Relapsing Remitting Multiple Sclerosis (RRMS)
Conditions
Keywords
Relapsing remitting multiple sclerosis, multiple sclerosis (MS), safety, tolerability, health outcomes, fingolimod, disease control, MRI
Brief summary
This study evaluated disease control during different lengths of treatment transition from natalizumab to fingolimod.
Detailed description
Patient were screened, signed an informed consent at visit 1, at the 2nd visit, all patient received a baseline infusion of Natalizumub and subsequently randomized to one of 3 treatment arms. At the randomization visit, the Washout Phase started, and eligible patients were randomized 1:1:1 to one of three treatment groups: * 8-week washout (8 weeks no treatment) followed by 24 weeks of treatment with fingolimod, * 12-week washout (8 weeks no treatment and 4 weeks placebo) followed by 20 weeks of treatment with fingolimod, or * 16-week washout (8 weeks no treatment and 8 weeks placebo) followed by 16 weeks of treatment with fingolimod.
Interventions
DRUGFingolimod
Fingolimod 0.5 mg capsules for oral administration once daily
DRUGPlacebo
Matching placebo in capsules for oral administration once daily.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Patients must: * Have relapsing remitting multiple sclerosis * Have been on treatment with natalizumab for at least 6 months prior to screening and discontinuation is an option.
Exclusion criteria
Patients with: * History of chronic immune disease * Crohn's disease * Certain cancers * Uncontrolled diabetes * Certain eye disorders * Negative for varicella-zoster virus IgG antibodies * Certain hepatic conditions * Low white blood cell count * On certain immunosuppressive medications or heart medications * Resting heart rate less than 45 bpm. * Certain heart conditions or certain lung conditions * Inability to undergo MRI scans Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Active (New or Newly Enlarging) T2 Lesions From the Last Natalizumab Infusion (Baseline) Through 8 Weeks of Fingolimod Treatment | Number of active T2 lesions from last natalizumab dose through 8 weeks of fingolimod treatment | Active lesions were measured on brain MRI scans, performed at week 8, compared to the prior scan. The primary variable was analyzed by fitting a negative binomial regression model adjusted for washout group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Active (New or Newly Enlarging) T2 Lesions During the First 8 Weeks of Fingolimod Treatment | Number of active T2 lesions during 8 wks of fingolimod treatment | Lesions were measured by MRIs and the number of active (new or newly enlarging) T2 lesions was calculated for first 8 weeks of fingolimod treatment. |
| Number of Active (New or Newly Enlarging) T2 Lesions During the 24 Weeks After the Last Natalizumab Infusion (Baseline) | Baseline up to 24 weeks | Lesions will be measured by MRIs and the number of active (new or newly enlarging) T2 lesions will be calculated for 24 weeks from baseline. |
| Change From Baseline in Expanded Disability Status Scale (EDSS) by Washout Group | Baseline to week 16 and week 32 | Kurtzke's Expanded Disability Status Scale (EDSS) measures the changes in neurologic impairment, either chronic (progression over time), or acute (MS relapses). The EDSS steps range from 0 (normal) to 10 (death due to MS). Relapse severity is assessed based on severity of neurologic impairment as evaluated using the EDSS. |
| Number of Active (New or Newly Enlarging) T2 Lesions From the Last Natalizumab Infusion (Baseline) up to the Initiation of Fingolimod Treatment | 8, 12 and 16 weeks (number of active T2 lesions during the washout period only) | Lesions were measured by MRIs and the number of active (new or newly enlarging) T2 lesions was calculated from baseline to beginning of treatment. |
| Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death During Washout Period | Baseline to maximum of 16 weeks | Adverse events were summarized by the number of patients having any adverse event overall. |
| Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death During Fingolimod Treatment | Baseline to maximum of 16 weeks | Adverse events were summarized by the number of patients having any adverse event overall. |
| Cumulative Number of Gadolinium-enhancing T1 Lesions From the Last Natalizumab Infusion | 8 weeks and 24 weeks | Gadolinium-enhancing lesions will be measured on post-contrast T1-weighted brain MRI scans |
Countries
Australia, Austria, Czechia, Finland, Germany, Greece, Hungary, Israel, Italy, Spain, Switzerland
Participant flow
Recruitment details
Of the 158 patients screened, 142 patients were randomized.
