Leveraging Pharmacogenomics in Asthma for Predication, Mechanism and Endotyping

Обзор

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.

Подробное описание

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.

Вмешательства

• Биопрепарат 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.
• Биопрепарат 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.

Первичные конечные точки

• Predicting asthma outcomes and therapeutic responses [Срок оценки: After 16 weeks (for each biologic)]
• Responses to the biologic therapies at the single cell level [Срок оценки: After 16 weeks (for each biologic)]
• Unique asthma subgroups clinical and molecular endotype approaches [Срок оценки: After 16 weeks (for each biologic)]

Вторичные конечные точки (4)

• Asthma Control Questionnaire (ACQ) [Срок оценки: Assessed through study completion, an average of 60 weeks]
• CompEx events [Срок оценки: Assessed through study completion, an average of 60 weeks]
• Asthma Quality of Life Questionnaire (AQLQ) [Срок оценки: Assessed through study completion, an average of 60 weeks]
• Forced expiratory volume in 1 second (FEV1) [Срок оценки: Assessed through study completion, an average of 60 weeks]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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:

• If <45 years old: Smoked for ≥5 pack-years\*
• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Перекрёстный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 3 центра

• Mayo Clinic — Scottsdale
• University of California, San Diego — La Jolla
• Yale University — New Haven

Публикации

• Bleecker ER, Menzies-Gow AN, Price DB, Bourdin A, Sweet S, Martin AL, Alacqua M, Tran TN. Systematic Literature Review of Systemic Corticosteroid Use for Asthma Management. Am J Respir Crit Care Med. 2020 Feb 1;201(3):276-293. doi: 10.1164/rccm.201904-0903SO. PMID 31525297
• Nelson RK, Bush A, Stokes J, Nair P, Akuthota P. Eosinophilic Asthma. J Allergy Clin Immunol Pract. 2020 Feb;8(2):465-473. doi: 10.1016/j.jaip.2019.11.024. Epub 2019 Nov 28. PMID 31786254
• Papi A, Brightling C, Pedersen SE, Reddel HK. Asthma. Lancet. 2018 Feb 24;391(10122):783-800. doi: 10.1016/S0140-6736(17)33311-1. Epub 2017 Dec 19. PMID 29273246
• Drazen JM, Harrington D. New Biologics for Asthma. N Engl J Med. 2018 Jun 28;378(26):2533-2534. doi: 10.1056/NEJMe1806037. Epub 2018 May 21. No abstract available. PMID 29782236
• Fuhlbrigge AL, Bengtsson T, Peterson S, Jauhiainen A, Eriksson G, Da Silva CA, Johnson A, Sethi T, Locantore N, Tal-Singer R, Fageras M. A novel endpoint for exacerbations in asthma to accelerate clinical development: a post-hoc analysis of randomised controlled trials. Lancet Respir Med. 2017 Jul;5(7):577-590. doi: 10.1016/S2213-2600(17)30218-7. Epub 2017 Jun 2. PMID 28583396
• Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, D'Agostino R Jr, Castro M, Curran-Everett D, Fitzpatrick AM, Gaston B, Jarjour NN, Sorkness R, Calhoun WJ, Chung KF, Comhair SA, Dweik RA, Israel E, Peters SP, Busse WW, Erzurum SC, Bleecker ER; National Heart, Lung, and Blood Institute's Severe Asthma Research Program. Identification of asthma phenotypes using cluster analysis in the Severe A PMID 19892860
• Phipatanakul W, Mauger DT, Sorkness RL, Gaffin JM, Holguin F, Woodruff PG, Ly NP, Bacharier LB, Bhakta NR, Moore WC, Bleecker ER, Hastie AT, Meyers DA, Castro M, Fahy JV, Fitzpatrick AM, Gaston BM, Jarjour NN, Levy BD, Peters SP, Teague WG, Fajt M, Wenzel SE, Erzurum SC, Israel E; Severe Asthma Research Program. Effects of Age and Disease Severity on Systemic Corticosteroid Responses in Asthma. Am PMID 27967215
• Holguin F, Cardet JC, Chung KF, Diver S, Ferreira DS, Fitzpatrick A, Gaga M, Kellermeyer L, Khurana S, Knight S, McDonald VM, Morgan RL, Ortega VE, Rigau D, Subbarao P, Tonia T, Adcock IM, Bleecker ER, Brightling C, Boulet LP, Cabana M, Castro M, Chanez P, Custovic A, Djukanovic R, Frey U, Frankemolle B, Gibson P, Hamerlijnck D, Jarjour N, Konno S, Shen H, Vitary C, Bush A. Management of severe as PMID 31558662

Идентификаторы

NCT: NCT06385236 · 804913 · R01HL161362

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