Investigating Dupilumab's Effect in Asthma by Genotype

Asthma Clinical Trial

— IDEA  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03694158
• Other study ID #: P00029072
• Secondary ID: U01AI143514
• Status: Recruiting
• Phase: Phase 4
• Start date: September 8, 2021
• Est. completion date: March 2027

Study information

• Verified date: February 2024
• Source: Boston Children's Hospital
• Contact: Wanda Phipatanakul, MD, MS
• Phone: 857-218-5336
• Email: Wanda.Phipatanakul[@]childrens.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 150
• Est. completion date: March 2027
• Est. primary completion date: September 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

Inclusion Criteria:

1. Ages 12 years and older

2. Ability to provide informed consent

3. Ability to perform pulmonary function tests

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

5. Female participants with reproductive potential must agree to use FDA-approved methods of birth control for the duration of the study2

6. Participant-reported physician or licensed medical practitioner diagnosis of asthma

7. 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

8. 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:

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

2. Current smoker or cessation of smoking =6 months prior to Visit 0 screening

3. 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

4. Pregnant or breast feeding

5. Any other condition or abnormality that, in the opinion of the Principal Investigator, would compromise the safety of the patient or quality of data

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

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

8. Currently participating in an investigational drug trial or participated in one within 30 days before screening

9. 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

10. History of respiratory illness requiring antibiotics or systemic corticosteroids, including asthma exacerbations, within the past 4 weeks (evaluated at time of screening visit)

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

12. Neutropenia (<1,000/mm3) or thrombocytopenia (<100,000/mm3) or hemoglobin < 100 g/L (10 g/dL) or blood eosinophils > 1500/mm3 at screening

13. Administration of a live vaccine within 4 weeks of screening

14. 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.

Related Conditions & MeSH terms

• Asthma

Intervention

Drug:
• Dupilumab
anti-IL4 receptor antagonist

Other:
• Placebo
Placebo for Dupilumab (packaged/administered the same as the active drug)

Locations

Country	Name	City	State
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Montefiore Einstein Clinical Research Center	Bronx	New York
United States	Atlantic Health System	Cedar Knolls	New Jersey
United States	MetroHealth System	Cleveland	Ohio
United States	Henry Ford Health System	Detroit	Michigan
United States	University of Pennsylvania	Philadelphia	Pennsylvania

Sponsors (6)

Lead Sponsor	Collaborator
Boston Children's Hospital	HealthBeacon Plc, Merck Sharp & Dohme LLC, National Institute of Allergy and Infectious Diseases (NIAID), Regeneron Pharmaceuticals, Sanofi

Country where clinical trial is conducted

United States, 

References & Publications (2)

Lai PS, Massoud AH, Xia M, Petty CR, Cunningham A, Chatila TA, Phipatanakul W. Gene-environment interaction between an IL4R variant and school endotoxin exposure contributes to asthma symptoms in inner-city children. J Allergy Clin Immunol. 2018 Feb;141(2):794-796.e3. doi: 10.1016/j.jaci.2017.08.023. Epub 2017 Sep 21. No abstract available. — View Citation

Massoud AH, Charbonnier LM, Lopez D, Pellegrini M, Phipatanakul W, Chatila TA. An asthma-associated IL4R variant exacerbates airway inflammation by promoting conversion of regulatory T cells to TH17-like cells. Nat Med. 2016 Sep;22(9):1013-22. doi: 10.1038/nm.4147. Epub 2016 Aug 1. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Change in CASI score	The change in CASI score from baseline	average of 4,12, 24, 36, and 48 week