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

Phase 3

Completed

Conditions: Chronic Obstructive Pulmonary Disease

Interventions: Drug: Dupilumab SAR231893
Drug: Inhaled Corticosteroid
Drug: Inhaled Long-Acting Beta Agonist
Drug: Inhaled Long-Acting Muscarinic Antagonist
Drug: Placebo

Registration Number: NCT04456673

Lead Sponsor: Sanofi

Brief Summary: 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 or 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 antidrug antibodies (ADA)

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

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 935

Inclusion Criteria

Participants with a physician diagnosis of COPD who met 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 participant was taking inhaled corticosteroid (ICS)/long-acting beta agonist (LABA)/long-acting muscarinic antagonist (LAMA) (or LABA/LAMA if ICS is contraindicated). Moderate exacerbations were recorded by the investigator and defined as AECOPD that required either systemic corticosteroids (intramuscular, intravenous, or oral) and/or antibiotics. One of the two required moderate exacerbations had to require the use of systemic corticosteroids. Severe exacerbations were 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: Participants with blood eosinophils ≥300 cells/microliter at Visit 1.

Exclusion Criteria

COPD diagnosis for less than 12 months prior to randomization.
Participants with current diagnosis of asthma according to the Global Initiative for Asthma (GINA) guidelines, or documented history of asthma.
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.
Long-term treatment with oxygen >4.0 L/min OR if a participant requires more than 2.0 L/min in order to maintain oxygen saturation >88%
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. Participants who were participating in the acute phase of a pulmonary rehabilitation program, ie, who started rehabilitation <4 weeks prior to screening (Note: participants 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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dupilumab	Dupilumab SAR231893	Participants received dupilumab 300 mg subcutaneous (SC) injection every 2 weeks (q2w) up to 52 weeks
Dupilumab	Inhaled Corticosteroid	Participants received dupilumab 300 mg subcutaneous (SC) injection every 2 weeks (q2w) up to 52 weeks
Dupilumab	Inhaled Long-Acting Beta Agonist	Participants received dupilumab 300 mg subcutaneous (SC) injection every 2 weeks (q2w) up to 52 weeks
Dupilumab	Inhaled Long-Acting Muscarinic Antagonist	Participants received dupilumab 300 mg subcutaneous (SC) injection every 2 weeks (q2w) up to 52 weeks
Placebo	Inhaled Corticosteroid	Participants received placebo matched to dupilumab 300 mg SC injection q2w up to 52 weeks
Placebo	Inhaled Long-Acting Beta Agonist	Participants received placebo matched to dupilumab 300 mg SC injection q2w up to 52 weeks
Placebo	Inhaled Long-Acting Muscarinic Antagonist	Participants received placebo matched to dupilumab 300 mg SC injection q2w up to 52 weeks
Placebo	Placebo	Participants received placebo matched to dupilumab 300 mg SC injection q2w up to 52 weeks

Primary Outcome Measures

Name	Time	Method
Annualized Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Over the 52-week Treatment Period	Baseline (Day 1) to Week 52	Moderate exacerbations were recorded by the Investigator and defined as acute exacerbation of COPD (AECOPD) event that required either systemic corticosteroids (such as intramuscular, intravenous, or oral) and/or antibiotics. Severe exacerbations were also recorded by the Investigator and defined as AECOPD event that required hospitalization or observation for \>24 hours in an emergency department/urgent care facility or resulted in death. For both moderate and severe events to be counted as separate events, they were separated by at least 14 days. Annualized event rate was the total number of events that occurred during the 52-week treatment period divided by the total number of participant-years followed in the 52-week treatment period.

