Safety and Efficacy of Fingolimod in Pediatric Patients With Multiple Sclerosis

Study Overview
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Brief Summary
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To evaluate the safety and efficacy of fingolimod vs. interferon beta-1a i.m. in pediatric patients with multiple sclerosis (MS)

Detailed Description
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The study is divided into a Core Phase, which includes the Double-Blind Treatment Period, and an Extension Phase in which all patients will be treated with fingolimod. The Core Phase is a 24-month, double-blind, randomized, active-controlled, parallel-group multicenter study phase to evaluate the efficacy and safety of fingolimod compared to IFN β-1a in children/adolescent patients aged 10-17 years old with MS. The Extension Phase is a 60-month (5 year) study phase for patients who complete the Core Phase of the study and meet all inclusion/exclusion criteria and for patients who will be recruited in the younger cohort to participate in the Extension Phase. The 'younger cohort' refers to the population of pediatric patients fulfilling any single one or a combination of the following criteria: being ≤12 years of age, or weighing ≤40 kg, or being prepubertal (i.e. pubertal status of Tanner stage <2). The recruitment of the younger cohort (up to 25 patients) was requested as a post- approval health authority commitment

Official Title
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A 2 Year, Double-blind, Randomized, Multicenter, Active-controlled Core Phase to Evaluate Safety & Efficacy of Daily Fingolimod vs Weekly Interferon β-1a im in Pediatric Patients With Multiple Sclerosis and 5 Year Fingolimod Extension Phase

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Interferon beta-1a
* Drug: Fingolimod
* Drug: Placebo capsule
* Drug: Placebo i.m. injection


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria Core Phase: diagnosis of multiple sclerosis at least one MS relapse during the previous year or two MS relapses in the previous 2 years or evidence of Gd enhancing lesions on MRI within 6 months EDSS score of 0 to 5.5, inclusive Key Exclusion Criteria Core Phase: patients with progressive MS patients with an active, chronic disease of the immune system other than MS patients meeting the definition of ADEM patients with severe cardiac disease or significant findings on the screening ECG. patients with severe renal insufficiency Key Inclusion Criteria Extension Phase: Applies to all patients participating in the Core Phase and then entering the Extension Phase. 1. Patients that originally met Core Phase Inclusion criteria and completed the Core phase on or off of study drug. Applies to patients newly recruited to participate in the Extension Phase. All newly recruited patients' that enroll directly into the Extension Phase must fulfill the local country health authority product label approved for pediatric age group for inclusion criteria. Central review (including initial MRI report) of the diagnosis of pediatric MS will be required for all newly recruited patients. Key Exclusion Criteria Extension Phase: Applies to patients who completed the Core Phase, but prematurely discontinued study drug. Premature discontinuation of the study drug during the Core Phase due to: an adverse event, serious adverse event, laboratory abnormality other conditions leading to permanent study drug discontinuation due to safety reasons Patients with known new events or concomitant medications (washout periods required prior to Visit 15) that would exclude them from the Core Phase exclusion criteria. Serological or other additional tests will not be required. Applies to patients newly recruited in the younger cohort to participate in the Extension Phase. 1. All newly recruited patients in the younger cohort that enroll directly into the Extension Phase must fulfill the exclusion criteria for the core phase.

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: There are 2 arms in the core phase. In the extension phase all participants are receiving open-label.study drug. A third arm has been added to enroll up to 25 new younger patients per HA post approval commitment.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fingolimod<br>Fingolimod was administered orally once daily at a dose of either 0.5 mg or 0.25 mg (depending on patient's body weight) with the aim to achieve systemic exposure in range of that in adults at the licensed 0.5 mg dose. Participants in this arm during core continued into extension and received open-label treatment | Drug: Fingolimod<br>* Administrated orally once daily: 0.5 mg capsule for patients over 40 kg or 0.25 mg capsule for patients 40 kg or less.<br>Drug: Placebo capsule<br>* Matching placebo capsule required for double-dummy masking to blind formulations.<br>|
| Active Comparator: Interferon beta-1a<br>An intramuscular (IM) injection of Interferon beta-1a was administered once weekly during core phase. Participants switched to receive open-label fingolimod in extension phase | Drug: Interferon beta-1a<br>* Administration once weekly via i.m. injections.<br>Drug: Placebo i.m. injection<br>* Matching placebo i.m. injection required for double-dummy masking to blind formulations.<br>|
| Experimental: Fingolimod-Younger Cohort<br>The 'younger cohort' refers to the new pediatric patients to be recruited in the extension phase who fulfill any single one or a combination of the following criteria: being ≤12 years of age, or weighing ≤40 kg, or being prepubertal (i.e. pubertal status of Tanner stage <2) | Drug: Fingolimod<br>* Administrated orally once daily: 0.5 mg capsule for patients over 40 kg or 0.25 mg capsule for patients 40 kg or less.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Relapses in Patients Treated for up to 24 Months | Frequency of relapses assessed by the annualized relapse rate (ARR). The ARR is defined as the average number of confirmed relapses per year (total number of confirmed relapses divided by the total days in the study multiplied by 365.25). | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| New/Newly Enlarged T2 Lesions | Annualized rate of the number of new/newly enlarged T2 lesions up to Month 24 | 24 months | 
| Time to First Relapse | Time to first relapse was determined. | 24 months | 
| Proportion of Patients Relapse-free | Proportion of patients relapse-free was determined | 24 months | 
| T1 Gd- Enhancing Lesions | Number of T1 Gd-enhancing lesions per scan up to Month 24 | 24 months | 
| Pharmacokinetics (Cavg) of Fingolimod-P | Cavg (average drug concentration over the dose interval) will be evaluated. | 24 months | 
| Pharmacokinetic/Pharmacodynamic Relationship for Fingolimod-P to Lymphocyte Levels | Population PK/PD modeling approaches were used to relate the individual fingolimod-P concentrations to lymphocyte counts. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pediatric, MS, multiple sclerosis, fingolimod, pre-pubertal, low weight, children, adolescent, core phase, extension phase, younger cohort