Effect of Mepolizumab on Severe Eosinophilic Asthma

NCT04641741 | Unknown FDA Drug

• 1 other identifier: FGBMEP202001
• Study Type: observational
• Target: 30
• Locations: 1 country
• Sites: 5

Brief Summary

Two parts: A:Case-control study including 15 healthy adult donors and 15 severe adult eosinophilic asthmatics selected for treatment with mepolizumab. B: A longitudinal cohort study,where the same patients once on mepolizumab treatment are followed over time (0, 4, 16 and 32 weeks). SCOPE: response to mepolizumab in severe adult eosinophilic asthma. INCLUSION CRITERIA: Male or female, 18-75 years-old, with severe eosinophilic asthma. EXCLUSION CRITERIA: Smoking history, recent exacerbations, other pulmonary or systemic disease with eosinophilia, malignancy, pregnancy, obesity (BMI \>35). OBJECTIVES: General objective: Discovery of predictive/prognostic biomarkers of response to mepolizumab using flow cytometry, transcriptomic, and proteomic technologies. OTHER OBJECTIVES: 1.-To identify changes in surface markers of eosinophils and eosinophil subpopulations in response to treatment with mepolizumab using flow cytometry techniques. 2.-Transcriptomic analysis to identify mRNAs within the eosinophil transcriptome displaying enhanced or reduced levels in response to treatment with mepolizumab.3.-Proteomic profiling to identify proteins with differential abundance within the eosinophils in response to treatment with mepolizumab.4.-Check whether late-onset severe eosinophilic asthmatics display elevated levels of IGF-1, IGF-BP3, IGF-ALS in serum samples, if the response of mepolizumab depends on the levels of this markers, and if treatment with this biological reduces the concentration in serum of these IGF-family members. 5.-Identify proteins with differential abundance within the deep serum proteome of patients with SEA in response to treatment with mepolizumab by means of non-targeted proteomic analysis. MEASUREMENTS: Flow cytometry assays with multimarker panels 1 (regulatory), 2 (activation), and 3 eosinophil subsets. Clinical, hematological, biochemical and flow cytometry data generated at times T4, T16 and T32. Total RNA extraction from eosinophil lysates, assay of quality and quantity of RNA, and storage at -80ºC. Evaluation of the levels of 770 human protein-coding mRNAs linked to the recruitment, activation, and effector functions of myeloid cells by means of a direct multiplexed molecular measurement platform named nCounter® NanoString) in combination with a pre-made "nCounter® Human Myeloid Innate Immunity Panel (v2)". Perform retrotranscription and qPCR analyses of those mRNAs in eosinophils displaying the greatest abundance changes in response to mepolizumab treatment according to the nCounter® study. In addition, some additional mRNAs not included in the "nanoString Myeloid Innate Immunity" panel, such as FOXP3 (regulatory function), CRLF2, ST2, or IL-7R (cytokine receptors; activation), will be analysed. HPRT1 gene will be used as a house-keeping gene in this set of RTqPCR experiments. Perform SWATH-MS analysis in samples from 15 healthy donors and 15 patients (T0, T4, T16, T32) ("information-dependent acquisition" method or IDA; "Targeted label-free proteomics") in eosinophil homogenates. High abundant serum protein depletion using two protocols (P1: affinity chromatography, and P2: DTT precipitation) and SWATH-MS analysis of medium-low abundant serum proteome in samples from 15 healthy donors and 15 patients (T0, T4, T16, T32) ("information-dependent acquisition" method or IDA; "Targeted label-free proteomics").

Conditions

Asthma; Eosinophilic Asthma

Keywords

Mepolizumab; mRNA; Transcriptomic; IGF; Proteomic

Outcome Measures

Primary Outcomes (2)

• Measure changes in surface markers of eosinophils and eosinophil subpopulations in response to treatment with mepolizumab using flow cytometry techniques

  Flow cytometry assays with multimarker panels 1 (regulatory), 2 (activation), and 3 (eosinophil subsets)

  32 weeks

• Measure changes in medium-low abundant serum proteins in response to treatment with mepolizumab using LC-MS/MS

  Changes in the levels of multiple proteins within the low abundant serum proteome from patients, measured as the ratio to baseline (T=0) at weeks 4 and 32 (SWATH-MS), and ratio to healthy controls (T=0) in patients at T=0.

  32 weeks

Secondary Outcomes (1)

• Transcriptomic analysis to identify mRNAs within the eosinophil transcriptome displaying enhanced or reduced levels in response to treatment with mepolizumab.

  32 weeks

Study Arms (2)

Control

Healthy adults

Severe eosinophilic asthma

Severe uncontrolled asthma according to ERS/ATS criteria and persistent eosinophilia in blood (\>300 cells/μL)

Drug: Mepolizumab 100 MG

Interventions

Mepolizumab 100 MG DRUG

Discovery of predictive/prognostic biomarkers of response to mepolizumab using flow cytometry, transcriptomic, and proteomic technologies.

Severe eosinophilic asthma

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Severe uncontrolled asthma according to ERS/ATS criteria Persistent eosinophilia in blood (\>300 cells/μL)

You may qualify if:

• Diagnosis of severe uncontrolled asthma according to ERS/ATS criteria
• Persistent eosinophilia in blood (\>300 cells/μL)
• Frequent exacerbations (≥ two per year)
• Signature of informed consent and agree to comply with all the visits of the study and all the procedures that this entails.

You may not qualify if:

• Smoking history: Current smokers or former smokers with a smoking history of ≥10 pack-years
• Clinically important pulmonary disease other than asthma (e.g. active lung infection, COPD, bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, lung cancer, alpha 1 anti-trypsin deficiency, and primary ciliary dyskinesia) or ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts
• Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, psychiatric, or major physical impairment that is not stable in the opinion of the Investigator.
• Malignancy: A current malignancy or previous history of cancer in remission.
• Acute upper or lower respiratory infections requiring antibiotics or antiviral medication within 30 days prior to the Visit 1.
• Xolair: Participants who have received omalizumab (Xolair) or another monoclonal antibody previously.
• Participants who have received systemic corticosteroids within 30 days before Visit 1 \[53\].
• Pregnancy: Participants who are pregnant or breastfeeding.
• Obesity class 2 or higher (BMI≥ 35 kg/m2)

Sponsors & Collaborators

• Hospital Clinico Universitario de Santiago: lead
• GlaxoSmithKline: collaborator

Study Sites (5)

Complejo Hospitalario Universitario de Ferrol

Ferrol, A Coruña, 15405, Spain

RECRUITING

Hospital Clínico Universitario de Santiago de Compostela

Santiago de Compostela, A Coruña, 15706, Spain

NOT YET RECRUITING

Hospital Povisa - Grupo Ribera Salud

Vigo, Pontevedra, 36211, Spain

NOT YET RECRUITING

Complexo Hospitalario Universitario A Coruña

A Coruña, 15006, Spain

NOT YET RECRUITING

Complexo Hospitalario Universitario de Ourense

Ourense, 32005, Spain

RECRUITING

Related Publications (9)

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  PMID: 19483109 BACKGROUND

• Lotvall J, Akdis CA, Bacharier LB, Bjermer L, Casale TB, Custovic A, Lemanske RF Jr, Wardlaw AJ, Wenzel SE, Greenberger PA. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol. 2011 Feb;127(2):355-60. doi: 10.1016/j.jaci.2010.11.037.

  PMID: 21281866 BACKGROUND

• Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012 May 4;18(5):716-25. doi: 10.1038/nm.2678.

  PMID: 22561835 BACKGROUND

• Kuruvilla ME, Lee FE, Lee GB. Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease. Clin Rev Allergy Immunol. 2019 Apr;56(2):219-233. doi: 10.1007/s12016-018-8712-1.

  PMID: 30206782 BACKGROUND

• Pavlidis S, Takahashi K, Ng Kee Kwong F, Xie J, Hoda U, Sun K, Elyasigomari V, Agapow P, Loza M, Baribaud F, Chanez P, Fowler SJ, Shaw DE, Fleming LJ, Howarth PH, Sousa AR, Corfield J, Auffray C, De Meulder B, Knowles R, Sterk PJ, Guo Y, Adcock IM, Djukanovic R, Fan Chung K; on behalf of the U-BIOPRED Study Group. "T2-high" in severe asthma related to blood eosinophil, exhaled nitric oxide and serum periostin. Eur Respir J. 2019 Jan 3;53(1):1800938. doi: 10.1183/13993003.00938-2018. Print 2019 Jan.

  PMID: 30578390 BACKGROUND

• Yancey SW, Bradford ES, Keene ON. Disease burden and efficacy of mepolizumab in patients with severe asthma and blood eosinophil counts of >/=150-300 cells/muL. Respir Med. 2019 May;151:139-141. doi: 10.1016/j.rmed.2019.04.008. Epub 2019 Apr 8.

  PMID: 31047111 BACKGROUND

• Kelly EA, Esnault S, Liu LY, Evans MD, Johansson MW, Mathur S, Mosher DF, Denlinger LC, Jarjour NN. Mepolizumab Attenuates Airway Eosinophil Numbers, but Not Their Functional Phenotype, in Asthma. Am J Respir Crit Care Med. 2017 Dec 1;196(11):1385-1395. doi: 10.1164/rccm.201611-2234OC.

  PMID: 28862877 BACKGROUND

• Gonzalez-Barcala FJ, San-Jose ME, Nieto-Fontarigo JJ, Carreira JM, Calvo-Alvarez U, Cruz MJ, Facal D, Garcia-Sanz MT, Valdes-Cuadrado L, Salgado FJ. Association between blood eosinophil count with asthma hospital readmissions. Eur J Intern Med. 2018 Jul;53:34-39. doi: 10.1016/j.ejim.2018.02.034. Epub 2018 Mar 4.

  PMID: 29514744 BACKGROUND

• Ortea I, Ruiz-Sanchez I, Canete R, Caballero-Villarraso J, Canete MD. Identification of candidate serum biomarkers of childhood-onset growth hormone deficiency using SWATH-MS and feature selection. J Proteomics. 2018 Mar 20;175:105-113. doi: 10.1016/j.jprot.2018.01.003. Epub 2018 Jan 6.

  PMID: 29317355 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Whole blood and serum

MeSH Terms

Conditions

Asthma; Pulmonary Eosinophilia

Interventions

mepolizumab

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Hypereosinophilic Syndrome; Eosinophilia; Leukocyte Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• FRANCISCO-JAVIER GONZALEZ-BARCALA, MD, PHD

  CLINIC UNIVERSITY HOSPITAL

  PRINCIPAL INVESTIGATOR

Central Study Contacts

FRANCISCO-JAVIER GONZALEZ-BARCALA, MD, PHD

CONTACT

+34981951173; francisco.javier.gonzalez.barcala@sergas.es

FRANCISCO-JAVIER SALGADO-CASTRO, PHD

CONTACT

+34981563100; franciscojavier.salgado@usc.es

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Target Duration: 32 Weeks
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: SPECIALIST RESPIRATORY MEDICINE

Study Record Dates

• First Submitted: November 18, 2020
• First Posted: November 24, 2020
• Study Start: April 1, 2021
• Primary Completion: December 31, 2023
• Study Completion: March 1, 2025
• Last Updated: September 25, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

ES (5)