Clinical trial NCT04843761: ACTIV-3b: Therapeutics for Severely Ill Inpatients With COVID-19
Official title: A Multicenter, Adaptive, Randomized, Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for Hospitalized Patients With Acute Respiratory Distress Syndrome Associated With COVID-19
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Covid19
Keywords: COVID-19
COVID 19
Coronaviridae Infections
Coronavirus Infections
RNA Virus Infections
Virus Diseases
Nidovirales Infections
SARS-CoV-2
SARS Coronavirus
ACTIV-3
ACTIV3
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)
name: University of Copenhagen
name: Medical Research Council
name: Kirby Institute
name: Washington D.C. Veterans Affairs Medical Center
name: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
name: National Heart, Lung, and Blood Institute (NHLBI)
name: US Department of Veterans Affairs
name: Prevention and Early Treatment of Acute Lung Injury
name: Cardiothoracic Surgical Trials Network
name: NeuroRx, Inc.
name: Gilead Sciences
First posted: 2021-04-14
Enrollment: 473
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 III platform study that allows investigational drugs to be added and dropped during the course of the study. This allows for efficient testing of new drugs 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 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 I 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.

Eligibility criteria: Inclusion Criteria:

* Signed informed consent.
* Requiring admission to hospital for acute medical care (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 (extracorporeal membrane oxygenation) 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.

Exclusion Criteria:

* 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 standard of care.
* 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

Agent-specific exclusion criteria

* Prior receipt of any dose of remdesivir during present illness (remdesivir agent).
* GFR (glomerular filtration rate) \< 30 ml/min and not receiving dialysis (remdesivir agent).
* ALT (alanine aminotransferase) or AST (aspartate aminotransferase) \> 10 times upper limit of normal (remdesivir agent).
* Unwillingness to commit to avoid sex that may result in pregnancy for at least 7 days after completion of remdesivir vs. placebo (remdesivir agent).
* Refractory hypotension (aviptadil agent).
* Severe diarrhea (Aviptadil agent).
* Current C. difficile infection (aviptadil agent).
* Pregnancy or current breast-feeding (aviptadil agent).
* End-stage liver disease (aviptadil agent).

