Phase 2
Completed N=527
ACTIV-5 / Big Effect Trial (BET-B) for the Treatment of COVID-19
Source: ClinicalTrials.gov NCT04583969 ↗Enrolled (actual)
527
Serious AEs
30.5%
Results posted
Jun 2023
Primary outcomePrimary: 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 — 0.85; 0.84 Proportion of participants — p=0.691
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.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY 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 |
0.85; 0.84 | 0.691 |
| SECONDARY Proportion of Participants Alive and Without Mechanical Ventilation Through Day 29 in Participants With Any Baseline Ordinal Score |
0.83; 0.80 | 0.378 |
| SECONDARY Time to Sustained Recovery in Participants With a Baseline Ordinal Score of 5 or 6, CRP<150mg/L and Age <85 Years |
8.0; 7.0 | 0.689 |
| SECONDARY Time to Sustained Recovery in Participants With Any Baseline Ordinal Score |
8.0; 8.0 | 0.718 |
| SECONDARY Number of Participants Meeting Criteria for Each of the 8 Ordinal Scale Categories on Day 8 |
36; 38; 71; 69; 3; 0 | 0.907 |
| SECONDARY Change From Baseline in C-Reactive Protein (CRP) |
-56.006; -41.259; -62.300; -36.272; -73.118; -49.618 | — |
| SECONDARY Change From Baseline in D-dimer |
496.548; 994.162; 1779.571; 2704.873; 2104.619; 1544.558 | — |
| SECONDARY Change From Baseline in Ferritin |
-156.894; -204.033; -303.466; -254.803; -494.266; -403.031 | — |
| SECONDARY Change From Baseline in Fibrinogen |
-90.5; -90.3; -94.3; -104.9; -126.6; -120.8 | — |
| SECONDARY Change From Baseline in Alanine Aminotransferase (ALT) |
6.4; 4.0; 29.3; 29.7; 19.7; 9.2 | — |
| SECONDARY Change From Baseline in Aspartate Transaminase (AST) |
-5.9; -7.5; -1.0; 12.2; -17.7; -1.8 | — |
| SECONDARY Change From Baseline in Creatinine |
-0.060; -0.028; -0.053; -0.019; -0.020; -0.038 | — |
| SECONDARY Change From Baseline in International Normalized Ratio (INR) |
0.01352; 0.05065; -0.00790; 0.10552; -0.07588; 0.13077 | — |
| SECONDARY Change From Baseline in Hemoglobin |
-0.27; -0.20; -0.31; -0.34; -0.50; -0.48 | — |
| SECONDARY Change From Baseline in Platelets Count |
52.99; 47.61; 84.38; 72.92; 103.33; 83.09 | — |
| SECONDARY Change From Baseline in Total Bilirubin |
-0.049; -0.039; 0.064; 0.007; 0.082; 0.068 | — |
| SECONDARY Change From Baseline in White Blood Cell (WBC) Count |
1.1678; 1.7775; 3.1761; 2.4411; 5.9017; 4.6654 | — |
| SECONDARY Change From Baseline in Neutrophils |
0.4146; 1.4128; 1.8626; 1.5750; 4.2520; 3.5547 | — |
| SECONDARY Change From Baseline in Eosinophils |
0.00234; 0.00298; 0.03413; 0.02668; 0.08446; 0.05383 | — |
| SECONDARY Change From Baseline in Basophils |
0.01003; 0.01082; 0.00944; 0.01103; 0.00680; 0.01679 | — |
| SECONDARY Change From Baseline in Lymphocytes |
0.4191; 0.2191; 0.4585; 0.2772; 0.6283; 0.2002 | — |
| SECONDARY Change From Baseline in Monocytes |
0.2490; 0.1750; 0.3012; 0.1275; 0.4774; 0.1794 | — |
| SECONDARY Number of Participants Reporting Grade 3, 4, or 5 Clinical and/or Laboratory Adverse Events (AEs) |
133; 124 | — |
| SECONDARY Number of Participants Reporting Serious Adverse Events (SAEs) |
76; 81 | — |
| SECONDARY Number of Participants Who Discontinued or Temporarily Suspended Study Treatment |
6; 20 | — |
| SECONDARY Duration of Hospitalization |
8.0; 8.0; 8.0; 8.0 | — |
| SECONDARY Days of Invasive Mechanical Ventilation/Extracorporeal Membrane Oxygenation (ECMO) Use |
0.0; 0.0 | — |
