Long-term Safety and Tolerability of 0.5 mg Fingolimod in Patients With Relapsing Forms of Multiple Sclerosis

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01201356
• Collaborator: (none)
• Enrollment: 4,125
• Locations: 458
• Arm: 1
• Actual Duration (Months): 97.2
• Patients Per Site: 9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study was to collect long-term safety and tolerability, long-term efficacy, and health outcome data in all patients currently ongoing in the fingolimod multiple sclerosis clinical development program. This study combined all currently ongoing Phase II and III fingolimod extension studies as well as ongoing and newly planned studies into one single long-term extension protocol that provided patients with continuous treatment until fingolimod was registered, commercially available, and reimbursed in the respective countries.

Condition or Disease	Intervention/Treatment	Phase
Relapsing Forms of Multiple Sclerosis	Drug: Fingolimod	Phase 3

Detailed Description

This study had two parts:

• Part 1, collecting long-term safety, tolerability, efficacy and health outcomes data through approximately 30-Jun-2016 until all end of study (EOS) visits of Part 1 and last follow-up visit through Jan-2017 and

• Part 2, collecting limited safety and tolerability data until approximately 30 Jun 2018, in a subset of patients who participated in Part 1, and other eligible patients from ongoing fingolimod trials.

Study Design

• Study Type: Interventional
• Actual Enrollment: 4125 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Single Arm, Open-label, Multicenter Study Evaluating the Long-term Safety and Tolerability of 0.5 mg Fingolimod (FTY720) Administered Orally Once Daily in Patients With Relapsing Forms of Multiple Sclerosis
• Actual Study Start Date: Sep 13, 2010
• Actual Primary Completion Date: Oct 19, 2018
• Actual Study Completion Date: Oct 19, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fingolimod 0.5 mg/day Open-label fingolimod 0.5 mg, taken orally once daily	Drug: Fingolimod; 0.5 mg/day; Other Names: FTY720

Outcome Measures

Primary Outcome Measures

1. Parts I and II: Number of Participants With Adverse Events, Serious Adverse Event, and Death [Baseline (Part I) to Month 6 Follow-up (Part II), up to 8 years]

   Analysis of absolute and relative frequencies for Adverse Event (AE), Serious Adverse Event (SAE) and Deaths by primary System Organ Class (SOC) to demonstrate that Fingolimod 0.5 mg/day is safe in patients with relapsing forms of Multiple Sclerosis (MS) through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis performed.

Secondary Outcome Measures

1. Part I: Aggregate Annualized Relapse Rates (ARR) From First Dose of Fingolimod [Month 0 (Core Baseline) to End of Follow-up Visit (an average of 162 months)]

   Annualized relapse rate (ARR) is defined as the number of all relapses (including both confirmed and unconfirmed relapses) experienced during a specific period of time adjusted to a one-year period. ARR is calculated as follows: (total number of all relapses) / (total number of days in the study for all patients for that specific period of time) x 365.25. Month 0 is the first dose of fingolimod study drug among all studies in which patient participated. Only descriptive analysis performed.

2. Part I: Number of Participants With Relapses (Confirmed and Unconfirmed) From First Dose of Fingolimod [Month 0 (Core Baseline) to End of Follow-up Visit (an average of 162 months)]

   A relapse is defined as the appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from 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. In Study Part One, a relapse must be confirmed by an Expanded Disability Status Scale (EDSS) certified Physician within 7 days of the onset of symptoms. A relapse is confirmed when it is accompanied by an increase of at least half a step (0.5) on the EDSS or an increase of 1 point on two different Functional Systems (FS) of the EDSS or 2 points on one of the FS (excluding Bowel/Bladder or Cerebral FS). Month 0 is the first dose of fingolimod study drug among all studies in which patient participated. Only descriptive analysis performed.

