Covid19
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
Brief summary
This study looks at the safety and effectiveness of Aviptadil 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 Aviptadil plus current standard of care (SOC), or with placebo plus current SOC.
Detailed description
This is a treatment trial of the ACTIV-3b/TESICO master protocol (NCT04843761) to evaluate the safety and efficacy of Aviptadil at improving outcomes for patients with acute respiratory failure related to COVID-19. This protocol will be adaptive, randomized, blinded and initially placebo-controlled. Participants will receive standard of care (SOC) treatment as part of the protocol. 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 3 study. 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 Aviptadil versus placebo with use of the ordinal outcome. The planned sample size is 320 participants. 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 (extracorporeal membrane oxygenation) at enrollment. Other agent-specific stratification factors may be considered. 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.
Interventions
BIOLOGICALAviptadil
Administered by IV infusion over 12 hours per day for 3 days. The Day 1 infusion rate is 50 pmol/kg/hr, the Day 2 infusion rate is 100 pmol/kg/hr, and the Day 3 infusion rate is 150 pmol/kg/hr.
BIOLOGICALAviptadil Placebo
Commercially available 0.9% sodium chloride solution. Administered by IV infusion over 12 hours per day for 3 days.
DRUGCorticosteroid
In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC.
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
US Department of Veterans Affairs
Prevention and Early Treatment of Acute Lung Injury (PETAL) Network
NeuroRx, Inc.
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 (NCT04843761)
Exclusion criteria
Refer to the master protocol (NCT04843761) Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a 6-category Primary Ordinal Outcome (Recovery) at Day 90 | Status on Day 90 | The primary outcome was a 6-category ordinal outcome defining the participant's status at Day 90: (1) at home (defined as the type of residence before hospitalization) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalized but either on supplemental oxygen or not at home, (5) hospitalized or in hospice care, or (6) dead. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Died Through Day 90 | Through Day 90 | — |
| Number of Participants With a Safety Outcome Through Day 5 | Through Day 5 | Composite safety outcome of a serious adverse event, Grade 3/4 adverse event, organ failure/serious infection, or death through Day 5 |
| Number of Participants With a Safety Outcome Through Day 28 | Through Day 28 | Composite safety outcome of a serious adverse event, Grade 3/4 adverse event, organ failure/serious infection, or death through Day 28 |
| Number of Participants Who Died Through Day 180 | Through Day 180 | — |
Countries
United States
Participant flow
Recruitment details
This substudy presents analysis for Aviptadil vs Aviptadil Placebo. Per protocol, this comparison was conducted among the pooled cohort of participants who were randomized to receive Active Aviptadil or Aviptadil Placebo within randomization strata 1, 2, and 4 of the master protocol.
Participants by arm
| Arm | Count |
|---|---|
| Aviptadil + SOC Arm includes all participants who received Aviptadil, and were randomized under strata 1, 2, and 4 from the master protocol (NCT04843761)
Aviptadil: Administered by IV infusion over 12 hours per day for 3 days. The Day 1 infusion rate is 50 pmol/kg/hr, the Day 2 infusion rate is 100 pmol/kg/hr, and the Day 3 infusion rate is 150 pmol/kg/hr.
Corticosteroid: In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC. | 231 |
| Placebo + SOC Arm includes all participants who received Aviptadil Placebo, and were randomized under strata 1, 2, and 4 from the master protocol (NCT04843761)
Aviptadil Placebo: Commercially available 0.9% sodium chloride solution. Administered by IV infusion over 12 hours per day for 3 days.
Corticosteroid: In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC. | 230 |
| Total | 461 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 4 |
Baseline characteristics
| Characteristic | Aviptadil + SOC | Placebo + SOC | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 75 Participants | 69 Participants | 144 Participants |
| Age, Categorical Between 18 and 65 years | 156 Participants | 161 Participants | 317 Participants |
| Age, Continuous | 56.6 years STANDARD_DEVIATION 14.7 | 56.2 years STANDARD_DEVIATION 15.1 | 56.4 years STANDARD_DEVIATION 14.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 62 Participants | 58 Participants | 120 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 169 Participants | 172 Participants | 341 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 2 Participants | 5 Participants | 7 Participants |
| Race/Ethnicity, Customized Race Asian | 7 Participants | 10 Participants | 17 Participants |
| Race/Ethnicity, Customized Race Black or African American | 40 Participants | 33 Participants | 73 Participants |
| Race/Ethnicity, Customized Race More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Pacific Islander | 3 Participants | 3 Participants | 6 Participants |
| Race/Ethnicity, Customized Race Only ethnicity (race unknown) | 40 Participants | 36 Participants | 76 Participants |
| Race/Ethnicity, Customized Race Other | 16 Participants | 11 Participants | 27 Participants |
| Race/Ethnicity, Customized Race White | 123 Participants | 132 Participants | 255 Participants |
| Sex: Female, Male Female | 94 Participants | 84 Participants | 178 Participants |
| Sex: Female, Male Male | 137 Participants | 146 Participants | 283 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 90 / 231 | 86 / 230 |
| other Total, other adverse events | 200 / 231 | 176 / 230 |
| serious Total, serious adverse events | 25 / 231 | 23 / 230 |
Outcome results
Primary
Number of Participants With a 6-category Primary Ordinal Outcome (Recovery) at Day 90
The primary outcome was a 6-category ordinal outcome defining the participant's status at Day 90: (1) at home (defined as the type of residence before hospitalization) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalized but either on supplemental oxygen or not at home, (5) hospitalized or in hospice care, or (6) dead.
