Clinical trial NCT04427501: A Study of LY3819253 (LY-CoV555) and LY3832479 (LY-CoV016) in Participants With Mild to Moderate COVID-19 Illness
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: COVID-19
Lead sponsor: Eli Lilly and Company
Sponsor class: INDUSTRY
Collaborators: name: AbCellera Biologics Inc.
name: Shanghai Junshi Bioscience Co., Ltd.
First posted: 2020-06-11
Enrollment: 3307
Sex: ALL
Minimum age (years): 0
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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 22), open-label addendum to evaluate the pharmacokinetics and safety of LY3819253 and LY3832479. Enrollment began on March 31, 2021, and completed on September 24, 2021.

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.


Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: Baseline through Day 29
measure: 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
timeFrame: Day 7
measure: Phase 2: Change From Baseline to Day 11 in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Viral Load
timeFrame: Baseline, Day 11
measure: Phase 2: Percentage of Participants Who Experience a Serious Adverse Event(s) SAE(s)
timeFrame: Baseline through Day 85
measure: Phase 3 and Phase 2/3 [Arm 22], Pharmacokinetics (PK): Mean Concentrations of LY3819253 (Bamlanivimab)
timeFrame: Day 29 Post-dose
measure: Phase 3 and Phase 2/3 [Arm 22], Pharmacokinetics (PK): Mean Concentrations of LY3832479 (Etesevimab)
timeFrame: Day 29 Post-dose
measure: Phase 2/3, PK: Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-∞) for Bebtelovimab [Arm 23]
timeFrame: Day 60 Post-dose
Secondary outcomes:
measure: Phase 3: Percentage of Participants Demonstrating Symptom Resolution
timeFrame: Day 11
measure: Phase 3: Percentage of Participants Demonstrating Symptom Improvement
timeFrame: Day 11
measure: Phase 3: Percentage of Participants Who Experience COVID-Related Hospitalization, COVID-Related Emergency Room (ER) Visit, or Death From Any Cause
timeFrame: Baseline through Day 85
measure: Phase 3: Change From Baseline to Day 7 in SARS-CoV-2 Viral Load
timeFrame: Baseline, Day 7
measure: Phase 3: Time to Sustained Symptom Resolution
timeFrame: Baseline through Day 29
measure: Phase 3: Time to SARS-CoV-2 Viral Clearance
timeFrame: Baseline through Day 29
measure: Phase 2: Change From Baseline to Day 11 in SARS-CoV-2 Viral Load Among Participants Enrolled With Recent Symptoms Prior to Randomization
timeFrame: Baseline, Day 11
measure: Phase 2: Percentage of Participants Demonstrating Symptom Resolution
timeFrame: Day 11
measure: Phase 2: Percentage of Participants Demonstrating Symptom Improvement
timeFrame: Day 11
measure: Phase 2, Pharmacokinetics (PK): Mean Concentration of Bamlanivimab Alone and in the Presence of Etesevimab
timeFrame: Day 29 Post-dose
measure: Phase 2, PK: Mean Concentration of Etesevimab in the Presence of Bamlanivimab
timeFrame: Day 29 Post-dose
measure: Phase 2: Percentage of Participants Who Experience COVID-Related Hospitalization, COVID-Related Emergency Room (ER) Visit, or Death From Any Cause
timeFrame: Baseline through Day 85
measure: Phase 2: Time to SARS-CoV-2 Viral Clearance
timeFrame: Baseline through Day 29
measure: Phase 2/3: Percentage of Participants Who Experience COVID-19 Related Hospitalization, COVID-Related Emergency Room (ER) Visit, or Death From Any Cause [Arm 22]
timeFrame: Baseline through Day 29
measure: Phase 2/3: Change From Baseline to Day 7 in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Viral Load [Arm 22]
timeFrame: Baseline, Day 7
measure: Phase 2/3: Percentage of Participants With SARS-CoV-2 Viral Load Greater Than a Prespecified Threshold [Arm 22]
timeFrame: Day 7
measure: Phase 2/3: Time to Complete Symptom Resolution [Arm 22]
timeFrame: Baseline through Day 29
measure: Phase 2/3: Time to Sustained Complete Symptom Resolution [Arm 22]
timeFrame: Baseline through Day 29
measure: Phase 2/3: Time to SARS-CoV-2 Viral Clearance [Arm 22]
timeFrame: Baseline through Day 29
Other outcomes:
Locations:
city: Redondo Beach
country: United States
facility: Clinnova Research - Redondo Beach
state: California
city: Miami
country: United States
facility: Bio-Medical Research, LLC
state: Florida
city: Union City
country: United States
facility: Rophe Adult and Pediatric Medicine
state: Georgia
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Worcester
country: United States
facility: U of MA Mem Med Ctr
state: Massachusetts
city: Bay City
country: United States
facility: Great Lakes Research Group, Inc.
state: Michigan
city: Detroit
country: United States
facility: Childrens Hospital of Michigan
state: Michigan
city: Fayette
country: United States
facility: Sky Clinical Prime and Health Wellness Clinic
state: Mississippi
city: Ridgeland
country: United States
facility: Sky Clin Resch - Quinn HC
state: Mississippi
city: Monroe
country: United States
facility: Monroe Biomed Research
state: North Carolina
city: Dallas
country: United States
facility: B S & W Med Center
state: Texas
city: San Antonio
country: United States
facility: Sun Research Institute
state: Texas
Study officials:
affiliation: Eli Lilly and Company
name: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)
role: STUDY_DIRECTOR
References:
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citation: Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.
citation: Nathan R, Shawa I, De La Torre I, Pustizzi JM, Haustrup N, Patel DR, Huhn G. A Narrative Review of the Clinical Practicalities of Bamlanivimab and Etesevimab Antibody Therapies for SARS-CoV-2. Infect Dis Ther. 2021 Dec;10(4):1933-1947. doi: 10.1007/s40121-021-00515-6. Epub 2021 Aug 10.
citation: Meng X, Wang P, Xiong Y, Wu Y, Lin X, Lu S, Li R, Zhao B, Liu J, Zeng S, Zeng L, Wu Y, Lu Y, Zhang J, Liu D, Wang S, Lu H. Safety, tolerability, pharmacokinetic characteristics, and immunogenicity of MW33: a Phase 1 clinical study of the SARS-CoV-2 RBD-targeting monoclonal antibody. Emerg Microbes Infect. 2021 Dec;10(1):1638-1648. doi: 10.1080/22221751.2021.1960900.
citation: Dougan M, Nirula A, Azizad M, Mocherla B, Gottlieb RL, Chen P, Hebert C, Perry R, Boscia J, Heller B, Morris J, Crystal C, Igbinadolor A, Huhn G, Cardona J, Shawa I, Kumar P, Adams AC, Van Naarden J, Custer KL, Durante M, Oakley G, Schade AE, Holzer TR, Ebert PJ, Higgs RE, Kallewaard NL, Sabo J, Patel DR, Dabora MC, Klekotka P, Shen L, Skovronsky DM; BLAZE-1 Investigators. Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19. N Engl J Med. 2021 Oct 7;385(15):1382-1392. doi: 10.1056/NEJMoa2102685. Epub 2021 Jul 14.
citation: Gottlieb RL, Nirula A, Chen P, Boscia J, Heller B, Morris J, Huhn G, Cardona J, Mocherla B, Stosor V, Shawa I, Kumar P, Adams AC, Van Naarden J, Custer KL, Durante M, Oakley G, Schade AE, Holzer TR, Ebert PJ, Higgs RE, Kallewaard NL, Sabo J, Patel DR, Klekotka P, Shen L, Skovronsky DM. Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial. JAMA. 2021 Feb 16;325(7):632-644. doi: 10.1001/jama.2021.0202.
citation: Chen P, Nirula A, Heller B, Gottlieb RL, Boscia J, Morris J, Huhn G, Cardona J, Mocherla B, Stosor V, Shawa I, Adams AC, Van Naarden J, Custer KL, Shen L, Durante M, Oakley G, Schade AE, Sabo J, Patel DR, Klekotka P, Skovronsky DM; BLAZE-1 Investigators. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. N Engl J Med. 2021 Jan 21;384(3):229-237. doi: 10.1056/NEJMoa2029849. Epub 2020 Oct 28.