Relapsing-remitting Multiple Sclerosis
Conditions
Keywords
fingolimod, Biomarker, Multiple sclerosis, Relapsing-remitting multiple sclerosis
Brief summary
The purpose of this single visit extension study is to explore immune status in RRMS patients treated for at least 48 months with fingolimod. Long-term changes in T cell counts will be compared to short-term changes in immune status (baseline to month 6) after treatment start with fingolimod as assessed in the original Biobank study (CFTY720DDE01).
Interventions
DRUGfingolimod
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written informed consent before any assessment was performed. 2. Randomized in study CFTY720DDE01 and received at least one dose of study drug (fingolimod) and completed the study. 3. Continuous intake of fingolimod after end of study CFTY720DDE01 with a maximum treatment interruption of 3 months in total before entering this study. 4. Parallel participation at study CFTY720DDE02 (Pangaea NIS) was allowed.
Exclusion criteria
t: 1. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human Chorionic Gonadotropin (hCG) laboratory test. 2. Patients with onset of an acute relapse had to postpone their evaluation until deemed stable from relapse by treating physician, but at least for 1 month since end of relapse. 3. Patients that received immunomodulating or immunosuppressive MS treatments other than fingolimod since completion of study CFTY720DDE01 as for example: Natalizumab,Alemtuzumab, Dimethyl fumarate, Teriflunomide, intravenous Immunoglobulins,Mitoxantrone, Methotrexate, Azathioprine or experimental immunomodulating-immunosuppressive therapies.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in T Cells Status (Decrease or Increase) at Month 48 (FAS) | Baseline up to approximately 48 months | Aim of trial was to was to show reduction of CD4+ and CD8+ naïve T cells (CCR7+CD45RA+), central memory T cells (CCR7+CD45RA-), central memory Th17 cells (CD4+ CCR4+ and CCR6+), and an elevation of 2 types of effector memory T cells TEM (CCR7- CD45RA-) and TEMRA (CCR7- CD45RA+) in peripheral venous blood. Changes from baseline to month 48 in biomarkers were analyzed for all patients in the FAS. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Disability Progression as Measured by Expanded Disability Status Scale (EDSS) (FAS) | Baseline up to approximately 48 months | EDSS is a scale for assessing neurologic impairment in MS. It is a two-part system including (1) a series of scores in each of eight functional systems, and (2) the EDSS steps (ranging from 0 (normal) to 10 (death due to MS). The definition of disability progression was based on increases in EDSS from baseline and depended on the EDSS baseline value: Disability progression was defined as a 1.5 increase in EDSS from baseline in subjects with a baseline EDSS score between 0.0 and 0.5, as a 1.0 increase in EDSS from baseline in subjects with a baseline EDSS score between 1.0 and 5.0 inclusive and 0.5 increase from baseline in subjects with EDSS score \> 5.0. |
| Change From Baseline in Disability Progression Assessed With the Expanded Disability Status Scale (EDSS) at Month 6 and Month 48 (FAS) | Baseline, month 6 up to approximately 48 months | EDSS is a scale for assessing neurologic impairment in MS. It is a two-part system including (1) a series of scores in each of eight functional systems, and (2) the EDSS steps (ranging from 0 (normal) to 10 (death due to MS). The definition of disability progression was based on increases in EDSS from baseline and depended on the EDSS baseline value: Disability progression was defined as a 1.5 increase in EDSS from baseline in subjects with a baseline EDSS score between 0.0 and 0.5, as a 1.0 increase in EDSS from baseline in subjects with a baseline EDSS score between 1.0 and 5.0 inclusive and 0.5 increase from baseline in subjects with EDSS score \> 5.0. |
| Change in Immune Status of B Cells, Monocytes and Natural Killer Cells (NK) Cells (FAS) | Baseline up to approximately 48 months | Changes in immune status of B cells (CD19+, CD20+, CD69+), monocytes (CD14+) and NK cells (CD56+) were analyzed as a percentage of parent cell population (CD4+, CD8+ or total lymphocytes) by flow cytometry |
Countries
Germany
Participant flow
Pre-assignment details
There were 133 patients enrolled in the study but only 130 received drug
Participants by arm
| Arm | Count |
|---|---|
| Fingolimod Patients did not receive any protocol specified treatment during this follow-up study. Patients remained on their current treatment regime (fingolimod), as determined by their regular treating physician (i.e. 0.5 mg fingolimod daily, single-arm). | 130 |
| Total | 130 |
Baseline characteristics
| Characteristic | Fingolimod |
|---|---|
| Age, Continuous | 40.1 years STANDARD_DEVIATION 8.54 |
| Multiple Sclerosis History at screening of CFTY720DDE01 (Core) Difference of dagnosis and tx start in Core | 8.6 years STANDARD_DEVIATION 6.23 |
| Multiple Sclerosis History at screening of CFTY720DDE01 (Core) Difference of first symptons and diagnosis | 2.4 years STANDARD_DEVIATION 3.56 |
| Sex: Female, Male Female | 83 Participants |
| Sex: Female, Male Male | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 1 / 130 |
| serious Total, serious adverse events | 0 / 130 |
Outcome results
Primary
Change in T Cells Status (Decrease or Increase) at Month 48 (FAS)
Aim of trial was to was to show reduction of CD4+ and CD8+ naïve T cells (CCR7+CD45RA+), central memory T cells (CCR7+CD45RA-), central memory Th17 cells (CD4+ CCR4+ and CCR6+), and an elevation of 2 types of effector memory T cells TEM (CCR7- CD45RA-) and TEMRA (CCR7- CD45RA+) in peripheral venous blood. Changes from baseline to month 48 in biomarkers were analyzed for all patients in the FAS.
Time frame: Baseline up to approximately 48 months
Population: required baseline and month 48 visit measurement of the respective cell count
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Fingolimod | Change in T Cells Status (Decrease or Increase) at Month 48 (FAS) | CD4+ Naïve T cells | -23.7 percentage of parent population | Standard Error 0.62 |
| Fingolimod | Change in T Cells Status (Decrease or Increase) at Month 48 (FAS) | CD4+Central memory T cells | -1.2 percentage of parent population | Standard Error 0.59 |
| Fingolimod | Change in T Cells Status (Decrease or Increase) at Month 48 (FAS) | CD4+ Effector memory T cells | 22.2 percentage of parent population | Standard Error 2.37 |
| Fingolimod | Change in T Cells Status (Decrease or Increase) at Month 48 (FAS) | CD8+ Naïve T cells | -37.2 percentage of parent population | Standard Error 0.38 |
| Fingolimod | Change in T Cells Status (Decrease or Increase) at Month 48 (FAS) | CD8+ Central memory T cells | -1.6 percentage of parent population | Standard Error 0.07 |
| Fingolimod | Change in T Cells Status (Decrease or Increase) at Month 48 (FAS) | CD8+ Effector memory T cells | -12.9 percentage of parent population | Standard Error 1.59 |
| Fingolimod | Change in T Cells Status (Decrease or Increase) at Month 48 (FAS) | TH17 central memory cells | -0.6 percentage of parent population | Standard Error 0.03 |
Comparison: TH17 central memory cellsp-value: <0.0001ANCOVA
Comparison: CD4+ Naïve T cellsp-value: <0.0001ANCOVA
Comparison: CD4+ Central memory T cellsp-value: 0.0493ANCOVA
Comparison: CD4+ Effector memory T cellsp-value: <0.0001ANCOVA
Comparison: CD8+ Naïve T cellsp-value: <0.0001ANCOVA
Comparison: CD8+ Central memory T cellsp-value: <0.0001ANCOVA
Comparison: CD8+ Effector memory T cellsp-value: <0.0001ANCOVA
Secondary
Change From Baseline in Disability Progression Assessed With the Expanded Disability Status Scale (EDSS) at Month 6 and Month 48 (FAS)
EDSS is a scale for assessing neurologic impairment in MS. It is a two-part system including (1) a series of scores in each of eight functional systems, and (2) the EDSS steps (ranging from 0 (normal) to 10 (death due to MS). The definition of disability progression was based on increases in EDSS from baseline and depended on the EDSS baseline value: Disability progression was defined as a 1.5 increase in EDSS from baseline in subjects with a baseline EDSS score between 0.0 and 0.5, as a 1.0 increase in EDSS from baseline in subjects with a baseline EDSS score between 1.0 and 5.0 inclusive and 0.5 increase from baseline in subjects with EDSS score \> 5.0.
Time frame: Baseline, month 6 up to approximately 48 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fingolimod | Change From Baseline in Disability Progression Assessed With the Expanded Disability Status Scale (EDSS) at Month 6 and Month 48 (FAS) | Baseline | 2.7 scores on a scale | Standard Deviation 1.17 |
| Fingolimod | Change From Baseline in Disability Progression Assessed With the Expanded Disability Status Scale (EDSS) at Month 6 and Month 48 (FAS) | Month 6 | 2.6 scores on a scale | Standard Deviation 1.38 |
| Fingolimod | Change From Baseline in Disability Progression Assessed With the Expanded Disability Status Scale (EDSS) at Month 6 and Month 48 (FAS) | Month 48 | 2.7 scores on a scale | Standard Deviation 1.52 |
| Fingolimod | Change From Baseline in Disability Progression Assessed With the Expanded Disability Status Scale (EDSS) at Month 6 and Month 48 (FAS) | Change from baseline to month 6 | -0.1 scores on a scale | Standard Deviation 0.69 |
| Fingolimod | Change From Baseline in Disability Progression Assessed With the Expanded Disability Status Scale (EDSS) at Month 6 and Month 48 (FAS) | Change from month 6 to month 48 | 0.2 scores on a scale | Standard Deviation 1.18 |
| Fingolimod | Change From Baseline in Disability Progression Assessed With the Expanded Disability Status Scale (EDSS) at Month 6 and Month 48 (FAS) | Change from baseline to month 48 | 0.0 scores on a scale | Standard Deviation 1.19 |
Secondary
Change in Immune Status of B Cells, Monocytes and Natural Killer Cells (NK) Cells (FAS)
Changes in immune status of B cells (CD19+, CD20+, CD69+), monocytes (CD14+) and NK cells (CD56+) were analyzed as a percentage of parent cell population (CD4+, CD8+ or total lymphocytes) by flow cytometry
Time frame: Baseline up to approximately 48 months
Population: analysis required valid samples for baseline and month 48
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Fingolimod | Change in Immune Status of B Cells, Monocytes and Natural Killer Cells (NK) Cells (FAS) | B cells | -7.2 percentage of parent population | Standard Error 0.42 |
| Fingolimod | Change in Immune Status of B Cells, Monocytes and Natural Killer Cells (NK) Cells (FAS) | Monocytes | 42.3 percentage of parent population | Standard Error 2.03 |
| Fingolimod | Change in Immune Status of B Cells, Monocytes and Natural Killer Cells (NK) Cells (FAS) | Natural Killer cells | 28.0 percentage of parent population | Standard Error 2.09 |
Secondary
Percentage of Participants With Disability Progression as Measured by Expanded Disability Status Scale (EDSS) (FAS)
EDSS is a scale for assessing neurologic impairment in MS. It is a two-part system including (1) a series of scores in each of eight functional systems, and (2) the EDSS steps (ranging from 0 (normal) to 10 (death due to MS). The definition of disability progression was based on increases in EDSS from baseline and depended on the EDSS baseline value: Disability progression was defined as a 1.5 increase in EDSS from baseline in subjects with a baseline EDSS score between 0.0 and 0.5, as a 1.0 increase in EDSS from baseline in subjects with a baseline EDSS score between 1.0 and 5.0 inclusive and 0.5 increase from baseline in subjects with EDSS score \> 5.0.
Time frame: Baseline up to approximately 48 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fingolimod | Percentage of Participants With Disability Progression as Measured by Expanded Disability Status Scale (EDSS) (FAS) | 21.54 percentage of participants |