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

NCT ID: NCT04843761

Last Updated: 2025-10-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 473 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-04-20
• Study Completion Date: 2022-11-20

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.

Conditions

Covid19

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Stratum 1 - Aviptadil + Remdesivir + SOC

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)

Group Type: EXPERIMENTAL

Remdesivir

Intervention Type: BIOLOGICAL

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

Aviptadil

Intervention Type: BIOLOGICAL

Administered by IV infusion over 12 hours per day for 3 days. The Day 1 infusion rate is 50 pmol/kg/hr, the Day 2 infusion rate is 100 pmol/kg/hr, and the Day 3 infusion rate is 150 pmol/kg/hr.

Corticosteroid

Intervention Type: DRUG

In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC.

Stratum 1 - Aviptadil + Remdesivir Placebo + SOC

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)

Group Type: EXPERIMENTAL

Remdesivir Placebo

Intervention Type: DRUG

Commercially available 0.9% sodium chloride solution. Administered by IV infusion daily for 10 days.

Aviptadil

Intervention Type: BIOLOGICAL

Administered by IV infusion over 12 hours per day for 3 days. The Day 1 infusion rate is 50 pmol/kg/hr, the Day 2 infusion rate is 100 pmol/kg/hr, and the Day 3 infusion rate is 150 pmol/kg/hr.

Corticosteroid

Intervention Type: DRUG

In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC.

Stratum 1 - Aviptadil Placebo + Remdesivir + SOC

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)

Group Type: EXPERIMENTAL

Remdesivir

Intervention Type: BIOLOGICAL

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

Aviptadil Placebo

Intervention Type: DRUG

Commercially available 0.9% sodium chloride solution. Administered by IV infusion over 12 hours per day for 3 days.

Corticosteroid

Intervention Type: DRUG

In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC.

Stratum 1 - Aviptadil Placebo + Remdesivir Placebo + SOC

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)

Group Type: PLACEBO_COMPARATOR

Remdesivir Placebo

Intervention Type: DRUG

Commercially available 0.9% sodium chloride solution. Administered by IV infusion daily for 10 days.

Aviptadil Placebo

Intervention Type: DRUG

Commercially available 0.9% sodium chloride solution. Administered by IV infusion over 12 hours per day for 3 days.

Corticosteroid

Intervention Type: DRUG

In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC.

Stratum 2 - Aviptadil + SOC

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)

Group Type: EXPERIMENTAL

Aviptadil

Intervention Type: BIOLOGICAL

Administered by IV infusion over 12 hours per day for 3 days. The Day 1 infusion rate is 50 pmol/kg/hr, the Day 2 infusion rate is 100 pmol/kg/hr, and the Day 3 infusion rate is 150 pmol/kg/hr.

Corticosteroid

Intervention Type: DRUG

In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC.

Stratum 2 - Aviptadil Placebo + SOC

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)

Group Type: PLACEBO_COMPARATOR

Aviptadil Placebo

Intervention Type: DRUG

Commercially available 0.9% sodium chloride solution. Administered by IV infusion over 12 hours per day for 3 days.

Corticosteroid

Intervention Type: DRUG

In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC.

Stratum 3 - Remdesivir + SOC

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)

Group Type: EXPERIMENTAL

Remdesivir

Intervention Type: BIOLOGICAL

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

Corticosteroid

Intervention Type: DRUG

In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC.

Stratum 3 - Remdesivir Placebo + SOC

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)

Group Type: PLACEBO_COMPARATOR

Remdesivir Placebo

Intervention Type: DRUG

Commercially available 0.9% sodium chloride solution. Administered by IV infusion daily for 10 days.

Corticosteroid

Intervention Type: DRUG

In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC.

Stratum 4 - Aviptadil + SOC

Eligible for Aviptadil and prior/current use of Remdesivir

Participants enrolled in this arm were analyzed in substudy H1 (NCT06729606)

Group Type: EXPERIMENTAL

Aviptadil

Intervention Type: BIOLOGICAL

Administered by IV infusion over 12 hours per day for 3 days. The Day 1 infusion rate is 50 pmol/kg/hr, the Day 2 infusion rate is 100 pmol/kg/hr, and the Day 3 infusion rate is 150 pmol/kg/hr.

Corticosteroid

Intervention Type: DRUG

In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC.

Stratum 4 - Aviptadil Placebo + SOC

Eligible for Aviptadil and prior/current use of Remdesivir

Participants enrolled in this arm were analyzed in substudy H1 (NCT06729606)

Group Type: PLACEBO_COMPARATOR

Aviptadil Placebo

Intervention Type: DRUG

Commercially available 0.9% sodium chloride solution. Administered by IV infusion over 12 hours per day for 3 days.

Corticosteroid

Intervention Type: DRUG

In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC.

Interventions

Remdesivir

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

Intervention Type: BIOLOGICAL

Remdesivir Placebo

Commercially available 0.9% sodium chloride solution. Administered by IV infusion daily for 10 days.

Intervention Type: DRUG

Aviptadil

Administered by IV infusion over 12 hours per day for 3 days. The Day 1 infusion rate is 50 pmol/kg/hr, the Day 2 infusion rate is 100 pmol/kg/hr, and the Day 3 infusion rate is 150 pmol/kg/hr.

Intervention Type: BIOLOGICAL

Aviptadil Placebo

Commercially available 0.9% sodium chloride solution. Administered by IV infusion over 12 hours per day for 3 days.

Intervention Type: DRUG

Corticosteroid

In line with NIH treatment guidelines, corticosteroids such as dexamethasone, prednisone, methylprednisolone or hydrocortisone may be administered as SOC.

Intervention Type: DRUG

Other Intervention Names

Vasoactive Intestinal Peptide; VIP

Eligibility Criteria

Inclusion Criteria

• 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.

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 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)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)

NETWORK

Sponsor Role: collaborator

University of Copenhagen

OTHER

Sponsor Role: collaborator

Medical Research Council

OTHER_GOV

Sponsor Role: collaborator

Kirby Institute

OTHER_GOV

Sponsor Role: collaborator

Washington D.C. Veterans Affairs Medical Center

FED

Sponsor Role: collaborator

Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections

NETWORK

Sponsor Role: collaborator

US Department of Veterans Affairs

FED

Sponsor Role: collaborator

Prevention and Early Treatment of Acute Lung Injury (PETAL) Network

UNKNOWN

Sponsor Role: collaborator

NeuroRx, Inc.

INDUSTRY

Sponsor Role: collaborator

Gilead Sciences

INDUSTRY

Sponsor Role: collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Samuel Brown, MD

Role: PRINCIPAL_INVESTIGATOR

Intermountain Medical Center/University of Utah

Prof. James Neaton

Role: STUDY_CHAIR

INSIGHT Statistical and Coordinating Centre, University of Minnesota

Locations

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

Denver Health Medical Center (Site 204-004), 780 Delaware Street, Pavilion B

Denver, Colorado, United States

MedStar Health Research Institute (Site 009-021), 110 Irving St., NW.

Washington D.C., District of Columbia, United States

Washington DC VA Medical Center (Site 009-004), 50 Irving Street, NW.

Washington D.C., District of Columbia, United States

Emory University (Site 301-008), Bldg. A, Suite 2236, 1365 Clifton Rd., NE.

Atlanta, Georgia, United States

Massachusetts General Hospital (Site 202-002), 55 Fruit Street

Boston, Massachusetts, United States

Baystate Medical Center (Site 201-001), Critical Care Research, 759 Chestnut Street

Springfield, Massachusetts, 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

Columbia University Irving Medical Center (Site 301-027), 177 Fort Washington Ave.

New York, New York, United States

Montefiore Medical Center - Moses Hospital (Site 206-001), 111 E. 210th Street

The Bronx, New York, United States

Montefiore Medical Center - Weiler campus (Site 206-003), 111 E. 210th Street

The Bronx, New York, United States

Duke University Hospital (Site 301-006), 2301 Erwin Road

Durham, North Carolina, United States

Wake Forest Baptist Health (Site 210-001), Medical Center Blvd

Winston-Salem, North Carolina, United States

University of Cincinnati Medical Center (Site 207-003), 234 Goodman Street, ML 0740

Cincinnati, Ohio, United States

Cleveland Clinic Fairview Hospital (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

Cleveland Clinic Marymount Campus (Site 207-006), 12300 McCracken Road

Garfield Heights, Ohio, United States

Cleveland Clinic Hillcrest Hospital (Site 207-007), 6780 Mayfield Road

Mayfield Heights, Ohio, United States

Oregon Health & Science University (Site 208-003), 3181 SW Sam Jackson Park Rd.

Portland, Oregon, United States

Medical University of South Carolina (Site 210-002), 96 Jonathan Lucas St., CSB 214

Charleston, South Carolina, United States

Vanderbilt University Medical Center (Site 212-001), 1211 Medical Center Drive

Nashville, Tennessee, United States

Baylor, Scott and White Health (Site 301-003), Baylor University Medical Center, 3500 Gaston Ave.

