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 β-1a i.m. once weekly in pediatric patients with multiple sclerosis with five-year fingolimod Extension Phase

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

26 Jul 2013 → ongoing

Decision date (initial)

2024-04-04

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Organization Novartis Pharma AG

External identifiers

EU CT number

2023-507556-68-00

EudraCT number

2011-005677-23

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

•To examine long-term safety, tolerability and efficacy parameters in patients treated with fingolimod
•To examine the effects of fingolimod on safety, tolerability and efficacy parameters in patients who were treated with interferon-β-1a in the Core Phase.
•To explore the long-term effects of fingolimod in patients on cognitive function and physical and sexual development.

Conditions and MedDRA coding

Multiple Sclerosis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 3

1. 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.
2. 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.
3. 2. Central review (including initial MRI report) of the diagnosis of pediatric MS (Thompson et al 2018) will be required for all newly recruited patients

Exclusion criteria 24

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 at Screening.
3. Patients with widespread and symmetric white matter alterations in the Screening MRI suggestive of other demyelinating disorders (e.g. metabolic disorders, mitochondrialdisorders).
4. 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).
5. 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.
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 varicellazoster 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: •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
13. 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).
14. 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)
15. 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).
16. Patients with severe renal insufficiency (GFR <30 ml/min/1.73 m2).
17. Patients with lymphocyte count < 800 cells (mm3).
18. 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
19. Patients unable to undergo MRI scans, including claustrophobia or history of hypersensitivity to gadolinium-DTPA.
20. 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
21. 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.
22. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes.
23. 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.
24. Patients who have received an investigational drug or therapy within 180 days or 5 half-lives of randomization, whichever is longer.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Annualized relapse rate (ARR) and time to relapse
2. The annualized rate of new/newly enlarged T2 lesion
3. Patients free of new or newly enlarged T2 lesions

Secondary endpoints 5

1. The number of Gd-enhanced T1 lesions
2. Patients free of Gd-enhanced T1 lesions
3. Number of CUA lesions
4. Change from baseline in T2 lesion/ T1 hypointense lesion volume
5. Percent brain volume change

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel Town

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 12

Locations

5 EU/EEA countries · 17 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 83 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications