Pharmacokinetics and Pharmacodynamics of Mepolizumab Administered Subcutaneously in Children
Condition: Asthma
MeSH terms: Asthma
Intervention: Mepolizumab
Intervention description: 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.
Phase: Phase 2
Study type: Interventional
Primary purpose: Other
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 36.0
Sex: All
Minimum age: 6 Years
Maximum age: 11 Years
Healthy volunteers: No
Keywords: pharmacokinetics; pediatric; Mepolizumab; subcutaneous; eosinophilic asthma; pharmacodynamics

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).