Study to Assess the Efficacy, Safety, and Tolerability of SAR440340/REGN3500/Itepekimab in Chronic Obstructive Pulmonary Disease (COPD) (AERIFY-2)

Study Overview
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Brief Summary
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Primary Objective: Primary population (former smokers cohort): Evaluate the efficacy of itepekimab compared with placebo on the annualized rate of acute moderate-or-severe COPD exacerbations in former smokers with moderate-to-severe COPD Secondary Objectives: Primary population (former smokers cohort): Evaluate the efficacy of itepekimab compared with placebo on pulmonary function in former smokers with moderate-to-severe COPD Evaluate the efficacy of itepekimab compared with placebo on occurrence of acute exacerbation of COPD (AECOPD) in former smokers with moderate-to-severe COPD Evaluate the efficacy of itepekimab compared with placebo on severe AECOPD in former smokers with moderate-to-severe COPD Evaluate the efficacy of itepekimab compared with placebo on corticosteroid-treated AECOPD in former smokers with moderate-to-severe COPD Evaluate the efficacy of itepekimab compared with placebo on respiratory symptoms in former smokers with moderate-to-severe COPD Evaluate the efficacy of itepekimab compared with placebo on Forced Expiratory Volume in 1 second (FEV1) slope in former smokers with moderate-to-severe COPD Evaluate the efficacy of itepekimab compared with placebo on health-related quality of life (HRQoL) as assessed by St. George's Respiratory Questionnaire (SGRQ) in former smokers with moderate-to-severe COPD Evaluate the safety and tolerability of itepekimab in former smokers with moderate-to-severe COPD Evaluate the pharmacokinetic (PK) profile of itepekimab in former smokers with moderate-to-severe COPD Evaluate immunogenicity to itepekimab in former smokers with moderate-to-severe COPD Secondary population (current smokers cohort) Estimate the efficacy of itepekimab compared with placebo on the annualized rate of acute moderate or severe COPD exacerbations in current smokers with moderate-to-severe COPD Estimate the efficacy of itepekimab compared with placebo on pulmonary function in current smokers with moderate-to-severe COPD Estimate the safety and tolerability of itepekimab in current smokers with moderate-to-severe COPD Estimate the PK profile of itepekimab in current smokers with moderate to severe COPD Estimate immunogenicity to itepekimab in current smokers with moderate-to-severe COPD

Detailed Description
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The study duration per participant: Screening period is 3-5 weeks Randomized investigational medicinal product (IMP) treatment period is 52 weeks for first cohort of randomized former smoker participants [approximately 930] and cohort of current smokers [approximately 280], and 24 to 52 weeks for potential additional randomized former smoker participants Post-IMP treatment follow-up period is 20 weeks for participants not transitioning to the extension study LTS18133 Note: A long-term, double-blinded extension study (LTS18133) will be implemented to allow participants in this study to continue receiving active IMP for an additional period. Only participants completing their End-of-Treatment (EOT) visit per this study protocol will be offered to participate in the LTS18133 study.

Official Title
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Randomized, Double-blind, Placebo-controlled, Parallel-group Phase 3 Study to Evaluate the Efficacy, Safety, and Tolerability of SAR440340/ REGN3500/ Itepekimab (Anti-IL-33 mAb) in Patients With Moderate-to-severe Chronic Obstructive Pulmonary Disease (COPD)

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: Itepekimab SAR440340
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Participant must be 40 to 85 years of age inclusive. Physician diagnosis of COPD for at least 1 year (based on Global Initiative for Chronic Obstructive Lung Disease [GOLD] definition). Smoking history of ≥10 pack-years: For former smokers: participants who report that they are not currently smoking and smoking cessation must have occurred ≥6 months prior to Screening (Visit 1A) with an intention to quit permanently. For current smokers: participants who report that they are currently smoking tobacco (participant smoked at least 1 cigarette per day on average during the past 7 days) at Screening (Visit 1A) and who are not currently participating in or planning to initiate a smoking cessation intervention at Screening (Visit 1A) or during Screening period. Participants with moderate-to-severe COPD Participant-reported history of signs and symptoms of chronic bronchitis (chronic productive cough for at least 3 months in the year prior to Screening in a participant in whom other causes of chronic cough [eg, inadequately treated gastroesophageal reflux or chronic rhinosinusitis; or clinical diagnosis of bronchiectasis] has been excluded). Documented history of high exacerbation risk defined as having had ≥2 moderate or ≥1 severe exacerbations within the year prior to Screening (Visit 1A), with at least 1 exacerbation treated with systemic corticosteroids. At least one exacerbation must have occurred while participants were on their current controller therapy: Moderate exacerbations will be recorded by the Investigator and are defined as acute worsening of respiratory symptoms that requires either systemic corticosteroids (IM, IV, or oral) and/or antibiotics. Severe exacerbations will be recorded by the Investigator and are defined as AECOPD that require hospitalization or observation for >24 hours in emergency department/urgent care facility. Participants with standard of care controller therapy, for ≥3 months prior to Screening (Visit 1A) and at a stable dose of controller therapy for at least 1 month prior to the Screening, including either: inhaled corticosteroid (ICS) + long-acting beta-agonist (LABA), long-acting muscarinic antagonist (LAMA) + LABA or LAMA + LABA + ICS. Body mass index (BMI) ≥18.0 kg/m^2, or BMI ≥16.0 kg/m^2 for participants enrolled in East-Asian countries. Female participant is not pregnant, not breastfeeding, and at least one of the following conditions applies: not a women of child-bearing potential (WOCBP) OR a WOCBP who agrees to follow the contraceptive guidance during the intervention period and for at least 20 weeks after the last dose of study intervention. - Exclusion criteria: Current diagnosis of asthma according to the Global Initiative for Asthma (GINA) guidelines, or documented history of asthma unless asthma resolved before 18 years of age and has not recurred. For former smokers: Active smoking or vaping of any products (eg, nicotine, tetrahydrocannabinol [THC]) within 6 months prior to Screening (Visit 1A). For current smokers: vaping of any products (eg, nicotine, THC) within 6 months prior to Screening (Visit 1A). Clinically significant new abnormal electrocardiogram (ECG) within 6 months prior to, or at Screening (Visit 1A) that may affect the participant's participation in the study. Clinically significant and current pulmonary disease other than COPD, eg, sarcoidosis, interstitial lung disease, bronchiectasis (clinical diagnosis), diagnosis of α-1 anti-trypsin deficiency, or another diagnosed pulmonary disease. Diagnosis of cor pulmonale, evidence of right cardiac failure, or moderate-to-severe pulmonary hypertension. Hypercapnia requiring bilevel positive airway pressure (BiPAP). Moderate or severe exacerbation of COPD (AECOPD) within 4 weeks prior to Screening (Visit 1A). Prior history of / planned: lung pneumonectomy for any reason, or lung volume reduction procedures (including bronchoscopic volume reduction) for COPD. Note: Surgical biopsy, or segmentectomy, or wedge resection, or lobectomy for other diseases would not be excluded. Unstable ischemic heart disease, including acute myocardial infarction within the past 1 year prior to Screening, or unstable angina in the 6 months prior to Screening (Visit 1A). Cardiac arrhythmias including paroxysmal (eg, intermittent) atrial fibrillation. Uncontrolled hypertension (ie, systolic blood pressure [BP] >180 mm Hg or diastolic BP >110 mm Hg with or without use of anti-hypertensive therapy). Participants with active tuberculosis (TB), latent TB, a history of incompletely treated TB, suspected extrapulmonary TB infection (TBI), or who are at high risk of contracting TB (such as close contact with individuals with active or latent TB) or received Bacillus Calmette-Guérin (BCG)-vaccination within 12 weeks prior to Screening (Visit 1A). History of human immunodeficiency virus (HIV) infection or positive HIV 1/2 serology at Screening (Visit 1A). Suspicion of, or confirmed, coronavirus disease 2019 (COVID-19) infection or in contact with known exposure to COVID-19 at Screening (Visit 1A); known history of COVID-19 infection within 4 weeks prior to Screening (Visit 1A); history of requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO) secondary to COVID-19 within 3 months prior to Screening (Visit 1A); participants who have had a COVID-19 infection prior Screening (Visit 1A) who have not yet sufficiently recovered to participate in the procedures of a clinical trial. Evidence of acute or chronic infection requiring systemic treatment with antibacterial, antiviral, antifungal, antiparasitic, or antiprotozoal medications within 4 weeks before Screening (Visit 1A), significant viral infections within 4 weeks before Screening (Visit 1A) that may not have been treated with antiviral treatment (eg, influenza receiving only symptomatic treatment). Participants with active autoimmune disease or participants using immunosuppressive therapy for autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis. History of malignancy within 5 years before Screening (Visit 1A), except completely treated in situ carcinoma of the cervix, completely treated and resolved nonmetastatic squamous or basal cell carcinoma of the skin. Previous use of itepekimab. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 85 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Itepekimab Q2W in former smokers<br>Subcutaneous (SC) administration of Itepekimab every 2 weeks (Q2W) for up to 52 weeks | Drug: Itepekimab SAR440340<br>* Pharmaceutical form: solution for injection in pre-filled syringe Route of administration: subcutaneous<br>* Other names: REGN3500;|
| Experimental: Itepekimab Q4W in former smokers<br>SC administration of Itepekimab every 4 weeks (Q4W) for up to 52 weeks, with alternating SC administration of matching placebo at the 2-week interval between active IMP | Drug: Itepekimab SAR440340<br>* Pharmaceutical form: solution for injection in pre-filled syringe Route of administration: subcutaneous<br>* Other names: REGN3500;Drug: Placebo<br>* Pharmaceutical form: solution for injection in pre-filled syringe Route of administration: subcutaneous<br>|
| Placebo Comparator: Placebo in former smokers<br>SC administration of matching placebo Q2W for up to 52 weeks | Drug: Placebo<br>* Pharmaceutical form: solution for injection in pre-filled syringe Route of administration: subcutaneous<br>|
| Experimental: Itepekimab Q2W in current smokers<br>SC administration of Itepekimab every 2 weeks (Q2W) for 52 weeks | Drug: Itepekimab SAR440340<br>* Pharmaceutical form: solution for injection in pre-filled syringe Route of administration: subcutaneous<br>* Other names: REGN3500;|
| Placebo Comparator: Placebo in current smokers<br>SC administration of matching placebo Q2W for 52 weeks | Drug: Placebo<br>* Pharmaceutical form: solution for injection in pre-filled syringe Route of administration: subcutaneous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized rate of moderate or severe acute exacerbation of COPD (AECOPD) in former smokers | Annualized rate of moderate or severe acute exacerbation of COPD (AECOPD) over the placebo-controlled treatment period. | Baseline up to End Of Treatment (EOT) (Week 52 for initial randomized participants, 24 to 52 weeks for potential additional randomized former smoker participants) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) in former smokers | FEV1 is the volume of air exhaled in the first second of a forced expiration as measured by spirometer. | Baseline to Week 24 | 
| Change from baseline in post-BD FEV1 in former smokers | FEV1 is the volume of air exhaled in the first second of a forced expiration as measured by spirometer. | Baseline to Week 24 and Week 52 | 
| Change from baseline in pre-BD FEV1 in former smokers | FEV1 is the volume of air exhaled in the first second of a forced expiration as measured by spirometer. | Baseline to Week 52 | 
| Time to first moderate or severe AECOPD in former smokers | Time to first moderate or severe AECOPD over the placebo-controlled treatment period. | Baseline through EOT (Week 52 for initial randomized participants, 24 to 52 weeks for potential additional randomized former smoker participants) | 
| Annualized rate of severe AECOPD in former smokers | Annualized rate of severe AECOPD over the placebo-controlled treatment period. | Baseline up to EOT (Week 52 for initial randomized participants, 24 to 52 weeks for potential additional randomized former smoker participants) | 
| Time to first severe AECOPD in former smokers | Time to first severe AECOPD over the placebo-controlled treatment period. | Baseline through EOT (Week 52 for initial randomized participants, 24 to 52 weeks for potential additional randomized former smoker participants) | 
| Annualized rate of corticosteroid-treated AECOPD in former smokers | Annualized rate of corticosteroid-treated AECOPD over the placebo-controlled treatment period. | Baseline up to EOT (Week 52 for initial randomized participants, 24 to 52 weeks for potential additional randomized former smoker participants) | 
| Change from baseline in Evaluating Respiratory Symptoms in COPD (E-RS:COPD) total score in former smokers | The E-RS: COPD is administered as a part of the 14-item EXACT questionnaire and is completed on a daily basis.The 11-item E-RS:COPD assesses severity of respiratory symptoms overall and severity of individual symptoms such as breathlessness, cough and sputum, and chest symptoms The total score of E-RS:COPD ranges from 0 to 40, with higher values indicating more severe respiratory symptoms. | Baseline to Week 24 and Week 52 | 
| Rate of change in post-BD FEV1 (L) from baseline (post-BD FEV1 slope) in former smokers |  | Baseline up to EOT (Week 52 for initial randomized participants, 24 to 52 weeks for potential additional randomized former smoker participants) | 
| Change from baseline in St. George's Respiratory Questionnaire (SGRQ) total score in former smokers | The SGRQ is a 50-item questionnaire designed to measure and quantify health status in adult participants with chronic airflow limitation. A global score ranges from 0 to 100. Scores by dimension are calculated for 3 domains: Symptoms, Activity and Impacts (Psycho-social) as well as a total score. A lower score indicates better quality of life. | Baseline to Week 24 and Week 52 | 
| Proportion of participants with a decrease from baseline of at least 4 points in SGRQ total score in former smokers | The SGRQ is a 50-item questionnaire designed to measure and quantify health status in adult participants with chronic airflow limitation. A global score ranges from 0 to 100. Scores by dimension are calculated for 3 domains: Symptoms, Activity and Impacts (Psycho-social) as well as a total score. A lower score indicates better quality of life. | Baseline to Week 24 and Week 52 | 
| Incidence of treatment-emergent adverse events (TEAEs), adverse event of special interests (AESIs), serious adverse events (SAEs), and adverse events (AEs) leading to permanent treatment discontinuation in former smokers |  | Baseline up to End-of-Study (EOS) (Up to Week 72 for participants not transitioning to the extension study LTS18133; Up to Week 52 for participants transitioning to the extension study LTS18133) | 
| Incidence of potentially clinically significant laboratory test, vital signs, and electrocardiogram (ECGs) abnormalities in former smokers |  | Baseline up to EOS (Up to Week 72 for participants not transitioning to the extension study LTS18133; Up to Week 52 for participants transitioning to the extension study LTS18133) | 
| Functional itepekimab concentrations in serum in former smokers |  | Baseline up to EOS (Up to Week 72 for participants not transitioning to the extension study LTS18133; Up to Week 52 for participants transitioning to the extension study LTS18133) | 
| Incidence of treatment-emergent anti-itepekimab antibodies responses in former smokers |  | Baseline up to EOS (Up to Week 72 for participants not transitioning to the extension study LTS18133; Up to Week 52 for participants transitioning to the extension study LTS18133) | 
| Annualized rate of moderate or severe AECOPD in current smokers | Annualized rate of moderate or severe AECOPD over the placebo-controlled treatment period. | Baseline up to Week 52 | 
| Change from baseline in pre-BD FEV1 in current smokers | FEV1 is the volume of air exhaled in the first second of a forced expiration as measured by spirometer. | Baseline up to Week 24 and Week 52 | 
| Incidence of TEAEs, AESIs, SAEs, and AEs leading to permanent treatment discontinuation in current smokers |  | Baseline up to EOS (Week 72 for participants not transitioning to the extension study LTS18133; Week 52 for participants transitioning to the extension study LTS18133) | 
| Incidence of potentially clinically significant laboratory, vital signs, and ECGs abnormalities in current smokers |  | Baseline up to EOS (Week 72 for participants not transitioning to the extension study LTS18133; Week 52 for participants transitioning to the extension study LTS18133) | 
| Functional itepekimab concentrations in serum in current smokers |  | Baseline up to EOS (Week 72 for participants not transitioning to the extension study LTS18133; Week 52 for participants transitioning to the extension study LTS18133) | 
| Incidence of treatment-emergent anti-itepekimab antibodies responses in current smokers |  | Baseline up to EOS (Week 72 for participants not transitioning to the extension study LTS18133; Week 52 for participants transitioning to the extension study LTS18133) |