Secondary Outcome Measures

Name	Time	Method
Annualized Rate of Severe Chronic Obstructive Pulmonary Disease Exacerbations Over the 52-week Treatment Period	Baseline (Day 1) to Week 52	Severe exacerbations were recorded by the Investigator and defined as AECOPD event that required hospitalization or observation for \>24 hours in an emergency department/urgent care facility or resulted in death. For both moderate and severe events to be counted as separate events, they were separated by at least 14 days. Annualized event rate was the total number of events that occurred during the 52-week treatment period divided by the total number of participant-years followed in the 52-week treatment period.
Change From Baseline in Forced Expiratory Flow (FEF) 25 to 75 Percent (%) to Weeks 2, 4, 8, 12, 24, 36, 44, and 52	Baseline (Day 1) and Weeks 2, 4, 8, 12, 24, 36, 44 and 52	FEF is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEF 25-75% was defined as the FEF at 25% to 75% of forced vital capacity (FVC), where FVC was defined as the volume of air that can be forcibly blown out after full inspiration in the upright position. Spirometry was performed after a wash out period of bronchodilators according to their action duration. Baseline was defined as the last available value up to randomization but prior to the first dose of study treatment.
Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) to Week 12	Baseline (Day 1) and Week 12	The FEV1 was defined as 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. Baseline was defined as the last available value up to randomization but prior to the first dose of study treatment.
Percentage of Participants With Abnormal Results for Urine Protein in Urinalysis	Baseline (Day 1), Weeks 4, 8, 12, 24, 36, 52 and 64	Urine dipstick samples were collected to determine the significant abnormalities in urine protein.
Change From Baseline in Saint George's Respiratory Questionnaire (SGRQ) Total Score to Week 52	Baseline (Day 1) and Week 52	The SGRQ is a 50-item self-administered questionnaire designed to measure and quantify health status in adult participants with chronic airflow limitation and rated on electronic diary. Scores by dimension were calculated for 3 domains: symptoms (respiratory symptoms: frequency and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). Each question's response had a unique empirically derived weight where lowest possible weight was 0 and the highest was 100. Total score was obtained by summing all positive responses in the questionnaire. The total score and domain score was derived from the relevant items and converted to a score of 0 to 100 with a higher score indicating worse health status/health related quality of life. Baseline was defined as the last available value up to randomization but prior to the first dose of study treatment.
Percentage of Participants With Saint George's Respiratory Questionnaire Improvement ≥4 Points at Week 52	Baseline (Day 1) and Week 52	A responder was defined as a participant with improvement from baseline in SGRQ total score at Week 52 by ≥4 points. Percentage of participants who achieved a clinically meaningful response in SGRQ total score (improvement by ≥4 points)/responders are reported. SGRQ is a 50-item self-administered questionnaire. Scores by dimension were calculated for 3 domains: symptoms (respiratory symptoms: frequency and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). Each question's response had unique empirically derived weight where lowest possible weight was 0 and highest was 100. Total score was obtained by summing all positive responses in questionnaire. Total score and domain score was derived from relevant items and converted to a score of 0 to 100; higher score indicating worse health status/health related quality of life.
Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second to Week 52	Baseline (Day 1) and Week 52	The FEV1 was defined as 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. Baseline was defined as the last available value up to randomization but prior to the first dose of study treatment.
Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second to Weeks 2, 4, 8, 24, 36, and 44	Baseline (Day 1) and Weeks 2, 4, 8, 24, 36 and 44	The FEV1 was defined as 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. Baseline was defined as the last available value up to randomization but prior to the first dose of study treatment.
Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in 1 Second to Weeks 2, 4, 8, 12, 24, 36, and 52	Baseline (Day 1) and Weeks 2, 4, 8, 12, 24, 36 and 52	The 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 consistent with the mechanism of action of reliever (30 minutes for albuterol or another short-acting beta agonists). Baseline was defined as the last available value up to randomization but prior to the first dose of study treatment.
Time to First Moderate or Severe Chronic Obstructive Pulmonary Disease Exacerbation Event During the 52-week Treatment Period	Baseline (Day 1) and up to Weeks 12, 24, 36 and 52	The time to first moderate or severe exacerbation was defined as date of the first event minus randomization date +1. Moderate exacerbations were recorded by the Investigator and defined as AECOPD event that required either systemic corticosteroids (such as intramuscular, intravenous, or oral) and/or antibiotics. Severe exacerbations were recorded by the Investigator and defined as AECOPD event that required hospitalization or observation for \>24 hours in an emergency department/urgent care facility or resulted in death. For both moderate and severe events to be counted as separate events, they were separated by at least 14 days. Median time as well as 95% confidence interval was calculated using Kaplan-Meier estimates.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)	From the first dose of study treatment (Day 1) up to the last dose of the study treatment + 98 days, up to 506 days	An AE was defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was defined as any untoward medical occurrence that, at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as AEs that developed or worsened or became serious during TE period (between the first administration of study treatment to the last administration of the study treatment + 98 days).
Percentage of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Hematology	From the first dose of study treatment (Day 1) up to the last dose of the study treatment + 98 days, up to 506 days	Blood samples were collected to determine PCSA in hematology. PCSA values were defined as abnormal values considered medically important by the Sponsor according to pre-defined criteria/thresholds based on literature review and defined by the Sponsor for clinical laboratory tests. Criteria for PCSA: Hemoglobin (Hb): ≤115 grams per liter (g/L) (Male\[M\]); ≤95 g/L (Female\[F\]), ≥185 g/L (M); ≥165 g/L (F), Decrease from baseline ≥20 g/L; Hematocrit: ≤0.37 volume per volume (v/v) (M); ≤0.32 v/v (F), ≥0.55 v/v (M); ≥0.5 v/v (F); Erythrocyte Count: ≥6 Tera/L; Platelet count: \<100 Giga/L, ≥700 Giga/L; Leukocytes: \<3 Giga/L (Non-Black \[NB\]); \<2 Giga/L (Black \[B\]), ≥16 Giga/L; Neutrophils: \<1.5 Giga/L (NB); \<1 Giga/L (B); Lymphocytes: \>4 Giga/L; Monocytes: \>0.7 Giga/L; Basophils: \>0.1 Giga/L; Eosinophils: \>0.5 Giga/L or \>upper limit of normal (ULN) (if ULN ≥0.5 Giga/L).
Percentage of Participants With Potentially Clinically Significant Abnormalities in Clinical Chemistry	From the first dose of study treatment (Day 1) up to the last dose of the study treatment + 98 days, up to 506 days	Blood samples were collected to determine PCSA in chemistry. PCSA criteria: Sodium: ≤129 millimoles (mmol)/L, ≥160 mmol/L; Potassium: \<3 mmol/L, ≥5.5 mmol/L; Chloride: \<80 mmol/L, \>115 mmol/L; Glucose: ≤3.9 mmol/L and \<lower limit of normal (LLN), ≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted);Total cholesterol: ≥7.74 mmol/L; Creatinine kinase: \>3 ULN, \>10 ULN; Creatinine: ≥150 micromoles (µmol)/L (adults), ≥30% change from baseline, ≥100% change from baseline, Creatinine Clearance (CG): ≥60 - \<90 milliliter per minute (mL/min), ≥30 - \<60 mL/min, ≥15 - \<30 mL/min, \<15 mL/min; Urea nitrogen: ≥17 mmol/L; Uric acid: \<120 μmol/L, \>408 μmol/L; Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST): \>3 ULN, \>5 ULN, \>10 ULN; Alkaline phosphatase (ALP): \>1.5 ULN; Total bilirubin (TB): \>1.5 ULN, \>2 ULN; ALT and TB: ALT \>3 ULN and Bilirubin \> 2 ULN; Direct bilirubin (DB) and TB: DB \>35% Bilirubin and Bilirubin \>1.5 ULN; Albumin: ≤25 g/L.
Number of Participants With Anti-Drug Antibodies (ADA) to Dupilumab	Up to Week 52	Plasma samples were collected to evaluate antibodies to dupilumab. Pre-existing immunoreactivity is defined as an ADA positive response in the assay at baseline with all post-treatment ADA results negative, or an ADA positive response at baseline with all post-treatment ADA responses less than 4-fold over baseline titer levels. Treatment-emergent response is defined as a positive response in the ADA assay post first dose, when baseline results are negative or missing. Treatment-boosted response is defined as an ADA positive response in the assay post first dose that is greater-than or equal to 4-fold over baseline titer levels, when baseline results are positive.

Trial Locations

Locations (334): Radiance Clinical Research Site Number : 8400029
🇺🇸
Lampasas, Texas, United States
Cullman Research Center, LLC Site Number : 8400095
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Cullman, Alabama, United States
Pulmonary & Sleep Associates of Jasper PC Site Number : 8400090
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Jasper, Alabama, United States
Scottsboro Quick Care Clinic Site Number : 8400116
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Scottsboro, Alabama, United States
Phoenix Medical Group Site Number : 8400061
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Peoria, Arizona, United States
Medical Advancement Center of Arizona Site Number : 8400107
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Tempe, Arizona, United States
Asthma and Allergy Institute Site Number : 8400022
🇺🇸
Little Rock, Arkansas, United States
Kern Research, Inc Site Number : 8400031
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Bakersfield, California, United States
NewportNativeMD, Inc Site Number : 8400032
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Newport Beach, California, United States
Prospective Research Innovations, Inc. Site Number : 8400063
🇺🇸
Rancho Cucamonga, California, United States
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Radiance Clinical Research Site Number : 8400029
🇺🇸Lampasas, Texas, United States