Trial Outcomes & Findings for An Extension Study of the Efficacy and Safety of Fingolimod (FTY720) in Patients With Relapsing Multiple Sclerosis (NCT NCT00670449)

Last Updated: 2013-09-04

Results Overview

To ensure consistency, MRI scans were evaluated centrally at the Institute of Neurotherapeutics in Kyoto, Japan. After checking the scans for completeness and quality, all scans were analyzed by blinded readers (experienced neurologists). The number of Gd-enhanced T1 weighted MRI lesions were counted and recorded. Lesions expanding through several slices were counted as only 1 lesion.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

143 participants

Primary outcome timeframe

Months 6, 9, 12, 18, 24, 36, and 48

Results posted on

2013-09-04

Participant Flow

Participant milestones

Participant milestones
Measure	Fingolimod 0.5 mg Patients who received fingolimod 0.5 orally once daily in the core study continued on the same dose in this extension study.	Fingolimod 1.25 mg Patients who received fingolimod 1.25 mg orally once daily in the core study continued on the same dose in this extension study.	Placebo-fingolimod 0.5 mg Patients who were randomized to placebo in the core study were re-randomized to either fingolimod 0.5 or 1.25 mg (1:1) orally once daily in this extension study.	Placebo-fingolimod 1.25 mg Patients who were randomized to placebo in the core study were re-randomized to either fingolimod 0.5 or 1.25 mg (1:1) orally once daily in this extension study.
Overall Study STARTED	47	46	27	23
Overall Study Switched to 0.5mg (Open Label)	45	41	23	17
Overall Study COMPLETED	38	36	18	15
Overall Study NOT COMPLETED	9	10	9	8

Reasons for withdrawal

Reasons for withdrawal
Measure	Fingolimod 0.5 mg Patients who received fingolimod 0.5 orally once daily in the core study continued on the same dose in this extension study.	Fingolimod 1.25 mg Patients who received fingolimod 1.25 mg orally once daily in the core study continued on the same dose in this extension study.	Placebo-fingolimod 0.5 mg Patients who were randomized to placebo in the core study were re-randomized to either fingolimod 0.5 or 1.25 mg (1:1) orally once daily in this extension study.	Placebo-fingolimod 1.25 mg Patients who were randomized to placebo in the core study were re-randomized to either fingolimod 0.5 or 1.25 mg (1:1) orally once daily in this extension study.
Overall Study Adverse Event	6	2	8	5
Overall Study Protocol Deviation	1	2	0	1
Overall Study Administrative Problems	0	2	0	1
Overall Study Subject Withdrew Consent	0	2	0	1
Overall Study Unsatisfactory Therapeutic Effect	2	0	1	0
Overall Study Abnormal Laboratory Value(s)	0	2	0	0

Baseline Characteristics

An Extension Study of the Efficacy and Safety of Fingolimod (FTY720) in Patients With Relapsing Multiple Sclerosis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Fingolimod 0.5 mg n=47 Participants Patients who received fingolimod 0.5 orally once daily in the core study continued on the same dose in this extension study.	Fingolimod 1.25 mg n=46 Participants Patients who received fingolimod 1.25 mg orally once daily in the core study continued on the same dose in this extension study.	Placebo-fingolimod 0.5 mg n=27 Participants Patients who were randomized to placebo in the core study were re-randomized to either fingolimod 0.5 or 1.25 mg (1:1) orally once daily in this extension study.	Placebo-fingolimod 1.25 mg n=23 Participants Patients who were randomized to placebo in the core study were re-randomized to either fingolimod 0.5 or 1.25 mg (1:1) orally once daily in this extension study.	Total n=143 Participants Total of all reporting groups
Age Continuous	34.9 years STANDARD_DEVIATION 8.95 • n=5 Participants	35.7 years STANDARD_DEVIATION 8.81 • n=7 Participants	34.2 years STANDARD_DEVIATION 9.08 • n=5 Participants	35.5 years STANDARD_DEVIATION 8.44 • n=4 Participants	35.1 years STANDARD_DEVIATION 8.78 • n=21 Participants
Sex: Female, Male Female	33 Participants n=5 Participants	31 Participants n=7 Participants	19 Participants n=5 Participants	14 Participants n=4 Participants	97 Participants n=21 Participants
Sex: Female, Male Male	14 Participants n=5 Participants	15 Participants n=7 Participants	8 Participants n=5 Participants	9 Participants n=4 Participants	46 Participants n=21 Participants

PRIMARY outcome

Timeframe: Months 6, 9, 12, 18, 24, 36, and 48

Population: Core full analysis set (FAS): All patients who were randomized in the core study and received at least 1 dose of core study drug. The study became open-label with all patients receiving FTY720 0.5 mg/day (by 22-Feb- 2010). (approximately 22 months before study completion)

Outcome measures

Outcome measures
Measure	Fingolimod 0.5 mg n=57 Participants Patients who received fingolimod 0.5 orally once daily in the core study continued on the same dose in this extension study.	Fingolimod 1.25 mg n=54 Participants Patients who received fingolimod 1.25 mg orally once daily in the core study continued on the same dose in this extension study.	Placebo-fingolimod n=57 Participants Patients randomized to placebo in the Core study. These patients were either subsequently re-randomized to FTY720 (either 1.25 mg or 0.5 mg) in the Extension study, or did not enter the Extension study.
Percentage of Patients Free of Gd-enhanced T1 Weighted Magnetic Resonance Imaging (MRI) Lesions Month 6 (N=44, 48, 50)	88.6 Percentage of patients	97.9 Percentage of patients	58.0 Percentage of patients
Percentage of Patients Free of Gd-enhanced T1 Weighted Magnetic Resonance Imaging (MRI) Lesions Month 9 (N=44, 39, 41)	90.9 Percentage of patients	94.9 Percentage of patients	92.7 Percentage of patients
Percentage of Patients Free of Gd-enhanced T1 Weighted Magnetic Resonance Imaging (MRI) Lesions Month 12 (N=44, 42, 36)	97.7 Percentage of patients	97.6 Percentage of patients	88.9 Percentage of patients
Percentage of Patients Free of Gd-enhanced T1 Weighted Magnetic Resonance Imaging (MRI) Lesions Month 18 (N=42, 40, 37)	92.9 Percentage of patients	92.5 Percentage of patients	94.6 Percentage of patients
Percentage of Patients Free of Gd-enhanced T1 Weighted Magnetic Resonance Imaging (MRI) Lesions Month 24 (N=38, 39, 33)	94.7 Percentage of patients	94.9 Percentage of patients	90.9 Percentage of patients
Percentage of Patients Free of Gd-enhanced T1 Weighted Magnetic Resonance Imaging (MRI) Lesions Month 36 (N=25, 21, 22)	92.0 Percentage of patients	85.7 Percentage of patients	90.9 Percentage of patients
Percentage of Patients Free of Gd-enhanced T1 Weighted Magnetic Resonance Imaging (MRI) Lesions Month 48 (N=3, 4, 1)	100.0 Percentage of patients	75.0 Percentage of patients	100.0 Percentage of patients

SECONDARY outcome

Timeframe: Months 0-3, 3-6, 6-9, 9-12, 12-18, 18-24, 24-36,36-48, and 48 to the end of the study (up to 4 years)

Population: Core full analysis set(FAS): All patients who were randomized in the core study and received at least 1 dose of core study drug. Study became open-label with all patients receiving FTY720 0.5 mg/day. The study became open-label with all patients receiving FTY720 0.5 mg/day (by 22-Feb-2010). (approximately 22 months before study completion)

To ensure consistency, MRI scans were evaluated centrally at the Institute of Neurotherapeutics in Kyoto, Japan. After checking the scans for completeness and quality, all scans were analyzed by blinded readers (experienced neurologists). The number of new or newly enlarged T2 weighted MRI lesions were counted and recorded. New lesions were identified by comparing each lesion with previous scans. Lesions expanding through several slices were counted as only 1 lesion.

