Clinical trial NCT05495932: Mepolizumab Pharmacokinetics Among Patients With Severe Asthma
Official title: Mepolizumab Pharmacokinetics Among Patients With Severe Asthma: Protocol for a Case Control Study Comparing Clinical Responders Versus Non Responders
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Asthma
Keywords: Severe asthma
Mepolizumab
Biologics
Response
Pharmacokinetics
Lead sponsor: University Hospital, Montpellier
Sponsor class: OTHER
First posted: 2022-08-10
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Case-control study including adult patients with severe asthma successfully treated with mepolizumab for at least 24 weeks, and then divided into two groups at inclusion : responders and non-responders according to the results of blood samples taken at inclusion, 1 month and 6 months during study follow-up

The clinical criteria used to define a complete response to mepolizumab are : Reduction of maintenance corticotherapy \> 50% reduction OR dose \>5mg/day; Reduction of exacerbation rate by \> 50%; ACQ-6 score \< 1.5 and no increase in score \> 0.5 since enrolment Patients lacking any one of the previous criteria are classified as non-responders.

Clinical response criteria are evaluated at each study visit, and the final classification at 6 months post-inclusion determines study groups to be matched and compared during statistical analyses
Primary purpose: OTHER

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Mepolizumab serum concentration
timeFrame: 1 month
Secondary outcomes:
measure: Mepolizumab serum concentration
timeFrame: 6 months
measure: Complete blood cell count at 1 month
timeFrame: 1 month
measure: Complete blood cell count at 6 months
timeFrame: 6 months
measure: Comparison of lung function by airway obstruction
timeFrame: 6 months
measure: Comparison of asthma control by ACQ-6 score
timeFrame: 6 months
measure: Comparison of chronic rhinosinusitis by SNOT-22 score
timeFrame: 6 months
measure: Comparison of exacerbation rate
timeFrame: 6 months
measure: Number of days alive and not exacerbating
timeFrame: 6 months
measure: Comparison of change in oral corticosteroid
timeFrame: 6 months
measure: Presence/absence of a >50% reduction in exacerbation rate
timeFrame: 6 months
measure: Presence/absence of monoclonal antibody switching
timeFrame: 6 months
Other outcomes:
Locations:
city: Montpellier
country: France
facility: university Hospital of Montpellier
city: Tours
country: France
facility: University Hospital of Tours
Study officials:
affiliation: University Hospital, Montpellier
name: Anne-Sophie GAMEZ, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: