Clinical trial NCT02377427: Pharmacokinetics and Pharmacodynamics of Mepolizumab Administered Subcutaneously in Children
Official title: An Open-label Study to Characterize the Pharmacokinetics and Pharmacodynamics of Mepolizumab Administered Subcutaneously in Children From 6 to 11 Years of Age With Severe Eosinophilic Asthma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Asthma
Keywords: pharmacokinetics
pediatric
Mepolizumab
subcutaneous
eosinophilic asthma
pharmacodynamics
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2015-03-03
Enrollment: 36
Sex: ALL
Minimum age (years): 6
Maximum age (years): 11
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: Mepolizumab is a humanized immunoglobulin G (IgG1) monoclonal antibody (mAb) that exhibits dose proportional and time-independent pharmacokinetics. The study will be conducted in 2 parts. Part A: it will be pharmacokinetic (PK) and pharmacodynamic (PD) study conducted to support the use of mepolizumab in children aged 6 to 11 years with severe eosinophilic asthma and characterize the PK/PD of mepolizumab 40 milligrams (mg) or 100 mg administered subcutaneously depending on participant body weight. Part B: It is a long-term safety / pharmacodynamic phase in which extended treatment for a further 52 weeks will be offered on an optional basis to those subjects eligible for continued treatment. Participants with bodyweight \<40 kilogram (kg) will be dosed with mepolizumab 40 mg and participants with body weight \>=40 kg will be dosed with mepolizumab 100 mg subcutaneously in upper arm or thigh at Visit 2 (Week 0). Approximately 40 male or female participants aged 6 to 11 years will be screened to achieve approximately 28 eligible participants entering the treatment phase to allow availability of 20 evaluable participants, with a minimum of six participants enrolled in the \<40 kg bodyweight group. The total duration of the study will be 22 weeks and will include a run-in period of 1-2 weeks, a treatment period of 12 weeks and a follow-up phase of 8 weeks. A participant will be considered having completed the study if the participant completes all phases of the study including the follow-up phase (Week 20 \[visit 8\]).


Eligibility criteria: Inclusion Criteria:

* Between 6 and 11 years of age inclusive, at the time of screening.
* Diagnosis of severe asthma, defined by the regional asthma guidelines (i.e., National Institute of Health (NIH), Global Initiative for Asthma (GINA), etc.), for at least 12 months prior to Visit 1. If the participant is naïve to the study site, the participant/guardian must self-report a physician diagnosis of asthma and the investigator must confirm by review of medical history with the participant/guardian.
* Eosinophilic airway inflammation that is related to asthma characterized as eosinophilic in nature as indicated by: elevated peripheral blood eosinophil count of \>=300 cells per microliter (cells/μL) demonstrated in the past 12 months OR elevated peripheral blood eosinophil count of \>=150/μL at visit 1.
* A well-documented requirement for regular treatment with inhaled corticosteroid (\>200 μg/day fluticasone propionate drug powder inhaler \[DPI\] or equivalent daily) in the 12 months prior to Visit 1 with or without maintenance oral corticosteroids (OCS). The ICS dose should represent medium or high dose in children aged 6-11 years of age \[GINA, 2015\].
* Current treatment with an additional controller medication for at least 3 months or a documented failure in the past 12 months of an additional controller medication for at least 3 successive months. \[e.g., long-acting beta-2-agonist (LABA), leukotriene receptor antagonist (LTRA), or theophylline.\]
* Forced expiratory volume in one second (FEV1): Persistent airflow obstruction at either Visit 1 or Visit 2 (FEV1 performed prior to first dose of study medication) as indicated by: A pre-bronchodilator FEV1 \<110% predicted (Quanjer, 2012) OR FEV1: Forced vital capacity (FVC) ratio \<0.8.
* Previously confirmed history of two or more exacerbations requiring treatment with systemic corticosteroids (CS) (intramuscular \[IM\], intravenous, or oral), in the 12 months prior to visit 1, despite the use of high-dose inhaled corticosteroids (ICS). For participants receiving maintenance CS, the CS treatment for the exacerbations must have been a two-fold increase or greater in the dose.
* No changes in the dose or regimen of baseline ICS and/or additional controller medication during the run-in period.
* Male or female: Females of childbearing potential must commit to consistent and correct use of an acceptable method of contraception for the duration of the trial and for 4 months after the last dose of investigational product. A urine pregnancy test is required of girls of childbearing potential. This test will be performed at the initial screening visit (visit 1) and will be performed at each scheduled study visit prior to the administration of investigational product, and during the early withdrawal and follow-up visits.
* Parent(s)/guardian able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form. If applicable, the participant must be able and willing to give assent to take part in the study according to the local requirement.
* For Part B: The subject has completed all study assessments up-to and including Visit 8 and received all 3 doses of investigational product (IP) in Part A
* For Part B: The Principal Investigator (PI) has performed a benefit/risk assessment and this assessment supports continued therapy with mepolizumab.
* The subject's parents (or guardian) have given consent and the subject has given assent for continued treatment

