ACTIV-3: Therapeutics for 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. 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 multiple investigational agents aimed at modifying the host immune response to SARS-CoV-2 infection, or directly enhancing viral control in order to limit disease progression. The protocol is for a randomized, blinded, controlled 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 placebo and standard of care (SOC) treatment within the same study. When more than one drug is being tested at the same time, participants will be randomly allocated to treatments or placebo. Randomization will be stratified by study site pharmacy and disease severity. There are 2 disease severity strata: Participants without organ failure (severity stratum 1); and participants with organ failure (severity stratum 2). An independent Data and Safety Monitoring Board (DSMB) will regularly review interim analyses and summarize safety and efficacy outcomes. For investigational drugs with minimal pre-existing safety knowledge, the pace of enrollment with be initially restricted, and there will be an early review of safety data by the DSMB. For the study of each agent, at the outset of the trial, only participants in disease severity stratum 1 will be enrolled. This will continue until approximately 300 participants are enrolled and followed for 5 days. The exact number will vary according to the speed of enrollment and the timing of DSMB meetings. Prior to expanding enrollment to also include patients in disease severity stratum 2, safety will be evaluated and a pre-specified futility assessment by the DSMB will be carried out using 2 ordinal outcomes assessed at Day 5. Both ordinal outcomes are used to assess futility because it is currently unclear whether the investigational agents under study will primarily influence non-pulmonary outcomes, for which risk is increased with SARS-CoV-2 infection, in part, through mechanisms that may be different from those that influence pulmonary outcomes. For investigational agents passing this futility assessment, enrollment of participants will be expanded, seamlessly and without any data unblinding, to include participants in disease severity stratum 2 as well as those in disease severity stratum 1. Future interim analyses will be based on the primary endpoint of sustained recovery and will use pre-specified guidelines to determine early evidence of benefit, harm or futility for the investigational agent. Participants will be followed for 18 months following randomization. The international trials within this protocol will be conducted in 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.

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 COVID-19

Conditions
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Covid19

Intervention / Treatment
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* Biological: LY3819253
* Drug: Placebo
* Biological: Remdesivir
* Biological: VIR-7831
* Biological: BRII-196/BRII-198
* Biological: AZD7442
* Drug: MP0420
* Drug: PF-07304814


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent. Positive test for COVID-19 and progressive disease suggestive of ongoing COVID-19 infection. Symptoms of COVID-19 for ≤ 12 days. Require admission to hospital for acute medical care (not for purely public health or quarantine purposes). Exclusion Criteria: Patients who have received plasma from a person who recovered from COVID-19 or who have received neutralizing monoclonal antibodies at any time prior to hospitalization. Patients not willing to abstain from participation in other COVID-19 treatment trials until after Day 5 of the study. Co-enrollment in certain trials that compare recommended Standard of Care treatments may be allowed, based on the opinion of the study leadership team. Any condition which, in the opinion of the responsible investigator, participation would not be in the best interest of the participant or that could prevent, limit, or confound the protocol-specified assessments. Patients considered unable to participate in study procedures. Women of child-bearing potential who are not already pregnant at study entry and who are unwilling to acknowledge strong advice to abstain from sexual intercourse with men or practice appropriate contraception through 18 months of the study. Women of child-bearing potential who are unwilling to acknowledge the strong advice to abstain from sexual intercourse with men or practice appropriate contraception through 5 weeks of the study (PF-07304814 investigational agent). Pregnant women (PF-07304814 investigational agents). Nursing mothers (PF-07304814 investigational agents). Men who are unwilling to acknowledge the strong advice to abstain from sexual intercourse with women of child-bearing potential or to use barrier contraception through 18 months of the study. Men who are unwilling to acknowledge the strong advice to abstain from sexual intercourse with women of child-bearing potential or to use barrier contraception through 5 weeks of the study (PF-07304814 investigational agent). Presence at study enrollment of any of the following: stroke meningitis encephalitis myelitis myocardial ischemia myocarditis pericarditis symptomatic congestive heart failure arterial or deep venous thrombosis or pulmonary embolism Current or imminent requirement for any of the following: invasive mechanical ventilation ECMO (extracorporeal membrane oxygenation) Mechanical circulatory support vasopressor therapy commencement of renal replacement therapy at this admission (i.e. not patients on chronic renal replacement therapy). Participants with moderate to severe hepatic impairment (i.e. Child-Pugh class B or C) or acute liver failure (PF-07304814 investigational agent). Participants receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450 (CYP) 3A4 (PF-07304814 investigational agent). Patients will be excluded if taking drugs which have a narrow therapeutic window that are substrates of CYP3A4, including but not limited to: astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, pimozide, quinidine, sirolimus, tacrolimus, and terfenadine (PF-07304814 investigational agent). Patients with a history of deep vein thrombosis or pulmonary thrombotic embolism (Prior to initial futility assessment of PF-07304814 investigational 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: ACTIV-3 Drug plus SOC<br>Participants in this study will be randomized to receive one of the ACTIV-3 drug treatments plus Standard of Care (SOC) or placebo plus SOC | Biological: LY3819253<br>* Participants are no longer being randomized to this intervention.<br>Biological: Remdesivir<br>* Provided to all study participants as SOC unless contraindicated for an individual patient.<br>Biological: VIR-7831<br>* Participants are no longer being randomized to this intervention.<br>Biological: BRII-196/BRII-198<br>* Participants are no longer being randomized to this intervention.<br>Biological: AZD7442<br>* Participants are no longer being randomized to this intervention.<br>* Other names: AZD8895 + AZD1061;Drug: MP0420<br>* Participants are no longer being randomized to this intervention.<br>* Other names: ensovibep;Drug: PF-07304814<br>* 250 mg per day for 5 days. Administered as a constant rate intravenous infusion. Suspended: Participants are not currently being randomized to this intervention.<br>|
| Placebo Comparator: Placebo plus SOC<br>The placebo arm may be pooled across more than one experimental arm if multiple investigational drugs are available to be tested at the same time. If it is not possible to use matching placebo over more than one experimental arm, additional placebo arms will be included in the study | Drug: Placebo<br>* Commercially available 0.9% sodium chloride solution. Administered by IV infusion<br>Biological: Remdesivir<br>* Provided to all study participants as SOC unless contraindicated for an individual patient.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time from randomization to sustained recovery | Sustained recovery defined as being discharged from the index hospitalization, followed by being alive and home for 14 consecutive days prior to Day 90. | Up to Day 90 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality |  | Thru Day 90 | 
| Composite of time to sustained recovery and mortality |  | Thru Day 90 | 
| Days alive outside short-term acute care hospital |  | Up to 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 | 
| Pulmonary+ ordinal outcome | Extrapulmonary complications and respiratory dysfunction 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 | 
| Incidence of clinical organ failure |  | Thru Day 28 | 
| Composite of death or serious clinical COVID-19 related events |  | Thru Day 90 | 
| 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 0 | 
| Composite of SAEs or death |  | Thru 18 months | 
| Change in SARS-CoV-2 neutralizing antibody levels |  | Baseline to Days 1, 3, 5, 28 and 90 | 
| Change in overall titers of antibodies |  | Baseline to Days 1, 3, 5, 28 and 90 | 
| Change in neutralizing antibody levels |  | Baseline to Days 1, 3, 5, 28 and 90 | 
| 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 | 18 months | 
| 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 | 

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