Pharmacokinetics and Pharmacodynamics of Mepolizumab Administered Subcutaneously in Children

NCT02377427 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 2003632014-002666-76
• Study Type: interventional
• Target: 36
• Locations: 4 countries
• Sites: 16

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 \[visit 8\]).

Conditions

Asthma

Keywords

pharmacokinetics; pediatric; Mepolizumab; subcutaneous; eosinophilic asthma; pharmacodynamics

Outcome Measures

Primary Outcomes (12)

• Maximum Plasma Concentration (Cmax) of Mepolizumab for Part A

  PK of mepolizumab was evaluated in participants using Cmax. PK samples were collected at pre-dose on Weeks 4 and 8; and at Weeks 9, 12, 16 and 20 post-dose. Cmax was evaluated by population PK methods and mean and standard error from the final model has been tabulated. Estimates have been presented from the final model centered to mean bodyweights of 27 kg, 50 kg and 70 kg. Note the average bodyweight of 70 kg (mean body weight observed in adults) was not investigated in the study. PK Population included all participants receiving at least one dose of mepolizumab beginning at Visit 2 (Week 0) and having at least one blood sample taken at Visit 3 (Week 4) or thereafter with measurable mepolizumab plasma concentration.

  Pre-dose on Weeks 4 and 8; Weeks 9, 12, 16 and 20 post-dose

• Area Under Concentration Time Curve to Infinity (AUC [0-inf]) of Mepolizumab for Part A

  PK of mepolizumab was evaluated in participants using AUC (0-inf). PK samples were collected at pre-dose on Weeks 4 and 8; and at Weeks 9, 12, 16 and 20 post-dose. AUC (0-inf) was evaluated by population PK methods and mean and standard error from the final model has been tabulated. Estimates have been presented from the final model centered to mean bodyweights of 27 kg, 50 kg and 70 kg. Note the average bodyweight of 70kg (mean body weight observed in adults) was not investigated in the study.

  Pre-dose on Weeks 4 and 8; Weeks 9, 12, 16 and 20 post-dose

• Terminal Phase Elimination Half-life (T1/2) of Mepolizumab During Treatment Period for Part A

  PK of mepolizumab was evaluated in participants using t1/2. PK samples were collected at pre-dose on Weeks 4 and 8; and at Weeks 9, 12, 16 and 20 post-dose. T1/2 was evaluated by population PK methods and mean and standard error from the final model has been tabulated. Estimates have been presented from the final model centered to mean bodyweights of 27 kg, 50 kg and 70 kg. Note the average bodyweight of 70kg (mean body weight observed in adults) was not investigated in the study.

  Pre-dose on Weeks 4 and 8; Weeks 9, 12, 16 and 20 post-dose

• Plasma Apparent Clearance (CL/F) of Mepolizumab in Part A

  PK of mepolizumab was evaluated in participants using CL/F. PK samples were collected at pre-dose on Weeks 4 and 8; and at Weeks 9, 12, 16 and 20 post-dose. CL was evaluated by population PK methods and mean and standard error from the final model has been tabulated. Estimates have been presented from the final model centered to mean bodyweights of 27 kg, 50 kg and 70 kg. Note the average bodyweight of 70kg (mean body weight observed in adults) was not investigated in the study.

  Pre-dose on Weeks 4 and 8; Weeks 9, 12, 16 and 20 post-dose

• Ratio to Baseline in Absolute Blood Eosinophil Count at Week 12 for Part A

  PD of mepolizumab was evaluated in participants using ratio to Baseline in absolute blood eosinophil count. Blood samples were collected at indicated time points. Baseline was defined as the latest value recorded prior to the first dose of mepolizumab. Ratio to Baseline was calculated as post-dose visit value/Baseline value. It was evaluated by Pharmacodynamic Eosinophils (PDe) Population which included all participants receiving at least one dose of mepolizumab beginning at Visit 2 (Week 0) and having at least one Part A blood sample evaluable for blood eosinophil count.

