Clinical trial NCT02201108: Efficacy, Safety and Pharmacokinetics of Teriflunomide in Pediatric Patients With Relapsing Forms of Multiple Sclerosis
Official title: A Two Year, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Trial to Evaluate Efficacy, Safety, Tolerability, and Pharmacokinetics of Teriflunomide Administered Orally Once Daily in Pediatric Patients With Relapsing Forms of Multiple Sclerosis Followed by an Open-Label Extension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Sclerosis
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2014-07-25
Enrollment: 166
Sex: ALL
Minimum age (years): 10
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Primary Objective:

To assess the effect of teriflunomide in comparison to placebo on disease activity measured by time to first clinical relapse after randomization in children and adolescents 10 to 17 years of age with relapsing forms of multiple sclerosis (MS).

Secondary Objective:

* To assess the effect of teriflunomide in comparison to placebo on disease activity/progression measured by brain magnetic resonance imaging (MRI) and on cognitive function.
* To evaluate the safety and tolerability of teriflunomide in comparison to placebo.
* To evaluate the pharmacokinetics (PK) of teriflunomide.

Detailed description: The study duration included a screening period up to 4 weeks, a double-blind treatment period of up to 96 weeks, an open-label period which included the remainder of the initial 96 weeks, where applicable, and a 96-week extension, i.e., up to a maximum of 192 weeks after randomization. There was a follow-up period of 4 weeks for participants discontinuing treatment.

Within the 96 weeks double-blind treatment period, the first 4 weeks were PK run-in phase in which PK samples (blood samples) were collected from participants and then 4 weeks of analysis (no samples drawn). The PK run-in phase (total 8 weeks) was intended to provide individual PK parameters to allow the dose adjustment to the 14 milligrams (mg) adult-equivalent dose for the rest of the study.

Participants who experienced a relapse after the PK run-in phase (8 weeks) and confirmed by the Relapse Adjudication Panel and participants who fulfilled MRI criteria (high number of new lesions at weeks 36, 48 or 72 compared to previous images) had the option to continue in an open-label teriflunomide treatment arm up to 192 weeks from randomization.

An optional additional extension period was available for young participants with teriflunomide until the participants are 18 years old and/or able to switch to commercial product, whichever comes first.

Eligibility criteria: * Participants with relapsing MS were eligible. Participants who met the criteria of MS based on McDonald criteria 2010 and International Pediatric Multiple Sclerosis Study Group (IPMSSG) criteria for pediatric MS, version of 2012 and had:

  * at least one relapse (or attack) in the 12 months preceding screening or,
  * at least two relapses (or attack) in the 24 months preceding screening.
* Less than 18 years of age and greater than or equal to (\>=) 10 years of age at randomization. Specific for the Russian Federation from 18 December 2014 to 26 July 2016, less than or equal to 17 years of age and \>= 13 years of age at randomization.
* Signed informed consent/assent obtained from participant and participant's legal representative (parents or guardians) according to local regulations.

Exclusion criteria:

* Expanded disability status scale score greater than 5.5 at screening or randomization visits.
* Relapse within 30 days prior to randomization.
* Treated with:

  * glatiramer acetate, interferons, or dimethyl fumarate within 1 month prior to randomization.
  * fingolimod, or intravenous immunoglobulins within 3 months prior to randomization.
  * natalizumab, other immunosuppressant or immunomodulatory agents such as cyclophosphamide, azathioprine, cyclosporine, methotrexate, mycophenolate, within 6 months prior to randomization.
  * cladribine or mitoxantrone within 2 years prior to randomization.
* Treated with alemtuzumab at any time.
* History of human immunodeficiency virus infection.
* Contraindication for MRI.
* Pregnant or breast-feeding females or those who plan to become pregnant during the study.
* Female participants of child-bearing potential not using highly effective contraceptive method (contraception in both female and male was required).

