Covid-19 living Data

Bamlanivimab+Etesevimab vs REGN-COV2 (RCT)

Mild outpatients

FOREST PLOTS -2023-01-27

Studies description

Trial NCT05205759
Publication MANTICO - Mazzaferri F, eLife (2022) (published paper)
Dates: 2021-12-09 to 2022-01-20
Funding: Public/non profit (Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA); the ORCHESTRA (Connecting European Cohorts to Increase Common and Effective Response to SARS-CoV-2 Pandemic) project, which has received funding from the European Union’s Horizon 2020 research and innovation programme)
Conflict of interest: No

Methods
	RCT Blinding: single blinding
	Location : Multicenter / Italy Follow-up duration (days): 28
Inclusion criteria	Outpatients aged 50 years or older presenting with a positive test (either direct antigen or nucleic acid SARS-CoV-2) mild to moderate COVID-19 symptoms within 4 days of the onset - cough, nasal congestion, sore throat, feeling hot or feverish, myalgia, fatigue, headache, anosmia/ageusia, nausea, vomiting, and/or diarrhoea
Exclusion criteria	Peripheral oxygen saturation level of 93% or less on room air respiratory rate of 30 or more breaths per minute heart rate of 125 or more beats per minute previous COVID-19 treatments with mAbs Known allergies to any of the components used in the formulation of the trial drugs 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 could potentially lead to hospitalization within 30 days Any co-morbidity requiring surgery within 7 days or that is considered life-threatening within 90 days History of positive SARS-CoV-2 test prior to 4 days of the eligibility assessment History of convalescent COVID-19 plasma treatment Participation in a clinical study involving an investigational intervention within the last 30 days Pregnancy or breast feeding Investigator site personnel directly affiliated with this study Sexually active women of childbearing potential or sexually active men who are unwilling to practice effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose Inability to participate to the study follow-up
Interventions
	Treatment Sotrovimab 500 mg of sotrovimab by intravenous infusion single dose Bamlanivimab+Etesevimab 700 mg of bamlanivimab + 1400 mg of etesevimab by intravenous infusion single dose
	Control REGN-COV2 600 mg of casirivimab + 600 mg of imdevimab by intravenous infusion single dose
Participants
	Randomized participants : REGN-COV2=106 Sotrovimab=107 Bamlanivimab+Etesevimab=106
	Characteristics of participants N= 319 Mean age : NR 170 males Severity : Mild: n= 311/ Asymptomatic: n=0
Primary outcome
	In the register COVID-19 progression [ Time Frame: 14 days ] (1) hospitalization or (2) need of supplemental oxygen therapy at home or (3) death within 14 days of randomisation
	In the report COVID-19 progression, defined as hospitalisation, need of supplemental oxygen therapy, or death from any cause through day 14.
Documents avalaible	Protocol NR Statistical plan NR 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 pre-print article, the trial registry was used in data extraction and assessment of risk of bias. There is no change from the trial registration in the intervention and control treatments. The primary outcome in the article reflects that in the registry. Results are reported per variant of concerns (delta and omicron). Adverse events are not reported. The trial (n = 319) did not achieve its target sample size (n = 1260) as recruitment was interrupted after the publication of in-vitro evidence that two treatments under investigation (bamlanivimab/etesevimab and casirivimab/imdevimab) were not effective against the new emerging viral Omicron VOC. This study was updated on January 19th, 2023 with data extracted from the published report.

Trial NCT04790786
Publication OPTIMISE-C19 - McCreary E, medRxiv (2021) (preprint)
Dates: 2021-03-10 to 2021-06-25
Funding: Public/non profit (Internal funding from the UPMC Hospital System. The U.S. federal government provided the monoclonal antibody treatments reported in this manuscript.)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / USA Follow-up duration (days): 28
Inclusion criteria	Adult and pediatric patients (12 years of age and older weighing at least 40 kg) positive SARS-CoV-2 antigen or PCR test within 10 days of symptom onset high risk of disease progression defined as patients who meet at least one of the following criteria: Body Mass Index (BMI) ≥35 Chronic Kidney Disease diabetes immunosuppressive disease currently receiving immunosuppressive treatment ≥65 years of age ≥55 years of age AND have cardiovascular disease, OR hypertension, OR chronic obstructive pulmonary disease/other chronic respiratory disease 12-17 years of age AND have: BMI ≥ 85th percentile for their age and gender based on CDC growth charts, OR sickle cell disease, OR congenital or acquired heart disease, OR neurodevelopmental disorders (e.g., cerebral palsy), OR a medical-related technological dependence, for example, tracheostomy or gastrostomy), OR asthma, reactive airway, or other respiratory disease that requires daily medication for control.
Exclusion criteria	Hospitalized for the treatment of COVID-19 Require oxygen therapy for the treatment of COVID-19 Require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity Have a known hypersensitivity to any antibody ingredient
Interventions
	Treatment Bamlanivimab 700 mg intravenously once-off Bamlanivimab+Etesevimab
	Control REGN-COV2 1200 mg + 1200 mg intravenously once-off
Participants
	Randomized NR Analyzed 1935 participants Bamlanivimab =128 Bamlanivimab+Etesevimab=885 REGN-COV2=922
	Characteristics of participants N= 1935 Mean age : NR 894 males Severity : Mild: n= 1935/ Asymptomatic: n=0
Primary outcome
	In the register Alive and Free from Hospitalization [ Time Frame: 28 days after initial participation ]
	In the report Hospital-free days up to day 28 after mAb treatment
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 pre-print article, the trial protocol, statistical analysis plan, registry and supplementary materials were used in data extraction and assessment of risk of bias. The primary outcome reported in the paper reflects the primary outcome indicated in registry and protocol. Ten laboratory and immunological outcomes in the registry were not reported. The study (n = 2466) did not achieve its target sample size (n = 5000) at time of reporting because two of the three study treatments were withdrawn, so that patients could no longer be randomized to these. The U.S. Department of Health and Human Services halted distribution of bamlanivimab alone on March 25, 2021, and of bamlanivimab-etesevimab on June 25, 2021, due to concern of lack of efficacy against certain SARS-CoV-2 variants that were predominant in the U.S. at those times. Recruitment continues to the Casirivimab + Imdevimab and Sotrovimab arms.