Relapsing Remitting Multiple Sclerosis
Conditions
Keywords
Relapsing Remitting Multiple Sclerosis (RRMS), Fingolimod, Disease Modifying Therapy (DMT), TSQM-9
Brief summary
A 6-month, Randomized, Active Comparator, Open-label, Multi-Center Study to Evaluate Patient Outcomes, Safety and Tolerability of (fingolimod) 0.5 mg/day in Patients with Relapsing Remitting Multiple Sclerosis who are candidates for MS therapy change from Previous Disease Modifying Therapy.
Interventions
DRUGFingolimod
0.5 mg orally once a day
DRUGInterferon beta - 1a (IFN)
44 mcg subcutaneously three times a week
20 mg subcutaneously once a day
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent must be obtained before any assessment is performed. * Patients must be diagnosed with relapsing remitting MS (RRMS) as defined by 2005 revised McDonald criteria (McDonald et al 2001, Polman et al 2005) (Appendix 2). * Patients who explicitly agree to be assigned to a treatment group that may receive or DMT after having been informed about their respective benefits and possible adverse events by the investigator. * Male or female patients aged 18-70 years. * An Expanded Disability Status Scale (EDSS) score of 0-6 inclusive. * Must have received continuous treatment with a single approved and indicated MS DMT for a minimum of 6 months prior to the screening visit. Patients must continue with this MS DMT until the randomization visit. * Naïve to treatment with fingolimod.
Exclusion criteria
* A manifestation of MS other than those defined in the inclusion criteria. * A history of chronic disease of the immune system other than MS or a known immunodeficiency syndrome. * History of malignancy of any organ system. * Diagnosis of macular edema during Screening Phase. * Patients with active systemic bacterial, viral or fungal infections, or known to have AIDS or to have positive HIV antibody test. * Patients who have received any live or live attenuated vaccines (including for varicella-zoster virus or measles) within 2 months prior to baseline. * Patients who have received total lymphoid irradiation or bone marrow transplantation. * History of selected immune system treatments and/or medications. * Any medically unstable condition, as assessed by the investigator. * Selected cardiovascular, or hepatic conditions * Selected abnormal laboratory values. * Patients with any other disease or clinical condition (including neurologic or psychiatric disorders) which may affect patient enrollment into the study and study medication use by the Investigators' opinion. * Participation in any clinical research study evaluating another not approved in Russia investigational drug or therapy within 6 months prior to baseline. * History of hypersensitivity to the study drug or to drugs of similar chemical classes. * Pregnant or nursing (lactating) women. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Patient-reported Treatment Satisfaction | Baseline, 6 months | The Treatment Satisfaction Questionnaire for Medication (TSQM) contains 14 items assessing the following 4 domains: effectiveness (items 1 - 3), side effects (items 4 - 8), convenience (items 9 - 11) and global satisfaction (items 12 - 14). The primary outcome was measured on the global satisfaction domain. Item 12 scored as 1 (not at all confident) to 5 (extremely confident); item 13 scored as 1 (not at all certain) to 5 (extremely certain); and item 14 scored as 1 (extremely dissatisfied) to 7 (extremely satisfied). Responses to items were summed and transformed: specifically, TSQM v 1.4 domain scale scores were computed by adding the items loading on each domain. The lowest possible score was subtracted from the composite score and divided by the greatest possible score range. This provided a transformed score between 0 and 1 that was then multiplied by 100. The final transformed score ranges from 0 to 100, with higher scores indicating better treatment satisfaction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death | 6 months | Participants were monitored for adverse events, serious adverse events and death throughout the study. |
| Changes in Patient-reported Effectiveness, Side Effects and Convenience | Baseline, 6 months | TSQM v 1.4 domains for effectiveness, side effects and convenience were used to evaluate this outcome. The effectiveness domain for items 1 - 3 was scored as: 1 (extremely dissatisfied) to 7 (extremely satisfied). For the side effects domain, item 4 scored as 0(no) or 1(yes); item 5 scored as 1 (extremely bothersome) to 5 (not at all bothersome); and items 6 - 8 scored as 1 (a great deal) to 5 (not at all). For the convenience domain, items 9 and 10 scored as 1(extremely difficult) to 7 (extremely easy), and item 11 scored as 1 (extremely inconvenient) to 7 (extremely convenient). For each domain, scale scores were computed by adding the items loading on each domain. The lowest possible score was subtracted from the composite score and divided by the greatest possible score range. This provided a transformed score between 0 and 1 that was then multiplied by 100. The final transformed score ranges from 0 to 100, with higher scores indicating better treatment satisfaction. |
| Change in Patient-reported Depression | Baseline, 6 months | The Beck Depression Inventory (BDI-I) scale was used to measure this outcome. The scale consists of 21 items to assess the intensity of depression in clinical and normal patients. Each item is a list of four statements arranged in increasing severity about a particular symptom of depression. Each item was scored from 0 - 3. If more than one score was provided for an item, the maximum score was considered the item score. The total score was calculated as the sum of all individual items and then compared to a key to determine the depression's severity. The standard key ranges were: 0 - 9 indicated minimal depression; 10 - 18 indicated mild depression; 19 - 29 indicated moderate depression and 30 - 63 indicated severe depression. Higher total scores indicate more severe depressive symptoms. |
| Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute) | Baseline, 6 months | The SF-36 is a health-related quality of life instrument used in numerous disease states, including MS (Brazier et al 1992). It is a self-administered survey that measures 8 domains of health including: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems and general mental health. Two summary scale scores can be calculated: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). Each domain was scored by adding the individual items from the domain and transforming the resulting scores into a 0 to 100 scale with higher scores indicating better health status or functioning. |
Countries
Russia
Participant flow
Recruitment details
Participants at screening received standard DMT with either interferon beta-1a or glatiramer acetate from day -30 to day -1.
Pre-assignment details
Eligible participants were then randomized in a 3:1 ratio to fingolimod or a standard DMT. For participants who were randomized to the standard DMT group, those who received IFN during screening were switched to GA at randomization and those who received GA during screening were switched to IFN at randomization.
Participants by arm
| Arm | Count |
|---|---|
| Fingolimod Participants received 0.5 mg orally once a day. | 230 |
| Standard Disease Modifying Therapy (DMT) Participants received interferon beta-1a (IFN), 44 mcg subcutaneously 3 times a week or glatiramer acetate (GA), 20 mg subcutaneously once a day. | 68 |
| Total | 298 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative problems | 1 | 0 |
| Overall Study | Adverse Event | 7 | 3 |
| Overall Study | Withdrawal by Subject | 4 | 7 |
Baseline characteristics
| Characteristic | Fingolimod | Standard Disease Modifying Therapy (DMT) | Total |
|---|---|---|---|
| Age, Continuous | 35.4 Years STANDARD_DEVIATION 9.9 | 36.4 Years STANDARD_DEVIATION 9.3 | 35.6 Years STANDARD_DEVIATION 9.8 |
| Sex: Female, Male Female | 162 Participants | 50 Participants | 212 Participants |
| Sex: Female, Male Male | 68 Participants | 18 Participants | 86 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 | 39 / 230 | 13 / 28 | 10 / 36 |
| serious Total, serious adverse events | 2 / 230 | 0 / 28 | 0 / 36 |
Outcome results
Primary
Change in Patient-reported Treatment Satisfaction
The Treatment Satisfaction Questionnaire for Medication (TSQM) contains 14 items assessing the following 4 domains: effectiveness (items 1 - 3), side effects (items 4 - 8), convenience (items 9 - 11) and global satisfaction (items 12 - 14). The primary outcome was measured on the global satisfaction domain. Item 12 scored as 1 (not at all confident) to 5 (extremely confident); item 13 scored as 1 (not at all certain) to 5 (extremely certain); and item 14 scored as 1 (extremely dissatisfied) to 7 (extremely satisfied). Responses to items were summed and transformed: specifically, TSQM v 1.4 domain scale scores were computed by adding the items loading on each domain. The lowest possible score was subtracted from the composite score and divided by the greatest possible score range. This provided a transformed score between 0 and 1 that was then multiplied by 100. The final transformed score ranges from 0 to 100, with higher scores indicating better treatment satisfaction.
