Primary Outcomes

Description: Blood pressure group: 1) Essential arterial hypotension, 2) normotension and 3) Essential arterial hypertension. Comorbidities: As describe in the protocol, as a summary: 1) cardiovascular, 2) metabolic, 3) Endocrine, 4) psychiatric disorders: depression and panic disorder, 5) orthostatic intolerance: neurally mediated syncope, vasovagal syncope, inappropriate sinus tachycardia, Postural orthostatic syndrome, carotid sinus hypersensitivity; 6) others: chronic fatigue syndrome, fibromyalgia, arthritis, autoimmune diseases, pulmonary thromboembolism, OSA (obstructive sleep apnea), Alzheimer disease, Parkinson disease, others dementias, epilepsia, nephropathies, and others. Cardiovascular mortality Total mortality

Measure: Relationship between Blood pressure group and comorbidities

Time: A 7-year prospective study

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Description: Adaptability group: Hyper adaptable, normal adaptability, hypo adaptable. Comorbidities: As describe in the protocol, as a summary: 1) cardiovascular, 2) metabolic, 3) Endocrine, 4) psychiatric disorders: depression and panic disorder, 5) orthostatic intolerance: neurally mediated syncope, vasovagal syncope, inappropriate sinus tachycardia, Postural orthostatic syndrome, carotid sinus hypersensitivity; 6) others: chronic fatigue syndrome, fibromyalgia, arthritis, autoimmune diseases, pulmonary thromboembolism, OSA (obstructive sleep apnea), Alzheimer disease, Parkinson disease, others dementias, epilepsia, nephropathies, and others. Cardiovascular mortality Total mortality

Measure: Relationship between adaptability group and comorbidities

Time: A 7-year prospective study

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Description: Blood pressure group: 1) Essential arterial hypotension, 2) normotension and 3) Essential arterial hypertension. Adaptability group: Hyper adaptable, normal adaptability, hypo adaptable. Comorbidities: As describe in the protocol, as a summary: 1) cardiovascular, 2) metabolic, 3) Endocrine, 4) psychiatric disorders: depression and panic disorder, 5) orthostatic intolerance: neurally mediated syncope, vasovagal syncope, inappropriate sinus tachycardia, Postural orthostatic syndrome, carotid sinus hypersensitivity; 6) others: chronic fatigue syndrome, fibromyalgia, arthritis, autoimmune diseases, pulmonary thromboembolism, OSA (obstructive sleep apnea), Alzheimer disease, Parkinson disease, others dementias, epilepsia, nephropathies, and others. Cardiovascular mortality Total mortality

Measure: Relationship between blood pressure group, adaptability group and comorbidities

Time: A 7-year prospective study

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Secondary Outcomes

Description: Blood pressure group: 1) Essential arterial hypotension, 2) normotension and 3) Essential arterial hypertension. Habits: smoke and drink Anthropometric variables: Body mass index, waist, hip Metabolic variables: Fasting glucose, 2 hs postprandial plasma glucose, insulin plasma levels, homoeostasis model assessment (HOMA), total cholesterol, LDL, HDL, triglycerides. Endocrine variables: plasma cortisol, free cortisol in 24 hs. urine, epinephrine, norepinephrine, metanephrines, vanilmandelic acid, ACTH, aldosterone, renin, thyrotropine, free thyroxine, triiodothyronine, testosterone Electrocardiogram: HR; PR interval, QRS complex, cQT interval Holter variables: HR, standard deviation of NN intervals (SDNN) and sympathovagal balance, at day, night and 24 hs. ABPM: Systolic, diastolic, and heart rate, at day, night and 24 hs., BP matinal surge.

Measure: Relationship between blood pressure group, habits and anthropometric, metabolic, endocrine, Electrocardiogram, Holter, ambulatory blood pressure monitoring (ABPM)

Time: A 7-year prospective study

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Description: Blood pressure group: 1) Essential arterial hypotension, 2) normotension and 3) Essential arterial hypertension. Adaptability group: Hyper adaptable, normal adaptability, hypo adaptable. Habits: smoke and drink Anthropometric variables: Body mass index, waist, hip Metabolic variables: Fasting glucose, 2 hs postprandial plasma glucose, insulin plasma levels, HOMA, total cholesterol, LDL, HDL, triglycerides. Endocrine variables: plasma cortisol, free cortisol in 24 hs. urine, epinephrine, norepinephrine, metanephrines, vanilmandelic acid, ACTH, aldosterone, renin, thyrotropine, free thyroxine, triiodothyronine, testosterone Electrocardiogram: PR interval, QRS complex, Heart rate, cQT interval Holter variables: HR, SDNN and sympathovagal balance, at day, night and 24 hs. ABPM: Systolic, diastolic, and heart rate, at day, night and 24 hs., BP matinal surge.

Measure: Relationship between blood pressure group, adaptability group, habits anthropometric, metabolic, endocrine, electrocardiographic, Holter, ambulatory arterial blood pressure monitoring.

Time: A 7-year prospective study

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Description: Blood pressure group: 1) Essential arterial hypotension, 2) normotension and 3) Essential arterial hypertension. Adaptability group: 1) Hyper adaptable, 2) normal adaptability and 3) hypo adaptable. Habits: smoke and drink, exercise Anthropometric variables: Body mass index, waist, hip Metabolic and other variables: Fasting glucose, 2 hs postprandial plasma glucose, insulin plasma levels, HOMA, total cholesterol, LDL, HDL, triglycerides; thyrotropine, Holter variables: HR, standard deviation of NN intervals (SDNN) and sympathovagal balance, at day, night and 24 hs. ABPM: Systolic, diastolic, and heart rate, at day, night and 24 hs., BP matinal surge.

Measure: For metabolic disorders what it matters the most: the anthropometric variables vs blood pressure group vs adaptability group

Time: A 7-year prospective study

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Description: Adaptability group: Hyper adaptable, normal adaptability, hypo adaptable. Habits: smoke and drink Anthropometric variables: Body mass index, waist, hip Metabolic variables: Fasting glucose, 2 hs postprandial plasma glucose, insulin plasma levels, HOMA, total cholesterol, LDL, HDL, triglycerides. Endocrine variables: plasma cortisol, free cortisol in 24 hs. urine, epinephrine, norepinephrine, metanephrines, vanilmandelic acid, ACTH, aldosterone, renin, thyrotropine, free thyroxine, triiodothyronine, testosterone Electrocardiogram: PR interval, QRS complex, Heart rate, cQT interval Holter variables: HR, SDNN and sympathovagal balance, at day, night and 24 hs. ABPM: Systolic, diastolic, and heart rate, at day, night and 24 hs., BP matinal surge.

Measure: Relationship between adaptability group, habits and anthropometric, metabolic, endocrine, Electrocardiogram, Holter, ambulatory blood pressure monitoring (ABPM)

Time: A 7-year prospective study

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Other Outcomes

Description: Clinical syncope characteristics (age of first syncope, number of syncope episodes, trauma, duration, clinical score, convulse, sphincter relaxation, etc.) Syncope cause Blood pressure group Adaptability group Prognosis

Measure: Syncope Registry

Time: Up 100 weeks

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Description: TTT protocol: describe the protocol, the time at positive response, nitroglycerine use, autonomic and hemodynamic variables. TTT outcome for syncope: positive or negative TTT other outcomes: 1) Chronotropic incompetence, 2) arterial orthostatic hypotension, 3) carotid hypersensitivity, 4) POTS, 5) IST The relationship between TTT results and Clinical score for syncope in regard to: syncope behaviour and other orthostatic intolerance entities, symptoms and comorbidities. The relationship between neurally mediated syncope response at the TTT and comorbidities.

Measure: Tilt table testing (TTT) registry

Time: Up to 100 weeks

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Description: EPS variables: AH, AV, CL, sino atrial conduction time (SACT), sinus node recovery time (SNRT), corrected sinus node recovery time (CSNRT), response to Isoproterenol, intrinsic heart rate Diagnosis: control, sick sinus syndrome, IST, chronotropic incompetence at the TTT HR at the ECG HR at the Holter monitoring HR at the TTT HRV at the Holter monitoring Syncope, cardiac or neurally mediated HR at the physical treadmill test Relationship with the blood pressure group Relationship with the adaptability group

Measure: Sinus node function at the electrophysiological study (EPS)

Time: Up to 100 weeks

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Description: Define how the blood pressure group and/or the adaptability group may add to the already known and include in this registry, in the diagnosis of cardiovascular complications as coronary artery disease, cerebrovascular disease, peripheral artery disease, nephropathy.

Measure: Score for coronary artery disease

Time: Up to 200 weeks

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Description: Blood pressure group: 1) Essential arterial hypotension, 2) normotension and 3) Essential arterial hypertension. Adaptability group: Hyper adaptable, normal adaptability, hypo adaptable. Comorbidities: As describe in the protocol, as a summary: 1) cardiovascular, 2) metabolic, 3) Endocrine, 4) psychiatric disorders: depression and panic disorder, 5) orthostatic intolerance: neurally mediated syncope, vasovagal syncope, inappropriate sinus tachycardia, Postural orthostatic syndrome, carotid sinus hypersensitivity; 6) others: chronic fatigue syndrome, fibromyalgia, arthritis, autoimmune diseases, pulmonary thromboembolism, OSA (obstructive sleep apnea), Alzheimer disease, Parkinson disease, others dementias, epilepsia, nephropathies, COPD, and others. Mortality

Measure: Neurally Mediated Syncope: further of the transient lost of consciousness (TLC)

Time: A 7-year prospective study

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Description: Blood pressure group: 1) Essential arterial hypotension, 2) normotension and 3) Essential arterial hypertension. Adaptability group: Hyper adaptable, normal adaptability, hypo adaptable. Psychiatric variables: Big Five Questionary (BFQ) for personality. Modify of the Coping Scale (Scale of modified coping strategies) Zung questionary for depression and anxiety MINI in those patients with moderate or severe depression and/or anxiety at the Zung questionary