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Primary outcomes:
measure: Time to First Confirmed Clinical Relapse
timeFrame: Baseline up to Week 96
Secondary outcomes:
measure: Probability of Participants Who Were Clinical Relapse Free at Weeks 24, 48, 72, 96, 120, 144, 168 and 192
timeFrame: Weeks 24, 48, 72, 96, 120, 144, 168 and 192
measure: Brain Magnetic Resonance Imaging (MRI) Assessment: Number of New or Enlarged T2 Lesions Per MRI Scan
timeFrame: Baseline up to Week 192
measure: Brain Magnetic Resonance Imaging Assessment: Number of T1 Gadolinium (Gd)-Enhancing T1 Lesions Per MRI Scan
timeFrame: Baseline up to Week 192
measure: Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192
timeFrame: Baseline, DB period: Weeks 24, 36, 48, 72 and 96; OL period: Weeks 48, 96, 144 and 192
measure: Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions
timeFrame: Baseline, DB period: Weeks 24, 36, 48, 72 and 96; OL period: Weeks 48, 96, 144 and 192
measure: Brain Magnetic Resonance Imaging Assessment: Number of New T1 Hypointense Lesions Per MRI Scan
timeFrame: Baseline up to Week 192
measure: Brain Magnetic Resonance Imaging Assessment: Percentage of Participants Free of New or Enlarged MRI T2-Lesions
timeFrame: Baseline, Weeks 24, 48, 72, 96, 144 and 192
measure: Brain Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192
timeFrame: Baseline, DB period: Weeks 24, 36, 48, 72 and 96; OL period: Weeks 48, 96, 144 and 192
measure: Cognitive Assessment: Change From Baseline in Total Number of Correct Substitutions Measured by Symbol Digit Modalities Test (SDMT) at Weeks 24, 48, 72, 96, 120, 144, 168 and 192
timeFrame: Baseline, DB period: Weeks 24, 48, 72 and 96; OL period: Weeks 24, 48, 72, 96, 120, 144, 168 and 192
measure: Cognitive Assessment: Change From Baseline in Number of Completed Items Measured by Symbol Digit Modalities Test at Weeks 24, 48, 72, 96, 120, 144, 168 and 192
timeFrame: Baseline, DB period: Weeks 24, 48, 72 and 96; OL period: Weeks 24, 48, 72, 96, 120, 144, 168 and 192
measure: Cognitive Assessment: Change From Baseline in Brief Visuospatial Memory Test-Revised (BVMT-R) Scores at Weeks 96 and 192
timeFrame: Baseline, Weeks 96 and 192
measure: Cognitive Assessment: Change From Baseline in Trail Making Test- Part A (TMT-A) Test Scores (in Seconds) at Week 96 and 192
timeFrame: Baseline, Weeks 96 and 192
measure: Cognitive Assessment: Change From Baseline in Trail Making Test B (TMT-B) Test Scores (in Seconds) at Weeks 96 and 192
timeFrame: Baseline, Weeks 96 and 192
measure: Cognitive Assessment: Change From Baseline in Beery Visual-motor Integration (BVMI) Scores at Weeks 96 and 192
timeFrame: Baseline, Weeks 96 and 192
measure: Cognitive Assessment: Change From Baseline in Wechsler Abbreviated Scale of Intelligence-II (WASI-II) Vocabulary Total Raw Scores at Weeks 96 and 192
timeFrame: Baseline, Weeks 96 and 192
measure: Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System (D-KEFS) Letter Fluency Total Correct Raw Score at Weeks 96 and 192
timeFrame: Baseline, Weeks 96 and 192
measure: Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System Category Fluency Total Correct Raw Score at Weeks 96 and 192
timeFrame: Baseline, Weeks 96 and 192
measure: Cognitive Assessment - Selective Reminding Test (SRT): Change From Baseline in Total Number of Words on Delayed Recall at Weeks 96 and 192
timeFrame: Baseline, Weeks 96 and 192
measure: DB: Pharmacokinetics: Steady-state Trough Concentration (Ctrough) of Teriflunomide
timeFrame: Predose on Week 36
measure: OL: Time to First Confirmed Clinical Relapse
timeFrame: Baseline up to Week 192
measure: OL: Pharmacokinetics: Steady-state Trough Concentration (Ctrough) of Teriflunomide
timeFrame: Pre-dose at Week 36
Other outcomes:
Locations:
city: Cullman
country: United States
facility: North Central Neurology Associates, PC Site Number : 840003
state: Alabama
city: Tampa
country: United States
facility: Axiom Clinical Research of Florida Site Number : 840012
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital Site Number : 840002
state: Massachusetts
city: Raleigh
country: United States
facility: Raleigh Neurology Associates Site Number : 840004
state: North Carolina
city: Gent
country: Belgium
facility: Investigational Site Number : 056002
city: Leuven
country: Belgium
facility: Investigational Site Number : 056001
city: Sofia
country: Bulgaria
facility: Investigational Site Number : 100001
city: Calgary
country: Canada
facility: Investigational Site Number : 124001
state: Alberta
city: Beijing
country: China
facility: Investigational Site Number : 156001
city: Beijing
country: China
facility: Investigational Site Number : 156002
city: Beijing
country: China
facility: Investigational Site Number : 156010
city: Changchun
country: China
facility: Investigational Site Number : 156006
city: Changsha
country: China
facility: Investigational Site Number : 156007
city: Chengdu
country: China
facility: Investigational Site Number : 156008
city: Chongqing
country: China
facility: Investigational Site Number : 156005
city: Guangzhou
country: China
facility: Investigational Site Number : 156012
city: Shanghai
country: China
facility: Investigational Site Number : 156003
city: Shanghai
country: China
facility: Investigational Site Number : 156004
city: Shijiazhuang
country: China
facility: Investigational Site Number : 156011
city: Taiyuan
country: China
facility: Investigational Site Number : 156009
city: Tallinn
country: Estonia
facility: Investigational Site Number : 233001
city: Le Kremlin Bicetre
country: France
facility: Investigational Site Number : 250001
city: Lyon Cedex 03
country: France
facility: Investigational Site Number : 250002
city: Rennes Cedex
country: France
facility: Investigational Site Number : 250003
city: Toulouse
country: France
facility: Investigational Site Number : 250005
city: Athens
country: Greece
facility: Investigational Site Number : 300002
city: Thessaloniki
country: Greece
facility: Investigational Site Number : 300001
city: Jerusalem
country: Israel
facility: Investigational Site Number : 376001
city: Tel HaShomer
country: Israel
facility: Investigational Site Number : 376003
city: Beirut
country: Lebanon
facility: Investigational Site Number : 422001
city: Kaunas
country: Lithuania
facility: Investigational Site Number : 440001
city: FES
country: Morocco
facility: Investigational Site Number : 504004
city: Marrakech
country: Morocco
facility: Investigational Site Number : 504005
city: Rotterdam
country: Netherlands
facility: Investigational Site Number : 528001
city: Skopje
country: North Macedonia
facility: Investigational Site Number : 807001
city: Stip
country: North Macedonia
facility: Investigational Site Number : 807002
city: Coimbra
country: Portugal
facility: Investigational Site Number : 620001
city: Moscow
country: Russian Federation
facility: Investigational Site Number : 643001
city: Nizhny Novgorod
country: Russian Federation
facility: Investigational Site Number : 643003
city: Novosibirsk
country: Russian Federation
facility: Investigational Site Number : 643004
city: Saint-Petersburg
country: Russian Federation
facility: Investigational Site Number : 643005
city: Saint-Petersburg
country: Russian Federation
facility: Investigational Site Number : 643002
city: Belgrade
country: Serbia
facility: Investigational Site Number : 688002
city: Murcia
country: Spain
facility: Investigational Site Number : 724002
city: La Manouba
country: Tunisia
facility: Investigational Site Number : 788001
city: Sfax
country: Tunisia
facility: Investigational Site Number : 788002
city: Sfax
country: Tunisia
facility: Investigational Site Number : 788004
city: Ankara
country: Turkey
facility: Investigational Site Number : 792002
city: Ankara
country: Turkey
facility: Investigational Site Number : 792001
city: Istanbul
country: Turkey
facility: Investigational Site Number : 792006
city: Istanbul
country: Turkey
facility: Investigational Site Number : 792003
city: Izmir
country: Turkey
facility: Investigational Site Number : 792008
city: İzmir
country: Turkey
facility: Investigational Site Number : 792007
city: Kharkiv
country: Ukraine
facility: Investigational Site Number : 804001
city: Kharkiv
country: Ukraine
facility: Investigational Site Number : 804002
city: London
country: United Kingdom
facility: Investigational Site Number : 826001
state: London, City Of
city: Birmingham
country: United Kingdom
facility: Investigational Site Number : 826003
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Chitnis T, Banwell B, Kappos L, Arnold DL, Gucuyener K, Deiva K, Skripchenko N, Cui LY, Saubadu S, Hu W, Benamor M, Le-Halpere A, Truffinet P, Tardieu M; TERIKIDS Investigators. Safety and efficacy of teriflunomide in paediatric multiple sclerosis (TERIKIDS): a multicentre, double-blind, phase 3, randomised, placebo-controlled trial. Lancet Neurol. 2021 Dec;20(12):1001-1011. doi: 10.1016/S1474-4422(21)00364-1.