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

National Institute of Allergy and Infectious Diseases (NIAID)527 enrolled

Overview

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

Eligibility

Sex: ALLMin age: 18 YearsMax age: 99 Years

Medical Language ↔ Plain English

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).

Outcomes

Primary Outcomes

Proportion of Participants Alive and Without Mechanical Ventilation Through Day 29 in Participants With Baseline Ordinal Score of 5 or 6, C-reactive Protein (CRP)<150mg/L and Age <85 Years

Ordinal scale categories include 7) Hospitalized, on Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation (ECMO) and 8) Death. Mechanical ventilation-free survival was assessed through Day 29, defined as the proportion of participants who had not died nor were hospitalized on invasive mechanical ventilation or ECMO from Day 1 through Day 29. Estimates for the proportions are estimated from a logistic regression model adjusted for baseline dexamethasone, baseline ordinal score, age (continuous), and baseline CRP.

Time frame: Day 1 through Day 29

Secondary Outcomes

Proportion of Participants Alive and Without Mechanical Ventilation Through Day 29 in Participants With Any Baseline Ordinal Score

Mechanical ventilation-free survival was assessed through Day 29, defined as the proportion of participants who had not died nor were hospitalized on invasive mechanical ventilation or ECMO from Day 1 through Day 29. Estimates for the proportions are estimated from a logistic regression model adjusted for baseline dexamethasone, baseline ordinal score, age (continuous), and baseline CRP.

Time frame: Day 1 through Day 29

Time to Sustained Recovery in Participants With a Baseline Ordinal Score of 5 or 6, CRP<150mg/L and Age <85 Years

Day of sustained recovery is defined as the first day on which the participant satisfies 1 of the following 3 categories from the clinical status ordinal scale (and does not return to a score of = 4 up to and including Study Day 60): 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.

Time frame: Day 1 through Day 60

Time to Sustained Recovery in Participants With Any Baseline Ordinal Score

Day of sustained recovery is defined as the first day on which the participant satisfies 1 of the following 3 categories from the clinical status ordinal scale (and does not return to a score of = 4 up to and including Study Day 60): 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.

Time frame: Day 1 through Day 60

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

Time frame: Day 8

Change From Baseline in C-Reactive Protein (CRP)

Blood was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge. Lower results are better, so a higher negative change from baseline indicates a more favorable outcome.