Covid-19 living Data

Bamlanivimab+Etesevimab vs Placebo (RCT)

Mild outpatients

FOREST PLOTS -2023-01-06

Studies description

Trial NCT04427501
Publication BLAZE-1 - BLAZE-1, Unpublished (2022) (results posted on registry)

Funding: Not reported/unclear
Conflict of interest: *

Methods
	RCT Blinding: double blinding
	Location : Multicenter / USA Follow-up duration (days): 85
Inclusion criteria	Are currently not hospitalized Have 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 Must have sample taken for test confirming viral infection no more than 3 days prior to starting the drug infusion Are males or females, including pregnant females who agree to contraceptive requirements Understand and agree to comply with planned study procedures Agree to the collection of nasopharyngeal swabs and venous blood The participant or legally authorized representative give signed informed consent and/or assent Are greater than or equal to (≥)18 years of age and must satisfy at least one of the following at the time of screening: Are pregnant Are ≥65 years of age Have a body mass index (BMI) ≥35 Have chronic kidney disease (CKD) Have type 1 or type 2 diabetes Have immunosuppressive disease Are currently receiving immunosuppressive treatment or Are ≥55 years of age AND have: cardiovascular disease (CVD), OR hypertension, OR chronic obstructive pulmonary disease (COPD) or other chronic respiratory disease Are 12-17 years of age (inclusive) AND satisfy at least one of the following at the time of screening: Are pregnant Have a body mass index (BMI) ≥85th percentile for their age and gender based on CDC growth charts, https://www.cdc.gov/growthcharts/clinical_charts.htm Have sickle cell disease Have congenital or acquired heart disease Have neurodevelopmental disorders, for example, cerebral palsy Have a medical-related technological dependence, for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19) Have asthma or reactive airway or other chronic respiratory disease that requires daily medication for control Have type 1 or type 2 diabetes Have chronic kidney disease Have immunosuppressive disease, or Are currently receiving immunosuppressive treatment
Exclusion criteria	Have 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 due to COVID-19 Require mechanical ventilation or anticipated impending need for mechanical ventilation due to COVID-19 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 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 received convalescent COVID-19 plasma treatment Have participated in a previous SARS-CoV-2 vaccine study or have received a SARS-CoV-2 vaccine 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 Mothers who are breast feeding
Interventions
	Treatment Bamlanivimab+Etesevimab 350/700mg intravenously single dose
	Control Placebo
Participants
	Randomized participants : Placebo=141 Bamlanivimab+Etesevimab=213
	Characteristics of participants N= 354 Mean age : NR 178 males Severity : Mild: n= 354/ Asymptomatic: n=0
Primary outcome
	In the register Percentage of Participants With SARS-CoV-2 Viral Load Greater Than a Prespecified Threshold in Arms 350 mg Bamlanivimab/700 mg Etesevimab and Placebo [ Time Frame: Day 7 ]
	In the report NR
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Not reported
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	This is an unpublished trial whose results have been reported in ClinicalTrials.gov. The trial registry, protocol and statistical analysis plan were used in data extraction and assessment of risk of bias. This study reports on the phase 3 results of the Bamlanivimab 350 mg and Etesevimab 700 mg arm. Time to negative conversion and time to clinical improvement outcomes were reported but the HRs do not include the CI.

Trial NCT04427501
Publication Dougan M, Clin Infect Dis (2021) (published paper)
Dates: 2020-12-09 to 2021-01-07
Funding: Private (Eli Lilly and Company)
Conflict of interest: Yes

Methods
	RCT Blinding: double blinding
	Location : Multicenter / USA and Puerto Rico Follow-up duration (days): 28
Inclusion criteria	≥12 years of age at the time of screening Currently not hospitalized ≥ 1 mild or moderate COVID-19 symptoms, per the FDA resource page - Fever, Cough, Sore throat, Malaise, Headache, Muscle pain, Gastrointestinal symptoms, or Shortness of breath with exertion Have sample collection for first positive SARS-CoV-2 viral infection determination ≤3 days prior to start of the infusion Males or non-pregnant females Any contraceptives used are consistent with local regulations for those participating in clinical studies Understand and agree to comply with planned study procedures Agree to the collection of nasopharyngeal swabs and venous blood Signed informed consent and/or assent ≥18 years of age and satisfy at least one of the following at the time of screening- Are ≥ 65 years of age, Have a BMI ≥ 35 (BMI is rounded to the nearest whole number, for example, 34.5 is rounded to 35), Have chronic kidney disease, Have type 1 or type 2 diabetes, Have immunosuppressive disease, Are currently receiving immunosuppressive treatment, or Are ≥ 55 years of age and have cardiovascular disease, or hypertension, or chronic obstructive pulmonary disease or other chronic respiratory disease Are 12-17 years of age (inclusive) and satisfy at least one of the following at the time of screening - Have a BMI ≥85th percentile for their age and gender based on CDC growth charts, Have sickle cell disease, Have congenital or acquired heart disease, Have neurodevelopmental disorders, for example, cerebral palsy, have a medical-related technological dependence, for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19), Have asthma or reactive airway or other chronic respiratory disease that requires daily medication for control, Have type 1 or type 2 diabetes, Have chronic kidney disease, Have immunosuppressive disease, or Are currently receiving immunosuppressive treatment.
Exclusion criteria	Have SpO2 ≤ 93% on room air at sea level or PaO2/FiO2 < 300, respiratory rate ≥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 received convalescent COVID-19 plasma treatment 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 Are pregnant or breast feeding Are investigator site personnel directly affiliated with this study Have body weight <40 kg
Interventions
	Treatment Bamlanivimab+Etesevimab 700mg/1400mg once-off intravenously
	Control Placebo
Participants
	Randomized participants : Bamlanivimab+Etesevimab=520 Placebo=262
	Characteristics of participants N= 782 Mean age : NR 361 males Severity : Mild: n= 769/ 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 ] Pharmacokinetics (PK): Area Under the Concentration-time Curve from 0 to Infinity (AUC0-inf) for both LY3819253 and LY3832479 [ Time Frame: Baseline through Day 85 ] Percentage of Participants who Experience a Serious Adverse Event(s) SAE(s) [ Time Frame: Baseline through Day 85 ]
	In the report proportion of patients that experienced a COVID-19-related hospitalization (≥24 hours of acute care) or any-cause death by Day 29
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 published article, the protocol, analysis plan, supplementary materials and study registry were used in data extraction and risk of bias assessment. The study (n = 769) achieved its target sample size (n = 750). There is no change from the trial registration in the intervention and control treatments. The primary outcome in the article was only one of five primary outcomes in the registry. Some other primary outcomes reported in the registry are described in the article as secondary." On April 7, 2022, another publication (Chen P, Open Forum Infect Dis, 2022) on the same trial was published. No COVID-NMA-defined outcomes were available/extracted from this publication. This study was updated on June 9, 2022 to correct an error in the risk of bias.

Trial NCT04427501
Publication BLAZE-1 - Dougan M, N Engl J Med (2021) (published paper)
Dates: 2020-09-04 to 2020-12-08
Funding: Private (Eli Lilly)
Conflict of interest: Yes

Methods
	RCT Blinding: double blinding
	Location : Multicenter / USA Follow-up duration (days): 29
Inclusion criteria	Tested positive for SARS-CoV-2 by means of either direct antigen or nucleic acid identification Have one or more mild or moderate COVID-19 symptoms 12 to 17 years of age with at least one of the following risk factors: BMI in at least the 85th percentile for age and sex, according to CDC growth charts sickle cell disease congenital or acquired heart disease neurodevelopmental disorders such as cerebral palsy dependence on a medical-related mechanical device or procedure such as tracheostomy, gastrostomy, or positive-pressure ventilation (not related to Covid-19) asthma, a reactive airway, or another chronic respiratory disease type 1 or type 2 diabetes mellitus and an immunocompromised condition or receipt of an immunosuppressive treatment. At least 18 years of age with at least one of the following risk factors: age of at least 65 years, a BMI of at least 35, chronic kidney disease, diabetes mellitus type 1 or type 2, immunosuppressive disease or receipt of immunosuppressive treatment, and an age of at least 55 years with cardiovascular disease, hypertension, or chronic obstructive pulmonary disease or another chronic respiratory disease.
Exclusion criteria	SpO2 ≤ 93% on room air at sea level or PaO2/FiO2 < 300, respiratory rate ≥30 per minute, heart rate ≥125 per minute (FDA May 2020) Require mechanical ventilation or anticipated impending need for mechanical ventilation known allergies to any of the components used in the formulation of the interventions 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 any co-morbidity requiring surgery within <7 days, or that is considered life threatening within 29 days any serious concomitant systemic disease, condition or disorder that, in the opinion of the investigator, should preclude participation in this study a history of a positive SARS-CoV-2 serology test a history of a positive SARS-CoV-2 test prior to the one serving as eligibility for this study received an investigational intervention for SARS-CoV-2 prophylaxis within 30 days before dosing received treatment with a SARS-CoV-2 specific monoclonal antibody received convalescent COVID-19 plasma treatment 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 concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study breast feeding investigator site personnel directly affiliated with this study body weight <40 kg.
Interventions
	Treatment Bamlanivimab+Etesevimab 2800 mg/2800mg IV single dose
	Control Placebo
Participants
	Randomized NR Analyzed 1035 participants Bamlanivimab+Etesevimab=518 Placebo=517
	Characteristics of participants N= 1035 Mean age : NR 0 males Severity : Mild: n= 800/ Asymptomatic: n=*
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 ]; Pharmacokinetics (PK): Area Under the Concentration-time Curve from 0 to Infinity (AUC0-inf) for both LY3819253 and LY3832479 [ Time Frame: Baseline through Day 85 ]; Percentage of Participants who Experience a Serious Adverse Event(s) SAE(s) [ Time Frame: Baseline through Day 85 ]
	In the report Covid-19–related hospitalization (acute care for ≥24 hours) or death from any cause by day 29
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: N
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 prospective registry, protocol and statistical analysis plan and supplementary materials were used in data extraction and assessment of risk of bias. Some primary outcomes in the registry are reported as secondary outcomes in the report, and some secondary outcomes in the registry (proportion of patients demonstrating symptom resolution or improvement, pharmacokinetics) are not reported. Otherwise there were no substantive differences in population, procedures, interventions or outcomes between the registry, protocol and statistical analysis plan and the published article. The study achieved its target sample size. On November 3rd, 2022, this study was updated with results published in the trial registry.

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.