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

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ClinicalTrials.gov Identifier: NCT04583969
Recruitment Status : Recruiting
First Posted : October 12, 2020
Last Update Posted : October 20, 2021
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 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.


Condition or disease Intervention/treatment Phase
COVID-19 Biological: Lenzilumab Other: Placebo Drug: Remdesivir 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 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. 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 to 1) 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

Email: DMIDClinicalTrials@niaid.nih.gov

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 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 19, 2020
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021

Arm Intervention/treatment
Experimental: Remdesivir + Lenzilumab
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=100.
Biological: Lenzilumab
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.

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

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 600-mg IV lenzilumab placebo infusion every 8 hours starting on Day 1 for a total of 3 doses. N=100.
Other: Placebo
Placebo for lenzilumab is commercially sourced 0.9% sodium chloride.

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




Primary Outcome Measures :
  1. Time to ventilation or death in subjects with a baseline score of 5 or 6 [ Time Frame: Day 1 through Day 29 ]

    Subjects in ordinal scores 5 or 6 at baseline with a CRP<150 mg/L at baseline and age<85 years, where the event is described as being in one of these two categories:

    7. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8. Death.



Secondary Outcome Measures :
  1. Change from baseline of inflammation and coagulation markers [ Time Frame: Day 1 through Day 29 ]
    Markers include C-reactive protein (CRP), ferritin, D-dimer, fibrinogen, and lactate dehydrogenase (LDH).

  2. Change in alanine aminotransferase (ALT) over time [ Time Frame: Day 1 through Day 29 ]
  3. Change in aspartate transaminase (AST) over time [ Time Frame: Day 1 through Day 29 ]
  4. Change in creatinine over time [ Time Frame: Day 1 through Day 29 ]
  5. Change in hemoglobin over time [ Time Frame: Day 1 through Day 29 ]
  6. Change in international normalized ratio (INR) over time [ Time Frame: Day 1 through Day 29 ]
  7. Change in platelets over time [ Time Frame: Day 1 through Day 29 ]
  8. Change in total bilirubin over time [ Time Frame: Day 1 through Day 29 ]
  9. Change in white blood cell (WBC) count with differential over time [ Time Frame: Day 1 through Day 29 ]
  10. Clinical status on an 8-point ordinal scale. [ Time Frame: Day 8 through Day 29 ]
    Clinical status assessed using ordinal scale: 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, continuous positive airway pressure (CPAP) or bilevel positive airway pressure (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 but 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 high flow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8) Death.

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

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

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

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

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

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

  19. Incidence of new non-invasive ventilation or high flow oxygen use [ Time Frame: Day 1 through Day 29 ]
  20. Incidence of ventilator/ extracorporeal membrane oxygenation (ECMO) use [ Time Frame: Day 1 through Day 29 ]
    Measured in days.

  21. Mean change in the ordinal scale [ Time Frame: Day 1 through Day 29 ]
    Clinical status assessed using ordinal scale: 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, continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP); 3) Hospitalized, not requiring new or increased supplemental oxygen - no longer requires ongoing medical care.

  22. Subject Mortality [ Time Frame: Day 1 through Day 60 ]
    Date and cause of death (if applicable)

  23. Supplemental oxygen use [ Time Frame: Day 1 through Day 29 ]
    Measured in days

  24. The proportion of subjects with any baseline score who are alive and without respiratory failure [ Time Frame: Day 29 ]
    Subjects who did not meet either of the following two categories on Day 29: 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8) Death.

  25. Time to an improvement of one category using an ordinal scale [ Time Frame: Day 1 through Day 29 ]
    Clinical status assessed using ordinal scale: 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8) Death.

  26. Time to an improvement of two categories using an ordinal scale [ Time Frame: Day 1 through Day 29 ]
    Clinical status assessed using ordinal scale: 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, continuous positive airway pressure (CPAP) or bilevel positive airway pressure (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 but 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 high flow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8) Death.

  27. Time to death [ Time Frame: Day 1 through Day 29 ]
  28. Time to Sustained Recovery in subjects with a baseline score of 5 or 6 [ Time Frame: Day 1 through Day 29 ]

    Day of recovery is defined as the first day on which the subject satisfies 1. of the following 3 categories from the ordinal scale (and does not return to a score of 4 or higher for the remainder of the study period):

    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;

  29. Time to sustained recovery of subjects with any baseline score [ Time Frame: Day 1 through Day 29 ]

    Day of recovery is defined as the first day on which the subject satisfies 1. of the following 3 categories from the ordinal scale (and does not return to a score of 4 or higher for the remainder of the study period):

    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

  30. Time to ventilation or death in subjects with any baseline score [ Time Frame: Day 1 through Day 29 ]

    Ventilation or death is defined as being in one of these two categories at any point through Day 29:

    7. Hospitalized, on invasive mechanical ventilation or ECMO (OS5 or 6 only); 8. Death. In those subjects who are at ordinal score 7 at baseline, the event is defined as death.


  31. Ventilator/ extracorporeal membrane oxygenation (ECMO) use [ Time Frame: Day 1 through Day 29 ]


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:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 </=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 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 intraperitoneal (IP) dosing.

    * 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 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 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 small molecule tyrosine kinase inhibitors, including Janus kinase (JAK) inhibitors (e.g., baricitinib, ibrutinib, acalabrutinib, imatinib, gefitinib), in the 4 weeks prior to screening.
  8. 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.
  9. 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.
  10. Received granulocyte-macrophage colony-stimulating factor (GM-CSF) agents (e.g., sargramostim) within 2 months prior to screening.
  11. 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).
  12. Received any live vaccine in the 4 weeks prior to screening.
  13. Known active tuberculosis.
  14. Known history of Human Immunodeficiency Virus (HIV), Hepatitis B (HBV) or untreated hepatitis C (HCV) infection.
  15. History of pulmonary alveolar proteinosis (PAP).
  16. Has a malignancy currently receiving immunosuppressive chemotherapy, immunodeficiency, uncontrolled opportunistic infection, or uncontrolled cirrhosis.
  17. Has a medical condition that could, in the judgment of the investigator, limit the interpretation and generalizability of trial results.
  18. Positive test for influenza virus during the current illness (influenza testing is not required by protocol).
  19. Previous participation in an ACTIV-5/Big Effect Trial (BET).

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): NCT04583969


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

Locations
Show Show 62 study locations
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT04583969    
Other Study ID Numbers: 20-0013B
First Posted: October 12, 2020    Key Record Dates
Last Update Posted: October 20, 2021
Last Verified: July 21, 2021

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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
Putative
Therapeutics
Additional relevant MeSH terms:
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COVID-19
Respiratory Tract Infections
Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Remdesivir
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents