Clinical Trial Results:
Exploratory Open Label Study to Investigate the Effect of Teriflunomide on Immune Cell Subsets in the Blood of subjects With Relapsing Forms of Multiple Sclerosis
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Summary
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EudraCT number |
2012-005324-16 |
Trial protocol |
BE NL DE |
Global end of trial date |
22 Jan 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
16 Apr 2016
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First version publication date |
16 Apr 2016
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
LPS13539
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01863888 | ||
WHO universal trial number (UTN) |
U1111-1139-8802 | ||
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Sponsors
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Sponsor organisation name |
Genzyme Corporation
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Sponsor organisation address |
500 Kendall Street, Cambridge, MA, United States, 02142
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Public contact |
Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
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Scientific contact |
Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
30 Mar 2015
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
22 Jan 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To measure the effect of teriflunomide on lymphocytes subsets in subjects with relapsing forms of multiple sclerosis (RMS) as compared with baseline values and those of a reference population of untreated healthy subjects.
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Protection of trial subjects |
Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
10 Oct 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 10
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Country: Number of subjects enrolled |
Belgium: 19
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Country: Number of subjects enrolled |
Germany: 41
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Worldwide total number of subjects |
70
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EEA total number of subjects |
70
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
70
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at 9 centers in 3 countries (for RMS subjects) and at a single site in Germany (for healthy subjects). A total of 87 subjects (56 RMS subjects and 31 healthy subjects) were screened between 10 October 2013 and 24 June 2014. | ||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Of 56 RMS subjects screened, 50 were included and treated in the treatment arm. Of 31 healthy subjects screened, 20 were included in the healthy subjects' arm. 17 subjects (6 RMS subjects and 11 healthy subjects) were screen failure due to unmet inclusion criteria. | ||||||||||||||||||||||||
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Period 1
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Period 1 title |
Main Study Period
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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RMS Subjects | ||||||||||||||||||||||||
Arm description |
Subjects with RMS received teriflunomide 14 mg once daily for 24 weeks. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Teriflunomide
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Investigational medicinal product code |
HMR1726
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Other name |
AUBAGIO®
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Teriflunomide 14 mg administered orally once daily.
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Arm title
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Healthy Subjects | ||||||||||||||||||||||||
Arm description |
Untreated Healthy subjects followed for 24 weeks. | ||||||||||||||||||||||||
Arm type |
No intervention | ||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Period 2
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Period 2 title |
Optional Extension Period (RMS Subjects)
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Is this the baseline period? |
No | ||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||
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Arms
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Arm title
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RMS Subjects | ||||||||||||||||||||||||
Arm description |
Subjects who could not receive the commercial drug due to unavailability at the time of completion of 24 week treatment period, were proposed the extension study and received teriflunomide 14 mg once daily till the availability of commercial teriflunomide. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Teriflunomide
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Investigational medicinal product code |
HMR1726
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Other name |
AUBAGIO®
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Teriflunomide 14 mg administered orally once daily.
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| Notes [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: Only subjects who could not receive the commercial drug due to unavailability at the time of completion of 24 weeks treatment period, were proposed to continue in the extension study. |
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Baseline characteristics reporting groups
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Reporting group title |
RMS Subjects
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Reporting group description |
Subjects with RMS received teriflunomide 14 mg once daily for 24 weeks. | ||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Healthy Subjects
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Reporting group description |
Untreated Healthy subjects followed for 24 weeks. | ||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
RMS Subjects
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Reporting group description |
Subjects with RMS received teriflunomide 14 mg once daily for 24 weeks. | ||
Reporting group title |
Healthy Subjects
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Reporting group description |
Untreated Healthy subjects followed for 24 weeks. | ||
Reporting group title |
RMS Subjects
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Reporting group description |
Subjects who could not receive the commercial drug due to unavailability at the time of completion of 24 week treatment period, were proposed the extension study and received teriflunomide 14 mg once daily till the availability of commercial teriflunomide. | ||
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End point title |
Change From Baseline In Lymphocytes Subsets [1] | ||||||||||||||||||
End point description |
Least square (LS) mean was estimated using mixed effect model with repeated measures (MMRM) approach adjusted on baseline. Analysis was performed on Per Protocol (PP) population consisted of all RMS subjects and healthy subjects with no major pharmacodynamics related protocol deviations who had at the very minimum pharmacodynamics evaluations at baseline and week 24. Number of subjects analyzed=subjects with available data for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline, Week 12, Week 24.
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive statistics were performed, treated and untreated arms were not compared. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change from Baseline in T-Cells Subset Parameters [2] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint. Here 'n' signifies number of subjects with available data for T-cells subset parameters.
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End point type |
Primary
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End point timeframe |
Baseline, Week 12, Week 24.
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive statistics were performed, treated and untreated arms were not compared. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Change from Baseline in T-Cells Subset Parameters (Continued) [3] | ||||||||||||||||||||||||||||||
End point description |
LS mean was estimated using a MMRM approach adjusted on baseline. Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline, Week 12, Week 24
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive statistics were performed, treated and untreated arms were not compared. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Change from Baseline in T-cells Subset Parameters [CD4+/CD8+ Ratio] [4] | ||||||||||||||||||
End point description |
A CD4+ (in % of CD3+)/CD8+ (in % of CD3+) ratio was performed. Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline, Week 12, Week 24
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive statistics were performed, treated and untreated arms were not compared. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change from Baseline in NK Cells Subset Parameters [5] | ||||||||||||||||||||||||
End point description |
Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline, Week 12, Week 24.
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive statistics were performed, treated and untreated arms were not compared. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Change from Baseline in NK Cells Subset Parameters (Continued) [6] | ||||||||||||||||||||||||||||||
End point description |
LS mean was estimated using a MMRM approach adjusted on baseline. Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline, Week 12, Week 24
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| Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive statistics were performed, treated and untreated arms were not compared. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Change from Baseline in NKT Cells Subset Parameters [7] | ||||||||||||||||||
End point description |
Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline, Week 12, Week 24
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive statistics were performed, treated and untreated arms were not compared. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change from Baseline in B Cells Subset Parameters [8] | ||||||||||||||||||
End point description |
Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline, Week 12, Week 24
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| Notes [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive statistics were performed, treated and untreated arms were not compared. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change from Baseline in Total Number of Different CD8+ T-Cell Clones | ||||||||||||||||||
End point description |
Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 12, Week 24.
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change from Baseline in Total Number of Unique CD8+ T-Cell Clones | ||||||||||||||||||
End point description |
LS mean was estimated using a MMRM approach adjusted on baseline. Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 12, Week 24.
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change from Baseline in Proliferating CD8+ T Cells | ||||||||||||||||||
End point description |
LS mean was estimated using a MMRM approach adjusted on baseline. Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 12, Week 24.
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change from Baseline in Proliferating CD8+ T Cells Upon in-vitro Exposure to 100µM Teriflunomide | ||||||||||||
End point description |
LS mean was estimated using a MMRM approach adjusted on baseline. Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, in-vitro exposure.
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change from Baseline in Cytokine Production Interleukin-2 (IL-2) Upon anti-CD3/CD28 Induction for 24 hours | ||||||||||||||||||
End point description |
Induction of cytokine production by anti- CD3/CD28 was assessed from samples of subjects at baseline, week 12 and week 24. Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 12, Week 24
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change from Baseline in Cytokine Production Tumor Necrosis Factor (TNFα) Upon anti-CD3/CD28 Induction for 24 hours | ||||||||||||||||||
End point description |
LS mean was estimated using a MMRM approach adjusted on baseline. Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 12, Week 24
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| No statistical analyses for this end point | |||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
All Adverse Events (AE) were collected from signature of informed consent form up to final visit of the subject regardless of seriousness or relationship to investigational product.
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Adverse event reporting additional description |
Reported AEs and deaths were AEs developed/worsened and deaths occurred during 'treatment-emergent period’(time from administration of first investigational study drug to last dose of study drug in extension period for those who entered in extension or to last data[lab,vital signs or AE] available for those who did not enter in extension period.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.1
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Reporting groups
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Reporting group title |
RMS Subjects
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Reporting group description |
Subjects with RMS who received at least one dose of teriflunomide 14 mg once daily during the study period (safety population). (Median exposure for main study period is 168 days and for extension period is 140 days) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Healthy Subjects
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Reporting group description |
Untreated healthy subjects followed for 24 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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28 Oct 2013 |
-Inclusion criteria was changed to define a wash-out period before switching to the study treatment teriflunomide. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
