Covid-19 living Data

Bamlanivimab vs Placebo (RCT)

Mild outpatients

FOREST PLOTS -2023-01-06

Studies description

Trial NCT04427501
Publication BLAZE-1 - Chen P, N Engl J Med (2020) (published paper)
Dates: 2020-06-17 to 2020-08-21
Funding: Private (Eli Lilly)
Conflict of interest: Yes

Methods
	RCT Blinding:
	Location : Multicenter / USA Follow-up duration (days): 29
Inclusion criteria	≥18 years of age at the time of randomization Not hospitalized One or more mild or moderate COVID-19 symptoms (Fever, cough, sore throat, malaise, headache, muscle pain, gastrointestinal symptoms, or shortness of breath with exertion) Sample taken for test confirming viral infection no more than 3 days prior to starting the drug infusion Men or non-pregnant women who agree to contraceptive requirements Understand and agree to comply with planned study procedures Agree to the collection of nasopharyngeal swabs and venous blood Participant or legally authorized representative give signed informed consent
Exclusion criteria	Oxygen saturation (SpO2) less than or equal to (≤)93 percent (%) on room air at sea level or ratio of arterial oxygen partial pressure (PaO2 in millimeters of mercury) to fractional inspired oxygen (FiO2) less than (<)300, respiratory rate greater than or equal to (≥)30 per minute, heart rate ≥125 per minute Require mechanical ventilation or anticipated impending need for mechanical ventilation Have known allergies to any of the components used in the formulation of the interventions Have hemodynamic instability requiring use of pressors within 24 hours of randomization Suspected or proven serious, active bacterial, fungal, viral, or other infection (besides COVID-19) that in the opinion of the investigator could constitute a risk when taking intervention Have any co-morbidity requiring surgery within <7 days, or that is considered life-threatening within 29 days Have any serious concomitant systemic disease, condition or disorder that, in the opinion of the investigator, should preclude participation in this study Have a history of a positive SARS-CoV-2 serology test Have a history of a positive SARS-CoV-2 test prior to the one serving as eligibility for this study Have received an investigational intervention for SARS-CoV-2 prophylaxis within 30 days before dosing Have received treatment with a SARS-CoV-2 specific monoclonal antibody Have a history of convalescent COVID-19 plasma treatment Have participated in a previous SARS-CoV-2 vaccine study Have participated, within the last 30 days, in a clinical study involving an investigational intervention. If the previous investigational intervention has a long half-life, 5 half-lives or 30 days, whichever is longer, should have passed Are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study Pregnant or breastfeeding
Interventions
	Treatment Bamlanivimab 700/2800/7000mg arms merged, IV, once off for 1 hour.
	Control Placebo
Participants
	Randomized participants : Bamlanivimab=317 Placebo=150
	Characteristics of participants N= 467 Mean age : NR 203 males Severity : Mild: n= 452/ Asymptomatic: n=0
Primary outcome
	In the register Change from Baseline to Day 11 in SARS-CoV-2 Viral Load
	In the report Change from baseline in the SARS-CoV-2 viral load at day 11 (±4 days) after positive results on testing.
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Low
General comment	In addition to the published article, the trial registry, protocol, statistical plan, supplementary materials and response from contact with authors were used in data extraction and assessment of risk of bias. The published report was a preplanned interim analysis of patients randomized to receive one of three doses of LY-CoV555 (also known as LY3819253) and placebo. The pre-stated sample sizes for these arms were reached. Additional arms in which patients are randomized to receive and combination of LY3819253 and LY3832479 are ongoing. There were some differences in the outcomes included in the trial registry and protocol and the published article. There were no differences in study treatments. This study was updated on December 29th with data received from contact with authors. The study was updated by Gotleib 2021 for all outcomes except hospitalization or death. We consider Gotleib as the updated report except for the outcome hospitalization or death that will be collected from this study.

Trial NCT04518410
Publication ACTIV-2/A5401 - Chew K, Nat Commun (2022) (published paper)
Dates: 2020-10-12 to 2020-11-17
Funding: Mixed (National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Study medication was donated by Eli Lilly and Company.)
Conflict of interest: Yes

Methods
	RCT Blinding: triple blinding
	Location : Multicenter / USA Follow-up duration (days): 168
Inclusion criteria	Adults 18 years of age or older documented SARS-CoV-2 infection by an FDA-authorized antigen or nucleic acid test from a sample collected within 7 days prior to anticipated study entry no more than 10 days of COVID-19 symptoms at time of anticipated study entry ongoing symptoms (not including loss of taste or smell) within 48 hours prior to study entry resting peripheral oxygen saturation levels >=92% without the need for hospitalization
Exclusion criteria	History of or current hospitalization for COVID-19 Any positive SARS-CoV2 nucleic acid or antigen tests from any respiratory tract specimen (e.g., oropharyngeal, NP, or nasal swab, or saliva) collected ˃240 hours prior to study entry Current need for hospitalization or immediate medical attention in the clinical opinion of the site investigator Use of any prohibited medication: hydroxychloroquine (unless used chronically for autoimmune diseases), chloroquine (unless used for a parasitic infection), ivermectin (unless used for a parasitic infection), any antibody-based therapy for COVID-19, remdesivir, fluvoxamine (unless used chronically), colchicine (unless used for reasons other than COVID-19), and HIV protease inhibitors (unless used chronically for HIV infection) and/or use of systemic or inhaled steroids for the purpose of COVID-19 treatment (new or increased dose from chronic baseline) within 30 days prior to study entry Receipt of convalescent COVID-19 plasma or other antibody-based anti-SARS-CoV-2 treatment or prophylaxis at any time prior to study entry Receipt of other available investigational treatments for SARS-CoV-2 at any time prior to study entry. This does not include drugs approved for other uses and taken for those uses. NOTE: This does not include COVID-19 vaccines Known allergy/sensitivity or any hypersensitivity to components of the investigational agent or placebo Any co-morbidity requiring surgery within 7 days prior to study entry, or that is considered life threatening in the opinion of the site investigator within 30 days prior to study entry Currently pregnant or breastfeeding
Interventions
	Treatment Bamlanivimab 700 mg intravenously over 60 minutes
	Control Placebo
Participants
	Randomized participants : Placebo=110 Bamlanivimab=110
	Characteristics of participants N= 220 Mean age : NR 110 males Severity : Mild: n= 225/ Asymptomatic: n=0
Primary outcome
	In the register 1) COVID-19 symptom duration (Phase 2) [ Time Frame: Up to Day 28 ]; 2) Quantification of SARS-CoV-2 RNA (Phase 2) [ Time Frame: Day 3, 7, 14 ]; 3) Proportion of participants with new adverse event (AE) ≥ Grade 3 (Phase 2) [ Time Frame: Thru Day 28 ];
	In the report 1) development of a Grade 3 or higher treatment emergent adverse event (TEAE) through 28 days; 2) detection (detectable versus undetectable)of SARS-CoV-2 RNA from NP swabs at days 3, 7, 14, 21, and 28; 3) duration of targeted COVID-19-associated symptoms from day 0.
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the pre-print article, the trial registry and the overall adaptive platform trial protocol and statistical analysis plan were used in data extraction and assessment of risk of bias. Supplementary materials referred to in the pre-print article were not available at time of extraction. There were minor differences between some primary outcomes in the article and the registry (an additional 28 day timepoint for RT-PCR in the article; additional 21 and 28 day timepoint for of detection (detectable versus undetectable) of SARS-CoV-2 RNA from NP swabs in the article; adverse events were only a phase 3 outcome in the registry); additional primary outcomes in the article were secondary outcomes in the registry. Two participants analyzed in the intervention group were originally randomized to the 7000mg versus placebo cohort in this platform study, but received 700mg in error and were analyzed in the 700mg bamlanivimab cohort. Two participants analyzed in the placebo group were also originally in the 7000mg versus placebo cohort study, but were analyzed against the 700mg group. The study (n=222) achieved the target sample size (n=220) specified in the protocol. This study was updated on November 18th, 2022 with data extracted from the peer-reviewed report.

Trial NCT04518410
Publication ACTIV-2/A5401 - Chew K, Nat Commun (2022) (published paper)
Dates: 2020-08-19 to 2020-11-15
Funding: Mixed (National Institute of Allergy and Infectious Diseases of the National Institutes of Health, US Dept. of Energy, NIH, Los Alamos National Laboratory, Eli Lilly.)
Conflict of interest: Yes

