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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 : March 28, 2019
Sponsor:
Information provided by (Responsible Party):
Wanda Phipatanakul, Boston Children’s Hospital

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.

Condition or disease Intervention/treatment Phase
Asthma Drug: Dupilumab Other: Placebo Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 126 participants
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
Official Title: Effect of IL-4RαR576 Polymorphism on Response to Dupilumab in Adolescents and Adults With Asthma
Estimated Study Start Date : October 2019
Estimated Primary Completion Date : October 2023
Estimated Study Completion Date : October 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Asthma
Drug Information available for: Dupilumab

Arm Intervention/treatment
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.
Drug: Dupilumab
anti-IL4 receptor antagonist
Other Name: Dupixent®

Placebo Comparator: Placebo group
Placebo (preparation, administration, packaging, and labeling all equivalent to the treatment) administered subcutaneously every two weeks.
Other: Placebo
Placebo for Dupilumab (packaged/administered the same as the active drug)




Primary Outcome Measures :
  1. 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)


Secondary Outcome Measures :
  1. 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



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Ages Eligible for Study:   12 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03694158


Contacts
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Contact: Wanda Phipatanakul, MD, MS 857-218-5336 Wanda.Phipatanakul@childrens.harvard.edu
Contact: Jennifer Rooney asthma@childrens.harvard.edu

Locations
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United States, Massachusetts
Boston Children's Hospital Not yet recruiting
Boston, Massachusetts, United States, 02115
Contact: Amparito Cunningham       Amparito.Cunningham@childrens.harvard.edu   
Principal Investigator: Wanda Phipatanakul, MD,MS         
Sponsors and Collaborators
Boston Children’s Hospital
Investigators
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Study Chair: Wanda Phipatanakul Boston Children’s Hospital

Publications:
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Responsible Party: Wanda Phipatanakul, Professor of Pediatrics, Boston Children’s Hospital
ClinicalTrials.gov Identifier: NCT03694158     History of Changes
Other Study ID Numbers: P00029072
First Posted: October 3, 2018    Key Record Dates
Last Update Posted: March 28, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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

Additional relevant MeSH terms:
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Asthma
Lung Diseases, Obstructive
Lung Diseases
Bronchial Diseases
Respiratory Tract Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs