Study Assessing the Long-term Effect of Dupilumab on Prevention of Lung Function Decline in Adult Patients With Uncontrolled Moderate to Severe Asthma

Study Overview
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Brief Summary
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This is an interventional, randomized, parallel group, treatment, Phase 3b/4, double blind, 2-arm study to assess the effect of dupilumab compared to standard of care therapy on preventing or slowing the rate of lung function decline in adult patients with uncontrolled moderate to severe asthma. The estimated duration is 4±1 weeks of screening and run-in period, followed by a 3-year double blinded treatment period. There will be a post-treatment follow-up (FU) period up to 12 weeks.

Official Title
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A Randomized, Double-Blind, Placebo Controlled Study Assessing the Long-term Effect of Dupilumab on Prevention of Lung Function Decline in Patients With Uncontrolled Moderate to Severe Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Dupilumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be at least 18 (or the legal age of consent in the jurisdiction in which the study is taking place) years of age inclusive, at the time of signing the informed consent. Patients with a physician diagnosis of asthma (according to Global Initiative for Asthma (GINA) 2021) for ≥12 months Treatment with medium to high dose inhaled corticosteroids (ICS) (≥250 mcg of fluticasone propionate twice daily or equipotent ICS daily dosage to a maximum of 2000 mcg/day of fluticasone propionate or equivalent) in combination with a second controller (eg, long-acting beta-2 adrenergic receptor agonists (LABA), LTRA) with a stable dose ≥1 month prior to Visit 1. Patients requiring a third controller for their asthma will be considered eligible for this study, and it should also be on stable dose ≥1 month prior to Visit 1. Pre-bronchodilator forced expiratory volume (FEV1) ≤ 80% of predicted normal for adults at Visits 1 and 2, prior to randomization Asthma Control Questionnaire 5-question version (ACQ-5) score ≥1.5 at Visits 1 and 2, prior to randomization. Bronchodilator reversibility (≥ 12% and 200 mL improvement in FEV1 post short-acting beta agonists (SABA) administration) during the screening period, prior to randomization, unless reversibility test meeting the inclusion criteria was done within 12 months prior to Visit 1. FeNO ≥35 ppb at Visit 2, prior to randomization. Up to 550 patients can be enrolled with baseline FeNO<35 ppb at Visit 2 History of ≥1 severe exacerbation(s) in the previous year before V1 defined as a deterioration of asthma requiring: Use of systemic corticosteroids for ≥3 days; or Hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids. - - - - Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: History or clinical evidence of chronic obstructive pulmonary disease (COPD) including Asthma-COPD Overlap Syndrome (ACOS) or any other significant lung disease (eg, emphysema, lung fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension, bronchiectasis, Churg-Strauss Syndrome). Severe asthma exacerbation requiring treatment with systemic corticosteroid (SCS) in the past month before visit 1 or during the screening period. Current acute bronchospasm or status asthmaticus. Diagnosed pulmonary (other than asthma) or systemic disease associated with elevated peripheral eosinophil counts. Severe concomitant illness(es) that, in the Investigator's judgment, would adversely affect the participant's participation in the study. Examples include, but are not limited to, participants with short life expectancy, uncontrolled diabetes, cardiovascular conditions, severe renal conditions (eg, participants on dialysis), or other severe endocrinological, gastrointestinal, metabolic, pulmonary, psychiatric, or lymphatic diseases. The specific justification for participants excluded under this criterion will be noted in the study documents (chart notes, case report forms [CRFs], etc). Patients with active tuberculosis (TB) or non-tuberculous mycobacterial infection, or a history of incompletely treated TB will be excluded from the study unless it is well documented by a specialist that the participant has been adequately treated and can now start treatment with a biologic agent, in the medical judgment of the Investigator and/or infectious disease specialist. Tuberculosis testing will be performed on a country by country basis, according to local guidelines if required by regulatory authorities or ethics boards, or if TB is suspected by the investigator Known or suspected immunodeficiency, including history of invasive opportunistic infections (eg, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, and aspergillosis) despite infection resolution, or otherwise recurrent infections of abnormal frequency or prolonged duration suggesting an immune-compromised status, as judged by the Investigator. Active malignancy or history of malignancy within 5 years before Visit 1 (screening visit), except completely treated in situ carcinoma of the cervix and completely treated and resolved non metastatic squamous or basal cell carcinoma of the skin. Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antifungals or receiving only symptomatic treatment (e.g. influenza or COVID-19) within 2 weeks before the screening visit (Visit 1) or during the screening period. History of human immunodeficiency virus (HIV) infection or positive HIV 1/2 serology at Visit 1 (screening visit). Diagnosed with, suspected of, or at high risk of endoparasitic infection, and/or use of antiparasitic drugs within 2 weeks before Visit 1 (screening visit) or during the screening and run-in period Current smoker (cigarette or e-cigarette) or cessation of smoking within 6 months prior to Visit 1. Previous smoker with a smoking history >10 pack-years. History of systemic hypersensitivity or anaphylaxis to dupilumab or any other biologic therapy, including any excipient. Any biologic therapy (including experimental treatments and dupilumab) or any other biologic therapy/immunosuppressant/immunomodulators within 4 weeks prior to V1 or 5 half-lives, whichever is longer. Treatment with a live (attenuated) vaccine within 4 weeks before Visit 1 (screening visit) or during the screening period. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dupilumab<br>Dupilumab administered every 2 weeks (Q2W) after an initial loading dose (2 injections) on Day 1 | Drug: Dupilumab<br>* solution for injection subcutaneous<br>|
