Investigating Dupilumab's Effect in Asthma by Genotype (IDEA)

• ClinicalTrials.gov Identifier: NCT03694158
• Recruitment Status: Recruiting
• First Posted: October 3, 2018
• Last Update Posted: April 27, 2023
• Sponsor: Boston Children's Hospital
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); Regeneron Pharmaceuticals; HealthBeacon Plc; Merck Sharp & Dohme LLC; Sanofi
• Information provided by (Responsible Party): Wanda Phipatanakul, Boston Children's Hospital

Tracking Information

• First Submitted Date: October 1, 2018
• First Posted Date: October 3, 2018
• Last Update Posted Date: April 27, 2023
• Actual Study Start Date: September 8, 2021
• Estimated Primary Completion Date: September 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 3, 2021)

The rate of asthma exacerbations [ Time Frame: 48 week treatment period ]

An exacerbation is an asthma attack for which a clinician prescribed a course of systemic steroids, whether or not the patient took the steroids.

Original Primary Outcome Measures (submitted: October 1, 2018)

The rate of asthma exacerbation [ Time Frame: 48 week treatment period ]

asthma exacerbation as defined as wheezing episode lasting >24 hours and associated with Albuterol and/or Levalbuterol use any of the following:

1. Systemic steroid (oral, intravenous, or intramuscular) use prescribed by a licensed medical provider for wheezing episode with or without a clinical visit
2. Unscheduled visit for acute asthma/wheezing care (physician office, urgent care intervention, emergency department, or hospitalization)

Current Secondary Outcome Measures (submitted: May 5, 2021)

• Change in pre-bronchodilator lung function [ Time Frame: average of week 4,12, 24,36 and 48 week ]
  the change in pre-bronchodilator FEV1% predicted from baseline
• Change in CASI score [ Time Frame: average of 4,12, 24, 36, and 48 week ]
  The change in CASI score from baseline

Original Secondary Outcome Measures (submitted: October 1, 2018)

Change in pre-bronchodilator lung function [ Time Frame: the change in FEV1% predicted from baseline will be measured at week 48 (the end of treatment) and at week 72 (the end of the observation period) ]

the change in pre-bronchodilator FEV1% predicted from baseline

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Investigating Dupilumab's Effect in Asthma by Genotype
• Official Title: Effect of IL-4RαR576 Polymorphism on Response to Dupilumab in Asthma, a Genotype-stratified, Randomized, Placebo- Controlled Trial
• 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.

• Study Type: Interventional
• Study Phase: Phase 4

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

This is a genotype stratified, double-blind, randomized, placebo-controlled, parallel-group, phase IV clinical trial

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Double blind, placebo controlled.

Primary Purpose: Treatment

• Condition: Asthma

Intervention

• Drug: Dupilumab
  anti-IL4 receptor antagonist
  Other Name: Dupixent®
• Other: Placebo
  Placebo for Dupilumab (packaged/administered the same as the active drug)

Study Arms

• Experimental: Treatment group
  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.
  Intervention: Drug: Dupilumab
• Placebo Comparator: Placebo group
  Placebo (preparation, administration, packaging, and labeling all equivalent to the treatment) administered subcutaneously every two weeks.
  Intervention: Other: Placebo

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 3, 2021): 150
• Original Estimated Enrollment (submitted: October 1, 2018): 126
• Estimated Study Completion Date: March 2024
• Estimated Primary Completion Date: September 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Wanda Phipatanakul, MD, MS; 857-218-5336; Wanda.Phipatanakul@childrens.harvard.edu

Contact: Claudina Luna; asthma@childrens.harvard.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03694158
• Other Study ID Numbers: P00029072; U01AI143514 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Wanda Phipatanakul, Boston Children's Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Boston Children's Hospital
• Original Study Sponsor: Same as current

Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)
• Regeneron Pharmaceuticals
• HealthBeacon Plc
• Merck Sharp & Dohme LLC
• Sanofi

Investigators

• Principal Investigator: Wanda Phipatanakul; Boston Children's Hospital

• PRS Account: Boston Children's Hospital
• Verification Date: April 2023