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

NCT04583969 | Completed Phase 2 Results FDA Drug

• 1 other identifier: 20-0013B
• Study Type: interventional
• Target: 527
• Locations: 2 countries
• Sites: 55

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.

Conditions

COVID-19

Keywords

Adults; COVID-19; Multicenter; Putative; Therapeutics

Outcome Measures

Primary Outcomes (1)

• Proportion of Participants Alive and Without Mechanical Ventilation Through Day 29 in Participants With Baseline Ordinal Score of 5 or 6, C-reactive Protein (CRP)<150mg/L and Age <85 Years

  Ordinal scale categories include 7) Hospitalized, on Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation (ECMO) and 8) Death. Mechanical ventilation-free survival was assessed through Day 29, defined as the proportion of participants who had not died nor were hospitalized on invasive mechanical ventilation or ECMO from Day 1 through Day 29. Estimates for the proportions are estimated from a logistic regression model adjusted for baseline dexamethasone, baseline ordinal score, age (continuous), and baseline CRP.

  Day 1 through Day 29

Secondary Outcomes (40)

• Proportion of Participants Alive and Without Mechanical Ventilation Through Day 29 in Participants With Any Baseline Ordinal Score

  Day 1 through Day 29

• Time to Sustained Recovery in Participants With a Baseline Ordinal Score of 5 or 6, CRP<150mg/L and Age <85 Years

  Day 1 through Day 60

• Time to Sustained Recovery in Participants With Any Baseline Ordinal Score

  Day 1 through Day 60

• Number of Participants Meeting Criteria for Each of the 8 Ordinal Scale Categories on Day 8

  Day 8

• Change From Baseline in C-Reactive Protein (CRP)

  Days 1, 3, 5, 8, 11, 15, 29

Study Arms (2)

Remdesivir + Lenzilumab

EXPERIMENTAL

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.

Biological: Lenzilumab; Drug: Remdesivir

Remdesivir + Placebo

ACTIVE COMPARATOR

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.

Other: Placebo; Drug: Remdesivir

Interventions

Lenzilumab 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 + Lenzilumab

Placebo OTHER

Placebo for lenzilumab is commercially sourced 0.9% sodium chloride.

Remdesivir + Placebo

Remdesivir DRUG

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

Remdesivir + Lenzilumab; Remdesivir + Placebo

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Admitted to a hospital with symptoms suggestive of Coronavirus Disease 2019 (COVID-19) and requires ongoing medical care.
• Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures.
• Subject (or legally authorized representative) understands and agrees to comply with planned study procedures.
• Male or non-pregnant female adult \>/= 18 years of age at time of enrollment.
• 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.
• 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).
• 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.
• 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.

You may not qualify if:

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 5 times the upper limit of normal.
• Subjects with a low glomerular filtration rate (eGFR), specifically:
• 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.
• All subjects with a glomerular filtration rate (eGFR) \<20 mL/min (including hemodialysis and hemofiltration) are excluded.
• Pregnancy or breast feeding.
• Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours of enrollment.
• Allergy to any study medication.
• Received five or more doses of remdesivir prior to screening.
• 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.
• 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.
• 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.
• Received granulocyte-macrophage colony-stimulating factor (GM-CSF) agents (e.g., sargramostim) within 2 months prior to screening.
• 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).
• Received any live vaccine in the 4 weeks prior to screening.
• Known active tuberculosis.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (55)

University of Alabama at Birmingham School of Medicine - Infectious Disease

Birmingham, Alabama, 35233, United States

Location

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

Tucson, Arizona, 85724-0001, United States

Location

University of Arkansas for Medical Sciences

Little Rock, Arkansas, 72205-7101, United States

Location

Kern Medical Center

Bakersfield, California, 93306-4018, United States

Location

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

Fresno, California, 93721, United States

Location

University of Southern California - Infectious Diseases

Los Angeles, California, 90089-0121, United States

Location

Hoag Hospital Newport Beach

Newport Beach, California, 92663, United States

Location

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

Stanford, California, 94305-2200, United States

Location

Penrose Hospital - Emergency Medicine

Colorado Springs, Colorado, 80907, United States

Location

St. Francis Medical Center

Colorado Springs, Colorado, 80923, United States

Location

St. Anthony Hospital

Lakewood, Colorado, 80228-1704, United States

Location

St. Anthony Hospital North Health Campus

Westminster, Colorado, 80023, United States

Location

Nuvance Health Danbury Hospital - Infectious Disease

Danbury, Connecticut, 06810, United States

Location

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

New Haven, Connecticut, 06519-1612, United States

Location

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

Norwalk, Connecticut, 06856, United States

Location

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

Gainesville, Florida, 32610, United States

Location

Mayo Clinic Florida

Jacksonville, Florida, 32224, United States

Location

Grady Memorial Hospital

Atlanta, Georgia, 30303, United States

Location

The Hope Clinic of Emory University

Decatur, Georgia, 30030-1705, United States

Location

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

Chicago, Illinois, 60612, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

Great Lakes Clinical Trials

Chicago, Illinois, 60640, United States

Location

Carle Foundation Hospital

Urbana, Illinois, 61801, United States

Location

Northwestern Medicine - Central DuPage Hospital - Infectious Disease

Winfield, Illinois, 60190, United States

Location

Norton Healthcare

Louisville, Kentucky, 40202, United States

Location

University of Louisville - Division of Infectious Diseases

Louisville, Kentucky, 40202, United States

Location

Brigham and Women's Hospital - Infectious Diseases

Boston, Massachusetts, 02115-6110, United States

Location

Boston Medical Center - Center for Infectious Diseases - Shapiro Center

Boston, Massachusetts, 02118, United States

Location

William Beaumont Hospital - Royal Oak Campus - Infectious Disease

Royal Oak, Michigan, 48073-6700, United States

Location

Hennepin Healthcare Research Institute

Minneapolis, Minnesota, 55415, United States

Location

Mayo Clinic, Rochester - Infectious Diseases

Rochester, Minnesota, 55905-0001, United States

Location

University of Nebraska Medical Center - Infectious Diseases

Omaha, Nebraska, 68105, United States

Location

Englewood Hospital

Englewood, New Jersey, 07631, United States

Location

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

Buffalo, New York, 14203, United States

Location

Mount Sinai School of Medicine - Medicine - Infectious Diseases

New York, New York, 10029-6504, United States

Location

Nuvance Health - Vassar Brothers Medical Center

Poughkeepsie, New York, 12601, United States

Location

Stony Brook Medicine - Stony Brook University Hospital

Stony Brook, New York, 11794, United States

Location

Jacobi Medical Center

The Bronx, New York, 10461-1119, United States

Location

Montefiore Medical Center - Infectious Diseases

The Bronx, New York, 10467-2401, United States

Location

Atrium Health ID Consultants & Infusion Care Specialists

Charlotte, North Carolina, 28209, United States

Location

Wake Forest Baptist Health - Infectious Diseases

Winston-Salem, North Carolina, 27157, United States

Location

University of Toledo Medical Center - Ruppert Clinic

Toledo, Ohio, 43614, United States

Location

St. Charles Health System - St. Charles Bend Hospital

Bend, Oregon, 97701, United States

Location

Doylestown Hospital

Doylestown, Pennsylvania, 18901, United States

Location

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

Hershey, Pennsylvania, 17033, United States

Location

Kent County Memorial Hospital

Warwick, Rhode Island, 02886, United States

Location

Monument Health - Clinical Research

Rapid City, South Dakota, 57701, United States

Location

Hendrick Health - Hendrick Medical Center

Abilene, Texas, 79601, United States

Location

Baptist Hospitals of Southeast Texas Site

Beaumont, Texas, 77701, United States

Location

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

Dallas, Texas, 75246, United States

Location

Methodist Hospital - Houston

Houston, Texas, 77030, United States

Location

University of Utah - Infectious Diseases

Salt Lake City, Utah, 84132, United States

Location

West Virginia University - Infectious Diseases Clinic

Morgantown, West Virginia, 26506, United States

Location

Seoul National University Bundang Hospital - Division of Infectious Diseases

Bundang-gu Seongnam-si, Gyeonggi-do, 13620, South Korea

Location

Seoul National University Hospital

Seoul, Jongno-gu, 03080, South Korea

Location

Related Publications (1)

• 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.

  PMID: 34473343 DERIVED

MeSH Terms

Conditions

COVID-19

Interventions

lenzilumab; remdesivir

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Results Point of Contact

• Title: John Beigel, MD
• Organization: NIAID

jbeigel@niaid.nih.gov

3014519881

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 9, 2020
• First Posted: October 12, 2020
• Study Start: October 23, 2020
• Primary Completion: April 22, 2022
• Study Completion: April 22, 2022
• Last Updated: June 5, 2023
• Results First Posted: June 5, 2023

Record last verified: 2022-01

Locations

US (53); KR (2)