- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04843761
ACTIV-3b: Therapeutics for Severely Ill Inpatients With COVID-19 (TESICO)
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 Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
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Arizona
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Tucson, Arizona, United States, 85719
- Banner University Medical Center Tucson (Site 206-004), 1625 N. Campbell Avenue
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California
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Fresno, California, United States, 93701
- UCSF Fresno (Site 203-005), 155 N. Fresno Street
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Loma Linda, California, United States, 92357
- VA Loma Linda Healthcare System (Site 074-017), 11201 Benton Street
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Los Angeles, California, United States, 90095
- Ronald Reagan UCLA Medical Center (Site 203-002), 757 Westwood Plaza
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Los Angeles, California, United States, 90048
- Cedars-Sinai Medical Center (Site 208-002), 8700 Beverly Boulevard
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San Francisco, California, United States, 94115
- UCSF Medical Center at Mount Zion (Site 203-007), 1600 Divisadero St.
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San Francisco, California, United States, 94143
- UCSF Medical Center (Site 203-001), Moffit-Long Hospital, 505 Parnassus Ave.
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Stanford, California, United States, 94305
- Stanford University Hospital & Clinics (Site 203-003), 300 Pasteur Dr.
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Colorado
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Aurora, Colorado, United States, 80045
- University of Colorado Hospital (Site 204-001), 12605 E. 16th Avenue
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Denver, Colorado, United States, 80204
- Denver Health Medical Center (Site 204-004), 780 Delaware Street, Pavilion B
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District of Columbia
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Washington, District of Columbia, United States, 20010
- MedStar Health Research Institute (Site 009-021), 110 Irving St., NW.
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Washington, District of Columbia, United States, 20422
- Washington DC VA Medical Center (Site 009-004), 50 Irving Street, NW.
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Georgia
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Atlanta, Georgia, United States, 30322
- Emory University (Site 301-008), Bldg. A, Suite 2236, 1365 Clifton Rd., NE.
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Massachusetts
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Boston, Massachusetts, United States, 02114
- Massachusetts General Hospital (Site 202-002), 55 Fruit Street
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Springfield, Massachusetts, United States, 01199
- Baystate Medical Center (Site 201-001), Critical Care Research, 759 Chestnut Street
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New York
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Bronx, New York, United States, 10467
- Montefiore Medical Center - Moses Hospital (Site 206-001), 111 E. 210th Street
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Bronx, New York, United States, 10467
- Montefiore Medical Center - Weiler campus (Site 206-003), 111 E. 210th Street
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New York, New York, United States, 10029
- Mount Sinai Medical Center (Site 301-012), Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place
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New York, New York, United States, 10032
- Columbia University Irving Medical Center (Site 301-027), 177 Fort Washington Ave.
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North Carolina
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Durham, North Carolina, United States, 27710
- Duke University Hospital (Site 301-006), 2301 Erwin Road
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Winston-Salem, North Carolina, United States, 27157
- Wake Forest Baptist Health (Site 210-001), Medical Center Blvd
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Ohio
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Cincinnati, Ohio, United States, 45219
- University of Cincinnati Medical Center (Site 207-003), 234 Goodman Street, ML 0740
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Cleveland, Ohio, United States, 44111
- Cleveland Clinic Fairview Hosptial (Site 207-005), 18101 Lorain Ave.
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Cleveland, Ohio, United States, 44195
- Cleveland Clinic Foundation (Site 207-001), 9500 Euclid Ave.
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Columbus, Ohio, United States, 43210
- The Ohio State University Wexner Medical Center (Site 207-004), 410 W. 10th Avenue
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Garfield Heights, Ohio, United States, 44125
- Cleveland Clinic Marymount Campus (Site 207-006), 12300 McCracken Road
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Mayfield Heights, Ohio, United States, 44124
- Cleveland Clinic Hillcrest Hospital (Site 207-007), 6780 Mayfield Road
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Oregon
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Portland, Oregon, United States, 97239-3098
- Oregon Health & Science University (Site 208-003), 3181 SW Sam Jackson Park Rd.
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South Carolina
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Charleston, South Carolina, United States, 29425
- Medical University of South Carolina (Site 210-002), 96 Jonathan Lucas St., CSB 214
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Tennessee
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Nashville, Tennessee, United States, 37232
- Vanderbilt University Medical Center (Site 212-001), 1211 Medical Center Drive
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Texas
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Dallas, Texas, United States, 75246
- Baylor, Scott and White Health (Site 301-003), Baylor University Medical Center, 3500 Gaston Ave.
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Houston, Texas, United States, 77030
- Texas Heart Institute (Site 301-017), 6770 Bertner, MC4-266
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Houston, Texas, United States, 77030
- Houston Methodist Hospital (Site 301-028), 6565 Fannin Street
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Houston, Texas, United States, 77030
- University of Texas Health Science Center (Site 203-006), 7000 Fannin St.
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Utah
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Murray, Utah, United States, 84107
- Intermountain Medical Center (Site 211-001), 5121 South Cottonwood Street
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Salt Lake City, Utah, United States, 84132
- University of Utah Hospital (Site 211-002), 50 North Medical Drive
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Virginia
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Charlottesville, Virginia, United States, 22908
- UVA School of Medicine (Site 210-003), University of Virginia Health System, University Hospital, 1215 Lee St.
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Washington
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Seattle, Washington, United States, 98104
- Harborview Medical Center (Site 208-001), 325 9th Ave.
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Seattle, Washington, United States, 98122
- Swedish Medical Center (Site 208-005), 747 Broadway
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West Virginia
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Morgantown, West Virginia, United States, 26506
- West Virginia University Medicine (Site 301-023), One Medical Center Drive
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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).
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Aviptadil + Remdesivir + SOC
|
Administered by IV infusion, daily for 10 days.
Initial loading dose is 200 mg with all subsequent doses 100 mg.
Administered by IV infusion over 12 hours per day for 3 days.
Participants are no longer being randomized to this intervention.
Other Names:
In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC.
|
Placebo Comparator: Aviptadil + Remdesivir Placebo + SOC
|
Administered by IV infusion over 12 hours per day for 3 days.
Participants are no longer being randomized to this intervention.
Other Names:
In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC.
Commercially available 0.9% sodium chloride solution.
Administered by IV infusion daily for 10 days.
|
Experimental: Aviptadil Placebo + Remdesivir + SOC
|
Administered by IV infusion, daily for 10 days.
Initial loading dose is 200 mg with all subsequent doses 100 mg.
In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC.
Commercially available 0.9% sodium chloride solution.
Administered by IV infusion over 12 hours per day for 3 days.
|
Experimental: Aviptadil Placebo + Remdesivir Placebo + SOC
|
In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC.
Commercially available 0.9% sodium chloride solution.
Administered by IV infusion daily for 10 days.
Commercially available 0.9% sodium chloride solution.
Administered by IV infusion over 12 hours per day for 3 days.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Recovery, assessed at 90 days
Time Frame: Thru Day 90
|
Recovery categorized as 1 (Best): At home and not receiving new supplemental oxygen for ≥ 77 consecutive days; 2: At home and not receiving new supplemental oxygen for 49-76 consecutive days; 3: At home and not receiving new supplemental oxygen for 1-48 consecutive days; 4: Discharged from hospital but either not yet home or home but receiving new supplemental oxygen; 5: Still hospitalized or receiving hospice care; 6 (Worst): Dead.
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Thru Day 90
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
All-cause mortality
Time Frame: Thru Day 90
|
Thru Day 90
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Pulmonary ordinal outcome
Time Frame: Days 1-7, 14 and 28
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Oxygen requirements measured by 7 categories (1 = least severe, 7 = most severe).
The participant's highest (i.e.
most severe) observed score is used.
|
Days 1-7, 14 and 28
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Composite of death or serious clinical COVID-19 related events
Time Frame: Thru Day 90
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Thru Day 90
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Composite of cardiovascular events and thromboembolic events
Time Frame: Thru Day 90
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Thru Day 90
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Composite of grade 3 and 4 clinical adverse events, serious adverse events (SAEs) or death
Time Frame: Thru Days 5 and 28
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Thru Days 5 and 28
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Incidence of no home use of supplemental oxygen above pre-morbid oxygen use
Time Frame: 14 days
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Measured as: Alive at home for an uninterrupted 14 day period and no use of continuous supplemental oxygen at end of 14 day time period.
|
14 days
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Time to death
Time Frame: Thru Day 90
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Thru Day 90
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Composite of time to recovery, days at home off new supplemental oxygen and time to death
Time Frame: Thru Day 90
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Measured in number of days
|
Thru Day 90
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Composite of alive, at home and off new supplemental oxygen
Time Frame: Thru Day 90
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Thru Day 90
|
|
Composite of recovered, alive and not recovered, and dead
Time Frame: Thru Day 90
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Recovery defined as alive, at home and off new supplemental oxygen
|
Thru Day 90
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Time from randomization to recovery
Time Frame: Thru Day 90
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Recovery defined as alive, at home and off oxygen (treating death as competing risk)
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Thru Day 90
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Days alive outside short-term acute care hospital
Time Frame: Up to Day 90
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Using "last off" method.
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Up to Day 90
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Incidence of clinical organ failure or serious infections
Time Frame: Thru Day 28
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Defined as any one or more of: Worsening respiratory dysfunction; cardiac and vascular dysfunction; renal dysfunction; hepatic dysfunction; neurological dysfunction, haematological dysfunction; serious infection
|
Thru Day 28
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Composite of death, clinical organ failure or serious infections
Time Frame: Thru Day 90
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Thru Day 90
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Composite of cardiovascular events and thromboembolic events
Time Frame: Thru Day 28
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Thru Day 28
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Incidence of infusion reactions
Time Frame: Thru Day 180
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Thru Day 180
|
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Percentage of participants for whom infusion was interrupted or stopped prior to completion for any reason
Time Frame: Thru Day 90
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Thru Day 90
|
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Percentage of participants for whom infusion was interrupted or stopped prior to completion due to adverse event
Time Frame: Thru Day 90
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Thru Day 90
|
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Composite of hospital readmissions or death
Time Frame: Thru Day 180
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Thru Day 180
|
|
Time to hospital discharge from initial hospitalization
Time Frame: Thru Day 180
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Thru Day 180
|
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Composite of SAEs or death
Time Frame: Thru Day 180
|
Thru Day 180
|
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Incidence of home use of supplemental oxygen above pre-morbid oxygen use
Time Frame: Thru Day 180
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Measured as: Alive at home and no use of continuous supplemental oxygen for an uninterrupted 14 day period
|
Thru Day 180
|
In category 4, 5 or 6 at Day 90 vs. in categories 1-3 at Day 90
Time Frame: Day 90
|
Categories are 1 (Best): At home an off oxygen for ≥ 77 consecutive days; 2: At home and off oxygen for 49-76 consecutive days; 3: At home and off oxygen for 1-48 consecutive days; 4: Not hospitalized and either at home on oxygen or not at home; 5: Hospitalized for medical care or in hospice care; 6 (Worst): Dead.
|
Day 90
|
In category 5 or 6 at Day 90 vs. in categories 1-4 at Day 90
Time Frame: Day 90
|
Categories are 1 (Best): At home an off oxygen for ≥ 77 consecutive days; 2: At home and off oxygen for 49-76 consecutive days; 3: At home and off oxygen for 1-48 consecutive days; 4: Not hospitalized and either at home on oxygen or not at home; 5: Hospitalized for medical care or in hospice care; 6 (Worst): Dead.
|
Day 90
|
Collaborators and Investigators
Collaborators
Investigators
- Study Chair: Prof. James Neaton, INSIGHT Statistical and Coordinating Centre, University of Minnesota
- Principal Investigator: Samuel Brown, MD, Intermountain Medical Center/University of Utah
Publications and helpful links
Helpful Links
- FDA Safety Alerts and Recalls
- CDC (Centers for Disease Control and Prevention): Coronavirus (COVID-19) website
- A Participant's Guide to Clinical Trials (NIAID)
- Find a Clinical Trial (NIAID)
- Clinical Trials at NIAID
- National Institute for Allergy and Infectious Diseases (NIAID)
- NIH COVID-19 treatment guidelines
- WHO COVID-19 treatment guidelines
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Coronavirus Infections
- Coronaviridae Infections
- Nidovirales Infections
- RNA Virus Infections
- Virus Diseases
- Infections
- Respiratory Tract Infections
- Respiratory Tract Diseases
- Pneumonia, Viral
- Pneumonia
- Lung Diseases
- COVID-19
- Physiological Effects of Drugs
- Adrenergic Antagonists
- Adrenergic Agents
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Antihypertensive Agents
- Vasodilator Agents
- Anti-Infective Agents
- Antiviral Agents
- Antimetabolites
- Gastrointestinal Agents
- Neuroprotective Agents
- Protective Agents
- Adrenergic alpha-Antagonists
- Remdesivir
- Vasoactive Intestinal Peptide
- Phentolamine
Other Study ID Numbers
- 015 / ACTIV-3b
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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