ACTIV-3b: Therapeutics for Severely Ill Inpatients With COVID-19

Covid19 Clinical Trial

— TESICO  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04843761
• Other study ID #: 015 / ACTIV-3b
• Status: Completed
• Phase: Phase 3
• Start date: April 20, 2021
• Est. completion date: November 20, 2022

Study information

• Verified date: May 2023
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 473
• Est. completion date: November 20, 2022
• Est. primary completion date: August 22, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• COVID-19
• Covid19

Intervention

Biological:
• Remdesivir
Administered by IV infusion, daily for 10 days. Initial loading dose is 200 mg with all subsequent doses 100 mg.

Drug:
• Remdesivir Placebo
Commercially available 0.9% sodium chloride solution. Administered by IV infusion daily for 10 days.

Biological:
• Aviptadil
Administered by IV infusion over 12 hours per day for 3 days. Participants are no longer being randomized to this intervention.

Drug:
• 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.

Locations

Country	Name	City	State
United States	Emory University (Site 301-008), Bldg. A, Suite 2236, 1365 Clifton Rd., NE.	Atlanta	Georgia
United States	University of Colorado Hospital (Site 204-001), 12605 E. 16th Avenue	Aurora	Colorado
United States	Massachusetts General Hospital (Site 202-002), 55 Fruit Street	Boston	Massachusetts
United States	Montefiore Medical Center - Moses Hospital (Site 206-001), 111 E. 210th Street	Bronx	New York
United States	Montefiore Medical Center - Weiler campus (Site 206-003), 111 E. 210th Street	Bronx	New York
United States	Medical University of South Carolina (Site 210-002), 96 Jonathan Lucas St., CSB 214	Charleston	South Carolina
United States	UVA School of Medicine (Site 210-003), University of Virginia Health System, University Hospital, 1215 Lee St.	Charlottesville	Virginia
United States	University of Cincinnati Medical Center (Site 207-003), 234 Goodman Street, ML 0740	Cincinnati	Ohio
United States	Cleveland Clinic Fairview Hosptial (Site 207-005), 18101 Lorain Ave.	Cleveland	Ohio
United States	Cleveland Clinic Foundation (Site 207-001), 9500 Euclid Ave.	Cleveland	Ohio
United States	The Ohio State University Wexner Medical Center (Site 207-004), 410 W. 10th Avenue	Columbus	Ohio
United States	Baylor, Scott and White Health (Site 301-003), Baylor University Medical Center, 3500 Gaston Ave.	Dallas	Texas
United States	Denver Health Medical Center (Site 204-004), 780 Delaware Street, Pavilion B	Denver	Colorado
United States	Duke University Hospital (Site 301-006), 2301 Erwin Road	Durham	North Carolina
United States	UCSF Fresno (Site 203-005), 155 N. Fresno Street	Fresno	California
United States	Cleveland Clinic Marymount Campus (Site 207-006), 12300 McCracken Road	Garfield Heights	Ohio
United States	Houston Methodist Hospital (Site 301-028), 6565 Fannin Street	Houston	Texas
United States	Texas Heart Institute (Site 301-017), 6770 Bertner, MC4-266	Houston	Texas
United States	University of Texas Health Science Center (Site 203-006), 7000 Fannin St.	Houston	Texas
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	Cleveland Clinic Hillcrest Hospital (Site 207-007), 6780 Mayfield Road	Mayfield Heights	Ohio
United States	West Virginia University Medicine (Site 301-023), One Medical Center Drive	Morgantown	West Virginia
United States	Intermountain Medical Center (Site 211-001), 5121 South Cottonwood Street	Murray	Utah
United States	Vanderbilt University Medical Center (Site 212-001), 1211 Medical Center Drive	Nashville	Tennessee
United States	Columbia University Irving Medical Center (Site 301-027), 177 Fort Washington Ave.	New York	New York
United States	Mount Sinai Medical Center (Site 301-012), Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place	New York	New York
United States	Oregon Health & Science University (Site 208-003), 3181 SW Sam Jackson Park Rd.	Portland	Oregon
United States	University of Utah Hospital (Site 211-002), 50 North Medical Drive	Salt Lake City	Utah
United States	UCSF Medical Center (Site 203-001), Moffit-Long Hospital, 505 Parnassus Ave.	San Francisco	California
United States	UCSF Medical Center at Mount Zion (Site 203-007), 1600 Divisadero St.	San Francisco	California
United States	Harborview Medical Center (Site 208-001), 325 9th Ave.	Seattle	Washington
United States	Swedish Medical Center (Site 208-005), 747 Broadway	Seattle	Washington
United States	Baystate Medical Center (Site 201-001), Critical Care Research, 759 Chestnut Street	Springfield	Massachusetts
United States	Stanford University Hospital & Clinics (Site 203-003), 300 Pasteur Dr.	Stanford	California
United States	Banner University Medical Center Tucson (Site 206-004), 1625 N. Campbell Avenue	Tucson	Arizona
United States	MedStar Health Research Institute (Site 009-021), 110 Irving St., NW.	Washington	District of Columbia
United States	Washington DC VA Medical Center (Site 009-004), 50 Irving Street, NW.	Washington	District of Columbia
United States	Wake Forest Baptist Health (Site 210-001), Medical Center Blvd	Winston-Salem	North Carolina

Sponsors (13)

Lead Sponsor

Collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

AIDS Clinical Trials Group, Cardiothoracic Surgical Trials Network (CTSN), Gilead Sciences, International Network for Strategic Initiatives in Global HIV Trials (INSIGHT), Kirby Institute, Medical Research Council, National Heart, Lung, and Blood Institute (NHLBI), NeuroRx, Inc., Prevention and Early Treatment of Acute Lung Injury (PETAL), University of Copenhagen, US Department of Veterans Affairs, Washington D.C. Veterans Affairs Medical Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Recovery, assessed at 90 days	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.	Thru Day 90
Secondary	All-cause mortality		Thru Day 90
Secondary	Time to death		Thru Day 90
Secondary	Composite of time to recovery, days at home off new supplemental oxygen and time to death	Measured in number of days	Thru Day 90
Secondary	Composite of alive, at home and off new supplemental oxygen		Thru Day 90
Secondary	Composite of recovered, alive and not recovered, and dead	Recovery defined as alive, at home and off new supplemental oxygen	Thru Day 90
Secondary	Time from randomization to recovery	Recovery defined as alive, at home and off oxygen (treating death as competing risk)	Thru Day 90
Secondary	Days alive outside short-term acute care hospital	Using "last off" method.	Up to Day 90
Secondary	Incidence of clinical organ failure or serious infections	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
Secondary	Composite of death, clinical organ failure or serious infections		Thru Day 90
Secondary	Composite of cardiovascular events and thromboembolic events		Thru Day 28
Secondary	Composite of cardiovascular events and thromboembolic events		Thru Day 90
Secondary	Composite of grade 3 and 4 clinical adverse events, serious adverse events (SAEs) or death		Thru Days 5 and 28
Secondary	Incidence of infusion reactions		Thru Day 180
Secondary	Percentage of participants for whom infusion was interrupted or stopped prior to completion for any reason		Thru Day 90
Secondary	Percentage of participants for whom infusion was interrupted or stopped prior to completion due to adverse event		Thru Day 90
Secondary	Composite of hospital readmissions or death		Thru Day 180
Secondary	Incidence of no home use of supplemental oxygen above pre-morbid oxygen use	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
Secondary	Time to hospital discharge from initial hospitalization		Thru Day 180
Secondary	Composite of death or serious clinical COVID-19 related events		Thru Day 90
Secondary	Pulmonary ordinal outcome	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
Secondary	Composite of SAEs or death		Thru Day 180
Secondary	Incidence of home use of supplemental oxygen above pre-morbid oxygen use	Measured as: Alive at home and no use of continuous supplemental oxygen for an uninterrupted 14 day period	Thru Day 180
Secondary	In category 4, 5 or 6 at Day 90 vs. in categories 1-3 at 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
Secondary	In category 5 or 6 at Day 90 vs. in categories 1-4 at 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

External Links

•   A Participant's Guide to Clinical Trials (NIAID)
•   CDC (Centers for Disease Control and Prevention): Coronavirus (COVID-19) website
•   Clinical Trials at NIAID
•   FDA Safety Alerts and Recalls
•   Find a Clinical Trial (NIAID)
•   National Institute for Allergy and Infectious Diseases (NIAID)
•   NIH COVID-19 treatment guidelines
•   WHO COVID-19 treatment guidelines