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-A stage will evaluate the combination of remdesivir with risankizumab vs remdesivir with a risankizumab 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.
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-A stage will evaluate the combination of remdesivir with risankizumab vs remdesivir
with a risankizumab 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 1) to
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
Other: Placebo
Risankizumab placebo will be given at an equal volume at the same schedule.
Drug: Remdesivir
Remdesivir is a single diastereomer monophosphoramidate prodrug for the intracellular delivery of a modified adenine nucleoside analog GS-441524.
Biological: Risankizumab
Risankizumab is a humanized immunoglobulin (Ig) G1 antagonistic monoclonal antibody (mAb) directed against the p19 subunit of the human cytokine interleukin-23. Risankizumab is formulated in a buffer of 4.4 mM disodium succinate hexahydrate/succinic acid, 225 mM sorbitol, 0.2 mg/mL polysorbate 20, and WFI in a 6R vial.
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
randomization.
6. Illness of any duration, and requiring, just prior to randomization, supplemental
oxygen (any flow), mechanical ventilation or 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 IP dosing.
Note: 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 an 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 an 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 two or more doses of > 60 mg of prednisone or equivalent in the 7 days prior
to screening.
8. 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.
9. 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.
10. 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.
11. Received Granulocyte-macrophage colony-stimulating factor (GM-CSF) agents (e.g.,
sargramostim) within 2 months prior to screening.
12. Received other immunosuppressants in the 4 weeks prior to screening and in the
judgment of the investigator, the risk of immunosuppression with risankizumab is
larger than the risk of Coronavirus Disease 2019 (COVID-19).
13. Received any live vaccine in the 4 weeks prior to screening.
14. Known active tuberculosis.
15. Known history of Human Immunodeficiency Virus (HIV), Hepatitis B (HBV) or untreated
hepatitis C (HCV) infection.
16. History of pulmonary alveolar proteinosis (PAP).
17. Has a malignancy and currently receiving immunosuppressive chemotherapy,
immunodeficiency, uncontrolled opportunistic infection, or uncontrolled cirrhosis.
18. Has a medical condition that could, in the judgment of the investigator, limit the
interpretation and generalizability of trial results.
19. Positive test for influenza virus during the current illness (influenza testing is not
required by protocol).
20. Previous participation in an ACTIV-5/Big Effect Trial (BET)
The University of Arizona - Banner University Medical Center Tucson Campus - Tucson
Tucson, Arizona, United States
Kern Medical Center
Bakersfield, 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
Grady Memorial Hospital
Atlanta, Georgia, United States
Emory Vaccine Center - The Hope Clinic
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
Brigham and Women's Hospital - Infectious Diseases
Boston, Massachusetts, United States
Boston Medical Center - Center for Infectious Diseases - Shapiro Center
Boston, Massachusetts, United States
Hennepin Healthcare Research Institute
Minneapolis, Minnesota, United States
University of Nebraska Medical Center- Infectious Diseases
Omaha, Nebraska, United States
Englewood Hospital
Englewood, New Jersey, United States
Jacobi Medical Center
Bronx, New York, 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
Wake Forest Baptist Health - Infectious Diseases
Winston-Salem, North Carolina, United States
University of Toledo Medical Center - Ruppert Clinic
Toledo, Ohio, United States
Doylestown Hospital
Doylestown, 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
West Virginia University - Infectious Diseases Clinic
Morgantown, West Virginia, United States