A Study of LY3819253 (LY-CoV555) and LY3832479 (LY-CoV016) in Participants With Mild to Moderate COVID-19 Illness

Study Overview
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Brief Summary
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The purpose of this study is to measure how well LY3819253 and LY3832479 work against the virus that causes COVID-19. LY3819253 and LY3832479 will be given to participants with early symptoms of COVID-19. Samples will be taken from the back of the nose to determine how much virus is in the body at various times during the study. Participation could last about 12 weeks and includes one required visit to the study site, with the remainder of assessments performed in the home or by phone. Pediatric participants, with mild to moderate COVID-19 illness, will enroll in a single-arm (Arm 23), open-label addendum to evaluate the pharmacokinetics and safety of LY3853113. Enrollment began on August 19, 2022 and completed on February 21, 2023.

Official Title
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A Randomized, Double-blind, Placebo-Controlled, Phase 2/3 Study to Evaluate the Efficacy and Safety of LY3819253 and LY3832479 in Participants With Mild to Moderate COVID-19 Illness

Conditions
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COVID-19

Intervention / Treatment
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* Drug: LY3819253
* Drug: LY3832479
* Drug: LY3853113
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are currently not hospitalized. (Not applicable to participants in treatment arm 22.) 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. (Not applicable to participants in treatment arm 22.) 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. (Not applicable to participants in treatment arms 20-21.) The participant or legally authorized representative give signed informed consent and/or assent Participants in treatment arms 7-9, 13-14, and 18-21 ONLY 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 Participants in treatment arm 22 ONLY - Are 0 (≥ 32 weeks gestational age AND ≥ 1.5 kilograms [kg]) to 17 years of age (inclusive) AND satisfy at least one of the following risk factors at the time of screening Are pregnant Have a 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, autism, or Down syndrome (FAIR Health 2020; Spreat et al. 2020) Have a medical-related technological dependence, for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19) Have asthma, cystic fibrosis, reactive airways disease 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, or Are less than (<) one year of age. Have one or more COVID-19 symptoms Shortness of breath/difficulty breathing Fever Sore throat Nausea Diarrhea Tiredness Headache New loss of taste Nasal congestion/runny nose Chills Stomachache Vomiting Cough Muscle/body aches and pain New loss of smell Poor appetite or poor feeding (in babies) Participants in treatment arm 23 ONLY: Must have first positive result sample of current SARS-CoV-2 viral infection ≤3 days prior to start of treatment administration. Participant can have COVID previously and still meet criteria for this addendum. Positive result needs to be from a current infection. Are 0 (≥ 38 weeks gestational age and ≥ 3.3 kg) to <12 years of age at the time of screening, or are 12 to 17 and weighing <40 kg; and Have mild to moderate COVID-19 disease, including one or more COVID-19 symptoms within the last 7 days Shortness of breath/difficulty breathing Fever Sore throat Nausea Diarrhea Tiredness Headache New loss of taste Nasal congestion/runny nose Chills Malaise Vomiting Cough Muscle/body aches and pain New loss of smell Poor appetite or poor feeding (in babies under 1 year old) 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 Participants in Treatment Arm 22 ONLY Have a diagnosis of Multisystem Inflammatory Syndrome in Children (MIS-C) in the opinion of the investigator Are currently hospitalized for treatment of COVID-19. Other reasons for hospitalization are acceptable. Participants in treatment arm 23 ONLY SpO2 ≤ 93% on room air at sea level, or while on chronic oxygen therapy and/or respiratory support due to underlying non-COVID-19 related comorbidity, respiratory rate ≥30 per minute, and heart rate ≥125 per minute due to COVID-19 (FDA February 2021) 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 received treatment with a SARS-CoV-2 specific monoclonal antibody or remdesivir within 90 days before dosing. Have received convalescent COVID-19 plasma treatment within 90 days before dosing 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 currently pregnant or breast feeding

Ages Eligible for Study
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Minimum Age: 0 Years

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
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY3819253<br>700 mg, 2800 mg, 7000 mg, LY3819253 administered intravenously (IV) | Drug: LY3819253<br>* Administered IV<br>* Other names: Bamlanivimab;|
| Experimental: LY3819253 + LY3832479<br>350 mg, 700 mg, 2800 mg LY3819253 + 700 mg, 1400 mg, 2800 mg LY3832479 administered IV or subcutaneously (SQ) | Drug: LY3819253<br>* Administered IV<br>* Other names: Bamlanivimab;Drug: LY3832479<br>* Administered IV<br>* Other names: Etesevimab;|
| Experimental: LY3853113 Open Label Addenda Arm 23<br>Administered IV | Drug: LY3853113<br>* Administered IV<br>* Other names: bebtelovimab;|
| Placebo Comparator: Placebo<br>Placebo administered IV | Drug: Placebo<br>* Administered IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 3: Percentage of Participants Who Experience COVID-Related Hospitalization or Death From Any Cause in 2800 mg Bamlanivumab/2800 mg Etesevimab, 700 mg Bamlanivimab/1400mg Etesevimab and Their Placebo Groups | COVID-19 Related Deterioration (yes/no) was defined as a participant experiencing COVID-19-related hospitalization (defined as 24 hours of acute care) or death from any cause by Day 29. | Baseline through Day 29 | 
| Phase 3: Percentage of Participants With SARS-CoV-2 Viral Load Greater Than a Prespecified Threshold in Arms 350 mg Bamlanivimab/700 mg Etesevimab and Placebo | SARS-CoV-2 persistent high viral load (yes/no) was defined as ribonuclease P(RP) normalized viral load >=5.27 vs otherwise. | Day 7 | 
| Phase 2: Change From Baseline to Day 11 in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Viral Load | SARS-CoV-2 viral load was based on nasopharyngeal swab sampling for reverse transcription polymerase chain reaction (RT-PCR) testing for SARS-CoV-2. Least squares (LS) mean values were determined using a mixed-effects model repeated-measures (MMRM) that included log base 10 transformed baseline as a covariate, treatment, day, treatment-by-day interaction as fixed effects. If Day 11 SARS-CoV-2 viral load was missing, the earliest measurement closest to the Day 11 visit, but within 4 days (Day 7-Day 15), was used for the Day 11 value. If no measurements were available, the Day 11 viral load was treated as missing at random (MAR) in the analysis. Viral load is reported as normalized viral load and is unitless. | Baseline, Day 11 | 
| Phase 2: Percentage of Participants Who Experience a Serious Adverse Event(s) SAE(s) | An SAE was defined as any untoward medical occurrence that, at any dose: results in death, is life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect and other different situations will have medical or scientific judgment to determine if they are SAE. A summary of SAEs and other non-serious adverse events (AEs), regardless of causality are reported in the Adverse Events section. | Baseline through Day 85 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 3: Percentage of Participants Demonstrating Symptom Resolution | Symptoms associated with COVID-19 were evaluated using a questionnaire that contains the following symptoms: cough, shortness of breath, feeling feverish, fatigue, body aches and pain, sore throat, chills, headache, loss of appetite, and changes in taste and smell. Each symptom was scored daily by the participant as experienced during the past 24 hours with following rating and score: None or absent (0), Mild (1), Moderate (2) and Severe (3). Symptom resolution (yes/no) is defined as a score of 0 for shortness of breath, feeling feverish, body aches and pains, sore throat, chills, and headache; and a score of 0 or 1 for cough and fatigue on the symptom questionnaire (excluding the loss of appetite and changes in taste and smell symptoms). Missing data were imputed using non-responder imputation (NRI) method. | Day 11 | 
| Phase 3: Percentage of Participants Demonstrating Symptom Improvement | Symptoms associated with COVID-19 were evaluated using a questionnaire that contains the following symptoms: cough, shortness of breath, feeling feverish, fatigue, body aches and pain, sore throat, chills, headache, loss of appetite, and changes in taste and smell. Each symptom will be scored daily by the participant as experienced during the past 24 hours with following rating and score: None or absent (0), Mild (1), Moderate (2) and Severe (3). Symptom improvement was defined as a participant experiencing both: Symptoms on the symptom questionnaire scored as moderate or severe at baseline are subsequently scored as mild or absent, and symptoms on the symptom questionnaire scored as mild or absent at baseline are subsequently scored as absent. Missing data were imputed using NRI method. | Day 11 | 
| Phase 3: Percentage of Participants Who Experience COVID-Related Hospitalization, COVID-Related Emergency Room (ER) Visit, or Death From Any Cause | COVID-19 Related Deterioration (yes/no) is defined as a patient experiencing COVID-19-related hospitalization, Emergency Room Visit, or Death from any causes vs otherwise. | Baseline through Day 85 | 
| Phase 3: Change From Baseline to Day 7 in SARS-CoV-2 Viral Load | Change from baseline to Day 7 (±2 days) in SARS-CoV-2 viral load was based on nasopharyngeal swab sampling for reverse transcription polymerase chain reaction (RT-PCR) testing for SARS-CoV-2. Least squares (LS) mean values were determined using a mixed-effects model repeated-measures (MMRM) that included log base 10 transformed baseline as a covariate, treatment, day, treatment-by-day interaction as fixed effects. If Day 7 SARS-CoV-2 viral load was missing, the earliest measurement closest to the Day 7 visit, but within 2 days (Day 5-Day 9), was used for the Day 7 value. If no measurements are available, the Day 7 viral load was treated as missing at random (MAR) in the analysis. Viral load is reported as normalized viral and is unitless. | Baseline, Day 7 | 
| Phase 3: Time to Sustained Symptom Resolution | Sustained symptom resolution was defined as 2 consecutive assessments with a score of 0 for shortness of breath, feeling feverish, body aches and pains, sore throat, chills, and headache; and a score of 0 or 1 for cough and fatigue on the symptom questionnaire. Participants who did not experience sustained symptom resolution by completion or early discontinuation of study were censored at the date of their last visit during. Additionally, participants who were hospitalized were censored at their date of hospitalization. | Baseline through Day 29 | 
| Phase 3: Time to SARS-CoV-2 Viral Clearance | Participants who did not experience SARS-CoV-2 viral clearance by completion or early discontinuation of study were censored at the date of their last visit. | Baseline through Day 29 | 
| Phase 2: Change From Baseline to Day 11 in SARS-CoV-2 Viral Load Among Participants Enrolled With Recent Symptoms Prior to Randomization | SARS-CoV-2 viral load was based on nasopharyngeal swab sampling for reverse transcription polymerase chain reaction (RT-PCR) testing for SARS-CoV-2. This analysis included only participants whose symptoms developed no more than 8 days prior to randomization. Least squares (LS) mean values were determined using a mixed-effects model repeated-measures (MMRM) that included log base 10 transformed baseline as a covariate, treatment, day, treatment-by-day interaction as fixed effects. If Day 11 SARS-CoV-2 viral load is missing, the earliest measurement closest to the Day 11 visit, but within 4 days (Day 7-Day 15), will be used for the Day 11 value. If no measurements are available, the Day 11 viral load will be treated as MAR in the analysis. | Baseline, Day 11 | 
| Phase 2: Percentage of Participants Demonstrating Symptom Resolution | Symptoms associated with COVID-19 were evaluated using a questionnaire that contains the following symptoms: cough, shortness of breath, feeling feverish, fatigue, body aches and pain, sore throat, chills, headache, loss of appetite, and changes in taste and smell. Each symptom will be scored daily by the participant as experienced during the past 24 hours with following rating and score: None or absent (0), Mild (1), Moderate (2) and Severe (3). Symptom resolution was defined as all symptoms (those scored 0-3) on the symptom questionnaire scored as absent (0). Symptom Resolution (yes/no) was defined as all symptoms (excluding the loss of appetite and changes in taste and smell symptoms) on the symptom questionnaire scored as absent vs otherwise. Missing data were imputed using non-responder imputation (NRI) method. | Day 11 | 
| Phase 2: Percentage of Participants Demonstrating Symptom Improvement | Symptoms associated with COVID-19 were evaluated using a questionnaire that contains the following symptoms: cough, shortness of breath, feeling feverish, fatigue, body aches and pain, sore throat, chills, headache, loss of appetite, and changes in taste and smell. Each symptom will be scored daily by the participant as experienced during the past 24 hours with following rating and score: None or absent (0), Mild (1), Moderate (2) and Severe (3). Symptom improvement was defined as a participant experiencing both: Symptoms on the symptom questionnaire scored as moderate or severe at baseline are subsequently scored as mild or absent, and Symptoms on the symptom questionnaire scored as mild or absent at baseline are subsequently scored as absent. Missing data were imputed using NRI method. | Day 11 | 
| Phase 2, Pharmacokinetics (PK): Mean Concentration of Bamlanivimab Alone and in the Presence of Etesevimab | (PK): Mean Concentration of Bamlanivimab alone and in the Presence of Etesevimab | Day 29 Post-dose | 
| Phase 2, PK: Mean Concentration of Etesevimab in the Presence of Bamlanivimab | PK: Mean Concentration of Etesevimab in the Presence of Bamlanivimab | Day 29 Post-dose | 
| Phase 2: Percentage of Participants Who Experience COVID-Related Hospitalization, COVID-Related Emergency Room (ER) Visit, or Death From Any Cause | Percentage of Participants Who Experience COVID-Related Hospitalization, COVID-Related ER Visit, or Death from Any Cause | Baseline through Day 85 | 
| Phase 2: Time to SARS-CoV-2 Viral Clearance | Participants who did not experience SARS-CoV-2 viral clearance by completion or early discontinuation of study were censored at the date of their last visit. | Baseline through Day 29 |