Safety and Efficacy of Fingolimod in Pediatric Patients With Multiple Sclerosis

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

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

Study Overview

• Status: Recruiting
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Drug: Fingolimod; Drug: Placebo capsule; Drug: Interferon beta-1a; Drug: Placebo i.m. injection

Detailed Description

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

• Study Type: Interventional
• Enrollment (Estimated): 235
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Novartis Pharmaceuticals; Phone Number: 1-888-669-6682; Email: novartis.email@novartis.com
• Study Contact Backup: Name: Novartis Pharmaceuticals; Phone Number: +41613241111

Study Locations

• Australia
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Active, not recruiting
      • Novartis Investigative Site
• Austria
  • Vienna, Austria, 1090
    • Completed
    • Novartis Investigative Site
• Belarus
  • Minsk, Belarus, 220114
    • Completed
    • Novartis Investigative Site
• Brazil
  • Goiania, Brazil, 74605 020
    • Completed
    • Novartis Investigative Site
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30150 221
      • Completed
      • Novartis Investigative Site
  • RJ
    • Rio de Janeiro, RJ, Brazil, 20270-004
      • Completed
      • Novartis Investigative Site
  • SP
    • Sao Paulo, SP, Brazil, 05403-000
      • Completed
      • Novartis Investigative Site
• Bulgaria
  • Sofia, Bulgaria, 1113
    • Completed
    • Novartis Investigative Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Completed
      • Novartis Investigative Site
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L1
      • Completed
      • Novartis Investigative Site
• Croatia
  • Osijek, Croatia, 31000
    • Completed
    • Novartis Investigative Site
• Estonia
  • Tallinn, Estonia, 10617
    • Terminated
    • Novartis Investigative Site
• France
  • Bordeaux Cedex, France, 33076
    • Completed
    • Novartis Investigative Site
  • Le Kremlin Bicetre, France, 94275
    • Recruiting
    • Novartis Investigative Site
  • Marseille Cedex 05, France, 13885
    • Completed
    • Novartis Investigative Site
  • Montpellier, France, 34295
    • Recruiting
    • Novartis Investigative Site
  • Toulouse Cedex, France, 31059
    • Completed
    • Novartis Investigative Site
• Germany
  • Bochum, Germany, 44791
    • Completed
    • Novartis Investigative Site
  • Bonn, Germany, 53111
    • Withdrawn
    • Novartis Investigative Site
  • Dresden, Germany, 01307
    • Completed
    • Novartis Investigative Site
  • Erlangen, Germany, 91054
    • Completed
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Withdrawn
    • Novartis Investigative Site
  • Freiburg, Germany, 79106
    • Active, not recruiting
    • Novartis Investigative Site
  • Gottingen, Germany, 37075
    • Completed
    • Novartis Investigative Site
  • Hamburg, Germany, 20246
    • Withdrawn
    • Novartis Investigative Site
  • Muenchen, Germany, 80337
    • Withdrawn
    • Novartis Investigative Site
  • Muenster, Germany, 48149
    • Withdrawn
    • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80131
    • Withdrawn
    • Novartis Investigative Site
  • BA
    • Bari, BA, Italy, 70124
      • Terminated
      • Novartis Investigative Site
  • BS
    • Montichiari, BS, Italy, 25018
      • Completed
      • Novartis Investigative Site
  • CT
    • Catania, CT, Italy, 95123
      • Active, not recruiting
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20132
      • Completed
      • Novartis Investigative Site
  • PA
    • Cefalu, PA, Italy, 90015
      • Terminated
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00133
      • Terminated
      • Novartis Investigative Site
    • Roma, RM, Italy, 00189
      • Active, not recruiting
      • Novartis Investigative Site
  • VA
    • Gallarate, VA, Italy, 21013
      • Completed
      • Novartis Investigative Site
• Latvia
  • Riga, Latvia, LV-1004
    • Completed
    • Novartis Investigative Site
• Lithuania
  • LTU
    • Kaunas, LTU, Lithuania, LT 50161
      • Completed
      • Novartis Investigative Site
• Mexico
  • D F
    • Ciudad De Mexico, D F, Mexico, 06700
      • Active, not recruiting
      • Novartis Investigative Site
  • Distrito Federal
    • Mexico, Distrito Federal, Mexico, 04530
      • Withdrawn
      • Novartis Investigative Site
    • Mexico, Distrito Federal, Mexico, 06720
      • Withdrawn
      • Novartis Investigative Site
    • Mexico, Distrito Federal, Mexico, 03310
      • Completed
      • Novartis Investigative Site
  • Yucatán
    • Merida, Yucatán, Mexico, 97125
      • Withdrawn
      • Novartis Investigative Site
• Netherlands
  • Rotterdam, Netherlands, 3015 CN
    • Completed
    • Novartis Investigative Site
• Poland
  • Lodz, Poland, 93-338
    • Completed
    • Novartis Investigative Site
  • Lublin, Poland, 20-093
    • Completed
    • Novartis Investigative Site
  • Poznan, Poland, 60-355
    • Completed
    • Novartis Investigative Site
  • Wroclaw, Poland, 50 420
    • Completed
    • Novartis Investigative Site
• Puerto Rico
  • Santurce, Puerto Rico, 00912
    • Completed
    • Novartis Investigative Site
• Romania
  • Bucuresti, Romania, 041914
    • Active, not recruiting
    • Novartis Investigative Site
• Russian Federation
  • Kazan, Russian Federation, 420043
    • Completed
    • Novartis Investigative Site
  • Moscow, Russian Federation, 119602
    • Completed
    • Novartis Investigative Site
  • Moscow, Russian Federation, 119991
    • Completed
    • Novartis Investigative Site
  • Novosibirsk, Russian Federation, 630087
    • Active, not recruiting
    • Novartis Investigative Site
  • St. Petersburg, Russian Federation, 197110
    • Completed
    • Novartis Investigative Site
• Serbia
  • Belgrade, Serbia, 11000
    • Recruiting
    • Novartis Investigative Site
  • Kragujevac, Serbia, 34000
    • Withdrawn
    • Novartis Investigative Site
  • Novi Sad, Serbia, 21000
    • Recruiting
    • Novartis Investigative Site
• Slovakia
  • Slovensko
    • Bratislava, Slovensko, Slovakia, 83340
      • Active, not recruiting
      • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28034
    • Recruiting
    • Novartis Investigative Site
  • Madrid, Spain, 28006
    • Active, not recruiting
    • Novartis Investigative Site
  • Andalucia
    • Malaga, Andalucia, Spain, 29010
      • Recruiting
      • Novartis Investigative Site
    • Sevilla, Andalucia, Spain, 41009
      • Completed
      • Novartis Investigative Site
  • Barcelona
    • Esplugues De Llobregat, Barcelona, Spain, 08950
      • Recruiting
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Withdrawn
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46010
      • Completed
      • Novartis Investigative Site
  • Pais Vasco
    • Barakaldo, Pais Vasco, Spain, 48903
      • Completed
      • Novartis Investigative Site
  • Pontevedra
    • Vigo, Pontevedra, Spain, 36212
      • Active, not recruiting
      • Novartis Investigative Site
• Sweden
  • Lund, Sweden, 221 85
    • Withdrawn
    • Novartis Investigative Site
• Turkey
  • Ankara, Turkey, 06500
    • Completed
    • Novartis Investigative Site
  • Ankara, Turkey, 06100
    • Completed
    • Novartis Investigative Site
  • Izmir, Turkey, 35340
    • Completed
    • Novartis Investigative Site
  • Konak-Izmir, Turkey, 35210
    • Withdrawn
    • Novartis Investigative Site
  • Samsun, Turkey, 55139
    • Completed
    • Novartis Investigative Site
  • TUR
    • Istanbul, TUR, Turkey, 34098
      • Completed
      • Novartis Investigative Site
• Ukraine
  • Cherkasy, Ukraine, 18000
    • Recruiting
    • Novartis Investigative Site
  • Dnipropetrovsk, Ukraine, 49027
    • Recruiting
    • Novartis Investigative Site
  • Kharkiv, Ukraine, 61068
    • Recruiting
    • Novartis Investigative Site
  • Kharkiv, Ukraine, 61091
    • Withdrawn
    • Novartis Investigative Site
  • Kiev, Ukraine, 03110
    • Completed
    • Novartis Investigative Site
  • Lviv, Ukraine, 79010
    • Recruiting
    • Novartis Investigative Site
  • Odesa, Ukraine, 65009
    • Completed
    • Novartis Investigative Site
  • Vinnytsa, Ukraine, 21029
    • Completed
    • Novartis Investigative Site
• United Kingdom
  • Edinburgh, United Kingdom, EH9 1LF
    • Recruiting
    • Novartis Investigative Site
  • London, United Kingdom, WC1N 1EH
    • Recruiting
    • Novartis Investigative Site
  • London, United Kingdom, WC1N 3BG
    • Withdrawn
    • Novartis Investigative Site
  • Birmingham
    • West Midlands, Birmingham, United Kingdom, B4 6NH
      • Completed
      • Novartis Investigative Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Completed
      • Novartis Investigative Site
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Withdrawn
      • Novartis Investigative Site
  • California
    • Los Angeles, California, United States, 90027
      • Recruiting
      • Novartis Investigative Site
      • Contact: Martha E. Arellano-Garcia; Phone Number: 323-361-5812; Email: margarcia@chla.usc.edu
    • San Francisco, California, United States, 94115
      • Completed
      • Novartis Investigative Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Withdrawn
      • Novartis Investigative Site
  • Florida
    • Miami, Florida, United States, 33136
      • Completed
      • Novartis Investigative Site
    • Orlando, Florida, United States, 32819
      • Withdrawn
      • Novartis Investigative Site
    • Tallahassee, Florida, United States, 32312
      • Completed
      • Novartis Investigative Site
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Withdrawn
      • Novartis Investigative Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Withdrawn
      • Novartis Investigative Site
    • Boston, Massachusetts, United States, 02114
      • Completed
      • Novartis Investigative Site
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Completed
      • Novartis Investigative Site
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Completed
      • Novartis Investigative Site
  • New York
    • Rochester, New York, United States, 14642
      • Withdrawn
      • Novartis Investigative Site
    • Stony Brook, New York, United States, 11794
      • Withdrawn
      • Novartis Investigative Site
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-9500
      • Withdrawn
      • Novartis Investigative Site
    • Durham, North Carolina, United States, 27710
      • Withdrawn
      • Novartis Investigative Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104 4399
      • Completed
      • Novartis Investigative Site
  • South Carolina
    • Greenville, South Carolina, United States, 29607
      • Withdrawn
      • Novartis Investigative Site
  • Texas
    • San Antonio, Texas, United States, 78229
      • Withdrawn
      • Novartis Investigative Site
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • Completed
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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.