  Baseline and Week 12

• Number of Participants With on Treatment Serious Adverse Events (SAEs) and Non-SAEs for Part B

  An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or all events of possible drug-induced liver injury with hyperbilirubinemia are to be categorized as SAE. On-treatment SAEs and non-SAEs are defined as events occurring from the first Part B dose until 28 days following the last Part B dose. Safety Population includes all participants who received at least one dose of mepolizumab beginning at Visit 9.

  From Week 20 and up to Week 72

• Number of Participants With Positive Anti-mepolizumab Binding Antibodies and Neutralizing Antibodies Response for Part B

  Blood sample were collected for the determination of anti-mepolizumab binding antibodies and neutralizing antibodies response in Part B at Weeks 44, 68 and 80 prior to study treatment administration. Participant was considered 'Positive' if they had at least one positive post-Baseline anti-drug antibody assay result. All Part B visits (including scheduled and unscheduled) post-Baseline were considered for Any-time Post-Baseline visit derivation. The number of participants with positive anti-mepolizumab binding antibodies and neutralizing antibodies response at Any Time Post Baseline has been presented. The neutralizing antibodies response results only presented for participants with positive anti-drug antibody assay.

  From Week 20 and up to Week 80

• Change From Baseline in Sitting Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) for Part B

  Sitting blood pressure measurements included SBP and DBP. Measurements were done pre-infusion/injection with the participant sitting, having rested in this position for at least 5 minutes before each reading. The Baseline was defined as the latest value recorded prior to the first dose of mepolizumab. Change from Baseline was defined as value at indicated time point minus Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).

  Baseline and Weeks 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 80

• Change From Baseline in Sitting Pulse Rate for Part B

  Sitting pulse rate measurements were performed pre-infusion/injection with the participant sitting, having rested in this position for at least 5 minutes before each reading. The Baseline was defined as the latest value recorded prior to the first dose of mepolizumab in Part A. Change from Baseline was defined as value at indicated time point minus Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).

  Baseline and Weeks 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 80

• Number of Participants With Any Time Change From Baseline Relative to Normal Range in Clinical Chemistry Parameters for Part B

  Blood samples were collected for analysis of alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), albumin, protein, bilirubin, creatinine, urate, direct bilirubin, calcium, carbon dioxide (CO2), chloride, glucose, potassium, sodium and urea. Baseline was defined as the latest value recorded prior to the first dose of mepolizumab in Part A. Change from Baseline was defined as value at indicated time point minus Baseline value. All Part B visits (scheduled and unscheduled) post-Baseline were considered for Any-time Post-Baseline visit derivation. If participant had at least one value for categories "To Low" and/or "To High" along with "To Normal or No Change" then participant was counted under "To Low" and/or "To High". If participant had values which belong only to "To Normal or No Change" then participant was counted under "To Normal or No Change" only. Any Time Post-Baseline values have been presented.

  Baseline, from Week 20 and up to Week 72

• Number of Participants With Any Time Change From Baseline Relative to Normal Range in Hematology Parameters for Part B

  Blood samples were collected for analysis of basophils, eosinophils, leukocyte, monocyte, neutrophils, lymphocyte, platelets, mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), hemoglobin (Hgb), mean corpuscular volume (MCV), erythrocytes, hematocrit, and reticulocytes/erythrocytes (Ret/Ery). Baseline was defined as the latest value recorded prior to first dose of mepolizumab in Part A. Change from Baseline was defined as value at indicated time point minus Baseline value. All Part B visits (scheduled and unscheduled) post-Baseline were considered for Any-time Post-Baseline visit derivation. If participant had at least one value for categories "To Low" and/or "To High" along with "To Normal or No Change" then participant was counted under "To Low" and/or "To High". If participant had values which belong only to "To Normal or No Change" then participant was counted under "To Normal or No Change" only. Any Time Post-Baseline values have been presented.

  Baseline, from Week 20 and up to Week 80

• Number of Participants With Abnormal Findings for Urinalysis Parameters in Part B

  Urine samples were collected from participants at indicated time points for analysis of urinalysis parameters including Specific gravity and potential of hydrogen (pH) of urine, presence of glucose, protein, blood and ketones in urine by dipstick test. Microscopic examination was performed if blood or protein was abnormal. Only those participants with data available at the specified time points were analyzed.

  From Week 20 and up to Week 72

Secondary Outcomes (13)

• Body Weight-adjusted Apparent Clearance of Mepolizumab for Part A

  Pre-dose on Weeks 4 and 8; Weeks 9, 12, 16 and 20 post-dose

• Change From Baseline in Asthma Control Questionnaire-7 (ACQ-7) at Week 12 in Part A

  Baseline and Week 12

• Change From Baseline in Asthma Control Questionnaire-7 (ACQ-7) at Weeks 4,8,16 and 20 in Part A

  Baseline and Weeks 4,8,16 and 20

• Change From Baseline in Childhood Asthma Control Test (C-ACT) at Week 12 for Part A

  Baseline and Week 12

• Change From Baseline in C-ACT at Weeks 4,8,16 and 20 in Part A

  Baseline and Weeks 4,8,16 and 20

Study Arms (2)

Mepolizumab 40 mg in Part A and B

EXPERIMENTAL

Participants with bodyweight \< 40 kg will receive 0.4 milliliter (mL) of reconstituted mepolizumab subcutaneously, in upper arm or thigh.

Drug: Mepolizumab

Mepolizumab 100 mg in Part A and B

EXPERIMENTAL

Participants with bodyweight \>= 40 kg will receive 1.0 mL of reconstituted mepolizumab subcutaneously, in upper arm or thigh.

Drug: Mepolizumab

Interventions

Mepolizumab DRUG

Mepolizumab is supplied as 100 mg lyophilised cake in sterile vials for subcutaneous administration in upper arm or thigh. The vial will be reconstituted with sterile water for injection prior to individual use.

Mepolizumab 100 mg in Part A and B; Mepolizumab 40 mg in Part A and B

Eligibility Criteria

• Age: 6 Years - 11 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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).

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (16)

GSK Investigational Site

San Diego, California, 92123, United States

Location

GSK Investigational Site

Oklahoma City, Oklahoma, 73112, United States

Location

GSK Investigational Site

Medford, Oregon, 97504, United States

Location

GSK Investigational Site

Madison, Wisconsin, 53792-9988, United States

Location

GSK Investigational Site

Fukuoka, 811-1394, Japan

Location

GSK Investigational Site

Hiroshima, 720-8520, Japan

Location

GSK Investigational Site

Hiroshima, 721-8511, Japan

Location

GSK Investigational Site

Wakayama, 646-8558, Japan

Location

GSK Investigational Site

Lodz, 90-329, Poland

Location

GSK Investigational Site

Tarnów, 33-100, Poland

Location

GSK Investigational Site

Glasgow, G514TF, United Kingdom

Location

GSK Investigational Site

Liverpool, L12 2AP, United Kingdom

Location

GSK Investigational Site

London, SE5 9RS, United Kingdom

Location

GSK Investigational Site

London, SW3 6NP, United Kingdom

Location

GSK Investigational Site

Oxford, OX3 9DU, United Kingdom

Location

GSK Investigational Site

Sheffield, S10 2TH, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 31502421 BACKGROUND

• 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.

  PMID: 31425781 BACKGROUND

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

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: February 26, 2015
• First Posted: March 3, 2015
• Study Start: August 25, 2015
• Primary Completion: December 7, 2016
• Study Completion: January 31, 2018
• Last Updated: December 3, 2019
• Results First Posted: November 29, 2017

Record last verified: 2019-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

US (4); GB (6); PL (2); JP (4)