes

Description: Change from baseline of Average FEV1 AUC0-4h post-dose at Week 12

Measure: Average FEV1 AUC0-4h post-dose at Week 12

Time: 12 weeks

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Description: Change from baseline of Peak FEV1 over 4 hours post-dose at Week 12

Measure: Peak FEV1 over 4 hours post-dose at Week 12

Time: 12 weeks

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Description: Change from baseline as a weekly average of Evaluating-Respiratory Symptoms (E-RS) Total Score at Week 24

Measure: Evaluating-Respiratory Symptoms (E-RS) Total Score at Week 24

Time: 24 weeks

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Description: Change from baseline of SGRQ total score at Week 24

Measure: St. George's Respiratory Questionnaire (SGRQ) total score at Week 24

Time: 24 weeks

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Description: Change from baseline of Morning trough FEV1 at Week 12

Measure: Morning trough FEV1 at Week 12

Time: 12 weeks

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Description: The proportion of St. George's Respiratory Questionnaire (SGRQ) responders at Week 24.

Measure: St. George's Respiratory Questionnaire (SGRQ) responders at Week 24

Time: 24 weeks

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Description: Change from baseline of Rescue medication use at Week 24

Measure: Rescue medication use at Week 24

Time: 24 weeks

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Description: Transitional Dyspnea Index (TDI) at Week 24

Measure: Transitional Dyspnea Index (TDI) at Week 24

Time: 24 weeks

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Description: Change from baseline Evening trough FEV1 at Week 12

Measure: Evening trough FEV1 at Week 12

Time: 12 weeks

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Description: Change from baseline Peak FEV1

Measure: Peak FEV1 at Week 6 and Week 24

Time: 6 or 24 weeks

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Description: Change from baseline morning trough FEV1

Measure: Morning trough FEV1 at Week 6 and Week 24

Time: 6 or 24 weeks

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Description: Change from baseline evening trough FEV1

Measure: Evening trough FEV1 at Week 6 and Week 24

Time: 6 or 24 weeks

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Description: Change from baseline FEV1 AUC0-4h

Measure: FEV1 AUC0-4h at Week 6 and Week 24

Time: 6 or 24 weeks

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Description: Change from baseline E-RS Total Score

Measure: Evaluating-Respiratory Symptoms (E-RS) Total Score at Week 6 and Week 12

Time: 6 or 12 weeks

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Description: Change from baseline SGRQ responder analysis

Measure: SGRQ responder analysis at Week 6 and Week 12

Time: 6 or 12 weeks

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Description: Change from baseline TDI

Measure: TDI at Week 6 and Week 12

Time: 6 or 12 weeks

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Description: Change from baseline of SGRQ total score

Measure: St. George's Respiratory Questionnaire (SGRQ) total score at Weeks 6 and 12

Time: 6 or 12 weeks

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Description: Change from baseline of Rescue medication use

Measure: Rescue medication use at Weeks 6 and 12

Time: 6 or 12 weeks

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Primary Outcomes

Description: The number of patients recruited into this study over a 12-month period

Measure: Feasibility: the number of patients recruited into this study over a 12-month period

Time: 12 months

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Primary Outcomes

Description: 28-day all-cause mortality

Measure: 28-day all-cause mortality

Time: Day 28

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Secondary Outcomes

Description: Time to 7-category ordinal scale of clinical status improvement (T7COSCSI)

Measure: Time to 7-category ordinal scale of clinical status improvement (T7COSCSI)

Time: Up to 60 days

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Description: Ventilator-free days (VFDs) within 28 days

Measure: Ventilator-free days (VFDs) within 28 days

Time: Up to 28 days

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Description: Organ failure-free days (OFFD)

Measure: Organ failure-free days (OFFD)

Time: Up to 60 days

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Description: Intensive care unit length of stay (ICU LOS)

Measure: Intensive care unit length of stay (ICU LOS)

Time: Up to 60 days

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Description: Hospital length of stay (HLOS)

Measure: Hospital length of stay (HLOS)

Time: Up to 60 days

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Description: In-hospital all-cause mortality (IHACM)

Measure: In-hospital all-cause mortality (IHACM)

Time: Up to 60 days

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Description: 60-day all-cause mortality (60DACM)

Measure: 60-day all-cause mortality (60DACM)

Time: Up to 60 days

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Description: Time to oxygenation improvement (TOI)

Measure: Time to oxygenation improvement (TOI)

Time: Up to 60 days

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Description: Duration of supplemental oxygen (DSO)

Measure: Duration of supplemental oxygen (DSO)

Time: Up to 60 days

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Description: Chest radiographic improvement (CRI)

Measure: Chest radiographic improvement (CRI)

Time: Up to 60 days

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Description: Time to National Early Warning Score 2 improvement (TNEWS2I)

Measure: Time to National Early Warning Score 2 improvement (TNEWS2I)

Time: Up to 60 days

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Description: Treatment-emergent adverse events (TEAEs)

Measure: Treatment-emergent adverse events (TEAEs)

Time: Up to 60 days

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Description: Plasma siltuximab concentrations (PSCs)

Measure: Plasma siltuximab concentrations (PSCs)

Time: Up to 60 days

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Description: Anti-siltuximab antibodies (ASA)

Measure: Anti-siltuximab antibodies (ASA)

Time: Up to 60 days

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Primary Outcomes

Description: Change in Forced Vital Capacity (FVC) at 180 days as compared to baseline. Forced vital capacity (FVC) is the amount of air that can be forcibly exhaled from your lungs after taking the deepest breath possible, as measured by spirometry.

Measure: Change in Forced Vital Capacity (FVC)

Time: Baseline and 180 days

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Secondary Outcomes

Description: Death within 90 days and 180 days from enrollment due to a respiratory cause

Measure: Number of deaths due to respiratory cause

Time: within 90-180 days

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Description: Quantitative Change in chest CT visual score graded by blinded chest radiologists. Data driven texture analysis (DTA) is a patented deep learning method to quantify lung fibrosis. DTA score is reported in percentage ranging from 0% to 100%. A minimally clinical important difference when comparing CT scans from the same subject is 4%. A higher percentage suggests worsening lung injury.

Measure: Chest CT visual score

Time: 180 days

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Description: The Saint George's Respiratory Questionnaire (SGRQ) is a self-reported disease-specific, health-related quality of life (QOL) questionnaire. 50-item instrument. Scores range from 0 to 100, with higher scores indicating more limitations.

Measure: St. George's Respiratory Questionnaire (SGRQ)

Time: Day 90

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Description: The Saint George's Respiratory Questionnaire (SGRQ) is a self-reported disease-specific, health-related quality of life (QOL) questionnaire. 50-item instrument. Scores range from 0 to 100, with higher scores indicating more limitations.

Measure: St. George's Respiratory Questionnaire (SGRQ)

Time: Day 180

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Description: The King's Brief Interstitial Lung Disease (KBILD) questionnaire is a self-administered, ILD-specific measure of health-related quality of life, comprising 15 items with three domains (Psychological (KBILD-P), Breathlessness and activities (KBILD-B), and Chest symptoms (KBILD-C)) combined in a total score (KBILD-T). The KBILD domain and total score ranges are 0-100; 100 represents best health status.

Measure: King's Brief Interstitial Lung Disease (KBILD)

Time: Day 90

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Description: The King's Brief Interstitial Lung Disease (KBILD) questionnaire is a self-administered, ILD-specific measure of health-related quality of life, comprising 15 items with three domains (Psychological (KBILD-P), Breathlessness and activities (KBILD-B), and Chest symptoms (KBILD-C)) combined in a total score (KBILD-T). The KBILD domain and total score ranges are 0-100; 100 represents best health status.

Measure: King's Brief ILD (KBILD)

Time: Day 180

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Description: The LCQ is a 19 item questionnaire that assesses cough-related QOL. It has 3 domains (physical, psychological and social). The domain scores range from 1-7 and total score range is 3-21 with a higher score indicating a better quality of life.

Measure: Leicester Cough Questionnaire (LCQ)

Time: Day 90

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Description: The LCQ is a 19 item questionnaire that assesses cough-related QOL. It has 3 domains (physical, psychological and social). The domain scores range from 1-7 and total score range is 3-21 with a higher score indicating a better quality of life.

Measure: Leicester Cough Questionnaire

Time: Day 180

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Description: The (36) Health Survey is a 36-item, patient-reported survey of patient health. The SF-36 is a measure of health status. Scores range from 0 - 100, with higher scores indicating less disability.

Measure: Short Form (SF) 36 Health Survey

Time: Day 90

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Description: The (36) Health Survey is a 36-item, patient-reported survey of patient health. The SF-36 is a measure of health status. Scores range from 0 - 100, with higher scores indicating less disability.

Measure: SF 36 Health Survey

Time: Day 180

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Description: Questionnaire with 7 items for anxiety and 7 items for depression, each item is scored on a 4 point response 0 - 3, with full range from 0 to 42, with higher score indicating more severe anxiety or depression. 14-items scale with responses scored from 0-3, scores for each subscale from 0 (normal) to 21 (severe symptoms). Scores for the entire scale is 0 to 42, with higher score indicating more distress.

Measure: Hospital Anxiety and Depression Scale (HADS)

Time: Day 90

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Description: Questionnaire with 7 items for anxiety and 7 items for depression, each item is scored on a 4 point response 0 - 3, with full range from 0 to 42, with higher score indicating more severe anxiety or depression. 14-items scale with responses scored from 0-3, scores for each subscale from 0 (normal) to 21 (severe symptoms). Scores for the entire scale is 0 to 42, with higher score indicating more distress.

Measure: Hospital Anxiety and Depression Scale (HADS)

Time: Day 180

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Description: Number of participants with Increase in liver transaminases

Measure: Number of participants with Increase in liver transaminases (AST and ALT) > 3 times the upper limit of normal

Time: day 90

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Description: Number of participants with Increase in liver transaminases

Measure: Number of participants with Increase in liver transaminases (AST and ALT) > 3 times the upper limit of normal

Time: day 180

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Description: Number of participants with Thrombotic events: venous or arterial thrombosis

Measure: Number of participants with Thrombotic events

Time: day 90

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Description: Number of participants with Thrombotic events: venous or arterial thrombosis

Measure: Number of participants with Thrombotic events

Time: day 180

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Description: Number of participants with 10% weight loss

Measure: Number of participants with 10% weight loss over 90 days

Time: day 90

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Description: Number of participants with 10% weight loss

Measure: Number of participants with 10% weight loss over 90 days

Time: day 180

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Description: Number of participants with Nausea/emesis/diarrhea not responsive to anti-emetics and anti-motility agents

Measure: Number of participants with GI events

Time: day 90

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Description: Number of participants with Nausea/emesis/diarrhea not responsive to anti-emetics and anti-motility agents

Measure: Number of participants with GI events

Time: day 180

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