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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04583956
Recruitment Status : Recruiting
First Posted : October 12, 2020
Last Update Posted : November 17, 2020
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

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 40 sites throughout the US. 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 100 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.


Condition or disease Intervention/treatment Phase
COVID-19 Other: Placebo Drug: Remdesivir Biological: Risankizumab Phase 2

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 40 sites throughout the US. 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 100 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 15, 22, 29, and 60 as an outpatient and this 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 Day 22 and Day 60 visits do not have laboratory tests or collection of samples and may also be conducted by phone.

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, as assessed by time to recovery, of different investigational therapeutics as compared to the control arm, and 2) to evaluate the proportion of subjects alive and without respiratory failure on Day 29.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Multicenter Platform Trial of Putative Therapeutics for the Treatment of COVID-19 in Hospitalized Adults
Actual Study Start Date : October 14, 2020
Estimated Primary Completion Date : January 8, 2021
Estimated Study Completion Date : July 1, 2021

Arm Intervention/treatment
Active Comparator: 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 1200-mg IV risankizumab placebo infusion (300-mg x 4 vials) once on Day 1. N=100.
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.

Experimental: Remdesivir + Risankizumab
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 1200-mg IV risankizumab infusion (300-mg x 4 vials) once on Day 1. N=100.
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.




Primary Outcome Measures :
  1. Clinical efficacy in adults hospitalized with COVID-19 according to clinical status on an 8-point ordinal scale. [ Time Frame: Day 8 ]
    Clinical status assessed using ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care; 4) Hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (COVID-19 related or otherwise); 5) Hospitalized, requiring supplemental oxygen; 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8) Death.


Secondary Outcome Measures :
  1. Change from baseline in C-reactive protein (CRP) concentration [ Time Frame: Day 1 through Day 29 ]
  2. Change from baseline in d-dimer concentration [ Time Frame: Day 1 through Day 29 ]
  3. Change from baseline in ferritin concentration [ Time Frame: Day 1 through Day 29 ]
  4. Change from baseline in fibrinogen concentration [ Time Frame: Day 1 through Day 29 ]
  5. Change from baseline in troponin concentration [ Time Frame: Day 1 through Day 29 ]
  6. Change in alanine aminotransferase (ALT) over time [ Time Frame: Day 1 through Day 29 ]
  7. Change in aspartate aminotransferase (AST) over time [ Time Frame: Day 1 through Day 29 ]
  8. Change in creatinine over time [ Time Frame: Day 1 through Day 29 ]
  9. Change in hemoglobin over time [ Time Frame: Day 1 through Day 29 ]
  10. Change in international normalized ratio (INR) over time [ Time Frame: Day 1 through Day 29 ]
  11. Change in National Early Warning Score (NEWS) from baseline [ Time Frame: Day 1 through Day 29 ]
    The NEW score has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is based on 7 clinical parameters (respiration rate, oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness). The NEW Score is being used as an efficacy measure.

  12. Change in platelets over time [ Time Frame: Day 1 through Day 29 ]
  13. Change in total bilirubin over time [ Time Frame: Day 1 through Day 29 ]
  14. Change in white blood cell (WBC) count with differential over time [ Time Frame: Day 1 through Day 29 ]
  15. Clinical efficacy, as assessed by time to recovery [ Time Frame: Day 1 through Day 29 ]
    Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care.

  16. Cumulative incidence of Grade 3 and 4 clinical and/or laboratory adverse events (AEs) [ Time Frame: Day 1 through Day 60 ]
  17. Cumulative incidence of serious adverse events (SAEs) [ Time Frame: Day 1 through Day 60 ]
  18. Discontinuation or temporary suspension of study product administration [ Time Frame: Day 1 through Day 29 ]
    For any reason.

  19. Duration of hospitalization [ Time Frame: Day 1 through Day 29 ]
    Measured in days.

  20. Duration of new mechanical ventilation or extracorporeal membrane oxygenation (ECMO) use [ Time Frame: Day 1 through Day 29 ]
    Measured in days.

  21. Duration of new non-invasive ventilation or high flow oxygen use during the study [ Time Frame: Day 1 through Day 29 ]
    Measured in days.

  22. Duration of new oxygen use [ Time Frame: Day 1 through Day 29 ]
    Measured in days; supplemental oxygen concentration or flow rate will be measured.

  23. Duration of non-invasive ventilation/high flow oxygen use [ Time Frame: Day 1 through Day 29 ]
    Measured in days.

  24. Incidence of new mechanical ventilation or extracorporeal membrane oxygenation (ECMO) use [ Time Frame: Day 1 through Day 29 ]
  25. Incidence of new non-invasive ventilation or high flow oxygen use [ Time Frame: Day 1 through Day 29 ]
  26. Incidence of new oxygen use [ Time Frame: Day 1 through Day 29 ]
    Supplemental oxygen concentration or flow rate will be measured.

  27. Mean change in the ordinal scale [ Time Frame: Day 1 through Day 29 ]
    Clinical outcome assessed using ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care; 4) Hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (COVID-19 related or otherwise); 5) Hospitalized, requiring supplemental oxygen; 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8) Death.

  28. Oxygenation use [ Time Frame: Day 1 through Day 29 ]
    Measured in days; supplemental oxygen concentration or flow rate will be measured.

  29. Proportion of subjects alive and without respiratory failure [ Time Frame: Day 1 to Day 29 ]
    A subject who is "alive and without respiratory failure" is defined as meeting any one of the following five categories from the ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3)Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 5) Hospitalized, requiring supplemental oxygen.

  30. Subject 14-day mortality [ Time Frame: Day 1 through Day 15 ]
    Date and cause of death (if applicable).

  31. Subject 29-day mortality [ Time Frame: Day 1 through Day 29 ]
    Date and cause of death (if applicable).

  32. Time to an improvement of one category using an ordinal scale [ Time Frame: Day 1 through Day 29 ]
    Clinical outcome assessed using ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care; 4) Hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (COVID-19 related or otherwise); 5) Hospitalized, requiring supplemental oxygen; 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8) Death.

  33. Time to an improvement of two categories using an ordinal scale [ Time Frame: Day 1 through Day 29 ]
    Clinical outcome assessed using ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care; 4) Hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (COVID-19 related or otherwise); 5) Hospitalized, requiring supplemental oxygen; 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8) Death.

  34. Time to death [ Time Frame: Day 1 through Day 29 ]
  35. Time to discharge or to a National Early Warning Score (NEWS) of < / = 2 and maintained for 24 hours, whichever occurs first [ Time Frame: Day 1 through Day 29 ]
    The NEW score has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is based on 7 clinical parameters (respiration rate, oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness). The NEW Score is being used as an efficacy measure.

  36. Ventilator/ extracorporeal membrane oxygenation (ECMO) use [ Time Frame: Day 1 through Day 29 ]
    Measured in days.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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. Has laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR) or other commercial or public health assay in any specimen, as documented by either of the following:

    • PCR positive in sample collected < 72 hours prior to randomization; OR
    • PCR positive in sample collected >/= 72 hours prior to randomization, but < 7 days prior to randomization AND progressive disease suggestive of ongoing SARS-CoV-2 infection.

    Note: if written documentation of the positive test result is not available at the time of enrollment (e.g., report came from other institution), the subject may be enrolled but the PCR should be repeated at the time of enrollment.

  6. Illness of any duration, and requiring supplemental oxygen, mechanical ventilation or Extracorporeal Membrane Oxygenation (ECMO).
  7. Women of childbearing potential must agree to either abstinence or use at least one primary form of contraception* not including hormonal contraception from the time of screening through day 29.

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

  8. Agrees to not participate in another clinical trial (both pharmacologic and other types of interventions) for the treatment of COVID-19 through Day 60.

Exclusion Criteria:

  1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 times the upper limit of normal.
  2. Subjects with an estimated glomerular filtration rate (eGFR) < 30 mL/min are excluded unless in the opinion of the principal investigator (PI), the potential benefit of receiving remdesivir outweighs the potential risk of study participation.
  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 three or more doses of remdesivir prior to study enrollment.
  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 (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 judgement of the investigator, the risk of immunosuppression with risankizumab is larger than the risk of COVID-19.
  13. Received any live vaccine in the 4 weeks prior to screening.
  14. Known active tuberculosis.
  15. Known history of HIV, Hepatitis B (HBV) or untreated hepatitis C (HCV) infection.
  16. History of pulmonary alveolar proteinosis (PAP).
  17. Has active malignancy, 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04583956


Contacts
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Contact: 20-0013 Central Contact 13017617948 DMIDClinicalTrials@niaid.nih.gov

Locations
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United States, Arizona
Mayo Clinic, Phoenix - Infectious Diseases Not yet recruiting
Phoenix, Arizona, United States, 85054-4502
The University of Arizona - Banner University Medical Center Tucson Campus - Tucson Not yet recruiting
Tucson, Arizona, United States, 85724-0001
United States, California
Kern Medical Center Not yet recruiting
Bakersfield, California, United States, 93306-4018
Stanford University - Stanford Hospital and Clinics - Pediatrics - Infectious Diseases Not yet recruiting
Stanford, California, United States, 94305-2200
United States, Florida
Advent Health Orlando - Critical Care Not yet recruiting
Orlando, Florida, United States, 32803
United States, Georgia
Emory Vaccine Center - The Hope Clinic Recruiting
Decatur, Georgia, United States, 30030-1705
United States, Illinois
Cook County Health and Hospitals System - Ruth M Rothstein CORE Center Not yet recruiting
Chicago, Illinois, United States, 60612
United States, Massachusetts
Brigham and Women's Hospital - Infectious Diseases Not yet recruiting
Boston, Massachusetts, United States, 02115-6110
United States, New Jersey
Virtua Health - Virtua Voorhees Hospital - Pulmonology Not yet recruiting
Voorhees, New Jersey, United States, 08043
United States, New York
Jacobi Medical Center Not yet recruiting
Bronx, New York, United States, 10461-1119
Mount Sinai School of Medicine - Medicine - Infectious Diseases Not yet recruiting
New York, New York, United States, 10029-6504
United States, North Carolina
Wake Forest Baptist Health - Infectious Diseases Not yet recruiting
Winston-Salem, North Carolina, United States, 27157
United States, Ohio
University of Toledo Medical Center - Ruppert Clinic Recruiting
Toledo, Ohio, United States, 43614
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT04583956    
Other Study ID Numbers: 20-0013A
First Posted: October 12, 2020    Key Record Dates
Last Update Posted: November 17, 2020
Last Verified: October 8, 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Adults
COVID-19
Multicenter
Platform
Putative
Therapeutics