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

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.

Time frame: Baseline (Day 1) to Week 52

Population: The Intent-to-treat (ITT) population included all randomized participants analyzed according to the treatment group allocated by randomization.

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.

Time frame: Baseline (Day 1) to Week 52

Population: The ITT population included all randomized participants analyzed according to the treatment group allocated by randomization.

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.

Time frame: Baseline (Day 1) and Weeks 2, 4, 8, 12, 24, 36, 44 and 52

Population: The ITT population with an opportunity to reach Week 52 included participants who had an opportunity to reach Week 52 assessments and were analyzed for all weeks up to Week 52. Only those participants with data collected at specified timepoints are reported.

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 frame: Baseline (Day 1) and Weeks 2, 4, 8, 12, 24, 36 and 52

Population: The ITT population with an opportunity to reach Week 52 included participants who had an opportunity to reach Week 52 assessments and were analyzed for all weeks up to Week 52. Only those participants with data collected at specified timepoints are reported.

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.

Time frame: Baseline (Day 1) and Week 12

Population: The ITT population included all randomized participants analyzed according to the treatment group allocated by randomization. Only those participants with data collected are reported.

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.

Time frame: Baseline (Day 1) and Week 52

Population: The ITT population with an opportunity to reach Week 52 included participants who had an opportunity to reach Week 52 assessments and were analyzed for the continuous and proportion type endpoints at Week 52. Only those participants with data collected are reported.

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.

Time frame: Baseline (Day 1) and Weeks 2, 4, 8, 24, 36 and 44

Population: The ITT population with an opportunity to reach Week 52 included participants who had an opportunity to reach Week 52 assessments and were analyzed for all weeks up to Week 52. Only those participants with data collected at specified timepoints are reported.

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.

Time frame: Baseline (Day 1) and Week 52

Population: The ITT population with an opportunity to reach Week 52 included participants who had an opportunity to reach Week 52 assessments and were analyzed for the continuous and proportion type endpoints at Week 52. Only those participants with data collected are reported.

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.

Time frame: Up to Week 52

Population: The ADA population included all participants in the safety population who had at least 1 reportable ADA result after first dose of the study treatment.

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).

Time frame: From the first dose of study treatment (Day 1) up to the last dose of the study treatment + 98 days, up to 506 days

Population: The Safety population included all participants who actually received at least 1 dose or partial of a dose of the study treatment, analyzed according to the treatment participants actually received. 1 participant was exposed to different treatment other than planned (was allocated to placebo arm but inadvertently received dupilumab 300 mg q2w on Day 113). The actual arm was considered as dupilumab 300 mg q2w. In safety analyses, the actual arms are used.

Urine dipstick samples were collected to determine the significant abnormalities in urine protein.

Time frame: Baseline (Day 1), Weeks 4, 8, 12, 24, 36, 52 and 64

Population: The Safety population included all participants who actually received at least 1 dose or partial of a dose of the study treatment, analyzed according to the treatment participants actually received. Only those participants with data collected at specified timepoints are reported.

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.

Time frame: From the first dose of study treatment (Day 1) up to the last dose of the study treatment + 98 days, up to 506 days

Population: The Safety population included all participants who actually received at least 1 dose or partial of a dose of the study treatment, analyzed according to the treatment participants actually received. Only those participants with data collected for specified categories are reported.

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).

Time frame: From the first dose of study treatment (Day 1) up to the last dose of the study treatment + 98 days, up to 506 days

Population: The Safety population included all participants who actually received at least 1 dose or partial of a dose of the study treatment, analyzed according to the treatment participants actually received. Only those participants with data collected for specified categories are reported.

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.

Time frame: Baseline (Day 1) and Week 52

Population: The ITT population with an opportunity to reach Week 52 included participants who had an opportunity to reach Week 52 assessments and were analyzed for the continuous and proportion type endpoints at Week 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.

Time frame: Baseline (Day 1) and up to Weeks 12, 24, 36 and 52

Population: The ITT population included all randomized participants analyzed according to the treatment group allocated by randomization.