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

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.

Study Overview

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

Interventional

Enrollment (Actual)

473

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Arizona
      • Tucson, Arizona, United States, 85719
        • Banner University Medical Center Tucson (Site 206-004), 1625 N. Campbell Avenue
    • California
      • Fresno, California, United States, 93701
        • UCSF Fresno (Site 203-005), 155 N. Fresno Street
      • Loma Linda, California, United States, 92357
        • VA Loma Linda Healthcare System (Site 074-017), 11201 Benton Street
      • Los Angeles, California, United States, 90095
        • Ronald Reagan UCLA Medical Center (Site 203-002), 757 Westwood Plaza
      • Los Angeles, California, United States, 90048
        • Cedars-Sinai Medical Center (Site 208-002), 8700 Beverly Boulevard
      • San Francisco, California, United States, 94115
        • UCSF Medical Center at Mount Zion (Site 203-007), 1600 Divisadero St.
      • San Francisco, California, United States, 94143
        • UCSF Medical Center (Site 203-001), Moffit-Long Hospital, 505 Parnassus Ave.
      • Stanford, California, United States, 94305
        • Stanford University Hospital & Clinics (Site 203-003), 300 Pasteur Dr.
    • Colorado
      • Aurora, Colorado, United States, 80045
        • University of Colorado Hospital (Site 204-001), 12605 E. 16th Avenue
      • Denver, Colorado, United States, 80204
        • Denver Health Medical Center (Site 204-004), 780 Delaware Street, Pavilion B
    • District of Columbia
      • Washington, District of Columbia, United States, 20010
        • MedStar Health Research Institute (Site 009-021), 110 Irving St., NW.
      • Washington, District of Columbia, United States, 20422
        • Washington DC VA Medical Center (Site 009-004), 50 Irving Street, NW.
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Emory University (Site 301-008), Bldg. A, Suite 2236, 1365 Clifton Rd., NE.
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital (Site 202-002), 55 Fruit Street
      • Springfield, Massachusetts, United States, 01199
        • Baystate Medical Center (Site 201-001), Critical Care Research, 759 Chestnut Street
    • New York
      • Bronx, New York, United States, 10467
        • Montefiore Medical Center - Moses Hospital (Site 206-001), 111 E. 210th Street
      • Bronx, New York, United States, 10467
        • Montefiore Medical Center - Weiler campus (Site 206-003), 111 E. 210th Street
      • 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
      • New York, New York, United States, 10032
        • Columbia University Irving Medical Center (Site 301-027), 177 Fort Washington Ave.
    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Duke University Hospital (Site 301-006), 2301 Erwin Road
      • Winston-Salem, North Carolina, United States, 27157
        • Wake Forest Baptist Health (Site 210-001), Medical Center Blvd
    • Ohio
      • Cincinnati, Ohio, United States, 45219
        • University of Cincinnati Medical Center (Site 207-003), 234 Goodman Street, ML 0740
      • Cleveland, Ohio, United States, 44111
        • Cleveland Clinic Fairview Hosptial (Site 207-005), 18101 Lorain Ave.
      • Cleveland, Ohio, United States, 44195
        • Cleveland Clinic Foundation (Site 207-001), 9500 Euclid Ave.
      • Columbus, Ohio, United States, 43210
        • The Ohio State University Wexner Medical Center (Site 207-004), 410 W. 10th Avenue
      • Garfield Heights, Ohio, United States, 44125
        • Cleveland Clinic Marymount Campus (Site 207-006), 12300 McCracken Road
      • Mayfield Heights, Ohio, United States, 44124
        • Cleveland Clinic Hillcrest Hospital (Site 207-007), 6780 Mayfield Road
    • Oregon
      • Portland, Oregon, United States, 97239-3098
        • Oregon Health & Science University (Site 208-003), 3181 SW Sam Jackson Park Rd.
    • South Carolina
      • Charleston, South Carolina, United States, 29425
        • Medical University of South Carolina (Site 210-002), 96 Jonathan Lucas St., CSB 214
    • Tennessee
      • Nashville, Tennessee, United States, 37232
        • Vanderbilt University Medical Center (Site 212-001), 1211 Medical Center Drive
    • Texas
      • Dallas, Texas, United States, 75246
        • Baylor, Scott and White Health (Site 301-003), Baylor University Medical Center, 3500 Gaston Ave.
      • Houston, Texas, United States, 77030
        • Texas Heart Institute (Site 301-017), 6770 Bertner, MC4-266
      • Houston, Texas, United States, 77030
        • Houston Methodist Hospital (Site 301-028), 6565 Fannin Street
      • Houston, Texas, United States, 77030
        • University of Texas Health Science Center (Site 203-006), 7000 Fannin St.
    • Utah
      • Murray, Utah, United States, 84107
        • Intermountain Medical Center (Site 211-001), 5121 South Cottonwood Street
      • Salt Lake City, Utah, United States, 84132
        • University of Utah Hospital (Site 211-002), 50 North Medical Drive
    • Virginia
      • Charlottesville, Virginia, United States, 22908
        • UVA School of Medicine (Site 210-003), University of Virginia Health System, University Hospital, 1215 Lee St.
    • Washington
      • Seattle, Washington, United States, 98104
        • Harborview Medical Center (Site 208-001), 325 9th Ave.
      • Seattle, Washington, United States, 98122
        • Swedish Medical Center (Site 208-005), 747 Broadway
    • West Virginia
      • Morgantown, West Virginia, United States, 26506
        • West Virginia University Medicine (Site 301-023), One Medical Center Drive

