ACTIV-3b: Therapeutics for Severely Ill Inpatients With COVID-19

Study Overview
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Brief Summary
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This study looks at the safety and effectiveness of different drugs in treating COVID-19 in people who have been hospitalized with the infection and who have acute respiratory failure. Participants in the study will be treated with either a study drug plus current standard of care (SOC), or with placebo plus current SOC.

Detailed Description
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This is a master protocol to evaluate the safety and efficacy of investigational agents aimed at improving outcomes for patients with acute respiratory failure related to COVID-19. Trials within this protocol will be adaptive, randomized, blinded and initially placebo-controlled. Participants will receive standard of care (SOC) treatment as part of the protocol. If an investigational agent shows superiority over placebo, SOC for the study of future investigational agents may be modified accordingly. The international trials within this protocol will be conducted in up to several hundred clinical sites. Participating sites are affiliated with networks funded by the United States National Institutes of Health (NIH) and the US Department of Veterans Affairs. The protocol is for a phase III platform study that allows investigational drugs to be added and dropped during the course of the study. This allows for efficient testing of new drugs against control within the same trial infrastructure. When more than one agent is being tested concurrently, participants may be randomly allocated across agents (as well as between the agent and its placebo) so the same control group can be shared, when feasible. In some situations, a factorial design may be used to study multiple agents. Participants will be followed for 90 days following randomization for the primary endpoint and most secondary endpoints. Selected secondary endpoints will be measured at 180 days. This study is planned to provide 80% power to detect an odds ratio of 1.5 for improvement in recovery status at Day 90 for an investigational agent versus placebo with use of the ordinal outcome. The planned sample size is 640 participants (320 per group) for each investigational agent/placebo. Sample size may be re-estimated before enrollment is complete based on an assessment of whether the pooled proportions of the outcome are still consistent with adequate power for the hypothesized difference measured by the odds ratio. Randomization will be stratified by study site pharmacy and by receipt of invasive mechanical ventilation, or ECMO at enrollment. Other agent-specific stratification factors may be considered. Investigational agents suitable for testing in the inpatient setting will be prioritized based on in vitro data, preclinical data, phase I pharmacokinetic and safety data, and clinical data from completed and ongoing trials. In some cases, a vanguard cohort/initial pilot phase may be incorporated into the trial. An independent Data and Safety Monitoring Board (DSMB) will review interim safety and efficacy data at least monthly. Pre-specified guidelines will be established to recommend early stopping of the trial for evidence of harm or substantial efficacy. The DSMB may recommend discontinuation of an investigational agent if the risks are judged to outweigh the benefits.

Official Title
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A Multicenter, Adaptive, Randomized, Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for Hospitalized Patients With Acute Respiratory Distress Syndrome Associated With COVID-19

Conditions
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Covid19

Intervention / Treatment
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* Biological: Remdesivir
* Drug: Remdesivir Placebo
* Biological: Aviptadil
* Drug: Aviptadil Placebo
* Drug: Corticosteroid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent. Requiring admission to hospital for acute medical care (not for purely public health or quarantine purposes). Current respiratory failure (i.e. receipt of high-flow nasal cannula, non-invasive ventilation, invasive mechanical ventilation, or ECMO (extracorporeal membrane oxygenation) used to treat acute hypoxemic respiratory failure). SARS-CoV-2 (COVID-19) infection, documented by a nucleic acid test (NAT) or equivalent testing with most recent rest within 14 days prior to randomization. Respiratory failure is believed to be due to SARS-CoV-2 pneumonia. Exclusion Criteria: Known allergy to investigational agent or vehicle. More than 4 days since initiation of support for respiratory failure. Chronic/home mechanical ventilation (invasive or non-invasive) for chronic lung or neuromuscular disease (non-invasive ventilation used solely for sleep-disordered breathing is not an exclusion). Moribund patient (i.e. not expected to survive 24 hours). Active use of comfort care or other hospice-equivalent standard of care. Expected inability to participate in study procedures. In the opinion of the investigator, any condition for which, participation would not be in the best interest of the participant or that could limit protocol-specified assessments. Previous enrollment in TESICO Agent-specific exclusion criteria Prior receipt of any dose of remdesivir during present illness (remdesivir agent). GFR (glomerular filtration rate) < 30 ml/min and not receiving dialysis (remdesivir agent). ALT (alanine aminotransferase) or AST (aspartate aminotransferase) > 10 times upper limit of normal (remdesivir agent). Unwillingness to commit to avoid sex that may result in pregnancy for at least 7 days after completion of remdesivir vs. placebo (remdesivir agent). Refractory hypotension (aviptadil agent). Severe diarrhea (Aviptadil agent). Current C. difficile infection (aviptadil agent). Pregnancy or current breast-feeding (aviptadil agent). End-stage liver disease (aviptadil agent).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aviptadil + Remdesivir + SOC<br> | Biological: Remdesivir<br>* Administered by IV infusion, daily for 10 days. Initial loading dose is 200 mg with all subsequent doses 100 mg.<br>Biological: Aviptadil<br>* Administered by IV infusion over 12 hours per day for 3 days. Participants are no longer being randomized to this intervention.<br>* Other names: VIP;Drug: Corticosteroid<br>* In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC.<br>|
| Placebo Comparator: Aviptadil + Remdesivir Placebo + SOC<br> | Drug: Remdesivir Placebo<br>* Commercially available 0.9% sodium chloride solution. Administered by IV infusion daily for 10 days.<br>Biological: Aviptadil<br>* Administered by IV infusion over 12 hours per day for 3 days. Participants are no longer being randomized to this intervention.<br>* Other names: VIP;Drug: Corticosteroid<br>* In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC.<br>|
| Experimental: Aviptadil Placebo + Remdesivir + SOC<br> | Biological: Remdesivir<br>* Administered by IV infusion, daily for 10 days. Initial loading dose is 200 mg with all subsequent doses 100 mg.<br>Drug: Aviptadil Placebo<br>* Commercially available 0.9% sodium chloride solution. Administered by IV infusion over 12 hours per day for 3 days.<br>Drug: Corticosteroid<br>* In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC.<br>|
| Experimental: Aviptadil Placebo + Remdesivir Placebo + SOC<br> | Drug: Remdesivir Placebo<br>* Commercially available 0.9% sodium chloride solution. Administered by IV infusion daily for 10 days.<br>Drug: Aviptadil Placebo<br>* Commercially available 0.9% sodium chloride solution. Administered by IV infusion over 12 hours per day for 3 days.<br>Drug: Corticosteroid<br>* In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recovery, assessed at 90 days | Recovery categorized as 1 (Best): At home and not receiving new supplemental oxygen for ≥ 77 consecutive days; 2: At home and not receiving new supplemental oxygen for 49-76 consecutive days; 3: At home and not receiving new supplemental oxygen for 1-48 consecutive days; 4: Discharged from hospital but either not yet home or home but receiving new supplemental oxygen; 5: Still hospitalized or receiving hospice care; 6 (Worst): Dead. | Thru Day 90 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality |  | Thru Day 90 | 
| Time to death |  | Thru Day 90 | 
| Composite of time to recovery, days at home off new supplemental oxygen and time to death | Measured in number of days | Thru Day 90 | 
| Composite of alive, at home and off new supplemental oxygen |  | Thru Day 90 | 
| Composite of recovered, alive and not recovered, and dead | Recovery defined as alive, at home and off new supplemental oxygen | Thru Day 90 | 
| Time from randomization to recovery | Recovery defined as alive, at home and off oxygen (treating death as competing risk) | Thru Day 90 | 
| Days alive outside short-term acute care hospital | Using last off method. | Up to Day 90 | 
| Incidence of clinical organ failure or serious infections | Defined as any one or more of: Worsening respiratory dysfunction; cardiac and vascular dysfunction; renal dysfunction; hepatic dysfunction; neurological dysfunction, haematological dysfunction; serious infection | Thru Day 28 | 
| Composite of death, clinical organ failure or serious infections |  | Thru Day 90 | 
| Composite of cardiovascular events and thromboembolic events |  | Thru Day 28 | 
| Composite of cardiovascular events and thromboembolic events |  | Thru Day 90 | 
| Composite of grade 3 and 4 clinical adverse events, serious adverse events (SAEs) or death |  | Thru Days 5 and 28 | 
| Incidence of infusion reactions |  | Thru Day 180 | 
| Percentage of participants for whom infusion was interrupted or stopped prior to completion for any reason |  | Thru Day 90 | 
| Percentage of participants for whom infusion was interrupted or stopped prior to completion due to adverse event |  | Thru Day 90 | 
| Composite of hospital readmissions or death |  | Thru Day 180 | 
| Incidence of no home use of supplemental oxygen above pre-morbid oxygen use | Measured as: Alive at home for an uninterrupted 14 day period and no use of continuous supplemental oxygen at end of 14 day time period. | 14 days | 
| Time to hospital discharge from initial hospitalization |  | Thru Day 180 | 
| Composite of death or serious clinical COVID-19 related events |  | Thru Day 90 | 
| Pulmonary ordinal outcome | Oxygen requirements measured by 7 categories (1 = least severe, 7 = most severe). The participant's highest (i.e. most severe) observed score is used. | Days 1-7, 14 and 28 | 
| Composite of SAEs or death |  | Thru Day 180 | 
| Incidence of home use of supplemental oxygen above pre-morbid oxygen use | Measured as: Alive at home and no use of continuous supplemental oxygen for an uninterrupted 14 day period | Thru Day 180 | 
| In category 4, 5 or 6 at Day 90 vs. in categories 1-3 at Day 90 | Categories are 1 (Best): At home an off oxygen for ≥ 77 consecutive days; 2: At home and off oxygen for 49-76 consecutive days; 3: At home and off oxygen for 1-48 consecutive days; 4: Not hospitalized and either at home on oxygen or not at home; 5: Hospitalized for medical care or in hospice care; 6 (Worst): Dead. | Day 90 | 
| In category 5 or 6 at Day 90 vs. in categories 1-4 at Day 90 | Categories are 1 (Best): At home an off oxygen for ≥ 77 consecutive days; 2: At home and off oxygen for 49-76 consecutive days; 3: At home and off oxygen for 1-48 consecutive days; 4: Not hospitalized and either at home on oxygen or not at home; 5: Hospitalized for medical care or in hospice care; 6 (Worst): Dead. | Day 90 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, COVID 19, Coronaviridae Infections, Coronavirus Infections, RNA Virus Infections, Virus Diseases, Nidovirales Infections, SARS-CoV-2, SARS Coronavirus, ACTIV-3, ACTIV3