NCT04583969

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

Completed Phase 2 Results posted Last updated 5 June 2023

What this trial tests

Phase 2 trial testing Lenzilumab in COVID-19 in 527 participants. Completed in 22 April 2022.

Timeline

23 October 2020

Primary endpoint
22 April 2022

22 April 2022

Quick facts

Lead sponsor	National Institute of Allergy and Infectious Diseases (NIAID)
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	527
Start date	23 October 2020
Primary completion	22 April 2022
Estimated completion	22 April 2022
Sites	55 locations across United States, South Korea

Drugs / interventions tested

• Lenzilumab — full drug profile →
• Placebo
• Remdesivir (remdesivir) — full drug profile →

Conditions studied

• COVID-19 — all drugs for COVID-19 →

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Who can join

Adults 18 to 99, any sex, with COVID-19. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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 Primary · Day 1 through Day 29

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.

Group	Value	95% CI
Remdesivir + Lenzilumab	0.85	0.80 – 0.90
Remdesivir + Placebo	0.84	0.78 – 0.89

Proportion of Participants Alive and Without Mechanical Ventilation Through Day 29 in Participants With Any Baseline Ordinal Score Secondary · Day 1 through Day 29

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.

Group	Value	95% CI
Remdesivir + Lenzilumab	0.83	0.78 – 0.87
Remdesivir + Placebo	0.80	0.75 – 0.85

Time to Sustained Recovery in Participants With a Baseline Ordinal Score of 5 or 6, CRP<150mg/L and Age <85 Years Secondary · Day 1 through Day 60

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 ongoin

Group	Value	95% CI
Remdesivir + Lenzilumab	8.0	6.0 – 9.0
Remdesivir + Placebo	7.0	6.0 – 8.0

Time to Sustained Recovery in Participants With Any Baseline Ordinal Score Secondary · Day 1 through Day 60

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.

Group	Value	95% CI
Remdesivir + Lenzilumab	8.0	7.0 – 9.0
Remdesivir + Placebo	8.0	6.0 – 9.0

Number of Participants Meeting Criteria for Each of the 8 Ordinal Scale Categories on Day 8 Secondary · 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

Group	Value	95% CI
Remdesivir + Lenzilumab	36
Remdesivir + Placebo	38
Remdesivir + Lenzilumab	71
Remdesivir + Placebo	69
Remdesivir + Lenzilumab	3
Remdesivir + Placebo	0
Remdesivir + Lenzilumab	8
Remdesivir + Placebo	8

Change From Baseline in C-Reactive Protein (CRP) Secondary · Days 1, 3, 5, 8, 11, 15, 29

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.

Day 3

Group	Value	95% CI
Remdesivir + Lenzilumab	-56.006	± 111.701
Remdesivir + Placebo	-41.259	± 67.158

Day 5

Group	Value	95% CI
Remdesivir + Lenzilumab	-62.300	± 125.644
Remdesivir + Placebo	-36.272	± 112.545

Day 8

Group	Value	95% CI
Remdesivir + Lenzilumab	-73.118	± 162.628
Remdesivir + Placebo	-49.618	± 88.759

Day 11

Group	Value	95% CI
Remdesivir + Lenzilumab	-33.713	± 112.260
Remdesivir + Placebo	-48.647	± 108.481

Day 15

Group	Value	95% CI
Remdesivir + Lenzilumab	-48.847	± 95.126
Remdesivir + Placebo	-61.548	± 75.000

Day 29

Group	Value	95% CI
Remdesivir + Lenzilumab	-65.175	± 82.724
Remdesivir + Placebo	-70.728	± 73.967

Change From Baseline in D-dimer Secondary · Days 1, 3, 5, 8, 11, 15, 29

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.

Day 3

Group	Value	95% CI
Remdesivir + Lenzilumab	496.548	± 5714.241
Remdesivir + Placebo	994.162	± 5752.139

Day 5

Group	Value	95% CI
Remdesivir + Lenzilumab	1779.571	± 7877.791
Remdesivir + Placebo	2704.873	± 11751.741

Day 8

Group	Value	95% CI
Remdesivir + Lenzilumab	2104.619	± 8930.666
Remdesivir + Placebo	1544.558	± 13145.089

Day 11

Group	Value	95% CI
Remdesivir + Lenzilumab	1937.748	± 9253.749
Remdesivir + Placebo	1304.639	± 6733.679

Day 15

Group	Value	95% CI
Remdesivir + Lenzilumab	184.022	± 6162.040
Remdesivir + Placebo	422.458	± 6104.354

Day 29

Group	Value	95% CI
Remdesivir + Lenzilumab	-328.954	± 5271.468
Remdesivir + Placebo	-736.771	± 4978.655

Change From Baseline in Ferritin Secondary · Days 1, 3, 5, 8, 11, 15, 29

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.

Day 3

Group	Value	95% CI
Remdesivir + Lenzilumab	-156.894	± 1248.855
Remdesivir + Placebo	-204.033	± 584.563

Day 5

Group	Value	95% CI
Remdesivir + Lenzilumab	-303.466	± 1400.684
Remdesivir + Placebo	-254.803	± 1396.688

Day 8

Group	Value	95% CI
Remdesivir + Lenzilumab	-494.266	± 1042.361
Remdesivir + Placebo	-403.031	± 889.021

Day 11

Group	Value	95% CI
Remdesivir + Lenzilumab	-453.304	± 1209.069
Remdesivir + Placebo	-426.838	± 1166.825

Day 15

Group	Value	95% CI
Remdesivir + Lenzilumab	-304.447	± 1013.592
Remdesivir + Placebo	-552.903	± 907.992

Day 29

Group	Value	95% CI
Remdesivir + Lenzilumab	-645.899	± 1246.980
Remdesivir + Placebo	-839.410	± 1002.701

Change From Baseline in Fibrinogen Secondary · Days 1, 3, 5, 8, 11, 15, 29

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. Higher results are better, so a higher positive change from baseline indicates a more favorable outcome.

Day 3

Group	Value	95% CI
Remdesivir + Lenzilumab	-90.5	± 109.1
Remdesivir + Placebo	-90.3	± 121.8

Day 5

Group	Value	95% CI
Remdesivir + Lenzilumab	-94.3	± 415.2
Remdesivir + Placebo	-104.9	± 171.6

Day 8

Group	Value	95% CI
Remdesivir + Lenzilumab	-126.6	± 200.5
Remdesivir + Placebo	-120.8	± 208.7

Day 11

Group	Value	95% CI
Remdesivir + Lenzilumab	-47.8	± 238.4
Remdesivir + Placebo	-83.5	± 260.9

Day 15

Group	Value	95% CI
Remdesivir + Lenzilumab	-53.4	± 229.6
Remdesivir + Placebo	-70.0	± 208.1

Day 29

Group	Value	95% CI
Remdesivir + Lenzilumab	-145.7	± 177.2
Remdesivir + Placebo	-118.9	± 191.4

Change From Baseline in Alanine Aminotransferase (ALT) Secondary · Days 1, 3, 5, 8, 11, 15, 29

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.

Day 3

Group	Value	95% CI
Remdesivir + Lenzilumab	6.4	± 42.6
Remdesivir + Placebo	4.0	± 34.0

Day 5

Group	Value	95% CI
Remdesivir + Lenzilumab	29.3	± 146.8
Remdesivir + Placebo	29.7	± 189.1

Day 8

Group	Value	95% CI
Remdesivir + Lenzilumab	19.7	± 108.8
Remdesivir + Placebo	9.2	± 108.3

Day 11

Group	Value	95% CI
Remdesivir + Lenzilumab	9.8	± 71.6
Remdesivir + Placebo	7.8	± 83.4

Day 15

Group	Value	95% CI
Remdesivir + Lenzilumab	15.7	± 71.5
Remdesivir + Placebo	-2.5	± 48.5

Day 29

Group	Value	95% CI
Remdesivir + Lenzilumab	17.3	± 158.5
Remdesivir + Placebo	12.4	± 256.0

Change From Baseline in Aspartate Transaminase (AST) Secondary · Days 1, 3, 5, 8, 11, 15, 29

Blood to evaluate AST 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.

Day 3

Group	Value	95% CI
Remdesivir + Lenzilumab	-5.9	± 41.2
Remdesivir + Placebo	-7.5	± 31.7

Day 5

Group	Value	95% CI
Remdesivir + Lenzilumab	-1.0	± 64.5
Remdesivir + Placebo	12.2	± 276.7

Day 8

Group	Value	95% CI
Remdesivir + Lenzilumab	-17.7	± 46.6
Remdesivir + Placebo	-1.8	± 243.0

Day 11

Group	Value	95% CI
Remdesivir + Lenzilumab	-16.6	± 77.7
Remdesivir + Placebo	1.5	± 194.7

Day 15

Group	Value	95% CI
Remdesivir + Lenzilumab	-9.6	± 55.7
Remdesivir + Placebo	-21.0	± 40.0

Day 29

Group	Value	95% CI
Remdesivir + Lenzilumab	-9.6	± 51.8
Remdesivir + Placebo	17.4	± 404.9

Change From Baseline in Creatinine Secondary · Days 1, 3, 5, 8, 11, 15, 29

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.

