Leveraging Pharmacogenomics in Asthma for Predication, Mechanism and Endotyping
Overview
- Phase
- Phase 4
- Intervention
- Not specified
- Conditions
- Moderate to Severe Asthma
- Sponsor
- University of California, San Diego
- Enrollment
- 120
- Locations
- 3
- Primary Endpoint
- Responses to the biologic therapies at the single cell level
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
In this study, a new method will be used to evaluate response to 2 approved biologic therapies, and assess how well each patient responds to each asthma treatment. This study will measure the response to these treatments using genomic and biologic measurements obtained from participants biosamples.
By evaluating response to 2 different biologic therapies, this study has the potential to provide an in-depth understanding of the mechanisms underlying severe asthma that will inform and change treatment decisions, and may ultimately lead to a change in the way that asthma patients are evaluated for potential personalized therapies and maximize the probability that the subject will respond to treatment.
Detailed Description
The study design mirrors standard of care for this study population (moderate to severe asthmatics) in that the procedures are drugs and not outside of standard of care and not experimental. The drugs were chosen based on safety, availability, and their use in patient care. The use of the drugs/biologics and other asthma related processes and procedures are not experimental. Eligible participants will have the option of receiving Symbicort as their controller medication, during their involvement in the study. The study focuses on a series of pre- and post-therapy characterizations or 'evoked phenotypes' that are not studied in traditional randomized clinical trials. Specifically, in a broad spectrum of 120 moderate-severe nonsmoking asthmatics, after evaluating pharmacologic response to systemic corticosteroids, each subject will undergo 'evoked phenotypes' with anti-IL-5R (benralizumab) and anti-IL-4Rα (dupilumab) in a random order along with comprehensive transcriptomic data interrogation prior to and during each therapeutic intervention. A specific strength of our approach is the longitudinal assessment of within individual response related to therapeutic immunomodulation combined with state-of-the-art computational methods that will further define disease biology. Current biomarkers are inadequate to distinguish responders and non-responders because they are not sensitive or specific enough for true predictive precision medicine. This study will use novel genomics approaches to assess and predict responses using therapy-induced phenotypes across a spectrum of asthma severity and endotypes.
Investigators
Praveen Akuthota
Professor of Clinical Medicine
University of California, San Diego
Eligibility Criteria
Inclusion Criteria
- •Stated willingness to comply with all study procedures and availability for the duration of the study.
- •Stable asthma medications: No change in asthma medications for the past 2 months:
- •Use of medium or high dose inhaled corticosteroids (ICS) AND
- •Use of an additional asthma controller medication.
- •Baseline poor or uncontrolled asthma.
- •Evidence of asthma demonstrated by either bronchodilator reversibility (either at screening or by historical evidence) or methacholine responsiveness (by historical evidence).
- •Agreement to adhere to Lifestyle Considerations throughout study duration.
Exclusion Criteria
- •Current participation in an interventional trial (e.g. drugs, diets, etc.).
- •Currently on an asthma biologic or having been on biologic within 3 months of screening.
- •Enrollment in a clinical trial where the study medication was administered within the past 60 days or within 5 half-lives (whichever is greater).
- •Physician diagnosis of other chronic pulmonary disorders associated with asthma-like symptoms, including, but not limited to, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, severe scoliosis or chest wall deformities that affect lung function, or congenital disorders of the lungs or airways.
- •Receiving one or more immune-modulating therapies for diseases other than asthma. This includes biologics that are also approved for asthma.
- •Receiving methotrexate, mycophenolate (CellCept®), or azathioprine (Imuran®).
- •Receiving aero allergen immunotherapy and not on at least 3 months of maintenance allergen immunotherapy.
- •Underwent a bronchial thermoplasty within the last two years.
- •Born before 30 weeks of gestation.
- •Uncontrolled hypertension, defined as systolic blood pressure \> 160 mm/Hg or diastolic blood pressure \> 100 mm/Hg.
Outcomes
Primary Outcomes
Responses to the biologic therapies at the single cell level
Time Frame: After 16 weeks (for each biologic)
Single cell (sc) RNA-Seq on sputum and blood samples will be assayed at baseline and after each evoked (drug) phenotype.
Unique asthma subgroups clinical and molecular endotype approaches
Time Frame: After 16 weeks (for each biologic)
Clinical and molecular endotype will be independently assessed for their prognostic association with treatment response through scRNA-seq and RNA-sequencing data at baseline and following therapy.
Predicting asthma outcomes and therapeutic responses
Time Frame: After 16 weeks (for each biologic)
The primary outcomes of our therapeutic assessments are the genomic signatures that will identify novel predictive biomarkers and provide mechanistic insights to the heterogeneous response to a specific therapy. Our genomic signatures will focus on global gene expression using RNA sequencing (RNA-Seq).
Secondary Outcomes
- Asthma Quality of Life Questionnaire (AQLQ)(Assessed through study completion, an average of 60 weeks)
- CompEx events(Assessed through study completion, an average of 60 weeks)
- Forced expiratory volume in 1 second (FEV1)(Assessed through study completion, an average of 60 weeks)
- Asthma Control Questionnaire (ACQ)(Assessed through study completion, an average of 60 weeks)