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| ID | Type | Description | Link |
|---|---|---|---|
| 2006-003134-14 | EudraCT Number | ||
| HMR1726D-2003 | Other Identifier | HMR |
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The primary objective was to estimate the tolerability and safety of 2 doses of teriflunomide administered once daily for 24 weeks, compared with placebo, in patients with multiple sclerosis [MS] with relapses who were on a stable dose of interferon-β [IFN-β].
Secondary objectives were:
The study period per participant was approximatively 44 weeks broken down as follows:
'*' participants successfully completing the week 24 visit were offered the opportunity to enter the optional long-term extension study LTS6047 - NCT00811395.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Teriflunomide 7 mg + IFN-β | Experimental | Teriflunomide 7 mg once daily concomitantly with Interferon-β (IFN-β) for 24 weeks |
|
| Teriflunomide 14 mg + IFN-β | Experimental | Teriflunomide 14 mg once daily concomitantly with Interferon-β (IFN-β) for 24 weeks |
|
| Placebo + IFN-β | Placebo Comparator | Placebo (for Teriflunomide) once daily concomitantly with Interferon-β (IFN-β) for 24 weeks |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Teriflunomide | Drug | Film-coated tablet Oral administration |
|
| Measure | Description | Time Frame |
|---|---|---|
| Overview of Adverse Events [AE] | AE are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study. | 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) |
| Overview of AE With Potential Risk of Occurrence | AE with potential risk of occurrence were defined as follows:
| 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) |
| Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | PCSA values are abnormal values considered medically important by the Sponsor according to predefined criteria based on literature review. Hepatic parameters thresholds were defined as follows:
| 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) |
| Measure | Description | Time Frame |
|---|---|---|
| Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) | Total lesion volume is the sum of the total volume of all T2-lesions and the total volume of all T1-hypointense post-gadolinium lesions measured through T2/proton density scan analysis and gadolinium-enhanced T1 scan analysis. Least-square means were estimated using a Mixed-effect model with repeated measures [MMRM] on cubic root transformed volume data (treatment group, region of enrollment, IFN-β dose level, visit, treatment-by-visit interaction, baseline value (cubic root transformed), and baseline-by-visit interaction as factors). |
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Inclusion Criteria:
Exclusion Criteria:
The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
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| Name | Affiliation | Role |
|---|---|---|
| ICD | Sanofi | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Sanofi-Aventis Administrative Office | Bridgewater | New Jersey | 08807 | United States | ||
| Sanofi-Aventis Administrative Office |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22622860 | Result | 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-beta in relapsing multiple sclerosis: a randomized phase II trial. Neurology. 2012 Jun 5;78(23):1877-85. doi: 10.1212/WNL.0b013e318258f7d4. Epub 2012 May 23. |
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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.
The recruitment initiated in May 2007 was completed in August 2008. A total of 159 patients were screened at 29 sites in 5 countries.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo + IFN-β | Placebo (for teriflunomide) once daily concomitantly with interferon-β (IFN-β) for 24 weeks |
| FG001 | Teriflunomide 7 mg + IFN-β | Teriflunomide 7 mg once daily concomitantly with interferon-β (IFN-β) for 24 weeks |
| FG002 | Teriflunomide 14 mg + IFN-β | Teriflunomide 14 mg once daily concomitantly with interferon-β (IFN-β) for 24 weeks |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo + IFN-β | Placebo (for teriflunomide) once daily concomitantly with interferon-β (IFN-β) for 24 weeks |
| BG001 | Teriflunomide 7 mg + IFN-β | Teriflunomide 7 mg once daily concomitantly with interferon-β (IFN-β) for 24 weeks |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | 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. |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Overview of Adverse Events [AE] | AE are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study. | All randomized and treated participants; Participants were included in the treatment group according to the drug actually received. | Posted | Number | participants | 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) |
|
All Adverse Events (AE) were collected regardless of seriousness or relationship to the drug, spanning from signature of the Informed Consent Form up to the last visit.
The analysis was performed on the exposed population and included all AE that developed or worsened from first study drug intake up to 112 days after last study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo + IFN-β | Placebo (for teriflunomide) once daily concomitantly with IFN-β for 24 weeks |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Deep vein thrombosis | Vascular disorders | MedDRA 11.1 | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nasopharyngitis | Infections and infestations | MedDRA 11.1 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Trial Transparency Team | sanofi-aventis | Contact_US@sanofi-aventis.com |
| ID | Term |
|---|---|
| D009103 | Multiple Sclerosis |
| D012008 | Recurrence |
| ID | Term |
|---|---|
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
| D003711 | Demyelinating Diseases |
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| ID | Term |
|---|---|
| C527525 | teriflunomide |
| D000068556 | Interferon beta-1a |
| D000068576 | Interferon beta-1b |
| ID | Term |
|---|---|
| D016899 | Interferon-beta |
| D007370 | Interferon Type I |
| D007372 | Interferons |
| D016207 | Cytokines |
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| Placebo (for Teriflunomide) | Drug | Film-coated tablet Oral administration |
|
| Interferon-β | Drug | Powder for reconstitution, of any licensed strength for either intramuscular or subcutaneous injection |
|
|
| baseline (before randomization) and 24 weeks |
| Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates) | Number of Gd-enhancing T1-lesions per scan is obtained from the total number of Gd-enhancing T1-lesions observed during the study divided by the total number of scans performed during the study. To account for the different number of scans among participants, a Poisson regression model with robust error variance was used (total number of Gd-enhancing T1-lesions as response variable; log-transformed number of scans as "offset" variable; treatment group, region of enrollment, IFN-β dose level and baseline number of Gd-enhancing T1-lesions as covariates). | 24 weeks |
| Cerebral MRI Assessment: Volume of Gd-enhancing T1-lesions Per Scan | Total volume of Gd-enhancing T1-lesions per scan is obtained from the sum of the volumes of Gd-enhancing T1-lesions observed during the study divided by the total number of scans performed during the study. | 24 weeks |
| Annualized Relapse Rate [ARR]: Poisson Regression Estimates | ARR is obtained from the total number of confirmed relapses that occured during the treatment period divided by the sum of the treatment durations. Each episode of relapse - appearance, or worsening of a clinical symptom that was stable for at least 30 days, that persisted for a minimum of 24 hours in the absence of fever - was to be confirmed by an increase in Expanded Disability Status Scale [EDSS] score or Functional System scores. To account for the different treatment durations among participants, a Poisson regression model with robust error variance was used (total number of confirmed relapses as response variable; log-transformed treatment duration as "offset" variable; treatment group, region of enrollment and IFN-β dose level as covariates). | 24 weeks |
| Pharmacokinetic [PK]: Teriflunomide Plasma Concentration | Plasma concentrations of teriflunomide were measured using validated liquid chromatography-tandem mass spectrometry methods. | 24 weeks |
| Laval |
| Canada |
| Sanofi-Aventis Administrative Office | Berlin | Germany |
| Sanofi-Aventis Administrative Office | Milan | Italy |
| Sanofi-Aventis Administrative Office | Barcelona | Spain |
| Protocol Violation |
|
| Progressive disease |
|
| Participant did not wish to continue |
|
| Other than above |
|
| BG002 | Teriflunomide 14 mg + IFN-β | Teriflunomide 14 mg once daily concomitantly with interferon-β (IFN-β) for 24 weeks |
| BG003 | Total | Total of all reporting groups |
| Mean |
| Standard Deviation |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Europe: Germany, Italy and Spain North America: Canada and United States | Number | participants |
|
| Time since first diagnosis of Multiple Sclerosis (MS) | Mean | Standard Deviation | years |
|
| Number of MS relapses | Median | Full Range | MS relapses |
|
| Time since most recent MS relapse onset | Mean | Standard Deviation | months |
|
| MS subtype | Number | participants |
|
| Baseline Expanded Disability Status Scale (EDSS) score | 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). | Mean | Standard Deviation | units on a scale |
|
| Dose level of interferon-β | '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 | Number | participants |
|
Teriflunomide 7 mg once daily concomitantly with interferon-β (IFN-β) for 24 weeks
| OG002 | Teriflunomide 14 mg + IFN-β | Teriflunomide 14 mg once daily concomitantly with interferon-β (IFN-β) for 24 weeks |
|
|
| Primary | Overview of AE With Potential Risk of Occurrence | AE with potential risk of occurrence were defined as follows:
| All randomized and treated participants; Participants were included in the treatment group according to the drug actually received. | Posted | Number | participants | 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) |
|
|
|
| Secondary | Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) | Total lesion volume is the sum of the total volume of all T2-lesions and the total volume of all T1-hypointense post-gadolinium lesions measured through T2/proton density scan analysis and gadolinium-enhanced T1 scan analysis. Least-square means were estimated using a Mixed-effect model with repeated measures [MMRM] on cubic root transformed volume data (treatment group, region of enrollment, IFN-β dose level, visit, treatment-by-visit interaction, baseline value (cubic root transformed), and baseline-by-visit interaction as factors). | All randomized and treated participants; Participants were included in the treatment group according to the drug actually received. | Posted | Least Squares Mean | Standard Error | mililiters | baseline (before randomization) and 24 weeks |
|
|
|
| Secondary | Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates) | Number of Gd-enhancing T1-lesions per scan is obtained from the total number of Gd-enhancing T1-lesions observed during the study divided by the total number of scans performed during the study. To account for the different number of scans among participants, a Poisson regression model with robust error variance was used (total number of Gd-enhancing T1-lesions as response variable; log-transformed number of scans as "offset" variable; treatment group, region of enrollment, IFN-β dose level and baseline number of Gd-enhancing T1-lesions as covariates). | All randomized and treated participants; Participants were included in the treatment group according to the drug actually received. | Posted | Number | 95% Confidence Interval | lesions per scan | 24 weeks |
|
|
|
| Secondary | Cerebral MRI Assessment: Volume of Gd-enhancing T1-lesions Per Scan | Total volume of Gd-enhancing T1-lesions per scan is obtained from the sum of the volumes of Gd-enhancing T1-lesions observed during the study divided by the total number of scans performed during the study. | All randomized and treated participants; Participants were included in the treatment group according to the drug actually received. | Posted | Number | mililiters per scan | 24 weeks |
|
|
|
| Primary | Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | PCSA values are abnormal values considered medically important by the Sponsor according to predefined criteria based on literature review. Hepatic parameters thresholds were defined as follows:
| All randomized and treated participants; Participants were included in the treatment group according to the drug actually received. | Posted | Number | participants | 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) |
|
|
|
| Secondary | Annualized Relapse Rate [ARR]: Poisson Regression Estimates | ARR is obtained from the total number of confirmed relapses that occured during the treatment period divided by the sum of the treatment durations. Each episode of relapse - appearance, or worsening of a clinical symptom that was stable for at least 30 days, that persisted for a minimum of 24 hours in the absence of fever - was to be confirmed by an increase in Expanded Disability Status Scale [EDSS] score or Functional System scores. To account for the different treatment durations among participants, a Poisson regression model with robust error variance was used (total number of confirmed relapses as response variable; log-transformed treatment duration as "offset" variable; treatment group, region of enrollment and IFN-β dose level as covariates). | All randomized and treated participants; Participants were included in the treatment group according to the drug actually received. | Posted | Number | 95% Confidence Interval | relapses per year | 24 weeks |
|
|
|
| Secondary | Pharmacokinetic [PK]: Teriflunomide Plasma Concentration | Plasma concentrations of teriflunomide were measured using validated liquid chromatography-tandem mass spectrometry methods. | All randomized and treated participants who had at least one PK sample. Participants were included in the treatment group according to the drug actually received. | Posted | Mean | Standard Deviation | micrograms/mililiter (μg/mL) | 24 weeks |
|
|
|
| 1 |
| 41 |
| 20 |
| 41 |
| EG001 | Teriflunomide 7 mg + IFN-β | Teriflunomide 7 mg once daily concomitantly with IFN-β for 24 weeks | 2 | 37 | 28 | 37 |
| EG002 | Teriflunomide 14 mg + + IFN-β | Teriflunomide 14 mg once daily concomitantly with IFN-β for 24 weeks | 0 | 38 | 29 | 38 |
| Musculoskeletal stiffness | Musculoskeletal and connective tissue disorders | MedDRA 11.1 | Non-systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA 11.1 | Non-systematic Assessment |
|
| Respiratory tract infection | Infections and infestations | MedDRA 11.1 | Non-systematic Assessment |
|
| Sinusitis | Infections and infestations | MedDRA 11.1 | Non-systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA 11.1 | Non-systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA 11.1 | Non-systematic Assessment |
|
| Anxiety | Psychiatric disorders | MedDRA 11.1 | Non-systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA 11.1 | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 11.1 | Non-systematic Assessment |
|
| Sciatica | Nervous system disorders | MedDRA 11.1 | Non-systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 11.1 | Non-systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA 11.1 | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 11.1 | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 11.1 | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 11.1 | Non-systematic Assessment |
|
| Alopecia | Skin and subcutaneous tissue disorders | MedDRA 11.1 | Non-systematic Assessment |
|
| Dry skin | Skin and subcutaneous tissue disorders | MedDRA 11.1 | Non-systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA 11.1 | Non-systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 11.1 | Non-systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 11.1 | Non-systematic Assessment |
|
| Fatigue | General disorders | MedDRA 11.1 | Non-systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA 11.1 | Non-systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA 11.1 | Non-systematic Assessment |
|
| Blood creatine phosphokinase increased | Investigations | MedDRA 11.1 | Non-systematic Assessment |
|
| Blood pressure increased | Investigations | MedDRA 11.1 | Non-systematic Assessment |
|
| Lipase increased | Investigations | MedDRA 11.1 | Non-systematic Assessment |
|
| Lymphocyte count decreased | Investigations | MedDRA 11.1 | Non-systematic Assessment |
|
| Neutrophil count decreased | Investigations | MedDRA 11.1 | Non-systematic Assessment |
|
| White blood cell count decreased | Investigations | MedDRA 11.1 | Non-systematic Assessment |
|
| Contusion | Injury, poisoning and procedural complications | MedDRA 11.1 | Non-systematic Assessment |
|
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.
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D036341 |
| Intercellular Signaling Peptides and Proteins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D011506 | Proteins |
| D001685 | Biological Factors |
|
| - Pancreatic disorder AE |
|
| - Pulmonary disorder AE |
|
| - Immune effects related AE |
|
| - Hair loss / Hair thinning AE |
|
| - Hypertension-related AE |
|
| - Peripheral neuropathy AE |
|
| - Hypersensitivity AE |
|
| - Malignancy AE |
|
| - Psychiatric disorder AE |
|
| Title | Measurements |
|---|---|
|
| AST >3 ULN |
|
| - AST >5 ULN |
|
| Alkaline Phosphatase >1.5 ULN |
|
| TB >1.5 ULN |
|
| ALT >3 ULN and TB >2 ULN |
|