Exclusion Criteria:

* Participants with any history of life threatening asthma (e.g. requiring intubation), immunosuppressive medications intake or immunodeficiency disorder.
* Participants with any medical condition or circumstance making the volunteer unsuitable for participation in the study.
* Significant abnormality of rate, interval, conduction or rhythm in the 12-lead electrocardiogram (ECG), determined by the investigator in conjunction with the age and gender of the child at Visit 1.
* Alanine aminotransferase (ALT), and bilirubin \>2x upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%) at Visit 1.
* Positive Hepatitis B Surface Antigen or positive Hepatitis C antibody at Visit 1.
* Parent/guardian has a history of psychiatric disease, intellectual deficiency, substance abuse, or other condition (e.g. inability to read, comprehend and write) which will limit the validity of consent to participate in this study.
* Unwillingness or inability of the participant or parent/guardian to follow the procedures outlined in the protocol.
* Participant who is mentally or legally incapacitated.
* Children who are wards of the state or government.
* A participant will not be eligible for this study if he/she is an immediate family member of the participating investigator, sub-investigator, study coordinator, or employee of the participating investigator.
* Omalizumab: Participants who have received omalizumab within 130 days of Visit 1.
* Other Biologics: Participants who have received any biological (other than omalizumab) to treat inflammatory disease within 5 half-lives of visit 1.
* History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
* Hypersensitivity: Participants with allergy/intolerance to a monoclonal antibody or biologic.
* The participant has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).

Primary outcomes:
measure: Maximum Plasma Concentration (Cmax) of Mepolizumab for Part A
timeFrame: Pre-dose on Weeks 4 and 8; Weeks 9, 12, 16 and 20 post-dose
measure: Area Under Concentration Time Curve to Infinity (AUC [0-inf]) of Mepolizumab for Part A
timeFrame: Pre-dose on Weeks 4 and 8; Weeks 9, 12, 16 and 20 post-dose
measure: Terminal Phase Elimination Half-life (T1/2) of Mepolizumab During Treatment Period for Part A
timeFrame: Pre-dose on Weeks 4 and 8; Weeks 9, 12, 16 and 20 post-dose
measure: Plasma Apparent Clearance (CL/F) of Mepolizumab in Part A
timeFrame: Pre-dose on Weeks 4 and 8; Weeks 9, 12, 16 and 20 post-dose
measure: Ratio to Baseline in Absolute Blood Eosinophil Count at Week 12 for Part A
timeFrame: Baseline and Week 12
measure: Number of Participants With on Treatment Serious Adverse Events (SAEs) and Non-SAEs for Part B
timeFrame: From Week 20 and up to Week 72
measure: Number of Participants With Positive Anti-mepolizumab Binding Antibodies and Neutralizing Antibodies Response for Part B
timeFrame: From Week 20 and up to Week 80
measure: Change From Baseline in Sitting Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) for Part B
timeFrame: Baseline and Weeks 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 80
measure: Change From Baseline in Sitting Pulse Rate for Part B
timeFrame: Baseline and Weeks 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 80
measure: Number of Participants With Any Time Change From Baseline Relative to Normal Range in Clinical Chemistry Parameters for Part B
timeFrame: Baseline, from Week 20 and up to Week 72
measure: Number of Participants With Any Time Change From Baseline Relative to Normal Range in Hematology Parameters for Part B
timeFrame: Baseline, from Week 20 and up to Week 80
measure: Number of Participants With Abnormal Findings for Urinalysis Parameters in Part B
timeFrame: From Week 20 and up to Week 72
Secondary outcomes:
measure: Body Weight-adjusted Apparent Clearance of Mepolizumab for Part A
timeFrame: Pre-dose on Weeks 4 and 8; Weeks 9, 12, 16 and 20 post-dose
measure: Change From Baseline in Asthma Control Questionnaire-7 (ACQ-7) at Week 12 in Part A
timeFrame: Baseline and Week 12
measure: Change From Baseline in Asthma Control Questionnaire-7 (ACQ-7) at Weeks 4,8,16 and 20 in Part A
timeFrame: Baseline and Weeks 4,8,16 and 20
measure: Change From Baseline in Childhood Asthma Control Test (C-ACT) at Week 12 for Part A
timeFrame: Baseline and Week 12
measure: Change From Baseline in C-ACT at Weeks 4,8,16 and 20 in Part A
timeFrame: Baseline and Weeks 4,8,16 and 20
measure: Number of Participants With on Treatment SAEs and Non-SAEs in Part A
timeFrame: Up to Week 20
measure: Number of Participants With Any Time Change From Baseline Relative to Normal Range in Hematology Parameters in Part A
timeFrame: Baseline and up to Week 20
measure: Number of Participants With Any Time Change From Baseline Relative to Normal Range in Clinical Chemistry Parameters in Part A
timeFrame: Baseline and up to Week 20
measure: Number of Participants With Abnormal Findings for Urinalysis in Part A
timeFrame: Up to Week 20
measure: Number of Participants With Positive Anti-mepolizumab Binding Antibodies and Neutralizing Antibodies Response in Part A
timeFrame: Baseline and Weeks 16 and 20
measure: Change From Baseline in Sitting SBP and DBP in Part A
timeFrame: Baseline and Weeks 4, 8, 9, 12, 16 and 20
measure: Change From Baseline in Sitting Pulse Rate in Part A
timeFrame: Baseline and Weeks 4, 8, 9, 12, 16 and 20
measure: Ratio to Baseline in Absolute Blood Eosinophil Count at Weeks 32, 44, 56, 68, 72 and 80 for Part B
timeFrame: Baseline and Weeks 32, 44, 56, 68, 72 and 80
Other outcomes:
Locations:
city: San Diego
country: United States
facility: GSK Investigational Site
state: California
city: Oklahoma City
country: United States
facility: GSK Investigational Site
state: Oklahoma
city: Medford
country: United States
facility: GSK Investigational Site
state: Oregon
city: Madison
country: United States
facility: GSK Investigational Site
state: Wisconsin
city: Fukuoka
country: Japan
facility: GSK Investigational Site
city: Hiroshima
country: Japan
facility: GSK Investigational Site
city: Hiroshima
country: Japan
facility: GSK Investigational Site
city: Wakayama
country: Japan
facility: GSK Investigational Site
city: Lodz
country: Poland
facility: GSK Investigational Site
city: Tarnow
country: Poland
facility: GSK Investigational Site
city: Glasgow
country: United Kingdom
facility: GSK Investigational Site
city: Liverpool
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Oxford
country: United Kingdom
facility: GSK Investigational Site
city: Sheffield
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Gupta A, Pouliquen I, Austin D, Price RG, Kempsford R, Steinfeld J, Bradford ES, Yancey SW. Subcutaneous mepolizumab in children aged 6 to 11 years with severe eosinophilic asthma. Pediatr Pulmonol. 2019 Dec;54(12):1957-1967. doi: 10.1002/ppul.24508. Epub 2019 Sep 9.
citation: Gupta A, Ikeda M, Geng B, Azmi J, Price RG, Bradford ES, Yancey SW, Steinfeld J. Long-term safety and pharmacodynamics of mepolizumab in children with severe asthma with an eosinophilic phenotype. J Allergy Clin Immunol. 2019 Nov;144(5):1336-1342.e7. doi: 10.1016/j.jaci.2019.08.005. Epub 2019 Aug 16.