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

Tracking Information

• First Submitted Date: April 26, 2019
• First Posted Date: April 29, 2019
• Results First Submitted Date: January 30, 2024
• Results First Posted Date: February 28, 2024
• Last Update Posted Date: February 28, 2024
• Actual Study Start Date: April 15, 2019
• Actual Primary Completion Date: February 8, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 30, 2024)

Annualized Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Over the 52-Week Treatment Period [ Time Frame: Baseline (Day 1) to Week 52 ]

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.

Original Primary Outcome Measures (submitted: April 26, 2019)

Annual rate of acute COPD exacerbation (AECOPD) [ Time Frame: Baseline to Week 52 ]

Annualized rate of moderate or severe COPD exacerbations over the 52-week treatment period compared to placebo

Current Secondary Outcome Measures (submitted: January 30, 2024)

• Change From Baseline in Pre-Bronchodilator (BD) Forced Expiratory Volume in One Second (FEV1) at Week 12 [ Time Frame: Baseline (Day 1) to Week 12 ]
  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.
• Change From Baseline in Pre-BD FEV1 at Week 52 [ Time Frame: Baseline (Day 1) to Week 52 ]
  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.
• 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) [ Time Frame: Baseline (Day 1) to Week 12 ]
  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.
• Change From Baseline in Pre-BD FEV1 at Week 52 in Subgroup of Participants With Baseline FeNO >=20 Ppb [ Time Frame: Baseline (Day 1) to Week 52 ]
  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.
• Change From Baseline in Saint (St.) George's Respiratory Questionnaire (SGRQ) Total Score at Week 52 [ Time Frame: Baseline (Day 1) to Week 52 ]
  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.
• Percentage of Participants With SGRQ Improvement >=4 Points at Week 52 [ Time Frame: Baseline (Day 1) to Week 52 ]
  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.
• Change From Baseline in Evaluating Respiratory Symptoms (E-RS) in COPD (E-RS: COPD) RS-Total Score at Week 52 [ Time Frame: Baseline (Day 1) to Week 52 ]
  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.
• Annualized Rate of Moderate or Severe COPD Exacerbation Over the 52-Week Treatment Period in Subgroup of Participants With Baseline FeNO >=20 Ppb [ Time Frame: Baseline (Day 1) to Week 52 ]
  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.
• Change From Baseline in Pre-BD FEV1 to Weeks 2, 4, 8, 24, 36 and 44 [ Time Frame: Baseline (Day 1) to Weeks 2, 4, 8, 24, 36 and 44 ]
  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.
• Change From Baseline in Post-BD FEV1 to Weeks 2, 4, 8, 12, 24, 36 and 52 [ Time Frame: Baseline (Day 1) to 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-BD FEV1 referred to the spirometry performed within 30 minutes after administration of bronchodilator.
• 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 [ Time Frame: Baseline (Day 1) to Weeks 2, 4, 8, 12, 24, 36, 44 and 52 ]
  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.
• Change From Baseline in Post-BD FEF 25-75% to Weeks 2, 4, 8, 12, 24, 36 and 52 [ Time Frame: Baseline (Day 1) to Weeks 2, 4, 8, 12, 24, 36 and 52 ]
  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.
• Annualized Rate of Severe COPD Exacerbations Over the 52-Week Treatment Period [ Time Frame: Baseline (Day 1) to Week 52 ]
  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 to First Moderate or Severe COPD Exacerbation During the 52-Week Treatment Period [ Time Frame: 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. 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.
• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) [ 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 ]
  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.
• Number of Participants With Anti-Drug Antibodies (ADA) to Dupilumab [ Time Frame: Up to Week 52 ]
  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.

Original Secondary Outcome Measures (submitted: April 26, 2019)

• Change in pre-bronchodilator FEV1 [ Time Frame: Baseline to Week 12 ]
  Change in pre-bronchodilator FEV1 from baseline to Week 12 compared to placebo
• Change in SGRQ [ Time Frame: Baseline to Week 52 ]
  Change from baseline to Week 52 in SGRQ total score compared to placebo
• Improvement in SGRQ [ Time Frame: Baseline to Week 52 ]
  Proportion of patients with SGRQ improvement ≥4 points at Week 52
• Change in pre-bronchodilator FEV1 from baseline to Week 52 [ Time Frame: Baseline to Week 52 ]
  Change in pre-bronchodilator FEV1 from baseline to Week 52 compared to placebo
• Change in pre-bronchodilator FEV1 from baseline to time points up to Week 48 [ Time Frame: Baseline to Weeks 2, 4, 8, 16, 20, 24, 28, 36, 44, 48 ]
  Change in pre-bronchodilator FEV1 from baseline to weeks other than 12 and 52 (i.e. Weeks 2, 4, 8, 16, 20, 24, 28, 36, 44 and 48) compared to placebo
• Change in post-bronchodilator FEV1 lung function [ Time Frame: Baseline to Weeks 2, 4, 8, 12, 24, 36, 52 ]
  Change in post-bronchodilator FEV1 from baseline at Weeks 2, 4, 8, 12, 24, 36 and 52 compared to placebo
• Change in forced expiratory flow (FEF) 25-75% [ Time Frame: Baseline to Weeks 2, 4, 8, 12, 16, 24, 28, 36, 44, 52 ]
  Change in FEF 25-75% from baseline to Weeks 2, 4, 8, 12, 16, 24, 28, 36, 44 and 52
• Annualized rate of severe AECOPD [ Time Frame: Baseline through Week 52 ]
  Annualized rate of severe COPD exacerbations compared to placebo over the 52-week treatment period
• Time to first AECOPD [ Time Frame: Baseline through Week 52 ]
  Time to first moderate or severe COPD exacerbation compared with placebo during the 52-week treatment period
• Adverse events [ Time Frame: Baseline through Week 64 ]
  Number of adverse events (AEs)/treatment-emergent adverse events (TEAEs)
• Potentially clinically significant abnormality (PCSA) in laboratory tests [ Time Frame: Baseline through Week 64 ]
  Percentage of patients with at least one incidence of PCSA
• Anti-drug antibodies [ Time Frame: Baseline to Week 64 ]
  Incidence of anti-drug antibodies against dupilumab

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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 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: Approximately 68 weeks including a 4-week screening period, a 52-week treatment period, and 12 weeks of follow-up.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Chronic Obstructive Pulmonary Disease

Intervention

• Drug: Dupilumab SAR231893

  Pharmaceutical form: Solution for injection

  Route of administration: Subcutaneous

  Other Name: Dupixent
• Drug: Inhaled Corticosteroid

  Pharmaceutical form: Inhaled Powder

  Route of administration: Oral inhalation

• Drug: Inhaled Long-Acting Beta Agonist

  Pharmaceutical form: Inhaled Powder

  Route of administration: Oral inhalation

• Drug: Inhaled Long-Acting Muscarinic Antagonist

  Pharmaceutical form: Inhaled Powder

  Route of administration: Oral inhalation

• Drug: Placebo

  Pharmaceutical form: Solution for injection

  Route of administration: Subcutaneous

Study Arms

• Experimental: Dupilumab
  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).
  Interventions:

  • Drug: Dupilumab SAR231893
  • Drug: Inhaled Corticosteroid
  • Drug: Inhaled Long-Acting Beta Agonist
  • Drug: Inhaled Long-Acting Muscarinic Antagonist
• Placebo Comparator: Placebo
  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).
  Interventions:

  • Drug: Inhaled Corticosteroid
  • Drug: Inhaled Long-Acting Beta Agonist
  • Drug: Inhaled Long-Acting Muscarinic Antagonist
  • Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 17, 2022): 939
• Original Estimated Enrollment (submitted: April 26, 2019): 924
• Actual Study Completion Date: May 2, 2023
• Actual Primary Completion Date: February 8, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 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 were recorded by the investigator and defined as acute exacerbation of COPD (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 was 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 were 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 could be included).
• Diagnosis of α-1 anti-trypsin deficiency.

The above information was not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 40 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Bulgaria, Canada, Chile, China, Czechia, Denmark, Finland, Germany, Hungary, Israel, Italy, Japan, Korea, Republic of, Mexico, Poland, Romania, Russian Federation, Slovakia, Spain, Sweden, Turkey, Ukraine, United States

Administrative Information

• NCT Number: NCT03930732
• Other Study ID Numbers: EFC15804; 2018-001953-28 ( EudraCT Number ); U1111-1211-8804 ( Other Identifier: UTN )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

• Current Responsible Party: Sanofi
• Original Responsible Party: Same as current
• Current Study Sponsor: Sanofi
• Original Study Sponsor: Same as current
• Collaborators: Regeneron Pharmaceuticals

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

• PRS Account: Sanofi
• Verification Date: January 2024