Pivotal Study to Assess the Efficacy, Safety and Tolerability of Dupilumab in Patients With Moderate-to-severe COPD With Type 2 Inflammation

Study Overview
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Brief Summary
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Primary Objective: To evaluate the efficacy of dupilumab administered every 2 weeks in patients with moderate-or severe Chronic Obstructive Pulmonary Disease (COPD) as measured by Annualized rate of acute moderate and severe COPD exacerbation (AECOPD) Secondary Objectives: To evaluate the effect of dupilumab administered every 2 weeks on Pre-bronchodilator forced expiratory volume in 1 second (FEV1) over 12 weeks compared to placebo Health related quality of life, assessed by the change from baseline to Week 52 in the St. George's Respiratory Questionnaire (SGRQ) Pre-bronchodilator FEV1 over 52 weeks compared to placebo Lung function assessments Moderate and severe COPD exacerbations To evaluate safety and tolerability To evaluate dupilumab systemic exposure and incidence of anti-drug antibodies (ADA)

Detailed Description
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Approximately 68 weeks including a 4-week screening period, a 52-week treatment period, and 12 weeks of follow-up.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Parallel-group, 52-week Pivotal Study to Assess the Efficacy, Safety and Tolerability of Dupilumab in Patients With Moderate-to-severe Chronic Obstructive Pulmonary Disease (COPD) With Type 2 Inflammation

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: Dupilumab SAR231893
* Drug: Inhaled Corticosteroid
* Drug: Inhaled Long-Acting Beta Agonist
* Drug: Inhaled Long-Acting Muscarinic Antagonist
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Participants with a physician diagnosis of COPD who meet the following criteria at screening: Current or former smokers with a smoking history of ≥10 pack-years. Moderate-to-severe COPD (post-bronchodilator FEV1/ forced vital capacity [FVC] ratio <0.70 and post-bronchodilator FEV1 % predicted >30% and ≤70%). Medical Research Council (MRC) Dyspnea Scale grade ≥2. Patient-reported history of signs and symptoms of chronic bronchitis (chronic productive cough) for 3 months in the year up to screening in the absence of other known causes of chronic cough. Documented history of high exacerbation risk defined as exacerbation history of ≥2 moderate or ≥1 severe within the year prior to inclusion. At least one exacerbation should have occurred while the patient was taking inhaled corticosteroid (ICS)/long acting beta agonist (LABA)/long acting muscarinic antagonist (LAMA) (or LABA/LAMA if ICS is contraindicated). Moderate exacerbations are recorded by the investigator and defined as acute exacerbation of COPD (AECOPD) that require either systemic corticosteroids (intramuscular, intravenous, or oral) and/or antibiotics. One of the two required moderate exacerbations has to require the use of systemic corticosteroids. Severe exacerbations are recorded by the investigator and defined as AECOPD requiring hospitalization or observation >24 hours in emergency department/urgent care facility. Background triple therapy (ICS + LABA + LAMA) for 3 months prior to randomization with a stable dose of medication for ≥1 month prior to Visit 1; Double therapy (LABA + LAMA) allowed if ICS is contraindicated. Evidence of Type 2 inflammation: Patients with blood eosinophils ≥300 cells/microliter at Visit 1. Exclusion criteria: COPD diagnosis for less than 12 months prior to randomization. A current diagnosis of asthma or history of asthma according to the 2018 Global Initiative for Asthma (GINA) guidelines or other accepted guidelines. Significant pulmonary disease other than COPD (e.g., lung fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension, bronchiectasis, Churg-Strauss Syndrome etc) or another diagnosed pulmonary or systemic disease associated with elevated peripheral eosinophil counts. Cor pulmonale, evidence of right cardiac failure. Treatment with oxygen of more than 12 hours per day. Hypercapnia requiring Bi-level ventilation. AECOPD as defined in inclusion criteria within 4 weeks prior to screening, or during the screening period. Respiratory tract infection within 4 weeks prior to screening, or during the screening period. History of, or planned pneumonectomy or lung volume reduction surgery. Patients who are participating in the acute phase of a pulmonary rehabilitation program, ie, who started rehabilitation <4 weeks prior to screening (Note: patients in the maintenance phase of a rehabilitation program can be included). Diagnosis of α-1 anti-trypsin deficiency. 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: 80 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: Dupilumab<br>Dupilumab administered every 2 weeks | Drug: Dupilumab SAR231893<br>* Pharmaceutical form: Solution for injection Route of administration: Subcutaneous<br>* Other names: Dupixent;Drug: Inhaled Corticosteroid<br>* Pharmaceutical form: Inhaled Powder Route of administration: Oral inhalation<br>Drug: Inhaled Long-Acting Beta Agonist<br>* Pharmaceutical form: Inhaled Powder Route of administration: Oral inhalation<br>Drug: Inhaled Long-Acting Muscarinic Antagonist<br>* Pharmaceutical form: Inhaled Powder Route of administration: Oral inhalation<br>|
| Placebo Comparator: Placebo<br>Placebo dose administered every 2 weeks | Drug: Inhaled Corticosteroid<br>* Pharmaceutical form: Inhaled Powder Route of administration: Oral inhalation<br>Drug: Inhaled Long-Acting Beta Agonist<br>* Pharmaceutical form: Inhaled Powder Route of administration: Oral inhalation<br>Drug: Inhaled Long-Acting Muscarinic Antagonist<br>* Pharmaceutical form: Inhaled Powder Route of administration: Oral inhalation<br>Drug: Placebo<br>* Pharmaceutical form: Solution for injection Route of administration: Subcutaneous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annual rate of acute COPD exacerbation (AECOPD) | Annualized rate of moderate or severe COPD exacerbations over the 52-week treatment period compared to placebo | Baseline to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in pre-bronchodilator FEV1 | Change in pre-bronchodilator FEV1 from baseline to Week 12 compared to placebo | Baseline to Week 12 | 
| Change in SGRQ | Change from baseline to Week 52 in SGRQ total score compared to placebo | Baseline to Week 52 | 
| Improvement in SGRQ | Proportion of patients with SGRQ improvement ≥4 points at Week 52 | Baseline to Week 52 | 
| Change in pre-bronchodilator FEV1 from baseline to Week 52 | Change in pre-bronchodilator FEV1 from baseline to Week 52 compared to placebo | Baseline to Week 52 | 
| Change in pre-bronchodilator FEV1 from baseline to time points up to Week 44 | Change in pre-bronchodilator FEV1 from baseline to weeks other than 12 and 52 (i.e. Weeks 2, 4, 8, 24, 36, and 44) compared to placebo | Baseline to Weeks 2, 4, 8, 24, 36, 44 | 
| Change in post-bronchodilator FEV1 lung function | Change in post-bronchodilator FEV1 from baseline at Weeks 2, 4, 8, 12, 24, 36 and 52 compared to placebo | Baseline to Weeks 2, 4, 8, 12, 24, 36, 52 | 
| Change in forced expiratory flow (FEF) 25-75% | Change in FEF 25-75% from baseline to Weeks 2, 4, 8, 12, 24, 36, 44 and 52 | Baseline to Weeks 2, 4, 8, 12, 24, 36, 44, 52 | 
| Annualized rate of severe AECOPD | Annualized rate of severe COPD exacerbations compared to placebo over the 52-week treatment period | Baseline through Week 52 | 
| Time to first AECOPD | Time to first moderate or severe COPD exacerbation compared with placebo during the 52-week treatment period | Baseline through Week 52 | 
| Adverse events | Number of adverse events (AEs)/treatment-emergent adverse events (TEAEs) | Baseline through Week 64 | 
| Potentially clinically significant abnormality (PCSA) in laboratory tests | Percentage of patients with at least one incidence of PCSA | Baseline through Week 64 | 
| Anti-drug antibodies | Incidence of anti-drug antibodies against dupilumab | Baseline to Week 64 |