Phase II Study of Teriflunomide as Adjunctive Therapy to Interferon-beta in Subjects With Multiple Sclerosis

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

Sanofi

ClinicalTrials.gov Identifier:

NCT00489489

First received: June 20, 2007

Last updated: November 5, 2012

Last verified: November 2012

History of Changes

Results First Received: October 3, 2012

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition:	Multiple Sclerosis
Interventions:	Drug: Teriflunomide Drug: Placebo (for Teriflunomide) Drug: Interferon-β

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
The recruitment initiated in May 2007 was completed in August 2008. A total of 159 patients were screened at 29 sites in 5 countries.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Randomization was stratified by country and dose level of interferon-β (high/low). Assignment to groups was done centrally using an Interactive Voice Response System (IVRS] in a 1:1:1 ratio after confirmation of the selection criteria. 118 participants were randomized.

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment

Randomization was stratified by country and dose level of interferon-β (high/low).

Assignment to groups was done centrally using an Interactive Voice Response System (IVRS] in a 1:1:1 ratio after confirmation of the selection criteria.

118 participants were randomized.

Reporting Groups

	Description
Placebo + IFN-β	Placebo (for teriflunomide) once daily concomitantly with interferon-β (IFN-β) for 24 weeks
Teriflunomide 7 mg + IFN-β	Teriflunomide 7 mg once daily concomitantly with interferon-β (IFN-β) for 24 weeks
Teriflunomide 14 mg + IFN-β	Teriflunomide 14 mg once daily concomitantly with interferon-β (IFN-β) for 24 weeks

Participant Flow: Overall Study

	Placebo + IFN-β	Teriflunomide 7 mg + IFN-β	Teriflunomide 14 mg + IFN-β
STARTED	41 ^[1]	37 ^[1]	40 ^[1]
Treated	41	36	39 ^[2]
COMPLETED	38 ^[3]	32 ^[3]	37 ^[3]
NOT COMPLETED	3	5	3
Not treated due to protocol violation	0	1	1
Adverse Event	1	1	1
Protocol Violation	1	0	1
Progressive disease	0	1	0
Participant did not wish to continue	1	1	0
Other than above	0	1	0

[1]	randomized
[2]	One participant received teriflunomide 7 mg instead of teriflunomide 14 mg
[3]	completed treatment period

Baseline Characteristics

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Reporting Groups

	Description
Placebo + IFN-β	Placebo (for teriflunomide) once daily concomitantly with interferon-β (IFN-β) for 24 weeks
Teriflunomide 7 mg + IFN-β	Teriflunomide 7 mg once daily concomitantly with interferon-β (IFN-β) for 24 weeks
Teriflunomide 14 mg + IFN-β	Teriflunomide 14 mg once daily concomitantly with interferon-β (IFN-β) for 24 weeks
Total	Total of all reporting groups

Baseline Measures

	Placebo + IFN-β	Teriflunomide 7 mg + IFN-β	Teriflunomide 14 mg + IFN-β	Total
Number of Participants [units: participants]	41	37	38	116
Age ^[1] [units: years] Mean ± Standard Deviation	39.2 ± 9.0	41.4 ± 6.8	39.6 ± 8.1	40.1 ± 8.0
Gender [units: participants]
Female	31	25	25	81
Male	10	12	13	35
Region of Enrollment ^[2] [units: participants]
Europe	28	25	24	77
North America	13	12	14	39
Time since first diagnosis of Multiple Sclerosis (MS) [units: years] Mean ± Standard Deviation	8.78 ± 5.62	8.35 ± 5.44	7.97 ± 6.59	8.38 ± 5.86
Number of MS relapses [units: MS relapses] Median ( Full Range )
Within the past year	1 ( 0 to 4 )	0 ( 0 to 3 )	1 ( 0 to 3 )	1 ( 0 to 4 )
Within the past 2 years	1 ( 0 to 5 )	1 ( 0 to 5 )	1 ( 0 to 4 )	1 ( 0 to 5 )
Time since most recent MS relapse onset [units: months] Mean ± Standard Deviation	27.68 ± 38.49	28.97 ± 34.06	24.71 ± 35.97	27.12 ± 36.03
MS subtype [units: participants]
Relapsing Remitting	38	30	34	102
Secondary Progressive	2	2	3	7
Progressive Relapsing	1	5	1	7
Baseline Expanded Disability Status Scale (EDSS) score ^[3] [units: units on a scale] Mean ± Standard Deviation	2.61 ± 1.26	2.41 ± 1.44	2.46 ± 1.57	2.50 ± 1.41
Dose level of interferon-β ^[4] [units: participants]
High dose	28	25	24	77
Low dose	13	12	14	39

[1]	Baseline characteristics of the population included in the analyses: the 2 participants not treated were not included, and the participant who received teriflunomide 7 mg instead of teriflunomide 14 mg was included in the teriflunomide 7 mg group.
[2]	Europe: Germany, Italy and Spain North America: Canada and United States
[3]	EDSS is an ordinal scale in half-point increments that qualifies disability in patients with MS. It consists of 8 ordinal rating scales assessing seven functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS).
[4]	'High dose': Rebif® 44 μg 3 times per week subcutaneously and, Betaseron® 0.25 mg every other day subcutaneously 'Low dose': Rebif® 22 μg 3 times per week subcutaneously and, Avonex® 30 μg once a week intramuscularly

Outcome Measures

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1. Primary:

Overview of Adverse Events [AE] [ Time Frame: from first study drug intake up to 112 days after last intake or up to the first intake in the extension study LTS6047, whichever occured first (40 weeks max) ]

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2. Primary:

Overview of AE With Potential Risk of Occurrence [ Time Frame: from first study drug intake up to 112 days after last intake or up to the first intake in the extension study LTS6047, whichever occured first (40 weeks max) ]

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3. Primary:

Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) [ Time Frame: from first study drug intake up to 112 days after last intake or up to the first intake in the extension study LTS6047, whichever occured first (40 weeks max) ]

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4. Secondary:

Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) [ Time Frame: baseline (before randomization) and 24 weeks ]

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5. Secondary:

Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates) [ Time Frame: 24 weeks ]

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6. Secondary:

Cerebral MRI Assessment: Volume of Gd-enhancing T1-lesions Per Scan [ Time Frame: 24 weeks ]

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7. Secondary:

Annualized Relapse Rate [ARR]: Poisson Regression Estimates [ Time Frame: 24 weeks ]

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8. Secondary:

Pharmacokinetic [PK]: Teriflunomide Plasma Concentration [ Time Frame: 24 weeks ]

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Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.

Restriction Description:

The investigator can publish only the results of the work performed pursuant to this protocol. Prior to publication, the investigator provides the sponsor with the manuscript for review and comment at least 45 days in advance of its submission for publication.

The sponsor can require the investigator to withhold publication an additional 90 days to allow for filing a patent application or taking such other measures as sponsor deems appropriate to establish and preserve its proprietary rights.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact:

Name/Title: Trial Transparency Team
Organization: sanofi-aventis
e-mail: Contact_US@sanofi-aventis.com

Publications of Results:

Freedman MS, Wolinsky JS, Wamil B, Confavreux C, Comi G, Kappos L, Olsson TP, Miller A, Benzerdjeb H, Li H, Simonson C, O'Connor PW; Teriflunomide Multiple Sclerosis Trial Group and the MRI Analysis Center. Teriflunomide added to interferon-β in relapsing multiple sclerosis: a randomized phase II trial. Neurology. 2012 Jun 5;78(23):1877-85. Epub 2012 May 23.

Responsible Party:	Sanofi
ClinicalTrials.gov Identifier:	NCT00489489 History of Changes
Other Study ID Numbers:	PDY6045, 2006-003134-14, HMR1726D-2003
Study First Received:	June 20, 2007
Results First Received:	October 3, 2012
Last Updated:	November 5, 2012
Health Authority:	Canada: Health Canada Germany: Paul-Ehrlich-Institut Spain: Spanish Agency of Medicines United States: Food and Drug Administration

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