Efficacy and Safety of Ofatumumab and Siponimod Compared to Fingolimod in Pediatric Patients With Multiple Sclerosis

Study Overview
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Brief Summary
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Efficacy and safety of ofatumumab and siponimod compared to fingolimod in pediatric patients with multiple sclerosis

Detailed Description
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The study is divided into a Core Part and Extension Part. The Core Part is a 24-month, double-blind, triple dummy, randomized, 3-arm active-controlled in children/adolescent patients aged 10-17 years old with Multiple Sclerosis (MS). The Extension Part is 60-month (5 year) open label (except for first 12 weeks transition which will remain double-blind) treatment for patients who complete the Core Part of the study and meet all inclusion/exclusion criteria. The targeted enrollment is 180 participants with multiple sclerosis which will include at least 5 participants with body weight (BW) ≤40 kg and at least 5 participants with age 10 to 12 years in each of the ofatumumab and siponimod arms. There is a minimum 6 month follow up period for all participants (core and extension). Total duration of the study could be up to 7 years.

Official Title
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A 2-year Randomized, 3-arm, Double-blind, Non-inferiority Study Comparing the Efficacy and Safety of Ofatumumab and Siponimod Versus Fingolimod in Pediatric Patients With Multiple Sclerosis Followed by an Open-label Extension

Conditions
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Multiple Sclerosis (MS)

Intervention / Treatment
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* Drug: Fingolimod
* Drug: Ofatumumab
* Drug: Siponimod
* Other: Fingolimod placebo
* Other: Siponimod placebo
* Other: Ofatumumab placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Between 10 to <18 years of age (i.e., have not yet had their 18th birthday) at randomization Diagnosis of multiple sclerosis EDSS score of 0 to 5.5, inclusive At least one MS relapse/attack during the previous year or two MS relapses in the previous two years prior or evidence of one or more new T2 lesions within 12 months Exclusion Criteria: Participants with progressive MS Participants with an active, chronic disease of the immune system other than MS Participants meeting the definition of ADEM Participants with severe cardiac disease or significant findings on the screening ECG. Participants with severe renal insufficiency

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ofatumumab - 20 mg injection/ placebo<br>Ofatumumab as a solution for injection in an autoinjector containing 20 mg ofatumumab (50 mg/mL, 0.4 mL content) for subcutaneous administration. A loading dose at Day1, Day 7 and Day 14 and then injections every 4 weeks/ 6 weeks (depending on patient's body weight). | Drug: Ofatumumab<br>* Ofatumumab as a solution for injection in an autoinjector containing 20 mg ofatumumab (50 mg/mL, 0.4 mL content) for subcutaneous administration. A loading dose at Day1, Day 7 and Day 14 and then injections every 4 weeks/ 6 weeks (depending on patient's body weight).<br>* Other names: OMB157;Other: Ofatumumab placebo<br>* Ofatumumab matching placebo autoinjector<br>|
| Experimental: siponimod - 0.5 mg, 1 mg or 2 mg/ placebo<br>Siponimod tablet administered orally once daily. Titration period, Day 1 to Day 6, first dose is either 0.1 mg or 0.25 mg up to daily dose of either 0.5 mg, 1 mg or 2 mg (depending on CYP2C9 genotype and body weight). | Drug: Siponimod<br>* Siponimod tablet administered orally once daily. Titration period, Day 1 to Day 6, first dose is either 0.1 mg or 0.25 mg up to daily dose of either 0.5 mg, 1 mg or 2 mg (depending on CYP2C9 genotype and body weight).<br>* Other names: BAF312;Other: Siponimod placebo<br>* Siponimod matching placebo tablet<br>|
| Active Comparator: fingolimod - 0.5 mg or 0.25 mg/ placebo<br>Fingolimod capsule administered orally once daily at a dose of either 0.5 mg or 0.25 mg (depending on patient's body weight). | Drug: Fingolimod<br>* Fingolimod capsule administered orally once daily at a dose of either 0.5 mg or 0.25 mg (depending on patient's body weight).<br>* Other names: FTY720;Other: Fingolimod placebo<br>* Fingolimod matching placebo capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized relapse rate (ARR) in target pediatric participants | 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). | Baseline up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized relapse rate (ARR) as compared to historical interferon β-1a data | Frequency of relapses assessed by the annualized relapse rate (ARR) to historical interferon β-1a data. The ARR is defined as the average number of confirmed relapses per year. The historical data for interferon β-1a will derived from prior phase 3 studies. | Baseline up to 24 months | 
| Annualized T2 lesion rate | Number of new/newly enlarged T2 lesions per year | Baseline up to 24 months | 
| Neurofilament light chain (NfL) concentrations | Neurofilament light chain (NfL) concentration in serum of ofatumumab and/or siponimod versus fingolimod | Day 1, Months 3,6,12,18,24 | 
| Plasma Concentrations of ofatumumab | Ofatumumab plasma concentrations | Day 1, pre-dose for Day 7, Months 2,3,5,6,12,18,24 | 
| Plasma Concentrations of siponimod | Siponimod plasma concentrations | Day 1 (2,3,4,6 h), Day 3 (2,3,4,6 h), pre-dose for Months 1 (pre, 3h), 3,5,12 | 
| Plasma Concentrations of siponimod metabolite (M17) | Siponimod metabolite (M17) plasma concentration | Pre-dose Month 3, 5 and Month 12 | 
| Percentage of participants with anti-ofatumumab antibodies | Anti-ofatumumab antibodies to demonstrate immunogenicity of ofatumumab | Day 1, Pre-Dose Months 2,3,5,6,12,18,24 | 
| Number of adverse events and serious adverse events | Any clinically relevant finding that meets the criteria of an adverse event (as determined by the investigator) identified during the safety assessments (ECG, laboratory and ophthalmological data, pulmonary function tests and vital signs) will be reported as an adverse event | Baseline up approximately 66 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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relapsing multiple sclerosis, pediatric, relapse, EDSS, ofatumumab, siponimod, fingolimod, RMS, MS