Leveraging Pharmacogenomics in Asthma for Predication, Mechanism and Endotyping

NCT06385236 | Recruiting Phase 4 DMC FDA Drug

• 2 other identifiers: 804913R01HL161362
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 3

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.

Conditions

Moderate to Severe Asthma

Keywords

Asthma

Outcome Measures

Primary Outcomes (3)

• Predicting asthma outcomes and therapeutic responses

  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

  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

  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 Outcomes (4)

• Asthma Control Questionnaire (ACQ)

  Assessed through study completion, an average of 60 weeks

• CompEx events

  Assessed through study completion, an average of 60 weeks

• Asthma Quality of Life Questionnaire (AQLQ)

  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

Study Arms (2)

Dupilumab

ACTIVE COMPARATOR

600 mg once subcutaneously (given as two 300 mg injections), followed by 300 mg subcutaneously every other week.

Biological: Dupilumab

Benralizumab

ACTIVE COMPARATOR

30 mg subcutaneously every 4 weeks.

Biological: Benralizumab

Interventions

Dupilumab BIOLOGICAL

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.

Also known as: Dupixent

Dupilumab

Benralizumab BIOLOGICAL

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.

Also known as: Fasenra

Benralizumab

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of California, San Diego: lead
• Mayo Clinic: collaborator
• Yale University: collaborator
• University of Arizona: collaborator
• Harvard University: collaborator
• Brigham and Women's Hospital: collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (3)

Mayo Clinic

Scottsdale, Arizona, 85259, United States

RECRUITING

University of California, San Diego

La Jolla, California, 92093, United States

RECRUITING

Yale University

New Haven, Connecticut, 06520, United States

RECRUITING

Related Publications (16)

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  PMID: 31525297 BACKGROUND

• 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 BACKGROUND

• 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.

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• 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 BACKGROUND

• 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 BACKGROUND

• 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 Asthma Research Program. Am J Respir Crit Care Med. 2010 Feb 15;181(4):315-23. doi: 10.1164/rccm.200906-0896OC. Epub 2009 Nov 5.

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• 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 J Respir Crit Care Med. 2017 Jun 1;195(11):1439-1448. doi: 10.1164/rccm.201607-1453OC.

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• 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 asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020 Jan 2;55(1):1900588. doi: 10.1183/13993003.00588-2019. Print 2020 Jan.

  PMID: 31558662 BACKGROUND

• Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, Adcock IM, Bateman ED, Bel EH, Bleecker ER, Boulet LP, Brightling C, Chanez P, Dahlen SE, Djukanovic R, Frey U, Gaga M, Gibson P, Hamid Q, Jajour NN, Mauad T, Sorkness RL, Teague WG. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014 Feb;43(2):343-73. doi: 10.1183/09031936.00202013. Epub 2013 Dec 12.

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• Fuhlbrigge A, Peden D, Apter AJ, Boushey HA, Camargo CA Jr, Gern J, Heymann PW, Martinez FD, Mauger D, Teague WG, Blaisdell C. Asthma outcomes: exacerbations. J Allergy Clin Immunol. 2012 Mar;129(3 Suppl):S34-48. doi: 10.1016/j.jaci.2011.12.983.

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• Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, MacIntyre NR, McKay RT, Wanger JS, Anderson SD, Cockcroft DW, Fish JE, Sterk PJ. Guidelines for methacholine and exercise challenge testing-1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med. 2000 Jan;161(1):309-29. doi: 10.1164/ajrccm.161.1.ats11-99. No abstract available.

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• Coates AL, Wanger J, Cockcroft DW, Culver BH; Bronchoprovocation Testing Task Force: Kai-Hakon Carlsen; Diamant Z, Gauvreau G, Hall GL, Hallstrand TS, Horvath I, de Jongh FHC, Joos G, Kaminsky DA, Laube BL, Leuppi JD, Sterk PJ. ERS technical standard on bronchial challenge testing: general considerations and performance of methacholine challenge tests. Eur Respir J. 2017 May 1;49(5):1601526. doi: 10.1183/13993003.01526-2016. Print 2017 May.

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• Tiwari A, Li J, Kho AT, Sun M, Lu Q, Weiss ST, Tantisira KG, McGeachie MJ. COPD-associated miR-145-5p is downregulated in early-decline FEV1 trajectories in childhood asthma. J Allergy Clin Immunol. 2021 Jun;147(6):2181-2190. doi: 10.1016/j.jaci.2020.11.048. Epub 2020 Dec 29.

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• Sharma S, Kho AT, Chhabra D, Qiu W, Gaedigk R, Vyhlidal CA, Leeder JS, Barraza-Villarreal A, London SJ, Gilliland F, Raby BA, Weiss ST, Tantisira KG. Glucocorticoid genes and the developmental origins of asthma susceptibility and treatment response. Am J Respir Cell Mol Biol. 2015 May;52(5):543-53. doi: 10.1165/rcmb.2014-0109OC.

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• Howrylak JA, Moll M, Weiss ST, Raby BA, Wu W, Xing EP. Gene expression profiling of asthma phenotypes demonstrates molecular signatures of atopy and asthma control. J Allergy Clin Immunol. 2016 May;137(5):1390-1397.e6. doi: 10.1016/j.jaci.2015.09.058. Epub 2016 Jan 12.

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• Hart SN, Therneau TM, Zhang Y, Poland GA, Kocher JP. Calculating sample size estimates for RNA sequencing data. J Comput Biol. 2013 Dec;20(12):970-8. doi: 10.1089/cmb.2012.0283. Epub 2013 Aug 20.

  PMID: 23961961 BACKGROUND

Related Links

• Most Recent National Asthma Data \| CDC. Accessed December 20, 2022.
• Global Initiative for Asthma - Global Initiative for Asthma - GINA. Accessed December 20, 2022.

MeSH Terms

Conditions

Asthma

Interventions

dupilumab; benralizumab

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Study Officials

• Kelan Tantisira, MD

  University of California, San Diego

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Clinical Trial Operations and Data Management Specialist UA-DCC

CONTACT

520-626-9552; bio5-epiphanydcc@arizona.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Clinical Medicine

Model Details: 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.

Study Record Dates

• First Submitted: April 2, 2024
• First Posted: April 26, 2024
• Study Start: February 19, 2024
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): January 31, 2028
• Last Updated: August 19, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: SAP, CSR, ANALYTIC CODE
• Time Frame: Data from this study may be requested from other researchers after the completion of the primary endpoint.
• 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.

Locations

US (3)