Day 3

Group	Value	95% CI
Remdesivir + Lenzilumab	-0.060	± 0.134
Remdesivir + Placebo	-0.028	± 0.215

Day 5

Group	Value	95% CI
Remdesivir + Lenzilumab	-0.053	± 0.307
Remdesivir + Placebo	-0.019	± 0.392

Day 8

Group	Value	95% CI
Remdesivir + Lenzilumab	-0.020	± 0.672
Remdesivir + Placebo	-0.038	± 0.379

Day 11

Group	Value	95% CI
Remdesivir + Lenzilumab	0.012	± 0.715
Remdesivir + Placebo	0.210	± 0.875

Day 15

Group	Value	95% CI
Remdesivir + Lenzilumab	-0.037	± 0.321
Remdesivir + Placebo	0.188	± 0.868

Day 29

Group	Value	95% CI
Remdesivir + Lenzilumab	0.049	± 0.612
Remdesivir + Placebo	0.155	± 0.986

Adverse events — posted to ClinicalTrials.gov

Time frame: Grade 3 and 4 serious and non-serious adverse events were collected for 60 days after the first dose. Laboratory values were systematically assessed at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Remdesivir + Lenzilumab

Serious: 76/264 (29%)

Deaths: 31/272

Remdesivir + Placebo

Serious: 81/250 (32%)

Deaths: 38/255

Serious adverse events (90 terms)

Reaction	System	Remdesivir + Lenzilumab	Remdesivir + Placebo
Respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—
Acute kidney injury	Renal and urinary disorders	—	—
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	—	—
Pneumonia	Infections and infestations	—	—
Septic shock	Infections and infestations	—	—
Pneumonia bacterial	Infections and infestations	—	—
Hypoxia	Respiratory, thoracic and mediastinal disorders	—	—
Pneumothorax	Respiratory, thoracic and mediastinal disorders	—	—
Respiratory distress	Respiratory, thoracic and mediastinal disorders	—	—
Shock	Vascular disorders	—	—
Sepsis	Infections and infestations	—	—
Deep vein thrombosis	Vascular disorders	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—
Arrhythmia	Cardiac disorders	—	—
COVID-19 pneumonia	Infections and infestations	—	—
Acute respiratory distress syndrome	Respiratory, thoracic and mediastinal disorders	—	—
Pneumomediastinum	Respiratory, thoracic and mediastinal disorders	—	—
Hypotension	Vascular disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Acute myocardial infarction	Cardiac disorders	—	—
Atrial fibrillation	Cardiac disorders	—	—
Cardiac arrest	Cardiac disorders	—	—
Pulseless electrical activity	Cardiac disorders	—	—
Gastrointestinal haemorrhage	Gastrointestinal disorders	—	—

Other adverse events (4 terms — click to expand)

Reaction	System	Remdesivir + Lenzilumab	Remdesivir + Placebo
Lymphocyte count decreased	Investigations	—	—
Hypertension	Vascular disorders	—	—
Hypoxia	Respiratory, thoracic and mediastinal disorders	—	—
Glomerular filtration rate decreased	Investigations	—	—

Most-reported serious reactions: Respiratory failure, Acute respiratory failure, Acute kidney injury, Pulmonary embolism, Pneumonia, Septic shock, Pneumonia bacterial, Hypoxia.

Data from ClinicalTrials.gov NCT04583969 adverse events section.

Sponsor's own 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. 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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. The signal pathways and treatment of cytokine storm in COVID-19.
   Yang L, Xie X, Tu Z, Fu J, et al · · 2021 · cited 429× · PMID 34234112 · DOI 10.1038/s41392-021-00679-0
2. Antibodies to watch in 2022.
   Kaplon H, Chenoweth A, Crescioli S, Reichert JM. · · 2022 · cited 245× · PMID 35030985 · DOI 10.1080/19420862.2021.2014296
3. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19.
   Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, et al · · 2021 · cited 126× · PMID 34473343 · DOI 10.1002/14651858.cd013825.pub2
4. Potential therapeutic options for COVID-19: an update on current evidence.
   Niknam Z, Jafari A, Golchin A, Danesh Pouya F, et al · · 2022 · cited 91× · PMID 35027080 · DOI 10.1186/s40001-021-00626-3
5. An update to monoclonal antibody as therapeutic option against COVID-19.
   Deb P, Molla MMA, Saif-Ur-Rahman KM. · · 2021 · cited 91× · PMID 33585808 · DOI 10.1016/j.bsheal.2021.02.001
6. Remdesivir for the treatment of COVID-19.
   Ansems K, Grundeis F, Dahms K, Mikolajewska A, et al · · 2021 · cited 89× · PMID 34350582 · DOI 10.1002/14651858.cd014962
7. COVID-19 in immunocompromised populations: implications for prognosis and repurposing of immunotherapies.
   Goldman JD, Robinson PC, Uldrick TS, Ljungman P. · · 2021 · cited 88× · PMID 34117116 · DOI 10.1136/jitc-2021-002630
8. Remdesivir for the treatment of COVID-19.
   Grundeis F, Ansems K, Dahms K, Thieme V, et al · · 2023 · cited 55× · PMID 36695483 · DOI 10.1002/14651858.cd014962.pub2