Efficacy, Safety and Pharmacokinetics of Teriflunomide in Pediatric Patients With Relapsing Forms of Multiple Sclerosis (TERIKIDS)

• ClinicalTrials.gov Identifier: NCT02201108
• Recruitment Status: Active, not recruiting
• First Posted: July 25, 2014
• Results First Posted: November 30, 2020
• Last Update Posted: November 30, 2020
• Sponsor: Genzyme, a Sanofi Company
• Information provided by (Responsible Party): Sanofi ( Genzyme, a Sanofi Company )

Tracking Information

• First Submitted Date: July 17, 2014
• First Posted Date: July 25, 2014
• Results First Submitted Date: October 20, 2020
• Results First Posted Date: November 30, 2020
• Last Update Posted Date: November 30, 2020
• Actual Study Start Date: July 16, 2014
• Actual Primary Completion Date: October 25, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 27, 2020)

Time to First Confirmed Clinical Relapse [ Time Frame: Baseline up to Week 96 ]

Time to first clinical relapse was defined as the duration (in weeks) between randomization and first confirmed clinical relapse. Clinical relapses were defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon neurological examination and documented by a standardized, quantified functional system score (FSSs) which included 8 items and items were rated on different scales: brain stem, cerebellar and cerebral functions rated on a scale of 0 to 5; visual, pyramidal, sensory and bowel/bladder rated on a scale of 0 to 6 and ambulation on a scale of 0 to 12, where higher score in each scale indicated worsened neurological function. Confirmed clinical relapse were reviewed and confirmed by an independent Relapse Adjudication Panel (RAP). A participant without confirmed clinical relapse, was considered as clinical relapse free until the end of Week 96.

• Original Primary Outcome Measures (submitted: July 24, 2014): Time to first clinical relapse after randomization [ Time Frame: over 96 weeks ]

Current Secondary Outcome Measures (submitted: November 27, 2020)

• Probability of Participants Who Were Clinical Relapse Free at Weeks 24, 48, 72 and 96 [ Time Frame: Weeks 24, 48, 72 and 96 ]
  Participant was considered as free of clinical relapse if participant had no confirmed clinical relapse before treatment discontinuation/completion in 96 weeks treatment period. Clinical relapses:defined as new/recurrent neurological symptoms not associated with fever/infection, lasted at least 24 hours, and accompanied by new objective neurological findings upon neurological examination and documented by standardized, quantified FSSs which included 8 items;items were rated on different scales:brain stem, cerebellar and cerebral functions rated on scale of 0 to 5;visual, pyramidal, sensory and bowel/bladder rated on scale of 0 to 6 and ambulation on scale of 0 to 12, where higher score in each scale indicated worsened neurological function. New/recurrent symptoms that occurred less than 30 days following onset of relapse were considered part of same relapse. Probability of participants who were clinical relapse free at specified weeks was estimated by Kaplan-Meier method and reported.
• Magnetic Resonance Imaging (MRI) Assessment: Number of New or Enlarged T2 Lesions Per MRI Scan [ Time Frame: Baseline up to Week 96 ]
  Number of new or enlarged T2 lesions per scan was defined as the total number of new or enlarged T2 lesion that occurred during the 96 weeks treatment period divided by the total number of scans performed during 96 weeks. To account for the different numbers of scans performed among the participants, a negative binomial regression model with robust variance estimation was used. The model included the total number of new or enlarged T2-lesions as the response variable, with treatment group, region, pubertal status and age as covariates and log-transformed number of scans as an offset variable.
• Magnetic Resonance Imaging Assessment: Number of T1 Gadolinium (Gd)-Enhancing T1 Lesions Per MRI Scan [ Time Frame: Baseline up to Week 96 ]
  The number of T1 Gd-Enhancing lesions per scan was defined as the total number of lesions that occurred during the 96 weeks treatment period divided by the total number of scans performed during 96 weeks. To account for the different number of scans performed among the participants, a negative binomial regression model with robust variance estimation was used. The model included the total number of T1-lesions as the response variable, with treatment group, region, pubertal status and age as covariates and log-transformed number of scans as an offset variable.
• Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 48, 72 and 96 [ Time Frame: Baseline, Weeks 24, 48, 72 and 96 ]
  Volume of T2 lesions was measured by MRI scan.
• Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions [ Time Frame: Baseline, Weeks 24, 48, 72 and 96 ]
  Volume of T1 hypointense lesions was measured by MRI scan.
• Magnetic Resonance Imaging Assessment: Number of New T1 Hypointense Lesions Per MRI Scan [ Time Frame: Baseline up to Week 96 ]
  The number of new T1 hypointense lesions were obtained from MRI scans.
• Magnetic Resonance Imaging Assessment: Percentage of Participants Free of New or Enlarged MRI T2-Lesions [ Time Frame: Weeks 48 and 96 ]
  Percentage of participants who were free of new or enlarged T2 lesions at Weeks 48 and 96 were reported.
• Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 48, 72 and 96 [ Time Frame: Baseline, Weeks 24, 48, 72 and 96 ]
  Percent change from baseline in brain volume (assessed using MRI scans of the Brain) at weeks 24, 48, 72 and 96 was reported.
• Cognitive Assessment: Change From Baseline in Total Number of Correct Substitutions Measured by Symbol Digit Modalities Test (SDMT) at Weeks 24, 48, 72 and 96 [ Time Frame: Baseline, Weeks 24, 48, 72 and 96 ]
  SDMT measures the time to pair abstract symbols with specific numbers. It is a simple substitution task that gives the examinee 90 seconds to pair specific numbers with given geometric figures as a measure for screening cognitive impairment. The score is the number of correct substitution and ranged from 0 (worst outcome) to 110 (best outcome), where higher score indicated better cognitive function.
• Cognitive Assessment: Change From Baseline in Number of Completed Items Measured by Symbol Digit Modalities Test at Weeks 24, 48, 72 and 96 [ Time Frame: Baseline, Weeks 24, 48, 72 and 96 ]
  SDMT measures the time to pair abstract symbols with specific numbers. It is a simple substitution task that gives the examinee 90 seconds to pair specific numbers with given geometric figures as a measure for screening cognitive impairment. The score is the number of completed items and ranged from 0 (worst outcome) to 110 (best outcome), where higher score indicated better cognitive function.
• Cognitive Assessment: Change From Baseline in Brief Visuospatial Memory Test-Revised (BVMT-R) Scores at Week 96 [ Time Frame: Baseline, Week 96 ]
  The BVMT consists of three trials in which participants must recall shapes by drawing figures on a blank page (response booklet) after being given the opportunity to memorize the figures (given in BMVT-R form) for 10 seconds. BMVT-R form consists of six figures. Points are awarded based on the accuracy of the drawn figure and by correct placement on the blank page. A minimum of 0 to 12 points/scores are awarded per trial, so a participant can score between 0 and 36 points for all three trials (by adding the points/score from each trial), where higher score indicates better outcome.
• Cognitive Assessment: Change From Baseline in Trail Making Test- Part A (TMT-A) Test Scores (in Seconds) at Week 96 [ Time Frame: Baseline, Week 96 ]
  'Trail Making Test Part A' is a neuropsychological test of visual attention and task switching. The task requires a participant to 'connect-the-dots' of 25 consecutive numbers (1,2, 3,etc.) in sequential order on a sheet of paper or computer screen. The goal of the participant is to finish the test as quickly as possible, and the time taken to complete the test used as the primary performance metric (in seconds). This is a timed test and the number of seconds to complete the task is recorded. Maximum time allowed is 300 seconds. A lower score indicates better cognitive function.
• Cognitive Assessment: Change From Baseline in Trail Making Test B (TMT-B) Test Scores (in Seconds) at Week 96 [ Time Frame: Baseline, Week 96 ]
  TMT-B is a cognitive test that gives a measure of various aspects of cognitive performance. It is used to measure cognitive fatigue. The test consists of 25 circles containing 13 sequential numbers (1-13) and 12 sequential letters (A-L) positioned. The test evaluates the time (in seconds) to correctly order letters and numbers in alternate order (1, A, 2, B etc.). Maximum time allowed is 300 seconds, where less time/lower score indicates better cognitive function/performance.
• Cognitive Assessment: Change From Baseline in Beery Visual-motor Integration (BVMI) Scores at Week 96 [ Time Frame: Baseline, Week 96 ]
  The Beery VMI is a non-verbal assessment that assessed the extent to which individuals can integrate their visual and motor abilities. The participants were provided with geometric designs ranging from simple line drawings to more complex figures and were asked to copy the designs. The test consisted of 24 figures. One point was scored for each successful copy of drawings and no scoring was given when the participant failed to copy the drawings properly. Each successful copying of drawings was summed up and the total was scored on a scale ranged from 0 to 24, where higher score indicated better visual construction skills/better visual and motor abilities and lower score indicated poor visual construction skills/poor visual and motor abilities.
• Cognitive Assessment: Change From Baseline in Wechsler Abbreviated Scale of Intelligence-II (WASI-II) Vocabulary Total Raw Scores at Week 96 [ Time Frame: Baseline, Week 96 ]
  The WASI-II: Vocabulary test is a quick estimate of an individual's level of intellectual functioning which comprised of 31 total items that require the participant to orally define 3 images and 28 words presented both orally and visually. Items 1 to 3 rated on a score of 0 or 1, items 4 and 5 rated on a score of 0 or 2, items 6 to 31 rated on a scale of 0 to 2. Each item score was summed up to derive the total score which was ranged from 0 (minimum score) to 59 (maximum score), where higher score indicated better level of intellectual functioning/higher level of intelligence.
• Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System (D-KEFS) Letter Fluency Total Correct Raw Score at Week 96 [ Time Frame: Baseline, Week 96 ]
  Letter Fluency is a condition measured in the Delis-Kaplan Executive Function System (D-KEFS). Participants are asked to name as many words as they can, starting with a specified letter for 60 seconds. The words cannot be names, places, numbers or grammatical variants of previous answers. Repeated answers are not scored as a correct response. There are 3 trials, with 3 different letters. The total number of correct responses is totaled for all 3 trials and a Letter Fluency Score is given. A higher score is considered better. There is no set range as the score depends on how many correct words the participant relays in the given time period.
• Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System Category Fluency Total Correct Raw Score at Week 96 [ Time Frame: Baseline, Week 96 ]
  Category Fluency is a condition measured in the D-KEFS. It measures participant's ability to generate words from three different categories (e.g., fruits, vegetables and animals), within a minute for each category. Total score is number of correct words for each category with no points for repetitions or non-words. Score range 0 to unlimited, where 0 = low score, higher score indicates better performance.
• Cognitive Assessment - Selective Reminding Test (SRT): Change From Baseline in Total Number of Words on Delayed Recall at Week 96 [ Time Frame: Baseline, Week 96 ]
  SRT is a test to assess verbal learning and memory. During the administration of the SRT only the examiner and the participant should be in the testing room. A list of twelve words is read aloud by the examiner at a rate of one word per two seconds. The participant is asked to recall all twelve words after a 30 minute delay. Only the words that are missed on the preceding trial are given in the consecutive trial. The total score represents a sum score of total 6 trials, therefore the range is from 0-72. The lower the value the worse the outcome, higher value indicates better recall.
• Pharmacokinetics: Steady-state Trough Concentration (Ctrough) of Teriflunomide [ Time Frame: Predose on Week 36 ]
  Ctrough was defined as the concentration reached by the drug before the next dose is administered. Data for this outcome measure was planned to be collected and analyzed separately for each dose of Teriflunomide.

Original Secondary Outcome Measures (submitted: July 24, 2014)

• Proportion of relapse free patients [ Time Frame: at 24, 48, 72 and 96 weeks ]
• Number of of new/newly enlarged T2 lesions [ Time Frame: at 24, 48, 72 and 96 weeks ]
• Number of T1 Gd-enhancing T1 lesions [ Time Frame: over 96 weeks ]
• Change in volume of T2 lesions [ Time Frame: over 96 weeks ]
• Change in volume of T1 hypointense lesions [ Time Frame: over 96 weeks ]
• Number of new T1 hypointense lesions [ Time Frame: over 96 weeks ]
• Proportion of patients free of new or enlarged MRI T2-lesions [ Time Frame: at 48 weeks and 96 weeks ]
• Brain atrophy [ Time Frame: over 96 weeks ]
• Change in performance on symbol digit modalities test (SDMT) and Cognitive Battery Test [ Time Frame: at randomization, then every 24 weeks (SDMT only) and at 96 weeks ]
• Safety, as assessed by clinical, laboratory, ECG, and vital signs events [ Time Frame: over 96 weeks ]
• Assessment of PK parameter - lowest concentration of drug in the blood measured after dosing (Ctrough) [ Time Frame: at Weeks 2, 3, 4, 8, 12, 24, 36 and 96 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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 is available for young participants with teriflunomide until the participants are 18 years old and/or able to switch to commercial product, whichever comes first.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Multiple Sclerosis

Intervention

• Drug: Teriflunomide
  Pharmaceutical form:film-coated tablet, Route of administration: oral
  Other Name: AUBAGIO, HMR1726
• Drug: Placebo
  Pharmaceutical form:tablet, Route of administration: oral

Study Arms

• Placebo Comparator: Placebo
  Matching placebo tablets
  Intervention: Drug: Placebo
• Experimental: Teriflunomide
  Teriflunomide oral tablet, three dosages (3.5, 7 or 14 mg) to reach 14 mg adult equivalent
  Intervention: Drug: Teriflunomide

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: November 27, 2020): 166
• Original Estimated Enrollment (submitted: July 24, 2014): 165
• Estimated Study Completion Date: September 29, 2021
• Actual Primary Completion Date: October 25, 2019 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 10 Years to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Bulgaria, Canada, China, Estonia, France, Greece, Israel, Lebanon, Lithuania, Morocco, Netherlands, North Macedonia, Portugal, Russian Federation, Serbia, Slovenia, Spain, Tunisia, Turkey, Ukraine, United Kingdom, United States
• Removed Location Countries: Australia, Macedonia, The Former Yugoslav Republic of, Poland

Administrative Information

• NCT Number: NCT02201108
• Other Study ID Numbers: EFC11759; 2011-005249-12 ( EudraCT Number ); U1111-1124-0983 ( Other Identifier: WHO Universal Trial Reference Number (UTRN) )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://www.clinicalstudydatarequest.com/.

• Responsible Party: Sanofi ( Genzyme, a Sanofi Company )
• Study Sponsor: Genzyme, a Sanofi Company
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

• PRS Account: Sanofi
• Verification Date: November 2020