Intravenous Mepolizumab In Children With Eosinophilic Esophagitis

GlaxoSmithKline84 enrolled

Overview

This study will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of intravenous mepolizumab in pediatric subjects with eosinophilic esophagitis.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Oesophagitis, Eosinophilic

Interventions

mepolizumabDRUG

Participants received mepolizumab 0.55 milligrams (mg)/kilogram (kg), 2.5 mg/kg , or 10 mg/kg by intravenous (IV) infusion for 30 minutes on Day 1, Week 4 and Week 8.

Eligibility

Sex: ALLMin age: 2 YearsMax age: 17 Years

Medical Language ↔ Plain English

Inclusion Criteria: * A subject will be eligible for inclusion in this study only if all of the following criteria apply. Inclusion criteria pertain to all subjects in both cohorts (treatment and observational) unless otherwise stated. * The subject signs and dates a written assent form (age appropriate) and the parent/guardian signs and dates a written informed consent form prior to the initiation of any study-related activities, including discontinuation of any prohibited medications. * Male or female subjects aged 2 to 17 years (from 2nd birthday up to and not including 18th birthday), who weigh \<=84.9kg (males)/ \<= 72.5 (females) and who have a BMI between 5 and 85% for age, who speak, read and write English as age appropriate and/or parent/guardian. NOTE: If subject is within weight requirements but close to the upper or lower limits at screening and the investigator anticipates that during the study the subject's weight will change a become outside the weight requirements, the subject should be excluded from the study. * To be eligible for entry in the treatment group of the study, a female subject is eligible to enter the study if she is: not pregnant or nursing; of non-childbearing potential. Non-childbearing potential is defined as a pre-menarcheal female who has not yet entered puberty as evidenced by lack of breast development (palpable glandular breast tissue); or a female who has documentation (medical report verification) of hysterectomy and/or bilateral oophorectomy; of childbearing potential. These females subjects must have a negative urine pregnancy test at the screening visit, and agree to consistent and correct use of one of the acceptable methods of birth control from at least the commencement of their last normal period prior to the first dose of study medication and to continue until the first normal period after treatment or after the Week 24 Follow-up visit, whichever is longest. * The subject has a diagnosis of eosinophilic esophagitis and current evidence on biopsy of isolated eosinophilic esophagitis defined as: * Peak esophageal eosinophil counts (highest count of eosinophils per HPF in at least one of all esophageal sites biopsied) of 20 or more eosinophils in a minimum of one HPF at 400X magnification on histology of esophageal biopsies from distal and mid-esophagus within two weeks of commencing study medication, as determined by the central histopathologist. * Inadequate response to or intolerant of therapy for eosinophilic esophagitis * The individual investigators will apply their clinical judgment to define whether a clinical response to therapy for eosinophilic esophagitis is inadequate. As guidance, inadequate response might consist of persistence under current or recent prior therapy, of symptoms of eosinophilic esophagitis such as eosinophilic esophagitis-related pain in stomach, chest or throat; regurgitation; vomiting; pain or difficulties associated with drinking fluids or nutritional supplements; or pain or difficulties associated with eating. An inadequate response might also consist of persistent eosinophilic infiltration of the esophagus, in the presence or in the absence of eosinophilic esophagitis-related symptoms. * Similarly, the individual investigators will apply their clinical judgment to define whether a patient is intolerant to therapy. For guidance, intolerance to therapy for eosinophilic esophagitis may consist of undesirable side-effects of long-term therapy; or side-effects of long-term therapy that are difficult to manage; or marked non-compliance to therapy or rejection of therapy by the individual patient, or by the parent/guardian, which in the opinion of the investigator interferes with the patient's optimal disease management. * The criteria used by the investigator to define inadequate response to or intolerance of therapy for eosinophilic esophagitis will be collected in the CRF. Exclusion Criteria: * A subject will not be eligible for inclusion in this study if any of the following criteria apply. Exclusion criteria pertain to all subjects in both cohorts (treatment and observational) unless otherwise stated. * Current evidence of eosinophilic gastrointestinal enteropathy (EGID), other than eosinophilic esophagitis. * Evidence of gastroesophageal reflux disease, or other causes of esophagitis which in the investigator's opinion is the predominant cause of the subject's esophageal eosinophilia so that the investigator's opinion is allowed. * Current presence, or history of (anytime in the past): hypereosinophilic syndromes, collagen vascular disease, vasculitis, allergic drug reaction as the cause of the peripheral eosinophilia, graft-versus host disease, chronic idiopathic inflammatory bowel disorders (ulcerative colitis, Crohn's disease, chronic granulomatous disease). * Current evidence, or history of celiac disease. * Current evidence of active H. pylori infection. * Abnormal 12-lead ECG at Screening which is clinically significant in the opinion of the investigator. Note that this exclusion criterion does not apply for subjects who are considered for enrollment in the observational cohort. * Use or administration of any of the prohibited medications from Screening and throughout completion of Week 34 follow-up. Note that this exclusion criterion does not apply for subjects who are considered for enrollment in the observational cohort. * Failure to remain on a stable dose of one (or more) permitted medication(s) for at least 1 month prior to the Screening visit and throughout completion of Week 24 follow-up assessments. Note that this exclusion criterion does not apply for subjects who are considered for enrollment in the observational cohort. * Failure to remain on stable elemental diet or dietary manipulations for at least 3 months prior to the Screening Visit and throughout completion of Week 34 follow-up assessments. Note that this exclusion criterion does not apply for subjects who are considered for enrollment in the observational cohort. * Known history of allergic reaction to previous antibody therapy. * Any previous treatment with anti-hIL-5, anti-IgE monoclonal antibody or other biological agents. * Use of an investigational drug within 30 days of entering the study. Note that this exclusion criterion does not apply for subjects who are considered for enrollment in the observational cohort. * Exhibits evidence of renal disease or serum creatinine \> 1.5 times upper limit of normal range (ULN). Note that this exclusion criterion does not apply for subjects who are considered for enrollment in the observational cohort. * Exhibits evidence of hepatic disease, impairment or abnormal liver function test i.e. AST, ALT \>1.5 times ULN, bilirubin \>1.5 times ULN. Note that this exclusion criterion does not apply for subjects who are considered for enrollment in the observational cohort. * Known evidence of the following infections/infestations: HIV, Hepatitis B or C, Bacterial infection, Parasitic infestation. * History or suspicion of current drug abuse and alcohol abuse within the last 6 months.

Locations (29)

Outcomes

Primary Outcomes

Number of Participants With Any Adverse Events (AE), Any Serious Adverse Event (SAE) and Drug-related AE During Treatment Phase (TP) and Follow-up Phase (FP)

An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event is defined as any untoward medical occurrence that, at any dose that Results in death, life-threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; a congenital anomaly/birth defect. Drug-related AE's were considered to have a reasonable possibility of being related to treatment by the investigator. AE, SAE and drug-related AEs are summarized by TP and FP.

Time frame: From first dose of study treatment (Day 1) up to Follow-up Phase (Week 24)

Number of Participants With Indicated Biochemistry Parameters Falling Outside of Reference Range (RR) in Any Vist Post-Basline During Study Period.

Blood samples were collected at Day 1, Weeks 4, 8, 12, 16, 20 and 24 to estimate the following biochemistry parameters: alanine amino transferase (ALT), aspartate amino transferase (AST), albumin (Ab), total protein (ToP), creatinine (Cr), total bilirubin (TB), calcium (Ca), bicarbonate (Bi), chloride (Cl), glucose (Glu), potassium (Pot), and sodium (Sod). Laboratory abnormalities outside the reference range (high and low values) at any time post baseline were presented. Any time post Baseline = all visits (including scheduled and unscheduled). If participant had given both high and low value at least once then participant is counted under both high and low category for this visit.

Time frame: From first dose of study treatment (Day 1) up to Follow-up Phase (Week 24)

Number of Participants With Indicated Hematology Parameters Falling Outside of Reference Range (RR) in Any Vist Post-Basline During the Study Period.

Blood samples were collected pre-infusion at Day 1, Week 4 and Week 8; and 24h and 72h post-infusion at Day 1, Week 4 and Week 8 time points and at Weeks 2, 6, 10, 12, 16, 20, 24, and 34 to estimate the following hematology parameters: basophils (Bas), percentage of basophils (% Bas), lymphocytes (Lym), percentage of Lym (% Lym), monocytes (Mon), percentage of Mon (% Mon), platelet count (PC), total neutrophils (TN), percentage of TN (% TN), white blood cell count (WBC), hematocrit (He), hemoglobin (Hg), and red blood cell count (RBC). Laboratory abnormalities outside the reference range (high and low values) at any time post baseline were presented. Any time post Baseline = all visits (including scheduled and unscheduled). If participant had given both high and low value at least once then participant is counted under both high and low category for this visit.

Data from ClinicalTrials.gov

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Secondary Outcomes

Change From Baseline in Pain in Stomach Severity Scores

Par.and/or parent/guardian recorded daily symptoms of eosinophilic esophagitis on a hand held personal digital assistant (electronic diary) during the Screening Phase, TP, and FP. A severity score of 0 was assigned for days on which pain in stomach was not experienced. If pain in stomach was reported, severity of pain was assessed as: 1=hurt a little, 2=hurt somewhat, 3=hurt quite a bit, and 4=hurt a whole lot. The average pain severity for the interval (Baseline, Weeks 9-12, Weeks 21-24) was calculated as the sum of the pain severity scores for that interval (including days assigned as 0) divided by the number of days in the interval. Screening phase was considered as the Baseline interval. Change from Baseline was calculated as the value for that interval minus the value for the Baseline interval. Analysis was performed using parametric Analysis of Covariance (ANCOVA) models with terms for the relevant Baseline score, treatment group, age group and treatment by age group interaction