Dallas, Texas, 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

Intermountain Medical Center (Site 211-001), 5121 South Cottonwood Street

Murray, Utah, United States

University of Utah Hospital (Site 211-002), 50 North Medical Drive

Salt Lake City, Utah, United States

UVA School of Medicine (Site 210-003), University of Virginia Health System, University Hospital, 1215 Lee St.

Charlottesville, Virginia, 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

West Virginia University Medicine (Site 301-023), One Medical Center Drive

Morgantown, West Virginia, United States

Countries

United States

References

Brown SM, Barkauskas CE, Grund B, Sharma S, Phillips AN, Leither L, Peltan ID, Lanspa M, Gilstrap DL, Mourad A, Lane K, Beitler JR, Serra AL, Garcia I, Almasri E, Fayed M, Hubel K, Harris ES, Middleton EA, Barrios MAG, Mathews KS, Goel NN, Acquah S, Mosier J, Hypes C, Salvagio Campbell E, Khan A, Hough CL, Wilson JG, Levitt JE, Duggal A, Dugar S, Goodwin AJ, Terry C, Chen P, Torbati S, Iyer N, Sandkovsky US, Johnson NJ, Robinson BRH, Matthay MA, Aggarwal NR, Douglas IS, Casey JD, Hache-Marliere M, Georges Youssef J, Nkemdirim W, Leshnower B, Awan O, Pannu S, O'Mahony DS, Manian P, Awori Hayanga JW, Wortmann GW, Tomazini BM, Miller RF, Jensen JU, Murray DD, Bickell NA, Zatakia J, Burris S, Higgs ES, Natarajan V, Dewar RL, Schechner A, Kang N, Arenas-Pinto A, Hudson F, Ginde AA, Self WH, Rogers AJ, Oldmixon CF, Morin H, Sanchez A, Weintrob AC, Cavalcanti AB, Davis-Karim A, Engen N, Denning E, Taylor Thompson B, Gelijns AC, Kan V, Davey VJ, Lundgren JD, Babiker AG, Neaton JD, Lane HC; ACTIV-3b/Therapeutics for Severely Ill Inpatients with COVID-19 (TESICO) Study Group. Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial. Lancet Respir Med. 2023 Sep;11(9):791-803. doi: 10.1016/S2213-2600(23)00147-9. Epub 2023 Jun 19.

Reference Type: DERIVED

PMID: 37348524 (View on PubMed)

Grundeis F, Ansems K, Dahms K, Thieme V, Metzendorf MI, Skoetz N, Benstoem C, Mikolajewska A, Griesel M, Fichtner F, Stegemann M. Remdesivir for the treatment of COVID-19. Cochrane Database Syst Rev. 2023 Jan 25;1(1):CD014962. doi: 10.1002/14651858.CD014962.pub2.

Reference Type: DERIVED

PMID: 36695483 (View on PubMed)

Tsiatis AA, Davidian M, Holloway ST. Estimation of the odds ratio in a proportional odds model with censored time-lagged outcome in a randomized clinical trial. Biometrics. 2023 Jun;79(2):975-987. doi: 10.1111/biom.13603. Epub 2021 Dec 17.

Reference Type: DERIVED

PMID: 34825704 (View on PubMed)

Provided Documents

Document Type: Study Protocol: Master

View Document

Document Type: Study Protocol: Aviptadil (H1)

View Document

Document Type: Study Protocol: Remdesivir (H2)

View Document

Document Type: Study Protocol: Overview of Study Documents

View Document

Document Type: Statistical Analysis Plan: Main

View Document

Document Type: Statistical Analysis Plan: Addendum

View Document

Document Type: Informed Consent Form

View Document

Related Links

http://www.fda.gov/Safety/MedWatch/SafetyInformation/default.htm

FDA Safety Alerts and Recalls

https://www.cdc.gov/coronavirus/2019-nCoV/index.html

CDC (Centers for Disease Control and Prevention): Coronavirus (COVID-19) website

https://www.niaid.nih.gov/clinical-trials/participant-guide

A Participant's Guide to Clinical Trials (NIAID)

https://www.niaid.nih.gov/clinical-trials/find-a-clinical-trial

Find a Clinical Trial (NIAID)

https://www.niaid.nih.gov/clinical-trials

Clinical Trials at NIAID

https://www.niaid.nih.gov/

National Institute for Allergy and Infectious Diseases (NIAID)

https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/patient-management

WHO COVID-19 treatment guidelines

Other Identifiers

015 / ACTIV-3b

Identifier Type: -

Identifier Source: org_study_id