Effect of IL-4RαR576 Polymorphism on Response to Dupilumab in Adolescents and Adults With Asthma
Effect of IL-4RαR576 Polymorphism on Response to Dupilumab in Adolescents and Adults With Asthma
The goal of this trial will be to link novel mechanistic findings with clinical phenotypes
 and outcomes in the context of an intervention (Dupilumab) that acts directly on our
 mechanistic findings, to directly inform endotype-direct targeted therapy in asthma. The
 potential impact is great, because an important knowledge gap is a practically obtained
 predictive biomarker that could inform which patients would more greatly benefit from such
 therapy. This trial will inform endotype personalized therapy on patients with uncontrolled
 asthma, who will likely benefit from Dupilumab as a first line therapy and prove the concept
 that a therapy that directly acts on mechanistic endotypes can help inform first line therapy
 which has not been well elucidated prior. This trial will allow us to expand our
 understanding of asthma immunopathogenesis utilizing a genotype approach to personalized
 therapy.
This is a double-blind, randomized, placebo-controlled parallel-group phase 2 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 2-4 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.
Inclusion Criteria:

 1. Ages 12-65

 2. Ability to provide informed consent

 3. Ability to perform pulmonary function tests

 4. Female subjects of childbearing potential must have a negative urine pregnancy test
 upon study entry .

 5. Female subjects with reproductive potential must agree to use FDA approved methods of
 birth control for the duration of the study.

 6. Clinically stable asthma at time of entry

 7. Participant reported Physician or Licensed Medical Practitioner Diagnosis of Asthma

 8. Treatment with medium to high dose ICS (400 mcg to maximum of 2000 mcq per day of
 fluticasone propionate or equivalent for at least 3 months with a stable dose ≥1 month
 prior to screening OR a biologic medication for asthma

 9. History of asthma exacerbation in the past year, . An exacerbation is defined as:

 1) a wheezing episode requiring treatment with systemic corticosteroid (oral, intravenous,
 or intramuscular) prescribed by a licensed medical providerand/or a biologic medication for
 asthma

 2)An increase in >50% of baseline corticosteroid dose for ≥3 days

 3.)An unscheduled visit for acute asthma/wheezing care (licensed medical practitioner/nurse
 office, urgent care intervention, emergency department, or hospitalization)

 Exclusion Criteria:

 1. Chronic lung disease other than asthma, which may impair lung function.

 2. Current smoker or cessation of smoking within 6 months prior to Visit 1.

 3. Comorbid disease that might interfere with the evaluation of the Investigational
 Product (Dupilumab).

 4. Pregnancy

 5. Other chronic pulmonary disorders associated with asthma-like symptoms, including (but
 not limited to) cystic fibrosis, chronic obstructive pulmonary disease, chronic
 bronchitis, vocal cord dysfunction (that is the sole cause of respiratory symptoms and
 at the PI's discretion), severe scoliosis or chest wall deformities that affect lung
 function, or congenital disorders of the lungs or airways

 6. History of premature birth (before 34 weeks gestation)

 7. The presence of clinically important co-morbidities. These include uncontrolled
 diabetes, uncontrolled coronary artery disease, acute or chronic renal failure, and
 uncontrolled hypertension, hepatic or renal insufficiency, gastrointestinal disease,
 arrhythmia, malignancy, diverticulitis, immunodeficiency (including HIV),
 opportunistic infection, hepatitis, or any other condition or abnormality that in the
 opinion of the Principal Investigator would compromise the safety of the patient or
 quality of data

 8. Evidence that the participant or family may be unreliable or poorly adherent to their
 asthma treatment or study procedures

 9. Administration of a live vaccine within 6 weeks of screening.

 10. Planning to relocate from the clinical center area before study completion

 11. Any other criteria that place the subject at unnecessary risk according to the
 judgment of the Principal Investigator and/or attending physician(s) of record.

 12. Currently participating in an investigational drug trial

 13. Being treated with immunosuppressive/immunodulatory or other investigational agents or
 biologics within 30 days or 5 half-lives of enrollment, whichever is longer

 14. History of recent respiratory illness including asthma exacerbations in the past 4
 weeks at screening requiring antibiotics or systemic corticosteroids.

 15. History of alcohol or illicit substance abuse within 6 months of screening

 16. Neutropenia (<1,000/mm3) or thrombocytopenia (<100,000/mm3) or hemoglobin < 100 g/L
 (10 g/dL) at screening

 17. Subjects will be excluded if they have any serious medical problems and cannot perform
 study procedures.

 1. Chronic lung disease other than asthma, which may impair lung function. 2. Current
 smoker or cessation of smoking < 6 months prior to Visit 1. 4. Pregnant or breast feeding
 5. History of premature birth (before 34 weeks gestation) 6. Any other condition or
 abnormality that in the opinion of the Principal Investigator would compromise the safety
 of the patient or quality of data 7. Evidence that the participant or family may be
 unreliable or poorly adherent to their asthma treatment or study procedures 8.
 Administration of a live vaccine within 6 weeks of screening. 9. Planning to relocate from
 the clinical center area before study completion 10. Any other criteria that place the
 subject at unnecessary risk according to the judgment of the Principal Investigator and/or
 attending physician(s) of record.

 11. Currently participating in an investigational drug trial 12. Being treated with
 immunosuppressive/immunodulatory or other investigational agents or biologics for
 conditions other than asthma 13. History of recent respiratory illness including asthma
 exacerbations in the past 4 weeks at screening requiring antibiotics or systemic
 corticosteroids.

 14. History of alcohol or illicit substance abuse within 6 months of screening 15.
 Neutropenia (<1,000/mm3) or thrombocytopenia (<100,000/mm3) or hemoglobin < 100 g/L (10
 g/dL) at screening