Primary outcomes:
measure: Recovery, assessed at 90 days
timeFrame: Thru Day 90
Secondary outcomes:
measure: All-cause mortality
timeFrame: Thru Day 90
measure: Time to death
timeFrame: Thru Day 90
measure: Composite of time to recovery, days at home off new supplemental oxygen and time to death
timeFrame: Thru Day 90
measure: Composite of alive, at home and off new supplemental oxygen
timeFrame: Thru Day 90
measure: Composite of recovered, alive and not recovered, and dead
timeFrame: Thru Day 90
measure: Time from randomization to recovery
timeFrame: Thru Day 90
measure: Days alive outside short-term acute care hospital
timeFrame: Up to Day 90
measure: Incidence of clinical organ failure or serious infections
timeFrame: Thru Day 28
measure: Composite of death, clinical organ failure or serious infections
timeFrame: Thru Day 90
measure: Composite of cardiovascular events and thromboembolic events
timeFrame: Thru Day 28
measure: Composite of cardiovascular events and thromboembolic events
timeFrame: Thru Day 90
measure: Composite of grade 3 and 4 clinical adverse events, serious adverse events (SAEs) or death
timeFrame: Thru Days 5 and 28
measure: Incidence of infusion reactions
timeFrame: Thru Day 180
measure: Percentage of participants for whom infusion was interrupted or stopped prior to completion for any reason
timeFrame: Thru Day 90
measure: Percentage of participants for whom infusion was interrupted or stopped prior to completion due to adverse event
timeFrame: Thru Day 90
measure: Composite of hospital readmissions or death
timeFrame: Thru Day 180
measure: Incidence of no home use of supplemental oxygen above pre-morbid oxygen use
timeFrame: 14 days
measure: Time to hospital discharge from initial hospitalization
timeFrame: Thru Day 180
measure: Composite of death or serious clinical COVID-19 related events
timeFrame: Thru Day 90
measure: Pulmonary ordinal outcome
timeFrame: Days 1-7, 14 and 28
measure: Composite of SAEs or death
timeFrame: Thru Day 180
measure: Incidence of home use of supplemental oxygen above pre-morbid oxygen use
timeFrame: Thru Day 180
measure: In category 4, 5 or 6 at Day 90 vs. in categories 1-3 at Day 90
timeFrame: Day 90
measure: In category 5 or 6 at Day 90 vs. in categories 1-4 at Day 90
timeFrame: Day 90
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Banner University Medical Center Tucson (Site 206-004), 1625 N. Campbell Avenue
state: Arizona
city: Fresno
country: United States
facility: UCSF Fresno (Site 203-005), 155 N. Fresno Street
state: California
city: Loma Linda
country: United States
facility: VA Loma Linda Healthcare System (Site 074-017), 11201 Benton Street
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center (Site 208-002), 8700 Beverly Boulevard
state: California
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center (Site 203-002), 757 Westwood Plaza
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center at Mount Zion (Site 203-007), 1600 Divisadero St.
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center (Site 203-001), Moffit-Long Hospital, 505 Parnassus Ave.
state: California
city: Stanford
country: United States
facility: Stanford University Hospital & Clinics (Site 203-003), 300 Pasteur Dr.
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital (Site 204-001), 12605 E. 16th Avenue
state: Colorado
city: Denver
country: United States
facility: Denver Health Medical Center (Site 204-004), 780 Delaware Street, Pavilion B
state: Colorado
city: Washington
country: United States
facility: MedStar Health Research Institute (Site 009-021), 110 Irving St., NW.
state: District of Columbia
city: Washington
country: United States
facility: Washington DC VA Medical Center (Site 009-004), 50 Irving Street, NW.
state: District of Columbia
city: Atlanta
country: United States
facility: Emory University (Site 301-008), Bldg. A, Suite 2236, 1365 Clifton Rd., NE.
state: Georgia
city: Boston
country: United States
facility: Massachusetts General Hospital (Site 202-002), 55 Fruit Street
state: Massachusetts
city: Springfield
country: United States
facility: Baystate Medical Center (Site 201-001), Critical Care Research, 759 Chestnut Street
state: Massachusetts
city: Bronx
country: United States
facility: Montefiore Medical Center - Moses Hospital (Site 206-001), 111 E. 210th Street
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center - Weiler campus (Site 206-003), 111 E. 210th Street
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center (Site 301-012), Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place
state: New York
city: New York
country: United States
facility: Columbia University Irving Medical Center (Site 301-027), 177 Fort Washington Ave.
state: New York
city: Durham
country: United States
facility: Duke University Hospital (Site 301-006), 2301 Erwin Road
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health (Site 210-001), Medical Center Blvd
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center (Site 207-003), 234 Goodman Street, ML 0740
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Fairview Hosptial (Site 207-005), 18101 Lorain Ave.
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation (Site 207-001), 9500 Euclid Ave.
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center (Site 207-004), 410 W. 10th Avenue
state: Ohio
city: Garfield Heights
country: United States
facility: Cleveland Clinic Marymount Campus (Site 207-006), 12300 McCracken Road
state: Ohio
city: Mayfield Heights
country: United States
facility: Cleveland Clinic Hillcrest Hospital (Site 207-007), 6780 Mayfield Road
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University (Site 208-003), 3181 SW Sam Jackson Park Rd.
state: Oregon
city: Charleston
country: United States
facility: Medical University of South Carolina (Site 210-002), 96 Jonathan Lucas St., CSB 214
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center (Site 212-001), 1211 Medical Center Drive
state: Tennessee
city: Dallas
country: United States
facility: Baylor, Scott and White Health (Site 301-003), Baylor University Medical Center, 3500 Gaston Ave.
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital (Site 301-028), 6565 Fannin Street
state: Texas
city: Houston
country: United States
facility: Texas Heart Institute (Site 301-017), 6770 Bertner, MC4-266
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center (Site 203-006), 7000 Fannin St.
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center (Site 211-001), 5121 South Cottonwood Street
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah Hospital (Site 211-002), 50 North Medical Drive
state: Utah
city: Charlottesville
country: United States
facility: UVA School of Medicine (Site 210-003), University of Virginia Health System, University Hospital, 1215 Lee St.
state: Virginia
city: Seattle
country: United States
facility: Harborview Medical Center (Site 208-001), 325 9th Ave.
state: Washington
city: Seattle
country: United States
facility: Swedish Medical Center (Site 208-005), 747 Broadway
state: Washington
city: Morgantown
country: United States
facility: West Virginia University Medicine (Site 301-023), One Medical Center Drive
state: West Virginia
Study officials:
affiliation: Intermountain Medical Center/University of Utah
name: Samuel Brown, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: INSIGHT Statistical and Coordinating Centre, University of Minnesota
name: Prof. James Neaton
role: STUDY_CHAIR
References: