Mepolizumab Pharmacokinetics Among Patients With Severe Asthma

Asthma Clinical Trial

— CESAM  

Official title:

Mepolizumab Pharmacokinetics Among Patients With Severe Asthma: Protocol for a Case Control Study Comparing Clinical Responders Versus Non Responders

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05495932
• Other study ID #: RECHMPL 22_0035
• Status: Recruiting
• Phase: N/A
• Start date: November 15, 2022
• Est. completion date: May 2025

Study information

• Verified date: September 2023
• Source: University Hospital, Montpellier
• Contact: Anne-Sophie GAMEZ, MD, PhD
• Phone: 4 67 33 60 91
• Email: as-gamez[@]chu-montpellier.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Asthma is a chronic disease characterized by inflammation and obstruction of the airways. Identification of the mechanisms of action of corticosteroids has made it possible to define the type 2 inflammation present in nearly 80% of patients with asthma.

Monoclonal antibodies (MAb) in severe asthma target type-2 inflammation. Mepolizumab is a humanized IgG1 (immunoglobulin gamma-1) kappa subclass monoclonal antibody directed specifically against interleukin 5 (IL-5). It acts specifically on eosinophil homeostasis, with IL-5 being a key interleukin in eosinophil maturation.

The investigators propose to measure the concentrations of mepolizumab in the serum of asthmatic patients treated with this mAb. The investigators hypothesize that the individual pharmacokinetics (PK) of mepolizumab may differ between clinical responders and non-responders.

Description:

Asthma is a chronic disease characterized by inflammation and obstruction of the airways. Understanding the biological effects of the corticosteroids allowed to identify and to define the type 2 inflammation present in nearly 80% of patients with asthma.

Monoclonal antibodies (MAb) in severe asthma target type-2 inflammation. Mepolizumab is a humanized IgG1 kappa subclass monoclonal antibody directed specifically against interleukin 5 (IL-5). It acts specifically on eosinophil homeostasis, since IL-5 is a key interleukin in eosinophil maturation.

Poor MAb responses can hypothetically arise in situations of poor treatment compliance. And after excluding the latter, several biological mechanisms have been mentioned: i) insufficient bioavailability of the MAb to reach the eosinophils of the bronchial compartment; ii) he development of autoimmunity with the formation of circulating immune complexes; and iii) immunization against mepolizumab, with the formation of neutralizing anti-drug antibodies (ADA).

ADA were detected in up to 20% of a treated population and were rarely neutralizing.

Interestingly, these ADA could also be detected in naïve populations, suggesting a possible cross-immunization related to previous exposure to MAbs and/or to insufficient assay specificity. In any case, all three possibilities have a common outcome, i.e. decreased circulating concentrations of the MAb in the blood.

The investigators propose to measure the concentrations of mepolizumab in the serum of asthmatic patients treated with this mAb. The investigators hypothesize that the individual pharmacokinetics (PK) of mepolizumab may differ between clinical responders and non-responders.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: May 2025
• Est. primary completion date: May 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Minimum age: 18 years old

• History of severe asthma diagnosed by a physician (according to Global Initiative for Asthma (GINA) criteria)

• Subject on a combination of high-dose (ICS equivalent to 1000 µg beclomethasone) and medium dose inhaled corticosteroid and long acting beta-agonists at least 12 months before inclusion

• Treatment with mepolizumab in line with the Marketing Authorization

• Having received at least 6 doses of mepolizumab (monthly subcutaneous administration)

• Documented initial clinical response to mepolizumab

Exclusion Criteria:

• Other respiratory diseases

• Potential interference from another study

• Immunosuppressive treatment (i.e methotrexate, polyvalent immunoglobulins, other monoclonal antibody for other condition such as cancer; oral and/or inhaled corticosteroids are allowed)

• Populations protected according to the French public health code

• Patient is unavailable, unable or unwilling to attend future visits

• Non-beneficiary of the French national health insurance system

• Lack of informed consent

Related Conditions & MeSH terms

• Asthma

Intervention

Diagnostic Test:
• blood sample
blood sample taken to measure serum mepolizumab concentration at baseline, 1 month and 6 months during study follow-up

Locations

Country	Name	City	State
France	university Hospital of Montpellier	Montpellier
France	University Hospital of Tours	Tours

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Montpellier

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Mepolizumab serum concentration	The primary outcome is the change in trough concentration of mepolizumab in serum at 1-month post-enrolment. Mepolizumab serum concentration will be determine by ELISA	1 month
Secondary	Mepolizumab serum concentration	Mepolizumab serum concentration will be determine by ELISA.	6 months
Secondary	Complete blood cell count at 1 month	comparison of number and % of eosinophils, basophils, neutrophils between responders and non-responders at baseline and 1-month	1 month
Secondary	Complete blood cell count at 6 months	comparison of number and % of eosinophils, basophils, neutrophils between responders and non-responders for the six-month follow-up period	6 months
Secondary	Comparison of lung function by airway obstruction	To describe the degree of airway obstruction, forced expiratory volume in one second (FEV1) and forced vital capacity will be measured using spirometry. The quantitative variables FEV1 and FEV1/FVC (Forced Vital Capacity) will be compared between responders and non-responders for the six-month follow-up period	6 months
Secondary	Comparison of asthma control by ACQ-6 score	Asthma control in terms of symptoms will be assessed by the six-item Asthma Control Questionnaire (ACQ-6). The ACQ-6 scores will be compared between responders and non-responders for the six-month follow-up period.; Patients are asked to recall how their asthma has been during the previous week by responding to one bronchodilator use question and 5 symptom questions.; Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The mean ACQ-6 score is the mean of the responses.; A score of 1.5 or more on the 6-item Asthma Control Questionnaire (ACQ-6) indicates that a patient has inadequate asthma control.	6 months
Secondary	Comparison of chronic rhinosinusitis by SNOT-22 score	The sino-nasal outcomes for chronic rhinosinusitis will be assessed by the 22-item sino-nasal outcome test (SNOT-22). The SNOT-22 scores will be compared between responders and non-responders for the six-month follow-up period.; The 22-question SNOT-22 is scored as 0 (no problem) to 5 (problem as bad as it can be) with a total range from 0 to 110. Higher scores indicate poorer outcomes.	6 months
Secondary	Comparison of exacerbation rate	Number, dates, and severity of exacerbations as defined by the Global Asthma Initiative (GINA) will be collected throughout the follow-up period. The number of exacerbations, the exacerbations rate and the number of days not exacerbating will be compared between responders and non-responders.	6 months
Secondary	Number of days alive and not exacerbating		6 months
Secondary	Comparison of change in oral corticosteroid	Oral corticosteroid use will be collected throughout the follow-up period. The % decrease of the initial corticosteroid therapy will be compared between responders and non-responders at 6 months.	6 months
Secondary	Presence/absence of a >50% reduction in exacerbation rate		6 months
Secondary	Presence/absence of monoclonal antibody switching		6 months