Measure: Psychobiotype: relationship between biological and psychological variables

Time: Up to 100 weeks

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Description: High sodium intake in the diet is recognized as a risk factor for hypertension development. Essential hypotension population is advised to increase the sodium (at least 10 grams a day) and water intake (at least 2 liters a day), or as much as possible, several have taken Fludrocortisone (is not a exclusion criteria). Normal blood pressure population are advised to have a normal or low sodium intake. Physical exercise is recommended in both groups. This registry is a good opportunity to test how important sodium diet is to induce hypertension, or if by the contrary adaptability could prevail over high sodium intake in this registry. Blood pressure groups: essential hypotension and normotension and those with new essential hypertension. Adaptability groups. The results will be adjusted for age, gender and BMI.

Measure: The role of high sodium intake in the development of essential hypertension. Comparison between essential hypotension (high sodium intake) vs normotension population (normal or low sodium intake) in the follow-up.

Time: 4 years

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Description: Consistent bradycardia in the ECG at the office and normal HR in the holter monitoring or the contrary. There are patients with complaints that may be attributed to bradycardia, low blood pressure, hypothyroidism, or other entities. Some patients very often have bradycardia in the ECG taken in the office and normal HR in the 24 Holter monitoring, the opposite is also possible. Patients with bradycardia (without medication or physiological condition as exersice affecting heart rate) in at least 2 ECG (less 60 bpm) and at least 2 Holter monitoring will be analyzed, Other variables to consider are: Age, gender, blood pressure group, adaptability group, maximum HR in the treadmill test, white coat or masked hypertension, Tilt-Table-test result or syncope cause, Electrophysiological study if available. The acknowledge of this phenomenon could have clinical implications in the diagnosis of sick sinus syndrome and physiopathological ones.

Measure: White coat effect in the heart rate or masked bradycardia.

Time: 1 year

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Description: Bradycardia is the classical presentation form for sinus node dysfunction, mainly when associated with symptoms. Chronotropic incompetence is also a manifestation. Absence of medications with effects on the heart rate (HR) must be ruled out. Variables HR at the ECG, Holter monitoring, stress text, and at the physical examination previous to pacemaker implantation, Electrophysiological study (EPS): Basic cycle length, Sino-atrial conduction time, Sinus node recovery time, Corrected sinus node recovery time, Intrinsic HR when available 3. Pacemaker variables: HR at day and night or rest time Percentage of stimulation in A and V chambers 4. Syncope: Clinical characteriscs and clinical score Tilt table test results Trans Thoracic Echocardiogram in rest and or stress text Hypothesis: patients with ANSD will start to decrease the percentage atrial stimulation.

Measure: Reversible Bradycardia Mimicking Sinus Node Dysfunction as a Manifestation of Subacute Autonomic Nervous System Dysfunction (ANSD).

Time: 2 years

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Description: A non invasive, beat to beat BP monitoring, with the ability to measure BP, HR, Cardiac Output and Systemic Vascular Resistance (SVR) was started to use in the EHAR registry since May 2017. A description of this variables in the three BP groups will be collected in the data base (DB). This will allow to characterize whether SVR and/or CO maintain BP. Until now BP levels are related with prognosis. In the prognosis model SVR and CO will be add them to know what matter the most: BP levels, SVR and/or CO? In the EHAR registry a collection of the variables recognized as a risk factor for several comorbidities are available to adjust in multivariable analysis.

Measure: Description of the blood pressure hemodynamic profile at a medical office and their prognostic implications.

Time: Three years

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Primary Outcomes

Description: Velocity of pulse wave traveling between carotid and femoral artery; validated measure of arterial stiffness

Measure: Carotid-femoral pulse wave velocity

Time: Phase 1 of study, change from baseline at the end of week 2 and week 4

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Description: Left ventricular mass indexed to height

Measure: Left ventricular mass index

Time: Phase 2 of study, change from baseline to 6 months

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Secondary Outcomes

Description: Ventricular stiffness k, by Parametrized Diastolic Formalism analysis

Measure: Ventricular stiffness

Time: Phase 1 of study, change from baseline at the end of week 2 and week 4

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Description: Global longitudinal left ventricular strain, a sensitive measure of ventricular systolic function

Measure: Global longitudinal left ventricular strain

Time: Phase 1 of study, change from baseline at the end of week 2 and week 4

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Description: Global left atrial strain, a novel measure of atrial function

Measure: Global left atrial strain

Time: Phase 1 of study, change from baseline at the end of week 2 and week 4

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Description: Velocity of pulse wave traveling between carotid and femoral artery; validated measure of arterial stiffness

Measure: Carotid-femoral pulse wave velocity

Time: Phase 2 of study, change from baseline to 6 months

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Description: Left atrial volume by 3D echocardiography

Measure: Left atrial volume

Time: Phase 2 of study, change from baseline to 6 months

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Other Outcomes

Description: Change in 24-hour mean of >= 8 mmHg will define the salt-sensitive blood pressure phenotype

Measure: Salt-sensitivity phenotype

Time: Phase 1 of study, change from baseline at the end of week 2 and week 4

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Description: Measure of dietary sodium intake

Measure: 24-hour urinary sodium excretion

Time: Phase 2 of study, change from baseline to 6 months

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Description: Sodium-restricted DASH diet score on Food Frequency Questionnaire, measured by complete or partial adherence to 9 dietary domains

Measure: Sodium-restricted DASH diet adherence

Time: Phase 2 of study, change from baseline to 6 months

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Description: Analysis of 3-day food diaries by a Registered Dietitian, utilizing the Nutrition Data System for Research

Measure: Sodium-restricted DASH diet adherence

Time: Phase 2 of study, months 1 and 6

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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: Development of an electronic (e-HEALTH) framework structure for management of patients with known cardiovascular disease in COVID19 pandemic social context

Measure: Providing a special electronic platform (e-health) for remote managing cardiovascular outpatients

Time: 6 months

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Description: patients come into direct contact with the case coordinator, who provides ongoing assistance, including for connecting to devices that ensure real-time data transmission and directing to specialist teams that establish stage diagnosis and management / therapy behavior (including adjustment). doses, decisions to discontinue medication or to add medication);

Measure: Number of patients included in this platform

Time: 6 months

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Secondary Outcomes

Description: Will be the number of sessions per patient multiplied with the number of patients included

Measure: Number of consultations/sessions given

Time: 6 months

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Primary Outcomes

Description: Maximum plasma furosemide concentration after administration by subcutaneous infusion or IV bolus

Measure: Pharmacokinetic - Cmax

Time: 0 to 24 hours

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Description: Area under the concentration versus time curve (AUC) from time 0 to the last measurable plasma furosemide concentration after administration by subcutaneous infusion or IV bolus

Measure: Pharmacokinetic - AUClast

Time: 0 to 24 hours

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Description: AUC from time 0 to infinity for plasma furosemide after administration by subcutaneous infusion or IV bolus

Measure: Pharmacokinetic - AUCinf

Time: 0 to 24 hours

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Secondary Outcomes

Description: Total collected urine volume after furosemide administration by subcutaneous infusion or IV bolus

Measure: Pharmacodynamic - Diuresis

Time: 0 to 8 hours

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Description: Total collected urine volume after furosemide administration by subcutaneous infusion or IV bolus

Measure: Pharmacodynamic - Diuresis

Time: 0 to 24 hours

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Description: Total sodium concentration in urine after furosemide administration by subcutaneous infusion or IV bolus

Measure: Pharmacodynamic - Natriuresis

Time: 0 to 8 hours

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Description: Total sodium concentration in urine after furosemide administration by subcutaneous infusion or IV bolus

Measure: Pharmacodynamic - Natriuresis

Time: 0 to 24 hours

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Primary Outcomes

Description: All-cause and cardiovascular mortality during index hospitalization.

Measure: In-hospital mortality.

Time: Hospitalization period, assessed up to 30 days

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Secondary Outcomes

Description: The duration of hospitalization on the intensive care unit.

Measure: The length of stay in the intensive care unit.

Time: Hospitalization period in the ICU, assessed up to 30 days

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Description: The total length of stay in the hospital.

Measure: The duration of hospitalization.

Time: Hospitalization period, assessed up to 30 days

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Measure: The need and duration of invasive mechanical ventilation.

Time: Hospitalization period, assessed up to 30 days

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Measure: Hospitalization for cardiovascular causes or cardiovascular deaths within 3 months after hospitalization.

Time: 3 months

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Measure: Hospitalization for cardiovascular causes or cardiovascular deaths within 6 months after hospitalization.

Time: 6 months

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Primary Outcomes

Description: Hospital mortality

Measure: Hospital mortality

Time: up to 90 days

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Secondary Outcomes

Description: Mortality Day 28

Measure: Mortality Day 28

Time: Day 28

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Description: Mortality Day 90

Measure: Mortality Day 90

Time: Day 90

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Description: Ventilator-free days

Measure: Ventilator-free days

Time: Day 28

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Description: ICU-free days

Measure: Intensive care unit-free days

Time: Day 28

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Description: Hospital-free days

Measure: Hospital-free days

Time: Day 28

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Primary Outcomes

Measure: Time to clinical recovery from initiation of pemziviptadil (PB1046)

Time: 28 days

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Secondary Outcomes

Measure: Time to clinical recovery (being well enough for hospital discharge or returning to normal baseline activity level prior to discharge)

Time: 28 days

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Measure: Time to hospital discharge

Time: Any time point between injection initiation and Day 28

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Measure: All-cause mortality

Time: 28 days

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Description: Composite of: Total hospital days, Total ICU days, Total days of ventilator use, Total days of ECMO, Total days of invasive hemodynamic monitoring, Total days of mechanical circulatory support, Total days of inotropic or vasopressor therapy

Measure: Reduction in hospital resource utilization defined as a composite of: total days: in hospital, in ICU, on ventilator, on ECMO, with invasive hemodynamic monitoring, with mechanical circulatory support, and with inotropic or vasopressor therapy

Time: 28 days

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Measure: Time to clinical improvement as defined by reduction of at least 2 points on an 8-category ordinal scale of clinical improvement or discharge from hospital, whichever comes first.

Time: Any time point between injection initiation and Day 28

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Measure: Change from baseline in cardiac marker troponin I (TrI)

Time: Any time point between injection initiation and Day 35+7

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Measure: Change from baseline in cardiac marker NT-proBNP/BNP

Time: Any time point between injection initiation and Day 35+7

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Measure: Change from baseline in TNF alpha

Time: Any time point between injection initiation and Day 35+7

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Measure: Change from baseline in IL-1

Time: Any time point between injection initiation and Day 35+7

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Measure: Change from baseline in IL-6

Time: Any time point between injection initiation and Day 35+7

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Measure: Incidence and severity of any treatment emergent adverse events (TEAEs) or serious adverse events (SAEs) as determined by clinical adverse events (AEs) and their relationship to pemziviptadil (PB1046).

Time: Any time point between injection initiation and Day 35+7

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Measure: Incidence and severity of any treatment emergent adverse events (TEAEs) or serious adverse events (SAEs) as determined by vital signs and their relationship to pemziviptadil (PB1046)

Time: Any time point between injection initiation and Day 35+7

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Measure: Incidence and severity of any treatment emergent adverse events (TEAEs) or serious adverse events (SAEs) as determined by laboratory results and their relationship to pemziviptadil (PB1046)

Time: Any time point between injection initiation and Day 35+7

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Measure: Incidence and severity of any treatment emergent adverse events (TEAEs) or serious adverse events (SAEs) as determined by electrocardiogram (ECG) abnormalities and their relationship to pemziviptadil (PB1046)

Time: Any time point between injection initiation and Day 35+7

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Measure: Incidence and severity of any treatment emergent adverse events (TEAEs) or serious adverse events (SAEs) as determined by incidence of anti-drug antibodies and their relationship to pemziviptadil (PB1046)

Time: Any time point between injection initiation and Day 35+7

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Other Outcomes

Measure: Impact on invasive hemodynamic parameters as measured by pulmonary artery pressure if patients require right-heart catherization

Time: Any time point between injection initiation and Day 35+7

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Measure: Impact on invasive hemodynamic parameters as measured by cardiac output if patients require right-heart catherization

Time: Any time point between injection initiation and Day 35+7

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Measure: Incidence of multi-system organ failure (MSOF)

Time: Any time point between injection initiation and Day 35+7

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Measure: Number of multi-system organ failure (MSOF) free days

Time: Any time point between injection initiation and Day 35+7

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Measure: Number of subjects requiring extracorporeal membrane oxygenation (ECMO)

Time: Any time point between injection initiation and Day 35+7

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Measure: Change in circulating ferritin

Time: Any time point between injection initiation and Day 35+7

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Measure: Change in circulating D-dimer

Time: Any time point between injection initiation and Day 35+7

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Measure: Change in liver function

Time: Any time point between injection initiation and Day 35+7

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Measure: Change in other blood chemistry

Time: Any time point between injection initiation and Day 35+7

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Measure: Change in hematology

Time: Any time point between injection initiation and Day 35+7

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Measure: Change in inflammatory markers

Time: Any time point between injection initiation and Day 35+7

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Measure: Change in coagulation markers

Time: Any time point between injection initiation and Day 35+7

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Measure: Percent of clinical failure

Time: Any time point between injection initiation and Day 35+7

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Primary Outcomes

Description: This outcome corresponds to the difference between the average gain in exercise capacity after cardiac rehabilitation between the two groups of patients Control and COVID-19.

Measure: Impact of COVID-19 on exercise capacity gain after cardiovascular rehabilitation

Time: Month 3

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Primary Outcomes

Description: Number of days patient found to have delirium using the Confusion Assessment Method for the ICU (CAM-ICU)

Measure: Duration of delirium

Time: From the date of admission to the Intensive Care Unit (ICU) until discharge from the ICU or death, whichever came first, up to 12 months.

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Secondary Outcomes

Description: CAM-ICU

Measure: Incidence of delirium

Time: From the date of admission to the Intensive Care Unit (ICU) until discharge from the ICU or death, whichever came first, up to 12 months.

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Description: Days

Measure: Length of critical care stay

Time: From the date of admission to the ICU until discharge from the ICU or death, whichever came first, up to 12 months.

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Description: Days

Measure: Length of hospital stay

Time: From the date of admission to the hospital until discharge from the hospital or death, whichever came first, up to 12 months.

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Measure: Doses of specified drugs during ICU admission

Time: From the date of admission to the ICU until discharge from the ICU or death, whichever came first, up to 12 months.

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Description: Days

Measure: Length of time ventilated

Time: From the date of admission to the ICU until discharge from the ICU or death, whichever came first, up to 12 months.

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Measure: Mortality

Time: 6 months

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Other Outcomes

Description: Semi structured interviews

Measure: Exploring the experiences of patients, relatives and staff of the visitation restrictions during the COVID-19 pandemic

Time: 18 months

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Primary Outcomes

Description: Evaluating the effect of AZD9977 and dapagliflozin in combination and alone compared with placebo on UACR.

Measure: Percent change from baseline in UACR at 12 weeks

Time: Baseline (Day 1) until Week 12 (Day 85)

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Secondary Outcomes

Description: Assessment of the dose-response relationship of placebo, AZD9977 (Dose C) alone, dapagliflozin (10 mg) alone and 3 doses of AZD9977 (A, B or C) combined with dapagliflozin (10 mg) on UACR.

Measure: Percent change from baseline in UACR at 12 weeks to assess dose-response relationship

Time: Baseline (Day 1) until Week 12 (Day 85)

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Description: Assessment of the general safety and tolerability of AZD9977 and dapagliflozin in combination and alone compared with placebo.

Measure: Number of participants with adverse events (AEs) and serious adverse events (SAEs)

Time: From baseline (Day 1) until Day 113 (Safety Follow-up)

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Description: Assessment of the effect of AZD9977 and dapagliflozin in combination and alone compared with placebo on serum potassium.

Measure: Absolute value of serum potassium over time

Time: Days 1, and 3 until Day 85

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Description: Assessment of the effect of AZD9977 and dapagliflozin in combination and alone compared with placebo on serum potassium.

Measure: Change from baseline in serum potassium over time

Time: From baseline (Day 1), Day 3 until Day 85

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Description: Assessment of the effect of AZD9977 and dapagliflozin in combination and alone compared with placebo on eGFR.

Measure: Absolute value of eGFR over time

Time: Days 1, and 3 until Day 85

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Description: Assessment of the effect of AZD9977 and dapagliflozin in combination and alone compared with placebo on eGFR.

Measure: Change from baseline in eGFR over time

Time: From baseline (Day 1), Day 3 until Day 85

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Primary Outcomes

Description: Area under curve (AUC) where maximum value is '1', describing ability of algorithm to discriminate low from not-low ejection fraction

Measure: Area under receiver operating curve

Time: up to 18 months

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Primary Outcomes

Description: Hypokinetic left ventricle function (left ventricle ejection fraction <45%)

Measure: Percentage of patients with left ventricle dysfunction (hypokinetic)

Time: 3 month

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Description: Acute cor pulmonale was defined as a dilated right ventricle (right ventricle end-diastolic area/left ventricle end-diastolic area ratio >0.6) associated with the presence of paradoxical septum motion

Measure: Percentage of patients with acute cor pulmonale

Time: 3 month

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Secondary Outcomes

Description: Respiratory system compliance is defined as the change in lung volume (Tidal volume, ml) produced by a unit change in pulmonary pressure (driving pressure, cmH2O). The reported value of respiratory system compliance will be reported in ml/cmH2O.

Measure: Differences in respiratory system compliance between patients with and without acute cor pulmonale

Time: Within the first 24 hours of mechanical ventilation.

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Description: Partial arterial pressure of carbon dioxide will be reported in mmHg.

Measure: Differences in partial arterial pressure of carbon dioxide (PCO2) between patients with and without acute cor pulmonale

Time: Within the first 24 hours of mechanical ventilation.

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Description: PaO2/FiO2 ratio is the ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2 expressed as a fraction). The reported value is a positive integer.

Measure: Differences in PaO2/FiO2 ratio between patients with and without acute cor pulmonale

Time: Within the first 24 hours of mechanical ventilation.

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Primary Outcomes

Description: Assessment of the safety and tolerability of single and multiple ascending doses of AZD3427.

Measure: Number of Participants Experiencing Adverse Events and Serious Adverse Events

Time: Part A: Day 1 until Day 50 or Early termination visit (E/T); Part B: Day 1 until Day 78 or E/T

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Secondary Outcomes

Description: Evaluation of the PK of single and multiple ascending doses of AZD3427.

Measure: Maximum Observed Serum (peak) Drug Concentration (Cmax) of AZD3427

Time: Part A: Day 1 (pre-dose, and 10 minutes [only for cohort 5a], 4hrs and 12hrs post-dose, and days 2, 3, 8, 15, 29, and Day 50 or E/T ; Part B: Day 1 (Pre-dose and post-dose), days 8, 15, 22, and 29 (pre-dose); and days 2, 3, 36, 57, 71 and 78 or E/T

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Description: Evaluation of the PK of single and multiple ascending doses of AZD3427.

Measure: Area Under the Serum Concentration-time Curve from Zero to the Last Quantifiable Concentration (AUClast)

Time: Part A: Day 1 (pre-dose, and 10 minutes [only for cohort 5a], 4hrs and 12hrs post-dose, and days 2, 3, 8, 15, 29, and Day 50 or E/T ; Part B: Day 1 (Pre-dose and post-dose), days 8, 15, 22, and 29 (pre-dose); and days 2, 3, 36, 57, 71 and 78 or E/T

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Description: Evaluation of the PK of single and multiple ascending doses of AZD3427.