Time frame: Baseline, 6 months
Population: Full Analysis Set (FAS): This set included all randomized participants who had taken at least one dose of study medication and had at least one post-baseline assessment of the TSQM. The last observation carried forward (LOCF) method was applied.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fingolimod | Change in Patient-reported Treatment Satisfaction | 22.69 scores on a scale | Standard Deviation 28.12 |
| Standard Disease Modifying Therapy (DMT) | Change in Patient-reported Treatment Satisfaction | 13.92 scores on a scale | Standard Deviation 30.63 |
Secondary
Change in Patient-reported Depression
The Beck Depression Inventory (BDI-I) scale was used to measure this outcome. The scale consists of 21 items to assess the intensity of depression in clinical and normal patients. Each item is a list of four statements arranged in increasing severity about a particular symptom of depression. Each item was scored from 0 - 3. If more than one score was provided for an item, the maximum score was considered the item score. The total score was calculated as the sum of all individual items and then compared to a key to determine the depression's severity. The standard key ranges were: 0 - 9 indicated minimal depression; 10 - 18 indicated mild depression; 19 - 29 indicated moderate depression and 30 - 63 indicated severe depression. Higher total scores indicate more severe depressive symptoms.
Time frame: Baseline, 6 months
Population: FAS: The LOCF method was applied.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fingolimod | Change in Patient-reported Depression | -2.88 scores on a scale | Standard Deviation 6.8 |
| Standard Disease Modifying Therapy (DMT) | Change in Patient-reported Depression | -1.86 scores on a scale | Standard Deviation 8.04 |
Secondary
Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute)
The SF-36 is a health-related quality of life instrument used in numerous disease states, including MS (Brazier et al 1992). It is a self-administered survey that measures 8 domains of health including: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems and general mental health. Two summary scale scores can be calculated: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). Each domain was scored by adding the individual items from the domain and transforming the resulting scores into a 0 to 100 scale with higher scores indicating better health status or functioning.
Time frame: Baseline, 6 months
Population: Participants from the full analysis set were considered for this analysis. However, for a given time frame, participants analyzed had both baseline and 6 month asssessment values.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fingolimod | Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute) | Physical functioning (n=225,61) | 3.62 scores on scale | Standard Deviation 16.23 |
| Fingolimod | Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute) | Role limitations due to physical health (n=226,61) | 6.50 scores on scale | Standard Deviation 21.99 |
| Fingolimod | Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute) | Bodily pain (n=225,61) | 5.24 scores on scale | Standard Deviation 23.79 |
| Fingolimod | Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute) | General health (n=226,61) | 4.28 scores on scale | Standard Deviation 17.72 |
| Fingolimod | Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute) | Vitality (n=226,61) | 7.72 scores on scale | Standard Deviation 18.61 |
| Fingolimod | Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute) | Social functioning (n=226,61) | 5.59 scores on scale | Standard Deviation 23.36 |
| Fingolimod | Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute) | Role limit. due to emotional problems (n=224,61) | 7.18 scores on scale | Standard Deviation 25.98 |
| Fingolimod | Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute) | Mental health (n=226,61) | 5.60 scores on scale | Standard Deviation 18.55 |
| Fingolimod | Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute) | Physical component summary (n=222,61) | 1.51 scores on scale | Standard Deviation 5.69 |
| Fingolimod | Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute) | Mental component summary (n=222,61) | 3.16 scores on scale | Standard Deviation 9.66 |
| Standard Disease Modifying Therapy (DMT) | Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute) | Mental health (n=226,61) | 2.79 scores on scale | Standard Deviation 22.09 |
| Standard Disease Modifying Therapy (DMT) | Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute) | Physical functioning (n=225,61) | 1.39 scores on scale | Standard Deviation 14.23 |
| Standard Disease Modifying Therapy (DMT) | Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute) | Social functioning (n=226,61) | 1.64 scores on scale | Standard Deviation 23.77 |
| Standard Disease Modifying Therapy (DMT) | Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute) | Role limitations due to physical health (n=226,61) | 4.30 scores on scale | Standard Deviation 27.52 |
| Standard Disease Modifying Therapy (DMT) | Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute) | Mental component summary (n=222,61) | 1.68 scores on scale | Standard Deviation 11.31 |
| Standard Disease Modifying Therapy (DMT) | Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute) | Bodily pain (n=225,61) | 0.93 scores on scale | Standard Deviation 22.95 |
| Standard Disease Modifying Therapy (DMT) | Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute) | Role limit. due to emotional problems (n=224,61) | 5.33 scores on scale | Standard Deviation 27 |
| Standard Disease Modifying Therapy (DMT) | Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute) | General health (n=226,61) | 4.43 scores on scale | Standard Deviation 22.57 |
| Standard Disease Modifying Therapy (DMT) | Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute) | Physical component summary (n=222,61) | 0.68 scores on scale | Standard Deviation 6.57 |
| Standard Disease Modifying Therapy (DMT) | Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute) | Vitality (n=226,61) | 1.95 scores on scale | Standard Deviation 21.97 |
Secondary
Changes in Patient-reported Effectiveness, Side Effects and Convenience
TSQM v 1.4 domains for effectiveness, side effects and convenience were used to evaluate this outcome. The effectiveness domain for items 1 - 3 was scored as: 1 (extremely dissatisfied) to 7 (extremely satisfied). For the side effects domain, item 4 scored as 0(no) or 1(yes); item 5 scored as 1 (extremely bothersome) to 5 (not at all bothersome); and items 6 - 8 scored as 1 (a great deal) to 5 (not at all). For the convenience domain, items 9 and 10 scored as 1(extremely difficult) to 7 (extremely easy), and item 11 scored as 1 (extremely inconvenient) to 7 (extremely convenient). For each domain, scale scores were computed by adding the items loading on each domain. The lowest possible score was subtracted from the composite score and divided by the greatest possible score range. This provided a transformed score between 0 and 1 that was then multiplied by 100. The final transformed score ranges from 0 to 100, with higher scores indicating better treatment satisfaction.
Time frame: Baseline, 6 months
Population: FAS: The LOCF method was applied.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fingolimod | Changes in Patient-reported Effectiveness, Side Effects and Convenience | Effectiveness | 21.57 scores on a scale | Standard Deviation 24.01 |
| Fingolimod | Changes in Patient-reported Effectiveness, Side Effects and Convenience | Side effects | 26.75 scores on a scale | Standard Deviation 35.83 |
| Fingolimod | Changes in Patient-reported Effectiveness, Side Effects and Convenience | Convenience | 25.38 scores on a scale | Standard Deviation 20.72 |
| Standard Disease Modifying Therapy (DMT) | Changes in Patient-reported Effectiveness, Side Effects and Convenience | Effectiveness | 11.56 scores on a scale | Standard Deviation 20.7 |
| Standard Disease Modifying Therapy (DMT) | Changes in Patient-reported Effectiveness, Side Effects and Convenience | Side effects | 13.07 scores on a scale | Standard Deviation 40.19 |
| Standard Disease Modifying Therapy (DMT) | Changes in Patient-reported Effectiveness, Side Effects and Convenience | Convenience | 10.57 scores on a scale | Standard Deviation 20.93 |
Secondary
Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death
Participants were monitored for adverse events, serious adverse events and death throughout the study.
Time frame: 6 months
Population: Safety Set: This set included all randomized participants who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fingolimod | Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death | Adverse events (serious and non-serious) | 73 Participants |
| Fingolimod | Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death | Serious adverse events | 2 Participants |
| Fingolimod | Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death | Deaths | 0 Participants |
| Standard Disease Modifying Therapy (DMT) | Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death | Adverse events (serious and non-serious) | 26 Participants |
| Standard Disease Modifying Therapy (DMT) | Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death | Serious adverse events | 0 Participants |
| Standard Disease Modifying Therapy (DMT) | Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death | Deaths | 0 Participants |