BRII-196/BRII-198 for Inpatients With COVID-19 (An ACTIV-3/TICO Treatment Trial)

Study Overview
=================
Brief Summary
-----------------
This study looks at the safety and effectiveness of BRII-196/BRII-198 in treating COVID-19 in people who have been hospitalized with the infection. Participants in the study will be treated with either BRII-196/BRII-198 plus current standard of care (SOC), or with placebo plus current SOC. This is ACTIV-3/TICO Treatment Trial H3.

Detailed Description
-----------------
This is a treatment trial of the ACTIV-3/TICO master protocol (NCT04501978) to evaluate the safety and efficacy of BRII-196/BRII-198 in hospitalized patients infected with COVID-19. This is a randomized, blinded, controlled sub-study of BRII-196/BRII-198 plus current standard of care (SOC) against placebo plus current SOC. The placebo arm may be shared across other sub-studies of the ACTIV-3/TICO master protocol. 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. The pace of enrollment with be initially restricted, and there will be an early review of safety data by the DSMB. 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. If BRII-196/BRII-198 passes the 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. This trial 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
-----------------
A Multicenter, Adaptive, Randomized, Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for Hospitalized Patients With COVID-19 (Trial H3: BRII-196/BRII-198)

Conditions
-----------------
COVID-19

Intervention / Treatment
-----------------
* Biological: BRII-196
* Biological: BRII-198
* Biological: Placebo
* Biological: Remdesivir


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Refer to the master protocol (NCT04501978) Exclusion Criteria: Refer to the master protocol (NCT04501978) Additional Exclusion Criteria: Pregnant women Nursing mothers In addition, prior to the initial futility assessment which is performed when approximately 150 participants have been enrolled on BRII-196/BRII-198 and 150 on placebo, patients on high-flow oxygen or non-invasive ventilation (category 5 of the pulmonary ordinal outcome) will be excluded. These patients may be eligible for the trial if the initial futility assessment is passed by this agent.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BRII-196/BRII-198 plus SOC<br>BRII-196 1000 mg solution; administered as IV infusion BRII-198 1000 mg solution; administered as IV infusion Remdesivir is provided to all study participants as SOC unless contraindicated for an individual patient; administered by IV infusion | Biological: BRII-196<br>* BRII-196 is a fully human immunoglobulin G (IgG)-1 monoclonal antibody (mAb) derived from antibody P2C-1F11 that was isolated directly from human B cells of a convalescent COVID-19 patient.<br>Biological: BRII-198<br>* BRII-198 is a fully human immunoglobulin G (IgG)-1 monoclonal antibody (mAb) derived from antibody P2B-1G5 that was isolated directly from human B cells of a convalescent COVID-19 patient.<br>Biological: Remdesivir<br>* Antiviral agent<br>* Other names: Veklury;|
| Placebo Comparator: Placebo plus SOC<br>Placebo administered by IV infusion Remdesivir is provided to all study participants as SOC unless contraindicated for an individual patient; administered by IV infusion | Biological: Placebo<br>* Commercially available 0.9% sodium chloride solution<br>Biological: Remdesivir<br>* Antiviral agent<br>* Other names: Veklury;|

What is the study measuring?
-----------------
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 |  | Through Day 90 | 
| Composite of time to sustained recovery and mortality |  | Through 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 organ failure |  | Through Day 28 | 
| Composite of death or serious clinical COVID-19 related events |  | Through Day 90 | 
| Composite of cardiovascular events and thromboembolic events |  | Through Day 90 | 
| Composite of grade 3 and 4 clinical adverse events, serious adverse events (SAEs) or death |  | Through Days 5 and 28 | 
| Incidence of infusion reactions |  | Through Day 0 | 
| Composite of SAEs or death |  | Through 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
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COVID-19, COVID 19, Coronaviridae Infections, Coronavirus Infections, RNA Virus Infections, Virus Infections, Nidovirales Infections, SARS-CoV-2, SARS Coronavirus, ACTIV-3, ACTIV3, TICO