Relapsing Multiple Sclerosis
Conditions
Keywords
Relapsing multiple sclerosis, MS, Immune response
Brief summary
This study will evaluate the effect of treatment with fingolimod on the immune response following seasonal influenza vaccination and tetanus booster injection in patients with relapsing MS.
Interventions
DRUGFingolimod
Fingolimod 0.5 mg capsules for oral administration.
DRUGPlacebo
Matching placebo capsules for oral administration.
BIOLOGICALSeasonal influenza vaccine
Commercially available injectable influenza vaccine for the 2010/11 influenza season.
BIOLOGICALTetanus toxoid vaccine
Commercially available tetanus toxoid vaccine booster injection.
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Must have relapsing MS * Must have lifetime tetanus vaccination * Agree to receive 2010/2011 seasonal influenza vaccine and tetanus toxoid booster injection
Exclusion criteria
* Patients with a type of MS that is not relapsing * Patients with history of chronic immune disease * Certain cancers * Diabetic patients with certain eye disorders * Patients who are on certain immunosuppressive medications or heart medications * Patients with certain heart conditions * Patients with certain lung conditions * Patients who have already received the 2010/2011 seasonal influenza vaccine Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Immune Response 3 Weeks After Seasonal Influenza Vaccination | Week 6 (pre-vaccination) and 3 weeks after vaccination (Study week 9) | Percentage of participants who responded to treatment with the seasonal influenza vaccine 3 weeks after vaccination. Response was defined as patients fulfilling one of the following criteria for at least one of the three strains contained in the seasonal influenza vaccine: * Seroconversion: The pre-vaccination antibody titer measurement was \<1:10 and the post-vaccination measurement is ≥1:40. * Significant increase in antibody titer: The pre-vaccination antibody titer measurement was ≥1:10 and the increase in antibody titer from this to the post-vaccination measurement is ≥ 4-fold. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Immune Response 3 Weeks After Tetanus Toxoid Booster | Week 6 (pre-vaccination) and 3 weeks after vaccination (Study Week 9) | Percentage of participants with an immune response to a single dose of tetanus toxoid three weeks after vaccination. A patient was considered a responder to tetanus toxoid booster vaccination if one of the following criteria was met: 1. Seroconversion: The pre-vaccination antibody titer measurement was \<0.1 IU/ml and the post-vaccination measurement was ≥0.4 IU/ml. 2. Significant increase: The pre-vaccination antibody titer measurement was ≥0.1 IU/ml and the increase in antibody titer from this to the post-vaccination measurement was ≥4- fold. |
| Immune Response 6 Weeks After Tetanus Toxoid Booster | Week 6 (pre-vaccination) and 6 weeks after vaccination (Study Week 12) | Percentage of participants with an immune response to a single dose of tetanus toxoid six weeks after vaccination. A patient was considered a responder to tetanus toxoid booster vaccination if one of the following criteria was met: 1. Seroconversion: The pre-vaccination antibody titer measurement was \<0.1 IU/ml and the post-vaccination measurement was ≥0.4 IU/ml. 2. Significant increase: The pre-vaccination antibody titer measurement was ≥0.1 IU/ml and the increase in antibody titer from this to the post-vaccination measurement was ≥4- fold. |
| Immune Response 6 Weeks After Seasonal Influenza Vaccination | Week 6 (pre-vaccination) and 6 weeks after vaccination (Study week 12). | Percentage of participants who responded to treatment with the seasonal influenza vaccine 6 weeks after vaccination. Response was defined as patients fulfilling one of the following criteria for at least one of the three strains contained in the seasonal influenza vaccine: * Seroconversion: The pre-vaccination antibody titer measurement was \<1:10 and the post-vaccination measurement is ≥1:40. * Significant increase in antibody titer: The pre-vaccination antibody titer measurement was ≥1:10 and the increase in antibody titer from this to the post-vaccination measurement is ≥ 4-fold. |
| Change From Baseline in Seasonal Influenza Vaccine Antibody-titer 6 Weeks After Vaccination | Pre-vaccination (Week 6) and 6 weeks after vaccination (Study Week 12). | Change from Baseline was expressed by the ratio of post-vaccination to pre-vaccination antibody titer for each of the three strains included in the seasonal influenza vaccine. Inhibition of an immune response to each strain included in the seasonal influenza vaccine was assessed by the relative difference of the geometric mean antibody titer ratio on fingolimod as compared to placebo six weeks after a single dose of seasonal influenza vaccine. |
| Number of Participants With Adverse Events (AEs) | From first dose of study drug until 45 days after the last dose of study drug (130 days). | Relationship to study drug was determined by the investigator (suspected/not suspected). A serious AE is defined as an event which fulfills one of the following criteria: * is fatal or life-threatening; * results in persistent or significant disability/incapacity; * constitutes a congenital anomaly/birth defect; * requires inpatient hospitalization or prolongation of existing hospitalization; * is medically significant, i.e., jeopardizes the patient or may require intervention to prevent one of the outcomes listed above. |
| Change From Baseline in Seasonal Influenza Vaccine Antibody-titer 3 Weeks After Vaccination | Pre-vaccination (Week 6) and 3 weeks after vaccination (Study Week 9). | Change from Baseline was expressed by the ratio of post-vaccination to pre-vaccination antibody titer for each of the three strains included in the seasonal influenza vaccine. Inhibition of an immune response to each strain included in the seasonal influenza vaccine was assessed by the relative difference of the geometric mean antibody titer ratio on fingolimod as compared to placebo three weeks after a single dose of seasonal influenza vaccine. |
Countries
Belgium, Canada, Finland, France, Guatemala, Poland, Spain, Switzerland, United Kingdom
Participant flow
Pre-assignment details
Participants were randomized in a 2:1 ratio to fingolimod 0.5 mg once daily or matching placebo.
Participants by arm
| Arm | Count |
|---|---|
| Fingolimod Participants received Fingolimod 0.5 mg capsules orally once daily for 12 weeks. At Week 6 of study treatment participants received a seasonal influenza vaccination and a tetanus booster vaccination. | 95 |
| Placebo Participants received placebo tablets orally once daily for 12 weeks. At Week 6 of study treatment participants received a seasonal influenza vaccination and a tetanus booster vaccination. | 43 |
| Total | 138 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative problems | 1 | 0 |
| Overall Study | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Fingolimod | Placebo | Total |
|---|---|---|---|
| Age Continuous | 37.4 years STANDARD_DEVIATION 8.37 | 39.2 years STANDARD_DEVIATION 8.67 | 37.9 years STANDARD_DEVIATION 8.48 |
| Age, Customized 18-30 | 25 participants | 8 participants | 33 participants |
| Age, Customized 31-40 | 35 participants | 14 participants | 49 participants |
| Age, Customized 41-55 | 35 participants | 21 participants | 56 participants |
| Sex: Female, Male Female | 65 Participants | 29 Participants | 94 Participants |
| Sex: Female, Male Male | 30 Participants | 14 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 51 / 95 | 22 / 43 |
| serious Total, serious adverse events | 1 / 95 | 2 / 43 |
Outcome results
Primary
Immune Response 3 Weeks After Seasonal Influenza Vaccination
Percentage of participants who responded to treatment with the seasonal influenza vaccine 3 weeks after vaccination. Response was defined as patients fulfilling one of the following criteria for at least one of the three strains contained in the seasonal influenza vaccine: * Seroconversion: The pre-vaccination antibody titer measurement was \<1:10 and the post-vaccination measurement is ≥1:40. * Significant increase in antibody titer: The pre-vaccination antibody titer measurement was ≥1:10 and the increase in antibody titer from this to the post-vaccination measurement is ≥ 4-fold.
Time frame: Week 6 (pre-vaccination) and 3 weeks after vaccination (Study week 9)
Population: The full analysis set which includes all patients who were randomized and received at least 1 dose of study drug, and for whom data were available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fingolimod | Immune Response 3 Weeks After Seasonal Influenza Vaccination | 53.3 percentage of participants |
| Placebo | Immune Response 3 Weeks After Seasonal Influenza Vaccination | 83.7 percentage of participants |
Secondary
Change From Baseline in Seasonal Influenza Vaccine Antibody-titer 3 Weeks After Vaccination
Change from Baseline was expressed by the ratio of post-vaccination to pre-vaccination antibody titer for each of the three strains included in the seasonal influenza vaccine. Inhibition of an immune response to each strain included in the seasonal influenza vaccine was assessed by the relative difference of the geometric mean antibody titer ratio on fingolimod as compared to placebo three weeks after a single dose of seasonal influenza vaccine.
Time frame: Pre-vaccination (Week 6) and 3 weeks after vaccination (Study Week 9).
Population: Full analysis set for whom data were available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fingolimod | Change From Baseline in Seasonal Influenza Vaccine Antibody-titer 3 Weeks After Vaccination | A/California/7/09(H1N1) | 2.45 ratio |
| Fingolimod | Change From Baseline in Seasonal Influenza Vaccine Antibody-titer 3 Weeks After Vaccination | A/Perth/16/2009(H3N2) | 0.49 ratio |
| Fingolimod | Change From Baseline in Seasonal Influenza Vaccine Antibody-titer 3 Weeks After Vaccination | B/Brisbane/60/2008 | 1.34 ratio |
| Placebo | Change From Baseline in Seasonal Influenza Vaccine Antibody-titer 3 Weeks After Vaccination | A/California/7/09(H1N1) | 4.14 ratio |
| Placebo | Change From Baseline in Seasonal Influenza Vaccine Antibody-titer 3 Weeks After Vaccination | A/Perth/16/2009(H3N2) | 0.36 ratio |
| Placebo | Change From Baseline in Seasonal Influenza Vaccine Antibody-titer 3 Weeks After Vaccination | B/Brisbane/60/2008 | 2.40 ratio |
Comparison: The inhibition of an immune response to the A/California/7/09 (H1N1) strain of the seasonal influenza vaccine was assessed by the relative difference of the geometric mean antibody titer ratio on fingolimod as compared to placebo three weeks after a single dose of seasonal influenza vaccine.
Comparison: The inhibition of an immune response to the A/Perth/16/2009 (H3N2) strain of the seasonal influenza vaccine was assessed by the relative difference of the geometric mean antibody titer ratio on fingolimod as compared to placebo three weeks after a single dose of seasonal influenza vaccine.
Comparison: The inhibition of an immune response to the B/Brisbane/60/2008 strain of the seasonal influenza vaccine was assessed by the relative difference of the geometric mean antibody titer ratio on fingolimod as compared to placebo three weeks after a single dose of seasonal influenza vaccine.
Secondary
Change From Baseline in Seasonal Influenza Vaccine Antibody-titer 6 Weeks After Vaccination
Change from Baseline was expressed by the ratio of post-vaccination to pre-vaccination antibody titer for each of the three strains included in the seasonal influenza vaccine. Inhibition of an immune response to each strain included in the seasonal influenza vaccine was assessed by the relative difference of the geometric mean antibody titer ratio on fingolimod as compared to placebo six weeks after a single dose of seasonal influenza vaccine.
Time frame: Pre-vaccination (Week 6) and 6 weeks after vaccination (Study Week 12).
Population: Full analysis set for whom data were available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fingolimod | Change From Baseline in Seasonal Influenza Vaccine Antibody-titer 6 Weeks After Vaccination | A/California/7/09(H1N1) | 1.81 ratio |
| Fingolimod | Change From Baseline in Seasonal Influenza Vaccine Antibody-titer 6 Weeks After Vaccination | A/Perth/16/2009(H3N2) | 0.36 ratio |
| Fingolimod | Change From Baseline in Seasonal Influenza Vaccine Antibody-titer 6 Weeks After Vaccination | B/Brisbane/60/2008 | 1.08 ratio |
| Placebo | Change From Baseline in Seasonal Influenza Vaccine Antibody-titer 6 Weeks After Vaccination | A/California/7/09(H1N1) | 2.91 ratio |
| Placebo | Change From Baseline in Seasonal Influenza Vaccine Antibody-titer 6 Weeks After Vaccination | A/Perth/16/2009(H3N2) | 0.28 ratio |
| Placebo | Change From Baseline in Seasonal Influenza Vaccine Antibody-titer 6 Weeks After Vaccination | B/Brisbane/60/2008 | 2.07 ratio |
Comparison: The inhibition of an immune response to the A/California/7/09 (H1N1) strain of the seasonal influenza vaccine was assessed by the relative difference of the geometric mean antibody titer ratio on fingolimod as compared to placebo six weeks after a single dose of seasonal influenza vaccine.
Comparison: The inhibition of an immune response to the A/Perth/16/2009 (H3N2) strain of the seasonal influenza vaccine was assessed by the relative difference of the geometric mean antibody titer ratio on fingolimod as compared to placebo six weeks after a single dose of seasonal influenza vaccine.
