Intravenous Mepolizumab In Children With Eosinophilic Esophagitis

NCT00358449 | Completed Phase 2 Results FDA Drug

• 1 other identifier: MEE103219
• Study Type: interventional
• Target: 84
• Locations: 4 countries
• Sites: 29

Brief Summary

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

Conditions

Oesophagitis, Eosinophilic

Keywords

eosinophilic; mepolizumab; esophagitis

Outcome Measures

Primary Outcomes (11)

• 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.

  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.

  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.

  From first dose of study treatment (Day 1) up to Long-term Follow-up Phase (Week 34)

• Number of Participants With the Indicated Change From Baseline in ECG Findings at Any Time Post-Baseline

  12-lead ECG assessments were obtained at the following time points: screening, and Weeks 4, 8 and 12.. Overall ECG findings were summarized using the worst case findings without regard to visits ie. "any time post Baseline". Change from Baseline in ECG findings were categorized as clinically significant change from Baseline; no clinically significant change from Baseline and not applicable.

  Screening, Weeks 4, 8 and 12

• Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Indicated Time Points

  SBP and DBP measurements were obtained at the following time points: screening, pre-infusion, 10 minutes (m), 30m, 1 hour (h), 2h post-infusion on Day 1, Week 4, Week 8; and Weeks 12, 16, 20 and 24. Screening value was considered as the Baseline value. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

  Screening, Day 1, Weeks 4, 8, 12, 16, 20, and 24

• Change From Baseline in Heart Rate at the Indicated Time Points

  Heart rate measurements were obtained at the following time points: Screening, pre-infusion, 10m, 30m, 1h, 2h post-infusion on Day 1, Week 4, Week 8; and Weeks 12, 16, 20 and 24. Screening value was considered as the Baseline value. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

  Screening, Day 1, Weeks 4, 8, 12, 16, 20, and 24

• Change From Baseline in Temperature at the Indicated Time Points

  Temperature measurements were obtained at the following time points: Screening, Day 1, and Weeks 4, 8, 12, 16, 20 and 24. Screening value was considered as the Baseline value. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

  Screening, Day 1, Weeks 4, 8, 12, 16, 20 and 24

• Number of Participants With Positive and Negative Anti-mepolizumab Antibody Results at Any Visit and Repeat Visit.

  Blood samples for testing anti-mepolizumab antibodies were collected on Day 1, Week 4 and 8 Infusion Visit (before the IV infusion) and at Week 12, 24 and 34 Week follow-up visits. The presence of anti-human mepolizumab antibodies was assessed using an immunoelectrochemiluminescent (ECL) assay. To address transient positive results, an assessment of repeated results were made. For any visit category: results were considered as positive if it was positive at any visit during the study, and results were considered as negative if it were negative at all visits during the study. For repeat visit category: results were considered as postive if the result was positive at \>1 visit, and results were considered as negative if the result was negative at all visits or was positive at only one visit.

  Day 1, Weeks 4, 8, 12, 24, and 34

• Number of Participants Achieving a Reduction in Peak Esophageal Eosinophil Count to < 5 Cells Per High Power Field (HPF) at Week 12

  A responder was defined as a participant achieving a reduction in esophageal eosinophils to \<5 cells per HPF as the highest count of eosinophils per HPF in all the esophageal sites biopsied at Week 12, confirmed by biopsy at Week 12 or at an early withdrawal visit prior to Week 12. A worst case (WC) approach was considered, if a particiapant withdrew prematurely : If a particiapnt dropped out of the study without having a biopsy taken, due to lack of efficacy or an adverse event, their response was imputed as not achieved. Participants who withdrew, without a biopsy, for other reasons (e.g. lost to follow-up) were considered non-evaluable for the primary analysis. For participants who withdrew early from the study and had a biopsy, the biopsy was used to determine their response.

  Week 12

• Central (V1), Periperial (V2) and Steady-State (Vss) Volume of Distribution of Mepolizumab

  Volume of distribution is defined as the theoretical volume in which the total amount of drug is uniformly distributed to produce the desired plasma concentration of a drug. Central volume of distribution is a hypothetical volume into which a drug initially distributes upon administration. Peripheral volume of distribution is the sum of all tissue spaces outside the central compartment. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state. Blood samples were obtained at pre-infusion and 5m, 2h, 24h, 72-96h post-infusion at Day 1, Weeks 4, 8; and Weeks 2, 6 10, 12, 16, 20, 24 and 34 from each participant to estimate central (V1) and periperial (V2) and Steady State (Vss) volume of distribution of mepolizumab.

  Day 1, Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, and 34

• Plasma Clearance (CL) of Mepolizumab

  Clearance is defined as the removal of drug from a volume of plasma in a given unit of time (drug loss from the body). Blood samples were obtained at pre-infusion and 5m, 2h, 24h, 72-96h post-infusion at Day 1, Weeks 4, 8; and Weeks 2, 6 10, 12, 16, 20, 24 and 34 from each participant to estimate plasma clearance of mepolizumab.

  Day 1, Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, and 34

Secondary Outcomes (21)

• Change From Baseline in Pain in Stomach Severity Scores

  Screening, Weeks 9-12 and Weeks 21-24

• Change From Baseline in Pain in Chest/Throat Severity Scores

  Screening, Weeks 9-12 and Weeks 21-24

• Change From Baseline in Percentage of Days With Pain in Stomach

  Screening, Weeks 9-12 and Weeks 21-24

• Change From Baseline in Percentage of Days With Pain in Chest/Throat

  Screening, Weeks 9-12 and Weeks 21-24

• Change From Baseline in Regurgitation Bothersome Scores

  Screening, Weeks 9-12 and Weeks 21-24

Study Arms (3)

Mepolizumab 0.55 mg/kg

EXPERIMENTAL

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

Drug: mepolizumab

Mepolizumab 2.5 mg/kg

EXPERIMENTAL

Participants received mepolizumab 2.5 mg/kg by IV infusion for 30 minutes on Day 1, Week 4 and Week 8.

Drug: mepolizumab

Mepolizumab 10 mg/kg

EXPERIMENTAL

Participants received mepolizumab 10 mg/kg by IV infusion for 30 minutes on Day 1, Week 4 and Week 8.

Drug: mepolizumab

Interventions

mepolizumab DRUG

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.

Mepolizumab 0.55 mg/kg; Mepolizumab 10 mg/kg; Mepolizumab 2.5 mg/kg

Eligibility Criteria

• Age: 2 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• Known history of allergic reaction to previous antibody therapy.
• Any previous treatment with anti-hIL-5, anti-IgE monoclonal antibody or other biological agents.
• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (29)

GSK Investigational Site

Birmingham, Alabama, 35205, United States

Location

GSK Investigational Site

San Diego, California, 92123, United States

Location

GSK Investigational Site

Tampa, Florida, 33613, United States

Location

GSK Investigational Site

Atlanta, Georgia, 30322, United States

Location

GSK Investigational Site

Springfield, Illinois, 62794, United States

Location

GSK Investigational Site

Evansville, Indiana, 47713, United States

Location

GSK Investigational Site

Indianapolis, Indiana, 46202, United States

Location

GSK Investigational Site

Worcester, Massachusetts, 01655, United States

Location

GSK Investigational Site

Southfield, Michigan, 48075, United States

Location

GSK Investigational Site

Troy, Michigan, 48098, United States

Location

GSK Investigational Site

Minneapolis, Minnesota, 55402, United States

Location

GSK Investigational Site

Kansas City, Missouri, 64108, United States

Location

GSK Investigational Site

St Louis, Missouri, 63104, United States

Location

GSK Investigational Site

New York, New York, 10029, United States

Location

GSK Investigational Site

Cincinnati, Ohio, 45229, United States

Location

GSK Investigational Site

Sioux Falls, South Dakota, 57108, United States

Location

GSK Investigational Site

Dallas, Texas, 75230, United States

Location

GSK Investigational Site

Dallas, Texas, 75235, United States

Location

GSK Investigational Site

Norfolk, Virginia, 23507, United States

Location

GSK Investigational Site

Milwaukee, Wisconsin, 53215, United States

Location

GSK Investigational Site

Brisbane, Queensland, 4029, Australia

Location

GSK Investigational Site

Hamilton, Ontario, L8N 3Z5, Canada

Location

GSK Investigational Site

Kingston, Ontario, K7L 5G2, Canada

Location

GSK Investigational Site

London, Ontario, N6A 5W9, Canada

Location

GSK Investigational Site

Montreal, Quebec, H3T 1C5, Canada

Location

GSK Investigational Site

Liverpool, L12 2AP, United Kingdom

Location

GSK Investigational Site

London, WC1N 3JH, United Kingdom

Location

GSK Investigational Site

Sheffield, S10 2TH, United Kingdom

Location

GSK Investigational Site

Watford, WD18 0HB, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 21835135 BACKGROUND

• Wong ECL, Gleave AL, Marshall JK, Narula N. Predictors of histologic response to mepolizumab in pediatric eosinophilic esophagitis. Eur J Gastroenterol Hepatol. 2023 Oct 1;35(10):1131-1136. doi: 10.1097/MEG.0000000000002623. Epub 2023 Jul 31.

  PMID: 37577798 DERIVED

Related Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

MeSH Terms

Conditions

Esophagitis

Interventions

mepolizumab

Condition Hierarchy (Ancestors)

Esophageal Diseases; Gastrointestinal Diseases; Digestive System Diseases; Gastroenteritis

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

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: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 27, 2006
• First Posted: July 31, 2006
• Study Start: September 11, 2006
• Primary Completion: November 25, 2008
• Study Completion: November 25, 2008
• Last Updated: July 24, 2018
• Results First Posted: March 10, 2016

Record last verified: 2018-06

Data Sharing

• IPD Sharing: Will share

Locations

GB (4); AU (1); US (20); CA (4)