Pre-assignment details
142 Participants were randomized to 3 washout groups in a ratio of 1:1:1
Participants by arm
| Arm | Count |
|---|---|
| 8-week Washout + Fingolimod (FTY720) 8-week washout (8 weeks no treatment) followed by 24 weeks of treatment with fingolimod 0.5mg once a day | 50 |
| 12-week Washout + Fingolimod (FTY720) 12-week washout (8 weeks no treatment and 4 weeks placebo) followed by 20 weeks of treatment with fingolimod 0.5mg once a day | 42 |
| 16-week Washout + Fingolimod (FTY720) 16-week washout (8 weeks no treatment and 8 weeks placebo) followed by 16 weeks of treatment with fingolimod | 50 |
| Total | 142 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | administrative problems | 4 | 5 | 5 |
| Overall Study | Adverse Event | 0 | 2 | 2 |
| Overall Study | Lack of Efficacy | 2 | 0 | 0 |
| Overall Study | Protocol Violation | 1 | 3 | 2 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 1 |
Baseline characteristics
| Characteristic | 8-week Washout + Fingolimod (FTY720) | 12-week Washout + Fingolimod (FTY720) | 16-week Washout + Fingolimod (FTY720) | Total |
|---|---|---|---|---|
| Age, Continuous | 41.2 Years STANDARD_DEVIATION 10.102 | 41.9 Years STANDARD_DEVIATION 7.445 | 41.8 Years STANDARD_DEVIATION 8.552 | 41.6 Years STANDARD_DEVIATION 8.78 |
| Sex: Female, Male Female | 39 Participants | 21 Participants | 32 Participants | 92 Participants |
| Sex: Female, Male Male | 11 Participants | 21 Participants | 18 Participants | 50 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 | 17 / 50 | 7 / 42 | 14 / 50 |
| serious Total, serious adverse events | 2 / 50 | 5 / 42 | 4 / 50 |
Outcome results
Primary
Number of Active (New or Newly Enlarging) T2 Lesions From the Last Natalizumab Infusion (Baseline) Through 8 Weeks of Fingolimod Treatment
Active lesions were measured on brain MRI scans, performed at week 8, compared to the prior scan. The primary variable was analyzed by fitting a negative binomial regression model adjusted for washout group.
Time frame: Number of active T2 lesions from last natalizumab dose through 8 weeks of fingolimod treatment
Population: The modified Full Analysis Set (mFAS) included all patients in the Full Analysis Set who completed 8 weeks of fingolimod treatment and provided an MRI scan at this time point. The analysis of primary variable was performed on the mFAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 8-week Washout + Fingolimod (FTY720) | Number of Active (New or Newly Enlarging) T2 Lesions From the Last Natalizumab Infusion (Baseline) Through 8 Weeks of Fingolimod Treatment | 2.1 Count of Active T2 Lesions | Standard Deviation 7.24 |
| 12-week Washout + Fingolimod (FTY720) | Number of Active (New or Newly Enlarging) T2 Lesions From the Last Natalizumab Infusion (Baseline) Through 8 Weeks of Fingolimod Treatment | 1.7 Count of Active T2 Lesions | Standard Deviation 3.78 |
| 16-week Washout + Fingolimod (FTY720) | Number of Active (New or Newly Enlarging) T2 Lesions From the Last Natalizumab Infusion (Baseline) Through 8 Weeks of Fingolimod Treatment | 8.2 Count of Active T2 Lesions | Standard Deviation 16.81 |
Secondary
Change From Baseline in Expanded Disability Status Scale (EDSS) by Washout Group
Kurtzke's Expanded Disability Status Scale (EDSS) measures the changes in neurologic impairment, either chronic (progression over time), or acute (MS relapses). The EDSS steps range from 0 (normal) to 10 (death due to MS). Relapse severity is assessed based on severity of neurologic impairment as evaluated using the EDSS.
Time frame: Baseline to week 16 and week 32
Population: The Full Analysis Set (FAS) included all randomized patients who had at least one recorded dose of natalizumab at the Week 0 visit, analyzed according to the washout group assigned at randomization.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 8-week Washout + Fingolimod (FTY720) | Change From Baseline in Expanded Disability Status Scale (EDSS) by Washout Group | Week 16 (n=40, 33, 39) | 0.11 Units on a scale | Standard Deviation 0.33 |
| 8-week Washout + Fingolimod (FTY720) | Change From Baseline in Expanded Disability Status Scale (EDSS) by Washout Group | Week 32 (n= 40,30,39) | 0.11 Units on a scale | Standard Deviation 0.625 |
| 12-week Washout + Fingolimod (FTY720) | Change From Baseline in Expanded Disability Status Scale (EDSS) by Washout Group | Week 16 (n=40, 33, 39) | -0.03 Units on a scale | Standard Deviation 0.529 |
| 12-week Washout + Fingolimod (FTY720) | Change From Baseline in Expanded Disability Status Scale (EDSS) by Washout Group | Week 32 (n= 40,30,39) | -0.13 Units on a scale | Standard Deviation 0.524 |
| 16-week Washout + Fingolimod (FTY720) | Change From Baseline in Expanded Disability Status Scale (EDSS) by Washout Group | Week 16 (n=40, 33, 39) | 0.23 Units on a scale | Standard Deviation 0.706 |
| 16-week Washout + Fingolimod (FTY720) | Change From Baseline in Expanded Disability Status Scale (EDSS) by Washout Group | Week 32 (n= 40,30,39) | 0.08 Units on a scale | Standard Deviation 0.748 |
Secondary
Cumulative Number of Gadolinium-enhancing T1 Lesions From the Last Natalizumab Infusion
Gadolinium-enhancing lesions will be measured on post-contrast T1-weighted brain MRI scans
Time frame: 8 weeks and 24 weeks
Population: The Full Analysis Set (FAS) included all randomized patients who had at least one recorded dose of natalizumab at the Week 0 visit, analyzed according to the washout group assigned at randomization.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 8-week Washout + Fingolimod (FTY720) | Cumulative Number of Gadolinium-enhancing T1 Lesions From the Last Natalizumab Infusion | Week 8 (n=1,1,0) | 25.0 Number of Gd enhanced T1 Lesions | Standard Deviation 0 |
| 8-week Washout + Fingolimod (FTY720) | Cumulative Number of Gadolinium-enhancing T1 Lesions From the Last Natalizumab Infusion | Week 24 (n=10,12,21) | 6.3 Number of Gd enhanced T1 Lesions | Standard Deviation 9.45 |
| 12-week Washout + Fingolimod (FTY720) | Cumulative Number of Gadolinium-enhancing T1 Lesions From the Last Natalizumab Infusion | Week 8 (n=1,1,0) | 2.0 Number of Gd enhanced T1 Lesions | Standard Deviation 0 |
| 12-week Washout + Fingolimod (FTY720) | Cumulative Number of Gadolinium-enhancing T1 Lesions From the Last Natalizumab Infusion | Week 24 (n=10,12,21) | 3.4 Number of Gd enhanced T1 Lesions | Standard Deviation 4.54 |
| 16-week Washout + Fingolimod (FTY720) | Cumulative Number of Gadolinium-enhancing T1 Lesions From the Last Natalizumab Infusion | Week 8 (n=1,1,0) | NA Number of Gd enhanced T1 Lesions | — |
| 16-week Washout + Fingolimod (FTY720) | Cumulative Number of Gadolinium-enhancing T1 Lesions From the Last Natalizumab Infusion | Week 24 (n=10,12,21) | 3.6 Number of Gd enhanced T1 Lesions | Standard Deviation 4.49 |
Secondary
Number of Active (New or Newly Enlarging) T2 Lesions During the 24 Weeks After the Last Natalizumab Infusion (Baseline)
Lesions will be measured by MRIs and the number of active (new or newly enlarging) T2 lesions will be calculated for 24 weeks from baseline.
Time frame: Baseline up to 24 weeks
Population: The Full Analysis Set (FAS) included all randomized patients who had at least one recorded dose of natalizumab at the Week 0 visit, analyzed according to the washout group assigned at randomization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 8-week Washout + Fingolimod (FTY720) | Number of Active (New or Newly Enlarging) T2 Lesions During the 24 Weeks After the Last Natalizumab Infusion (Baseline) | 3.2 Count of Active T2 Lesions | Standard Deviation 10.07 |
| 12-week Washout + Fingolimod (FTY720) | Number of Active (New or Newly Enlarging) T2 Lesions During the 24 Weeks After the Last Natalizumab Infusion (Baseline) | 4.4 Count of Active T2 Lesions | Standard Deviation 16.01 |
| 16-week Washout + Fingolimod (FTY720) | Number of Active (New or Newly Enlarging) T2 Lesions During the 24 Weeks After the Last Natalizumab Infusion (Baseline) | 7.7 Count of Active T2 Lesions | Standard Deviation 16.28 |
Secondary
Number of Active (New or Newly Enlarging) T2 Lesions During the First 8 Weeks of Fingolimod Treatment
Lesions were measured by MRIs and the number of active (new or newly enlarging) T2 lesions was calculated for first 8 weeks of fingolimod treatment.
Time frame: Number of active T2 lesions during 8 wks of fingolimod treatment
Population: The Full Analysis Set (FAS) included all randomized patients who had at least one recorded dose of natalizumab at the Week 0 visit, analyzed according to the washout group assigned at randomization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 8-week Washout + Fingolimod (FTY720) | Number of Active (New or Newly Enlarging) T2 Lesions During the First 8 Weeks of Fingolimod Treatment | 1.5 Count of Active T2 Lesions | Standard Deviation 4.56 |
| 12-week Washout + Fingolimod (FTY720) | Number of Active (New or Newly Enlarging) T2 Lesions During the First 8 Weeks of Fingolimod Treatment | 2.1 Count of Active T2 Lesions | Standard Deviation 5.5 |
| 16-week Washout + Fingolimod (FTY720) | Number of Active (New or Newly Enlarging) T2 Lesions During the First 8 Weeks of Fingolimod Treatment | 4.2 Count of Active T2 Lesions | Standard Deviation 10.24 |
Secondary
Number of Active (New or Newly Enlarging) T2 Lesions From the Last Natalizumab Infusion (Baseline) up to the Initiation of Fingolimod Treatment
Lesions were measured by MRIs and the number of active (new or newly enlarging) T2 lesions was calculated from baseline to beginning of treatment.
Time frame: 8, 12 and 16 weeks (number of active T2 lesions during the washout period only)
Population: The Full Analysis Set (FAS) included all randomized patients who had at least one recorded dose of natalizumab at the Week 0 visit, analyzed according to the washout group assigned at randomization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 8-week Washout + Fingolimod (FTY720) | Number of Active (New or Newly Enlarging) T2 Lesions From the Last Natalizumab Infusion (Baseline) up to the Initiation of Fingolimod Treatment | 0.4 Count of active T2 lesions | Standard Deviation 2.71 |
| 12-week Washout + Fingolimod (FTY720) | Number of Active (New or Newly Enlarging) T2 Lesions From the Last Natalizumab Infusion (Baseline) up to the Initiation of Fingolimod Treatment | 2.1 Count of active T2 lesions | Standard Deviation 11.15 |
| 16-week Washout + Fingolimod (FTY720) | Number of Active (New or Newly Enlarging) T2 Lesions From the Last Natalizumab Infusion (Baseline) up to the Initiation of Fingolimod Treatment | 3.6 Count of active T2 lesions | Standard Deviation 7.54 |
Secondary
Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death During Fingolimod Treatment
Adverse events were summarized by the number of patients having any adverse event overall.
Time frame: Baseline to maximum of 16 weeks
Population: The Safety Set included all randomized patients, analyzed according to the washout group most closely corresponding to the day on which they first received fingolimod
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 8-week Washout + Fingolimod (FTY720) | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death During Fingolimod Treatment | Serious Adverse Events | 2 participants |
| 8-week Washout + Fingolimod (FTY720) | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death During Fingolimod Treatment | Any Adverse Events | 35 participants |
| 8-week Washout + Fingolimod (FTY720) | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death During Fingolimod Treatment | Death | 0 participants |
| 12-week Washout + Fingolimod (FTY720) | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death During Fingolimod Treatment | Serious Adverse Events | 5 participants |
| 12-week Washout + Fingolimod (FTY720) | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death During Fingolimod Treatment | Any Adverse Events | 20 participants |
| 12-week Washout + Fingolimod (FTY720) | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death During Fingolimod Treatment | Death | 0 participants |
| 16-week Washout + Fingolimod (FTY720) | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death During Fingolimod Treatment | Any Adverse Events | 28 participants |
| 16-week Washout + Fingolimod (FTY720) | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death During Fingolimod Treatment | Death | 0 participants |
| 16-week Washout + Fingolimod (FTY720) | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death During Fingolimod Treatment | Serious Adverse Events | 3 participants |
Secondary
Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death During Washout Period
Adverse events were summarized by the number of patients having any adverse event overall.
Time frame: Baseline to maximum of 16 weeks
Population: The Safety Set included all randomized patients, analyzed according to the washout group most closely corresponding to the day on which they first received fingolimod
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 8-week Washout + Fingolimod (FTY720) | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death During Washout Period | Serious Adverse Events | 0 participants |
| 8-week Washout + Fingolimod (FTY720) | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death During Washout Period | Any Adverse Events | 13 participants |
| 8-week Washout + Fingolimod (FTY720) | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death During Washout Period | Death | 0 participants |
| 12-week Washout + Fingolimod (FTY720) | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death During Washout Period | Serious Adverse Events | 0 participants |
| 12-week Washout + Fingolimod (FTY720) | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death During Washout Period | Any Adverse Events | 12 participants |
| 12-week Washout + Fingolimod (FTY720) | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death During Washout Period | Death | 0 participants |
| 16-week Washout + Fingolimod (FTY720) | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death During Washout Period | Any Adverse Events | 25 participants |
| 16-week Washout + Fingolimod (FTY720) | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death During Washout Period | Death | 0 participants |
| 16-week Washout + Fingolimod (FTY720) | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) and Death During Washout Period | Serious Adverse Events | 1 participants |