Comparison: The inhibition of an immune response to the B/Brisbane/60/2008 strain of the seasonal influenza vaccine was assessed by the relative difference of the geometric mean antibody titer ratio on fingolimod as compared to placebo six weeks after a single dose of seasonal influenza vaccine.
Secondary
Immune Response 3 Weeks After Tetanus Toxoid Booster
Percentage of participants with an immune response to a single dose of tetanus toxoid three weeks after vaccination. A patient was considered a responder to tetanus toxoid booster vaccination if one of the following criteria was met: 1. Seroconversion: The pre-vaccination antibody titer measurement was \<0.1 IU/ml and the post-vaccination measurement was ≥0.4 IU/ml. 2. Significant increase: The pre-vaccination antibody titer measurement was ≥0.1 IU/ml and the increase in antibody titer from this to the post-vaccination measurement was ≥4- fold.
Time frame: Week 6 (pre-vaccination) and 3 weeks after vaccination (Study Week 9)
Population: Full analysis set for whom data were available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fingolimod | Immune Response 3 Weeks After Tetanus Toxoid Booster | 40.0 percentage of participants |
| Placebo | Immune Response 3 Weeks After Tetanus Toxoid Booster | 60.5 percentage of participants |
Secondary
Immune Response 6 Weeks After Seasonal Influenza Vaccination
Percentage of participants who responded to treatment with the seasonal influenza vaccine 6 weeks after vaccination. Response was defined as patients fulfilling one of the following criteria for at least one of the three strains contained in the seasonal influenza vaccine: * Seroconversion: The pre-vaccination antibody titer measurement was \<1:10 and the post-vaccination measurement is ≥1:40. * Significant increase in antibody titer: The pre-vaccination antibody titer measurement was ≥1:10 and the increase in antibody titer from this to the post-vaccination measurement is ≥ 4-fold.
Time frame: Week 6 (pre-vaccination) and 6 weeks after vaccination (Study week 12).
Population: Full analysis set for whom data were available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fingolimod | Immune Response 6 Weeks After Seasonal Influenza Vaccination | 43.2 percentage of participants |
| Placebo | Immune Response 6 Weeks After Seasonal Influenza Vaccination | 74.4 percentage of participants |
Secondary
Immune Response 6 Weeks After Tetanus Toxoid Booster
Percentage of participants with an immune response to a single dose of tetanus toxoid six weeks after vaccination. A patient was considered a responder to tetanus toxoid booster vaccination if one of the following criteria was met: 1. Seroconversion: The pre-vaccination antibody titer measurement was \<0.1 IU/ml and the post-vaccination measurement was ≥0.4 IU/ml. 2. Significant increase: The pre-vaccination antibody titer measurement was ≥0.1 IU/ml and the increase in antibody titer from this to the post-vaccination measurement was ≥4- fold.
Time frame: Week 6 (pre-vaccination) and 6 weeks after vaccination (Study Week 12)
Population: Full analysis set for whom data were available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fingolimod | Immune Response 6 Weeks After Tetanus Toxoid Booster | 37.5 percentage of participants |
| Placebo | Immune Response 6 Weeks After Tetanus Toxoid Booster | 48.8 percentage of participants |
Secondary
Number of Participants With Adverse Events (AEs)
Relationship to study drug was determined by the investigator (suspected/not suspected). A serious AE is defined as an event which fulfills one of the following criteria: * is fatal or life-threatening; * results in persistent or significant disability/incapacity; * constitutes a congenital anomaly/birth defect; * requires inpatient hospitalization or prolongation of existing hospitalization; * is medically significant, i.e., jeopardizes the patient or may require intervention to prevent one of the outcomes listed above.
Time frame: From first dose of study drug until 45 days after the last dose of study drug (130 days).
Population: Safety set - all patients who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fingolimod | Number of Participants With Adverse Events (AEs) | Any adverse event | 82 participants |
| Fingolimod | Number of Participants With Adverse Events (AEs) | AE related to study drug | 42 participants |
| Fingolimod | Number of Participants With Adverse Events (AEs) | Serious adverse event | 1 participants |
| Fingolimod | Number of Participants With Adverse Events (AEs) | Adverse events leading to discontinuation | 1 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Adverse events leading to discontinuation | 0 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Any adverse event | 34 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Serious adverse event | 2 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | AE related to study drug | 11 participants |