Clinical trial NCT04988035: ACTIV-5 / Big Effect Trial (BET-C) for the Treatment of COVID-19
Official title: A Multicenter Platform Trial of Putative Therapeutics for the Treatment of COVID-19 in Hospitalized Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: COVID-19
Keywords: Adults
covid-19
Multicenter
Putative
Therapeutics
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2021-08-03
Enrollment: 201
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 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. The key secondary objectives are 1) to evaluate the clinical efficacy of danicopan as assessed by time to recovery compared to the control arm 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

Eligibility criteria: Inclusion Criteria:

1. Admitted to a hospital with symptoms suggestive of 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 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 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.
7. 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.
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. aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 5 times the upper limit of normal.
2. Subjects with a low glomerular filtration rate (eGFR), specifically:

   1. 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.
   2. All subjects with an eGFR \<15 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. Treatment with a complement inhibitor in the prior 8 weeks.\*
8. Has active uncontrolled opportunistic infection, or uncontrolled cirrhosis.\*
9. History of infection with N. meningitidis.\*
10. Known history of hypersensitivity to danicopan or its excipients.\*
11. Has a medical condition that could, in the judgment of the investigator, limit the interpretation and generalizability of trial results.
12. Positive test for influenza virus during the current illness (influenza testing is not required by protocol).
13. History of liver cirrhosis.\*
14. Previous participation in an ACTIV-5/BET trial.
15. Refuses to refrain from breastfeeding from the time of screening through 30 days after the last dose of danicopan.\*
16. Refuses to receive prophylactic antibiotics against meningococcal infections if the subject has not been vaccinated in the 3 years prior to Study Day 1.

Primary outcomes:
measure: Number of Participants Meeting Criteria for Each of the 8 Ordinal Scale Categories on Day 8
timeFrame: Day 8
Secondary outcomes:
measure: Proportion of Participants Not Meeting Criteria for One of Two Ordinal Scale Categories Through Day 29
timeFrame: Day 1 through Day 29
measure: Time to Sustained Recovery
timeFrame: Day 1 through Day 60
measure: Number of Participants Meeting Criteria for Each of the 8 Ordinal Scale Categories on Day 15
timeFrame: Day 15
measure: Number of Participants Meeting Criteria for Each of the 8 Ordinal Scale Categories on Day 29
timeFrame: Day 29
measure: Change From Baseline in C-Reactive Protein (CRP)
timeFrame: Days 1, 3, 5, 8, 11, 15, 29
measure: Change From Baseline in Ferritin
timeFrame: Days 1, 3, 5, 8, 11, 15, 29
measure: Change From Baseline in D-dimer
timeFrame: Days 1, 3, 5, 8, 11, 15, 29
measure: Change From Baseline in Fibrinogen
timeFrame: Days 1, 3, 5, 8, 11, 15, 29
measure: Change From Baseline in Alanine Aminotransferase (ALT)
timeFrame: Days 1, 3, 5, 8, 11, 15, 29
measure: Change From Baseline in Aspartate Transaminase (AST)
timeFrame: Days 1, 3, 5, 8, 11, 15, 29
measure: Change From Baseline in Creatinine
timeFrame: Days 1, 3, 5, 8, 11, 15, 29
measure: Change From Baseline in International Normalized Ratio (INR)
timeFrame: Days 1, 3, 5, 8, 11, 15, 29
measure: Change From Baseline in Hemoglobin
timeFrame: Days 1, 3, 5, 8, 11, 15, 29
measure: Change From Baseline in Platelets Count
timeFrame: Days 1, 3, 5, 8, 11, 15, 29
measure: Change From Baseline in Total Bilirubin
timeFrame: Days 1, 3, 5, 8, 11, 15, 29
measure: Change From Baseline in White Blood Cell (WBC) Count
timeFrame: Days 1, 3, 5, 8, 11, 15, 29
measure: Change From Baseline in Neutrophils
timeFrame: Days 1, 3, 5, 8, 11, 15, 29
measure: Change From Baseline in Eosinophils
timeFrame: Days 1, 3, 5, 8, 11, 15, 29
measure: Change From Baseline in Basophils
timeFrame: Days 1, 3, 5, 8, 11, 15, 29
measure: Change From Baseline in Lymphocytes
timeFrame: Days 1, 3, 5, 8, 11, 15, 29
measure: Change From Baseline in Monocytes
timeFrame: Days 1, 3, 5, 8, 11, 15, 29
measure: Number of Participants Reporting Grade 3 ,4, or 5 Clinical and/or Laboratory Adverse Events (AEs)
timeFrame: Day 1 through Day 60
measure: Number of Participants Reporting Serious Adverse Events (SAEs)
timeFrame: Day 1 through Day 60
measure: Number of Participants Who Discontinued or Temporarily Suspended Study Treatment
timeFrame: Day 1 through Day 29
measure: Duration of Hospitalization
timeFrame: Day 1 through Day 29
measure: Duration of Intensive Care Unit (ICU) Stay
timeFrame: Day 1 through Day 29
measure: Days of Invasive Mechanical Ventilation/Extracorporeal Membrane Oxygenation (ECMO) Use
timeFrame: Day 1 through Day 29
measure: Days of New Mechanical Ventilation or Extracorporeal Membrane Oxygenation (ECMO) Use
timeFrame: Day 1 through Day 29
measure: Days of New Non-invasive Ventilation/High Flow Oxygen Use
timeFrame: Day 1 through Day 29
measure: Days of Non-invasive Ventilation/High Flow Oxygen Use
timeFrame: Day 1 through Day 29
measure: Days of Supplemental Oxygen Use
timeFrame: Day 1 through Day 29
measure: Number of Participants With New Invasive Mechanical Ventilation / Extracorporeal Membrane Oxygenation (ECMO) Use
timeFrame: Day 1 through Day 29
measure: Number of Participants With New Non-invasive Ventilation/High Flow Oxygen Use
timeFrame: Day 1 through Day 29
measure: Mean Change in Ordinal Scale
timeFrame: Days 1, 3, 5, 8, 11, 15, 22, 29
measure: Proportion of Participants Not Meeting Criteria for One of Two Ordinal Scale Categories at Day 29
timeFrame: Day 29
measure: 14-day Participant Mortality
timeFrame: Day 1 through Day 15
measure: 28-day Participant Mortality
timeFrame: Day 1 through Day 29
measure: 59-day Participant Mortality
timeFrame: Day 1 through Day 60
measure: Time to an Improvement of One Category From Baseline Using an Ordinal Scale
timeFrame: Day 1 through Day 60
measure: Time to an Improvement of Two Categories From Baseline Using an Ordinal Scale
timeFrame: Day 1 through Day 60
measure: Time to Death
timeFrame: Day 1 through Day 29
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham School of Medicine - Infectious Disease
state: Alabama
city: Bakersfield
country: United States
facility: Kern Medical Center
state: California
city: Fresno
country: United States
facility: UCSF Fresno Center for Medical Education and Research - Clinical Research Center
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles Medical Center - Westwood Clinic
state: California
city: Newport Beach
country: United States
facility: Hoag Hospital Newport Beach
state: California
city: Colorado Springs
country: United States
facility: Penrose Hospital - Emergency Medicine
state: Colorado
city: Colorado Springs
country: United States
facility: St. Francis Medical Center
state: Colorado
city: Lakewood
country: United States
facility: St. Anthony Hospital
state: Colorado
city: Westminster
country: United States
facility: St. Anthony Hospital North Health Campus
state: Colorado
city: Danbury
country: United States
facility: Nuvance Health Danbury Hospital - Infectious Disease
state: Connecticut
city: New Haven
country: United States
facility: Yale School of Medicine - The Anlyan Center for Medical Research & Education - Immunobiology
state: Connecticut
city: Norwalk
country: United States
facility: Nuvance Health - Norwalk Hospital - Asthma Pulmonary and Critical Care Medicine
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida Health - Shands Hospital - Division of Infectious Diseases and Global Medicine
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic Florida
state: Florida
city: Chicago
country: United States
facility: Great Lakes Clinical Trials
state: Illinois
city: Urbana
country: United States
facility: Carle Foundation Hospital
state: Illinois
city: Winfield
country: United States
facility: Northwestern Medicine - Central DuPage Hospital - Infectious Disease
state: Illinois
city: Louisville
country: United States
facility: Norton Healthcare
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville - Division of Infectious Diseases
state: Kentucky
city: Boston
country: United States
facility: Brigham and Women's Hospital - Infectious Diseases
state: Massachusetts
city: Royal Oak
country: United States
facility: William Beaumont Hospital - Royal Oak Campus - Infectious Disease
state: Michigan
city: Minneapolis
country: United States
facility: Hennepin Healthcare Research Institute
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic, Rochester - Infectious Diseases
state: Minnesota
city: Omaha
country: United States
facility: University of Nebraska Medical Center - Infectious Diseases
state: Nebraska
city: Bronx
country: United States
facility: Jacobi Medical Center
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center - Infectious Diseases
state: New York
city: Buffalo
country: United States
facility: The State University of New York - University at Buffalo - Department of Medicine
state: New York
city: New York
country: United States
facility: Mount Sinai School of Medicine - Medicine - Infectious Diseases
state: New York
city: Poughkeepsie
country: United States
facility: Nuvance Health - Vassar Brothers Medical Center
state: New York
city: Stony Brook
country: United States
facility: Stony Brook Medicine - Stony Brook University Hospita
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health - Infectious Diseases
state: North Carolina
city: Bend
country: United States
facility: St. Charles Health System - St. Charles Bend Hospital
state: Oregon
city: Doylestown
country: United States
facility: Doylestown Hospital
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Health Milton S. Hershey Medical Center - Division of Infectious Diseases
state: Pennsylvania
city: Warwick
country: United States
facility: Kent County Memorial Hospital
state: Rhode Island
city: Abilene
country: United States
facility: Hendrick Health - Hendrick Medical Center
state: Texas
city: Dallas
country: United States
facility: Baylor Scott & White Health - Baylor University Medical Center - North Texas Infectious Disease Consultants
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah - Infectious Diseases
state: Utah
city: Morgantown
country: United States
facility: West Virginia University - Infectious Diseases Clinic
state: West Virginia
Study officials:
References: