ACTIV-3b: Therapeutics for Severely Ill Inpatients With COVID-19
- Conditions
- Covid19
- Interventions
- Registration Number
- NCT04843761
- Brief Summary
This study looks at the safety and effectiveness of different drugs 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 either a study drug plus current standard of care (SOC), or with placebo plus current SOC.
Substudy H1: Aviptadil for Severely Ill Inpatients With COVID-19 (NCT06729606)
Substudy H2: Remdesivir for Severely Ill Inpatients With COVID-19 (NCT06729593)
- Detailed Description
This is a master protocol to evaluate the safety and efficacy of investigational agents aimed at improving outcomes for patients with acute respiratory failure related to COVID-19.
Trials within this protocol will be adaptive, randomized, blinded and initially placebo-controlled. Participants will receive standard of care (SOC) treatment as part of the protocol. If an investigational agent shows superiority over placebo, SOC for the study of future investigational agents may be modified accordingly.
The international trials within 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 platform study that allows investigational agents to be added and dropped during the course of the study. This allows for efficient testing of new agents against control within the same trial infrastructure. When more than one agent is being tested concurrently, participants may be randomly allocated across agents (as well as between the agent and its placebo) so the same control group can be shared, when feasible. In some situations, a factorial design may be used to study multiple agents.
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 an investigational agent versus placebo with use of the ordinal outcome. The planned sample size is 640 participants (320 per group) for each investigational agent/placebo. 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.
Investigational agents suitable for testing in the inpatient setting will be prioritized based on in vitro data, preclinical data, Phase 1 pharmacokinetic and safety data, and clinical data from completed and ongoing trials. In some cases, a vanguard cohort/initial pilot phase may be incorporated into the trial.
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 473
- Signed informed consent.
- Requiring admission for inpatient hospital acute medical care for clinical manifestations of COVID-19 (not for purely public health or quarantine purposes).
- Current respiratory failure (i.e. receipt of high-flow nasal cannula, non-invasive ventilation, invasive mechanical ventilation, or ECMO used to treat acute hypoxemic respiratory failure).
- SARS-CoV-2 (COVID-19) infection, documented by a nucleic acid test (NAT) or equivalent testing with most recent rest within 14 days prior to randomization.
- Respiratory failure is believed to be due to SARS-CoV-2 pneumonia.
- Known allergy to investigational agent or vehicle.
- More than 4 days since initiation of support for respiratory failure.
- Chronic/home mechanical ventilation (invasive or non-invasive) for chronic lung or neuromuscular disease (non-invasive ventilation used solely for sleep-disordered breathing is not an exclusion).
- Moribund patient (i.e. not expected to survive 24 hours).
- Active use of "comfort care" or other hospice-equivalent SOC.
- Expected inability to participate in study procedures.
- In the opinion of the investigator, any condition for which, participation would not be in the best interest of the participant or that could limit protocol-specified assessments.
- Previous enrollment in TESICO
Additional agent-specific criteria also apply, and are listed in the substudy records Substudy H1: Aviptadil for Severely Ill Inpatients With COVID-19 (NCT06729606) Substudy H2: Remdesivir for Severely Ill Inpatients With COVID-19 (NCT06729593)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Stratum 1 - Aviptadil + Remdesivir + SOC Remdesivir Eligible for both Aviptadil and Remdesivir and no prior use of Remdesivir Participants enrolled in Stratum 1 were analyzed in both substudies (H1: NCT06729606; H2: NCT06729593) Stratum 1 - Aviptadil + Remdesivir + SOC Aviptadil Eligible for both Aviptadil and Remdesivir and no prior use of Remdesivir Participants enrolled in Stratum 1 were analyzed in both substudies (H1: NCT06729606; H2: NCT06729593) Stratum 1 - Aviptadil + Remdesivir + SOC Corticosteroid Eligible for both Aviptadil and Remdesivir and no prior use of Remdesivir Participants enrolled in Stratum 1 were analyzed in both substudies (H1: NCT06729606; H2: NCT06729593) Stratum 1 - Aviptadil + Remdesivir Placebo + SOC Remdesivir Placebo Eligible for both Aviptadil and Remdesivir and no prior use of Remdesivir Participants enrolled in Stratum 1 were analyzed in both substudies (H1: NCT06729606; H2: NCT06729593) Stratum 1 - Aviptadil + Remdesivir Placebo + SOC Aviptadil Eligible for both Aviptadil and Remdesivir and no prior use of Remdesivir Participants enrolled in Stratum 1 were analyzed in both substudies (H1: NCT06729606; H2: NCT06729593) Stratum 1 - Aviptadil + Remdesivir Placebo + SOC Corticosteroid Eligible for both Aviptadil and Remdesivir and no prior use of Remdesivir Participants enrolled in Stratum 1 were analyzed in both substudies (H1: NCT06729606; H2: NCT06729593) Stratum 1 - Aviptadil Placebo + Remdesivir + SOC Remdesivir Eligible for both Aviptadil and Remdesivir and no prior use of Remdesivir Participants enrolled in Stratum 1 were analyzed in both substudies (H1: NCT06729606; H2: NCT06729593) Stratum 1 - Aviptadil Placebo + Remdesivir + SOC Aviptadil Placebo Eligible for both Aviptadil and Remdesivir and no prior use of Remdesivir Participants enrolled in Stratum 1 were analyzed in both substudies (H1: NCT06729606; H2: NCT06729593) Stratum 1 - Aviptadil Placebo + Remdesivir + SOC Corticosteroid Eligible for both Aviptadil and Remdesivir and no prior use of Remdesivir Participants enrolled in Stratum 1 were analyzed in both substudies (H1: NCT06729606; H2: NCT06729593) Stratum 1 - Aviptadil Placebo + Remdesivir Placebo + SOC Remdesivir Placebo Eligible for both Aviptadil and Remdesivir and no prior use of Remdesivir Participants enrolled in Stratum 1 were analyzed in both substudies (H1: NCT06729606; H2: NCT06729593) Stratum 1 - Aviptadil Placebo + Remdesivir Placebo + SOC Aviptadil Placebo Eligible for both Aviptadil and Remdesivir and no prior use of Remdesivir Participants enrolled in Stratum 1 were analyzed in both substudies (H1: NCT06729606; H2: NCT06729593) Stratum 1 - Aviptadil Placebo + Remdesivir Placebo + SOC Corticosteroid Eligible for both Aviptadil and Remdesivir and no prior use of Remdesivir Participants enrolled in Stratum 1 were analyzed in both substudies (H1: NCT06729606; H2: NCT06729593) Stratum 2 - Aviptadil + SOC Aviptadil Eligible for Aviptadil and Remdesivir contraindicated * Contraindications: eGFR less than 30 or ALT/AST greater than 10x the upper limit of normal Participants enrolled in this arm were analyzed in substudy H1 (NCT06729606) Stratum 2 - Aviptadil + SOC Corticosteroid Eligible for Aviptadil and Remdesivir contraindicated * Contraindications: eGFR less than 30 or ALT/AST greater than 10x the upper limit of normal Participants enrolled in this arm were analyzed in substudy H1 (NCT06729606) Stratum 2 - Aviptadil Placebo + SOC Aviptadil Placebo Eligible for Aviptadil and Remdesivir contraindicated * Contraindications: eGFR less than 30 or ALT/AST greater than 10x the upper limit of normal Participants enrolled in this arm were analyzed in substudy H1 (NCT06729606) Stratum 2 - Aviptadil Placebo + SOC Corticosteroid Eligible for Aviptadil and Remdesivir contraindicated * Contraindications: eGFR less than 30 or ALT/AST greater than 10x the upper limit of normal Participants enrolled in this arm were analyzed in substudy H1 (NCT06729606) Stratum 3 - Remdesivir + SOC Remdesivir Eligible for Remdesivir and Aviptadil contraindicated * Contraindications: refractory hypotension (norepinephrine equivalent greater than or equal to 0.1 mcg/kg/min), severe diarrhea, end-stage liver disease, c-diff infection Participants enrolled in this arm were analyzed in substudy H2 (NCT06729593) Stratum 3 - Remdesivir + SOC Corticosteroid Eligible for Remdesivir and Aviptadil contraindicated * Contraindications: refractory hypotension (norepinephrine equivalent greater than or equal to 0.1 mcg/kg/min), severe diarrhea, end-stage liver disease, c-diff infection Participants enrolled in this arm were analyzed in substudy H2 (NCT06729593) Stratum 3 - Remdesivir Placebo + SOC Remdesivir Placebo Eligible for Remdesivir and Aviptadil contraindicated * Contraindications: refractory hypotension (norepinephrine equivalent greater than or equal to 0.1 mcg/kg/min), severe diarrhea, end-stage liver disease, c-diff infection Participants enrolled in this arm were analyzed in substudy H2 (NCT06729593) Stratum 3 - Remdesivir Placebo + SOC Corticosteroid Eligible for Remdesivir and Aviptadil contraindicated * Contraindications: refractory hypotension (norepinephrine equivalent greater than or equal to 0.1 mcg/kg/min), severe diarrhea, end-stage liver disease, c-diff infection Participants enrolled in this arm were analyzed in substudy H2 (NCT06729593) Stratum 4 - Aviptadil + SOC Aviptadil Eligible for Aviptadil and prior/current use of Remdesivir Participants enrolled in this arm were analyzed in substudy H1 (NCT06729606) Stratum 4 - Aviptadil + SOC Corticosteroid Eligible for Aviptadil and prior/current use of Remdesivir Participants enrolled in this arm were analyzed in substudy H1 (NCT06729606) Stratum 4 - Aviptadil Placebo + SOC Aviptadil Placebo Eligible for Aviptadil and prior/current use of Remdesivir Participants enrolled in this arm were analyzed in substudy H1 (NCT06729606) Stratum 4 - Aviptadil Placebo + SOC Corticosteroid Eligible for Aviptadil and prior/current use of Remdesivir Participants enrolled in this arm were analyzed in substudy H1 (NCT06729606)
- Primary Outcome Measures
Name Time Method Substudy Analysis Cohorts Screening, within 24 hours The primary analysis for each agent was to pool across applicable groups to compare each agent vs. matched placebo. Refer to the agent-specific records for results by agent (H1 \[Aviptadil\]: NCT06729606; H2 \[Remdesivir\]: NCT06729593).
- Secondary Outcome Measures
Name Time Method
Related Research Topics
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Trial Locations
- Locations (40)
Cleveland Clinic Fairview Hospital (Site 207-005), 18101 Lorain Ave.
🇺🇸Cleveland, Ohio, United States
Banner University Medical Center Tucson (Site 206-004), 1625 N. Campbell Avenue
🇺🇸Tucson, Arizona, United States
UCSF Fresno (Site 203-005), 155 N. Fresno Street
🇺🇸Fresno, California, United States
VA Loma Linda Healthcare System (Site 074-017), 11201 Benton Street
🇺🇸Loma Linda, California, United States
Cedars-Sinai Medical Center (Site 208-002), 8700 Beverly Boulevard
🇺🇸Los Angeles, California, United States
Ronald Reagan UCLA Medical Center (Site 203-002), 757 Westwood Plaza
🇺🇸Los Angeles, California, United States
UCSF Medical Center at Mount Zion (Site 203-007), 1600 Divisadero St.
🇺🇸San Francisco, California, United States
UCSF Medical Center (Site 203-001), Moffit-Long Hospital, 505 Parnassus Ave.
🇺🇸San Francisco, California, United States
Stanford University Hospital & Clinics (Site 203-003), 300 Pasteur Dr.
🇺🇸Stanford, California, United States
University of Colorado Hospital (Site 204-001), 12605 E. 16th Avenue
🇺🇸Aurora, Colorado, United States
Scroll for more (30 remaining)Cleveland Clinic Fairview Hospital (Site 207-005), 18101 Lorain Ave.🇺🇸Cleveland, Ohio, United States