Effect of IL-4RαR576 Polymorphism on Response to Dupilumab in Children With Asthma
Sponsor:
Boston Children’s Hospital
Collaborators:
Information provided by (Responsible Party):
Wanda Phipatanakul，Boston Children’s Hospital
| Tracking Information | |||
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| First Submitted Date ICMJE | October 1, 2018 | ||
| First Posted Date ICMJE | October 3, 2018 | ||
| Last Update Posted Date | October 3, 2018 | ||
| Actual 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 |
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: Systemic steroid (oral, intravenous, or intramuscular) use prescribed by a licensed medical provider for wheezing episode with or without a clinical visit Unscheduled visit for acute asthma/wheezing care (physician office, urgent care intervention, emergency department, or hospitalization) |
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| Original Primary Outcome Measures ICMJE | Same as current | ||
| Current Secondary Outcome Measures ICMJE |
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| Descriptive Information | |||
| Brief Title ICMJE | Effect of IL-4RαR576 Polymorphism on Response to Dupilumab in Children With Asthma |
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| Official Title ICMJE | Effect of IL-4RαR576 Polymorphism on Response to Dupilumab in Children With Asthma |
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| 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 and 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 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. |
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| 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 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). Within each genotype, randomization will be stratified by race and sex. 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 | Phase 2 | ||
| 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: Interventional Masking Description:Double blind, placebo controlled. Primary Purpose: Treatment |
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| Intervention ICMJE |
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| Recruitment Information | |||
| Recruitment Status ICMJE | Not yet recruiting | ||
| Estimated Enrollment ICMJE |
126 | ||
| Original Estimated Enrollment ICMJE | Same as current | ||
| Estimated Study Completion Date | October 2023 | ||
| Estimated Primary Completion Date | October 2023 (Final data collection date for primary outcome measure) | ||
| Eligibility Criteria ICMJE | Inclusion Criteria: 1. Ages 5-17 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 2. Unscheduled visit for acute asthma/wheezing care (physician 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. Abnormal Liver Function Tests (LFTs) (ALT/AST/bilirubin > 1.5 X upper limit of normal) at screening or other significant liver disease. 15. History of recent respiratory illness including asthma exacerbations in the past 6 weeks at screening requiring antibiotics or systemic corticosteroids. 16. History of alcohol or illicit substance abuse within 6 months of screening 17. Neutropenia (<1,000/mm3) or thrombocytopenia (<100,000/mm3) or hemoglobin < 100 g/L (10 g/dL) at screening 18. Subjects will be excluded if they have any serious medical problems and cannot perform study procedures. | ||
| Sex/Gender |
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| Ages | 5 Years and older (Adult, Older Adult) | ||
| Accepts Healthy Volunteers | No | ||
| Listed Location Countries ICMJE | United States | ||
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| Administrative Information | 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 |
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| IPD Sharing Statement |
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| Responsible Party | Wanda Phipatanakul，Boston Children’s Hospital | ||
| Study Sponsor ICMJE | Boston Children’s Hospital | ||
| Collaborators ICMJE | |||
| Investigators ICMJE |
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| PRS Account | Boston Children’s Hospital | ||
| Verification Date | October 2018 | ||
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ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |
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