Cognition: Fingolimod Versus Interferon Beta 1b in Cognitive Symptoms

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01333501
• Collaborator: (none)
• Enrollment: 151
• Locations: 26
• Arms: 2
• Duration (Months): 52
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this pilot study is to evaluate, by means of a specific cognitive test battery (Brief Repeatable Battery and Delis-Kaplan Executive Function System scale), the slowing/reduction of cognitive dysfunction progression in RRMS patients after 18 months of treatment with fingolimod in comparison with interferon beta 1b treatment, and to evaluate which test of the battery is the most sensitive in detecting differences between treatment groups.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis	Drug: Fingolimod; Drug: Interferon beta 1b	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 151 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 18-month, Open-label, Rater-blinded, Randomized, Multi-center, Active-controlled, Parallel-group Pilot Study to Assess Efficacy and Safety of Fingolimod in Comparison to Interferon Beta 1b in Treating the Cognitive Symptoms Associated to Relapsing-remitting Multiple Sclerosis and to Assess Possible Relationship of These Effects to Regional Brain Atrophy
• Study Start Date: May 1, 2011
• Actual Primary Completion Date: Sep 1, 2015
• Actual Study Completion Date: Sep 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fingolimod 0.5 mg in capsules for oral administration once daily	Drug: Fingolimod; 0.5 mg in capsules for oral administration once daily
Active Comparator: Interferon beta 1b 250 μg injected s.c. every other day	Drug: Interferon beta 1b; 250 μg injected s.c. every other day

Outcome Measures

Primary Outcome Measures

1. Change From Screening in Selective Reminding Test - Long-Term Storage (SRT-LTS) Raw Score [Screening (-1month), 18 month]

   Brief Repeatable Battery (BRB)- widely used as a clinical and research tool, with 68% sensitivity and 85% specificity. It consists of the serial administration of 5 tests. One of the tests is SRT (Selective Reminding Test) for episodic memory (verbal learning and delayed recall). A word recalled on two consecutive trials is considered to have entered long-term storage (LTS) on the first of these trials and scored as LTS on all following trials. The total of the words in LTS of all six trials is then summed. The total score ranged from 0 to 72. Higher values represent a better outcome.

2. Change From Screening in Selective Reminding Test - Consistent Long Term Retrieval (SRT-CLTR) Raw Score [Screening (-1month), 18 month]

   Brief Repeatable Battery (BRB)- widely used as a clinical and research tool, with 68% sensitivity and 85% specificity. It consists of the serial administration of 5 tests. One of the tests is SRT (Selective Reminding Test) for episodic memory (verbal learning and delayed recall). A word recalled on two consecutive trials is considered to have entered long-term storage (LTS) on the first of these trials and scored as LTS on all following trials. The total of the words in LTS of all six trials is then summed. If a word in LTS is consistently recalled on all subsequent trials, it is then scored as Consistent Long Term Retrieval (CLTR). The total of the words in CLTR of all six trials is summed. The total score ranged from 0 to 72. Higher values represent a better outcome.

3. Change From Screening in Spatial Recall Test (SPART) Raw Score [Screening (-1month), 18 month]

   Spatial Recall Test (SPART) for visuospatial learning and delayed recall.Spatial Recall Test (10/36): The spatial recall test assesses visuospatial learning and delayed recall (10/36-D). A checkerboard with ten checkers arranged in a pattern is shown to the subject for ten seconds. The subject is then asked to reproduce the same pattern with ten checkers on an empty checkerboard. The test includes three consecutive trials. The score is the total number of correct responses for the tree trials. The total score ranged from 0 to 30. Higher values represent a better outcome.

4. Change From Screening in Symbol Digit Modalities Test (SDMT) Raw Score [Screening (-1month), 18 month]

   Symbol Digit Modality Test (SDMT) for sustained attention and information processing speed. It presents a series of nine symbols, each of which is paired with a single digit labeled 1-9 in a key at the top of the sheet. The reminder of the page has a pseudo-randomized sequence of symbols, and the patient must respond with the digit associated with each of these as quickly as possible. The score is the number of correct answers in 90 seconds. The total score ranged from 0 to 110. Higher values represent a better outcome.

5. Change From Screening in Paced Auditory Serial Addition Test - 3 Seconds (PASAT 3) Raw Score [Screening (-1month), 18 month]

   Paced Auditory Serial Addition Test (PASAT) for working memory (and sustained attention and information processing speed). The patient hears a series of numbers from recordings that are presented at the rate of one every 3 seconds in the first part of the test (PASAT-3). The patient is asked to add each consecutive digit to the one immediately preceding it. Sixty-one digits are presented for each part, and each part has a maximum of 60 correct answers. The total score ranged from 0 to 60. Higher values represent a better outcome.

6. Change From Screening in Paced Auditory Serial Addition Test - 2 (PASAT 2) Raw Score [Screening (-1month), 18 month]

   Paced Auditory Serial Addition Test (PASAT) for working memory (and sustained attention and information processing speed). The patient hears a series of numbers from recordings that are presented at the rate of one every 2 seconds in the second part of the test (PASAT-2). The patient was asked to add each consecutive digit to the one immediately preceding it. Sixty-one digits are presented for each part, and each part has a maximum of 60 correct answers. The total score ranged from 0 to 60. Higher values represent a better outcome.

7. Change From Screening in Selective Reminding Test - Delayed Recall (SRT-D) Raw Score [Screening (-1month), 18 month]

   The tests SRT (Selective Reminding Test) for episodic memory (verbal learning and delayed recall). The Delayed SRT test is the total number of words recalled after a delayed period. The total score ranged from 0 to 12. Higher values represent a better outcome.

8. Change From Screening in Spatial Recall Test - Delayed Recall (SPART-D) [Screening (-1month), 18 month]

   Spatial Recall Test (SPART) for visuospatial learning and delayed recall.Spatial Recall Test (10/36): The spatial recall test assesses visuospatial learning and delayed recall (10/36-D). A checkerboard with ten checkers arranged in a pattern was shown to the subject for ten seconds. The subject was then asked to reproduce the same pattern with ten checkers on an empty checkerboard. The test includes three consecutive trials. The score was the total number of correct responses for the tree trials. The total score ranged from 0 to 10. Higher values represent a better outcome.

9. Change From Screening in Word List Generation (WLG) [Screening (-1month), 18 month]

   Word List Generation (COWAT/WLG): The COWAT assesses verbal fluency on semantic stimulus by asking the patient to produce as many words as possible belonging to a semantic category. The test assessed the verbal fluency, recorded all the possible correct word that a patients should give in 90 sec. No maximum range is available. Higher values represent a better outcome. The score was the number of correct words. The more words the patient pronounces, the better it is. We can imagine that the minimum value might be zero words, , but it is not a score scale.

10. Change From Screening in Delis-Kaplan Executive Function System (DKEFS) Condition 1: Free Sorting, Confirmed Correct Sort- Card Set 1+2 [Screening (-1month), 18 month]

    The Delis-Kaplan Executive Function System - Sorting Test is one of the nine tests presented in the DKEFS manual and explores the patient's executive abilities. It has a standard form (version A, administered at screening and Month-18 visit) and an alternate form (version B, administered at Month-9 visit). The standard form consists of the practice card set, card set 1 and card set 2. The alternate form consists of the same practice card set, card set 3 and card set 4. The DKFES test consisted of two testing procedures: free sorting and sort recognition. In free sorting, six scores were obtained: Confirmed Correct sorts for card sets 1 and 2 (or 3 and 4 for version B), sum of confirmed Correct Sorts. In sort recognition, a description score for card set 1 and 2 (or 3 and 4 for version B) was obtained, as well as the sum of description scores of both sets. The total score ranged from 0 to 16. Higher values represent a better outcome

11. Change From Screening in DKEFS Condition 1: Free Sorting, Free Sorting, Description Score, Card Set 1+2 [Screening (-1month), 18 month]

    The Delis-Kaplan Executive Function System - Sorting Test is one of the nine tests presented in the DKEFS manual and explores the patient's executive abilities. It has a standard form (version A, administered at screening and Month-18 visit) and an alternate form (version B, administered at Month-9 visit). The standard form consists of the practice card set, card set 1 and card set 2. The alternate form consists of the same practice card set, card set 3 and card set 4. In free sorting, six scores were obtained: Confirmed Correct sorts for card sets 1 and 2 (or 3 and 4 for version B), sum of confirmed Correct Sorts, Free Sorting Description score for card set 1 and 2 (or 3 and 4 for version B) and sum of Free Sorting Description scores. In sort recognition, a description score for card set 1 and 2 (or 3 and 4 for version B) was obtained, as well as the sum of description scores of both sets. The total score ranged from 0 to 64. Higher values represent a better outcome

12. Change From Screening in DKEFS Condition 2: Sort Recognition, Sort Recognition Description Score- Card Set 1+2 [Screening (-1month), 18 month]

    The Delis-Kaplan Executive Function System - Sorting Test is one of the nine tests presented in the DKEFS manual and explores the patient's executive abilities. It has a standard form (version A, administered at screening and Month-18 visit) and an alternate form (version B, administered at Month-9 visit). The standard form consists of the practice card set, card set 1 and card set 2. The alternate form consists of the same practice card set, card set 3 and card set 4. Free sorting and sort recognition. In free sorting, six scores were obtained: Confirmed Correct sorts for card sets 1 and 2 (or 3 and 4 for version B), sum of confirmed Correct Sorts, Free Sorting Description score for card set 1 and 2 (or 3 and 4 for version B) and sum of Free Sorting Description scores. The total score ranged from 0 to 64. Higher values represent a better outcome.

Secondary Outcome Measures

1. Change From Screening in the Volume of Total T2 Lesions [Screening (-1 month), 18 months]

   Change in volume of total T2-weighted lesions by visit were summarized. Negative values indicate improvement (reduction in lesion volume) and positive values worsening (increase in lesion volume

2. Change From Screening in Montgomery-Asberg Depression Rating Scale (MADRS) [Screening (-1month), 18 month]

   MADRS measures the overall severity of depressive symptoms. The MADRS had a 10-item checklist. Items are rated on a scale of 0-6, for a total numeric range of scores from 0 (depressive symptoms absent) to 60 (numerically highest level of depressive symptoms).

3. Changes in Quality of Life, by Means of the Multiple Sclerosis Quality of Life (MSQoL-54) [Baseline, 18 months]

   A 54 question measure covers 12 domains; assesses mental and physical health. The physical health composite score is a weighted average of the physical health scales, such as physical function, health perceptions, and energy. The mental health composite score is a weighted average of the mental health scales, such as overall quality of life, cognitive function, and health distress. Each domain has a range from 0 to 100 where higher means better.

4. Changes From Baseline in Fatigue Impact Scale (mFIS, Total Score and Scores of the 3 Individual Domains). [Baseline, 18 months]

   Modified Fatigue Impact Scale (mFIS) questionnaire is described at each time point to evaluate fatigue by means of usual descriptive statistics. Three domains were also defined: Physical Subscale (sum of items 4, 6, 7, 10, 13, 14, 17, 20, 21 and therefore ranging from 0 to 36), Cognitive Subscale (sum of items 1, 2, 3, 5, 11, 12, 15, 16, 18, 19 and therefore ranging from 0 to 40) and Psychosocial Subscale (sum of items 8, 9 and therefore ranging from 0 to 8). Finally, mFIS - overall score ranged from 0 to 80. The mFIS total score was computed as the sum of scores for each item. Lower values represent a better outcome.

5. Change From Screening in the Number of New T2 Lesions [Screening (-1month), 18 month]

   New T2 lesions at a specific visit were assessed relative to the previous visit scan. The total number of lesions (visit 8 to 18 month) is calculated as the sum of the number of lesions.

6. Change From Screening in the Volume of Total T1 Hypointense Lesions [Screening (-1month), 18 month]

   Volume of hypointense post-gadolinium T1 lesion component was measured by MRI scan. Means were estimated using a Mixed-effect model with repeated measures (MMRM) by-visit interaction.

7. Change From Screening in the Number of T1 Gd+ Enhancing Lesions [Screening (-1month), 18 month]

   Total number of post-baseline Gd-enhanced lesions is calculated as a sum of all Gd-enhanced lesions seen on post-baseline scans per visit. Real (not per slice) lesions are counted in this analysis

8. Change From Screening in the Percentage of Brain Volume Change [Screening (-1month), 18 month]

   Calculations of brain volume change were performed using the structural image evaluation of normalized atrophy (SIENA), software included in the Functional Magnetic Resonance Imaging of the Brain (FMRIB) software library. SIENA is a fully automated method for estimating temporal brain volume change.

9. Changes in the Environmental Status Scale Score (ESS) [Baseline, 18 month]

   The Environmental Status Scale (ESS) is used to quickly evaluate a patient for handicap. It was derived from a measure of socio-economic status. It consists of seven parameters: (1) actual work status, (2) financial and economic status, (3) personal residence or home, (4) personal assistance required, (5) transportation, (6) community services, (7) social activity. Each parameter has a single score from minimum 0 to maximum 5. ESS score is the sum of the points for all 7 parameters: minimum score: 0; maximum score: 35. The higher the score the greater the handicap

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with relapsing-remitting forms of MS defined by 2005 revised McDonald criteria.

• Patients with active disease, defined as at least one clinical relapse in the last year, or two clinical relapses in the last two years if there are signs of disease activity at one brain MRI scan performed in the last six months.

• Patients with cognitive impairment at screening, defined as at least one test of the Rao's Brief Repeatable Battery with scores falling outside the 90th percentile of the normative data.

Exclusion Criteria:

• Patients who had already been treated with multiweekly interferon (interferon beta 1b, or beta 1a multiweekly) and had an unsatisfactory response according to the judgment of the investigator.

• Patients with hyperactive forms of the MS disease according to the judgment of the investigator.

• Patients with an EDSS score higher than 5.

• Patients with a prior or current diagnosis of Major Depression according to DSM-IV.

• Patients with a history of chronic disease of the immune system other than MS such as known immunodeficiency syndrome.

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Alzenau		Germany	63755
2	Novartis Investigative Site	Bamberg		Germany	96049
3	Novartis Investigative Site	Leipzig		Germany	04103
4	Novartis Investigative Site	Würzburg		Germany	97080
5	Novartis Investigative Site	Ancona	AN	Italy	60126
6	Novartis Investigative Site	Bari	BA	Italy	70124
7	Novartis Investigative Site	Bergamo	BG	Italy	24128
8	Novartis Investigative Site	Montichiari	BS	Italy	25018
9	Novartis Investigative Site	Chieti	CH	Italy	66100
10	Novartis Investigative Site	Catania	CT	Italy	95122
11	Novartis Investigative Site	Catania	CT	Italy	95123
12	Novartis Investigative Site	Firenze	FI	Italy	50134
13	Novartis Investigative Site	Genova	GE	Italy	16132
14	Novartis Investigative Site	Pozzilli	IS	Italy	86077
15	Novartis Investigative Site	Messina	ME	Italy	98121
16	Novartis Investigative Site	Milano	MI	Italy	20122
17	Novartis Investigative Site	Milano	MI	Italy	20132
18	Novartis Investigative Site	Cefalù	PA	Italy	90015
19	Novartis Investigative Site	Pavia	PV	Italy	27100
20	Novartis Investigative Site	Roma	RM	Italy	00133
21	Novartis Investigative Site	Roma	RM	Italy	00161
22	Novartis Investigative Site	Roma	RM	Italy	00179
23	Novartis Investigative Site	Roma	RM	Italy	00189
24	Novartis Investigative Site	Gallarate	VA	Italy	21013
25	Novartis Investigative Site	Napoli		Italy	80131
26	Novartis Investigative Site	Napoli		Italy	80138

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01333501
• Other Study ID Numbers: CFTY720DIT01; 2010-023023-19
• First Posted: Apr 12, 2011
• Last Update Posted: Mar 21, 2017
• Last Verified: Jan 1, 2017

• Keywords provided by Novartis Pharmaceuticals: Multiple sclerosis; cognitive symptoms; relapsing-remitting multiple sclerosis (RRMS); fingolimod; Magnetic resonance imaging (MRI)
• Additional relevant MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Neurobehavioral Manifestations; Sclerosis; Interferons; Interferon-beta; Fingolimod Hydrochloride; Interferon beta-1b

Study Results

Participant Flow

Pre-assignment Detail	Total patients randomized in the study (157). Patients who took at least one dose of study drug are 151. The study there were 6 patients who were enrolled but who never took any dose of study drug.

Arm/Group Title	Fingolimod	Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day
Period Title: Overall Study
STARTED	106	51
Full Analysis Set (FAS)	80	28
Safety Population	104	47
COMPLETED	97	30
NOT COMPLETED	9	21

Baseline Characteristics

Arm/Group Title	Fingolimod	Interferon Beta 1b	Total
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day	Total of all reporting groups
Overall Participants	104	47	151
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	39.53 (9.28)	37.53 (9.27)	38.91 (9.29)
Sex: Female, Male (Count of Participants)
Female	68 65.4%	30 63.8%	98 64.9%
Male	36 34.6%	17 36.2%	53 35.1%

Outcome Measures

1. Primary Outcome

Title	Change From Screening in Selective Reminding Test - Long-Term Storage (SRT-LTS) Raw Score
Description	Brief Repeatable Battery (BRB)- widely used as a clinical and research tool, with 68% sensitivity and 85% specificity. It consists of the serial administration of 5 tests. One of the tests is SRT (Selective Reminding Test) for episodic memory (verbal learning and delayed recall). A word recalled on two consecutive trials is considered to have entered long-term storage (LTS) on the first of these trials and scored as LTS on all following trials. The total of the words in LTS of all six trials is then summed. The total score ranged from 0 to 72. Higher values represent a better outcome.
Time Frame	Screening (-1month), 18 month

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of both primary efficacy variables (i.e. non-missing information about the BRB and DKEFS - Sorting test) without any major protocol violations.

Arm/Group Title	Fingolimod	Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day
Measure Participants	80	28
Least Squares Mean (Standard Error) [raw score]	6.32 (1.33)	4.46 (2.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fingolimod, Interferon Beta 1b
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4940
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.86
	Confidence Interval	(2-Sided) 95%; -3.51 to 7.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.70
	Estimation Comments

2. Primary Outcome

Title	Change From Screening in Selective Reminding Test - Consistent Long Term Retrieval (SRT-CLTR) Raw Score
Description	Brief Repeatable Battery (BRB)- widely used as a clinical and research tool, with 68% sensitivity and 85% specificity. It consists of the serial administration of 5 tests. One of the tests is SRT (Selective Reminding Test) for episodic memory (verbal learning and delayed recall). A word recalled on two consecutive trials is considered to have entered long-term storage (LTS) on the first of these trials and scored as LTS on all following trials. The total of the words in LTS of all six trials is then summed. If a word in LTS is consistently recalled on all subsequent trials, it is then scored as Consistent Long Term Retrieval (CLTR). The total of the words in CLTR of all six trials is summed. The total score ranged from 0 to 72. Higher values represent a better outcome.
Time Frame	Screening (-1month), 18 month

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of both primary efficacy variables (i.e. non-missing information about the BRB and DKEFS - Sorting test) without any major protocol violations.

Arm/Group Title	Fingolimod	Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day
Measure Participants	80	28
Least Squares Mean (Standard Error) [Raw score]	5.93 (1.49)	3.96 (2.56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fingolimod, Interferon Beta 1b
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5183
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.97
	Confidence Interval	(2-Sided) 95%; -4.06 to 7.99
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.03
	Estimation Comments

3. Primary Outcome

Title	Change From Screening in Spatial Recall Test (SPART) Raw Score
Description	Spatial Recall Test (SPART) for visuospatial learning and delayed recall.Spatial Recall Test (10/36): The spatial recall test assesses visuospatial learning and delayed recall (10/36-D). A checkerboard with ten checkers arranged in a pattern is shown to the subject for ten seconds. The subject is then asked to reproduce the same pattern with ten checkers on an empty checkerboard. The test includes three consecutive trials. The score is the total number of correct responses for the tree trials. The total score ranged from 0 to 30. Higher values represent a better outcome.
Time Frame	Screening (-1month), 18 month

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of both primary efficacy variables (i.e. non-missing information about the BRB and DKEFS - Sorting test) without any major protocol violations

Arm/Group Title	Fingolimod	Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day
Measure Participants	80	28
Least Squares Mean (Standard Error) [Raw score]	1.46 (0.52)	3.06 (0.89)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fingolimod, Interferon Beta 1b
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1334
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.60
	Confidence Interval	(2-Sided) 95%; -3.69 to 0.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.05
	Estimation Comments

4. Primary Outcome

Title	Change From Screening in Symbol Digit Modalities Test (SDMT) Raw Score
Description	Symbol Digit Modality Test (SDMT) for sustained attention and information processing speed. It presents a series of nine symbols, each of which is paired with a single digit labeled 1-9 in a key at the top of the sheet. The reminder of the page has a pseudo-randomized sequence of symbols, and the patient must respond with the digit associated with each of these as quickly as possible. The score is the number of correct answers in 90 seconds. The total score ranged from 0 to 110. Higher values represent a better outcome.
Time Frame	Screening (-1month), 18 month

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of both primary efficacy variables (i.e. non-missing information about the BRB and DKEFS - Sorting test) without any major protocol violations

Arm/Group Title	Fingolimod	Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day
Measure Participants	80	28
Least Squares Mean (Standard Error) [Raw score]	2.19 (1.12)	3.93 (1.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fingolimod, Interferon Beta 1b
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4501
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.73
	Confidence Interval	(2-Sided) 95%; -6.27 to 2.81
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.29
	Estimation Comments

5. Primary Outcome

Title	Change From Screening in Paced Auditory Serial Addition Test - 3 Seconds (PASAT 3) Raw Score
Description	Paced Auditory Serial Addition Test (PASAT) for working memory (and sustained attention and information processing speed). The patient hears a series of numbers from recordings that are presented at the rate of one every 3 seconds in the first part of the test (PASAT-3). The patient is asked to add each consecutive digit to the one immediately preceding it. Sixty-one digits are presented for each part, and each part has a maximum of 60 correct answers. The total score ranged from 0 to 60. Higher values represent a better outcome.
Time Frame	Screening (-1month), 18 month

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of both primary efficacy variables (i.e. non-missing information about the BRB and DKEFS - Sorting test) without any major protocol violations

Arm/Group Title	Fingolimod	Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day
Measure Participants	80	28
Least Squares Mean (Standard Error) [Raw score]	7.14 (1.24)	6.68 (2.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fingolimod, Interferon Beta 1b
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8561
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.46
	Confidence Interval	(2-Sided) 95%; -4.57 to 5.49
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.53
	Estimation Comments

6. Primary Outcome

Title	Change From Screening in Paced Auditory Serial Addition Test - 2 (PASAT 2) Raw Score
Description	Paced Auditory Serial Addition Test (PASAT) for working memory (and sustained attention and information processing speed). The patient hears a series of numbers from recordings that are presented at the rate of one every 2 seconds in the second part of the test (PASAT-2). The patient was asked to add each consecutive digit to the one immediately preceding it. Sixty-one digits are presented for each part, and each part has a maximum of 60 correct answers. The total score ranged from 0 to 60. Higher values represent a better outcome.
Time Frame	Screening (-1month), 18 month

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of both primary efficacy variables (i.e. non-missing information about the BRB and DKEFS - Sorting test) without any major protocol violations

Arm/Group Title	Fingolimod	Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day
Measure Participants	80	28
Least Squares Mean (Standard Error) [Raw score]	4.79 (1.25)	4.42 (2.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fingolimod, Interferon Beta 1b
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8858
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.37
	Confidence Interval	(2-Sided) 95%; -4.67 to 5.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.53
	Estimation Comments

7. Primary Outcome

Title	Change From Screening in Selective Reminding Test - Delayed Recall (SRT-D) Raw Score
Description	The tests SRT (Selective Reminding Test) for episodic memory (verbal learning and delayed recall). The Delayed SRT test is the total number of words recalled after a delayed period. The total score ranged from 0 to 12. Higher values represent a better outcome.
Time Frame	Screening (-1month), 18 month

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of both primary efficacy variables (i.e. non-missing information about the BRB and DKEFS - Sorting test) without any major protocol violations

Arm/Group Title	Fingolimod	Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day
Measure Participants	80	28
Least Squares Mean (Standard Error) [Raw score]	0.57 (0.23)	0.39 (0.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fingolimod, Interferon Beta 1b
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7119
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.17
	Confidence Interval	(2-Sided) 95%; -0.76 to 1.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.47
	Estimation Comments

8. Primary Outcome

Title	Change From Screening in Spatial Recall Test - Delayed Recall (SPART-D)
Description	Spatial Recall Test (SPART) for visuospatial learning and delayed recall.Spatial Recall Test (10/36): The spatial recall test assesses visuospatial learning and delayed recall (10/36-D). A checkerboard with ten checkers arranged in a pattern was shown to the subject for ten seconds. The subject was then asked to reproduce the same pattern with ten checkers on an empty checkerboard. The test includes three consecutive trials. The score was the total number of correct responses for the tree trials. The total score ranged from 0 to 10. Higher values represent a better outcome.
Time Frame	Screening (-1month), 18 month

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of both primary efficacy variables (i.e. non-missing information about the BRB and DKEFS - Sorting test) without any major protocol violations

Arm/Group Title	Fingolimod	Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day
Measure Participants	80	28
Least Squares Mean (Standard Error) [Raw score]	0.41 (0.21)	0.44 (0.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fingolimod, Interferon Beta 1b
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9496
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 95%; -0.86 to 0.81
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.42
	Estimation Comments

9. Primary Outcome

Title	Change From Screening in Word List Generation (WLG)
Description	Word List Generation (COWAT/WLG): The COWAT assesses verbal fluency on semantic stimulus by asking the patient to produce as many words as possible belonging to a semantic category. The test assessed the verbal fluency, recorded all the possible correct word that a patients should give in 90 sec. No maximum range is available. Higher values represent a better outcome. The score was the number of correct words. The more words the patient pronounces, the better it is. We can imagine that the minimum value might be zero words, , but it is not a score scale.
Time Frame	Screening (-1month), 18 month

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of both primary efficacy variables (i.e. non-missing information about the BRB and DKEFS - Sorting test) without any major protocol violations

Arm/Group Title	Fingolimod	Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day
Measure Participants	80	28
Least Squares Mean (Standard Error) [Raw score]	0.39 (0.58)	0.24 (0.99)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fingolimod, Interferon Beta 1b
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8944
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95%; -2.18 to 2.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.18
	Estimation Comments

10. Primary Outcome

Title	Change From Screening in Delis-Kaplan Executive Function System (DKEFS) Condition 1: Free Sorting, Confirmed Correct Sort- Card Set 1+2
Description	The Delis-Kaplan Executive Function System - Sorting Test is one of the nine tests presented in the DKEFS manual and explores the patient's executive abilities. It has a standard form (version A, administered at screening and Month-18 visit) and an alternate form (version B, administered at Month-9 visit). The standard form consists of the practice card set, card set 1 and card set 2. The alternate form consists of the same practice card set, card set 3 and card set 4. The DKFES test consisted of two testing procedures: free sorting and sort recognition. In free sorting, six scores were obtained: Confirmed Correct sorts for card sets 1 and 2 (or 3 and 4 for version B), sum of confirmed Correct Sorts. In sort recognition, a description score for card set 1 and 2 (or 3 and 4 for version B) was obtained, as well as the sum of description scores of both sets. The total score ranged from 0 to 16. Higher values represent a better outcome
Time Frame	Screening (-1month), 18 month

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of both primary efficacy variables (i.e. non-missing information about the BRB and DKEFS - Sorting test) without any major protocol violations

Arm/Group Title	Fingolimod	Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day
Measure Participants	80	28
Least Squares Mean (Standard Error) [Raw score]	0.57 (0.31)	0.82 (0.48)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fingolimod, Interferon Beta 1b
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6757
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 95%; -1.42 to 0.92
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.59
	Estimation Comments

11. Primary Outcome

Title	Change From Screening in DKEFS Condition 1: Free Sorting, Free Sorting, Description Score, Card Set 1+2
Description	The Delis-Kaplan Executive Function System - Sorting Test is one of the nine tests presented in the DKEFS manual and explores the patient's executive abilities. It has a standard form (version A, administered at screening and Month-18 visit) and an alternate form (version B, administered at Month-9 visit). The standard form consists of the practice card set, card set 1 and card set 2. The alternate form consists of the same practice card set, card set 3 and card set 4. In free sorting, six scores were obtained: Confirmed Correct sorts for card sets 1 and 2 (or 3 and 4 for version B), sum of confirmed Correct Sorts, Free Sorting Description score for card set 1 and 2 (or 3 and 4 for version B) and sum of Free Sorting Description scores. In sort recognition, a description score for card set 1 and 2 (or 3 and 4 for version B) was obtained, as well as the sum of description scores of both sets. The total score ranged from 0 to 64. Higher values represent a better outcome
Time Frame	Screening (-1month), 18 month

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of both primary efficacy variables (i.e. non-missing information about the BRB and DKEFS - Sorting test) without any major protocol violations

Arm/Group Title	Fingolimod	Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day
Measure Participants	80	28
Least Squares Mean (Standard Error) [Raw score]	1.52 (1.23)	3.69 (1.92)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fingolimod, Interferon Beta 1b
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3585
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.16
	Confidence Interval	(2-Sided) 95%; -6.82 to 2.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.34
	Estimation Comments

12. Primary Outcome

Title	Change From Screening in DKEFS Condition 2: Sort Recognition, Sort Recognition Description Score- Card Set 1+2
Description	The Delis-Kaplan Executive Function System - Sorting Test is one of the nine tests presented in the DKEFS manual and explores the patient's executive abilities. It has a standard form (version A, administered at screening and Month-18 visit) and an alternate form (version B, administered at Month-9 visit). The standard form consists of the practice card set, card set 1 and card set 2. The alternate form consists of the same practice card set, card set 3 and card set 4. Free sorting and sort recognition. In free sorting, six scores were obtained: Confirmed Correct sorts for card sets 1 and 2 (or 3 and 4 for version B), sum of confirmed Correct Sorts, Free Sorting Description score for card set 1 and 2 (or 3 and 4 for version B) and sum of Free Sorting Description scores. The total score ranged from 0 to 64. Higher values represent a better outcome.
Time Frame	Screening (-1month), 18 month

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of both primary efficacy variables (i.e. non-missing information about the BRB and DKEFS - Sorting test) without any major protocol violations

Arm/Group Title	Fingolimod	Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day
Measure Participants	80	28
Least Squares Mean (Standard Error) [Raw score]	2.15 (1.90)	7.38 (2.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fingolimod, Interferon Beta 1b
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1610
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-5.24
	Confidence Interval	(2-Sided) 95%; -12.62 to 2.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.69
	Estimation Comments

13. Secondary Outcome

Title	Change From Screening in the Volume of Total T2 Lesions
Description	Change in volume of total T2-weighted lesions by visit were summarized. Negative values indicate improvement (reduction in lesion volume) and positive values worsening (increase in lesion volume
Time Frame	Screening (-1 month), 18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fingolimod	Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day
Measure Participants	68	27
Mean (Standard Deviation) [mm^3]	176.25 (1355.31)	711.81 (1584.42)

14. Secondary Outcome

Title	Change From Screening in Montgomery-Asberg Depression Rating Scale (MADRS)
Description	MADRS measures the overall severity of depressive symptoms. The MADRS had a 10-item checklist. Items are rated on a scale of 0-6, for a total numeric range of scores from 0 (depressive symptoms absent) to 60 (numerically highest level of depressive symptoms).
Time Frame	Screening (-1month), 18 month

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of both primary efficacy variables (i.e. non-missing information about the BRB and DKEFS - Sorting test) without any major protocol violations

Arm/Group Title	Fingolimod	Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day
Measure Participants	80	28
Least Squares Mean (Standard Error) [Raw score]	-0.77 (0.79)	0.13 (1.31)

15. Secondary Outcome

Title	Changes in Quality of Life, by Means of the Multiple Sclerosis Quality of Life (MSQoL-54)
Description	A 54 question measure covers 12 domains; assesses mental and physical health. The physical health composite score is a weighted average of the physical health scales, such as physical function, health perceptions, and energy. The mental health composite score is a weighted average of the mental health scales, such as overall quality of life, cognitive function, and health distress. Each domain has a range from 0 to 100 where higher means better.
Time Frame	Baseline, 18 months

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of both primary efficacy variables (i.e. non-missing information about the BRB and DKEFS - Sorting test) without any major protocol violations

Arm/Group Title	Fingolimod	Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day
Measure Participants	80	28
Mental health composite score	4.76 (2.01)	-2.31 (3.36)
Physical health composite score	-1.80 (1.41)	-4.75 (2.46)

16. Secondary Outcome

Title	Changes From Baseline in Fatigue Impact Scale (mFIS, Total Score and Scores of the 3 Individual Domains).
Description	Modified Fatigue Impact Scale (mFIS) questionnaire is described at each time point to evaluate fatigue by means of usual descriptive statistics. Three domains were also defined: Physical Subscale (sum of items 4, 6, 7, 10, 13, 14, 17, 20, 21 and therefore ranging from 0 to 36), Cognitive Subscale (sum of items 1, 2, 3, 5, 11, 12, 15, 16, 18, 19 and therefore ranging from 0 to 40) and Psychosocial Subscale (sum of items 8, 9 and therefore ranging from 0 to 8). Finally, mFIS - overall score ranged from 0 to 80. The mFIS total score was computed as the sum of scores for each item. Lower values represent a better outcome.
Time Frame	Baseline, 18 months

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of both primary efficacy variables (i.e. non-missing information about the BRB and DKEFS - Sorting test) without any major protocol violations

Arm/Group Title	Fingolimod	Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day
Measure Participants	80	28
Least Squares Mean (Standard Error) [Score]	2.36 (1.68)	6.67 (2.72)

17. Secondary Outcome

Title	Change From Screening in the Number of New T2 Lesions
Description	New T2 lesions at a specific visit were assessed relative to the previous visit scan. The total number of lesions (visit 8 to 18 month) is calculated as the sum of the number of lesions.
Time Frame	Screening (-1month), 18 month

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of both primary efficacy variables (i.e. non-missing information about the BRB and DKEFS - Sorting test) without any major protocol violations

Arm/Group Title	Fingolimod	Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day
Measure Participants	80	28
Mean (Standard Deviation) [Number of new lesions]	1.25 (2.05)	3.33 (4.44)

18. Secondary Outcome

Title	Change From Screening in the Volume of Total T1 Hypointense Lesions
Description	Volume of hypointense post-gadolinium T1 lesion component was measured by MRI scan. Means were estimated using a Mixed-effect model with repeated measures (MMRM) by-visit interaction.
Time Frame	Screening (-1month), 18 month

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of both primary efficacy variables (i.e. non-missing information about the BRB and DKEFS - Sorting test) without any major protocol violations

Arm/Group Title	Fingolimod	Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day
Measure Participants	80	28
Mean (Standard Deviation) [mm^3]	391.96 (986.85)	213.93 (312.24)

19. Secondary Outcome

Title	Change From Screening in the Number of T1 Gd+ Enhancing Lesions
Description	Total number of post-baseline Gd-enhanced lesions is calculated as a sum of all Gd-enhanced lesions seen on post-baseline scans per visit. Real (not per slice) lesions are counted in this analysis
Time Frame	Screening (-1month), 18 month

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of both primary efficacy variables (i.e. non-missing information about the BRB and DKEFS - Sorting test) without any major protocol violations

Arm/Group Title	Fingolimod	Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day
Measure Participants	80	28
Mean (Standard Deviation) [Number of new lesions]	-0.64 (1.27)	0.59 (3.98)

20. Secondary Outcome

Title	Change From Screening in the Percentage of Brain Volume Change
Description	Calculations of brain volume change were performed using the structural image evaluation of normalized atrophy (SIENA), software included in the Functional Magnetic Resonance Imaging of the Brain (FMRIB) software library. SIENA is a fully automated method for estimating temporal brain volume change.
Time Frame	Screening (-1month), 18 month

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of both primary efficacy variables (i.e. non-missing information about the BRB and DKEFS - Sorting test) without any major protocol violations

Arm/Group Title	Fingolimod	Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day
Measure Participants	80	28
Mean (Standard Deviation) [percentage of brain volume]	-0.60 (0.83)	-0.96 (0.71)

21. Secondary Outcome

Title	Changes in the Environmental Status Scale Score (ESS)
Description	The Environmental Status Scale (ESS) is used to quickly evaluate a patient for handicap. It was derived from a measure of socio-economic status. It consists of seven parameters: (1) actual work status, (2) financial and economic status, (3) personal residence or home, (4) personal assistance required, (5) transportation, (6) community services, (7) social activity. Each parameter has a single score from minimum 0 to maximum 5. ESS score is the sum of the points for all 7 parameters: minimum score: 0; maximum score: 35. The higher the score the greater the handicap
Time Frame	Baseline, 18 month

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all randomized patients who received at least one dose of study drug and had at least one post-baseline assessment of both primary efficacy variables (i.e. non-missing information about the BRB and DKEFS - Sorting test) without any major protocol violations

Arm/Group Title	Fingolimod	Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily	250 μg injected s.c. every other day
Measure Participants	80	28
Mean (Standard Deviation) [Score]	1.08 (3.45)	0.91 (1.98)

Adverse Events

Arm/Group Title	Fingolimod 0.5 mg		Interferon Beta 1b
Arm/Group Description	0.5 mg in capsules for oral administration once daily		250 μg injected s.c. every other day
All Cause Mortality
	Fingolimod 0.5 mg		Interferon Beta 1b
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Fingolimod 0.5 mg		Interferon Beta 1b
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/104 (8.7%)		1/47 (2.1%)
Cardiac disorders
Atrioventricular block second degree	1/104 (1%)		0/47 (0%)
Infections and infestations
Bronchopneumonia	1/104 (1%)		0/47 (0%)
Urinary tract infection	1/104 (1%)		0/47 (0%)
Injury, poisoning and procedural complications
Facial bones fracture	1/104 (1%)		0/47 (0%)
Head injury	1/104 (1%)		0/47 (0%)
Traumatic brain injury	1/104 (1%)		0/47 (0%)
Ulna fracture	1/104 (1%)		0/47 (0%)
Investigations
Blood glucose abnormal	0/104 (0%)		1/47 (2.1%)
Nervous system disorders
Epilepsy	1/104 (1%)		0/47 (0%)
Renal and urinary disorders
Nephrolithiasis	1/104 (1%)		0/47 (0%)
Renal colic	2/104 (1.9%)		0/47 (0%)
Surgical and medical procedures
Uterine polypectomy	1/104 (1%)		0/47 (0%)
Other (Not Including Serious) Adverse Events
	Fingolimod 0.5 mg		Interferon Beta 1b
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	44/104 (42.3%)		22/47 (46.8%)
General disorders
Influenza like illness	1/104 (1%)		5/47 (10.6%)
Pyrexia	6/104 (5.8%)		4/47 (8.5%)
Infections and infestations
Nasopharyngitis	4/104 (3.8%)		3/47 (6.4%)
Investigations
Alanine aminotransferase increased	9/104 (8.7%)		1/47 (2.1%)
Blood triglycerides increased	0/104 (0%)		3/47 (6.4%)
Transaminases increased	4/104 (3.8%)		4/47 (8.5%)
Metabolism and nutrition disorders
Hypercholesterolaemia	7/104 (6.7%)		2/47 (4.3%)
Musculoskeletal and connective tissue disorders
Back pain	3/104 (2.9%)		3/47 (6.4%)
Nervous system disorders
Headache	11/104 (10.6%)		4/47 (8.5%)
Multiple sclerosis relapse	2/104 (1.9%)		4/47 (8.5%)
Psychiatric disorders
Depression	7/104 (6.7%)		3/47 (6.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.