Adaptive COVID-19 Treatment Trial 3 (ACTT-3)

NCT ID: NCT04492475

Last Updated: 2022-03-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 969 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-08-05
• Study Completion Date: 2020-12-21

Brief Summary

ACTT-3 will evaluate the combination of interferon beta-1a and remdesivir compared to remdesivir alone. Subjects will be assessed daily while hospitalized. If the subjects are discharged from the hospital, they will have a study visit at Days 15, 22, and 29. For discharged subjects, it is preferred that the Day 15 and 29 visits are in person to obtain safety laboratory tests and oropharyngeal (OP) swab and blood (serum only) samples for secondary research as well as clinical outcome data. However, infection control or other restrictions may limit the ability of the subject to return to the clinic. In this case, these visits may be conducted by phone, and only clinical data will be obtained. The Day 22 visit does not have laboratory tests or collection of samples and is conducted by phone. The primary outcome is time to recovery by Day 29.

Detailed Description

This study is an adaptive randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of novel therapeutic agents in hospitalized adults diagnosed with COVID-19. The study is a multicenter trial that will be conducted in up to approximately 100 sites globally. The study will compare different investigational therapeutic agents to a control arm. New arms can be introduced according to scientific and public health needs. There will be interim monitoring to allow early stopping for futility, efficacy, or safety. If one therapy proves to be efficacious, then this treatment may become the control arm for comparison(s) with new experimental treatment(s). Any such change would be accompanied by an updated sample size. This adaptive platform is used to rapidly evaluate different therapeutics in a population of those hospitalized with moderate to severe COVID-19. The platform will provide a common framework sharing a similar population, design, endpoints, and safety oversight. New stages with new therapeutics can be introduced. One independent Data and Safety Monitoring Board (DSMB) will actively monitor interim data in all stages to make recommendations about early study closure or changes to study arms.

ACTT-3 will evaluate the combination of interferon beta-1a and remdesivir compared to remdesivir alone. Subjects will be assessed daily while hospitalized. If the subjects are discharged from the hospital, they will have a study visit at Days 15, 22, and 29. For discharged subjects, it is preferred that the Day 15 and 29 visits are in person to obtain safety laboratory tests and oropharyngeal (OP) swab and blood (serum only) samples for secondary research as well as clinical outcome data. However, infection control or other restrictions may limit the ability of the subject to return to the clinic. In this case, these visits may be conducted by phone, and only clinical data will be obtained. The Day 22 visit does not have laboratory tests or collection of samples and is conducted by phone.

All subjects will undergo a series of efficacy, safety, and laboratory assessments. Safety laboratory tests and blood (serum and plasma) research samples and oropharyngeal (OP) swabs will be obtained on Days 1 (prior to infusion) and Days 3, 5, 8, and 11 (while hospitalized). OP swabs and blood (serum only) plus safety laboratory tests will be collected on Day 15 and 29 (if the subject attends an in-person visit or are still hospitalized).

The primary outcome is time to recovery by Day 29 for patients with baseline ordinal score 4, 5 and 6. A key secondary outcome evaluates treatment-related improvements in the 8-point ordinal scale at Day 15. Each stage may prioritize different secondary endpoints for the purpose of multiple comparison analyses.

Contacts:

20-0006 Central Contact

Telephone: 1 (301) 7617948

Email: DMIDClinicalTrials@niaid.nih.gov

Conditions

COVID-19

Study Design

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

Study Groups

Remdesivir plus Interferon Beta-1a

200 mg of Remdesivir administered intravenously on Day 1, followed by a 100 mg once-daily maintenance dose of Remdesivir while hospitalized for up to a 10-day total course and 44 mcg of interferon beta-1a administered by a 0.5 mL subcutaneous injection on Days 1, 3, 5, and 7 while hospitalized for a total of 4 doses.

Group Type: EXPERIMENTAL

Interferon beta-1a

Intervention Type: DRUG

Rebif (R) is a purified 166 amino acid human interferon beta glycoprotein with an amino acid sequence identical to natural fibroblast derived human interferon beta. Each 0.5 mL prefilled syringe contains 44 mcg of interferon beta-1a, 4 mg human albumin, USP; 27.3 mg mannitol, USP; 0.4 mg sodium acetate; and water for injection, USP.

Remdesivir

Intervention Type: DRUG

Drug Remdesivir is a single diastereomer monophosphoramidate prodrug designed for the intracellular delivery of a modified adenine nucleoside analog GS-441524. In addition to the active ingredient, the lyophilized formulation of Remdesivir contains the following inactive ingredients: water for injection, sulfobutylether beta-cyclodextrin sodium (SBECD), and hydrochloric acid and/or sodium hydroxide.

Remdesivir plus Placebo

200 mg of Remdesivir administered intravenously on Day 1, followed by a 100 mg once-daily maintenance dose of Remdesivir while hospitalized for up to a 10-day total course and a 0.5 mL placebo injection administered subcutaneously on Days 1, 3, 5, and 7 while hospitalized for a total of 4 doses.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

The interferon beta-1a placebo contains either 0.5 mL 0.9% normal saline or 0.5 mL sterile water for injection.

Remdesivir

Intervention Type: DRUG

Drug Remdesivir is a single diastereomer monophosphoramidate prodrug designed for the intracellular delivery of a modified adenine nucleoside analog GS-441524. In addition to the active ingredient, the lyophilized formulation of Remdesivir contains the following inactive ingredients: water for injection, sulfobutylether beta-cyclodextrin sodium (SBECD), and hydrochloric acid and/or sodium hydroxide.

Interventions

Interferon beta-1a

Rebif (R) is a purified 166 amino acid human interferon beta glycoprotein with an amino acid sequence identical to natural fibroblast derived human interferon beta. Each 0.5 mL prefilled syringe contains 44 mcg of interferon beta-1a, 4 mg human albumin, USP; 27.3 mg mannitol, USP; 0.4 mg sodium acetate; and water for injection, USP.

Intervention Type: DRUG

Placebo

The interferon beta-1a placebo contains either 0.5 mL 0.9% normal saline or 0.5 mL sterile water for injection.

Intervention Type: OTHER

Remdesivir

Drug Remdesivir is a single diastereomer monophosphoramidate prodrug designed for the intracellular delivery of a modified adenine nucleoside analog GS-441524. In addition to the active ingredient, the lyophilized formulation of Remdesivir contains the following inactive ingredients: water for injection, sulfobutylether beta-cyclodextrin sodium (SBECD), and hydrochloric acid and/or sodium hydroxide.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Admitted to a hospital with symptoms suggestive of COVID-19.

2. Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures.

3. Subject (or legally authorized representative) understands and agrees to comply with planned study procedures.

4. Male or non-pregnant female adult > / = 18 years of age at time of enrollment.

5. Has laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR) or other commercial or public health assay in any respiratory specimen or saliva, as documented by either of the following:

• PCR or other assay positive in sample collected < 72 hours prior to randomization; OR
• PCR or other assay positive in sample collected >/= 72 hours but < 7 days prior to randomization AND progressive disease suggestive of ongoing SARS-CoV-2 infection.

Note: if written documentation of the positive test result is not available at enrollment (e.g., report from other institution), the subject may be enrolled but the PCR should be repeated at the time of enrollment.

6. Illness of any duration, and at least one of the following:

• Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR
• SpO2 < / = 94% on room air, OR
• Requiring supplemental oxygen.

7. Women of childbearing potential must agree to either abstinence or use at least one primary form of contraception not including hormonal contraception from the time of screening through Day 29.

8. Agrees to not participate in another clinical trial (both pharmacologic and other types of interventions) for the treatment of COVID-19 through Day 29.

Exclusion Criteria

1. Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours.

2. Subject meets criteria for ordinal scale category 6 or 7 at the time of screening.

3. Subject has a positive test for influenza virus during this current hospital admission.

4. Subjects with an estimated glomerular filtration rate (eGFR) < 30 mL/min are excluded unless in the opinion of the PI, the potential benefit of receiving remdesivir outweighs the potential risk of study participation.

5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 times the upper limits of normal.

6. Total white cell blood cell count (WBC) <1500 cells/microliter.

7. Platelet count <50,000/microliter.

8. History of chronic liver disease (e.g., jaundice, ascites, hepatic encephalopathy, history of bleeding esophageal or gastric varices). No laboratory testing is needed.

9. Pregnancy or breast feeding (lactating women who agree to discard breast milk from Day 1 until three weeks after the last study product is given are not excluded).

10. Allergy to any study medication including history of hypersensitivity to natural or recombinant interferon beta or human albumin.

11. Patient has a chronic or acute medical condition or is taking a medication that cannot be discontinued at enrollment, that in the judgement of the PI, places them at unacceptable risk for a poor clinical outcome if they were to participate in the study.

12. Received three or more doses of remdesivir, including the loading dose, outside of the study for COVID-19.

13. Received convalescent plasma or intravenous immunoglobulin [IVIg] for the treatment of COVID-19.

14. Received any interferon product within two weeks of screening, either for the treatment of COVID-19 or for a chronic medical condition (e.g., multiple sclerosis, HCV infection).

15. Received any of the following in the two weeks prior to screening as treatment of COVID-19:

• Small molecule tyrosine kinase inhibitors (e.g. baricitinib, imatinib, gefitinib, acalabrutinib, etc.);
• Monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab], etc.);
• Monoclonal antibodies targeting T-cells or B-cells as treatment for COVID-19.

16. Prior enrollment in ACTT-3.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

University of Alabama at Birmingham School of Medicine - Infectious Disease

Birmingham, Alabama, United States

UCSF Fresno Center for Medical Education and Research - Clinical Research Center

Fresno, California, United States

University of California San Diego Health - Jacobs Medical Center

La Jolla, California, United States

University of California Los Angeles Medical Center - Westwood Clinic

Los Angeles, California, United States

University of California Irvine Medical Center - Infectious Disease

Orange, California, United States

VA Palo Alto Health Care System - Infectious Diseases

Palo Alto, California, United States

Stanford University - Stanford Hospital and Clinics - Pediatrics - Infectious Diseases

Palo Alto, California, United States

University of California Davis Medical Center - Internal Medicine - Infectious Disease

Sacramento, California, United States

Naval Medical Center San Diego - Infectious Disease Clinic

San Diego, California, United States

University of California San Francisco - Zuckerberg San Francisco General Hospital - Division of HIV, ID, and Global Medicine

San Francisco, California, United States

Cedars Sinai Medical Center

West Hollywood, California, United States

Eastern Colorado Health Care System

Aurora, Colorado, United States

Denver Health Division of Hospital Medicine - Main Campus

Denver, Colorado, United States

University of Florida Health - Shands Hospital - Division of Infectious Diseases and Global Medicine

Gainesville, Florida, United States

University of Florida Health - Jacksonville - Department of Emergency Medicine

Jacksonville, Florida, United States

University of Miami Miller School of Medicine - Infectious Diseases

Miami, Florida, United States

Emory Vaccine Center - The Hope Clinic

Decatur, Georgia, United States

Atlanta VA Medical Center - Infectious Diseases Clinic

Decatur, Georgia, United States

Tripler Army Medical Center (TAMC)

Honolulu, Hawaii, United States

Northwestern Hospital - Infectious Disease

Chicago, Illinois, United States

University of Illinois at Chicago Division of Infectious Diseases

Chicago, Illinois, United States

University of Iowa Hospitals & Clinics - Department of Internal Medicine

Iowa City, Iowa, United States

Ochsner Medical Center - Kenner - Department of Infectious Diseases

Kenner, Louisiana, United States

Southeast Louisiana Veterans Health Care System - Section of Infectious Diseases

New Orleans, Louisiana, United States

University of Maryland School of Medicine - Center for Vaccine Development - Baltimore

Baltimore, Maryland, United States

Johns Hopkins Hospital - Medicine - Infectious Diseases

Baltimore, Maryland, United States

Walter Reed National Military Medical Center

Bethesda, Maryland, United States

National Institutes of Health - Clinical Center, National Institute of Allergy and Infectious Diseases Laboratory Of Immunoregulation, Clinical Research Section

Bethesda, Maryland, United States

Massachusetts General Hospital - Infectious Diseases

Boston, Massachusetts, United States

University of Massachusetts Medical School - Infectious Diseases and Immunology

Worcester, Massachusetts, United States

University of Minnesota Medical Center, Fairview - Infectious Diseases and International Medicine

Minneapolis, Minnesota, United States

Saint Louis University - Center for Vaccine Development

St Louis, Missouri, United States

University of Nebraska Medical Center - Infectious Diseases

Omaha, Nebraska, United States

University of New Mexico Clinical and Translational Science Center

Albuquerque, New Mexico, United States

New York University School of Medicine - Langone Medical Center - Microbiology - Parasitology

New York, New York, United States

University of Rochester Medical Center - Vaccine Research Unit

Rochester, New York, United States

Montefiore Medical Center - Infectious Diseases

The Bronx, New York, United States

Duke Human Vaccine Institute - Duke Vaccine and Trials Unit

Durham, North Carolina, United States

Womack Army Medical Center - Pulmonary and Respiratory Services

Fort Bragg, North Carolina, United States

Kaiser Permanente Northwest - Center for Health Research

Portland, Oregon, United States

Penn State Health Milton S. Hershey Medical Center - Division of Infectious Diseases

Hershey, Pennsylvania, United States

Hospital of the University of Pennsylvania - Infectious Diseases

Philadelphia, Pennsylvania, United States

Baylor Scott & White Health - Baylor University Medical Center - North Texas Infectious Disease Consultants

Dallas, Texas, United States

University of Texas Southwestern Medical Center - Internal Medicine - Infectious Diseases

Dallas, Texas, United States

Brooke Army Medical Center

Fort Sam Houston, Texas, United States

University of Texas Medical Branch - Division of Infectious Disease

Galveston, Texas, United States

Baylor College of Medicine - Molecular Virology and Microbiology

Houston, Texas, United States

Methodist Hospital - Houston

Houston, Texas, United States

University of Texas Health Science Center at San Antonio - Infectious Diseases

San Antonio, Texas, United States

University of Utah - Infectious Diseases

Salt Lake City, Utah, United States

University of Virginia - Acute Care Surgery

Charlottesville, Virginia, United States

Naval Medical Center Portsmouth - Infectious Disease Division

Portsmouth, Virginia, United States

EvergreenHealth Infectious Disease Service

Kirkland, Washington, United States

Providence Sacred Heart Medical Center

Spokane, Washington, United States

Madigan Army Medical Center - Infectious Disease Clinic

Tacoma, Washington, United States

National Center for Global Health and Medicine Hospital - Disease Control and Prevention Center

Tokyo, , Japan

Instituto Nacional de Enfermedades Respiratorias (INER) - Ismael Cosío Villegas

Mexico City, , Mexico

Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubirán - Departamento de Infectologia

Mexico City, , Mexico

National University Health System - Division of Infectious Diseases

Singapore, , Singapore

National Centre for Infectious Diseases (NCID)

Singapore, , Singapore

Changi General Hospital - Clinical Trials and Research Unit (CTRU)

Singapore, , Singapore

Ng Teng Fong General Hospital - Infectious Disease Service

Singapore, , Singapore

Seoul National University Bundang Hospital - Division of Infectious Diseases

Seongnam-si, Gyeonggi-do, South Korea

Seoul National University Hospital

Seoul, Jongno-gu, South Korea

Countries

United States; Japan; Mexico; Singapore; South Korea

References

Potter GE, Bonnett T, Rubenstein K, Lindholm DA, Rapaka RR, Doernberg SB, Lye DC, Mularski RA, Hynes NA, Kline S, Paules CI, Wolfe CR, Frank MG, Rouphael NG, Deye GA, Sweeney DA, Colombo RE, Davey RT Jr, Mehta AK, Whitaker JA, Castro JG, Amin AN, Colombo CJ, Levine CB, Jain MK, Maves RC, Marconi VC, Grossberg R, Hozayen S, Burgess TH, Atmar RL, Ganesan A, Gomez CA, Benson CA, Lopez de Castilla D, Ahuja N, George SL, Nayak SU, Cohen SH, Lalani T, Short WR, Erdmann N, Tomashek KM, Tebas P. Temporal Improvements in COVID-19 Outcomes for Hospitalized Adults: A Post Hoc Observational Study of Remdesivir Group Participants in the Adaptive COVID-19 Treatment Trial. Ann Intern Med. 2022 Dec;175(12):1716-1727. doi: 10.7326/M22-2116. Epub 2022 Nov 29.

Reference Type: DERIVED

PMID: 36442063 (View on PubMed)

Kalil AC, Mehta AK, Patterson TF, Erdmann N, Gomez CA, Jain MK, Wolfe CR, Ruiz-Palacios GM, Kline S, Regalado Pineda J, Luetkemeyer AF, Harkins MS, Jackson PEH, Iovine NM, Tapson VF, Oh MD, Whitaker JA, Mularski RA, Paules CI, Ince D, Takasaki J, Sweeney DA, Sandkovsky U, Wyles DL, Hohmann E, Grimes KA, Grossberg R, Laguio-Vila M, Lambert AA, Lopez de Castilla D, Kim E, Larson L, Wan CR, Traenkner JJ, Ponce PO, Patterson JE, Goepfert PA, Sofarelli TA, Mocherla S, Ko ER, Ponce de Leon A, Doernberg SB, Atmar RL, Maves RC, Dangond F, Ferreira J, Green M, Makowski M, Bonnett T, Beresnev T, Ghazaryan V, Dempsey W, Nayak SU, Dodd L, Tomashek KM, Beigel JH; ACTT-3 study group members. Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial. Lancet Respir Med. 2021 Dec;9(12):1365-1376. doi: 10.1016/S2213-2600(21)00384-2. Epub 2021 Oct 18.

Reference Type: DERIVED

PMID: 34672949 (View on PubMed)

Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.

Reference Type: DERIVED

PMID: 34473343 (View on PubMed)

Azzi Y, Bartash R, Scalea J, Loarte-Campos P, Akalin E. COVID-19 and Solid Organ Transplantation: A Review Article. Transplantation. 2021 Jan 1;105(1):37-55. doi: 10.1097/TP.0000000000003523.

Reference Type: DERIVED

PMID: 33148977 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

20-0006 ACTT-3

Identifier Type: -

Identifier Source: org_study_id