Investigating Dupilumab's Effect in Asthma by Genotype

Study Overview
=================
Brief Summary
-----------------
The Goal of this study is to investigate if individuals ages 12 years and older, carrying the IL-4RαR576 gene variant, will have a greater response to therapy acting directly on the anti-IL-4R. This will be conducted by examining the effect of a 48 week therapy with dupilumab on the rate of asthma exacerbations.

Detailed Description
-----------------
This is a double-blind, randomized, placebo-controlled parallel-group phase 4 clinical trial. Patients will be genotyped and categorized as those with: 1) the wild type allele (Q576/Q576), 2) heterozygous allele (Q576/R576), or 3) homozygous mutant allele (R576/R576); the genotype associated with more severe disease. After a run-in period of 2-12 weeks to determine asthma control, subjects who fulfill all inclusion/exclusion criteria will be randomized to receive either subcutaneous Dupilumab or placebo (1:1 randomization allocation ratio). This study addresses fundamental mechanisms by which the IL-4Rα-R576 variant drives the TH2/TH17 disease endotype and the influence of this variant on response to Dupilumab therapy. It brings together individuals with deep clinical and scientific expertise in allergic diseases, including epidemiology, genetics, inflammation, and tolerance mechanisms to investigate, in a coordinated strategy, the hypothesis that the IL-4Rα-R576 variant drives TH2/TH17 cell inflammation by subverting allergen-specific iTreg cells into TH17 cells. Asthmatics bearing this endotype will be particularly likely to favorably respond to Dupilumab therapy by virtue of its prevention of iTreg cell reprogramming into TH17-like cells, potentially leading to their long-term stability and potential for sustained immune tolerance.

Official Title
-----------------
Effect of IL-4RαR576 Polymorphism on Response to Dupilumab in Asthma, a Genotype-stratified, Randomized, Placebo- Controlled Trial

Conditions
-----------------
Asthma

Intervention / Treatment
-----------------
* Drug: Dupilumab
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Ages 12 years and older Ability to provide informed consent Ability to perform pulmonary function tests Female participants of childbearing potential must have a negative urine pregnancy test upon study entry Female participants with reproductive potential must agree to use FDA-approved methods of birth control for the duration of the study2 Participant-reported physician or licensed medical practitioner diagnosis of asthma Treatment with medium to high dose ICS (400 mcg to maximum of 2000 mcg per day of fluticasone propionate or equivalent) for at least 3 months with a stable dose ≥1 month prior to screening OR used a biologic medication for asthma within the past 8 weeks History of asthma exacerbation in the past year An exacerbation is an asthma attack for which a clinician prescribed a course of systemic (oral, IV, IM) steroids whether or not the patient took the steroids OR An increase of >50% of baseline inhaled corticosteroid dose for ≥3 days OR An unscheduled visit for acute asthma attack (licensed medical practitioner/nurse office, urgent care intervention, emergency department, or hospitalization) Exclusion Criteria: Chronic lung disease other than asthma, which may impair lung function Current smoker or cessation of smoking ≤6 months prior to Visit 0 screening Current use of any electronic (e) vaping device (e.g., e-cigarette, e-cig, mod, vape pen, JUUL, e-cigar, e-hookah, e-pipe, vape pods) or cessation ≤ 6 months prior to screening Pregnant or breast feeding Any other condition or abnormality that, in the opinion of the Principal Investigator, would compromise the safety of the patient or quality of data Evidence that the participant or family may be unreliable or poorly adherent to their asthma treatment or study procedures Planning to relocate away from the clinical center area before study completion Currently participating in an investigational drug trial or participated in one within 30 days before screening Currently being treated with immunosuppressive/immunomodulatory or other investigational agents or biologics for conditions other than asthma, or used a biologic for a non-asthma indication within the past 6 months History of respiratory illness requiring antibiotics or systemic corticosteroids, including asthma exacerbations, within the past 4 weeks (evaluated at time of screening visit) History of alcohol or illicit substance abuse within 6 months of screening Neutropenia (<1,000/mm3) or thrombocytopenia (<100,000/mm3) or hemoglobin < 100 g/L (10 g/dL) or blood eosinophils > 1500/mm3 at screening Administration of a live vaccine within 4 weeks of screening Currently receiving allergen immunotherapy (food or aeroallergen) other than an established maintenance regimen implemented continuously for a minimum of 2 months. Individuals receiving aeroallergen immunotherapy must be willing to stay on it for the duration of the study.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a genotype stratified, double-blind, randomized, placebo-controlled, parallel-group, phase IV clinical trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment group<br>Dupilumab (Dupixent®) administered subcutaneously every two weeks. An initial dose of 600 mg (two 300 mg injections) followed by 300 mg given every other week. | Drug: Dupilumab<br>* anti-IL4 receptor antagonist<br>* Other names: Dupixent®;|
| Placebo Comparator: Placebo group<br>Placebo (preparation, administration, packaging, and labeling all equivalent to the treatment) administered subcutaneously every two weeks. | Other: Placebo<br>* Placebo for Dupilumab (packaged/administered the same as the active drug)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The rate of asthma exacerbations | An exacerbation is an asthma attack for which a clinician prescribed a course of systemic steroids, whether or not the patient took the steroids. | 48 week treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in pre-bronchodilator lung function | the change in pre-bronchodilator FEV1% predicted from baseline | average of week 4,12, 24,36 and 48 week | 
| Change in CASI score | The change in CASI score from baseline | average of 4,12, 24, 36, and 48 week |