Measure: Area Under Serum Concentration-time Curve From Zero to Infinity (AUCinf)

Time: Part A: Day 1 (pre-dose, and 10 minutes [only for cohort 5a], 4hrs and 12hrs post-dose, and days 2, 3, 8, 15, 29, and Day 50 or E/T ; Part B: Day 1 (Pre-dose and post-dose), days 8, 15, 22, and 29 (pre-dose); and days 2, 3, 36, 57, 71 and 78 or E/T

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Description: Evaluation of the PK of single and multiple ascending doses of AZD3427.

Measure: Area Under the Serum Concentration-time Curve from Zero to 168 Hours Post-dose Administration (AUC0-168)

Time: Part A: Day 1 (pre-dose, and 10 minutes [only for cohort 5a], 4hrs and 12hrs post-dose, and days 2, 3, 8, 15, 29, and Day 50 or E/T ; Part B: Day 1 (Pre-dose and post-dose), days 8, 15, 22, and 29 (pre-dose); and days 2, 3, 36, 57, 71 and 78 or E/T

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Description: Evaluation of the PK of single and multiple ascending doses of AZD3427.

Measure: Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (tmax)

Time: Part A: Day 1 (pre-dose, and 10 minutes [only for cohort 5a], 4hrs and 12hrs post-dose, and days 2, 3, 8, 15, 29, and Day 50 or E/T ; Part B: Day 1 (Pre-dose and post-dose), days 8, 15, 22, and 29 (pre-dose); and days 2, 3, 36, 57, 71 and 78 or E/T

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Description: Evaluation of the PK of single and multiple ascending doses of AZD3427.

Measure: Half-life Associated with Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz)

Time: Part A: Day 1 (pre-dose, and 10 minutes [only for cohort 5a], 4hrs and 12hrs post-dose, and days 2, 3, 8, 15, 29, and Day 50 or E/T ; Part B: Day 1 (Pre-dose and post-dose), days 8, 15, 22, and 29 (pre-dose); and days 2, 3, 36, 57, 71 and 78 or E/T

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Description: Evaluation of the immunogenicity of single and multiple ascending doses of AZD3427.

Measure: Number of Participants Testing Positive for the Presence of Anti-drug Antibodies (ADA) and Neutralizing Antibodies (NAb) to AZD3427

Time: Part A: Day 1 (pre-dose), Days 15, 29, and 50 or E/T; Part B: Days 1, 15, 29 (Pre-dose), Days 57 and 78 or E/T

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Description: Evaluation of the immunogenicity of single and multiple ascending doses of AZD3427.

Measure: Evaluation of Positive Anti-drug Antibodies Titer

Time: Part A: Day 1 (pre-dose), Days 15, 29, and 50 or E/T; Part B: Days 1, 15, 29 (Pre-dose), Days 57 and 78 or E/T

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Description: Evaluation of the immunogenicity of single and multiple ascending doses of AZD3427.

Measure: Evaluation of Neutralizing Antibodies Titer

Time: Part A: Day 1 (pre-dose), Days 15, 29, and 50 or E/T; Part B: Days 1, 15, 29 (Pre-dose), Days 57 and 78 or E/T

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Primary Outcomes

Description: will explore nurses' perception regarding the assessment and management of depression and anxiety in heart failure by undertaking an online focus group with community heart failure nurses.

Measure: Explore community heart failure nurses' perception of assessing, managing and treating depression and anxiety in HF and the use of web-based interventions.

Time: This will take place before the introduction of COMPASS web-based intervention.

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Description: will explore patients' perception regarding the assessment and management of depression and anxiety in heart failure. This will be done by undertaking online\telephone interviews with community-based heart failure patients.

Measure: Explore community heart failure patients' perception of assessing, managing and treating depression and anxiety in HF and the use of web-based interventions.

Time: This will take place before the introduction of COMPASS web-based intervention.

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Description: will explore nurses' perception regarding the use of web-based COMPASS intervention for the management of depression and anxiety in heart failure in an online focus group.

Measure: Explore nurses' perception of using web-based COMPASS intervention for depression and anxiety management in HF

Time: This will take place 30 minutes after the introduction and demonstration of COMPASS web-based intervention.

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Description: will explore patients' perception regarding the use of web-based COMPASS intervention for the management of depression and anxiety in heart failure. This will be done by conducting online\telephone interviews with community-based heart failure patients.

Measure: Explore patients' perception of using web-based COMPASS intervention for depression and anxiety management in HF

Time: This will take place 30 minutes after the introduction and demonstration of COMPASS web-based intervention.

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Secondary Outcomes

Description: will discuss with community HF nurses the impact of COVID-19 on the psychological wellbeing of community-based HF patients and how it changed their access to psychological intervention. This will form part of the online focus group.

Measure: Explore with community HF nurses the impact of COVID-19 pandemic on HF patients' depression and anxiety level and changes to management processes.

Time: This will take place before the introduction of COMPASS web-based intervention.

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Description: will explore with community HF patients the impact of COVID-19 on the psychological wellbeing of community-based HF patients and how it changed their access to psychological intervention. This will form part of the online/telephone interviews.

Measure: Explore with community HF patients the impact of COVID-19 pandemic on HF patients' depression and anxiety level and changes to management processes.

Time: This will take place before the introduction of COMPASS web-based intervention.

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Primary Outcomes

Description: The number of participants recruited at the end of rollout and participant experience.

Measure: Recruitment

Time: Through study completion, an average of 12 weeks

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Description: The number of participants retained at post-rollout end

Measure: Retention

Time: Through study completion, an average of 12 weeks

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Description: The percentage of exercise sessions completed

Measure: Adherence

Time: Through study completion, an average of 12 weeks

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Description: A semi-structured interview will ask about participant experience, satisfaction, learning needs, and suggested adaptations to the program. A semi-structured interview guide has been designed to conduct exit interviews and follow up interviews with each participant over the phone or web conference. Interviews will be audio-recorded and transcribed verbatim. One researcher will perform content analyses using NVivo version 12 Pro or higher (QSR International Pty Ltd, 2019) to describe participant experience, satisfaction, learning needs and suggested adaptations to the program. Analyses will be verified by another researcher through member checking. The exercise physiologist will be given a spreadsheet to record any protocol adaptations, challenges, and successes to inform future trials.

Measure: Participant experience

Time: Week 12

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Secondary Outcomes

Description: A Physical Activity Screen (PAS) will be used to capture average minutes of moderate-to-vigorous physical activity each week. This tool was created based on questions used by Exercise is Medicine in the Physical Activity Vital Sign questionnaire (Greenwood et al., 2010). The results will be compared to national exercise guidelines for older adults that promote ≥150 minutes and ≥2 session of muscle strengthening per week (Tremblay et al., 2011).

Measure: Physical activity

Time: Baseline, week 9, week 12

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Description: A modified version of the Exercise Self-Efficacy Scale will be used to capture levels of planning and execution of exercise related activities (Resnick & Jenkins, 2000). The lowest response option to each question is "Not true at all", while the highest is "Exactly true". Responses closer to "Exactly true" indicate a better outcome.

Measure: Exercise self-efficacy scale

Time: Baseline, week 9, week 12

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Description: The 30-second Chair Stand will be used to access lower extremity muscle function (Bohannon, 1995; Jones et al., 1999). The instructions for this test have been adapted and will be self-administered under the remote supervisor supervision of the exercise physiologist. A higher score on this test indicates a better outcome.

Measure: 30-second Chair Stand

Time: Baseline, week 9, week 12

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Description: Static balance will be measured using the 3-point scale from the Short Performance Physical Battery (J. M. Guralnik et al., 1994). The instructions for this test have been adapted and will be self-administered under the remote supervisor supervision of the exercise physiologist. A higher score on this test indicates a better outcome.

Measure: Static balance

Time: Baseline, week 9, week 12

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Description: Fatigue will be assessed with the Center for Epidemiologic Studies Depression Scale-fatigue questions (CES-D) Depression Scale (Radloff, 1977). Only two questions on the CES-D will be used: "I felt that everything I did was an effort, "I could not get going". The lowest response option is "Rarely (<1 day)", and the highest response option is "Nearly every day". Responses closer to the lowest response option indicate a better outcome.

Measure: Fatigue

Time: Baseline, week 9, week 12

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Description: Warwick-Edinburgh Mental Well-being Scale focuses on positive aspects of mental health. It is short, yet robust and showed high correlations with other mental health and well-being scales. The lowest response option is "None of the time", and the highest response option is "All of the time". Responses closer to the highest response option indicate a better outcome.

Measure: Mental health and social isolation

Time: Baseline, week 9, week 12

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Description: The EuroQol Group 5 Dimension 5 Level questionnaire is a multi-attribute health related quality of life tool (Herdman et al., 2011). The system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems to extreme problems five dimensions can be combined into a 5-digit number that describes the self rated patient's health state. Responses to each dimension are scored as a number from 1-5. Responses scored as 1 indicate a better outcome.

Measure: Quality of life score

Time: Baseline, week 9, week 12

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Description: The SCREEN tool is a valid and reliable nutrition questionnaire designed specifically for older adults (Keller et al., 2005). This tool will be used to assess changes in weight, appetite, eating habits and promote viable self-management.

Measure: Dietary intake

Time: Baseline, week 9, week 12

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Description: ASA24®-Canada is a guided web-based tool used for 24-hour diet recalls. All food and drinks consumed by the participant on two weekdays and one weekend day (3 days in total) will be reported to track protein intake (Subar et al., 2012).

Measure: Nutrition tracking

Time: Baseline, week 9, week 12

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Description: We will ask participants to report adverse events, using Health Canada definitions. We will report all serious and non-serious adverse events and identify those attributable to intervention. Safety outcomes will include all falls, fractures, and serious and non-serious adverse events. Any fractures or falls that are attributable to intervention will be considered under both fall or fracture outcomes, and harms.

Measure: Number of adverse events

Time: Through study completion, an average of 12 weeks

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