| Placebo Comparator: Placebo<br>Matching placebo administered Q2W after an initial loading dose (2 injections) on Day 1 | Drug: Placebo<br>* solution for injection subcutaneous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of change from week 8 to week 52 on post-BD FEV1 slope in FeNO population | Rate of change from week 8 to week 52 on post-bronchodilator (BD) forced expiratory volume in one second (FEV1) slope in FeNO population. | Week 8 to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of change from week 8 to week 52 on post-BD FEV1 slope in the Total population | Rate of change from week 8 to week 52 on post-BD FEV1 slope in the Total population. | Week 8 to Week 52 | 
| Rate of change from week 8 to week 104 on post-BD FEV1 slope in the FeNO population | Rate of change from week 8 to week 104 on post-BD FEV1 slope in the FeNO population. | Week 8 to Week 104 | 
| Change from baseline to week 52 in pre-BD FEV1 in FeNO and Total populations | Change from baseline to week 52 in pre-BD FEV1 in FeNO and Total populations. | Baseline to Week 52 | 
| Change from baseline to week 52 in post-BD FEV1 in FeNO and Total populations | Change from baseline to week 52 in post-BD FEV1 in FeNO and Total populations. | Baseline to Week 52 | 
| Annualized severe exacerbation rate during the 52-week period in FeNO and Total populations | Exacerbation defined as a deterioration of asthma requiring use of systemic corticosteroids for ≥3 days; or hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids. | Baseline to Week 52 | 
| Change from baseline to week 52 in fractional exhaled nitric oxide (FeNO) levels in FeNO and Total populations | Change from baseline to week 52 in FeNO levels in FeNO and Total populations. | Baseline to Week 52 | 
| Change from baseline to week 52 in Asthma Control Questionnaire 7 items (ACQ-7) in FeNO and Total populations | ACQ-7 was designed to measure both the adequacy of asthma control and change in asthma control. A global score ranges between 0 (totally controlled) and 6 (severely uncontrolled). Higher score indicates lower asthma control. | Baseline to Week 52 | 
| Change from baseline to week 52 in pre-BD FEV1 % predicted in FeNO and Total populations | Change from baseline to week 52 in pre-BD FEV1 % predicted in FeNO and Total populations. | Baseline to Week 52 | 
| Change from baseline to week 52 in Forced Vital Capacity (FVC) in FeNO and Total populations | Change from baseline to week 52 in FVC in FeNO and Total populations. | Baseline to Week 52 | 
| Rate of change from week 8 to week 104 on post-BD FEV1 slope in Total Population | Rate of change from week 8 to week 104 on post-BD FEV1 slope in Total Population. | Week 8 to Week 104 | 
| Change from baseline to week 104 in pre-BD FEV1 in FeNO and Total populations | Change from baseline to week 104 in pre-BD FEV1 in FeNO and Total populations. | Baseline to Week 104 | 
| Change from baseline to week 104 in post-BD FEV1 in FeNO and Total populations | Change from baseline to week 104 in post-BD FEV1 in FeNO and Total populations. | Baseline to Week 104 | 
| Annualized severe exacerbation rate during the 104-week period in FeNO and Total populations | Exacerbation defined as a deterioration of asthma requiring use of systemic corticosteroids for ≥3 days; or hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids. | Baseline to Week 104 | 
| Change from baseline to week 104 in FeNO levels in FeNO and Total populations | Change from baseline to week 104 in FeNO levels in FeNO and Total populations. | Baseline to Week 104 | 
| Change from baseline to week 104 in ACQ-7 in FeNO and Total populations | ACQ-7 was designed to measure both the adequacy of asthma control and change in asthma control. A global score ranges between 0 (totally controlled) and 6 (severely uncontrolled). Higher score indicates lower asthma control. | Baseline to Week 104 | 
| Change from baseline to week 104 in pre-BD FEV1 % predicted in FeNO and Total populations | Change from baseline to week 104 in pre-BD FEV1 % predicted in FeNO and Total populations. | Baseline to Week 104 | 
| Change from baseline to week 104 FVC in FeNO and Total populations | Change from baseline to week 104 FVC in FeNO and Total populations. | Baseline to Week 104 | 
| Change from baseline to week 52 in Asthma Quality Of Life Questionnaire with Standardized Activities (AQLQ(S)) in FeNO and Total populations | The AQLQ (S) was designed as a self-administered patient reported outcome to measure the functional impairments that are most troublesome to patients as a result of their asthma. A global score is calculated ranging from 1 to 7. Higher scores indicate better quality of life. | Baseline to Week 52 | 
| Change from baseline to week 104 in AQLQ(S) in FeNO and Total populations | The AQLQ (S) was designed as a self-administered patient reported outcome to measure the functional impairments that are most troublesome to patients as a result of their asthma. A global score is calculated ranging from 1 to 7. Higher scores indicate better quality of life. | Baseline to Week 104 | 
| Rate of change from week 8 to week 156 on post-BD FEV1 slope in FeNO and Total populations | Rate of change from week 8 to week 156 on post-BD FEV1 slope in FeNO and Total populations. | Week 8 to Week 156 | 
| Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) | Incidence of TEAEs and SAEs. | Baseline to Week 168 | 
| Incidence of adverse events of special interest (AESIs) | Incidence of AESIs. | Baseline to Week 168 |