Clinical trial NCT00358449: Intravenous Mepolizumab In Children With Eosinophilic Esophagitis
Official title: A Randomized, Double-blind, Parallel Group Clinical Trial to Assess Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenous Mepolizumab (SB240563)(0.55mg/kg, 2.5mg/kg or 10mg/kg) in Pediatric Subjects With Eosinophilic Esophagitis, Aged 2 to 17 Years (Study MEE103219)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Oesophagitis, Eosinophilic
Keywords: eosinophilic
mepolizumab
esophagitis
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2006-07-31
Enrollment: 84
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


Eligibility criteria: 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.

Primary outcomes:
measure: 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)
timeFrame: From first dose of study treatment (Day 1) up to Follow-up Phase (Week 24)
measure: Number of Participants With Indicated Biochemistry Parameters Falling Outside of Reference Range (RR) in Any Vist Post-Basline During Study Period.
timeFrame: From first dose of study treatment (Day 1) up to Follow-up Phase (Week 24)
measure: Number of Participants With Indicated Hematology Parameters Falling Outside of Reference Range (RR) in Any Vist Post-Basline During the Study Period.
timeFrame: From first dose of study treatment (Day 1) up to Long-term Follow-up Phase (Week 34)
measure: Number of Participants With the Indicated Change From Baseline in ECG Findings at Any Time Post-Baseline
timeFrame: Screening, Weeks 4, 8 and 12
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Indicated Time Points
timeFrame: Screening, Day 1, Weeks 4, 8, 12, 16, 20, and 24
measure: Change From Baseline in Heart Rate at the Indicated Time Points
timeFrame: Screening, Day 1, Weeks 4, 8, 12, 16, 20, and 24
measure: Change From Baseline in Temperature at the Indicated Time Points
timeFrame: Screening, Day 1, Weeks 4, 8, 12, 16, 20 and 24
measure: Number of Participants With Positive and Negative Anti-mepolizumab Antibody Results at Any Visit and Repeat Visit.
timeFrame: Day 1, Weeks 4, 8, 12, 24, and 34
measure: Number of Participants Achieving a Reduction in Peak Esophageal Eosinophil Count to < 5 Cells Per High Power Field (HPF) at Week 12
timeFrame: Week 12
measure: Central (V1), Periperial (V2) and Steady-State (Vss) Volume of Distribution of Mepolizumab
timeFrame: Day 1, Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, and 34
measure: Plasma Clearance (CL) of Mepolizumab
timeFrame: Day 1, Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, and 34
Secondary outcomes:
measure: Change From Baseline in Pain in Stomach Severity Scores
timeFrame: Screening, Weeks 9-12 and Weeks 21-24
measure: Change From Baseline in Pain in Chest/Throat Severity Scores
timeFrame: Screening, Weeks 9-12 and Weeks 21-24
measure: Change From Baseline in Percentage of Days With Pain in Stomach
timeFrame: Screening, Weeks 9-12 and Weeks 21-24
measure: Change From Baseline in Percentage of Days With Pain in Chest/Throat
timeFrame: Screening, Weeks 9-12 and Weeks 21-24
measure: Change From Baseline in Regurgitation Bothersome Scores
timeFrame: Screening, Weeks 9-12 and Weeks 21-24
measure: Change From Baseline in Percentage of Days With Regurgitation Bothersome Scores
timeFrame: Screening, Weeks 9-12 and Weeks 21-24
measure: Change From Baseline in Frequency of Vomiting
timeFrame: Screening, Weeks 9-12 and Weeks 21-24
measure: Change From Baseline in Percentage of Days With Vomiting
timeFrame: Screening, Weeks 9-12 and Weeks 21-24
measure: Change From Baseline in Daily Degree of Difficulty With Drinking
timeFrame: Screening, Weeks 9-12 and Weeks 21-24
measure: Change From Baseline in Pain With Drinking Severity Scores
timeFrame: Screening, Weeks 9-12 and Weeks 21-24
measure: Change From Baseline in Percentage of Days on Which the Participant Drank
timeFrame: Screening, Weeks 9-12 and Weeks 21-24
measure: Change From Baseline in Difficulty With Eating Solid Foods
timeFrame: Screening, Weeks 9-12 and Weeks 21-24
measure: Change in Baseline in Pain With Eating Solid Foods Severity Scores
timeFrame: Screening, Weeks 9-12 and Weeks 21-24
measure: Change From Baseline in the Percentage of Days Participants Ate Solid Foods
timeFrame: Screening, Weeks 9-12 and Weeks 21-24
measure: Change From Baseline in Feeling of Something Stuck in Throat Bothersome Scores (for Par. 8-17 Years Only)
timeFrame: Screening, Weeks 9-12 and Weeks 21-24
measure: Change From Baseline in Percentage of Days With Feeling of Something Stuck in Throat (for Par. 8-17 Years)
timeFrame: Screening, Weeks 9-12 and Weeks 21-24
measure: Number of Participants With Maintenance of Response
timeFrame: Week 12 and Week 24
measure: Mean Change From Baseline in Peak Esophageal Eosinophil Counts at Weeks 12 and 24
timeFrame: Baseline, Weeks 12 and 24
measure: Change From Baseline in Mean Esophageal Eosinophil Counts at Weeks 12 and 24
timeFrame: Baseline, Weeks 12 and 24
measure: Absolute Blood Eosinophils Count at the Indicated Time Points
timeFrame: Screening, Day 1, Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24 and 34
measure: Plasma Concentration of Mepolizumab
timeFrame: Day 1, Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24 and 34
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
city: San Diego
country: United States
facility: GSK Investigational Site
state: California
city: Tampa
country: United States
facility: GSK Investigational Site
state: Florida
city: Atlanta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Springfield
country: United States
facility: GSK Investigational Site
state: Illinois
city: Evansville
country: United States
facility: GSK Investigational Site
state: Indiana
city: Indianapolis
country: United States
facility: GSK Investigational Site
state: Indiana
city: Worcester
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Southfield
country: United States
facility: GSK Investigational Site
state: Michigan
city: Troy
country: United States
facility: GSK Investigational Site
state: Michigan
city: Minneapolis
country: United States
facility: GSK Investigational Site
state: Minnesota
city: Kansas City
country: United States
facility: GSK Investigational Site
state: Missouri
city: Saint Louis
country: United States
facility: GSK Investigational Site
state: Missouri
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Cincinnati
country: United States
facility: GSK Investigational Site
state: Ohio
city: Sioux Falls
country: United States
facility: GSK Investigational Site
state: South Dakota
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Norfolk
country: United States
facility: GSK Investigational Site
state: Virginia
city: Milwaukee
country: United States
facility: GSK Investigational Site
state: Wisconsin
city: Brisbane
country: Australia
facility: GSK Investigational Site
state: Queensland
city: Hamilton
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Kingston
country: Canada
facility: GSK Investigational Site
state: Ontario
city: London
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Liverpool
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Sheffield
country: United Kingdom
facility: GSK Investigational Site
city: Watford
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Assa'ad AH, Gupta SK, Collins MH, Thomson M, Heath AT, Smith DA, Perschy TL, Jurgensen CH, Ortega HG, Aceves SS. An antibody against IL-5 reduces numbers of esophageal intraepithelial eosinophils in children with eosinophilic esophagitis. Gastroenterology. 2011 Nov;141(5):1593-604. doi: 10.1053/j.gastro.2011.07.044. Epub 2011 Aug 9.