Covid-19 living Data

Bamlanivimab vs Placebo (RCT)

Hospitalized patients

FOREST PLOTS -2022-10-07

Studies description

Trial NCT04411628
Publication J2W-MC-PYAA - Chen P, Clin Pharmacol Ther (2021) (published paper)
Dates: 2020-05-29 to 2020-06-28
Funding: Private (Eli Lilly and Company)
Conflict of interest: Yes

Methods
	RCT Blinding: triple blinding
	Location : Multicenter / USA Follow-up duration (days): 60
Inclusion criteria	18–85 years of age Hospitalized or in the process of being admitted to a hospital Laboratory confirmed COVID-19 infection (Initial laboratory confirmation of COVID-19 was required ≤ 14 days at the time of randomization) Having moderate to severe COVID-19 based on FDA guidelines Men or non-pregnant women 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, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
Exclusion criteria	Require invasive mechanical ventilation or anticipated impending need for invasive mechanical ventilation Anticipate transfer to another hospital which is not a study site within 5 days of randomization 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 Were resident in a nursing home or long-term care facility immediately prior to current hospitalization 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 prior history of hepatic impairment, such as a) severe liver cirrhosis Child-Pugh B or worse, b) cirrhosis with a history of hepatic encephalopathy, c) clinically meaningful ascites requiring ongoing treatment with diuretics and/or paracentesis, or d) history of hepatorenal syndrome Have any serious concomitant systemic disorder that, in the opinion of the investigator, would preclude participation in the study Current diagnosis of active malignancy that, in the opinion of the investigator, could constitute a risk when taking investigational product Received convalescent COVID-19 plasma treatment prior to enrollment Have an SpO2 <88% while breathing room air at rest. If on supplemental oxygen at the time of screening, use the last time point of measurement on room air up to 48 hours prior Have alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5X upper limit of normal (ULN) Have acute kidney disease with an eGFR <30 mL/min/1.73 m2 based on the chronic kidney disease epidemiology collaboration equation (CKD-EPI) Chronic kidney disease is allowable, if judged to be stable for the past 3 months, in the opinion of the investigator Are pregnant or breast feeding Are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study Are Lilly employees Are investigator site personnel directly affiliated with this study or their immediate families
Interventions
	Treatment Bamlanivimab 700 mg 700 mg (50 mL) administered intravenously at 100 mL/hr for 30 minutes on Day 1 Bamlanivimab 2800 mg 2800 mg (75 mL) administered intravenously at 100 mL/hr for 45 minutes on Day 1 Bamlanivimab 7000 mg 7000 mg (50 mL) administered intravenously at 100 mL/hr for 60 minutes on Day 1 Bamlanivimab 700 mg (50 mL) administered intravenously at 100 mL/hr for 30 minutes on Day 1
	Control Placebo
Participants
	Randomized participants : Bamlanivimab 700 mg =6 Bamlanivimab 2800 mg =7 Bamlanivimab 7000 mg=6 Placebo=7 Bamlanivimab=19
	Characteristics of participants N= 45 Mean age : NR 17 males Severity : Mild: n=10 / Moderate: n=20 / Severe: n=0 Critical: n=0
Primary outcome
	In the register Number of Participants With One or More Serious Adverse Event(s) (SAEs) Considered by the Investigator to be Related to Study Drug Administration [ Time Frame: Baseline through Day 60 ] An SAE is any adverse event that results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. The number of participants with 1 or more SAEs considered by the investigator to be related to study drug administration is reported. A summary of SAEs and other non-serious adverse events (AEs), regardless of causality, were reported in the Reported Adverse Events module.
	In the report Safety and tolerability, including adverse events (AEs), serious adverse events (SAEs), and discontinuations due to AEs
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	High
General comment	This is a first-in-human study. In addition to the published article and its supplement, the protocol, SAP and study registry were used in data extraction and risk of bias assessment. There is no change from the trial registration in the intervention and control treatments. The registry primary outcome does not fully reflect the reported primary outcome. Sample size was very small, with n=6 analyzed per arm. The study (n=26) did not achieve the target sample size specified in the trial registry (n=40).

Trial NCT04501978
Publication ACTIV-3/TICO - Lundgren J, J Ann Intern Med (2021) (published paper)
Dates: 2020-08-05 to 2020-10-13
Funding: Mixed (U.S. Operation Warp Speed; National Institute of Allergy & Infectious Diseases; Leidos Biomedical Research; National Heart, Lung & Blood Institute; Research Triangle Institute; U.S. Dept of Veterans Affairs; Denmark, Aus)
Conflict of interest: Yes

Methods
	RCT Blinding: quadruple blinding
	Location : Multicenter / Denmark, Singapore, USA Follow-up duration (days): 90
Inclusion criteria	Age ≥ 18 years Informed consent by the patient or the patient’s legally-authorized representative SARS-CoV-2 infection, documented by PCR or other nucleic acid test (NAT) within 3 days prior to randomization OR documented by NAT more than 3 days prior to randomization AND progressive disease suggestive of ongoing SARS-CoV-2 infection per the responsible investigator Duration of symptoms attributable to COVID-19 ≤ 12 days per the responsible investigator Requiring admission for inpatient hospital acute medical care for clinical manifestations of COVID-19, per the responsible investigator, and NOT for purely public health or quarantine purposes.
Exclusion criteria	Prior receipt of Any SARS-CoV-2 hIVIG, convalescent plasma from a person who recovered from COVID-19 or SARS-CoV-2 nMAb at any time prior to hospitalization Not willing to abstain from participation in other COVID-19 treatment trials until after Day 5 In the opinion of the responsible investigator, any condition for which, participation would not be in the best interest of the participant or that could limit protocol-specified assessments Expected inability to participate in study procedures Women of child-bearing potential who are not already pregnant at study entry and who are unwilling to abstain from sexual intercourse with men or practice appropriate contraception through Day 90 of the study. Men who are unwilling to abstain from sexual intercourse with women of child-bearing potential or who are unwilling to use barrier contraception through Day 90 of the study. Presence at enrollment of any of the following: a. stroke b. meningitis c. encephalitis d. myelitis e. myocardial infarction f. myocarditis g. pericarditis h. symptomatic congestive heart failure (NYHA class III-IV) i. arterial or deep venous thrombosis or pulmonary embolism
Interventions
	Treatment Bamlanivimab 7000 mg IV infusion once-off
	Control Placebo
Participants
	Randomized participants : Bamlanivimab=169 Placebo=157
	Characteristics of participants N= 326 Mean age : NR 177 males Severity : Mild: n=86 / Moderate: n=* / Severe: n=* Critical: n=0
Primary outcome
	In the register Pulmonary ordinal outcome [ Time Frame: Day 5 ] Oxygen requirements measured by 7 categories (1 = least severe, 7 = most severe). The participant's highest (i.e. most severe) observed score is used ; Pulmonary+ ordinal outcome [ Time Frame: Day 5 ] Extrapulmonary complications and respiratory dysfunction measured by 7 categories (1= least severe, 7 = most severe). The participant's highest (i.e. most severe) observed score is used. Time from randomization to sustained recovery [Time Frame: Up to Day 90 ] Sustained recovery defined as being discharged from the index hospitalization, followed by being alive and home for 14 consecutive days prior to Day 90.
	In the report Two ordinal outcomes termed “pulmonary” and “pulmonary- plus” assessed at day 5 after infusion were used to assess futility after at least 300 patients. Time to a sustained recovery, which was defined as hospital discharge to home and remaining at home for at least 14 days.
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 trial registry, study protocol, statistical analysis plan and supplementary materials were used in data extraction and assessment of risk of bias. There were no substantive differences between the published article and the trial registry, study protocol and statistical analysis plan. The trial did not achieve its pre-stated sample size as it was terminated for futility on the recommendation of the data and safety monitoring board. Quote: "In order to respond to pandemic dynamics, this platform protocol incorporates an early futility and safety evaluation after the enrollment of 300 patients (stage 1). Stage 1 is then followed by enrollment to the full sample size (stage 2) for agents that pass the initial futility and safety assessment." "The analysis data set was locked on November 6, 2020, and includes deaths, serious adverse events, organfailure events, and hospital discharges that occurred up to October 26." Chance imbalances in illness severity at baseline were detected and reported by the authors, but adjusted analyses did not suggest benefit for LY-CoV555 in this patient population. This trial was updated on July 29th, 2021 with data from a preprint article reporting final results. This study was updated on January 20th, 2022 with data from the published article reporting on final results