1. 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
2. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fingolimod; 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; Administrated orally once daily: 0.5 mg capsule for patients over 40 kg or 0.25 mg capsule for patients 40 kg or less.; Drug: Placebo capsule; Matching placebo capsule required for double-dummy masking to blind formulations.
Active Comparator: Interferon beta-1a; 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; Administration once weekly via i.m. injections.; Drug: Placebo i.m. injection; Matching placebo i.m. injection required for double-dummy masking to blind formulations.
Experimental: Fingolimod-Younger Cohort; 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; Administrated orally once daily: 0.5 mg capsule for patients over 40 kg or 0.25 mg capsule for patients 40 kg or less.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Deiva K, Huppke P, Banwell B, Chitnis T, Gartner J, Krupp L, Waubant E, Stites T, Pearce GL, Merschhemke M. Consistent control of disease activity with fingolimod versus IFN beta-1a in paediatric-onset multiple sclerosis: further insights from PARADIGMS. J Neurol Neurosurg Psychiatry. 2020 Jan;91(1):58-66. doi: 10.1136/jnnp-2019-321124. Epub 2019 Aug 29.
• Chitnis T, Arnold DL, Banwell B, Bruck W, Ghezzi A, Giovannoni G, Greenberg B, Krupp L, Rostasy K, Tardieu M, Waubant E, Wolinsky JS, Bar-Or A, Stites T, Chen Y, Putzki N, Merschhemke M, Gartner J; PARADIGMS Study Group. Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis. N Engl J Med. 2018 Sep 13;379(11):1017-1027. doi: 10.1056/NEJMoa1800149.

Helpful Links

• Recruitment website

Study record dates

Study Major Dates

• Study Start (Actual): July 26, 2013
• Primary Completion (Actual): July 14, 2017
• Study Completion (Estimated): July 12, 2029

Study Registration Dates

• First Submitted: May 8, 2013
• First Submitted That Met QC Criteria: July 1, 2013
• First Posted (Estimated): July 4, 2013

Study Record Updates

• Last Update Posted (Actual): April 23, 2024
• Last Update Submitted That Met QC Criteria: April 22, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: MS; pediatric; adolescent; children; multiple sclerosis; fingolimod; pre-pubertal; low weight; core phase; extension phase; younger cohort
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Adjuvants, Immunologic; Sphingosine 1 Phosphate Receptor Modulators; Interferons; Interferon beta-1a; Fingolimod Hydrochloride; Interferon-beta
• Other Study ID Numbers: CFTY720D2311; 2011-005677-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No