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Effect of IL-4RαR576 Polymorphism on Response to Dupilumab in Adolescents and Adults With Asthma (I-DAG)

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ClinicalTrials.gov Identifier: NCT03694158
Recruitment Status : Not yet recruiting
First Posted : October 3, 2018
Last Update Posted : May 2, 2019
Sponsor:
Information provided by (Responsible Party):
Wanda Phipatanakul, Boston Children’s Hospital

Tracking Information
First Submitted Date  ICMJE October 1, 2018
First Posted Date  ICMJE October 3, 2018
Last Update Posted Date May 2, 2019
Estimated Study Start Date  ICMJE October 2019
Estimated Primary Completion Date October 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 1, 2018)
The rate of asthma exacerbations [ 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)
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03694158 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effect of IL-4RαR576 Polymorphism on Response to Dupilumab in Adolescents and Adults With Asthma
Official Title  ICMJE Effect of IL-4RαR576 Polymorphism on Response to Dupilumab in Adolescents and Adults With Asthma
Brief Summary 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.
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
This is a genotype stratified, double-blind, randomized, placebo-controlled, parallel-group, phase 2 clinical trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
Double blind, placebo controlled.
Primary Purpose: Treatment
Condition  ICMJE Asthma
Intervention  ICMJE
  • Drug: Dupilumab
    anti-IL4 receptor antagonist
    Other Name: Dupixent®
  • Other: Placebo
    Placebo for Dupilumab (packaged/administered the same as the active drug)
Study Arms  ICMJE
  • Experimental: Treatment group
    Dupilumab (Dupixent®) administered subcutaneously every two weeks. An initial dose of 400 mg (two 200 mg injections) followed by 200 mg given every other week or an initial dose of 600 mg (two 300 mg injections) followed by 300 mg given every other week for patients requiring concomitant oral corticosteroids or with comorbid moderate-to-severe atopic dermatitis for which DUPIXENT is indicated, start with an initial dose of 600 mg 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 *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: October 1, 2018)
126
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 2023
Estimated Primary Completion Date October 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Ages 12-65
  2. Ability to provide informed consent
  3. Ability to perform pulmonary function tests and other procedures in protocol in order to define the phenotype assignments as defined in the protocol
  4. Child with persistent asthma, defined as those children with asthma requiring:

    1. Physician Diagnosis of Asthma and
    2. Existing treatment with ICS with a second controller (eg. long-acting beta agonist, leukotriene receptor antagonist) and/or a third controller for their asthma with a stable dose ≥1 month prior to screening.
  5. History of asthma exacerbation in the past year, defined as a wheezing episode lasting >24 hours and associated with albuterol and/or levalbuterol use and associated with any of the following:

    1. Systemic corticosteroid (oral, intravenous, or intramuscular) use prescribed by a licensed medical provider for wheezing episode with or without a clinical visit and/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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years to 65 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Wanda Phipatanakul, MD, MS 857-218-5336 Wanda.Phipatanakul@childrens.harvard.edu
Contact: Jennifer Rooney asthma@childrens.harvard.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03694158
Other Study ID Numbers  ICMJE P00029072
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  ICMJE
Plan to Share IPD: No
Responsible Party Wanda Phipatanakul, Boston Children’s Hospital
Study Sponsor  ICMJE Boston Children’s Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Wanda Phipatanakul Boston Children’s Hospital
PRS Account Boston Children’s Hospital
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP