Safety, Tolerability, and Efficacy of Anti-Spike (S) SARS-CoV-2 Monoclonal Antibodies for the Treatment of Ambulatory Adult and Pediatric Patients With COVID-19

Study Overview
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Brief Summary
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Phase 1 To evaluate the safety and tolerability of REGN10933+REGN10987 compared to placebo To evaluate the virologic efficacy of REGN10933+REGN10987 compared to placebo in reducing viral load of SARS-CoV-2 Phase 2 • To evaluate the virologic efficacy of REGN10933+REGN10987 compared to placebo in reducing viral load of SARS-CoV-2 Phase 3 Cohort 1 (≥18 Years Old, Not Pregnant at Randomization) • To evaluate the clinical efficacy of REGN10933+REGN10987 compared to placebo as measured by COVID-19-related hospitalizations or all-cause death Cohort 2 (<18 Years Old, Not Pregnant at Randomization) To evaluate the safety and tolerability of REGN10933+REGN10987 compared to placebo To further characterize the concentrations of REGN10933 and REGN10987 in serum over time Cohort 3 (Pregnant at Randomization) • To evaluate the safety and tolerability of REGN10933+REGN10987

Official Title
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A Master Protocol Assessing the Safety, Tolerability, and Efficacy of Anti-Spike (S) SARS-CoV-2 Monoclonal Antibodies for the Treatment of Ambulatory Patients With COVID-19

Conditions
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COVID-19

Intervention / Treatment
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* Drug: casirivimab+imdevimab combination therapy


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Has SARS-CoV-2-positive diagnostic test (from a sample collected ≤72 hours prior to randomization, using a validated SARS-CoV-2 antigen, RT-PCR, or other molecular diagnostic assay, and an appropriate sample such as nasopharyngeal [NP], nasal, oropharyngeal [OP], or saliva) Has symptoms consistent with COVID-19, as determined by the investigator, with onset ≤7 days before randomization Maintains O2 saturation ≥93% on room air Is able to understand and complete study-related questionnaires (patients aged ≥12 years only) Key Exclusion Criteria: Was admitted to a hospital for COVID-19 prior to randomization, or is hospitalized (inpatient) 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 (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 NOTE: Other Protocol defined Inclusion/Exclusion criteria apply
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Phase 1/Phase 2/Phase 3
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: casirivimab+imdevimab low dose<br>Low dose or body-weight equivalent for those under 18 years of age. | Drug: casirivimab+imdevimab combination therapy<br>* Administered intravenously (IV) single dose<br>* Other names: Ronapreve™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) - [Ph1, Ph2, Ph3 Cohort 1 - Cohort 3] | Primary: Phase 1, Phase 3 (Cohort 2 and Cohort 3) Secondary: Phase 2, Phase 3 (Cohort 1) | Through Day 29 | 
| Number of Participants With Infusion-related Reactions (Ph1, Ph2, Ph3 Cohort 1 - Cohort 3) | Primary: Phase 1, Phase 3 (Cohort 2 and Cohort 3) Secondary: Phase 2, Phase 3 (Cohort 1) | Through Day 4 | 
| Number of Participants With Hypersensitivity Reactions (Ph1, Ph2, Ph3 Cohort 1 - Cohort 3) | Primary: Phase 1, Phase 3 (Cohort 2 and Cohort 3) Secondary: Phase 2, Phase 3 (Cohort 1) | Through Day 29 | 
| Time-weighted Average Change From Baseline in Viral Load (log10 Copies/mL) From Day 1 to Day 7, as Measured by Quantitative Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) in Nasopharyngeal (NP) Swab Samples (Ph1, Ph2) | Primary: Phase 1, Phase 2 | Baseline up to Day 7 | 
| Proportion of Participants With at Least One (≥1) COVID-19-related Hospitalization or All-cause Death (Ph3 Cohort 1- 1.2g vs Placebo) | Phase 3 Cohort 1 | Through Day 29 | 
| Proportion of Participants With at Least One (≥1) COVID-19-related Hospitalization or All-cause Death (Ph3 Cohort 1 - 2.4g vs Placebo) | Primary: Phase 3 (Cohort 1) | Through Day 29 | 
| Concentration of REGN10983 + REGN10987 in Serum Over Time (Ph3 Cohort 2) | Phase 3 Cohort 2 [Nominal Sampling Time] = [Clinical Study Time (Visit Day - 1)] | Up to Nominal Sampling Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to COVID-19 Symptoms Resolution (Ph3 Cohort 1 - 1.2g vs Placebo) | Phase 3 Cohort 1 | Up to Day 29 | 
| Time to COVID-19 Symptoms Resolution (Ph3 Cohort 1 - 2.4g vs Placebo) | Phase 3 (Cohort 1) | Through Day 29 | 
| Proportion of Participants With ≥1 COVID-19-related Hospitalization or All-cause Death From Day 4 Through Day 29 (Ph3 Cohort 1 - 1.2g vs. Placebo) | Phase 3 (Cohort 1) | Day 4 thru Day 29 | 
| Proportion of Participants With ≥1 COVID-19-related Hospitalization or All-cause Death From Day 4 Through Day 29 (Ph3 Cohort 1 - 2.4g vs. Placebo) | Phase 3 (Cohort 1) | From Day 4 Through Day 29 | 
| Change From Baseline in Viral Load at Each Visit, as Measured by RT-qPCR in Nasopharyngeal Swabs (Next Phase 2 Cohort) | Next Phase 2 Symptomatic | Day 5, Day 7, Day 15, Day 29 | 
| Time-weighted Average Change From Baseline in Viral Load (log10 Copies/mL) From Day 1 to Post-baseline Study Days (Ph1, Ph2) | Phase 1, Phase 2 | Day 1 to Day 29 | 
| Percentage of Participants With ≥1 COVID-19-related Medically-attended Visit Through Day 29 (Ph1, Ph2) | Phase 1, Phase 2 | Through Day 29 | 
| Percentage of Participants With ≥1 COVID-19 Related Hospitalization, Emergency Room, or Urgent Care Visit Through Day 29 (Ph1, Ph2) | Phase 1, Phase 2 | Through Day 29 | 
| Time to First Onset of Symptoms Consistent With COVID-19 (Phase 2 Asymptomatic Cohort Only) | Phase 2 Only | Up to Day 29 | 
| Proportion of Participants With ≥1 COVID-19-related Hospitalization, Emergency Room Visit, or All-cause Death (Ph3 Cohort 1) - Placebo vs. 1.2g IV | Phase 3 Cohort 1 - Placebo vs. 1.2 g IV | Through Day 29 | 
| Proportion of Participants With ≥1 COVID-19-related Hospitalization, Emergency Room Visit, or All-cause Death (Ph3 Cohort 1) - Placebo vs. 2.4g IV | Phase 3 (Cohort 1) | Through day 29 | 
| Concentration of REGN10933 + REGN10987 in Serum Over Time (Ph1 Cohort 1, Ph2 Cohort 1, Ph3 Cohort 1 and Cohort 3) | Secondary: Phase 1, Phase 2, Phase 3 (Cohort 1 and Cohort 3) - Symptomatic Participants [Nominal Sampling Time] = [Clinical Study Time (Visit Day - 1)] | Up to Nominal Sampling Day 28 | 
| Assessment of Pharmacokinetic (PK) Parameter: Maximum Serum Concentration Observed (Cmax) of REGN10933+REGN10987 (Phase 1) | Phase 1 Only | Through Day 29 | 
| Assessment of PK Parameter: Time to Cmax (Tmax) for REGN10933+REGN10987 (Phase 1) | Phase 1 Only | Through Day 29 | 
| Assessment of PK Parameter: Area Under the Curve (AUC) Computed From Time Zero to Day 28 Concentration (AUC 0-28) for REGN10933+REGN10987 (Phase 1) | Phase 1 Only | Through Day 29 | 
| Immunogenicity as Measured by Anti-drug (ADA) to REGN10933 (Ph1 Cohort 1, Ph2 Cohort 1, Ph3 Cohort 1) | Phase 1, Phase 2, Phase 3 (Cohort 1) - Pooled Symptomatic Participants | Through Day 29 | 
| Immunogenicity as Measured by Anti-drug (ADA) to REGN10933 (Ph3 Cohort 2 - Cohort 3) | Symptomatic Participants Phase 3 Cohort 2 Participants Phase 3 Cohort 3 Participants | Through Day 29 | 
| Immunogenicity as Measured by ADA to REGN10987 (Ph1 Cohort 1, Ph2 Cohort 1, Ph3 Cohort 1) | Phase 1, Phase 2, Phase 3 (Cohort 1) - Pooled Symptomatic Participants | Through Day 29 | 
| Immunogenicity as Measured by ADA to REGN10987 (Ph3 Cohort 2 and Cohort 3) | Symptomatic Participants Phase 3 Cohort 2 Participants Phase 3 Cohort 3 Participants | Through Day 29 | 
| Immunogenicity as Measured by Neutralizing Antibodies (NAbs) to REGN10933 (Ph3 Cohort 2, Ph3 Cohort 3) | Symptomatic Participants Phase 3 Cohort 2 Participants Phase 3 Cohort 3 Participants (TE&TB+;NAb+) = TE = Treatment-emergent; TB = Treatment-boosted; NAb+ = Positive in NAb assay | Through Day 29 | 
| Immunogenicity as Measured by NAbs to REGN10987 (Ph3 Cohort 2 - Cohort 3) | Phase 3 Cohort 2 Participants Phase 3 Cohort 3 Participants (TE&TB+;NAb+) = TE = Treatment-emergent; TB = Treatment-boosted; NAb+ = Positive in NAb assay | Through Day 29 | 
| Number of Participants With at Least One (≥1) COVID-19-related Hospitalization or All-cause Death (Phase 3 Cohort 2) | Phase 3 (Cohort 2) | Through Day 29 | 
| Percentage of Participants With ≥1 COVID-19-related Medically-attended Visit (Phase 1, Phase 2) | Phase 1, Phase 2 Medically-attended Visits include Hospitalizations, ER visits, Urgent Care Clinic visits, Outpatient/physician office/telemedicine visits | Through Day 29 | 
| Percentage of Participants With ≥2 COVID-19-related Medically-attended Visit - (Ph3 Cohort 1) - Placebo vs. 1.2g IV | Phase 3 (Cohort 1) | Through Day 29 | 
| Percentage of Participants With ≥2 COVID-19-related Medically-attended Visit - (Ph3 Cohort 1) - Placebo vs. 2.4g IV | Phase 3 Cohort 1 | Through Day 29 | 
| Total Number of COVID-19-related Medically-attended Visits (Phase 1 and Phase 2) | Phase 1 and Phase 2 | Through Day 29 | 
| Assessment of Pharmacokinetic (PK) Parameter: Maximum Serum Concentration Observed (Cmax) of REGN10933 and REGN10987 (Phase 1 Only) | Phase 1 Only | Through Day 29 | 
| Assessment of PK Parameter: Cmax-to-dose Ratio (Cmax/Dose) of REGN10933 and REGN10987 (Phase 1 Only) | Phase 1 Only | Though Day 29 | 
| Assessment of PK Parameter: Time to Cmax (Tmax) for REGN10933 and REGN10987 (Phase 1 Only) | Phase 1 Only | Through Day 29 | 
| Assessment of PK Parameter: Area Under the Curve (AUC) Computed From Time Zero to the Time of the Last Positive Concentration (AUClast) for REGN10933 - (Phase 1 Only) | Phase 1 Only - Tlast (Time of last quantifiable concentration) | Through Day 29 | 
| Proportion of Participants With at Least One (≥1) COVID-19-related Hospitalization or All-cause Death From Day 4 Through Day 29 (Ph3 Cohort 1- 1.2g vs Placebo) | Phase 3 Cohort 1 | Day 4 Through Day 29 | 
| Proportion of Participants With at Least One (≥1) COVID-19-related Hospitalization or All-cause Death From Day 4 Through Day 29 (Ph3 Cohort 1- 2.4g vs Placebo) | Phase 3 Cohort 1 | Day 4 Through Day 29 | 
| Proportion of Participants With at Least One (≥1) COVID-19-related Medically-attended Visit or All-cause Death Through Day 29 (Ph3 Cohort 1- 1.2g vs Placebo) | Phase 3 Cohort 1 | Through Day 29 | 
| Proportion of Participants With at Least One (≥1) COVID-19-related Medically-attended Visit or All-cause Death Through Day 29 (Ph3 Cohort 1- 2.4g vs Placebo) | Phase 3 Cohort 1 | Through Day 29 | 
| Number of Participants With at Least One (≥1) COVID-19-related Medically-attended Visit or All-cause Death Through Day 29 (Phase 3 Cohort 2) | Phase 3 (Cohort 2) | Through Day 29 | 
| Proportion of Participants With at Least One (≥1) COVID-19-related Medically-attended Visit by Type of Visit Through Day 29 (Ph3 Cohort 1- 1.2g vs Placebo) | Phase 3 Cohort 1 | Through Day 29 | 
| Proportion of Participants With at Least One (≥1) COVID-19-related Medically-attended Visit by Type of Visit Through Day 29 (Ph3 Cohort 1- 2.4g vs Placebo) | Phase 3 Cohort 1 | Through Day 29 | 
| Total Number of COVID-19-related Medically-attended Visits by Type of Visit Through Day 29 (Phase 3 Cohort 2) | Phase 3 (Cohort 2) | Through Day 29 | 
| Cumulative Incidence Percentage of Patients With COVID-19-related Hospitalization or All-cause Death Through Day 29 (Ph3 Cohort 1- 1.2g vs Placebo) | Phase 3 Cohort 1 | Through Day 29 | 
| Cumulative Incidence Percentage of Patients With COVID-19-related Hospitalization or All-cause Death Through Day 29 (Ph3 Cohort 1- 2.4g vs Placebo) | Phase 3 Cohort 1 | Through Day 29 | 
| Cumulative Incidence Percentage of Patients With COVID-19-related Hospitalization, Emergency Room (ER) or All-cause Death Through Day 29 (Ph3 Cohort 1- 1.2g vs Placebo) | Phase 3 Cohort 1 | Through Day 29 | 
| Cumulative Incidence Percentage of Patients With COVID-19-related Hospitalization, Emergency Room (ER) or All-cause Death Through Day 29 (Ph3 Cohort 1- 2.4g vs Placebo) | Phase 3 Cohort 1 | Through Day 29 | 
| Cumulative Incidence Percentage of Patients With COVID-19-related Medically-attended Visit or All-cause Death Through Day 29 (Ph3 Cohort 1- 1.2g vs Placebo) | Phase 3 Cohort 1 | Through Day 29 | 
| Cumulative Incidence Percentage of Patients With COVID-19-related Medically-attended Visit or All-cause Death Through Day 29 (Ph3 Cohort 1- 2.4g vs Placebo) | Phase 3 Cohort 1 | Through Day 29 | 
| Proportion of Participants Requiring Supplemental Oxygen Due to COVID-19 by Day 29 (Ph3 Cohort 1- 1.2g vs Placebo) | Phase 3 Cohort 1 | Through Day 29 | 
| Proportion of Participants Requiring Supplemental Oxygen Due to COVID-19 by Day 29 (Ph3 Cohort 1- 2.4g vs Placebo) | Phase 3 Cohort 1 | Through Day 29 | 
| Percentage of Participants With All-Cause Death (Ph3 Cohort 1) Placebo vs. 1.2g | Phase 3 Cohort 1 | by Day 29, Day 120, and Day 169 | 
| Percentage of Participants With All-Cause Death (Ph3 Cohort 1) Placebo vs. 2.4g | Phase 3 Cohort 1 Placebo vs. 2.4g IV | by Day 29, Day 120, and Day 169 | 
| Proportion of Participants With High Viral Load at Each Visit - (Phase 2 Only) | Next Phase 2 Only | Through Day 29 | 
| Correlation of RT-qPCR Results Over Time Between Different Sample Types (NP, Nasal, and Saliva) - (Phase 1 Only) | Phase 1 Only | Up to Day 29 | 
| Change From Baseline in Viral Load at Each Visit, as Measured by RT-qPCR in Nasal Swabs - (Phase 1 Only) | Phase 1 Only | Baseline Up To Day 29 | 
| Change From Baseline in Viral Load at Each Visit, as Measured by RT-qPCR in Saliva Samples - (Phase 1 Only) | Phase 1 Only | Baseline Up to Day 29 | 
| Concordance of RT-qPCR Results Over Time Between Different Sample Types (NP, Nasal, and Saliva) - (Phase 1 Only) | Phase 1 Only | Up To Day 29 | 
| Time-weighted Average Change From Baseline in Viral Load (log10 Copies/mL), as Measured by RT-qPCR in Saliva Samples - (Phase 1) | Phase 1 Only | Baseline up to Day 22 | 
| Number of Participants With Viral Loads Below the Limit of Detection at Each Visit - (Phase 2 Only) | Phase 2 Only | Through Day 29 | 
| Duration of Symptoms Consistent With COVID-19 (Phase 2 Only) | Phase 2 Only | Through Day 29 | 
| Time to First Onset of Symptoms Consistent With COVID-19 (Phase 2 Asymptomatic Cohort Only) | Phase 2 Only | Through Day 29 | 
| Number of Participants Admitted to a Hospital Due to COVID-19 (Phase 1, Phase 2) | Phase 1, Phase 2 | Through Day 29 | 
| Time to Negative RT-qPCR in All Tested Samples With no Subsequent Positive RT-qPCR in Any Tested Samples - (Phase 1 Only) | Phase 1 Only | Through Day 29 | 
| Proportion of Participants With All-cause Mortality (Phase 2 Asymptomatic) | Phase 2 Asymptomatic | Through Day 29 | 
| Time to All-cause Death (Ph3 Cohort 1- 1.2g vs Placebo) | Phase 3 Cohort 1 (1.2g IV) | Through Day 169 | 
| Time to All-cause Death (Ph3 Cohort 1- 2.4g vs Placebo) | Phase 3 Cohort 1 (2.4g IV) | Through Day 169 | 
| Time to All-cause Death (Phase 3 Cohort 2) | Phase 3 (Cohort 2) | Through Day 29 | 
| Proportion of Participants Requiring Mechanical Ventilation Due to COVID-19 (Ph3 Cohort 1- 1.2g vs Placebo) |  | Through Day 29 | 
| Proportion of Participants Requiring Mechanical Ventilation Due to COVID-19 (Ph3 Cohort 1- 2.4g vs Placebo) |  | Through Day 29 | 
| Proportion of Participants Requiring Mechanical Ventilation Due to COVID-19 (Phase 3 Cohort 2) | Phase 3 (Cohort 2) | Through Day 29 | 
| Change From Baseline in Viral Load at Each Visit, as Measured by RT-qPCR in Nasopharyngeal Swabs - (Phase 3 Cohort 1 - 1.2g vs. Placebo) | Phase 3 Cohort 1 | Baseline up to Day 29 | 
| Change From Baseline in Viral Load at Each Visit, as Measured by RT-qPCR in Nasopharyngeal Swabs - (Phase 3 Cohort 1 - 2.4g vs. Placebo) | Phase 3 Cohort 1 | Baseline up to Day 29 | 
| Change From Baseline in Viral Load at Each Visit, as Measured by RT-qPCR in Nasopharyngeal Swabs - (Phase 3 Cohort 2) | Phase 3 Cohort 2 | Baseline up to Day 29 | 
| Time-weighted Average Change From Baseline in Viral Load (log10 Copies/mL), as Measured by Quantitative Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) in Nasopharyngeal (NP) Swab Samples (Ph3 Cohort 1) | Phase 3 (Cohort 1) | Baseline to Day 7 | 
| Time-weighted Average Change From Baseline in Viral Load (log10 Copies/mL), as Measured by Quantitative Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) in Nasopharyngeal (NP) Swab Samples (Ph3 Cohort 2) | Phase 3 (Cohort 2) | Baseline to Day 7 | 
| Proportion of Participants With Viral Loads Below the Lower Limit of Detection at Each Visit - (Phase 2 Only) | Next Phase 2 Symptomatic | Day 0, Day 5, Day 7, Day 15, Day 29 | 
| Proportion of Participants With Viral Loads Below the Lower Limit of Quantitation at Each Visit - (Phase 2 Only) | Next Phase 2 Symptomatic | Day 0, Day 5, Day 7, Day 15, Day 29 | 
| Number of Days of Hospitalization Due to COVID-19 (Ph3 Cohort 1) Placebo vs. 1.2g IV | Phase 3 (Cohort 1) | Through Day 29 | 
| Number of Days of Hospitalization Due to COVID-19 (Ph3 Cohort 1) Placebo vs. 2.4g IV | Phase 3 (Cohort 1) | Through Day 29 | 
| Number of Days of Hospitalization Due to COVID-19 (Ph3 Cohort 2) | Phase 3 (Cohort 2) | Through Day 29 | 
| Number of Days of Hospitalization Due to COVID-19 (Phase 2 Asymptomatic) | Phase 2 Only | Up to Day 29 | 
| Proportion of Participants Admitted to an Intensive Care Unit (ICU) Due to COVID-19 - (Ph 3 Cohort 1) Placebo vs. 1.2g IV | Phase 3 (Cohort 1) | Through Day 29 | 
| Percentage of Participants Admitted to an Intensive Care Unit (ICU) Due to COVID-19 - (Ph 3 Cohort 1) Placebo vs. 2.4g IV | Phase 3 (Cohort 1) | Through Day 29 | 
| Proportion of Participants Admitted to an Intensive Care Unit (ICU) Due to COVID-19 - (Ph 3 Cohort 2) | Phase 3 (Cohort 2) | Through Day 29 | 
| Proportion of Participants Admitted to an Intensive Care Unit (ICU) Due to COVID-19 - (Next Phase 2) #87 | Next Phase 2 | Through Day 29 | 
| Total Number of COVID-19-related Medically-attended Visits (Phase 3 Cohort 1) Placebo vs. 1.2g | Phase 3 Cohort 1 | Through Day 29 | 
| Total Number of COVID-19-related Medically-attended Visits (Phase 3 Cohort 1) Placebo vs. 2.4g | Phase 3 Cohort 1 | Through Day 29 | 
| Total Number of COVID-19-related Medically-attended Visits (Phase 3 Cohort 2) | Phase 3 Cohort 2 | Through Day 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), coronavirus