Clinical trial NCT06385236: Leveraging Pharmacogenomics in Asthma for Predication, Mechanism and Endotyping
Official title: Leveraging Pharmacogenomics in Asthma for Predication, Mechanism and Endotyping
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Moderate to Severe Asthma
Keywords: Asthma
Lead sponsor: University of California, San Diego
Sponsor class: OTHER
Collaborators: name: Mayo Clinic
name: Yale University
name: University of Arizona
name: Harvard University
name: Brigham and Women's Hospital
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2024-04-26
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: The study is significant in determining molecular disease endotypes in a large group of moderate to severe asthmatics. By evaluating within-person genomic level changes and 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.
Primary purpose: TREATMENT

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.

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:

  1. Use of medium or high dose inhaled corticosteroids (ICS) AND
  2. 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.
* History of malignancy except non-melanoma skin cancer within the last five years.
* History of smoking:

  1. If \<45 years old: Smoked for ≥5 pack-years\*
  2. If ≥45 years old: Smoked ≥ 10 pack years.
* Active use of any inhalant \>1 time per month in the past year.
* Substance abuse within the last year.
* Unwillingness to practice medically acceptable birth control or complete abstinence during the study, current pregnancy, or lactation.
* Requirement for daily systemic corticosteroids at the time of screening.
* Respiratory infection within 1 month of screening.
* Intubation for asthma in the last 12 months.
* Any clinically significant abnormal findings in the history, physical examination, vital signs, electrocardiogram, hematology or clinical chemistry during run-in period, which in the opinion of the site investigator, may put the participant at risk because of his/her participation in the study, or may influence the results of the study, or the participant's ability to complete the entire duration of the study.
* BMI \> 38.
* Allergic to any of the drugs, biologics or chemicals used in this study.

Primary outcomes:
measure: Predicting asthma outcomes and therapeutic responses
timeFrame: After 16 weeks (for each biologic)
measure: Responses to the biologic therapies at the single cell level
timeFrame: After 16 weeks (for each biologic)
measure: Unique asthma subgroups clinical and molecular endotype approaches
timeFrame: After 16 weeks (for each biologic)
Secondary outcomes:
measure: Asthma Control Questionnaire (ACQ)
timeFrame: Assessed through study completion, an average of 60 weeks
measure: CompEx events
timeFrame: Assessed through study completion, an average of 60 weeks
measure: Asthma Quality of Life Questionnaire (AQLQ)
timeFrame: Assessed through study completion, an average of 60 weeks
measure: Forced expiratory volume in 1 second (FEV1)
timeFrame: Assessed through study completion, an average of 60 weeks
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic
state: Arizona
city: La Jolla
country: United States
facility: University of California, San Diego
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
Study officials:
affiliation: University of California, San Diego
name: Kelan Tantisira, MD
role: PRINCIPAL_INVESTIGATOR
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