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

NCT04988035 | Completed Phase 2 Results FDA Drug

• 1 other identifier: 20-0013C
• Study Type: interventional
• Target: 201
• Locations: 1 country
• Sites: 39

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 COVID-19. 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-C stage will evaluate the combination of remdesivir with danicopan vs remdesivir with a 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, plasma and RNA) research samples on Day 1 (prior to study product administration) and Days 3, 5, 8, and 11 while hospitalized. 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 danicopan 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)

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

  The ordinal scale categories are defined as: 1) Not hospitalized, no new or increased limitations on activities; 2) Not hospitalized, but new or increased limitation on activities and/or requiring new or increased home oxygen, CPAP, or BiPAP; 3) Hospitalized, not requiring new or increased supplemental oxygen - no longer requires ongoing medical care; 4) Hospitalized, not requiring new or increased supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 5) Hospitalized, requiring new or increased supplemental oxygen; 6) Hospitalized, requiring new or increased non-invasive ventilation or highflow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8) Death

  Day 8

Secondary Outcomes (41)

• Proportion of Participants Not Meeting Criteria for One of Two Ordinal Scale Categories Through Day 29

  Day 1 through Day 29

• Time to Sustained Recovery

  Day 1 through Day 60

• Number of Participants Meeting Criteria for Each of the 8 Ordinal Scale Categories on Day 15

  Day 15

• Number of Participants Meeting Criteria for Each of the 8 Ordinal Scale Categories on Day 29

  Day 29

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

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

Study Arms (4)

Remdesivir + Danicopan (< 70 years)

EXPERIMENTAL

For participants \< 70 years, 200 mg intravenous (IV) loading dose of Remdesivir on Day 1, followed by a 100 mg once-daily IV maintenance dose up to a 10-day total course while hospitalized, and 400 mg oral (PO) (or via nasogastric \[NG\] or gastrostomy \[G\] tube) loading dose danicopan, followed by 250 mg 4 times daily (QID) for the duration of the hospitalization up to a 14-day total course. End of danicopan treatment tapered as 250 mg 3 times daily (TID) for 2 days, followed by 250 mg twice daily (BID) for 2 days, until complete cessation (total treatment duration up to 18 days or 4 days after discharge). Total danicopan participants, N=100.

Drug: Danicopan; Drug: Remdesivir

Remdesivir + Danicopan (>/= 70 years)

EXPERIMENTAL

For participants \>/= 70 years, 200 mg intravenous (IV) loading dose of Remdesivir on Day 1, followed by a 100 mg once-daily IV maintenance dose up to a 10-day total course while hospitalized, and 300 mg oral (PO) (or via nasogastric \[NG\] or gastrostomy \[G\] tube) loading dose danicopan, followed by 200 mg 4 times daily (QID) for the duration of the hospitalization up to a 14-day total course. End of danicopan treatment tapered as 200 mg 3 times daily (TID) for 2 days, followed by 200 mg twice daily (BID) for 2 days, until complete cessation (total treatment duration up to 18 days or 4 days after discharge). Total danicopan participants, N=100.

Drug: Danicopan; Drug: Remdesivir

Remdesivir + Placebo (< 70 years)

ACTIVE COMPARATOR

For participants \< 70 years, 200 mg intravenous (IV) loading dose of Remdesivir on Day 1, followed by a 100 mg once-daily IV maintenance dose up to a 10-day total course while hospitalized, and 400 mg oral (PO) (or via nasogastric \[NG\] or gastrostomy \[G\] tube) loading dose danicopan matching placebo, followed by 250 mg 4 times daily (QID) for the duration of the hospitalization up to a 14-day total course. End of danicopan matching placebo treatment tapered as 250 mg 3 times daily (TID) for 2 days, followed by 250 mg twice daily (BID) for 2 days, until complete cessation (total treatment duration up to 18 days or 4 days after discharge). Total danicopan matching placebo participants, N=100.

Other: Placebo; Drug: Remdesivir

Remdesivir + Placebo (>/= 70 years)

ACTIVE COMPARATOR

For participants \>/= 70 years, 200 mg intravenous (IV) loading dose of Remdesivir on Day 1, followed by a 100 mg once-daily IV maintenance dose up to a 10-day total course while hospitalized and 300 mg oral (PO) (or via nasogastric \[NG\] or gastrostomy \[G\] tube) of loading dose danicopan matching placebo followed by 200 mg 4 times daily (QID) for the duration of the hospitalization up to a 14-day total course. End of danicopan matching placebo treatment tapered as 200 mg 3 times daily (TID) for 2 days, followed by 200 mg twice daily (BID) for 2 days, until complete cessation (total treatment duration up to 18 days or 4 days after discharge). Total danicopan matching placebo participants, N=100.

Other: Placebo; Drug: Remdesivir

Interventions

Danicopan DRUG

Danicopan is a small molecule, orally administered complement factor D (FD) inhibitor

Remdesivir + Danicopan (< 70 years); Remdesivir + Danicopan (>/= 70 years)

Placebo OTHER

Danicopan matching placebo tablet

Remdesivir + Placebo (< 70 years); Remdesivir + Placebo (>/= 70 years)

Remdesivir DRUG

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

Remdesivir + Danicopan (< 70 years); Remdesivir + Danicopan (>/= 70 years); Remdesivir + Placebo (< 70 years); Remdesivir + Placebo (>/= 70 years)

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 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 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 scale category 5, 6, or 7).\*
• \*If written documentation of the positive test result is not available at the time of enrollment (e.g., report came from other institution), the test should be repeated and the subject may be enrolled if positive.
• Women of childbearing potential and men must agree to either abstinence or use at least one acceptable method of contraception\*\* from the time of screening through 30 days after the last dose of danicopan for women and 90 days after the last dose for men.
• \*\*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:

• aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 5 times the upper limit of normal.
• Subjects with a low glomerular filtration rate (eGFR), specifically:
• Subjects with an eGFR 15-30 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 an eGFR \<15 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.
• Treatment with a complement inhibitor in the prior 8 weeks.\*
• Has active uncontrolled opportunistic infection, or uncontrolled cirrhosis.\*
• History of infection with N. meningitidis.\*
• Known history of hypersensitivity to danicopan or its excipients.\*
• Has a medical condition that could, in the judgment of the investigator, limit the interpretation and generalizability of trial results.
• Positive test for influenza virus during the current illness (influenza testing is not required by protocol).
• History of liver cirrhosis.\*

Sponsors & Collaborators

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

Study Sites (39)

University of Alabama at Birmingham School of Medicine - Infectious Disease

Birmingham, Alabama, 35233, 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 California Los Angeles Medical Center - Westwood Clinic

Los Angeles, California, 90095, United States

Location

Hoag Hospital Newport Beach

Newport Beach, California, 92663, 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

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

William Beaumont Hospital - Royal Oak Campus - Infectious Disease

Royal Oak, Michigan, 48073, 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

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 Hospita

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

Wake Forest Baptist Health - Infectious Diseases

Winston-Salem, North Carolina, 27157, 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

Hendrick Health - Hendrick Medical Center

Abilene, Texas, 79601, United States

Location

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

Dallas, Texas, 75246, 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

MeSH Terms

Conditions

COVID-19

Interventions

danicopan; 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: July 29, 2021
• First Posted: August 3, 2021
• Study Start: August 3, 2021
• Primary Completion: April 23, 2022
• Study Completion: April 23, 2022
• Last Updated: June 8, 2023
• Results First Posted: June 8, 2023

Record last verified: 2021-07

Locations

US (39)