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

• ClinicalTrials.gov Identifier: NCT03930732
• Recruitment Status: Completed
• First Posted: April 29, 2019
• Results First Posted: February 28, 2024
• Last Update Posted: February 28, 2024
• Sponsor: Sanofi
• Collaborator: Regeneron Pharmaceuticals
• Information provided by (Responsible Party): Sanofi

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: 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
• Enrollment: 939

Participant Flow

Recruitment Details	The study was conducted at 275 centers in 24 countries. A total of 2599 participants were screened from 15 Apr 2019 to 12 Jan 2022, of which 1660 were screen failures due to not meeting eligibility criteria.
Pre-assignment Details	A total of 939 participants were randomized in a 1:1 ratio to receive either dupilumab 300 milligrams (mg) every 2 weeks (q2w) or matching placebo for 52 weeks.

Arm/Group Title	Placebo	Dupilumab 300 mg q2w
Arm/Group Description	Participants received placebo matched to dupilumab 300 mg as subcutaneous (SC) injections q2w 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 treatment i.e., at Week 52).	Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).
Period Title: Overall Study
Started [1]	471	468
Safety Population [2]	470	469
Completed	434	440
Not Completed	37	28
Reason Not Completed
Adverse Event	9	7
Poor compliance to protocol	0	1
Withdrawal by Subject	23	11
Other reason related to Coronavirus Disease-2019 (COVID-19)	0	1
Other reason not related to COVID-19	5	8
[1] Randomized; [2] One participant was exposed to different treatment other than planned (was randomized to placebo arm but received dupilumab on Day 40). The actual arm was considered as dupilumab 300 mg q2w. In safety analyses, the actual arms are used.

Baseline Characteristics

Arm/Group Title		Placebo	Dupilumab 300 mg q2w	Total
Arm/Group Description		Participants received placebo matched to dupilumab 300 mg as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).	Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).	Total of all reporting groups
Overall Number of Baseline Participants		471	468	939
Baseline Analysis Population Description		The Randomized population consisted of any participant who was allocated to a randomized treatment regardless of whether the treatment kit was used.
Age, Continuous; Median (Standard Deviation); Unit of measure: Years
	Number Analyzed	471 participants	468 participants	939 participants
		65.2 (8.1)	65.0 (8.0)	65.1 (8.1)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	471 participants	468 participants	939 participants
	Female	149	170	319
	Male	322	298	620
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	471 participants	468 participants	939 participants
	American Indian or Alaska Native	4	3	7
	Asian	67	67	134
	Native Hawaiian or Other Pacific Islander	1	0	1
	Black or African American	2	3	5
	White	397	393	790
	More than one race	0	2	2
	Unknown or Not Reported	0	0	0

Outcome Measures

1. Primary Outcome

Title	Annualized Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Over the 52-Week Treatment Period
Description	Moderate exacerbations were recorded by the Investigator and defined as acute exacerbation of COPD (AECOPD) 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 requiring hospitalization, or observation for >24 hours in an emergency department/urgent care facility or resulting 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 exacerbations that occurred during the treatment period divided by the total number of participant-years treated. Events were adjudicated by independent third party.
Time Frame	Baseline (Day 1) to Week 52

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population consisted of the randomized population analyzed according to the treatment group allocated by randomization.

Arm/Group Title	Placebo	Dupilumab 300 mg q2w
Arm/Group Description:	Participants received placebo matched to dupilumab 300 mg as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).	Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).
Overall Number of Participants Analyzed	471	468
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: exacerbation per participant-year
	1.01; (0.931 to 1.301)	0.776; (0.645 to 0.934)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dupilumab 300 mg q2w
	Comments	Derived using negative binomial model with the total number of the events occurring during the 52-week treatment period as the response variable, and treatment group, region (pooled country), inhaled corticosteroid (ICS) dose, smoking status at screening, baseline disease severity, and number of moderate or severe COPD exacerbation events within one year prior to the study as covariates, and log-transformed treatment duration as an offset variable.
	Type of Statistical Test	Superiority
	Comments	A hierarchical testing procedure was used to control type I error and handle primary and a few secondary endpoint analyses at a 2-sided significance level of 0.049. Testing was then performed sequentially in the order the endpoints are reported (till OM 9). The hierarchical testing sequence continued only when the previous endpoint was statistically significant at 0.049 level.
Statistical Test of Hypothesis	P-Value	0.0005
	Comments	[Not Specified]
	Method	Negative binomial model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-0.324
	Confidence Interval	(2-Sided) 95%; -0.508 to -0.140
	Estimation Comments	Derived using delta method.

2. Secondary Outcome

Title	Change From Baseline in Pre-Bronchodilator (BD) Forced Expiratory Volume in One Second (FEV1) at Week 12
Description	The 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.
Time Frame	Baseline (Day 1) to Week 12

Outcome Measure Data

Analysis Population Description

The ITT population consisted of the randomized population analyzed according to the treatment group allocated by randomization. Only those participants with data available were analyzed.

Arm/Group Title	Placebo	Dupilumab 300 mg q2w
Arm/Group Description:	Participants received placebo matched to dupilumab 300 mg as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).	Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).
Overall Number of Participants Analyzed	469	466
Least Squares Mean (Standard Error); Unit of Measure: liters
	0.077 (0.018)	0.160 (0.018)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dupilumab 300 mg q2w
	Comments	Derived from mixed-effect model with repeated measures (MMRM) model with the change from baseline in pre-BD FEV1 up to Week 12 as response variables, and treatment group, age, sex, height, region (pooled country), ICS dose, smoking status at screening, visit, treatment-by-visit interaction, baseline pre-BD FEV1, and FEV1 baseline-by-visit interaction as covariates. Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.049 level.
	Method	MMRM model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	0.083
	Confidence Interval	(2-Sided) 95%; 0.042 to 0.125
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Change From Baseline in Pre-BD FEV1 at Week 52
Description	The 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.
Time Frame	Baseline (Day 1) to Week 52

Outcome Measure Data

Analysis Population Description

The ITT population consisted of the randomized population analyzed according to the treatment group allocated by randomization. Only those participants with data available were analyzed.

Arm/Group Title	Placebo	Dupilumab 300 mg q2w
Arm/Group Description:	Participants received placebo matched to dupilumab 300 mg as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).	Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).
Overall Number of Participants Analyzed	469	466
Least Squares Mean (Standard Error); Unit of Measure: liters
	0.070 (0.019)	0.153 (0.019)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dupilumab 300 mg q2w
	Comments	Derived from MMRM model with the change from baseline in pre-BDFEV1 up to Week 52 as response variables, and treatment group, age, sex, height, region (pooled country), ICS dose, smoking status at screening, visit, treatment-by-visit interaction, baseline pre-BD FEV1, and FEV1 baseline-by-visit interaction as covariates. Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0003
	Comments	Threshold for significance at 0.049 level.
	Method	MMRM model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.083
	Confidence Interval	(2-Sided) 95%; 0.038 to 0.128
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Change From Baseline in Pre-BD FEV1 at Week 12 in Subgroup of Participants With Baseline Fractional Exhaled Nitric Oxide (FeNO) >=20 Parts Per Billion (Ppb)
Description	FeNO is a demonstrated biomarker of type 2 airway inflammation in respiratory diseases. FeNO was analyzed using a NIOX instrument or similar analyzer using a flow rate of 50 milliliter per second (mL/s) and reported in ppb. This assessment was conducted prior to spirometry and following a fast of at least 1 hour.
Time Frame	Baseline (Day 1) to Week 12

Outcome Measure Data

Analysis Population Description

The subgroup of participants with baseline FeNO >=20 ppb within the ITT population were included. Only those participants with data available were analyzed.

Arm/Group Title	Placebo	Dupilumab 300 mg q2w
Arm/Group Description:	Participants received placebo matched to dupilumab 300 mg as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).	Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).
Overall Number of Participants Analyzed	186	193
Least Squares Mean (Standard Error); Unit of Measure: liters
	0.108 (0.035)	0.232 (0.034)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dupilumab 300 mg q2w
	Comments	Derived from MMRM model with the change from baseline in pre-BD FEV1 up to Week 12 as response variables, and treatment group, age, sex, height, region (pooled country), ICS dose, smoking status at screening, visit, treatment-by-visit interaction, baseline pre-BD FEV1, and FEV1 baseline-by-visit interaction as covariates. Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0022
	Comments	Threshold for significance at 0.049 level.
	Method	MMRM model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.124
	Confidence Interval	(2-Sided) 95%; 0.045 to 0.203
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Change From Baseline in Pre-BD FEV1 at Week 52 in Subgroup of Participants With Baseline FeNO >=20 Ppb
Description	FeNO is a demonstrated biomarker of type 2 airway inflammation in respiratory diseases. FeNO was analyzed using a NIOX instrument or similar analyzer using a flow rate of 50 mL/s and reported in ppb. This assessment was conducted prior to spirometry and following a fast of at least 1 hour.
Time Frame	Baseline (Day 1) to Week 52

Outcome Measure Data

Analysis Population Description

The subgroup of participants with baseline FeNO >=20 ppb within the ITT population were included. Only those participants with data available were analyzed.

Arm/Group Title	Placebo	Dupilumab 300 mg q2w
Arm/Group Description:	Participants received placebo matched to dupilumab 300 mg as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).	Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).
Overall Number of Participants Analyzed	186	193
Least Squares Mean (Standard Error); Unit of Measure: liters
	0.120 (0.037)	0.247 (0.036)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dupilumab 300 mg q2w
	Comments	Derived from MMRM model with the change from baseline in pre-BD FEV1 up to Week 52 as response variables, and treatment group, age, sex, height, region (pooled country), ICS dose, smoking status at screening, visit, treatment-by-visit interaction, baseline pre-BD FEV1, and FEV1 baseline-by-visit interaction as covariates. Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0034
	Comments	Threshold for significance at 0.049 level.
	Method	MMRM model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.127
	Confidence Interval	(2-Sided) 95%; 0.042 to 0.212
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Change From Baseline in Saint (St.) George's Respiratory Questionnaire (SGRQ) Total Score at Week 52
Description	The SGRQ was 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, activity and impacts (psycho-social) as well as a total score. Global and domain scores range from 0 to 100, with 100 representing the worst possible health status and 0 indicating the best possible health status. Higher score indicates worse health status/heath related quality of life.
Time Frame	Baseline (Day 1) to Week 52

Outcome Measure Data

Analysis Population Description

The ITT population consisted of the randomized population analyzed according to the treatment group allocated by randomization. Only those participants with data available were analyzed.

Arm/Group Title	Placebo	Dupilumab 300 mg q2w
Arm/Group Description:	Participants received placebo matched to dupilumab 300 mg as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).	Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).
Overall Number of Participants Analyzed	456	456
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	-6.369 (0.816)	-9.732 (0.810)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dupilumab 300 mg q2w
	Comments	Derived from MMRM model with the change from baseline in SGRQ total score up to Week 52 as response variables, and treatment group, region (pooled country), ICS dose, smoking status at screening, treatment-by-visit interaction, baseline SGRQ total score, and SGRQ baseline-by-visit interaction as covariates. Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0017
	Comments	Threshold for significance at 0.049 level.
	Method	MMRM model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-3.363
	Confidence Interval	(2-Sided) 95%; -5.459 to -1.266
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Percentage of Participants With SGRQ Improvement >=4 Points at Week 52
Description	A responder was defined as a participant with improvement from baseline in SGRQ total score at Week 52 by >=4 points. Participants with improvement <4 points or with missing values were considered as non-responders. The percentage of participants who achieved a clinically meaningful response in SGRQ total score (reduction [improvement] by >=4 points)/responders are reported.
Time Frame	Baseline (Day 1) to Week 52

Outcome Measure Data

Analysis Population Description

The ITT population consisted of the randomized population analyzed according to the treatment group allocated by randomization.

Arm/Group Title	Placebo	Dupilumab 300 mg q2w
Arm/Group Description:	Participants received placebo matched to dupilumab 300 mg as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).	Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).
Overall Number of Participants Analyzed	471	468
Measure Type: Number; Unit of Measure: percentage of participants
	43.1	51.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dupilumab 300 mg q2w
	Comments	Derived from logistic regression model which includes treatment group, region (pooled country), ICS dose, smoking status at screening, and baseline SGRQ total score as covariates. Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0089
	Comments	Threshold for significance at 0.049 level.
	Method	Regression, Logistic
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.439
	Confidence Interval	(2-Sided) 95%; 1.096 to 1.890
	Estimation Comments	[Not Specified]

8. Secondary Outcome

Title	Change From Baseline in Evaluating Respiratory Symptoms (E-RS) in COPD (E-RS: COPD) RS-Total Score at Week 52
Description	The E-RS in COPD scale was a part of the exacerbations of chronic pulmonary disease tool (EXACT). It was a derivative instrument used to measure the effect of treatment on the severity of respiratory symptoms in stable COPD. E-RS: COPD RS-Total Score was derived based on weekly averages of daily assessed 11 respiratory symptom items contained in the 14-item EXACT questionnaire. The RS-Total score represented overall respiratory symptom severity, ranged from 0 to 40. Summation procedure was used to derive the three daily domain scores: 1). RS-Breathlessness (range 0-17), 2) RS-Cough and Sputum (score range 0-11), 3) RS-Chest Symptoms (score range 0-12). The higher the score, more severe were the symptoms.
Time Frame	Baseline (Day 1) to Week 52

Outcome Measure Data

Analysis Population Description

The ITT population consisted of the randomized population analyzed according to the treatment group allocated by randomization. Only those participants with data available were analyzed.

Arm/Group Title	Placebo	Dupilumab 300 mg q2w
Arm/Group Description:	Participants received placebo matched to dupilumab 300 mg as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).	Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).
Overall Number of Participants Analyzed	467	461
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	-1.558 (0.256)	-2.694 (0.257)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dupilumab 300 mg q2w
	Comments	Derived from MMRM model with the change from baseline in E-RS: COPD RS-Total Score to Week 52 as response variables, and treatment group, region (pooled country), ICS dose, smoking status at screening, visit, treatment-by-visit interaction, baseline E-RS: COPD RS-Total Score, and baseline E-RS: COPD RS-Total Score-by-visit interaction as covariates. Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0012
	Comments	Threshold for significance at 0.049 level.
	Method	MMRM model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.137
	Confidence Interval	(2-Sided) 95%; -1.823 to -0.450
	Estimation Comments	[Not Specified]

9. Secondary Outcome

Title	Annualized Rate of Moderate or Severe COPD Exacerbation Over the 52-Week Treatment Period in Subgroup of Participants With Baseline FeNO >=20 Ppb
Description	Moderate exacerbations were recorded by the Investigator and defined as AECOPD 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 requiring hospitalization, or observation for >24 hours in an emergency department/urgent care facility or resulting 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 among participants with baseline FeNO >=20 ppb was the total number of exacerbations that occurred during the treatment period divided by the total number of participant-years treated. Events were adjudicated by independent third party.
Time Frame	Baseline (Day 1) to Week 52

Outcome Measure Data

Analysis Population Description

The subgroup of participants with baseline FeNO >=20 ppb within the ITT population were included.

Arm/Group Title	Placebo	Dupilumab 300 mg q2w
Arm/Group Description:	Participants received placebo matched to dupilumab 300 mg as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).	Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).
Overall Number of Participants Analyzed	188	195
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: exacerbation per participant-year
	1.117; (0.831 to 1.502)	0.699; (0.510 to 0.958)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dupilumab 300 mg q2w
	Comments	Derived using negative binomial model with the total number of the events occurring during the 52-week treatment period as the response variable, and treatment group, region (pooled country), ICS dose, smoking status at screening, baseline disease severity, and number of moderate or severe COPD exacerbation events within one year prior to the study as covariates, and log-transformed treatment duration as an offset variable.
	Type of Statistical Test	Superiority
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
Statistical Test of Hypothesis	P-Value	0.0052
	Comments	Threshold for significance at 0.049 level.
	Method	Negative binomial model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-0.418
	Confidence Interval	(2-Sided) 95%; -0.728 to -0.109
	Estimation Comments	Derived using delta method.

10. Secondary Outcome

Title	Change From Baseline in Pre-BD FEV1 to Weeks 2, 4, 8, 24, 36 and 44
Description	The 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.
Time Frame	Baseline (Day 1) to Weeks 2, 4, 8, 24, 36 and 44

Outcome Measure Data

Analysis Population Description

The ITT population consisted of the randomized population analyzed according to the treatment group allocated by randomization. Only those participants with data available were analyzed.

Arm/Group Title	Placebo	Dupilumab 300 mg q2w
Arm/Group Description:	Participants received placebo matched to dupilumab 300 mg as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).	Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).
Overall Number of Participants Analyzed	469	466
Least Squares Mean (Standard Error); Unit of Measure: liters
Week 2	0.075 (0.017)	0.159 (0.017)
Week 4	0.069 (0.017)	0.163 (0.017)
Week 8	0.069 (0.017)	0.149 (0.017)
Week 24	0.068 (0.018)	0.170 (0.018)
Week 36	0.072 (0.018)	0.155 (0.018)
Week 44	0.089 (0.019)	0.176 (0.019)

11. Secondary Outcome

Title	Change From Baseline in Post-BD FEV1 to Weeks 2, 4, 8, 12, 24, 36 and 52
Description	The FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. Post-BD FEV1 referred to the spirometry performed within 30 minutes after administration of bronchodilator.
Time Frame	Baseline (Day 1) to Weeks 2, 4, 8, 12, 24, 36 and 52

Outcome Measure Data

Analysis Population Description

The ITT population consisted of the randomized population analyzed according to the treatment group allocated by randomization.

Arm/Group Title	Placebo	Dupilumab 300 mg q2w
Arm/Group Description:	Participants received placebo matched to dupilumab 300 mg as subcutaneous (SC) injections q2w 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 treatment i.e., at Week 52).	Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).
Overall Number of Participants Analyzed	469	467
Least Squares Mean (Standard Error); Unit of Measure: liters
Week 2	0.071 (0.017)	0.158 (0.017)
Week 4	0.080 (0.017)	0.158 (0.017)
Week 8	0.077 (0.018)	0.153 (0.018)
Week 12	0.084 (0.018)	0.156 (0.018)
Week 24	0.072 (0.019)	0.169 (0.019)
Week 36	0.072 (0.019)	0.155 (0.019)
Week 52	0.058 (0.019)	0.138 (0.019)

12. Secondary Outcome

Title	Change From Baseline in Pre-BD Forced Expiratory Flow at 25 Percent (%) to 75% (FEF 25-75%) of Forced Vital Capacity (FVC) to Weeks 2, 4, 8, 12, 24, 36, 44, and 52
Description	FEF is the amount of air (in liters) which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEF 25-75% was defined as the mean FEF between 25% and 75% of the FVC, where FVC was defined as the volume of air (in liters) 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.
Time Frame	Baseline (Day 1) to Weeks 2, 4, 8, 12, 24, 36, 44 and 52

Outcome Measure Data

Analysis Population Description

The ITT population consisted of the randomized population analyzed according to the treatment group allocated by randomization. Only those participants with data available were analyzed.

Arm/Group Title	Placebo	Dupilumab 300 mg q2w
Arm/Group Description:	Participants received placebo matched to dupilumab 300 mg as subcutaneous (SC) injections q2w 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 treatment i.e., at Week 52).	Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).
Overall Number of Participants Analyzed	469	466
Least Squares Mean (Standard Error); Unit of Measure: liters/second
Week 2	0.065 (0.016)	0.110 (0.016)
Week 4	0.066 (0.015)	0.115 (0.015)
Week 8	0.069 (0.016)	0.114 (0.016)
Week 12	0.076 (0.016)	0.137 (0.016)
Week 24	0.080 (0.017)	0.142 (0.017)
Week 36	0.087 (0.017)	0.132 (0.017)
Week 44	0.091 (0.017)	0.162 (0.017)
Week 52	0.088 (0.017)	0.135 (0.017)

13. Secondary Outcome

Title	Change From Baseline in Post-BD FEF 25-75% to Weeks 2, 4, 8, 12, 24, 36 and 52
Description	FEF is the amount of air (in liters) which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEF 25-75% was defined as the mean FEF between 25% and 75% of the FVC, where FVC was defined as the volume of air (in liters) 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.
Time Frame	Baseline (Day 1) to Weeks 2, 4, 8, 12, 24, 36 and 52

Outcome Measure Data

Analysis Population Description

The ITT population consisted of the randomized population analyzed according to the treatment group allocated by randomization. Only those participants with data available were analyzed.

Arm/Group Title	Placebo	Dupilumab 300 mg q2w
Arm/Group Description:	Participants received placebo matched to dupilumab 300 mg as subcutaneous (SC) injections q2w 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 treatment i.e., at Week 52).	Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).
Overall Number of Participants Analyzed	469	467
Least Squares Mean (Standard Error); Unit of Measure: liters/second
Week 2	0.074 (0.017)	0.135 (0.017)
Week 4	0.087 (0.017)	0.144 (0.017)
Week 8	0.083 (0.017)	0.144 (0.017)
Week 12	0.089 (0.018)	0.161 (0.018)
Week 24	0.093 (0.019)	0.169 (0.019)
Week 36	0.093 (0.019)	0.161 (0.018)
Week 52	0.093 (0.019)	0.153 (0.019)

14. Secondary Outcome

Title	Annualized Rate of Severe COPD Exacerbations Over the 52-Week Treatment Period
Description	Moderate exacerbations were recorded by the Investigator and defined as AECOPD 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 requiring hospitalization, or observation for >24 hours in an emergency department/urgent care facility or resulting 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 exacerbations that occurred during the treatment period divided by the total number of participant-years treated. Events were adjudicated by independent third party.
Time Frame	Baseline (Day 1) to Week 52

Outcome Measure Data

Analysis Population Description

The ITT population consisted of the randomized population analyzed according to the treatment group allocated by randomization.

Arm/Group Title	Placebo	Dupilumab 300 mg q2w
Arm/Group Description:	Participants received placebo matched to dupilumab 300 mg as subcutaneous (SC) injections q2w 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 treatment i.e., at Week 52).	Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).
Overall Number of Participants Analyzed	471	468
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: exacerbation per participant-year
	0.086; (0.050 to 0.147)	0.072; (0.040 to 0.132)

15. Secondary Outcome

Title	Time to First Moderate or Severe COPD Exacerbation During the 52-Week Treatment Period
Description	The time to first moderate or severe exacerbation was defined as date of the first event minus randomization date +1. The median time to first severe exacerbation was derived from Cox regression model. 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 were recorded by the Investigator and defined as AECOPD requiring hospitalization, or observation for >24 hours in an emergency department/urgent care facility or resulting in death. For both moderate and severe events to be counted as separate events, they were separated by at least 14 days.
Time Frame	Baseline (Day 1) and up to Weeks 12, 24, 36 and 52

Outcome Measure Data

Analysis Population Description

The ITT population consisted of the randomized population analyzed according to the treatment group allocated by randomization.

Arm/Group Title	Placebo	Dupilumab 300 mg q2w
Arm/Group Description:	Participants received placebo matched to dupilumab 300 mg as subcutaneous (SC) injections q2w 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 treatment i.e., at Week 52).	Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).
Overall Number of Participants Analyzed	471	468
Median (95% Confidence Interval); Unit of Measure: weeks
Up to Week 12	0.019; (0.009 to 0.035)	0.024; (0.013 to 0.041)
Up to Week 24	0.039; (0.024 to 0.059)	0.034; (0.021 to 0.054)
Up to Week 36	0.045; (0.029 to 0.067)	0.039; (0.024 to 0.059)
Up to Week 52	0.061; (0.042 to 0.086)	0.043; (0.027 to 0.065)

16. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
Description	An Adverse Event (AE) was defined as any untoward medical occurrence in a participant temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAEs were defined as AEs that developed or worsened in grade or became serious during TE period which was defined as the period from the time of first dose of study treatment until the last visit in the study. Serious adverse events (SAE) were 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 or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event.
Time Frame	TEAEs were collected from the time from the first administration of study treatment to the last administration of the study treatment + 98 days, up to 491 days

Outcome Measure Data

Analysis Population Description

The Safety population consisted of 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. One participant was exposed to different treatment other than planned (was randomized to placebo arm but received dupilumab on Day 40). The actual arm was considered as dupilumab 300 mg q2w. In safety analyses, the actual arms are used.

Arm/Group Title	Placebo	Dupilumab 300 mg q2w
Arm/Group Description:	Participants received placebo matched to dupilumab 300 mg as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).	Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).
Overall Number of Participants Analyzed	470	469
Measure Type: Count of Participants; Unit of Measure: Participants
Any TEAE	359	365
Any TESAE	74	65

17. Secondary Outcome

Title	Number of Participants With Anti-Drug Antibodies (ADA) to Dupilumab
Description	Number of participants with treatment-emergent response to dupilumab with peak post-baseline titers during the on-treatment period are reported. Treatment-emergent response was defined as a positive response in the ADA assay post first dose, when baseline results were negative or missing. Categories were based on titer values and included: low (Titer <1000); moderate (1000<=Titer<=10,000); and high (Titer >10,000). On-treatment period was defined as last study treatment administration plus 14 days; that is, Week 52.
Time Frame	Up to Week 52

Outcome Measure Data

Analysis Population Description

The ADA population consisted of all participants in the Safety population with at least 1 reportable ADA results (either 'ADA negative' or 'ADA positive') after first dose of the study treatment.

Arm/Group Title	Placebo	Dupilumab 300 mg q2w
Arm/Group Description:	Participants received placebo matched to dupilumab 300 mg as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).	Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).
Overall Number of Participants Analyzed	453	462
Measure Type: Count of Participants; Unit of Measure: Participants
Low titer	7	27
Moderate titer	0	1
High titer	0	2

Adverse Events

Time Frame	TEAEs were collected from the time from the first administration of study treatment to the last administration of the study treatment + 98 days, up to 491 days
Adverse Event Reporting Description	Analysis was performed on the Safety population. One participant was exposed to different treatment other than planned (was randomized to placebo arm but received dupilumab on Day 40). The actual arm was considered as dupilumab 300 mg q2w. In safety analyses, the actual arms are used.
Arm/Group Title	Placebo		Dupilumab 300 mg q2w
Arm/Group Description	Participants received placebo matched to dupilumab 300 mg as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).		Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).
All-Cause Mortality
	Placebo		Dupilumab 300 mg q2w
	Affected / at Risk (%)		Affected / at Risk (%)
Total	9/470 (1.91%)		8/469 (1.71%)
Serious Adverse Events
	Placebo		Dupilumab 300 mg q2w
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	74/470 (15.74%)		65/469 (13.86%)
Blood and lymphatic system disorders
Anaemia † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Blood Loss Anaemia † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Polycythaemia † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Cardiac disorders
Acute Coronary Syndrome † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Acute Myocardial Infarction † 1	2/470 (0.43%)	2	1/469 (0.21%)	1
Angina Unstable † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Arrhythmia † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Atrial Fibrillation † 1	1/470 (0.21%)	1	1/469 (0.21%)	1
Atrioventricular Block Complete † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Atrioventricular Block Second Degree † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Cardiac Failure † 1	2/470 (0.43%)	2	2/469 (0.43%)	2
Cardiac Failure Congestive † 1	2/470 (0.43%)	2	0/469 (0.00%)	0
Cor Pulmonale Acute † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Coronary Artery Disease † 1	1/470 (0.21%)	1	2/469 (0.43%)	2
Myocardial Infarction † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Nodal Rhythm † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Tachycardia † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Endocrine disorders
Hyperparathyroidism † 1	1/470 (0.21%)	2	0/469 (0.00%)	0
Gastrointestinal disorders
Abdominal Pain † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Colitis † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Gastritis † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Intestinal Ischaemia † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Intestinal Polyp † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Pancreatitis † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Pancreatitis Acute † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Rectal Haemorrhage † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Umbilical Hernia † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Upper Gastrointestinal Haemorrhage † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
General disorders
Chest Pain † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Pyrexia † 1	1/470 (0.21%)	1	1/469 (0.21%)	1
Sudden Cardiac Death † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Hepatobiliary disorders
Bile Duct Stone † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Cholecystitis † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Cholecystitis Acute † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Cholelithiasis † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Hepatic Failure † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Hepatic Function Abnormal † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Hepatorenal Syndrome † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Immune system disorders
Anaphylactic Reaction † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Hypersensitivity † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Infections and infestations
Abdominal Wall Abscess † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Appendicitis † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Bronchitis † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Bronchitis Bacterial † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Bronchopulmonary Aspergillosis † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Covid-19 † 1	4/470 (0.85%)	4	3/469 (0.64%)	3
Covid-19 Pneumonia † 1	5/470 (1.06%)	5	2/469 (0.43%)	2
Cholecystitis Infective † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Epiglottitis † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Herpes Zoster † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Influenza † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Lower Respiratory Tract Infection † 1	2/470 (0.43%)	2	3/469 (0.64%)	4
Pneumonia † 1	12/470 (2.55%)	13	6/469 (1.28%)	7
Pneumonia Bacterial † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Pneumonia Pneumococcal † 1	2/470 (0.43%)	2	0/469 (0.00%)	0
Pulmonary Tuberculosis † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Respiratory Tract Infection † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Septic Shock † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Subcutaneous Abscess † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Upper Respiratory Tract Infection † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Urinary Tract Infection † 1	1/470 (0.21%)	1	1/469 (0.21%)	1
Injury, poisoning and procedural complications
Ankle Fracture † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Femoral Neck Fracture † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Femur Fracture † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Fibula Fracture † 1	1/470 (0.21%)	1	1/469 (0.21%)	1
Head Injury † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Pneumothorax Traumatic † 1	1/470 (0.21%)	1	1/469 (0.21%)	1
Rib Fracture † 1	2/470 (0.43%)	2	0/469 (0.00%)	0
Road Traffic Accident † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Skin Abrasion † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Spinal Compression Fracture † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Tibia Fracture † 1	1/470 (0.21%)	1	1/469 (0.21%)	1
Metabolism and nutrition disorders
Diabetes Mellitus Inadequate Control † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Hypokalaemia † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Hyponatraemia † 1	1/470 (0.21%)	2	0/469 (0.00%)	0
Type 2 Diabetes Mellitus † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Musculoskeletal and connective tissue disorders
Rhabdomyolysis † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder Transitional Cell Carcinoma † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Ductal Adenocarcinoma Of Pancreas † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Glioblastoma † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Invasive Ductal Breast Carcinoma † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Lung Adenocarcinoma † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Lung Carcinoma Cell Type Unspecified Stage Iv † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Lung Neoplasm † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Lung Neoplasm Malignant † 1	1/470 (0.21%)	1	1/469 (0.21%)	1
Pancreatic Carcinoma Metastatic † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Prostate Cancer † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Rectal Cancer † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Squamous Cell Carcinoma Of Lung † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Squamous Cell Carcinoma Of Skin † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Nervous system disorders
Basal Ganglia Haemorrhage † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Cerebral Haemorrhage † 1	0/470 (0.00%)	0	2/469 (0.43%)	2
Cerebral Infarction † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Cerebrovascular Accident † 1	1/470 (0.21%)	2	0/469 (0.00%)	0
Generalised Tonic-Clonic Seizure † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Ischaemic Stroke † 1	2/470 (0.43%)	2	1/469 (0.21%)	1
Presyncope † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Seizure † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Syncope † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Transient Ischaemic Attack † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Psychiatric disorders
Psychotic Disorder † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Renal and urinary disorders
Acute Kidney Injury † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Chronic Kidney Disease † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Glomerulonephritis † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Haematuria † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Nephritis † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Renal Failure † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Reproductive system and breast disorders
Ovarian Cyst † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Acute Pulmonary Oedema † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Acute Respiratory Distress Syndrome † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Acute Respiratory Failure † 1	2/470 (0.43%)	2	2/469 (0.43%)	2
Atelectasis † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Bronchospasm † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Chronic Obstructive Pulmonary Disease † 1	26/470 (5.53%)	34	28/469 (5.97%)	37
Chronic Respiratory Failure † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Pneumothorax † 1	1/470 (0.21%)	1	1/469 (0.21%)	2
Pneumothorax Spontaneous † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Pulmonary Oedema † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Respiratory Failure † 1	3/470 (0.64%)	3	1/469 (0.21%)	1
Vascular disorders
Deep Vein Thrombosis † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Hypertensive Crisis † 1	0/470 (0.00%)	0	1/469 (0.21%)	1
Hypertensive Emergency † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Peripheral Artery Occlusion † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
Peripheral Vascular Disorder † 1	1/470 (0.21%)	1	0/469 (0.00%)	0
1 Term from vocabulary, MedDRA 25.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo		Dupilumab 300 mg q2w
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	172/470 (36.60%)		168/469 (35.82%)
Gastrointestinal disorders
Diarrhoea † 1	17/470 (3.62%)	18	25/469 (5.33%)	34
Infections and infestations
Nasopharyngitis † 1	45/470 (9.57%)	60	45/469 (9.59%)	55
Upper Respiratory Tract Infection † 1	46/470 (9.79%)	66	37/469 (7.89%)	49
Injury, poisoning and procedural complications
Accidental Overdose † 1	30/470 (6.38%)	36	26/469 (5.54%)	28
Musculoskeletal and connective tissue disorders
Back Pain † 1	16/470 (3.40%)	17	25/469 (5.33%)	27
Nervous system disorders
Headache † 1	33/470 (7.02%)	39	38/469 (8.10%)	57
Vascular disorders
Hypertension † 1	28/470 (5.96%)	32	17/469 (3.62%)	17
1 Term from vocabulary, MedDRA 25.1; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Trial Transparency Team
• Organization: Sanofi aventis recherche & développement
• Phone: 800-633-1610 ext 6#
• EMail: Contact-US@sanofi.com

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT03930732
• Other Study ID Numbers: EFC15804; 2018-001953-28 ( EudraCT Number ); U1111-1211-8804 ( Other Identifier: UTN )
• First Submitted: April 26, 2019
• First Posted: April 29, 2019
• Results First Submitted: January 30, 2024
• Results First Posted: February 28, 2024
• Last Update Posted: February 28, 2024