Methods
	RCT Blinding: triple blinding
	Location : Multicenter / USA Follow-up duration (days): 168
Inclusion criteria	Adults 18 years of age or older Documented SARS-CoV-2 infection by an FDA-authorized antigen or nucleic acid test from a sample collected within 7 days prior to anticipated study entry No more than 10 days of COVID-19 symptoms at time of anticipated study entry Ongoing symptoms (not including loss of taste or smell) within 48 hours prior to study entry Resting peripheral oxygen saturation levels >=92% Without the need for hospitalization
Exclusion criteria	History of or current hospitalization for COVID-19 Any positive SARS-CoV2 nucleic acid or antigen tests from any respiratory tract specimen (e.g., oropharyngeal, NP, or nasal swab, or saliva) collected ˃240 hours prior to study entry Current need for hospitalization or immediate medical attention in the clinical opinion of the site investigator Use of any prohibited medication: hydroxychloroquine (unless used chronically for autoimmune diseases), chloroquine (unless used for a parasitic infection), ivermectin (unless used for a parasitic infection), any antibody-based therapy for COVID-19, remdesivir, fluvoxamine (unless used chronically), colchicine (unless used for reasons other than COVID-19), and HIV protease inhibitors (unless used chronically for HIV infection) and/or use of systemic or inhaled steroids for the purpose of COVID-19 treatment (new or increased dose from chronic baseline) within 30 days prior to study entry Receipt of convalescent COVID-19 plasma or other antibody-based anti-SARS-CoV-2 treatment or prophylaxis at any time prior to study entry Receipt of other available investigational treatments for SARS-CoV-2 at any time prior to study entry. This does not include drugs approved for other uses and taken for those uses. NOTE: This does not include COVID-19 vaccines Known allergy/sensitivity or any hypersensitivity to components of the investigational agent or placebo Any co-morbidity requiring surgery within 7 days prior to study entry, or that is considered life threatening in the opinion of the site investigator within 30 days prior to study entry Currently pregnant or breastfeeding
Interventions
	Treatment Bamlanivimab 7000 mg intravenously over 60 minutes
	Control Placebo
Participants
	Randomized participants : Placebo=48 Bamlanivimab =49
	Characteristics of participants N= 97 Mean age : NR 45 males Severity : Mild: n= 98/ Asymptomatic: n=0
Primary outcome
	In the register 1) COVID-19 symptom duration (Phase 2) [ Time Frame: Up to Day 28 ]; 2) Quantification of SARS-CoV-2 RNA (Phase 2) [ Time Frame: Day 3, 7, 14 ]; 3) Proportion of participants with new adverse event (AE) ≥ Grade 3 (Phase 2) [ Time Frame: Thru Day 28 ];
	In the report 1) development of a Grade 3 or higher treatment emergent adverse event (TEAE) through 28 days; 2) detection (detectable versus undetectable)of SARS-CoV-2 RNA from NP swabs at days 3, 7, 14, 21, and 28; 3) duration of targeted COVID-19-associated symptoms from day 0.
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the pre-print article, the trial registry and the overall adaptive platform trial protocol and statistical analysis plan were used in data extraction and assessment of risk of bias. Supplementary materials referred to in the pre-print article were not available at time of extraction. There were minor differences between some primary outcomes in the article and the registry (an additional 28 day timepoint for RT-PCR in the article; additional 21 and 28 day timepoint for of detection (detectable versus undetectable) of SARS-CoV-2 RNA from NP swabs in the article; adverse events were only a phase 3 outcome in the registry); additional primary outcomes in the article were secondary outcomes in the registry. One participant analyzed in the intervention group was originally randomized to the 700mg versus placebo cohort in this platform study, but received 7000mg in error and was analyzed in the 7000mg bamlanivimab cohort. Recruitment to the trial (n = 97) of a 7000mg dose was terminated following outside evidence of no dose-response, and the protocol was adapted to assess a 700mg dose instead. This study was updated on November 18th, 2022 with data extracted from the peer-reviewed report.

Trial NCT04427501
Publication BLAZE-1 - Gottlieb R, JAMA (2021) (published paper)
Dates: 2020-06-17 to 2020-09-03
Funding: Private (Eli Lilly and Company)
Conflict of interest: Yes

Methods
	RCT Blinding: Participants, outcome assessor and health care pro
	Location : Multicenter / USA Follow-up duration (days): 29
Inclusion criteria	1. Are ≥18 years of age at the time of randomization 2. Are currently not hospitalized 3. Have one or more mild or moderate COVID-19 symptoms i. Fever ii. Cough iii. Sore throat iv. Malaise v. Headache vi. Muscle pain vii. Gastrointestinal symptoms, or viii. Shortness of breath with exertion 4. Must have sample collection for first positive SARS-CoV-2 viral infection determination ≤3 days prior to start of the infusion 5. Are men or non-pregnant women Contraceptive use by men or women should be consistent with local regulations for those participating in clinical studies 6. Understand and agree to comply with planned study procedures 7. Agree to the collection of nasopharyngeal swabs and venous blood 8. The participant or legally authorized representative give signed informed consent
Exclusion criteria	9. Have SpO2 ≤ 93% on room air at sea level or PaO2/FiO2 < 300, respiratory rate ≥30 per minute, heart rate ≥125 per minute (FDA resource page, WWW) 10. Require mechanical ventilation or anticipated impending need for mechanical ventilation 11. Have known allergies to any of the components used in the formulation of the interventions 12. Have hemodynamic instability requiring use of pressors within 24 hours of randomization 13. Suspected or proven serious, active bacterial, fungal, viral, or other infection (besides COVID-19) that in the opinion of the investigator could constitute a risk when taking intervention 14. Have any co-morbidity requiring surgery within <7 days, or that is considered life-threatening within 29 days 15. Have any serious concomitant systemic disease, condition or disorder that, in the opinion of the investigator, should preclude participation in this study. 16. Have a history of a positive SARS-CoV-2 serology test 17. Have a history of a positive SARS-CoV-2 test prior to the one serving as eligibility for this study 18. Have received an investigational intervention for SARS-CoV-2 prophylaxis within 30 days before dosing 19. Have received treatment with a SARS-CoV-2 specific monoclonal antibody 20. Have a history of convalescent COVID-19 plasma treatment 21. Have participated in a previous SARS-CoV-2 vaccine study 22. Have participated, within the last 30 days, in a clinical study involving an investigational intervention. If the previous investigational intervention has a long half-life, 5 half-lives or 30 days, whichever is longer, should have passed. 23. Are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study 24. Are pregnant or breast feeding 25. Are investigator site personnel directly affiliated with this study.
Interventions
	Treatment Bamlanivimab 700 mg IV single dose for 1 hour Bamlanivimab 700 mg 700 mg IV single dose for 1 hour Bamlanivimab 2800 mg 2800 mg IV single dose for 1 hour Bamlanivimab 7000 mg 7000 mg IV single dose for 1 hour Bamlanivimab+Etesevimab LY-CoV555: 2800 mg IV single dose for 1 hour LY-CoV016: 2800 mg IV single dose for 1 hour
	Control Placebo
Participants
	Randomized participants : Bamlanivimab=317 Bamlanivimab 700 mg=104 Bamlanivimab 2800 mg=109 Bamlanivimab 7000 mg=104 Bamlanivimab+Etesevimab =114 Placebo=161
	Characteristics of participants N= 909 Mean age : NR 300 males Severity : Mild: n= 678/ Asymptomatic: n=0
Primary outcome
	In the register Percentage of Participants Who Experience COVID-Related Hospitalization or Death from Any Cause [ Time Frame: Baseline through Day 29 ]; Change from Baseline to Day 11 in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Viral Load [ Time Frame: Baseline, Day 11 ]; Percentage of Participants with SARS-CoV-2 Viral Load Greater than a Prespecified Threshold [ Time Frame: Day 7 ]
	In the report Change in SARS- CoV-2 log viral load from baseline to day 11 (+/-4 days).
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: No
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the trial registry, study protocol, statistical analysis plan, and supplementary materials were used in data extraction and assessment of risk of bias. Two outcomes described as primary in the trial registry are described as secondary in the protocol and reported as secondary outcomes. Otherwise there were no substantive differences between the published article and the trial registry, study protocol ad statistical analysis plan. The database lock occurred when the last patient randomized to treatment of bamlanivimab and etesevimab reached day 29. As a result, the target sample size specified in the registry was not achieved. This is a phase 2/3 trial of previously published trial, Chen P, N Engl J Med, 2020 included in this review. Quote: "Interim results from the Blocking Viral Attachment and Cell Entry with SARS-CoV-2 Neutralizing Antibodies (BLAZE-1) trial with data for the 3 monotherapy doses of the neutralizing antibody bamlanivimab have been published. The current report presents the final data set for patients randomized to the 4 treatment groups and the placebo group in the initial portion of the trial, including findings for the bamlanivimab and etesevimab combination group, the 3 bamlanivimab monotherapy groups, and the placebo group." This study was updated on November 3rd, 2022 with the results published in the trial registry.