Time frame: Status on Day 90
Population: 6 participants in the Aviptadil+SOC arm and 5 participants in the Placebo+SOC arm did not have the day 90 status available to compute the primary endpoint. These participants were excluded from the analysis.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aviptadil + SOC | Number of Participants With a 6-category Primary Ordinal Outcome (Recovery) at Day 90 | category 3 = at home and off oxygen for 1-48 days | 43 Participants |
| Aviptadil + SOC | Number of Participants With a 6-category Primary Ordinal Outcome (Recovery) at Day 90 | category 1 = at home and off oxygen (recovered) for at least 77 days | 36 Participants |
| Aviptadil + SOC | Number of Participants With a 6-category Primary Ordinal Outcome (Recovery) at Day 90 | category 2 = at home and off oxygen for 49-76 days | 37 Participants |
| Aviptadil + SOC | Number of Participants With a 6-category Primary Ordinal Outcome (Recovery) at Day 90 | category 4 = not hospitalized but either on supplemental oxygen or not at home | 15 Participants |
| Aviptadil + SOC | Number of Participants With a 6-category Primary Ordinal Outcome (Recovery) at Day 90 | category 5 = hospitalized or in hospice care | 8 Participants |
| Aviptadil + SOC | Number of Participants With a 6-category Primary Ordinal Outcome (Recovery) at Day 90 | category 6 = died | 86 Participants |
| Placebo + SOC | Number of Participants With a 6-category Primary Ordinal Outcome (Recovery) at Day 90 | category 5 = hospitalized or in hospice care | 13 Participants |
| Placebo + SOC | Number of Participants With a 6-category Primary Ordinal Outcome (Recovery) at Day 90 | category 4 = not hospitalized but either on supplemental oxygen or not at home | 31 Participants |
| Placebo + SOC | Number of Participants With a 6-category Primary Ordinal Outcome (Recovery) at Day 90 | category 1 = at home and off oxygen (recovered) for at least 77 days | 31 Participants |
| Placebo + SOC | Number of Participants With a 6-category Primary Ordinal Outcome (Recovery) at Day 90 | category 6 = died | 83 Participants |
| Placebo + SOC | Number of Participants With a 6-category Primary Ordinal Outcome (Recovery) at Day 90 | category 2 = at home and off oxygen for 49-76 days | 35 Participants |
| Placebo + SOC | Number of Participants With a 6-category Primary Ordinal Outcome (Recovery) at Day 90 | category 3 = at home and off oxygen for 1-48 days | 32 Participants |
p-value: 0.5495% CI: [0.8, 1.55]Proportional odds model
Secondary
Number of Participants Who Died Through Day 180
Time frame: Through Day 180
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aviptadil + SOC | Number of Participants Who Died Through Day 180 | 90 Participants |
| Placebo + SOC | Number of Participants Who Died Through Day 180 | 86 Participants |
p-value: 0.7195% CI: [0.79, 1.42]Cox proportional hazards model
Secondary
Number of Participants Who Died Through Day 90
Time frame: Through Day 90
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aviptadil + SOC | Number of Participants Who Died Through Day 90 | 86 Participants |
| Placebo + SOC | Number of Participants Who Died Through Day 90 | 83 Participants |
p-value: 0.7895% CI: [0.77, 1.41]Cox proportional hazards model
Secondary
Number of Participants With a Safety Outcome Through Day 28
Composite safety outcome of a serious adverse event, Grade 3/4 adverse event, organ failure/serious infection, or death through Day 28
Time frame: Through Day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aviptadil + SOC | Number of Participants With a Safety Outcome Through Day 28 | 181 Participants |
| Placebo + SOC | Number of Participants With a Safety Outcome Through Day 28 | 172 Participants |
p-value: 0.1595% CI: [0.95, 1.44]Cox proportional hazards model
Secondary
Number of Participants With a Safety Outcome Through Day 5
Composite safety outcome of a serious adverse event, Grade 3/4 adverse event, organ failure/serious infection, or death through Day 5
Time frame: Through Day 5
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aviptadil + SOC | Number of Participants With a Safety Outcome Through Day 5 | 146 Participants |
| Placebo + SOC | Number of Participants With a Safety Outcome Through Day 5 | 129 Participants |
p-value: 0.195% CI: [0.94, 2.08]Regression, Logistic