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

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:
  • Vasoactive Intestinal Peptide
  • VIP
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:
  • Vasoactive Intestinal Peptide
  • VIP
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.
Thru Day 90

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
All-cause mortality
Time Frame: Thru Day 90
Thru Day 90
Pulmonary ordinal outcome
Time Frame: Days 1-7, 14 and 28
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
Composite of death or serious clinical COVID-19 related events
Time Frame: Thru Day 90
Thru Day 90
Composite of cardiovascular events and thromboembolic events
Time Frame: Thru Day 90
Thru Day 90
Composite of grade 3 and 4 clinical adverse events, serious adverse events (SAEs) or death
Time Frame: Thru Days 5 and 28
Thru Days 5 and 28
Incidence of no home use of supplemental oxygen above pre-morbid oxygen use
Time Frame: 14 days
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
Time to death
Time Frame: Thru Day 90
Thru Day 90
Composite of time to recovery, days at home off new supplemental oxygen and time to death
Time Frame: Thru Day 90
Measured in number of days
Thru Day 90
Composite of alive, at home and off new supplemental oxygen
Time Frame: Thru Day 90
Thru Day 90
Composite of recovered, alive and not recovered, and dead
Time Frame: Thru Day 90
Recovery defined as alive, at home and off new supplemental oxygen
Thru Day 90
Time from randomization to recovery
Time Frame: Thru Day 90
Recovery defined as alive, at home and off oxygen (treating death as competing risk)
Thru Day 90
Days alive outside short-term acute care hospital
Time Frame: Up to Day 90
Using "last off" method.
Up to Day 90
Incidence of clinical organ failure or serious infections
Time Frame: Thru Day 28
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
Composite of death, clinical organ failure or serious infections
Time Frame: Thru Day 90
Thru Day 90
Composite of cardiovascular events and thromboembolic events
Time Frame: Thru Day 28
Thru Day 28
Incidence of infusion reactions
Time Frame: Thru Day 180
Thru Day 180
Percentage of participants for whom infusion was interrupted or stopped prior to completion for any reason
Time Frame: Thru Day 90
Thru Day 90
Percentage of participants for whom infusion was interrupted or stopped prior to completion due to adverse event
Time Frame: Thru Day 90
Thru Day 90
Composite of hospital readmissions or death
Time Frame: Thru Day 180
Thru Day 180
Time to hospital discharge from initial hospitalization
Time Frame: Thru Day 180
Thru Day 180
Composite of SAEs or death
Time Frame: Thru Day 180
Thru Day 180
Incidence of home use of supplemental oxygen above pre-morbid oxygen use
Time Frame: Thru Day 180
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

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 20, 2021

Primary Completion (Actual)

August 22, 2022

Study Completion (Actual)

November 20, 2022

Study Registration Dates

First Submitted

April 9, 2021

First Submitted That Met QC Criteria

April 9, 2021

First Posted (Actual)

April 14, 2021

Study Record Updates

Last Update Posted (Actual)

May 3, 2023

Last Update Submitted That Met QC Criteria

May 1, 2023

Last Verified

May 1, 2023

More Information

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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