A Phase 4, Randomized, Double-blind, Placebo-controlled,Multicenter, Parallel-group Study of the Effect of Dupilumab on Sleep Disturbance in Patients With Uncontrolled Persistent Asthma

Study Overview
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Brief Summary
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Primary Objective: To assess the effect of dupilumab on sleep Secondary Objectives: To evaluate the effect of dupilumab on additional patient reported sleep outcomes To evaluate the effect of dupilumab on objective sleep assessment To evaluate the effect of dupilumab on asthma symptoms To evaluate the effect of dupilumab on lung function To evaluate the safety of dupilumab

Detailed Description
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Study duration per participant will be approximately 16 weeks and up to 29 weeks including up to 5 weeks screening period, a 12-week treatment period and up to 12 weeks post-treatment follow-up period or until the participant switches to commercialized dupilumab (or other biologic product), whichever comes first.

Official Title
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A Phase 4, Randomized, Double-blind, Placebo-controlled, Multicenter, Parallel-group Study of the Effect of Dupilumab on Sleep Disturbance in Patients With Uncontrolled Persistent Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: SAR231893
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Physician diagnosis of asthma based on the Global Initiative for Asthma (GINA) 2020 Guidelines for ≥12 months treated with medium to high dose inhaled corticosteroid (ICS) and a second controller (ie, long-acting beta agonist, leukotriene receptor antagonist). A third controller is allowed but not mandatory. The dose regimen should be stable for at least 1 month before the study and during the screening period History of at least one severe asthma exacerbation within 1 year prior to screening. Severe exacerbation is defined as deterioration of asthma that results in emergency treatment, hospitalization due to asthma, or treatment with systemic steroids (oral or injectable) Eosinophils ≥150 cells/μL and fractional exhaled nitric oxide (FeNO) ≥25 ppb during screening, prior to randomization NOTES: Historical values of blood eosinophil count meeting the eligibility criterion measured within 6 months prior to screening Visit 1 in the absence of oral corticosteroid (OCS) treatment are allowed FeNO value to be checked for eligibility at Visit 2 as well Asthma control questionnaire (ACQ)-5 ≥2.5 at screening Visit 1 and Visit 2, prior to randomization Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) ≤ 80% of predicted normal during screening, prior to randomization Exhibit bronchodilator reversibility (≥12% and 200 mL improvement in FEV1 post short-acting beta agonist administration) during screening period, prior to randomization, unless reversibility test meeting the inclusion criteria was done within 6 months prior to screening Visit 1 Weekly average nocturnal awakenings due to asthma symptoms in the week prior to screening Visit 1 is ≥1 Exclusion Criteria: Current smoker Former smoker for 10 years with a smoking history of >10 pack-years Severe asthma exacerbation during screening, prior to randomization History or clinical evidence of chronic obstructive pulmonary disease (COPD) including Asthma-COPD Overlap Syndrome (ACOS) or any other significant lung disease (eg, lung fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension, bronchiectasis, Churg-Strauss Syndrome) History of or current evidence of clinically significant non-respiratory diseases that in the opinion of the investigator may interfere with the aims of the study or put the participant at undue risk Active tuberculosis (TB) or non-tuberculous mycobacterial infection, or a history of incompletely treated TB will be excluded 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 would be performed on a country by country basis, according to local guidelines if required by Regulatory Authorities or ethics boards Diagnosed active endoparasitic infection; suspected or high risk of endoparasitic infection, unless clinical and (if necessary) laboratory assessment have ruled out active infection before randomization History of human immunodeficiency (HIV) infection or positive HIV test at screening Visit 1 Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiprotozoals, or antifungals within 2 weeks before screening Known or suspected immunodeficiency including history of invasive opportunistic infections, despite infection resolution Current evidence of clinically significant oncological disease History of systemic hypersensitivity or anaphylaxis to any biologic therapy Severe uncontrolled depression Sleep disturbances not related to asthma, including sleep apnea, hypersomnia, or insomnia secondary to chronic pain, atopic dermatitis (AD), COPD or other conditions Participant who works night shift (ie, any work between 8 pm and 6 am) Erratic sleep habits, as determined by the Investigator Restless leg syndrome or periodic limb movement disorder Chronic treatment with oral corticosteroid (OCS) for more than 2 weeks before screening Visit 1 Participant taking sedative, anxiolytic, or hypnotic treatments, including melatonin, within 3 months before randomization Participant taking systemic sedative antihistamines (excluding newer generations of antihistamines) or theophylline Current treatment with antidepressants, lipophilic beta blockers, clonidine, opioids, or other medications known to interfere with sleep and may confound the study assessments, as determined by the Investigator Participant who has taken biologic therapy (including dupilumab)/systemic immunosuppressant to treat inflammatory disease or autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc) within 2 months or 5 half-lives before screening Visit 1, whichever is longer Treatment with live (attenuated) vaccine within 4 weeks before screening Visit 1 NOTE: For participants who have vaccination with live, attenuated vaccines planned during the course of the study (based on national vaccination schedule/local guidelines), it will be determined, after consultation with a physician, whether the administration of vaccine can be postponed until after the end of the study, (i.e. after the 12 week follow-up period off-treatment or until the participant switches to commercialized dupilumab or other biologic product, whichever comes first), or preponed to before the start of the study without compromising the health of the participant: Participant for whom administration of live (attenuated) vaccine can be safely postponed would be eligible to enroll into the study Participant who have their vaccination preponed can enroll in the study only after a gap of 4 weeks following administration of the vaccine 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
Maximum Age: 65 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
Interventional Model Description: Interim analysis for sample size re-estimation
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dupilumab<br>2 x dupilumab injections as loading dose on Day 1, followed by 1 dupilumab maintenance dose injection every 2 weeks (Q2W) during 12 weeks | Drug: SAR231893<br>* Pharmaceutical form: Solution for injection; Route of administration: Subcutaneous<br>* Other names: Dupixent;|
| Placebo Comparator: Placebo<br>2 x placebo injections on Day 1, then 1 placebo injection Q2W during 12 weeks | Drug: Placebo<br>* Pharmaceutical form: Solution for injection; Route of administration: Subcutaneous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in sleep disturbance score in Asthma Sleep Disturbance Questionnaire | Change from baseline to Week 12 in sleep disturbance score using the Asthma Sleep Disturbance Questionnaire | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the number of nocturnal awakenings in Sleep Diary | Change from baseline to Week 12 in the number of nocturnal awakenings as recorded in Sleep Diary | Baseline to Week 12 | 
| Change in PROMIS sleep-related impairment assessment | Change from baseline to Week 12 in Patient-Reported Outcomes Measurement Information System (PROMIS) sleep-related impairment 8a scale | Baseline to Week 12 | 
| Change in sleep quality in Sleep Diary | Change from baseline to Week 12 in sleep quality (Sleep Diary) | Baseline to Week 12 | 
| Change in restorative sleep in Sleep Diary | Change from baseline to Week 12 in restorative sleep (Sleep Diary) | Baseline to Week 12 | 
| Change in WASO in Sleep Diary | Change from baseline to Week 12 in wake after sleep onset (WASO) (Sleep Diary) | Baseline to Week 12 | 
| Change in WASO (actigraphy data) | Change from baseline to Week 12 in WASO based on actigraphy data | Baseline to Week 12 | 
| Change in daytime and nighttime asthma symptoms in Asthma Daytime Symptom Diary (ADSD) and Asthma Nighttime Symptom Diary (ANSD) | Change from baseline to Week 12 in Asthma Daytime Symptom Diary (ADSD) and Asthma Nighttime Symptom Diary (ANSD) | Baseline to Week 12 | 
| Change in pre-bronchodilator (BD) FEV1 | Change from baseline to Week 12 in prebronchodilator forced expiratory volume in 1 second (pre-BD FEV1) | Baseline to Week 12 | 
| Incidence of adverse events | Incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and adverse events of special interest (AESI), including clinically significant changes in vital signs considered to be adverse events | Baseline up to Week 24 |