Proof-of-Concept Study to Assess the Efficacy, Safety and Tolerability of SAR440340 (Anti-IL-33 mAb) in Patients With Moderate-to-severe Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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Primary Objective: To investigate effects of SAR440340 (anti-interleukin-33 [IL-33] monoclonal antibody [mAb]) compared with placebo, on the annualized rate of moderate-to-severe acute exacerbations of COPD (AECOPD) over up to 52 weeks of treatment. Moderate exacerbations were recorded by the Investigator and defined as AECOPD that require either systemic corticosteroids (such as intramuscular, intravenous or oral) and/or antibiotics. Severe exacerbations were recorded by the Investigator and defined as AECOPD requiring hospitalization, emergency medical care visit or resulting in death. Secondary Objectives: To investigate effects of SAR440340 compared with placebo, on improving respiratory function, as assessed by pre-bronchodilator forced exploratory volume in 1 second (FEV1). To evaluate effects of SAR440340 compared with placebo, on post-bronchodilator FEV1. To evaluate effects of SAR440340 compared with placebo, on duration from baseline to first moderate or severe AECOPD event. To evaluate effects of SAR440340 compared with placebo, on safety and tolerability.

Detailed Description
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Study participation for each participant were up to a total of 46 weeks to 76 weeks including up to 10 days to 4 weeks of screening, 24-to-52 week treatment period on investigational medical product (IMP), and 20 weeks of post IMP treatment period.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Parallel-group, Proof-of-Concept (PoC) Study to Assess the Efficacy, Safety and Tolerability of SAR440340, 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: SAR440340
* Drug: Placebo
* Drug: Any Inhaled Corticosteroids as prescribed by treating physician as standard of care
* Drug: Any Long Acting Beta Agonist as prescribed by treating physician as standard of care
* Drug: Any Long Acting Muscarinic Agonist as prescribed by treating physician as standard of care
* Drug: Any short-acting β agonist as prescribed by treating physician as standard of care


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Participants with a diagnosis of chronic obstructive pulmonary disease (COPD) for at least 1 year (based on Global Initiative for Chronic Obstructive Lung Disease [GOLD] definition). Participants with moderate-to-severe COPD (post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity [FVC] less than [<] 70 percent (%) and post-bronchodilator FEV1% predicted <80%, but greater than equal to [>=] 30%). Participants with COPD assessment test (CAT) score >=10 at Screening. Participants with reported history of signs and symptoms of chronic bronchitis (chronic productive cough for 3 months in the year up to screening in a participant in whom other causes of chronic cough [e.g., gastroesophageal reflux, chronic rhinosinusitis, bronchiectasis] had been excluded). Participants with a documented history (e.g., medical record verification) of >=2 moderate exacerbations or >=1 severe exacerbation within the year prior to screening. A moderate exacerbation was defined as an acute exacerbation of COPD (AECOPD) requiring systemic corticosteroids (oral, intravenous, or intramuscular) and/or treatment with antibiotics (however, use of antibiotics alone does not qualify as a moderate exacerbation unless documentation was available that use of antibiotics was necessary for treatment of worsening symptoms of COPD). A severe exacerbation was defined as an AECOPD that required a hospitalization. Participants with standard of care background therapy, for 3 months and at a stable dose for at least 1 month, including either: Double therapy: Long acting beta agonist (LABA) + Long acting muscarinic agonist (LAMA) or inhaled corticosteroid (ICS) + LABA or ICS + LAMA. or Triple therapy: LABA + LAMA + ICS. Current or former smokers with a smoking history of >=10 packs/year. Exclusion criteria: Concomitant severe diseases or diseases for which the use of ICS (e.g., active pulmonary tuberculosis, etc.) or LABA were contraindicated (e.g., diagnosis of a history of significant cardiovascular diseases, insulin-dependent diabetes mellitus, hyperthyroidism, thyrotoxicosis, pheochromocytoma, hypokalemia). Use of injectable glucocorticosteroids or oral systemic glucocorticosteroids within previous 1 month or more than 4 courses of intravenous glucocorticosteroids within the previous 6 months. Participants with bronchial thermoplasty procedure (up to 3 years prior to Visit 1). A current diagnosis of asthma according to the Global Initiative for Asthma (GINA) guidelines. Significant pulmonary disease other than COPD (e.g., lung fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension, bronchiectasis, eosinophilic granulomatosis with polyangiitis, significant sleep apnea on Bilevel Positive Airway Pressure, etc.) or another diagnosed pulmonary or systemic disease associated with elevated peripheral eosinophil counts. Diagnosis of α-1 anti-trypsin deficiency. Advanced COPD with need for chronic (greater than [>] 15 hours/day) oxygen support. Participant with a moderate or severe acute exacerbation of COPD event within previous 4 weeks. A participant who has experienced an upper or lower respiratory tract infection within previous 4 weeks. Prior history of or planned pneumonectomy or lung volume reduction surgery. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 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 |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received placebo matched to SAR440340 administered as 2 subcutaneous (SC) injections every 2 weeks (Q2W). Participants were treated for a minimum of 24 weeks and up to a maximum of 52 weeks (last dose administered at Week 50, End of Treatment (EOT) visit occurred 2 weeks after last administration of IMP i.e., at Week 52). | Drug: Placebo<br>* Pharmaceutical form: Solution for injection; Route of administration: SC<br>Drug: Any Inhaled Corticosteroids as prescribed by treating physician as standard of care<br>* Pharmaceutical form: Aerosol or Dry Powder inhaler Route of administration: Inhaled<br>Drug: Any Long Acting Beta Agonist as prescribed by treating physician as standard of care<br>* Pharmaceutical form: Aerosol or Dry Powder inhaler; Route of administration: Inhaled<br>Drug: Any Long Acting Muscarinic Agonist as prescribed by treating physician as standard of care<br>* Pharmaceutical form: Aerosol or Dry Powder inhaler; Route of administration: Inhaled<br>Drug: Any short-acting β agonist as prescribed by treating physician as standard of care<br>* Pharmaceutical form: Aerosol or Dry Powder inhaler; Route of administration: inhaled<br>|
| Experimental: SAR440340<br>Participants received SAR440340 300 milligrams (mg) administered as 2 SC injections Q2W. Participants were treated for a minimum of 24 weeks and up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of IMP i.e., at Week 52). | Drug: SAR440340<br>* Pharmaceutical form: Solution for injection; Route of administration: SC<br>* Other names: REGN3500;Drug: Any Inhaled Corticosteroids as prescribed by treating physician as standard of care<br>* Pharmaceutical form: Aerosol or Dry Powder inhaler Route of administration: Inhaled<br>Drug: Any Long Acting Beta Agonist as prescribed by treating physician as standard of care<br>* Pharmaceutical form: Aerosol or Dry Powder inhaler; Route of administration: Inhaled<br>Drug: Any Long Acting Muscarinic Agonist as prescribed by treating physician as standard of care<br>* Pharmaceutical form: Aerosol or Dry Powder inhaler; Route of administration: Inhaled<br>Drug: Any short-acting β agonist as prescribed by treating physician as standard of care<br>* Pharmaceutical form: Aerosol or Dry Powder inhaler; Route of administration: inhaled<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized Rate of Moderate to Severe Acute Exacerbation Events in Chronic Obstructive Pulmonary Disease (AECOPD) Participants | Moderate exacerbations events were recorded by the investigator and defined as AECOPD that require either systemic corticosteroids (such as intramuscular, intravenous or oral) and/or antibiotics. Severe exacerbations events were defined as AECOPD requiring hospitalization, emergency medical care visit or resulting in death. Annualized event rate was the total number of exacerbations that occurred during the treatment period divided by the total number of participant-years treated. | From Baseline up to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Change in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) From Baseline to Week 16 Through Week 24 | FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. Spirometry was performed after a wash out period of bronchodilators according to their action duration. A mixed-effect model with repeated measures (MMRM) was first used to model the change from baseline at each post randomization timepoint up to Week 24, then the predicted values of Week 16 to Week 24 were averaged to provide an overall assessment of change from baseline in FEV1. | From Baseline to Week 16 through Week 24 | 
| Change From Baseline in Post-bronchodilator Forced Expiratory Volume (FEV1) in 1 Second at Week 24 | FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. Post-bronchodilator FEV1 referred to the spirometry performed within 30 minutes after administration of bronchodilator (4 puffs of salbutamol/albuterol [100 micrograms {mcg}] or ipratropium bromide [20 mcg]). | Baseline, Week 24 | 
| Time to First Moderate or Severe Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) | The time to first moderate or severe exacerbation was defined as onset date of first moderate or severe AECOPD minus randomization date + 1. The median time to first severe exacerbation was derived from Kaplan-Meier estimates. Moderate exacerbations events were recorded by the investigator and defined as AECOPD that require either systemic corticosteroids (such as intramuscular, intravenous or oral) and/or antibiotics. Severe exacerbations events were defined as AECOPD requiring hospitalization, emergency medical care visit or resulting in death. | From Baseline up to 52 weeks |