COVID-19
Conditions
Keywords
COVID-19, COVID 19, Coronaviridae Infections, Coronavirus Infections, RNA Virus Infections, Virus Diseases, Nidovirales Infections, SARS-CoV-2, SARS Coronavirus, ACTIV-3, ACTIV3, TICO
Brief summary
This study looks at the safety and effectiveness of AZD7442 in treating COVID-19 in people who have been hospitalized with the infection. Participants in the study will be treated with either a AZD7442 plus current standard of care (SOC), or with placebo plus current SOC. This is ACTIV-3/TICO Treatment Trial H4.
Detailed description
This is a treatment trial of the ACTIV-3/TICO master protocol (NCT04501978) to evaluate the safety and efficacy of AZD7442 in hospitalized patients infected with COVID-19. This is a randomized, blinded, controlled sub-study of AZD7442 plus current 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 AZD7442 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
BIOLOGICALAZD7442
AZD8895 and AZD1061, known collectively as AZD7442, are two fully human neutralizing immunoglobulin G (IgG)-1 kappa monoclonal antibodies (mAb) that target two distinct epitopes on the receptor-binding domain of the spike protein of SARS-CoV- 2.
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
AstraZeneca
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 Sustained Recovery | Through Day 90 | The primary endpoint is the proportion of subjects with sustained recovery, which is defined as being discharged from the index hospitalization, followed by being alive and home for 14 consecutive days prior to Day 90. Home is defined as the level of residence or facility where the participant was residing prior to hospital admission leading to enrollment in this protocol. Readmission from home may occur, and if this occurs within 14 days of the first discharge to home, then the primary endpoint will not be reached until such time as the participant has been at home for 14 consecutive days. |
| 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 With a Safety Outcome Through Day 5 | Through Day 5 | Safety outcomes are defined as Death, SAE, clinical organ failure, serious infections, or Grade 3 or 4 event through Day 5. Seriousness was based on the definition of the term at 21CFR312.32 AEs were graded for severity by the treating investigator, according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (also known at the DAIDS AE Grading Table), U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1. \[July 2017\]. Available from: https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf). The following generic grading descriptions from the DAIDS AE Grading Table are provided for context: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=potentially life-threatening |
| Number of Participants With a Safety Outcome Through Day 28 | Through Day 28 | Safety outcomes are defined as Death, SAE, clinical organ failure, serious infections, or Grade 3 or 4 event through Day 28. Seriousness was based on the definition of the term at 21CFR312.32 AEs were graded for severity by the treating investigator, according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (also known at the DAIDS AE Grading Table), U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1. \[July 2017\]. Available from: https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf). The following generic grading descriptions from the DAIDS AE Grading Table are provided for context: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=potentially life-threatening |
| Number of Participants With a Safety Outcome Through Day 90 | Through Day 90 | Safety outcomes are defined as Death, SAE, clinical organ failure, serious infections, or Grade 3 or 4 event through Day 90. Seriousness was based on the definition of the term at 21CFR312.32 AEs were graded for severity according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (also known at the DAIDS AE Grading Table). |
| Number of Participants Who Died From All Causes | Through Day 90 | All-cause Mortality |
Countries
Denmark, Greece, Poland, Singapore, Spain, Switzerland, Uganda, United Kingdom, United States
Participant flow
Recruitment details
Subjects were enrolled from 81 sites in 8 countries (Denmark, Poland, Singapore, Spain, Switzerland, Uganda, UK, USA). The first subject was enrolled on 10 Feb 2021 and the last subject was enrolled on 30 Sep 2021.
Pre-assignment details
The number of participants consented was not collected, so these numbers are the number of participants randomized.
Participants by arm
| Arm | Count |
|---|---|
| AZD7442 Plus SOC * AZD7442 600 mg solution (separate vials containing 300 mg each of AZD88995 and AZD1061); administered by IV infusion
* Remdesivir is provided to all study participants as SOC unless contraindicated for an individual patient; administered by IV infusion
AZD7442: AZD8895 and AZD1061, known collectively as AZD7442, are two fully human neutralizing immunoglobulin G (IgG)-1 kappa monoclonal antibodies (mAb) that target two distinct epitopes on the receptor-binding domain of the spike protein of SARS-CoV- 2.
Remdesivir: Antiviral agent | 710 |
| 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 | 707 |
| Total | 1,417 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 22 | 16 |
Baseline characteristics
| Characteristic | AZD7442 Plus SOC | Total | Placebo Plus SOC |
|---|---|---|---|
| Age, Continuous | 55.2 years STANDARD_DEVIATION 14.7 | 55.1 years STANDARD_DEVIATION 14.8 | 55.0 years STANDARD_DEVIATION 15 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 4 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian | 33 Participants | 57 Participants | 24 Participants |
| Race/Ethnicity, Customized Black or African American | 175 Participants | 347 Participants | 172 Participants |
| Race/Ethnicity, Customized More than one race | 3 Participants | 7 Participants | 4 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 3 Participants | 8 Participants | 5 Participants |
| Race/Ethnicity, Customized Only ethnicity reported | 67 Participants | 150 Participants | 83 Participants |
| Race/Ethnicity, Customized Other | 15 Participants | 36 Participants | 21 Participants |
| Race/Ethnicity, Customized White | 413 Participants | 808 Participants | 395 Participants |
| Sex: Female, Male Female | 299 Participants | 594 Participants | 295 Participants |
| Sex: Female, Male Male | 411 Participants | 823 Participants | 412 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 61 / 710 | 86 / 707 |
| other Total, other adverse events | 176 / 710 | 184 / 707 |
| serious Total, serious adverse events | 36 / 710 | 39 / 707 |
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) |
|---|---|---|---|
| AZD7442 Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 5 = Non-invasive ventilation or high flow oxygen | 102 Participants |
| AZD7442 Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 3 = Supplement oxgen (<4 L/min or <4 L/min above baseline, but not high flow oxygen) | 127 Participants |
| AZD7442 Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 6 = Invasive ventilation, ECMO, mechanical circulatory support, new renal replacement therapy | 32 Participants |
| AZD7442 Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 2 = Limiting symptoms due to COVID-19, but no need of new or increased oxygen from baseline | 215 Participants |
| AZD7442 Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 4 = Supplement oxgen (≥4 L/min or ≥4 L/min above baseline, but not high flow oxygen) | 92 Participants |
| AZD7442 Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 1 = No limiting symptoms due to COVID-19 | 117 Participants |
| AZD7442 Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 7 = Death | 10 Participants |
| Placebo Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 1 = No limiting symptoms due to COVID-19 | 117 Participants |
| Placebo Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 7 = Death | 13 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 | 29 Participants |
| Placebo Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 5 = Non-invasive ventilation or high flow oxygen | 99 Participants |
| Placebo Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 4 = Supplement oxgen (≥4 L/min or ≥4 L/min above baseline, but not high flow oxygen) | 106 Participants |
| Placebo Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 3 = Supplement oxgen (<4 L/min or <4 L/min above baseline, but not high flow oxygen) | 126 Participants |
| Placebo Plus SOC | Number of Participants With an Ordinal Outcome on Day 5 | 2 = Limiting symptoms due to COVID-19, but no need of new or increased oxygen from baseline | 199 Participants |
Primary
Number of Participants With Sustained Recovery
The primary endpoint is the proportion of subjects with sustained recovery, which is defined as being discharged from the index hospitalization, followed by being alive and home for 14 consecutive days prior to Day 90. Home is defined as the level of residence or facility where the participant was residing prior to hospital admission leading to enrollment in this protocol. Readmission from home may occur, and if this occurs within 14 days of the first discharge to home, then the primary endpoint will not be reached until such time as the participant has been at home for 14 consecutive days.
Time frame: Through Day 90
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AZD7442 Plus SOC | Number of Participants With Sustained Recovery | 617 Participants |
| Placebo Plus SOC | Number of Participants With Sustained Recovery | 594 Participants |
Secondary
Number of Participants Who Died From All Causes
All-cause Mortality
Time frame: Through Day 90
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AZD7442 Plus SOC | Number of Participants Who Died From All Causes | 61 Participants |
| Placebo Plus SOC | Number of Participants Who Died From All Causes | 86 Participants |
Secondary
Number of Participants With a Safety Outcome Through Day 28
Safety outcomes are defined as Death, SAE, clinical organ failure, serious infections, or Grade 3 or 4 event through Day 28. Seriousness was based on the definition of the term at 21CFR312.32 AEs were graded for severity by the treating investigator, according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (also known at the DAIDS AE Grading Table), U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1. \[July 2017\]. Available from: https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf). The following generic grading descriptions from the DAIDS AE Grading Table are provided for context: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=potentially life-threatening
Time frame: Through Day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AZD7442 Plus SOC | Number of Participants With a Safety Outcome Through Day 28 | 226 Participants |
| Placebo Plus SOC | Number of Participants With a Safety Outcome Through Day 28 | 250 Participants |
Secondary
Number of Participants With a Safety Outcome Through Day 5
Safety outcomes are defined as Death, SAE, clinical organ failure, serious infections, or Grade 3 or 4 event through Day 5. Seriousness was based on the definition of the term at 21CFR312.32 AEs were graded for severity by the treating investigator, according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (also known at the DAIDS AE Grading Table), U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1. \[July 2017\]. Available from: https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf). The following generic grading descriptions from the DAIDS AE Grading Table are provided for context: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=potentially life-threatening
Time frame: Through Day 5
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AZD7442 Plus SOC | Number of Participants With a Safety Outcome Through Day 5 | 181 Participants |
| Placebo Plus SOC | Number of Participants With a Safety Outcome Through Day 5 | 202 Participants |
Secondary
Number of Participants With a Safety Outcome Through Day 90
Safety outcomes are defined as Death, SAE, clinical organ failure, serious infections, or Grade 3 or 4 event through Day 90. Seriousness was based on the definition of the term at 21CFR312.32 AEs were graded for severity according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (also known at the DAIDS AE Grading Table).
Time frame: Through Day 90
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AZD7442 Plus SOC | Number of Participants With a Safety Outcome Through Day 90 | 179 Participants |
| Placebo Plus SOC | Number of Participants With a Safety Outcome Through Day 90 | 214 Participants |