Leveraging Pharmacogenomics in Asthma for Predication, Mechanism and Endotyping (EPIPHANY)

August 16, 2024 updated by: Praveen Akuthota, University of California, San Diego

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.

Study Overview

Status

Recruiting

Conditions

Intervention / 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.

Study Type

Interventional

Enrollment (Estimated)

120

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Arizona
      • Scottsdale, Arizona, United States, 85259
        • Recruiting
        • Mayo Clinic
        • Contact:
        • Principal Investigator:
          • Gene R Bleecker, MD
        • Principal Investigator:
          • Deborah A Meyers, PhD
    • California
      • La Jolla, California, United States, 92093
        • Recruiting
        • University of California, San Diego
        • Principal Investigator:
          • Praveen Akuthota, MD
        • Principal Investigator:
          • Kelan Tantisira, MD
        • Contact:
    • Connecticut
      • New Haven, Connecticut, United States, 06520
        • Recruiting
        • Yale University
        • Contact:
        • Principal Investigator:
          • Geoffrey L Chupp, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Dupilumab
600 mg once subcutaneously (given as two 300 mg injections), followed by 300 mg subcutaneously every other week.
Biological: Dupilumab

Dupilumab, an interleukin-4 receptor treatment, will be administered through a subcutaneous injection, the initial dose of 600 mg will be administered at two different injection sites (300 mg per injection), followed by a single dose of 300 mg administered every other week (Q2W).

Participants may self-administer injection after proper training.

Other Names:
  • Dupixent
Active Comparator: Benralizumab
30 mg subcutaneously every 4 weeks.
Biological: Benralizumab

Benralizumab, an interleukin-5 receptor treatment, will be administered through a subcutaneous injection every 4 weeks (Q4W).

Participants may self-administer injection after proper training.

Other Names:
  • Fasenra

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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).
After 16 weeks (for each biologic)
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.
After 16 weeks (for each biologic)
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.
After 16 weeks (for each biologic)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Asthma Control Questionnaire (ACQ)
Time Frame: Assessed through study completion, an average of 60 weeks
A simple questionnaire (6-item questionnaire) to measure the adequacy of asthma control and change in asthma control which occurs either spontaneously or as a result of treatment
Assessed through study completion, an average of 60 weeks
CompEx events
Time Frame: Assessed through study completion, an average of 60 weeks
CompEx is a composite outcome specific to asthma that combines clinically relevant deteriorations captured by diary events with exacerbations, thereby providing an increase in power compared to using exacerbations alone. CompEx events include exacerbations and deterioration events.
Assessed through study completion, an average of 60 weeks
Asthma Quality of Life Questionnaire (AQLQ)
Time Frame: Assessed through study completion, an average of 60 weeks
A disease-specific health-related quality of life instrument that taps both physical and emotional impact of disease. (32 items with 2-week recall)
Assessed through study completion, an average of 60 weeks
Forced expiratory volume in 1 second (FEV1)
Time Frame: Assessed through study completion, an average of 60 weeks
Lung function (FEV1) will be measured prior to bronchodilator administration by spirometry test.
Assessed through study completion, an average of 60 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of California, San Diego

Collaborators

Mayo Clinic
National Heart, Lung, and Blood Institute (NHLBI)
Yale University
Brigham and Women's Hospital
Harvard University
University of Arizona

Investigators

  • Principal Investigator: Kelan Tantisira, MD, University of California, San Diego

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 19, 2024

Primary Completion (Estimated)

June 30, 2027

Study Completion (Estimated)

January 31, 2028

Study Registration Dates

First Submitted

April 2, 2024

First Submitted That Met QC Criteria

April 23, 2024

First Posted (Actual)

April 26, 2024

Study Record Updates

Last Update Posted (Actual)

August 19, 2024

Last Update Submitted That Met QC Criteria

August 16, 2024

Last Verified

August 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 804913
  • R01HL161362 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

This study will be conducted in accordance with the following publication and data sharing policies and regulations:

National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the published results of NIH funded research. It requires scientists to submit final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for publication.

This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As such, this study will be registered at ClinicalTrials.gov, and results information from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals.

IPD Sharing Time Frame

Data from this study may be requested from other researchers after the completion of the primary endpoint.

IPD Sharing Access Criteria

Data from this study may be requested from other by contacting NHLBI's BioLINCC. Industry partners who are providing study agents will be provided with serious adverse events reports that occur when participants are receiving their product.

In addition, this study will comply with the NIH Genomic Data Sharing Policy, which applies to all NIH-funded research that generates large-scale human or non-human genomic data, as well as the use of these data for subsequent research. Large-scale data include genome-wide association studies (GWAS), SNP arrays, and genome sequence, transcriptomic, epigenomic, and gene expression data. Only genetic data contributing directly to prognostic testing will be publicly available with the rest of deidentified genetic data results residing behind a firewall accessible only via direct query to the Epiphany investigators and establishment of a data use agreement.

IPD Sharing Supporting Information Type

  • SAP
  • ANALYTIC_CODE
  • CSR

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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