Multiple Sclerosis
Conditions
Brief summary
Primary Objective: Assess the antibody response to influenza vaccine in patients with relapsing form of multiple sclerosis (RMS) treated with teriflunomide compared to a reference population. Secondary Objectives: * Assess the effect of teriflunomide on immunoglobulin levels; * Assess the safety of influenza vaccination in patients with RMS treated with teriflunomide. The reference population was defined as multiple sclerosis (MS) patients with a stable treatment with interferon-β-1. Antibody response was measured using hemagglutination inhibition assay (HIA) and the hemagglutinin antigens representing the stains of H3N2, H1N1, and B as present in the influenza vaccine used.
Detailed description
The maximum duration of the study period for a participant was approximatively 49 days broken down as follows: * Screening period of up to 21 days; * Influenza vaccination at Day 1; * Follow-up period of 28 days (±2 days). MS treatment (Teriflunomide or interferon-β-1) was to be continued during the course of the study.
Interventions
DRUGteriflunomide
Film-coated tablet Oral administration
DRUGInterferon-β-1
Powder for reconstitution, of any licensed strength for either intramuscular or subcutaneous injection
BIOLOGICALInfluenza vaccine
Inactivated, split-virion influenza vaccine 2011-2012 One administration by intramuscular or intradermal route as per product specification
Sponsors
Sanofi
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 59 Years
Healthy volunteers
No
Inclusion criteria
\- Male or female patient \<60 years old with relapsing multiple sclerosis (RMS) either treated for at least 6 months with 7 or 14 mg teriflunomide in one of the studies LTS6048 or LTS6050, or treated with a stable dose of interferon-β-1 for at least 6 months.
Exclusion criteria
* Concomitant infectious pathology at the time of vaccination; * MS relapse within 1 month before vaccination; * Systemic corticosteroids within 1 month before the vaccination; * Any contraindication to influenza vaccine; * Any vaccination within the last 6 months; * Prior use of any investigational drug or participation to a clinical trial within 1 year (only for patients under interferon-β-1); * Prior or concomitant use (for a minimum of 1 year before study entry) of cladribine, mitoxantrone, or other immunosuppressant agents such as azathioprine, cyclophosphamide, cyclosporin, methotrexate, mycophenolate, natalizumab (Tysabri®), leflunomide or fingolimod or other immunomodulator/immunosuppressant in development; * Prior or concomitant use of glatiramer acetate within 1 year before study entry; * Prior or concomitant use of intravenous immunoglobulins within 3 months before study entry; * Pregnant or breast feeding women; * Woman of childbearing potential without adequate contraception. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Antibody Titer ≥40 at 28 Days Post Vaccination | 28 days post vaccination | For each viral strain (H1N1, H3N2, and B), the antibody titer, level of antibodies in blood sample when exposed to antigen, was calculated as the mean of two replicates. If the titer was below or above the limit of detection, the threshold value was used. The percentage of participants achieving a titer of 40 or more, as well as the 90% confidence interval (CI) using normal approximation were calculated for each strain and treatment group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With 2 Fold or More Increase in Antibody Titer at 28 Days Post Vaccination | pre vaccination (baseline) and 28 days post vaccination | Percentages of participants with an increase from baseline of 2-fold or more in antibody titers and 90% CIs using normal approximation were calculated for each strain and treatment group. |
| Percentage of Participants With 4 Fold or More Increase in Antibody Titer at 28 Days Post Vaccination | pre vaccination (baseline) and 28 days post vaccination | Percentages of participants with an increase from baseline of 4-fold or more in antibody titers and 90% CIs using normal approximation were calculated for each strain and treatment group. |
| Geometric Mean of Titers (GMT) Ratio Post/Pre Vaccination | pre vaccination (baseline) and 28 days post vaccination | — |
| Immunoglobulin Levels | pre vaccination (baseline) and 28 days post vaccination | — |
Countries
Austria, Canada, Germany, Russia, Ukraine
Participant flow
Recruitment details
The recruitment initiated in September 2011 was completed in December 2011. A total of 137 patients were screened at 14 sites in 5 countries. Participants treated with teriflunomide were recruited in the LTS6048-NCT00228163 study and in the LTS6050-NCT00803049 study.
Pre-assignment details
In order to ensure at least 40 participants were enrolled in the teriflunomide 14 mg group while maintaining the blind in the study LTS6050 an interactive voice response system (IVRS) was set up to include participants from both studies LTS6048 and LTS6050 into this study. 128 participants were enrolled and vaccinated at 14 sites.
Participants by arm
| Arm | Count |
|---|---|
| Teriflunomide 7 mg Influenza vaccine in participants treated with teriflunomide 7 mg for at least 6 months | 41 |
| Teriflunomide 14 mg Influenza vaccine in participants treated with teriflunomide 14 mg for at least 6 months | 41 |
| IFN-β-1 Influenza vaccine in participants treated with a stable dose of interferon-β-1 (IFN-β-1) for at least 6 months | 46 |
| Total | 128 |
Baseline characteristics
| Characteristic | Total | IFN-β-1 | Teriflunomide 14 mg | Teriflunomide 7 mg |
|---|---|---|---|---|
| Age, Continuous | 45.0 years STANDARD_DEVIATION 9.2 | 45.1 years STANDARD_DEVIATION 10.8 | 43.8 years STANDARD_DEVIATION 8.5 | 46.1 years STANDARD_DEVIATION 7.9 |
| pre-vaccination antibody titer - B strain <10 | 0 participants | 0 participants | 0 participants | 0 participants |
| pre-vaccination antibody titer - B strain ≥40 | 82 participants | 25 participants | 28 participants | 29 participants |
| pre-vaccination antibody titer - B strain Between 10 and 40 (<) | 46 participants | 21 participants | 13 participants | 12 participants |
| pre-vaccination antibody titer - H1N1 strain <10 | 1 participants | 0 participants | 1 participants | 0 participants |
| pre-vaccination antibody titer - H1N1 strain ≥40 | 111 participants | 41 participants | 36 participants | 34 participants |
| pre-vaccination antibody titer - H1N1 strain Between 10 and 40 (<) | 16 participants | 5 participants | 4 participants | 7 participants |
| pre-vaccination antibody titer - H3N2 strain <10 | 7 participants | 2 participants | 3 participants | 2 participants |
| pre-vaccination antibody titer - H3N2 strain ≥40 | 68 participants | 22 participants | 23 participants | 23 participants |
| pre-vaccination antibody titer - H3N2 strain Between 10 and 40 (<) | 53 participants | 22 participants | 15 participants | 16 participants |
| Sex: Female, Male Female | 89 Participants | 32 Participants | 29 Participants | 28 Participants |
| Sex: Female, Male Male | 39 Participants | 14 Participants | 12 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 41 | 6 / 41 | 13 / 46 |
| serious Total, serious adverse events | 0 / 41 | 0 / 41 | 0 / 46 |
Outcome results
Primary
Percentage of Participants With Antibody Titer ≥40 at 28 Days Post Vaccination
For each viral strain (H1N1, H3N2, and B), the antibody titer, level of antibodies in blood sample when exposed to antigen, was calculated as the mean of two replicates. If the titer was below or above the limit of detection, the threshold value was used. The percentage of participants achieving a titer of 40 or more, as well as the 90% confidence interval (CI) using normal approximation were calculated for each strain and treatment group.
Time frame: 28 days post vaccination
Population: Per-protocol population: Enrolled and vaccinated participants with antibody assessments at Day 28, but excluding those with important events/deviations potentially impacting analysis (multiple sclerosis relapse, poor compliance to treatment, interfering concomitant drug). Participants were considered according to the treatment actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Teriflunomide 7 mg | Percentage of Participants With Antibody Titer ≥40 at 28 Days Post Vaccination | H3N2 strain | 90.0 percentage of participants |
| Teriflunomide 7 mg | Percentage of Participants With Antibody Titer ≥40 at 28 Days Post Vaccination | H1N1 strain | 97.5 percentage of participants |
| Teriflunomide 7 mg | Percentage of Participants With Antibody Titer ≥40 at 28 Days Post Vaccination | B strain | 97.5 percentage of participants |
| Teriflunomide 14 mg | Percentage of Participants With Antibody Titer ≥40 at 28 Days Post Vaccination | H3N2 strain | 76.9 percentage of participants |
| Teriflunomide 14 mg | Percentage of Participants With Antibody Titer ≥40 at 28 Days Post Vaccination | H1N1 strain | 97.4 percentage of participants |
| Teriflunomide 14 mg | Percentage of Participants With Antibody Titer ≥40 at 28 Days Post Vaccination | B strain | 97.4 percentage of participants |
| IFN-β-1 | Percentage of Participants With Antibody Titer ≥40 at 28 Days Post Vaccination | H1N1 strain | 97.7 percentage of participants |
| IFN-β-1 | Percentage of Participants With Antibody Titer ≥40 at 28 Days Post Vaccination | B strain | 93.0 percentage of participants |
| IFN-β-1 | Percentage of Participants With Antibody Titer ≥40 at 28 Days Post Vaccination | H3N2 strain | 90.7 percentage of participants |
Secondary
Geometric Mean of Titers (GMT) Ratio Post/Pre Vaccination
Time frame: pre vaccination (baseline) and 28 days post vaccination
Population: Per-protocol population as previously defined
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Teriflunomide 7 mg | Geometric Mean of Titers (GMT) Ratio Post/Pre Vaccination | H3N2 strain | 2.6 ratio post/pre vaccination |
| Teriflunomide 7 mg | Geometric Mean of Titers (GMT) Ratio Post/Pre Vaccination | H1N1 strain | 2.5 ratio post/pre vaccination |
| Teriflunomide 7 mg | Geometric Mean of Titers (GMT) Ratio Post/Pre Vaccination | B strain | 3.1 ratio post/pre vaccination |
| Teriflunomide 14 mg | Geometric Mean of Titers (GMT) Ratio Post/Pre Vaccination | H3N2 strain | 2.6 ratio post/pre vaccination |
| Teriflunomide 14 mg | Geometric Mean of Titers (GMT) Ratio Post/Pre Vaccination | H1N1 strain | 2.3 ratio post/pre vaccination |
| Teriflunomide 14 mg | Geometric Mean of Titers (GMT) Ratio Post/Pre Vaccination | B strain | 3.0 ratio post/pre vaccination |
| IFN-β-1 | Geometric Mean of Titers (GMT) Ratio Post/Pre Vaccination | H1N1 strain | 3.4 ratio post/pre vaccination |
| IFN-β-1 | Geometric Mean of Titers (GMT) Ratio Post/Pre Vaccination | B strain | 4.7 ratio post/pre vaccination |
| IFN-β-1 | Geometric Mean of Titers (GMT) Ratio Post/Pre Vaccination | H3N2 strain | 4.1 ratio post/pre vaccination |
Secondary
Immunoglobulin Levels
Time frame: pre vaccination (baseline) and 28 days post vaccination
Population: Per-protocol population as previously defined
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Teriflunomide 7 mg | Immunoglobulin Levels | Immunoglobulin M - pre vaccination | 1.28 g/L | Standard Deviation 0.57 |
| Teriflunomide 7 mg | Immunoglobulin Levels | Immunoglobulin M - 28-day post vaccination | 1.30 g/L | Standard Deviation 0.56 |
| Teriflunomide 7 mg | Immunoglobulin Levels | Immunoglobulin G - pre vaccination | 9.35 g/L | Standard Deviation 1.82 |
| Teriflunomide 7 mg | Immunoglobulin Levels | Immunoglobulin G - 28-day post vaccination | 9.57 g/L | Standard Deviation 2.08 |
| Teriflunomide 7 mg | Immunoglobulin Levels | Immunoglobulin A - pre vaccination | 1.65 g/L | Standard Deviation 0.66 |
| Teriflunomide 7 mg | Immunoglobulin Levels | Immunoglobulin A - 28-day post vaccination | 1.63 g/L | Standard Deviation 0.68 |
| Teriflunomide 14 mg | Immunoglobulin Levels | Immunoglobulin A - 28-day post vaccination | 1.50 g/L | Standard Deviation 0.63 |
| Teriflunomide 14 mg | Immunoglobulin Levels | Immunoglobulin M - pre vaccination | 1.23 g/L | Standard Deviation 0.59 |
| Teriflunomide 14 mg | Immunoglobulin Levels | Immunoglobulin G - 28-day post vaccination | 9.09 g/L | Standard Deviation 2.25 |
| Teriflunomide 14 mg | Immunoglobulin Levels | Immunoglobulin A - pre vaccination | 1.51 g/L | Standard Deviation 0.64 |
| Teriflunomide 14 mg | Immunoglobulin Levels | Immunoglobulin M - 28-day post vaccination | 1.27 g/L | Standard Deviation 0.6 |
| Teriflunomide 14 mg | Immunoglobulin Levels | Immunoglobulin G - pre vaccination | 9.12 g/L | Standard Deviation 2.24 |
| IFN-β-1 | Immunoglobulin Levels | Immunoglobulin M - 28-day post vaccination | 1.16 g/L | Standard Deviation 0.54 |
| IFN-β-1 | Immunoglobulin Levels | Immunoglobulin G - pre vaccination | 12.03 g/L | Standard Deviation 3.01 |
| IFN-β-1 | Immunoglobulin Levels | Immunoglobulin A - 28-day post vaccination | 2.33 g/L | Standard Deviation 1.07 |
| IFN-β-1 | Immunoglobulin Levels | Immunoglobulin G - 28-day post vaccination | 12.25 g/L | Standard Deviation 2.69 |
| IFN-β-1 | Immunoglobulin Levels | Immunoglobulin M - pre vaccination | 1.14 g/L | Standard Deviation 0.58 |
| IFN-β-1 | Immunoglobulin Levels | Immunoglobulin A - pre vaccination | 2.27 g/L | Standard Deviation 1.07 |
Secondary
Percentage of Participants With 2 Fold or More Increase in Antibody Titer at 28 Days Post Vaccination
Percentages of participants with an increase from baseline of 2-fold or more in antibody titers and 90% CIs using normal approximation were calculated for each strain and treatment group.
Time frame: pre vaccination (baseline) and 28 days post vaccination
Population: Per-protocol population as previously defined
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Teriflunomide 7 mg | Percentage of Participants With 2 Fold or More Increase in Antibody Titer at 28 Days Post Vaccination | H3N2 strain | 35.0 percentage of participants |
| Teriflunomide 7 mg | Percentage of Participants With 2 Fold or More Increase in Antibody Titer at 28 Days Post Vaccination | H1N1 strain | 35.0 percentage of participants |
| Teriflunomide 7 mg | Percentage of Participants With 2 Fold or More Increase in Antibody Titer at 28 Days Post Vaccination | B strain | 47.5 percentage of participants |
| Teriflunomide 14 mg | Percentage of Participants With 2 Fold or More Increase in Antibody Titer at 28 Days Post Vaccination | H3N2 strain | 41.0 percentage of participants |
| Teriflunomide 14 mg | Percentage of Participants With 2 Fold or More Increase in Antibody Titer at 28 Days Post Vaccination | H1N1 strain | 30.8 percentage of participants |
| Teriflunomide 14 mg | Percentage of Participants With 2 Fold or More Increase in Antibody Titer at 28 Days Post Vaccination | B strain | 51.3 percentage of participants |
| IFN-β-1 | Percentage of Participants With 2 Fold or More Increase in Antibody Titer at 28 Days Post Vaccination | H1N1 strain | 46.5 percentage of participants |
| IFN-β-1 | Percentage of Participants With 2 Fold or More Increase in Antibody Titer at 28 Days Post Vaccination | B strain | 58.1 percentage of participants |
| IFN-β-1 | Percentage of Participants With 2 Fold or More Increase in Antibody Titer at 28 Days Post Vaccination | H3N2 strain | 51.2 percentage of participants |
Secondary
Percentage of Participants With 4 Fold or More Increase in Antibody Titer at 28 Days Post Vaccination
Percentages of participants with an increase from baseline of 4-fold or more in antibody titers and 90% CIs using normal approximation were calculated for each strain and treatment group.
Time frame: pre vaccination (baseline) and 28 days post vaccination
Population: Per-protocol population as previously defined
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Teriflunomide 7 mg | Percentage of Participants With 4 Fold or More Increase in Antibody Titer at 28 Days Post Vaccination | B strain | 37.5 percentage of participants |
| Teriflunomide 7 mg | Percentage of Participants With 4 Fold or More Increase in Antibody Titer at 28 Days Post Vaccination | H3N2 strain | 25.0 percentage of participants |
| Teriflunomide 7 mg | Percentage of Participants With 4 Fold or More Increase in Antibody Titer at 28 Days Post Vaccination | H1N1 strain | 22.5 percentage of participants |
| Teriflunomide 14 mg | Percentage of Participants With 4 Fold or More Increase in Antibody Titer at 28 Days Post Vaccination | B strain | 30.8 percentage of participants |
| Teriflunomide 14 mg | Percentage of Participants With 4 Fold or More Increase in Antibody Titer at 28 Days Post Vaccination | H1N1 strain | 20.5 percentage of participants |
| Teriflunomide 14 mg | Percentage of Participants With 4 Fold or More Increase in Antibody Titer at 28 Days Post Vaccination | H3N2 strain | 23.1 percentage of participants |
| IFN-β-1 | Percentage of Participants With 4 Fold or More Increase in Antibody Titer at 28 Days Post Vaccination | B strain | 51.2 percentage of participants |
| IFN-β-1 | Percentage of Participants With 4 Fold or More Increase in Antibody Titer at 28 Days Post Vaccination | H3N2 strain | 41.9 percentage of participants |
| IFN-β-1 | Percentage of Participants With 4 Fold or More Increase in Antibody Titer at 28 Days Post Vaccination | H1N1 strain | 39.5 percentage of participants |