The Effect of Dupilumab on Lung Inflammation and Related Changes in Airway Volumes Detectable by Functional Respiratory Imaging in Patients With Moderate-severe Asthma

Study Overview
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Brief Summary
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Primary Objective: • To assess the effect of dupilumab on lung inflammation and related changes in airway volumes detectable by functional respiratory imaging Secondary Objective: To evaluate the effect of dupilumab at Week 24 on bronchodynamics, hyperinflation, airway resistance, airway wall thickness, ventilation defects and mucus plugging derived from high-resolution computed tomography (HRCT) scans, patient-reported outcomes, FeNO and spirometry. To evaluate safety of dupilumab

Detailed Description
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The study duration for each participant will be a total of minimum 29 weeks and up to 41 weeks. This includes 4 weeks +/-1 week screening period, 24 weeks of treatment period and a follow-up period up to 12 weeks or until the patients switch to commercialized dupilumab (or other biologic products), whatever comes first.

Official Title
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Randomized, Double Blind, Placebo Controlled Study to Evaluate the Effect of Dupilumab on Airway Inflammation Through Assessments of Lung Function, Mucus Plugging and Other Lung Imaging Parameters in Patients With 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: 18 to 70 years of age inclusive with the diagnosis of asthma based on Global Strategy for Asthma Management and Prevention (GINA) 2019 at the time of signing the informed consent History of ≥1 exacerbation(s) in the previous year Uncontrolled moderate to severe asthma (ACQ-5 ≥1.5) at V1 and V2, prior to randomization Pre-bronchodilator FEV1 ≤80% of predicted normal at V1 and V2, prior to randomization Exhibit bronchodilator reversibility (≥12% and 200 mL improvement in FEV1 post SABA administration) during screening, prior to randomization Blood eosinophil ≥300 cells /µL and 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 SV1 in the absence of OCS treatment are allowed. FeNO value to be checked for eligibility at V2 as well. -Existing treatment with medium to high dose ICS in combination with a second controller (e.g. LABA, LTRA) ± a third controller. The dose regimen should be stable ≥1 month prior V1 and during screening. Exclusion Criteria: Current smoker (cigarette or e-cigarette) or cessation of smoking within 1 year prior randomization Previous smoker with a smoking history &gt;10 pack-years Known hypersensitivity to dupilumab or any of its excipients A subject who experiences an asthma exacerbation (defined as a deterioration of asthma that results in emergency treatment, hospitalization due to asthma, or treatment with systemic steroids) during screening -Current acute bronchospasm or status asthmaticus Diagnosed pulmonary (other than asthma) or systemic disease associated with elevated peripheral eosinophil counts 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, etc) Active tuberculosis, latent untreated tuberculosis or a history of incompletely treated tuberculosis or non-tuberculous mycobacterial infection unless it is well documented by a specialist that the participants has been adequately treated and the treatment with a biologic agent can be initiated, in the medical judgment of the Investigator and/or infectious disease specialist. Tuberculosis testing would only be performed on a country by country basis according to the routine clinical practice and the local guidelines, if required by regulatory authorities or ethics committees History of or current evidence of clinically significant disease in any non-respiratory system (e.g. cardiovascular, hepatic, nervous system, gastrointestinal, endocrinological, rheumatological, dermatological), which, in the judgment of the Investigator, could interfere with the study or require treatment that might interfere with the study Current evidence of clinically significant oncological disease, which in the opinion of the investigator may interfere with the objectives of the study or put the subject at undue risk Participants with any of the following results at Visit (V) 1: Positive (or indeterminate) hepatitis B surface antigen (HBs Ag) or Positive Hepatitis B IgM core antibody (IgM HBc Ab) or Positive total hepatitis B core antibody (total HBc Ab) confirmed by positive HBV DNA or Positive hepatitis C antibody (HCV Ab) confirmed by positive HCV RNA History of human immunodeficiency virus (HIV) infection or positive HIV serology at V 1 Any biologic therapy (including experimental treatments and dupilumab) or any other biologic therapy/immunosuppressant within 3 months prior to V1 Treatment with live (attenuated) vaccine within 4 weeks before V1. 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, or preponed to before the start of the study without compromising the health of the participant: Participants for whom administration of live (attenuated) vaccine can be safely postponed would be eligible to enroll into the study. Participants who have their vaccination preponed can enroll in the study only after a gap of 4 weeks following administration of the vaccine. Treatment with oral corticosteroids (OCS) within 2 weeks prior to V1 Enrolled in other ongoing studies regardless of the investigational product Treatment with an investigational drug within 1 month or within 5 half-lives (if known), whichever is longer, prior to V1 Suspected or high risk of parasitic infection (helminthic infection), unless clinical and (if necessary) laboratory assessments have ruled out active infection prior to randomization Females who are lactating, breastfeeding, or who are pregnant Individuals accommodated in an institution because of regulatory or legal order; prisoners or subjects who are legally institutionalized Participants are dependent on the Sponsor or Investigator (in conjunction with Section 1.61 of the ICH GCP Ordinance E6) Participants are employees of the clinical study site or other individuals directly involved in the conduct of the study, or immediate family members of such individuals Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the Investigator, contraindicates participation in the study Any country-related specific regulation that would prevent the subject from entering the study 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: 70 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dupilumab<br>2 x loading dose on Day 1, followed by 1 x maintenance dose every 2 weeks (Q2W) during 24 weeks. | Drug: Dupilumab<br>* solution for injection subcutaneous<br>* Other names: SAR231893 Dupixent;|
| Placebo Comparator: Placebo<br>2 x placebo injections on Day 1, then 1 placebo injection Q2W during 24 weeks. | 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 |
| --- | --- | --- |
| Proportion of participants achieving FeNO <25 parts per billion (ppb) at Week 24 | Proportion of participants achieving FeNO <25 parts per billion (ppb) at Week 24 | Week 24 | 
| Percent change from baseline to Week 24 in untrimmed distal airway volumes corrected for lung volume ([s]iVaw) at total lung capacity (TLC) | Percent change from baseline to Week 24 in untrimmed distal airway volumes corrected for lung volume ([s]iVaw) at total lung capacity (TLC). | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change from baseline to Week 24 in untrimmed distal airway volumes corrected for lung volume ([s]iVaw) at functional residual capacity (FRC) | Percent change from baseline to Week 24 in untrimmed distal airway volumes corrected for lung volume ([s]iVaw) at functional residual capacity (FRC). | Baseline to Week 24 | 
| Percent change from baseline to Week 24 in untrimmed distal airway resistance corrected for lung volume ([s]iRaw) at TLC | Percent change from baseline to Week 24 in untrimmed distal airway resistance corrected for lung volume ([s]iRaw) at TLC. | Baseline to Week 24 | 
| Percent change from baseline to Week 24 in untrimmed distal airway resistance corrected for lung volume ([s]iRaw) at FRC | Percent change from baseline to Week 24 in untrimmed distal airway resistance corrected for lung volume ([s]iRaw) at FRC. | Baseline to Week 24 | 
| Change from baseline to Week 24 in global lung lobar volumes (iVlobes) at TLC | Absolute change from baseline to Week 24 in global lung lobar volumes (iVlobes) at TLC. | Baseline to Week 24 | 
| Change from baseline to Week 24 in HRCT-based internal airflow distribution (IAD) for each lung zone | Absolute Change from baseline to Week 24 in HRCT-based internal airflow distribution (IAD) for each lung zone. | Baseline to Week 24 | 
| Change from baseline to Week 24 in image-based ventilation/perfusion (iV/Q) at TLC for each lung zone | Absolute change from baseline to Week 24 in image-based ventilation/perfusion (iV/Q) at TLC for each lung zone. | Baseline to Week 24 | 
| Change from baseline to Week 24 in global lung mucus scoring (UCSF mucus scoring) | University of California, San Francisco (UCSF) mucus scoring is a scoring system to quantify mucus plugs in lung images generated using computerized tomography. The scoring system is based on bronchopulmonary segmental anatomy. Each bronchopulmonary segment is given a score of 1 (mucus plug(s) present) or 0 (mucus plug(s) absent). The segment scores of each lobe are summed to generate a total mucus score for both lungs, yielding a mucus score ranging from 0-20. | Baseline to Week 24 | 
| Change from baseline to Week 24 in FeNO | Absolute change from baseline to Week 24 in FeNO. | Baseline to Week 24 | 
| Change from baseline to Week 24 in pre-bronchodilator FEV1 | Change from baseline to Week 24 in pre-bronchodilator FEV1 | Week 24 | 
| Change from baseline to Week 24 in post-bronchodilator FEV1 | Change from baseline to Week 24 in post-bronchodilator FEV1. | Baseline to Week 24 | 
| Change from baseline to Week 24 in Asthma Control Questionnaire 7 (ACQ-7) | The ACQ-7 is a validated asthma assessment tool that consists of 6 self-assessment questions. The overall scale ranges from 0 = 'totally controlled' to 6 = 'severely uncontrolled. | Baseline to Week 24 | 
| Incidence of treatment emergent adverse events (TEAE) and serious adverse events (SAE) including clinically significant changes in vital signs and laboratory abnormalities | The incidence of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) including clinically significant changes in vital signs and laboratory abnormalities. | Baseline to Week 36 | 
| Incidence of adverse events of special interest (AESI ) | The incidence of AESI. | Baseline to Week 36 |