COVID-19
Conditions
Keywords
COVID-19, COVID 19, Coronaviridae Infections, Coronavirus Infections, RNA Virus Infections, Virus Infections, Nidovirales Infections, SARS-CoV-2, SARS Coronavirus, ACTIV-3, ACTIV3, TICO
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.
Interventions
BIOLOGICALBRII-196
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.
BIOLOGICALBRII-198
BRII-198 is a fully human IgG-1 mAb derived from antibody P2B-1G5 that was isolated directly from human B cells of a convalescent COVID-19 patient.
BIOLOGICALPlacebo
Commercially available 0.9% sodium chloride solution
BIOLOGICALRemdesivir
Antiviral agent
Sponsors
International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)
University of Copenhagen
Medical Research Council
Kirby Institute
Washington D.C. Veterans Affairs Medical Center
Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
National Heart, Lung, and Blood Institute (NHLBI)
US Department of Veterans Affairs
Prevention and Early Treatment of Acute Lung Injury
Cardiothoracic Surgical Trials Network
Brii Biosciences Limited
University of Minnesota
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Refer to the master protocol (NCT04501978)
Exclusion criteria
* Refer to the master protocol (NCT04501978) * Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With an Ordinal Outcome on Day 5 | Status on Day 5 | Ordinal outcome with 7 mutually exclusive categories |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Died From All Causes | Through Day 90 | All-cause mortality |
| Number of Participants With a Safety Outcome Through Day 5 | Through Day 5 | Death, SAE, clinical organ failure, serious infections, or Grade 3 or 4 event through Day 5 |
| Number of Participants With a Safety Outcome Through Day 28 | Through Day 28 | Death, SAE, clinical organ failure, serious infections, or Grade 3 or 4 event through Day 28 |
| Number of Participants With a Safety Outcome Through Day 90 | Through Day 90 | Death, SAE, clinical organ failure, serious infections through Day 90 |
Countries
Denmark, Poland, Singapore, Spain, Switzerland, Uganda, United Kingdom, United States
Participant flow
Recruitment details
Subjects were enrolled from 43 sites in 4 countries (Denmark, Switzerland, Poland, USA). The first subject was enrolled on 16 Dec 2020 and the last subject was enrolled on 1 Mar 2021.
Participants by arm
| Arm | Count |
|---|---|
| BRII-196/BRII-198 Plus SOC * 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
BRII-196: 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.
BRII-198: 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.
Remdesivir: Antiviral agent | 176 |
| Placebo Plus SOC * Placebo administered by IV infusion
* Remdesivir is provided to all study participants as SOC unless contraindicated for an individual patient; administered by IV infusion
Placebo: Commercially available 0.9% sodium chloride solution
Remdesivir: Antiviral agent | 177 |
| Total | 353 |
Baseline characteristics
| Characteristic | Placebo Plus SOC | Total | BRII-196/BRII-198 Plus SOC |
|---|---|---|---|
| Age, Continuous | 59.5 years STANDARD_DEVIATION 14.8 | 59.8 years STANDARD_DEVIATION 14.5 | 60.2 years STANDARD_DEVIATION 14.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 32 Participants | 66 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 145 Participants | 287 Participants | 142 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 9 Participants | 21 Participants | 12 Participants |
| Race/Ethnicity, Customized Black or African American | 37 Participants | 74 Participants | 37 Participants |
| Race/Ethnicity, Customized More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Only ethnicity reported | 15 Participants | 28 Participants | 13 Participants |
| Race/Ethnicity, Customized Other | 5 Participants | 13 Participants | 8 Participants |
| Race/Ethnicity, Customized White | 108 Participants | 213 Participants | 105 Participants |
| Sex: Female, Male Female | 74 Participants | 152 Participants | 78 Participants |
| Sex: Female, Male Male | 103 Participants | 201 Participants | 98 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 15 / 176 | 13 / 177 |
| other Total, other adverse events | 45 / 176 | 40 / 177 |
| serious Total, serious adverse events | 13 / 176 | 11 / 177 |
Outcome results
Primary
Number of Participants With an Ordinal Outcome on Day 5
Ordinal outcome with 7 mutually exclusive categories
Time frame: Status on Day 5
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BRII-196/BRII-198 Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 5 = Non-invasive ventilation or high flow oxygen | 15 Participants |
| BRII-196/BRII-198 Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 3 = Supplement oxygen (<4 L/min or <4 L/min above baseline, but not high flow oxygen) | 33 Participants |
| BRII-196/BRII-198 Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 6 = Invasive ventilation, ECMO, mechanical circulatory support, new renal replacement therapy | 4 Participants |
| BRII-196/BRII-198 Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 2 = Limiting symptoms due to COVID-19, but not need of new or increased oxygen from baseline | 58 Participants |
| BRII-196/BRII-198 Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 4 = Supplement oxygen (≥4 L/min or ≥4 L/min above baseline, but not high flow oxygen) | 18 Participants |
| BRII-196/BRII-198 Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 1 = No limiting symptoms due to COVID-19 | 44 Participants |
| BRII-196/BRII-198 Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 7 = Death | 1 Participants |
| Placebo Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 1 = No limiting symptoms due to COVID-19 | 40 Participants |
| Placebo Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 7 = Death | 1 Participants |
| Placebo Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 6 = Invasive ventilation, ECMO, mechanical circulatory support, new renal replacement therapy | 3 Participants |
| Placebo Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 5 = Non-invasive ventilation or high flow oxygen | 14 Participants |
| Placebo Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 4 = Supplement oxygen (≥4 L/min or ≥4 L/min above baseline, but not high flow oxygen) | 20 Participants |
| Placebo Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 3 = Supplement oxygen (<4 L/min or <4 L/min above baseline, but not high flow oxygen) | 42 Participants |
| Placebo Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 2 = Limiting symptoms due to COVID-19, but not need of new or increased oxygen from baseline | 57 Participants |
Secondary
Number of Participants Who Died From All Causes
All-cause mortality
Time frame: Through Day 90
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BRII-196/BRII-198 Plus SOC | Number of Participants Who Died From All Causes | 15 Participants |
| Placebo Plus SOC | Number of Participants Who Died From All Causes | 13 Participants |
Secondary
Number of Participants With a Safety Outcome Through Day 28
Death, SAE, clinical organ failure, serious infections, or Grade 3 or 4 event through Day 28
Time frame: Through Day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BRII-196/BRII-198 Plus SOC | Number of Participants With a Safety Outcome Through Day 28 | 58 Participants |
| Placebo Plus SOC | Number of Participants With a Safety Outcome Through Day 28 | 57 Participants |
Secondary
Number of Participants With a Safety Outcome Through Day 5
Death, SAE, clinical organ failure, serious infections, or Grade 3 or 4 event through Day 5
Time frame: Through Day 5
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BRII-196/BRII-198 Plus SOC | Number of Participants With a Safety Outcome Through Day 5 | 46 Participants |
| Placebo Plus SOC | Number of Participants With a Safety Outcome Through Day 5 | 43 Participants |
Secondary
Number of Participants With a Safety Outcome Through Day 90
Death, SAE, clinical organ failure, serious infections through Day 90
Time frame: Through Day 90
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BRII-196/BRII-198 Plus SOC | Number of Participants With a Safety Outcome Through Day 90 | 45 Participants |
| Placebo Plus SOC | Number of Participants With a Safety Outcome Through Day 90 | 47 Participants |