Covid-19 living Data

Casirivimab+Imdevimab (REGN-COV2) vs Standard care/Placebo (RCT)

Mild outpatients

FOREST PLOTS -2022-12-06

Studies description

Trial NCT04452318
Publication O'Brien M, JAMA (2022) (published paper)
Dates: 2020-07-13 to 2021-01-28
Funding: Mixed (Regeneron Pharmaceuticals, Inc.; F. Hoffmann-La Roche Ltd.; COVID-19 Prevention Network (CoVPN) )
Conflict of interest: Yes

Methods
	RCT Blinding: double blinding
	Location : Multicenter / Moldova, Romania, USA Follow-up duration (days): 226
Inclusion criteria	Adults (aged ≥18 years) and adolescents (aged ≥12 to <18 years) Were household contacts of the first known household member with SARS-CoV-2 infection (index case) and who were asymptomatic (having no active respiratory or nonrespiratory symptoms consistent with COVID-19) Part B participants were SARS-CoV-2 positive by RT-qPCR central laboratory testing. COVID-19 vaccination was prohibited prior to enrollment but was allowed after completing the 28-day efficacy assessment period.
Exclusion criteria	Taken verbatim from the supplementary appendix (includes criteria for Part A and Part B) Participant-reported history of prior positive SARS-CoV-2 RT-PCR test or positive SARS CoV-2 serology test at any time before the screening Participant has lived with individuals who have had previous SARS-CoV-2 infection or currently lives with individuals who have SARS-CoV-2 infection, with the exception of the index case(s), the first individual(s) known to be infected in the household Active respiratory or non-respiratory symptoms consistent with Covid-19 History of respiratory illness with sign/symptoms of SARS-CoV-2 infection, in the opinion of the investigator, within the prior 6 months to screening Nursing home resident Any physical examination findings, and/or history of any illness, concomitant medications or recent live vaccines that, in the opinion of the study investigator, might confound the results of the study or pose an additional risk to the participant by their participation in the study Current hospitalization or was hospitalized (i.e., >24 hours) for any reason within 30 days of the screening visit Has a history of significant multiple and/or severe allergies (e.g.,latex gloves),or has had an anaphylactic reaction to prescription or non-prescription drugs or food. This is to avoid possible confounding of the safety analysis and not due to any presumed increased risk of these individuals to a reaction to the investigational product Treatment with another investigational agent in the last 30 days or within 5 half- lives of the investigational drug, whichever is longer, prior to the screening visit Received an investigational or approved SARS-CoV-2 vaccine Received investigational or approved passive antibodies for SARS-CoV-2 infection prophylaxis (e.g., convalescent plasma or sera, monoclonal antibodies, hyperimmune globulin) Use of hydroxychloroquine/chloroquine for prophylaxis/treatment of SARS-CoV-2 or anti-SARS-viral agents, e.g., remdesivir, within 60 days of screening Hydroxychloroquine/chloroquine for other uses, ego, for use in autoimmune diseases is allowed Member of the clinical site study team and/or immediate family Exclusion criterion #14 excluding sexually active men who are unwilling to use the following forms of medically acceptable birth control during the study drug follow-up period and for 8 months after single dose of study drug was removed since enrollment was expanded to include all women in protocol amendment 4 Exclusion criterion #15 excluding pregnant or breastfeeding women was removed since enrollment was expanded to all women in protocol amendment 4 Exclusion criterion #16 excluding women of childbearing potential (WOCBP)* and girls at or beyond menarche (≥12 to <18 years of age) who were unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 8 months after the last dose was removed since enrollment was expanded to all women in protocol amendment 4
Interventions
	Treatment REGN-COV2 1200 mg subcutaneously once-off on day 1
	Control Placebo
Participants
	Randomized participants : REGN-COV2=156 Placebo=158
	Characteristics of participants N= 314 Mean age : NR 141 males Severity : Mild: n= 0/ Asymptomatic: n=314
Primary outcome
	In the register Proportion of participants who subsequently develop signs and symptoms (broad-term) within 14 days of a positive RT-qPCR at baseline or during the EAP [ Time Frame: Up to 1 month ]
	In the report The proportion of participants who had a positive RT-qPCR result at baseline or during the 28-day efficacy assessment period and who developed signs and symptoms of COVID-19 within 14 days of the positive RT-qPCR result.
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 report, the 2 versions of the pre-print article, the prospective registry (2020-06-30), protocol and supplementary appendices (including supplementary methods and statistical analysis methods) were used in data extraction and assessment of risk of bias. The original phase 1-3 protocol was available. There were no substantive differences between the population, procedures, interventions or outcomes in the pre-print article and supplementary appendices and the final registry. Considerable changes were made to outcomes in the registry during and after the trial, but these do not affect the data extracted. The article reports the adult/adolescent treatment part of a larger two-part trial that includes both treatment of asymptomatic RT-PCR-positive COVID patients (adults/adolescents and children) to prevent development of symptoms and prophylaxis in RT-PCR-negative contacts (adults/adolescents and children) of confirmed cases. The article also reports the proportion of participants who had a hospitalization related to a confirmed SARS-CoV-2 infection up to day 29. This was used in the composite hospitalization or death outcome extracted. Of note, "the trial was ongoing at the time of this report, so while all participants completed the 28-day efficacy assessment period, some were early in the follow-up period". Hence, all data were extracted under the day 28 timepoint until the updated completed report is available. This study was updated on October 6th, 2021 with data from the updated pre-print article and data gained from contact with authors. This study was updated on March 2nd, 2022 with data from the published report.

Trial NCT04666441
Publication Portal Celhay C, JAMA Netw Open (2022) (results posted on registry)
Dates: 2020-12-15 to 2021-02-26
Funding: Private (Regeneron Pharmaceuticals, Inc, and Hoffman-La Roche. Employees of Regeneron Pharmaceuticals participated in the development and review of the manuscript.)
Conflict of interest: Yes

Methods
	RCT Blinding: triple blinding
	Location : Multicenter / USA Follow-up duration (days): 169
Inclusion criteria	Outpatients Aged 18 years and older Positive SARS-CoV-2 diagnostic test (using a local SARS-CoV-2 antigen, quantitative reverse transcription–polymerase chain reaction [RT-qPCR], or other molecular diagnostic assay) from a sample (such as NP, nasal, oropharyngeal, or saliva) collected within 72 hours prior to randomization Either asymptomatic or symptomatic within 7 days before randomization Eligible symptomatic patients were required to be at low risk for developing severe COVID-19, defined as meeting all the following criteria: Body mass index (calculated as weight in kilograms divided by height in meters squared) less than 30 Age 50 years or younger Not pregnant No cardiovascular disease or hypertension, chronic lung disease or asthma, type 1 or 2 diabetes, chronic kidney disease, or chronic liver disease Eligible asymptomatic patients, with or without risk factors, could not have symptoms consistent with COVID-19 currently or at any time within 2 months and could not have received a COVID-19 vaccination prior to randomization The presence or absence of COVID-19 symptoms was determined at the discretion of investigators
Exclusion criteria	Immunosuppressed patients Has participated, or is participating, in a clinical research study evaluating COVID-19 convalescent plasma, mAbs against SARS-CoV-2, or intravenous immunoglobulin (IVIG) within 3 months or within 5 half-lives of the investigational product (whichever is longer) prior to the screening visit Prior, current, or planned future use of any of the following treatments: COVID-19 convalescent plasma, mAbs against SARS-CoV-2 (eg, bamlanivimab), IVIG (any indication), systemic corticosteroids (any indication), or COVID-19 treatments (authorized, approved, or investigational). Note: prior use is defined as the past 30 days or within than 5 half-lives of the investigational product (whichever is longer) from screening Prior use (prior to randomization), current use (at randomization), or planned use (within time period given per CDC guidance but no sooner than 22 days of study drug administration) of any authorized or approved vaccine for COVID-19. Note: As of 02 March 2021, CDC guidance recommends deferral of SARS-CoV-2 vaccination for at least 90 days after administration of passive antibody therapy Has known active infection with influenza or other non-SARS-CoV-2 respiratory pathogen, confirmed by a diagnostic test Has known allergy or hypersensitivity to components of study drug Has been discharged, or is planned to be discharged, to a quarantine center Has participated, is participating, or plans to participate in a clinical research study evaluating any authorized, approved, or investigational vaccine for COVID-19 Is a member of the clinical site study team or is an immediate family member of the site study team
Interventions
	Treatment REGN-COV2 2400mg Casirivimab 1200 mg + Imdevimab 1200 mg intravenously single dose REGN-COV2 1200mg Casirivimab 600 mg + Imdevimab 600 mg intravenously single dose REGN-COV2 Casirivimab 600 mg + Imdevimab 600 mg intravenously single dose
	Control Placebo
Participants
	Randomized participants : Placebo=82 REGN-COV2 2400mg=166 REGN-COV2 1200mg=165 REGN-COV2=331
	Characteristics of participants N= 744 Mean age : NR 292 males Severity : Mild: n= / Asymptomatic: n=
Primary outcome
	In the register Time-Weighted Average Daily Change From Day 1 in Viral Load in NP Swab Samples [ Time Frame: Day 1 to Day 7 ] Time-weighted average daily change from Day 1 in viral load (log10 copies/mL), as measured by reverse transcription quantitative polymerase chain reaction (RT-qPCR) in nasopharyngeal (NP) swab samples.
	In the report Time-weighted average daily change from baseline (TWACB) in viral load (log10 copies per milliliter) to day 7, as measured by RT-qPCR of NP swab samples in patients who had a central laboratory–determined RT-qPCR positive test at baseline and were seronegative (ie, negative for anti-spike [S1] IgA, anti-spike [S1] IgG, and anti-nucleocapsid IgG)
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	Low
General comment	In addition to the published article, the protocol, statistical analysis plan, supplemental materials and study registry were used in data extraction and risk of bias assessment. Only the interventions and placebo arms given IV were extracted. Registry posted results were extracted as the report published only interim results (at day 7, early database lock in Feb 2021, whereas the registry has longer follow-up results, posted Apr 2022, and reports on a larger sample size). The registry primary outcome reflects the reported primary outcome. Some outcomes (e.g. total adverse events, serious adverse events, mortality) are reported in the paper, and were pre-specified in the protocol but not the registry. Adverse events were reported in the publication reporting interim results but were not extractable from the registry with longer follow up. Viral negative conversion event were reported as well but data was presented for the pooled IV/SC placebo and could not be extracted.

Trial NCT04425629
Publication Weinreich D, N Engl J Med (2021) (published paper)
Dates: 2020-09-24 to 2021-01-17
Funding: Mixed (Regeneron Pharmaceuticals, Inc.; Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority)
Conflict of interest: Yes

Methods
	RCT Blinding: double blinding
	Location : Multicenter / Mexico, USA Follow-up duration (days): 28
Inclusion criteria	≥18 years of age Non-hospitalized Confirmed local SARS-CoV-2-positive diagnostic test result ≤72 hours and onset of any Covid-19 symptom as determined by the investigator, ≤7 days before randomization ≥1 risk factor for severe Covid-19.
Exclusion criteria	Admitted to a hospital for COVID-19 prior to randomization, or is hospitalized (inpatient) for any reason at randomization Participated, or is participating, in a clinical research study evaluating COVID-19 convalescent plasma, mAbs against SARS-CoV-2 (eg, bamlanivimab), or intravenous immunoglobulin (IVIG) within 3 months or within 5 half-lives of the investigational product (whichever is longer) prior to the screening visit Prior, current, or planned future use of any of the following treatments: COVID-19 convalescent plasma, mAbs against SARS-CoV-2 (eg, bamlanivimab), IVIG (any indication), systemic corticosteroids (any indication), or COVID-19 treatments (authorized, approved, or investigational) Prior use (prior to randomization), current use (at randomization) or planned use (within 90 days of study drug administration or per current CDC recommendations, as applicable) of any authorized or approved vaccine for COVID-19 Has participated, is participating or plans to participate in a clinical research study evaluation any authorized, approved or investigational vaccine for COVID-19
Interventions
	Treatment REGN-COV2 2400 mg IV once-off on day 1
	Control Placebo
Participants
	Randomized participants : REGN-COV2=1529 Placebo=1500
	Characteristics of participants N= 3029 Mean age : NR 1289 males Severity : Mild: n= 2696/ Asymptomatic: n=0
Primary outcome
	In the register Proportion of patients with at least one (≥1) COVID-19-related hospitalization or all-cause death [ Time Frame: Through Day 29 ]
	In the report The proportion of patients with ≥1 Covid-19-related hospitalization or all-cause death through 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 pre-print article, the prospective study registry, the supplementary appendices, protocol and statistical analysis plan were used in data extraction and risk of bias assessment. The overall study was a phase 1/2/3 trial recruiting 3 cohorts of COVID-19 outpatients: patients ≥18 years, patients <18 years, and patients pregnant at randomization. Initially, patients were randomized to receive either IV placebo, REGEN-COV 2400mg (1200mg each of casirivimab and imdevimab), or REGEN-COV 8000mg (4000mg each antibody). Based upon phase 1/2 results, the trial was amended so that subsequent patients enrolled all had ≥1 risk factor for severe Covid-19 and were randomized to receive either IV placebo, REGEN-COV 1200mg (600mg each antibody) IV, or REGEN-COV 2400mg. In February 2021, an independent data monitoring committee recommended stopping enrolment of patients into the placebo group because the accumulated data indicated efficacy of REGEN-COV. The reported analysis included only patients ≥ 18 years of age with ≥1 risk factor for severe COVID-19, randomized to REGEN-COV 2400mg or 1200mg, with their concurrent placebo groups serving as a control. Patients randomized in the early stages of the trial who had no risk factors for severe COVID-19 were excluded from analyses. There is no change from the trial registration in the intervention and control treatments. The primary outcomes indicated in the registry reflects the primary outcome reported in the paper. Some outcomes from the registry are not reported in the paper (e.g., proportion of participants requiring supplemental oxygen due to COVID-19 by day 29, all-cause death by day 120).

Trial NCT04425629
Publication Weinreich D (2), N Engl J Med (2021) (published paper)
Dates: 2020-09-24 to 2021-01-17
Funding: Mixed (Regeneron Pharmaceuticals, Inc.; Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority)
Conflict of interest: Yes

Methods
	RCT Blinding: double blinding
	Location : Multicenter / Mexico, USA Follow-up duration (days): 28
Inclusion criteria	≥18 years of age Non-hospitalized Confirmed local SARS-CoV-2-positive diagnostic test result ≤72 hours and onset of any Covid-19 symptom as determined by the investigator, ≤7 days before randomization ≥1 risk factor for severe Covid-19.
Exclusion criteria	Admitted to a hospital for COVID-19 prior to randomization, or is hospitalized (inpatient) for any reason at randomization Participated, or is participating, in a clinical research study evaluating COVID-19 convalescent plasma, mAbs against SARS-CoV-2 (eg, bamlanivimab), or intravenous immunoglobulin (IVIG) within 3 months or within 5 half-lives of the investigational product (whichever is longer) prior to the screening visit Prior, current, or planned future use of any of the following treatments: COVID-19 convalescent plasma, mAbs against SARS-CoV-2 (eg, bamlanivimab), IVIG (any indication), systemic corticosteroids (any indication), or COVID-19 treatments (authorized, approved, or investigational) Prior use (prior to randomization), current use (at randomization) or planned use (within 90 days of study drug administration or per current CDC recommendations, as applicable) of any authorized or approved vaccine for COVID-19 Has participated, is participating or plans to participate in a clinical research study evaluation any authorized, approved or investigational vaccine for COVID-19
Interventions
	Treatment REGN-COV2 1200 mg IV once-off on day 1
	Control Placebo
Participants
	Randomized participants : REGN-COV2=838 Placebo=840
	Characteristics of participants N= 1678 Mean age : NR 716 males Severity : Mild: n= 1484/ Asymptomatic: n=0
Primary outcome
	In the register Proportion of patients with at least one (≥1) COVID-19-related hospitalization or all-cause death [ Time Frame: Through Day 29 ]
	In the report The proportion of patients with ≥1 Covid-19-related hospitalization or all-cause death through 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 pre-print article, the prospective study registry, the supplementary appendices, protocol and statistical analysis plan were used in data extraction and risk of bias assessment. . The overall study was a phase 1/2/3 trial recruiting 3 cohorts of COVID-19 outpatients: patients ≥18 years, patients <18 years, and patients pregnant at randomization. Initially, patients were randomized to receive either IV placebo, REGEN-COV 2400mg (1200mg each of casirivimab and imdevimab), or REGEN-COV 8000mg (4000mg each antibody). Based upon phase 1/2 results, the trial was amended so that subsequent patients enrolled all had ≥1 risk factor for severe Covid-19 and were randomized to receive either IV placebo, REGEN-COV 1200mg (600mg each antibody) IV, or REGEN-COV 2400mg. In February 2021, an independent data monitoring committee recommended stopping enrollment of patients into the placebo group because the accumulated data indicated efficacy of REGEN-COV. The reported analysis included only patients ≥ 18 years of age with ≥1 risk factor for severe COVID-19, randomized to REGEN-COV 2400mg or 1200mg, with their concurrent placebo groups serving as a control. Patients randomized in the early stages of the trial who had no risk factors for severe COVID-19 were excluded from analyses. There is no change from the trial registration in the intervention and control treatments. The primary outcomes indicated in the registry reflects the primary outcome reported in the paper. Some outcomes from the registry are not reported in the paper (e.g., proportion of participants requiring supplemental oxygen due to COVID-19 by day 29, all-cause death by day 120).

Trial NCT04425629
Publication Weinreich DM, N Engl J Med (2020) (published paper)
Dates: 2020-06-16 to 2020-08-13
Funding: Mixed (Regeneron Pharmaceuticals; Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services)
Conflict of interest: Yes

Methods
	RCT Blinding:
	Location : Multicenter / USA Follow-up duration (days): 29
Inclusion criteria	Outpatients aged 18 years of age or older SARS-CoV-2–positive test result received no more than 72 hours before randomization and symptom onset no more than 7 days before randomization maintains O2 saturation ≥93% on room air.
Exclusion criteria	Admitted to a hospital for COVID-19 prior to randomization, or hospitalized for any reason at randomization has participated, or is participating in a clinical research study evaluating COVID-19 convalescent plasma, mAbs against SARS-CoV-2, or intravenous immunoglobulin (IVIG) within 3 months or within 5 half-lives of the investigational product (whichever is longer) prior to the screening visit prior, current, or planned future use of any of the following treatments: COVID-19 convalescent plasma, mAbs against SARS-CoV-2, IVIG (any indication), systemic corticosteroids (any indication), or COVID-19 treatments (authorized, approved, or investigational)
Interventions
	Treatment REGN-COV2 2.4 g/8.0 g in a 250 mL normal saline solution IV once off, over a period of 1 hour.
	Control Placebo
Participants
	Randomized participants : REGN-COV2=182 Placebo=93
	Characteristics of participants N= 275 Mean age : NR 134 males Severity : Mild: n= 275/ Asymptomatic: n=
Primary outcome
	In the register Proportion of patients with treatment-emergent serious adverse events (SAEs) [ Time Frame: Through Day 29 ] Proportion of patients with infusion-related reactions [ Time Frame: Through Day 4 ] Proportion of patients with hypersensitivity reactions
	In the report Time-weighted average change in viral load from baseline (day 1) through day 7 and the percentage of patients with at least one Covid-19–related medically attended visit through day 29
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 analysis plan and supplementary materials were used in data extraction. This is an interim analysis reporting early Phase I/II results from an ongoing operationally seamless (continual enrollment) Phase I/II/III trial. The data cutoff for this interim analysis was September 4, 2020. There were no substantive differences between the published article and the trial registry, protocol and statistical analysis plan in population, procedures and interventions. Several Phase I/II clinical outcomes included in the protocol were not reported. A fourth Phase II arm, REGN10989 included in the protocol dependent upon regulatory clearance, was not reported. The population in the interim report did not achieve the pre-stated Phase I/II sample size. Quote: "One center was found to have violations of Good Clinical Practice guidelines (not related to the collection of data on efficacy or safety end points) and was withdrawn from the trial after analyses had been completed." The study is updated under a new publication Weinreich D, medrxiv, 2021. We present only data on outcome serious adverse events since it was reported in Weinreich D, medrxiv, 2021.