ACTIV-5 / Big Effect Trial (BET-B) for the Treatment of COVID-19

NCT ID: NCT04583969

Last Updated: 2023-06-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 527 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-10-23
• Study Completion Date: 2022-04-22

Brief Summary

This is a platform trial to conduct a series of randomized, double-blind, placebo-controlled trials using common assessments and endpoints in hospitalized adults diagnosed with Coronavirus Disease 2019 (COVID-19). Big Effect Trial (BET) is a proof-of-concept study with the intent of identifying promising treatments to enter a more definitive study. The study will be conducted in up to 70 domestic sites and 5 international sites. The study will compare different investigational therapeutic agents to a common control arm and determine which have relatively large effects. In order to maintain the double blind, each intervention will have a matched placebo. However, the control arm will be shared between interventions and may include participants receiving the matched placebo for a different intervention.

The goal is not to determine clear statistical significance for an intervention, but rather to determine which products have clinical data suggestive of efficacy and should be moved quickly into larger studies. Estimates produced from BET will provide an improved basis for designing the larger trial, in terms of sample size and endpoint selection. Products with little indication of efficacy will be dropped on the basis of interim evaluations. In addition, some interventions may be discontinued on the basis of interim futility or efficacy analyses.

One or more interventions may be started at any time. The number of interventions enrolling are programmatic decisions and will be based on the number of sites and the pace of enrollment. At the time of enrollment, subjects will be randomized to receive any one of the active arms they are eligible for or placebo. Approximately 200 (100 treatment and 100 shared placebo) subjects will be assigned to each arm entering the platform and a given site will generally have no more than 3 interventions at once.

The BET-B stage will evaluate the combination of remdesivir with lenzilumab vs remdesivir with a lenzilumab placebo. The primary objective is to evaluate the clinical efficacy of different investigational therapeutics relative to the control arm in adults hospitalized with COVID-19 according to clinical status (8-point ordinal scale) at Day 8.

Detailed Description

This is a platform trial to conduct a series of randomized, double-blind, placebo-controlled trials using common assessments and endpoints in hospitalized adults diagnosed with Coronavirus Disease 2019 (COVID-19). Big Effect Trial (BET) is a proof-of-concept study with the intent of identifying promising treatments to enter a more definitive study. The study will be conducted in up to 70 domestic sites and 5 international sites. The study will compare different investigational therapeutic agents to a common control arm and determine which have relatively large effects. In order to maintain the double blind, each intervention will have a matched placebo. However, the control arm will be shared between interventions and may include participants receiving the matched placebo for a different intervention.

The goal is not to determine clear statistical significance for an intervention, but rather to determine which products have clinical data suggestive of efficacy and should be moved quickly into larger studies. Estimates produced from BET will provide an improved basis for designing the larger trial, in terms of sample size and endpoint selection. Products with little indication of efficacy will be dropped on the basis of interim evaluations. In addition, some interventions may be discontinued on the basis of interim futility or efficacy analyses.

One or more interventions may be started at any time. The number of interventions enrolling are programmatic decisions and will be based on the number of sites and the pace of enrollment. At the time of enrollment, subjects will be randomized to receive any one of the active arms they are eligible for or placebo. Approximately 200 (100 treatment and 100 shared placebo) subjects will be assigned to each arm entering the platform and a given site will generally have no more than 3 interventions at once.

The BET-B stage will evaluate the combination of remdesivir with lenzilumab vs remdesivir with a lenzilumab placebo. Subjects will be assessed daily while hospitalized. Once subjects are discharged from the hospital, they will have a study visit at Days 8, 15, 22, 29, and 60 as an outpatient. The Day 8, Day 22 and Day 60 visits do not have laboratory tests or collection of samples and may be conducted by phone. All subjects will undergo a series of efficacy and safety laboratory assessments. Safety laboratory tests and blood (serum and plasma) research samples and oropharyngeal (OP) swabs will be obtained on Day 1 (prior to study product administration) and Days 3, 5, 8, and 11 while hospitalized. OP swabs (oropharyngeal swabs are preferred, but if these are not obtainable, saliva or nasopharyngeal or nasal swabs may be substituted) and blood research samples plus safety laboratory tests will be collected on Day 15 and 29 if the subject attends an in-person visit or is still hospitalized. However, if infection control considerations or other restrictions prevent the subject from returning to the clinic, Day 15 and 29 visits may be conducted by phone and only clinical data will be obtained.

The primary objective is to evaluate the clinical efficacy of different investigational therapeutics relative to the control arm in adults hospitalized with COVID-19 according to clinical status (8-point ordinal scale) at Day 8. The key secondary objectives are to 1) evaluate the clinical efficacy of different investigational therapeutics as assessed by time to recovery compared to the control arm, and 2) to evaluate the proportion of subjects alive and without respiratory failure through Day 29.

Contacts:

20-0013 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 + Lenzilumab

200-mg intravenous (IV) remdesivir loading dose on Day 1, followed by a 100-mg once-daily IV maintenance dose up to a 10-day total course while hospitalized and 600-mg IV lenzilumab infusion every 8 hours starting on Day 1 for a total of 3 doses. N=275.

Group Type: EXPERIMENTAL

Lenzilumab

Intervention Type: BIOLOGICAL

Lenzilumab is a first-in-class recombinant monoclonal antibody targeting soluble human GM-CSF, with potential immunomodulating activity, high binding affinity in the pM range, and 94% specificity to the human germline, which reduces immunogenicity.

Remdesivir

Intervention Type: DRUG

Remdesivir is a single diastereomer monophosphoramidate prodrug designed for the intracellular delivery of a modified adenine nucleoside analog GS-441524.

Remdesivir + Placebo

200-mg intravenous (IV) remdesivir loading dose on Day 1, followed by a 100-mg once-daily IV maintenance dose up to a 10-day total course while hospitalized and 600-mg IV lenzilumab placebo infusion every 8 hours starting on Day 1 for a total of 3 doses. N=275.

Group Type: ACTIVE_COMPARATOR

Placebo

Intervention Type: OTHER

Placebo for lenzilumab is commercially sourced 0.9% sodium chloride.

Remdesivir

Intervention Type: DRUG

Remdesivir is a single diastereomer monophosphoramidate prodrug designed for the intracellular delivery of a modified adenine nucleoside analog GS-441524.

Interventions

Lenzilumab

Lenzilumab is a first-in-class recombinant monoclonal antibody targeting soluble human GM-CSF, with potential immunomodulating activity, high binding affinity in the pM range, and 94% specificity to the human germline, which reduces immunogenicity.

Intervention Type: BIOLOGICAL

Placebo

Placebo for lenzilumab is commercially sourced 0.9% sodium chloride.

Intervention Type: OTHER

Remdesivir

Remdesivir is a single diastereomer monophosphoramidate prodrug designed for the intracellular delivery of a modified adenine nucleoside analog GS-441524.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Admitted to a hospital with symptoms suggestive of Coronavirus Disease 2019 (COVID-19) and requires ongoing medical care.

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. Illness of any duration and has laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as determined by polymerase chain reaction (PCR) or other commercial or public health assay (e.g., Nucleic Acid Amplification Test [NAAT], antigen test) in any respiratory specimen, or saliva </=14 days prior to randomization.

6. Illness of any duration, and requiring, just prior to randomization, supplemental oxygen (any flow), mechanical ventilation or Extracorporeal Membrane Oxygenation (ECMO) (ordinal score 5, 6, or 7).

7. Women of childbearing potential must agree to either abstinence or use at least one acceptable method of contraception* from the time of screening through 5 months post study intraperitoneal (IP) dosing.

• Acceptable methods include barrier contraceptives (condoms or diaphragm) with spermicide, intrauterine devices (IUDs), hormonal contraceptives, oral contraceptive pills, and surgical sterilization.

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

Exclusion Criteria

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

2. Subjects with a low glomerular filtration rate (eGFR), specifically:

1. Subjects with a glomerular filtration rate (eGFR) 20-30 mL/min are excluded unless in the opinion of the principal investigator (PI), the potential benefit of participation outweighs the potential risk of study participation.

2. All subjects with a glomerular filtration rate (eGFR) <20 mL/min (including hemodialysis and hemofiltration) are excluded.

3. Pregnancy or breast feeding.

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

5. Allergy to any study medication.

6. Received five or more doses of remdesivir prior to screening.

7. Received small molecule tyrosine kinase inhibitors, including Janus kinase (JAK) inhibitors (e.g., baricitinib, ibrutinib, acalabrutinib, imatinib, gefitinib), in the 4 weeks prior to screening.

8. Received monoclonal antibodies targeting cytokines (e.g., tumor necrosis factor (TNF) inhibitors, anti-IL-1 [e.g., anakinra, canakinumab], anti-IL-6 [e.g., tocilizumab, sarilumab, sitlukimab]), or T-cells (e.g., abatacept) in the 4 weeks prior to screening.

9. Received monoclonal antibodies targeting B-cells (e.g., rituximab, and including any targeting multiple cell lines including B-cells) in the 3 months prior to screening.

10. Received granulocyte-macrophage colony-stimulating factor (GM-CSF) agents (e.g., sargramostim) within 2 months prior to screening.

11. Received other immunosuppressants in the 4 weeks prior to screening and in the judgement of the investigator, the risk of immunosuppression with lenzilumab is larger than the risk of Coronavirus Disease 2019 (COVID-19).

12. Received any live vaccine in the 4 weeks prior to screening.

13. Known active tuberculosis.

14. Known history of Human Immunodeficiency Virus (HIV), Hepatitis B (HBV) or untreated hepatitis C (HCV) infection.

15. History of pulmonary alveolar proteinosis (PAP).

16. Has a malignancy currently receiving immunosuppressive chemotherapy, immunodeficiency, uncontrolled opportunistic infection, or uncontrolled cirrhosis.

17. Has a medical condition that could, in the judgment of the investigator, limit the interpretation and generalizability of trial results.

18. Positive test for influenza virus during the current illness (influenza testing is not required by protocol).

19. Previous participation in an ACTIV-5/Big Effect Trial (BET).

• 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

The University of Arizona - Banner University Medical Center Tucson Campus - Tucson

Tucson, Arizona, United States

University of Arkansas for Medical Sciences

Little Rock, Arkansas, United States

Kern Medical Center

Bakersfield, California, United States

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

Fresno, California, United States

University of Southern California - Infectious Diseases

Los Angeles, California, United States

Hoag Hospital Newport Beach

Newport Beach, California, United States

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

Stanford, California, United States

Penrose Hospital - Emergency Medicine

Colorado Springs, Colorado, United States

St. Francis Medical Center

Colorado Springs, Colorado, United States

St. Anthony Hospital

Lakewood, Colorado, United States

St. Anthony Hospital North Health Campus

Westminster, Colorado, United States

Nuvance Health Danbury Hospital - Infectious Disease

Danbury, Connecticut, United States

Yale School of Medicine - The Anlyan Center for Medical Research & Education - Immunobiology

New Haven, Connecticut, United States

Nuvance Health - Norwalk Hospital - Asthma Pulmonary and Critical Care Medicine

Norwalk, Connecticut, United States

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

Gainesville, Florida, United States

Mayo Clinic Florida

Jacksonville, Florida, United States

Grady Memorial Hospital

Atlanta, Georgia, United States

The Hope Clinic of Emory University

Decatur, Georgia, United States

Cook County Health and Hospitals System - Ruth M Rothstein CORE Center

Chicago, Illinois, United States

Rush University Medical Center

Chicago, Illinois, United States

Great Lakes Clinical Trials

Chicago, Illinois, United States

Carle Foundation Hospital

Urbana, Illinois, United States

Northwestern Medicine - Central DuPage Hospital - Infectious Disease

Winfield, Illinois, United States

Norton Healthcare

Louisville, Kentucky, United States

University of Louisville - Division of Infectious Diseases

Louisville, Kentucky, United States

Brigham and Women's Hospital - Infectious Diseases

Boston, Massachusetts, United States

Boston Medical Center - Center for Infectious Diseases - Shapiro Center

Boston, Massachusetts, United States

William Beaumont Hospital - Royal Oak Campus - Infectious Disease

Royal Oak, Michigan, United States

Hennepin Healthcare Research Institute

Minneapolis, Minnesota, United States

Mayo Clinic, Rochester - Infectious Diseases

Rochester, Minnesota, United States

University of Nebraska Medical Center - Infectious Diseases

Omaha, Nebraska, United States

Englewood Hospital

Englewood, New Jersey, United States

The State University of New York - University at Buffalo - Department of Medicine

Buffalo, New York, United States

Mount Sinai School of Medicine - Medicine - Infectious Diseases

New York, New York, United States

Nuvance Health - Vassar Brothers Medical Center

Poughkeepsie, New York, United States

Stony Brook Medicine - Stony Brook University Hospital

Stony Brook, New York, United States

Jacobi Medical Center

The Bronx, New York, United States

Montefiore Medical Center - Infectious Diseases

The Bronx, New York, United States

Atrium Health ID Consultants & Infusion Care Specialists

Charlotte, North Carolina, United States

Wake Forest Baptist Health - Infectious Diseases

Winston-Salem, North Carolina, United States

University of Toledo Medical Center - Ruppert Clinic

Toledo, Ohio, United States

St. Charles Health System - St. Charles Bend Hospital

Bend, Oregon, United States

Doylestown Hospital

Doylestown, Pennsylvania, United States

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

Hershey, Pennsylvania, United States

Kent County Memorial Hospital

Warwick, Rhode Island, United States

Monument Health - Clinical Research

Rapid City, South Dakota, United States

Hendrick Health - Hendrick Medical Center

Abilene, Texas, United States

Baptist Hospitals of Southeast Texas Site

Beaumont, Texas, United States

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

Dallas, Texas, United States

Methodist Hospital - Houston

Houston, Texas, United States

University of Utah - Infectious Diseases

Salt Lake City, Utah, United States

West Virginia University - Infectious Diseases Clinic

Morgantown, West Virginia, United States

Seoul National University Bundang Hospital - Division of Infectious Diseases

Bundang-gu Seongnam-si, Gyeonggi-do, South Korea

Seoul National University Hospital

Seoul, Jongno-gu, South Korea

Countries

United States; South Korea

References

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)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

20-0013B

Identifier Type: -

Identifier Source: org_study_id