Evaluation of Fingolimod Versus Interferon Beta-1a in Pediatric Multiple Sclerosis: A Two-Year, Double-Blind, Randomized, Multicenter Study

Trial ID: 2023-507556-68-00
Protocol: CFTY720D2311
Sponsor: Novartis Pharma AG

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Diseases & Conditions

Multiple sclerosis

Objectives

The primary objective of this study is to evaluate the long-term **safety**, tolerability, and efficacy of **fingolimod** in pediatric patients with **Multiple Sclerosis**. This is clinically relevant as it aims to provide insights into the sustained effects of fingolimod, a disease-modifying therapy, which could potentially improve the management of Multiple Sclerosis in a younger population. Additionally, the study seeks to assess the effects of fingolimod on patients who were initially treated with **interferon-β-1a** during the Core Phase, further contributing to understanding the comparative benefits and risks of these treatments. The study also explores the long-term impact of fingolimod on cognitive function and physical and sexual development, which are critical aspects of pediatric patient care.

Participants

The clinical trial involves a total of **6 participants** diagnosed with **Multiple Sclerosis**. The study population includes both male and female subjects, encompassing a vulnerable population. Participants are selected based on their completion of the Core Phase or as newly recruited individuals meeting specific criteria for the Extension Phase. The age range of the trial subjects is categorized under code 2, which typically includes pediatric patients. The trial considers lifestyle factors such as body weight and pubertal status, particularly for the younger cohort, which includes patients aged 12 years or younger, weighing 40 kg or less, or being pre-pubertal. The selection process ensures that all newly recruited patients fulfill the local country health authority product label approved for the pediatric age group. The trial does not specify additional lifestyle considerations such as diet or physical activity. The sponsor has not provided further information regarding the general health status of the participants.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, and active-controlled study to evaluate the safety and efficacy of **fingolimod** in pediatric patients with **multiple sclerosis**. The trial consists of a two-year Core Phase followed by a five-year Extension Phase. Participants will be randomly assigned to receive either **fingolimod** administered orally once daily or interferon β-1a administered intramuscularly once weekly. The primary objective is to assess the long-term safety, tolerability, and efficacy of **fingolimod**, with secondary objectives including the evaluation of its effects on cognitive function and physical and sexual development.

The trial will commence with an inclusion (screening) visit to determine eligibility based on the principal inclusion criteria, which require participants to have completed the Core Phase or meet specific criteria for the Extension Phase. The study will include regular follow-up visits to monitor safety and efficacy endpoints, such as the annualized relapse rate and the number of new or newly enlarged T2 lesions. Secondary endpoints include the number of Gd-enhanced T1 lesions and changes in brain volume. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any necessary follow-up care is arranged.

The expected duration of participant involvement is up to seven years, encompassing both the Core and Extension Phases. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent. The trial is estimated to end by July 2029, with recruitment having started in July 2013. The study is not classified as low intervention and is categorized as a Phase 3 trial, reflecting its comprehensive evaluation of **fingolimod** in a pediatric population.

Treatment

The clinical trial involves the administration of **Gilenya** in two different dosages, specifically 0.5 mg and 0.25 mg, both formulated as hard capsules. The active substance in these capsules is **fingolimod**, a chemical compound. The pharmaceutical form is a hard capsule, and the route of administration is oral. Participants in the trial will receive a daily dose of either 0.5 mg or 0.25 mg, with the maximum daily dose not exceeding 0.5 mg. The treatment period is set for a maximum of 60 days. The capsules are manufactured by Novartis Europharm Limited and are authorized for use in the European Union under marketing authorization numbers EU/1/11/677/001 and EU/1/11/677/007, respectively.

In addition to the experimental treatment with **fingolimod**, the study includes a comparator treatment with interferon β-1a, administered intramuscularly once weekly. This comparator serves as the standard-of-care therapy for pediatric patients with multiple sclerosis. The trial is designed to evaluate the safety and efficacy of **fingolimod** in comparison to interferon β-1a over a two-year period, followed by a five-year extension phase to assess long-term effects. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol.

Efficacy

The efficacy of **fingolimod** in the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **Annualized Relapse Rate (ARR)** and the time to relapse, as well as the annualized rate of new or newly enlarged T2 lesions and the proportion of patients free of new or newly enlarged T2 lesions. Secondary endpoints will focus on the number of Gd-enhanced T1 lesions, the proportion of patients free of Gd-enhanced T1 lesions, the number of combined unique active (CUA) lesions, changes from baseline in T2 lesion and T1 hypointense lesion volume, and percent brain volume change.

These efficacy parameters will be measured and collected at specified intervals throughout the trial, utilizing validated imaging techniques and clinical assessments. The trial is designed as a two-year, double-blind, randomized, multicenter, active-controlled study, with an additional five-year extension phase. The primary and secondary endpoints will be analyzed to determine the long-term effects of fingolimod on pediatric patients with multiple sclerosis, comparing its efficacy to that of interferon β-1a administered intramuscularly once weekly. The trial aims to provide comprehensive data on the safety, tolerability, and efficacy of fingolimod in this patient population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Criterion 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.
Criteria applies to patients newly recruited to participate in the Extension Phase. The 'younger cohort’ is defined as 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 pre-pubertal (i.e. pubertal status of Tanner stage <2). 1. 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. Countries that do not have the 0.25mg dose formulation of fingolimod approved according to local label, may only enroll patients within the younger cohort who have a body weight above 40 kg and be prescribed the 0.5mg dose level according to local label.
Central review (including initial MRI report) of the diagnosis of pediatric MS (Thompson et al 2018) will be required for all newly recruited patients

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Exclusion Criteria

Patients with progressive MS.
Patients with an active, chronic disease (or stable but treated with immune therapy) of the immune system other than MS (e.g. Sjögren’s disease, systemic lupus erythematosus) or with a known immunodeficiency syndrome (AIDS, hereditary immune deficiency, drug induced immune deficiency) or tested positive for HIV at Screening.
Patients with widespread and symmetric white matter alterations in the Screening MRI suggestive of other demyelinating disorders (e.g. metabolic disorders, mitochondrialdisorders).
Patients meeting the definition of ADEM (Krupp et al. 2013); patients meeting criteria for neuromyelitis optica (Wingerchuk et al 2006) or tested positive for aquaporin 4 (AQP4) at Screening. Patients who tested positive for anti-MOG (applicable for patients enrolling in the new younger cohort in extension phase).
Patients treated with: •Systemic corticosteroids or adrenocorticotropic hormone (ACTH) in the 30 days prior to Screening MRI scan •High dose intravenous immunoglobulin within 2 months prior to randomization/first dose in the extension •Natalizumab within 3 months or teriflunomide within 3 ½ months prior to randomization/first dose in the extension •Immunosuppressive/immunomodulatory medications such as, azathioprine, methotrexate, laquinimod, ofatumumab, ocrelizumab within 6 months prior to randomization/first dose in the extension. •Alemtuzumab, cladribine, cyclophosphamide, mitoxantrone or rituximab at any time •Fingolimod at any time •The following antiarrhythmic drugs at Screening: Class Ia (e.g. quinidine, disopyramide) or Class III (e.g. amiodarone, sotalol) anti-arrhythmics •Concurrently treated with heart-rate-lowering drugs at Screening e.g.: Beta blockers, heart-rate lowering calcium channel blockers (e.g. verapamil, diltiazem or ivabradine), digoxin, anticholinesteratic agents, pilocarpine. Advice from a cardiologist should be sought regarding the switch to non-heart-rate lowering medicinal products.
Patients diagnosed with macular edema during the screening period.
Patients with active systemic bacterial, viral or fungal infections, including tuberculosis.
Patients without acceptable evidence of immunity to varicella-zoster virus, mumps, measles, rubella, diphtheria, tetanus and pertussis at Randomization/first dose in the extension (See Appendix 3 Guidance on vaccinations for guidance on acceptable evidence of immunity and requirements for serologic testing).
Patients who have received any live or live attenuated vaccines (including for varicellazoster virus or measles) within one month prior to randomization/first dose in the extension.
Patients with a history or presence of malignancy.
Patients with any medically unstable condition, as assessed by the investigator.
Patients with any severe cardiac disease or significant findings on the screening ECG, such as: •History of symptomatic bradycardia or recurrent syncope •Known ischaemic heart disease •History of congenital heart disease (except conditions such as small patent ductus arteriosus, atrial septal defect, ventricular septal defect, or an ECG or rhythm abnormality, which have been assessed by a pediatric cardiologist and considered to be clinically insignificant). •Cerebrovascular disease •History of myocardial infarction •Congestive heart failure •History of cardiac arrest •Uncontrolled hypertension despite prescribed medications •Resting (sitting) heart rate <55 bpm (in patients 12 years or older) and <60 bpm (in patients below 12 years) •Severe untreated sleep apnea •Sick sinus syndrome or sino-atrial heart block •QTcF interval >450 msec in males and >460 msec in females or relevant risk factors for QT prolongation (e.g. hypokalaemia, hypomagnesemia, congenital QT prolongation) or treatment with QT prolonging drugs with a known risk of Torsades de pointes (e.g. citalopram, chlorpromazine, haloperidol, methadone, erythromycin) or history of familial long QT syndrome or known family history of Torsades de Pointes. •Second degree Mobitz type II or higher AV block
Patients with any pulmonary conditions, as determined by the investigator, including severe asthma defined as per the 2010 WHO uniform definition on severe asthma (Bousquet et al 2010).
Positive results of screening period testing for serological markers for hepatitis A, B, C and E indicating acute or chronic infection: •anti-HAV IgM •HBs Ag and/or anti-HBc IgM •anti-HCV IgG or HCV-RNA PCR •anti- HEV IgM or IgG (if positive IgG: do HEV-RNA PCR: if negative, patient can be included)
Patients with any of the following hepatic conditions: •Chronic liver or biliary disease, acute or chronic pancreatitis, with the exception of Gilbert’s syndrome; •Liver enzymes •ALT, AST, alkaline phosphatase, GGT, >2 x upper limit of normal (ULN) range for age (for pre-pubertal patients > 1 X ULN or > 2X ULN if currently treated with IFN or glatiramer acetate). Elevations of alkaline phosphatase should not be used in isolation to exclude subjects, and would require Investigator discretion. •Bilirubin elevations not in the context of Gilberts Syndrome: Total and conjugated bilirubin >1.5 X ULN (for pre-pubertal patients >1 X ULN or > 1.5 X ULN if currently treated with IFN or glatiramer acetate).
Patients with severe renal insufficiency (GFR <30 ml/min/1.73 m2).
Patients with lymphocyte count < 800 cells (mm3).
Patients with any of the following neurologic/psychiatric disorder: •History of any type of epileptic seizure(s) as well as psychogenic non-epileptic seizure(s) during the past 12 months before screening; •History of substance abuse (drug or alcohol) or any other factor (i.e., serious psychiatric condition) that may interfere with the subject’s ability to cooperate and comply with the study procedures; •Progressive neurological disorder, other than MS, which may affect participation in the study or require the use of medications not allowed by the protocol
Patients unable to undergo MRI scans, including claustrophobia or history of hypersensitivity to gadolinium-DTPA.
Pregnant or nursing females, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive HCG laboratory test
Female patients of childbearing potential, defined as all females physiologically capable of becoming pregnant, unless they agree to abstinence or, if sexually active, the use of contraception as defined in Section 6.6.
History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes.
Patients with a score of “yes” on item 4 or 5 of the Suicidal Ideation section of the C-SSRS, if this ideation occurred in the past 6 months, or with a score of “yes” on any item of the Suicidal Behavior section, except for “Non-Suicidal Self Injurious Behavior”, if this behavior occurred in the past 2 years.
Patients who have received an investigational drug or therapy within 180 days or 5 half-lives of randomization, whichever is longer.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
France	Not Recruiting	26 Jul 2013	25
Germany	Not Recruiting	26 Jul 2013	1
Romania	Not Recruiting	26 Jul 2013	3
Slovakia	Not Recruiting	26 Jul 2013	5
Spain	Not Recruiting	26 Jul 2013	1