| SECONDARY Days of New Mechanical Ventilation or Extracorporeal Membrane Oxygenation (ECMO) Use |
0.0; 0.0 | — |
| SECONDARY Days of Non-invasive Ventilation/High Flow Oxygen Use |
1.0; 2.0 | — |
| SECONDARY Days of New Non-invasive Ventilation/High Flow Oxygen Use |
0.0; 0.0 | — |
| SECONDARY Days of Supplemental Oxygen Use |
13.5; 14.0 | — |
| SECONDARY Number of Participants With New Invasive Mechanical Ventilation / Extracorporeal Membrane Oxygenation (ECMO) Use |
44; 47 | — |
| SECONDARY Number of Participants With New Non-invasive Ventilation/High Flow Oxygen Use |
49; 62 | — |
| SECONDARY Mean Change in Ordinal Scale |
0.0; 0.1; -0.3; -0.2; -1.3; -1.3 | — |
| SECONDARY 14-day Participant Mortality |
0.05; 0.07 | — |
| SECONDARY 28-day Participant Mortality |
0.10; 0.12 | — |
| SECONDARY 59-day Participant Mortality |
0.12; 0.16 | — |
| SECONDARY Proportion of Participants Not Meeting Criteria for One of Two Ordinal Scale Categories at Day 29 |
0.86; 0.83 | — |
| SECONDARY Time to an Improvement of One Category From Baseline Using an Ordinal Scale |
8.0; 7.0 | 0.609 |
| SECONDARY Time to an Improvement of Two Categories From Baseline Using an Ordinal Scale |
13.0; 13.0 | 0.708 |
| SECONDARY Time to Death |
NA; NA | — |
Eligibility Criteria
Inclusion Criteria
- Admitted to a hospital with symptoms suggestive of Coronavirus Disease 2019 (COVID-19) and requires ongoing medical care.
- Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures.
- Subject (or legally authorized representative) understands and agrees to comply with planned study procedures.
- Male or non-pregnant female adult >/= 18 years of age at time of enrollment.
- 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 5 times the upper limit of normal.
- Subjects with a low glomerular filtration rate (eGFR), specifically:
- 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.
- All subjects with a glomerular filtration rate (eGFR) <20 mL/min (including hemodialysis and hemofiltration) are excluded.
- Pregnancy or breast feeding.
- Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours of enrollment.
- Allergy to any study medication.
- Received five or more doses of remdesivir prior to screening.
- 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.
- 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.
- 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.
- Received granulocyte-macrophage colony-stimulating factor (GM-CSF) agents (e.g., sargramostim) within 2 months prior to screening.
- 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).
- Received any live vaccine in the 4 weeks prior to screening.
- Known active tuberculosis.
- Known history of Human Immunodeficiency Virus (HIV), Hepatitis B (HBV) or untreated hepatitis C (HCV) infection.
- History of pulmonary alveolar proteinosis (PAP).
- Has a malignancy currently receiving immunosuppressive chemotherapy, immunodeficiency, uncontrolled opportunistic infection, or uncontrolled cirrhosis.
- Has a medical condition that could, in the judgment of the investigator, limit the interpretation and generalizability of trial results.
- Positive test for influenza virus during the current illness (influenza testing is not required by protocol).
- Previous participation in an ACTIV-5/Big Effect Trial (BET).
Data sourced from ClinicalTrials.gov (NCT04583969). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.