Outcome measures

Outcome measures
Measure	Fingolimod 0.5 mg n=57 Participants Patients who received fingolimod 0.5 orally once daily in the core study continued on the same dose in this extension study.	Fingolimod 1.25 mg n=54 Participants Patients who received fingolimod 1.25 mg orally once daily in the core study continued on the same dose in this extension study.	Placebo-fingolimod n=57 Participants Patients randomized to placebo in the Core study. These patients were either subsequently re-randomized to FTY720 (either 1.25 mg or 0.5 mg) in the Extension study, or did not enter the Extension study.
Percentage of Patients Free of New or Newly Enlarged T2 Weighted MRI Lesions Month 36 to 48 (N=3, 4, 1)	100.0 Percentage of patients	100.0 Percentage of patients	100.0 Percentage of patients
Percentage of Patients Free of New or Newly Enlarged T2 Weighted MRI Lesions Month 0 to 3 (N=49, 50, 51)	69.4 Percentage of patients	60.0 Percentage of patients	45.1 Percentage of patients
Percentage of Patients Free of New or Newly Enlarged T2 Weighted MRI Lesions Month 3 to 6 (N=43, 47, 48)	86.0 Percentage of patients	91.5 Percentage of patients	43.8 Percentage of patients
Percentage of Patients Free of New or Newly Enlarged T2 Weighted MRI Lesions Month 6 to 9 (N=44, 39, 40)	88.6 Percentage of patients	92.3 Percentage of patients	70.0 Percentage of patients
Percentage of Patients Free of New or Newly Enlarged T2 Weighted MRI Lesions Month 9 to 12 (N=44, 42, 35)	93.2 Percentage of patients	95.2 Percentage of patients	85.7 Percentage of patients
Percentage of Patients Free of New or Newly Enlarged T2 Weighted MRI Lesions Month 12 to 18 (N=43, 40, 37)	88.4 Percentage of patients	90.0 Percentage of patients	91.9 Percentage of patients
Percentage of Patients Free of New or Newly Enlarged T2 Weighted MRI Lesions Month 18 to 24 (N=39, 39, 33)	94.9 Percentage of patients	92.3 Percentage of patients	87.9 Percentage of patients
Percentage of Patients Free of New or Newly Enlarged T2 Weighted MRI Lesions Month 24 to 36 (N=25, 21, 22)	92.0 Percentage of patients	90.5 Percentage of patients	90.9 Percentage of patients
Percentage of Patients Free of New or Newly Enlarged T2 Weighted MRI Lesions Month 48 to end of study (N=3, 3, 1)	100.0 Percentage of patients	100.0 Percentage of patients	100.0 Percentage of patients

SECONDARY outcome

Timeframe: Months 0-6, 6-12, 12-24, 24-36, 36-48, and 48 to the end of the study (up to 4 years)

The ARR was defined as the total number of relapses for all patients in the treatment arm / total number of days in the study for all patients in the treatment arm for the specific period of time × 365.25. General definition of relapse: Appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from the onset of a preceding clinical demyelinating event. The abnormality must be present for at least 24 hours and occur in the absence of fever (\< 37.5°C) or infection. A relapse was to be confirmed by a neurologist trained on the Expanded Disability Status Scale (EDSS). A relapse must be accompanied by an increase of at least half a step (0.5) on the EDSS or an increase of 1 point on 2 different Functional Systems (FS) of the EDSS or 2 points on 1 of the FS (excluding Bowel/Bladder or Cerebral FS).

Outcome measures

Outcome measures
Measure	Fingolimod 0.5 mg n=57 Participants Patients who received fingolimod 0.5 orally once daily in the core study continued on the same dose in this extension study.	Fingolimod 1.25 mg n=54 Participants Patients who received fingolimod 1.25 mg orally once daily in the core study continued on the same dose in this extension study.	Placebo-fingolimod n=57 Participants Patients randomized to placebo in the Core study. These patients were either subsequently re-randomized to FTY720 (either 1.25 mg or 0.5 mg) in the Extension study, or did not enter the Extension study.
Aggregate Annualized Relapse Rate (ARR) Based on Confirmed Relapses Month 0 to 6 (N=57, 54, 57)	0.539 Relapses per year	0.404 Relapses per year	1.131 Relapses per year
Aggregate Annualized Relapse Rate (ARR) Based on Confirmed Relapses Month 24 to 36 (N=41, 40, 34)	0.191 Relapses per year	0.058 Relapses per year	0.162 Relapses per year
Aggregate Annualized Relapse Rate (ARR) Based on Confirmed Relapses Month 48 to end of study (N=8, 6, 3)	0.000 Relapses per year	0.000 Relapses per year	0.000 Relapses per year
Aggregate Annualized Relapse Rate (ARR) Based on Confirmed Relapses Month 6 to 12 (N=47, 46, 50)	0.227 Relapses per year	0.284 Relapses per year	0.232 Relapses per year
Aggregate Annualized Relapse Rate (ARR) Based on Confirmed Relapses Month 12 to 24 (N=44, 43, 39)	0.166 Relapses per year	0.223 Relapses per year	0.222 Relapses per year
Aggregate Annualized Relapse Rate (ARR) Based on Confirmed Relapses Month 36 to 48 (N=28, 23, 23)	0.164 Relapses per year	0.075 Relapses per year	0.309 Relapses per year

SECONDARY outcome

Timeframe: Baseline to the end of the study (up to 4 years)

Patients who did not experience any relapses confirmed by a neurologist during the study were regarded as relapse-free patients.

Outcome measures

Outcome measures
Measure	Fingolimod 0.5 mg n=57 Participants Patients who received fingolimod 0.5 orally once daily in the core study continued on the same dose in this extension study.	Fingolimod 1.25 mg n=54 Participants Patients who received fingolimod 1.25 mg orally once daily in the core study continued on the same dose in this extension study.	Placebo-fingolimod n=57 Participants Patients randomized to placebo in the Core study. These patients were either subsequently re-randomized to FTY720 (either 1.25 mg or 0.5 mg) in the Extension study, or did not enter the Extension study.
Percentage of Patients Relapse-free at the End of the Study	45.2 Percentage of patients Interval 26.87 to 61.95	62.1 Percentage of patients Interval 46.63 to 74.26	48.3 Percentage of patients Interval 33.29 to 61.77

SECONDARY outcome

Timeframe: Baseline to the end of the study (up to 4 years)

Disability progression was measured by the EDSS score. A trained neurologist grades the multiple sclerosis (MS) disability of the patient on a scale of 0-5 (no to severe disability) in 8 Functional Systems (FS): Pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral (or mental), and other. The EDSS score ranges from 0-10 (normal to dead) with higher scores indicating greater disability. A 3-month confirmed disability progression was defined as a 3-month sustained increase from baseline in the EDSS score, that is, every EDSS score obtained (scheduled or unscheduled) within 3-months after the first progression met the following progression criteria: One point (1) increase from baseline in patients with baseline EDSS score from 0 to 5.0; or half a point (0.5) increase in patients with baseline EDSS score of 5.5 or above. A 6-month confirmed disability progression was defined exactly the same except that the sustained progression had to last 6 months.

Outcome measures

Outcome measures
Measure	Fingolimod 0.5 mg n=57 Participants Patients who received fingolimod 0.5 orally once daily in the core study continued on the same dose in this extension study.	Fingolimod 1.25 mg n=54 Participants Patients who received fingolimod 1.25 mg orally once daily in the core study continued on the same dose in this extension study.	Placebo-fingolimod n=57 Participants Patients randomized to placebo in the Core study. These patients were either subsequently re-randomized to FTY720 (either 1.25 mg or 0.5 mg) in the Extension study, or did not enter the Extension study.
Percentage of Patients Free From 3-month and 6-month Confirmed Disability Progression at Their Last Expanded Disability Status Scale (EDSS) Assessment Free from 3-month confirmed disability progression	74.3 Percentage of patients Interval 55.04 to 86.31	82.4 Percentage of patients Interval 67.73 to 90.87	90.6 Percentage of patients Interval 78.63 to 95.99
Percentage of Patients Free From 3-month and 6-month Confirmed Disability Progression at Their Last Expanded Disability Status Scale (EDSS) Assessment Free from 6-month confirmed disability progression	87.1 Percentage of patients Interval 73.4 to 94.03	90.7 Percentage of patients Interval 76.94 to 96.44	92.3 Percentage of patients Interval 80.51 to 97.06

SECONDARY outcome

Timeframe: Baseline to Months 12, 24, 36, 48, and end of study (up to 4 years)

Population: Core full analysis set (FAS): All patients who were randomized in the core study and received at least 1 dose of core study drug. • The study became open-label with all patients receiving FTY720 0.5 mg/day (by 22-Feb- 2010). (approximately 22 months before study completion)

Outcome measures

Outcome measures
Measure	Fingolimod 0.5 mg n=57 Participants Patients who received fingolimod 0.5 orally once daily in the core study continued on the same dose in this extension study.	Fingolimod 1.25 mg n=54 Participants Patients who received fingolimod 1.25 mg orally once daily in the core study continued on the same dose in this extension study.	Placebo-fingolimod n=57 Participants Patients randomized to placebo in the Core study. These patients were either subsequently re-randomized to FTY720 (either 1.25 mg or 0.5 mg) in the Extension study, or did not enter the Extension study.
Change From Core Study Baseline in the Expanded Disability Status Scale (EDSS) Score Month 36 (N=25, 21, 23)	0.16 Units on a scale Standard Deviation 1.441	-0.07 Units on a scale Standard Deviation 0.912	-0.37 Units on a scale Standard Deviation 0.678
Change From Core Study Baseline in the Expanded Disability Status Scale (EDSS) Score End of study (N=37, 36, 32)	0.00 Units on a scale Standard Deviation 1.225	-0.17 Units on a scale Standard Deviation 0.902	-0.31 Units on a scale Standard Deviation 0.830
Change From Core Study Baseline in the Expanded Disability Status Scale (EDSS) Score Month 12 (N=45, 43, 40)	-0.02 Units on a scale Standard Deviation 0.464	-0.02 Units on a scale Standard Deviation 0.831	-0.23 Units on a scale Standard Deviation 0.800
Change From Core Study Baseline in the Expanded Disability Status Scale (EDSS) Score Month 24 (N=42, 40, 35)	-0.12 Units on a scale Standard Deviation 0.723	-0.06 Units on a scale Standard Deviation 1.033	-0.21 Units on a scale Standard Deviation 0.789
Change From Core Study Baseline in the Expanded Disability Status Scale (EDSS) Score Month 48 (N=3, 4, 1)	1.17 Units on a scale Standard Deviation 0.764	-0.63 Units on a scale Standard Deviation 0.946	0.00 Units on a scale Standard Deviation 0.000

Adverse Events

Fingolimod 1.25 mg

Serious events: 5 serious events

Other events: 43 other events

Deaths: 0 deaths

Fingolimod 0.5 mg

Serious events: 8 serious events

Other events: 42 other events

Deaths: 0 deaths

Placebo-fingolimod 1.25 mg

Serious events: 5 serious events

Other events: 21 other events

Deaths: 0 deaths

Placebo-fingolimod 0.5 mg

Serious events: 1 serious events

Other events: 25 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862 778-8300

Results disclosure agreements

Principal investigator is a sponsor employee 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 (ie, data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Measure	Fingolimod 1.25 mg n=46 participants at risk Patients who received fingolimod 1.25 mg orally once daily in the core study continued on the same dose in this extension study.	Fingolimod 0.5 mg n=47 participants at risk Patients who received fingolimod 0.5 orally once daily in the core study continued on the same dose in this extension study.	Placebo-fingolimod 1.25 mg n=23 participants at risk Patients who were randomized to placebo in the core study were re-randomized to either fingolimod 0.5 or 1.25 mg (1:1) orally once daily in this extension study.	Placebo-fingolimod 0.5 mg n=27 participants at risk Patients who were randomized to placebo in the core study were re-randomized to either fingolimod 0.5 or 1.25 mg (1:1) orally once daily in this extension study.
Cardiac disorders Bradycardia	0.00% 0/46 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/47 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	8.7% 2/23 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/27 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.
Eye disorders Cataract	2.2% 1/46 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/47 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/23 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/27 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.
Gastrointestinal disorders Tooth impacted	2.2% 1/46 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/47 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/23 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/27 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.
Immune system disorders Food allergy	0.00% 0/46 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	2.1% 1/47 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/23 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/27 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.
Infections and infestations Appendicitis	2.2% 1/46 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/47 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/23 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/27 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.
Infections and infestations Urinary tract infection	2.2% 1/46 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/47 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/23 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/27 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.
Injury, poisoning and procedural complications Eyeball rupture	2.2% 1/46 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/47 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/23 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/27 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.
Injury, poisoning and procedural complications Hip fracture	0.00% 0/46 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	2.1% 1/47 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/23 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/27 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/46 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	2.1% 1/47 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/23 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/27 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Central nervous system lymphoma	0.00% 0/46 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	2.1% 1/47 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/23 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/27 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.
Nervous system disorders Convulsion	0.00% 0/46 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	2.1% 1/47 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/23 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/27 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.
Nervous system disorders Leukoencephalopathy	0.00% 0/46 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/47 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	4.3% 1/23 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/27 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.
Nervous system disorders Multiple sclerosis relapse	0.00% 0/46 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	2.1% 1/47 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/23 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/27 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.
Nervous system disorders Myoclonus	0.00% 0/46 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	2.1% 1/47 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/23 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/27 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.
Nervous system disorders Neuromyelitis optica	0.00% 0/46 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/47 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/23 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	3.7% 1/27 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.
Nervous system disorders Radiculitis	0.00% 0/46 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/47 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	4.3% 1/23 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/27 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.
Nervous system disorders Status epilepticus	2.2% 1/46 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/47 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/23 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/27 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.
Respiratory, thoracic and mediastinal disorders Haemothorax	0.00% 0/46 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	2.1% 1/47 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/23 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/27 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	2.2% 1/46 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/47 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/23 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/27 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.
Surgical and medical procedures Abortion induced	2.2% 1/46 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/47 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	4.3% 1/23 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.	0.00% 0/27 Extension safety population: All patients who received at least 1 dose of study drug in the extension study.