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

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ClinicalTrials.gov Identifier: NCT04456673
Recruitment Status : Recruiting
First Posted : July 2, 2020
Last Update Posted : April 8, 2021
Sponsor:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Sanofi

Tracking Information
First Submitted Date  ICMJE June 30, 2020
First Posted Date  ICMJE July 2, 2020
Last Update Posted Date April 8, 2021
Actual Study Start Date  ICMJE June 12, 2020
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 30, 2020)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 17, 2020)
  • 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 44 [ Time Frame: Baseline to weeks 2, 4, 8, 24, 36, 44 ]
    Change in pre-bronchodilator FEV1 from baseline to weeks other than 12 and 52 (i.e. Weeks 2, 4, 8, 24, 36, and 44) compared to placebo
  • 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, 24, 36, 44, 52 ]
    Change in FEF 25-75% from baseline to Weeks 2, 4, 8, 12, 24, 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 through week 64 ]
    Incidence of anti-drug antibodies against dupilumab
Original Secondary Outcome Measures  ICMJE
 (submitted: June 30, 2020)
  • 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 through 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  ICMJE Pivotal Study to Assess the Efficacy, Safety and Tolerability of Dupilumab in Patients With Moderate to Severe COPD With Type 2 Inflammation
Official Title  ICMJE 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 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
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Chronic Obstructive Pulmonary Disease
Intervention  ICMJE
  • 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  ICMJE
  • Experimental: Dupilumab
    Dupilmab administered every 2 weeks
    Interventions:
    • Drug: Dupilumab SAR231893
    • Drug: Inhaled Corticosteroid
    • Drug: Inhaled Long-Acting Beta Agonist
    • Drug: Inhaled Long-Acting Muscarinic Antagonist
  • Placebo Comparator: Placebo
    Placebo dose administered every 2 weeks
    Interventions:
    • Drug: Inhaled Corticosteroid
    • Drug: Inhaled Long-Acting Beta Agonist
    • Drug: Inhaled Long-Acting Muscarinic Antagonist
    • Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 30, 2020)
924
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2023
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

  • Participants with a physician diagnosis of COPD who meet the following criteria at screening:

    • Current or former smokers with a smoking history of ≥10 pack-years.
    • Moderate-to-severe COPD (post-bronchodilator FEV1/ forced vital capacity [FVC] ratio <0.70 and post-bronchodilator FEV1 % predicted >30% and ≤70%).
    • Medical Research Council (MRC) Dyspnea Scale grade ≥2.
    • Patient-reported history of signs and symptoms of chronic bronchitis (chronic productive cough) for 3 months in the year up to screening in the absence of other known causes of chronic cough.
    • Documented history of high exacerbation risk defined as exacerbation history of ≥2 moderate or ≥1 severe within the year prior to inclusion. At least one exacerbation should have occurred while the patient was taking inhaled corticosteroid (ICS)/long acting beta agonist (LABA)/long acting muscarinic antagonist (LAMA) (or LABA/LAMA if ICS is contraindicated). Moderate exacerbations are recorded by the investigator and defined as AECOPD that require either systemic corticosteroids (intramuscular, intravenous, or oral) and/or antibiotics. One of the two required moderate exacerbations has to require the use of systemic corticosteroids. Severe exacerbations are recorded by the investigator and defined as AECOPD requiring hospitalization or observation > 24 hours in emergency department/urgent care facility.
    • Background triple therapy (ICS + LABA + LAMA) for 3 months prior to randomization with a stable dose of medication for ≥1 month prior to Visit 1; Double therapy (LABA + LAMA) allowed if ICS is contraindicated.
  • Evidence of Type 2 inflammation: Patients with blood eosinophils ≥300 cells/microliter at Visit 1.

Exclusion criteria:

  • COPD diagnosis for less than 12 months prior to randomization.
  • A current diagnosis of asthma or history of asthma according to the 2018 Global Initiative for Asthma (GINA) guidelines or other accepted guidelines.
  • Significant pulmonary disease other than COPD (e.g., lung fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension, bronchiectasis, Churg-Strauss Syndrome etc) or another diagnosed pulmonary or systemic disease associated with elevated peripheral eosinophil counts.
  • Cor pulmonale, evidence of right cardiac failure.
  • Treatment with oxygen of more than 12 hours per day.
  • Hypercapnia requiring Bi-level ventilation.
  • AECOPD as defined in inclusion criteria within 4 weeks prior to screening, or during the screening period.
  • Respiratory tract infection within 4 weeks prior to screening, or during the screening period.
  • History of, or planned pneumonectomy or lung volume reduction surgery. Patients who are participating in the acute phase of a pulmonary rehabilitation program, ie, who started rehabilitation <4 weeks prior to screening (Note: patients in the maintenance phase of a rehabilitation program can be included).
  • Diagnosis of α-1 anti-trypsin deficiency.

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Trial Transparency email recommended (Toll free number for US & Canada) 800-633-1610 ext option 6 Contact-US@sanofi.com
Listed Location Countries  ICMJE Argentina,   Australia,   Belgium,   Bulgaria,   Canada,   Chile,   Czechia,   France,   Germany,   Greece,   Hungary,   Latvia,   Lithuania,   Netherlands,   Peru,   Poland,   Portugal,   Romania,   Russian Federation,   Serbia,   Slovakia,   South Africa,   Spain,   Ukraine,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04456673
Other Study ID Numbers  ICMJE EFC15805
2018-001954-91 ( EudraCT Number )
U1111-1211-8837 ( 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  ICMJE
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://www.clinicalstudydatarequest.com/
Responsible Party Sanofi
Study Sponsor  ICMJE Sanofi
Collaborators  ICMJE Regeneron Pharmaceuticals
Investigators  ICMJE
Study Director: Clinical Sciences & Operations Sanofi
PRS Account Sanofi
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP