Safety and efficacy of fingolimod in pediatric patients with multiple sclerosis

• Register: EUCTR
• Last refreshed on: 16 May 2022
• Main ID: EUCTR2011-005677-23-AT
• Date of registration: 19/12/2013
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Services AG
• Public title: Safety and efficacy of fingolimod in pediatric patients with multiple sclerosis
• Scientific title: A two-year, double-blind, randomized, multicenter, active-controlled Core Phase study to evaluate the safety and efficacy of fingolimod administered orally once daily versus interferon ß-1a i.m. once weekly in pediatric patients with multiple sclerosis with five-year fingolimod Extension Phase
• Date of first enrolment: 24/01/2014
• Target sample size: 240
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-005677-23
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Austria, Belarus, Brazil, Bulgaria, Canada, Croatia, Estonia, France, Germany, Italy, Latvia, Lithuania, Mexico, Netherlands, Poland, Romania, Russian Federation, Serbia, Slovakia, South Africa, Spain, Sweden, Turkey, Ukraine, United Kingdom, United States

Contacts

• Name: Drug Regulatory Affairs
• Affiliation: Novartis Pharma GmbH

• Name: Drug Regulatory Affairs
• Affiliation: Novartis Pharma GmbH

Key inclusion & exclusion criteria

Inclusion criteria:
Core Phase:
1. Written informed consent / assent must be obtained before any assessment is performed.
2. Male and female patients aged 10-17 years old*, inclusive (i.e., have not yet had their 18th birthday) at randomization.
3. A diagnosis of MS as defined by the revised consensus definition for pediatric MS, (Krupp et al 2013, Polman et al 2011).
4. Central review of the diagnosis of pediatric MS will be required for all patients prior to randomization.
5. At least one MS relapse/attack during the previous year or two MS relapses in the previous two years prior to screening, or evidence of one or more Gd enhancing lesions on MRI within 6 months prior to randomization (including screening MRI).
6. Expanded Disability Status Scale (EDSS) score of 0 to 5.5, inclusive.
*Exception: If, in a specific country, use of interferon-ß-1a IM in children below a certain age is included in the Contraindications section of Avonex (interferon-ß-1a IM) local product information, inclusion of such patients is not permitted in that country. E.g. the Russian Avonex product information lists use in children below the age of 12 years as a contraindication.

Fingolimod Extension Phase:
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.
Criterion apply 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).
•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 (Thompson et al 2018) will be required for all newly recruited patients.
Are the trial subjects under 18? yes
Number of subjects for this age range: 240
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
Core & Extension Phase:
1. Patients with progressive MS.
2. 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.
3. Patients with widespread and symmetric white matter alterations in the Screening MRI suggestive of other demyelinating disorders (e.g. metabolic disorders, mitochondrial disorders).
4. Patients meeting the definition of ADEM (Krupp et al 2013); patients meeting critieria for neuromyelitis optica (Wingerchuk et al 2006) or tested positive for aquaporin 4 (AQP4) at Screening; Patients who have tested positive for anti-MOG (applicable for patients enrolling in the new younger cohort in extension phase).
5. Patients treated with:
o Systemic corticosteroids or adrenocorticotropic hormone (ACTH) in the 30 days prior to Screening MRI scan
o High dose intravenous immunoglobulin within 2 months prior to randomization/first dose in the extension
o Natalizumab within 3 months or teriflunomide within 3 ½ months prior to randomization/ first dose in the extension
o Immunosuppressive/immunomodulatory medications such as azathioprine, methotrexate, laquinimod, ofatumumab, ocrelizumab within 6 months prior to randomization/ first dose in the extension
o Alemtuzumab, cladribine, cyclophosphamide, mitoxantrone or rituximab at any time
o Fingolimod at any time
o The following antiarrhythmic drugs at Screening: Class Ia (e.g. quinidine, disopyramide) or Class III (e.g. amiodarone, sotalol) anti-arrhythmics
o 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-heartrate lowering medicinal products.
6. Patients diagnosed with macular edema during the screening period.
7. Patients with active systemic bacterial, viral or fungal infections, including tuberculosis.
8. 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).
9. Patients who have received any live or live attenuated vaccines (including for varicella-zoster virus or measles) within one month prior to randomization/ first dose in the extension.
10. Patients with a history or presence of malignancy.
11. Patients with any medically unstable condition, as assessed by the investigator.
12. Patients with any severe cardiac disease or significant findings on the screening ECG, such as:
o History of symptomatic bradycardia or recurrent syncope
o Known ischaemic heart disease
o 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).
o Cerebrovascular disease
o History of myocardial infarction
o Congestive heart failure
o History of cardiac arrest
o Uncontrolled hypertension despite prescribed medications
o Resting (sitting) hear

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Relapsing multiple sclerosis
MedDRA version: 20.0 Level: PT Classification code 10048393 Term: Multiple sclerosis relapse System Organ Class: 10029205 - Nervous system disorders

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Trade Name: Gilenya
Product Name: Gilenya
Product Code: FTY720
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: fingolimod
CAS Number: 162359-56-0
Current Sponsor code: FTY720
Other descriptive name: FINGOLIMOD HYDROCHLORIDE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.5-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Trade Name: Avonex
Product Name: Avonex
Pharmaceutical Form: Solution for injection in pre-filled syringe
INN or Proposed INN: interferon beta-1a
CAS Number: 220581-49-7
Other descriptive name: INTERFERON BETA-1A
Concentration unit: µg/ml microgram(s)/millilitre
Concentration type: equal
Concentration number: 60 -
Pharmaceutical form of the placebo: Solution for injection in pre-filled syringe
Route of administration of the placebo: Intramuscular use

Product Name: fingolimod
Product Code: FTY720
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: fingolimod
CAS Number: 162359-56-0
Current Sponsor code: FTY720
Other descriptive name: FINGOLIMOD HYDROCHLORIDE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.25-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: up to 24 months

Main Objective: Core Phase:
To evaluate the efficacy of fingolimod relative to intramuscular IFN ß-1a in reducing the frequency of relapses as assessed by the annualized relapse rate in children/adolescent MS patients aged 10 to less than 18 years treated for up to 24 months.

Primary end point(s): To evaluate the efficacy of fingolimod relative to intramuscular interferon B-1a in reducing the frequency of relapses as assess by the annualized relapse rate (ARR) in children/adolescent MS patients aged 10 to less than 18 years treated for up to 24 months.

Secondary Objective: To evaluate the efficacy of fingolimod relative to IFN ß-1a in reducing the number of new/newly enlarging T2 (n/neT2) lesions in children/adolescent MS patients aged 10 to less than 18 years treated for up to 24 months.
Other secondary objectives
• To evaluate the safety of fingolimod relative to IFN ß-1a in children/adolescent MS patients.
• To evaluate the effect of fingolimod relative to IFN ß-1a in children/adolescent MS patients on other relapse-related parameters:
o Time to first relapse
o Proportion of patients relapse-free
• To evaluate the effect of fingolimod relative to IFN ß-1a in children/adolescent MS patients on T1 Gd-enhancing lesions on brain MRI.
• To study the pharmacokinetics of fingolimod and fingolimod-P in children/adolescent MS patients treated for up to 24 months.

...

See the complete list of objectives including the Extension Phase objectives in the protocol

Secondary Outcome(s)

Secondary end point(s): To evaluate the efficacy of fingolimode relative to IFN B-1a in reducing the number of new/newly enlarging T2 (n/ne T2)lesions in children/adolescent MS patients aged 10 to less than 18 years treated for up to 24 months

Timepoint(s) of evaluation of this end point: up to 24 months

Secondary ID(s)

CFTY720D2311

2011-005677-23-IT

Source(s) of Monetary Support

Novartis Pharma Service AG

Ethics review

Status: Approved
Approval date: 14/01/2014
Contact: