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)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 84
- 试验地点
- 1
- 主要终点
- Number of Participants With Indicated Hematology Parameters Falling Outside of Reference Range (RR) in Any Vist Post-Basline During the Study Period.
研究概览
简要总结
This study will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of intravenous mepolizumab in pediatric subjects with eosinophilic esophagitis.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 2 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Mepolizumab 0.55 mg/kg
Participants received mepolizumab 0.55 milligrams (mg)/kilogram (kg) by intravenous (IV) infusion for 30 minutes on Day 1, Week 4 and Week 8.
干预措施: mepolizumab (Drug)
Mepolizumab 2.5 mg/kg
Participants received mepolizumab 2.5 mg/kg by IV infusion for 30 minutes on Day 1, Week 4 and Week 8.
干预措施: mepolizumab (Drug)
Mepolizumab 10 mg/kg
Participants received mepolizumab 10 mg/kg by IV infusion for 30 minutes on Day 1, Week 4 and Week 8.
干预措施: mepolizumab (Drug)
结局指标
主要结局
Number of Participants With Indicated Hematology Parameters Falling Outside of Reference Range (RR) in Any Vist Post-Basline During the Study Period.
时间窗: From first dose of study treatment (Day 1) up to Long-term Follow-up Phase (Week 34)
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.
Number of Participants With the Indicated Change From Baseline in ECG Findings at Any Time Post-Baseline
时间窗: Screening, Weeks 4, 8 and 12
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.
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)
时间窗: From first dose of study treatment (Day 1) up to Follow-up Phase (Week 24)
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.
Number of Participants With Indicated Biochemistry Parameters Falling Outside of Reference Range (RR) in Any Vist Post-Basline During Study Period.
时间窗: From first dose of study treatment (Day 1) up to Follow-up Phase (Week 24)
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.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Indicated Time Points
时间窗: Screening, Day 1, Weeks 4, 8, 12, 16, 20, and 24
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.
Change From Baseline in Heart Rate at the Indicated Time Points
时间窗: Screening, Day 1, Weeks 4, 8, 12, 16, 20, and 24
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.
Change From Baseline in Temperature at the Indicated Time Points
时间窗: Screening, Day 1, Weeks 4, 8, 12, 16, 20 and 24
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.
Number of Participants With Positive and Negative Anti-mepolizumab Antibody Results at Any Visit and Repeat Visit.
时间窗: Day 1, Weeks 4, 8, 12, 24, and 34
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.
Number of Participants Achieving a Reduction in Peak Esophageal Eosinophil Count to < 5 Cells Per High Power Field (HPF) at Week 12
时间窗: 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.
Central (V1), Periperial (V2) and Steady-State (Vss) Volume of Distribution of Mepolizumab
时间窗: Day 1, Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, and 34
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.
Plasma Clearance (CL) of Mepolizumab
时间窗: Day 1, Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, and 34
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.
次要结局
- 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)
- Change From Baseline in Percentage of Days With Regurgitation Bothersome Scores(Screening, Weeks 9-12 and Weeks 21-24)
- Change From Baseline in Frequency of Vomiting(Screening, Weeks 9-12 and Weeks 21-24)
- Change From Baseline in Percentage of Days With Vomiting(Screening, Weeks 9-12 and Weeks 21-24)
- Change From Baseline in Daily Degree of Difficulty With Drinking(Screening, Weeks 9-12 and Weeks 21-24)
- Change From Baseline in Pain With Drinking Severity Scores(Screening, Weeks 9-12 and Weeks 21-24)
- Change From Baseline in Percentage of Days on Which the Participant Drank(Screening, Weeks 9-12 and Weeks 21-24)
- Change From Baseline in Difficulty With Eating Solid Foods(Screening, Weeks 9-12 and Weeks 21-24)
- Change in Baseline in Pain With Eating Solid Foods Severity Scores(Screening, Weeks 9-12 and Weeks 21-24)
- Change From Baseline in the Percentage of Days Participants Ate Solid Foods(Screening, Weeks 9-12 and Weeks 21-24)
- Plasma Concentration of Mepolizumab(Day 1, Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24 and 34)
- Change From Baseline in Feeling of Something Stuck in Throat Bothersome Scores (for Par. 8-17 Years Only)(Screening, Weeks 9-12 and Weeks 21-24)
- Change From Baseline in Percentage of Days With Feeling of Something Stuck in Throat (for Par. 8-17 Years)(Screening, Weeks 9-12 and Weeks 21-24)
- Number of Participants With Maintenance of Response(Week 12 and Week 24)
- Mean Change From Baseline in Peak Esophageal Eosinophil Counts at Weeks 12 and 24(Baseline, Weeks 12 and 24)
- Change From Baseline in Mean Esophageal Eosinophil Counts at Weeks 12 and 24(Baseline, Weeks 12 and 24)
- Absolute Blood Eosinophils Count at the Indicated Time Points(Screening, Day 1, Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24 and 34)