3. Part I: Annualized Rates of New or Newly Enlarging T2 Lesions (ARneT2) Compared With First Dose of Fingolimod [Month 0 (Core Baseline) to End of Study (an average of Month 156)]

   Annualized rate of new/newly enlarging T2 lesions (ARneT2) is defined as the number of new or newly enlarging T2 lesions experienced during a specific period of time adjusted to a one-year period. ARneT2 was calculated as follows: (total number of new/newly enlarging T2 lesions) / (total number of days in the study for all patients for that specific period of time) x 365.25.Month 0 is the first dose of fingolimod study drug among all studies in which patient participated. Only descriptive analysis performed.

4. Part I: Change From First Dose of Fingolimod in Total T2 Lesions Volume [Month 3 to End of Study (Study Completion Visit)]

   Total volume of T2 lesions was summarized by presenting descriptive statistics for change from first dose of fingolimod baseline values by visit.

5. Part I: Change From First Dose of Fingolimod in Total T1 Hypointense Lesions Volume [Month 3 to End of Study (Study Completion Visit)]

   T1 hypointense lesion (black hole) volume was summarized by presenting descriptive statistics for change from first dose of fingolimod baseline values by visit.

6. Part I: Percent Brain Volume Change (PBVC) Relative to First Dose of Fingolimod [Month 3 to Month 156]

   Descriptive statistics on percent brain volume change from first dose of fingolimod baseline were presented by visit. A negative change from baseline indicates improvement.

7. Part I: Annualized Rate of Brain Atrophy (ARBA) Relative to First Dose of Fingolimod [Month 3 to Month 156]

   The annualized rate of brain volume change is an "averaged annual percentage change" in brain volume. ARBA was calculated as: ARBA = [(SIENA/100+1) ^ (365.25/#days)-1]*100 where SIENA=(Vk/V0-1)*100 and Vk is the brain volume at time k, V0 is the brain volume at time 0 and k is the total number of days in the study for all patients for that specific period of time) × 365.25. Only descriptive analysis performed.

8. Part I: Number of Participants With Confirmed 6-month Disability Progression After First Dose of Fingolimod [Month 12 to Month 156]

   Disability progression was defined based on an increase in the EDSS score by 1.5 point for patients with a first dose of fingolimod (FDF) baseline EDSS score of 0, 1 point for patients with FDF baseline EDSS of >=1 and <=5.5, and by 0.5 points for patients with an FDF baseline EDSS>5.5, confirmed after 6 months and all intermediate EDSS assessments. A 6-month confirmed disability progression was defined as a 6-month sustained increase from the reference (potential onset of progression) value in the EDSS scores. i.e., every EDSS score (scheduled or unscheduled) within a 6-month duration after the first progression should meet the progression criteria as specified above. The confirmation could only happen at a scheduled visit and in the absence of a relapse. Only descriptive analysis performed.

9. Part I: Number of Participants With Categorized Change From First Dose of Fingolimod in Expanded Disability Status Scale (EDSS) Overall Score [Month 3 to Month 6 Follow-up]

   The EDSS is a scale for assessing neurological impairment in MS (Kurtzke 1983) including (1) a series of scores in each of eight functional systems, and (2) the EDSS steps (ranging from 0 (normal) to 10 (death due to MS). The functional systems are Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel and Bladder, Cerebral and Other functions. Based on the assessment of each FS, the participant's overall score is categorized as Improvement, Stable or Deterioration. If baseline EDSS score is <=5, improvement is indicated by an EDSS score change of <= -1, stable is indicated by an EDSS score change of > -1 and <= 0.5, deterioration is indicated by an EDSS score change of > 0.5; if baseline EDSS score is > 5, improvement is indicated by an EDSS score change of <= -0.5, stable is indicated by an EDSS score change of > -0.5 and <= 0, deterioration is indicated by an EDSS score change of > 0. Only descriptive analysis performed.

10. Part I: Change From First Dose of Fingolimod in Expanded Disability Status Scale (EDSS) [Month 0 (Core Baseline) to End of Follow-up Visit (an average of 162 months)]

    The EDSS is a scale for assessing neurological impairment in MS (Kurtzke 1983) including (1) a series of scores in each of eight functional systems, and (2) the EDSS steps (ranging from 0 (normal) to 10 (death due to MS). The functional systems are Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel and Bladder, Cerebral and Other functions. Based on the assessment of each FS, the participant's overall score is determined between 0 to 10. A negative change from baseline indicates improvement. Only descriptive analysis performed.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Patients who have completed selected ongoing or planned trials with FTY720.

Key Exclusion Criteria:

• Premature permanent discontinuation of a previous fingolimod study.

• Pregnant or nursing (lactating) women.

• Women of child-bearing potential, UNLESS they are using two birth control methods, at least 1 of which must be hormonal contraception, tubal sterilization, partner's vasectomy or intrauterine device.

• Chronic disease of the immune system, other than multiple sclerosis, which may require immunosuppressive treatment.

• Diabetic patients with moderate or severe non-proliferative diabetic retinopathy or proliferative diabetic retinopathy and uncontrolled diabetic patients with HbA1c > 8%.

• Active systemic bacterial, viral or fungal infections, or known to have AIDS, Hepatitis B, Hepatitis C infection or have positive HIV antibody, Hepatitis B surface antigen or Hepatitis C antibody tests.

• Previous treatment with cladribine, cyclophosphamide or mitoxantrone.

• Treatment with immunoglobulins and/or monoclonal antibodies (including Natalizumab) in the past 3 months during the previous fingolimod study:

• Any of the following cardiovascular conditions that have developed during the previous fingolimod study:

• Myocardial infarction within the past 6 months prior to entry in the extension study or with current unstable ischemic heart disease;

• Cardiac failure (Class III, according to New York Heart Association Classification) or any severe cardiac disease as determined by the investigator;

• Arrhythmia requiring current treatment with Class III antiarrhythmic drugs (e.g., amiodarone, bretylium, sotalol, ibutilide, azimilide, dofetilide)

• History or presence of a third degree AV block

• Proven history of sick sinus syndrome or sino-atrial heart block

• Known history of angina pectoris due to coronary spasm or Raynaud's phenomenon

• Any of the following pulmonary conditions during the previous fingolimod study:

• Severe respiratory disease or pulmonary fibrosis diagnosed (during the previous fingolimod study)

• Active tuberculosis

• Alcohol abuse, chronic liver disease during the previous fingolimod study.

The patient must have participated in a previous fingolimod trial to be eligible to participate in this trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Cullman	Alabama	United States	35058
2	Novartis Investigative Site	Oceanside	California	United States	92056
3	Novartis Investigative Site	Sacramento	California	United States	95817
4	Novartis Investigative Site	San Francisco	California	United States	94143
5	Novartis Investigative Site	Washington	District of Columbia	United States	20007
6	Novartis Investigative Site	Jacksonville	Florida	United States	32209
7	Novartis Investigative Site	Maitland	Florida	United States	32751
8	Novartis Investigative Site	Miami	Florida	United States	33136
9	Novartis Investigative Site	Sunrise	Florida	United States	33351
10	Novartis Investigative Site	Tallahassee	Florida	United States	32308
11	Novartis Investigative Site	Tampa	Florida	United States	33609
12	Novartis Investigative Site	Vero Beach	Florida	United States	32960
13	Novartis Investigative Site	Atlanta	Georgia	United States	30327
14	Novartis Investigative Site	Kansas City	Kansas	United States	66160
15	Novartis Investigative Site	Lenexa	Kansas	United States	66212
16	Novartis Investigative Site	Baltimore	Maryland	United States	21201
17	Novartis Investigative Site	Baltimore	Maryland	United States	21287
18	Novartis Investigative Site	Kansas City	Missouri	United States	64111
19	Novartis Investigative Site	Lebanon	New Hampshire	United States	03756
20	Novartis Investigative Site	Albuquerque	New Mexico	United States	87131-0001
21	Novartis Investigative Site	New York	New York	United States	10021
22	Novartis Investigative Site	Durham	North Carolina	United States	27710
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99	Novartis Investigative Site	Olomouc	CZE	Czechia	775 20
100	Novartis Investigative Site	Ostrava-Poruba		Czechia	708 00
101	Novartis Investigative Site	Pardubice		Czechia	532 03
102	Novartis Investigative Site	Plzen - Lochotin		Czechia	30460
103	Novartis Investigative Site	Prague 5		Czechia	150 00
104	Novartis Investigative Site	Praha		Czechia	12808
105	Novartis Investigative Site	Rychnov nad Kneznou		Czechia	516 01
106	Novartis Investigative Site	Teplice		Czechia	415 29
107	Novartis Investigative Site	Aarhus		Denmark	DK-8000
108	Novartis Investigative Site	Copenhagen		Denmark	DK-2100
109	Novartis Investigative Site	Alexandria		Egypt	21131
110	Novartis Investigative Site	Cairo		Egypt	11566
111	Novartis Investigative Site	Cairo		Egypt
112	Novartis Investigative Site	Tallinn		Estonia	10617
113	Novartis Investigative Site	Helsinki		Finland	00930
114	Novartis Investigative Site	Seinajoki		Finland	60220
115	Novartis Investigative Site	Tampere		Finland	33100
116	Novartis Investigative Site	Turku		Finland	20520
117	Novartis Investigative Site	Nancy	Cedex	France	54035
118	Novartis Investigative Site	Bordeaux Cedex		France	F-33076
119	Novartis Investigative Site	Bron		France	69677
120	Novartis Investigative Site	CAEN Cedex		France	14033
121	Novartis Investigative Site	Clermont-Ferrand Cedex 1		France	63003
122	Novartis Investigative Site	Dijon		France	21034
123	Novartis Investigative Site	Lille Cedex		France	59037
124	Novartis Investigative Site	Marseille cedex 05		France	13385
125	Novartis Investigative Site	Montpellier		France	34295
126	Novartis Investigative Site	Nice Cedex 1		France	06602
127	Novartis Investigative Site	Paris Cedex 13		France	75651
128	Novartis Investigative Site	Poissy		France	78303
129	Novartis Investigative Site	Rennes		France	35043
130	Novartis Investigative Site	St Herblain		France	44800
131	Novartis Investigative Site	Strasbourg Cedex		France	67091
132	Novartis Investigative Site	Toulouse cedex 9		France	31059
133	Novartis Investigative Site	Ostfildern	Baden-Wuerttemberg	Germany	73760
134	Novartis Investigative Site	Munich	Bavaria	Germany	81241
135	Novartis Investigative Site	Regensburg	Bavaria	Germany	93053
136	Novartis Investigative Site	Koeln	Nordrhein-Westfalen	Germany	50937
137	Novartis Investigative Site	Aachen		Germany	52062
138	Novartis Investigative Site	Aalen		Germany	73430
139	Novartis Investigative Site	Abensberg		Germany	93326
140	Novartis Investigative Site	Achim		Germany	28832
141	Novartis Investigative Site	Alzenau		Germany	63755
142	Novartis Investigative Site	Aschaffenburg		Germany	63739
143	Novartis Investigative Site	Augsburg		Germany	86179
144	Novartis Investigative Site	Bad Honnef		Germany	53604
145	Novartis Investigative Site	Bad Krozingen		Germany	79189
146	Novartis Investigative Site	Bad Mergentheim		Germany	97980
147	Novartis Investigative Site	Bad Neustadt		Germany	97616
148	Novartis Investigative Site	Bamberg		Germany	96049
149	Novartis Investigative Site	Bamberg		Germany	96052
150	Novartis Investigative Site	Bayreuth		Germany	95445
151	Novartis Investigative Site	Berlin		Germany	10178
152	Novartis Investigative Site	Berlin		Germany	10625
153	Novartis Investigative Site	Berlin		Germany	10713
154	Novartis Investigative Site	Berlin		Germany	10785
155	Novartis Investigative Site	Berlin		Germany	120999
156	Novartis Investigative Site	Berlin		Germany	12101
157	Novartis Investigative Site	Berlin		Germany	12163
158	Novartis Investigative Site	Berlin		Germany	12351
159	Novartis Investigative Site	Berlin		Germany	13347
160	Novartis Investigative Site	Berlin		Germany	13353
161	Novartis Investigative Site	Berlin		Germany	13439
162	Novartis Investigative Site	Berlin		Germany	13507
163	Novartis Investigative Site	Berlin		Germany	14163
164	Novartis Investigative Site	Bielefeld		Germany	33602
165	Novartis Investigative Site	Bielefeld		Germany	33611
166	Novartis Investigative Site	Bielefeld		Germany	33647
167	Novartis Investigative Site	Boblingen		Germany	71032
168	Novartis Investigative Site	Bochum		Germany	44787
169	Novartis Investigative Site	Bochum		Germany	44789
170	Novartis Investigative Site	Bochum		Germany	44892
171	Novartis Investigative Site	Bogen		Germany	94327
172	Novartis Investigative Site	Bonn		Germany	53111
173	Novartis Investigative Site	Buchholz in der Nordheide		Germany	21244
174	Novartis Investigative Site	Buchholz		Germany	21244
175	Novartis Investigative Site	Chemnitz		Germany	09117
176	Novartis Investigative Site	Dillingen		Germany	89407
177	Novartis Investigative Site	Dresden		Germany	01307
178	Novartis Investigative Site	Düsseldorf		Germany	40211
179	Novartis Investigative Site	Emden		Germany	26721
180	Novartis Investigative Site	Emmendingen		Germany	79312
181	Novartis Investigative Site	Erbach		Germany	64711
182	Novartis Investigative Site	Erfurt		Germany	99089
183	Novartis Investigative Site	Erlangen		Germany	91054
184	Novartis Investigative Site	Essen		Germany	45131
185	Novartis Investigative Site	Essen		Germany	45147
186	Novartis Investigative Site	Frankfurt		Germany	60590
187	Novartis Investigative Site	Freiburg		Germany	79106
188	Novartis Investigative Site	Greifswald		Germany	17475
189	Novartis Investigative Site	Grevenbroich		Germany	41515
190	Novartis Investigative Site	Hamburg		Germany	20099
191	Novartis Investigative Site	Hamburg		Germany	20249
192	Novartis Investigative Site	Hamburg		Germany	20354
193	Novartis Investigative Site	Hamburg		Germany	22083
194	Novartis Investigative Site	Hannover		Germany	30161
195	Novartis Investigative Site	Hannover		Germany	30171
196	Novartis Investigative Site	Hannover		Germany	30625
197	Novartis Investigative Site	Heidelberg		Germany	69120
198	Novartis Investigative Site	Hennigsdorf		Germany	16761
199	Novartis Investigative Site	Herborn		Germany	35745
200	Novartis Investigative Site	Homburg		Germany	66421
201	Novartis Investigative Site	Ibbenbueren		Germany	49477
202	Novartis Investigative Site	Itzehoe		Germany	25524
203	Novartis Investigative Site	Jena		Germany	07743
204	Novartis Investigative Site	Kaltenkirchen		Germany	24568
205	Novartis Investigative Site	Kassel		Germany	34121
206	Novartis Investigative Site	Koeln		Germany	51109
207	Novartis Investigative Site	Koln		Germany	50935
208	Novartis Investigative Site	Krefeld		Germany	47805
209	Novartis Investigative Site	Landshut		Germany	84028
210	Novartis Investigative Site	Lappersdorf		Germany	93138
211	Novartis Investigative Site	Leipzig		Germany	04103
212	Novartis Investigative Site	Leipzig		Germany	04275
213	Novartis Investigative Site	Lohr am Main		Germany	79816
214	Novartis Investigative Site	Ludwigshafen		Germany	67063
215	Novartis Investigative Site	Magdeburg		Germany	39120
216	Novartis Investigative Site	Mainz		Germany	55131
217	Novartis Investigative Site	Mannheim		Germany	68159
218	Novartis Investigative Site	Marburg		Germany	35039
219	Novartis Investigative Site	Muenchen		Germany	80331
220	Novartis Investigative Site	Muenchen		Germany	80377
221	Novartis Investigative Site	Muenchen		Germany	81377
222	Novartis Investigative Site	Muenster		Germany	48149
223	Novartis Investigative Site	München		Germany	81829
224	Novartis Investigative Site	Nagold		Germany	72202
225	Novartis Investigative Site	Neu-Ulm		Germany	89231
226	Novartis Investigative Site	Neuburg an der Donau		Germany	86633
227	Novartis Investigative Site	Neuruppin		Germany	16816
228	Novartis Investigative Site	Oldenburg		Germany	26122
229	Novartis Investigative Site	Osnabrück		Germany	49076
230	Novartis Investigative Site	Pforzheim		Germany	75172
231	Novartis Investigative Site	Potsdam		Germany	14471
232	Novartis Investigative Site	Prien		Germany	83209
233	Novartis Investigative Site	Rostock		Germany	18057
234	Novartis Investigative Site	Ruelzheim		Germany	76761
235	Novartis Investigative Site	Rüdersdorf		Germany	15562
236	Novartis Investigative Site	Schwarzenbruck		Germany	90592
237	Novartis Investigative Site	Schwendi		Germany	88477
238	Novartis Investigative Site	Siegen		Germany	57076
239	Novartis Investigative Site	Sinsheim		Germany	74889
240	Novartis Investigative Site	Stade		Germany	21682
241	Novartis Investigative Site	Stuttgart		Germany	70174
242	Novartis Investigative Site	Stuttgart		Germany	70176
243	Novartis Investigative Site	Stuttgart		Germany	70178
244	Novartis Investigative Site	Stuttgart		Germany	70182
245	Novartis Investigative Site	Teupitz		Germany	15755
246	Novartis Investigative Site	Trier		Germany	54292
247	Novartis Investigative Site	Tübingen		Germany	72076
248	Novartis Investigative Site	Ulm		Germany	89073
249	Novartis Investigative Site	Ulm		Germany	89081
250	Novartis Investigative Site	Unterhaching		Germany	82008
251	Novartis Investigative Site	Wendlingen		Germany	73240
252	Novartis Investigative Site	Wermsdorf		Germany	04779
253	Novartis Investigative Site	Wiesbaden		Germany	65191
254	Novartis Investigative Site	Wuerzburg		Germany	97080
255	Novartis Investigative Site	Wuppertal		Germany	42283
256	Novartis Investigative Site	Würzburg		Germany	97070
257	Novartis Investigative Site	Alexandroupolis	Evros	Greece	681 00
258	Novartis Investigative Site	Athens	GR	Greece	115 25
259	Novartis Investigative Site	Athens	GR	Greece	115 27
260	Novartis Investigative Site	Thessaloniki	GR	Greece	570 10
261	Novartis Investigative Site	Athens		Greece	106 76
262	Novartis Investigative Site	Athens		Greece	115 21
263	Novartis Investigative Site	Athens		Greece	11526
264	Novartis Investigative Site	Athens		Greece	15123
265	Novartis Investigative Site	Heraklion Crete		Greece	711 10
266	Novartis Investigative Site	Patras		Greece	265 00
267	Novartis Investigative Site	Thessaloniki		Greece	57001
268	Novartis Investigative Site	Thessaloniki		Greece	GR 54636
269	Novartis Investigative Site	Guatemala City		Guatemala	01010
270	Novartis Investigative Site	Guatemala City		Guatemala	01014
271	Novartis Investigative Site	Budapest	HUN	Hungary	1204
272	Novartis Investigative Site	Budapest		Hungary	1076
273	Novartis Investigative Site	Budapest		Hungary	1085
274	Novartis Investigative Site	Budapest		Hungary	1115
275	Novartis Investigative Site	Budapest		Hungary	1145
276	Novartis Investigative Site	Debrecen		Hungary	4032
277	Novartis Investigative Site	Gyor		Hungary	9024
278	Novartis Investigative Site	Miskolc		Hungary	3526
279	Novartis Investigative Site	Pecs		Hungary	7623
280	Novartis Investigative Site	Szeged		Hungary	6725
281	Novartis Investigative Site	Szekesfehervar		Hungary	H-8000
282	Novartis Investigative Site	Veszprem		Hungary	H 8200
283	Novartis Investigative Site	Dublin 4		Ireland	D04 T6F
284	Novartis Investigative Site	Dublin		Ireland	DUBLIN 9
285	Novartis Investigative Site	Ashkelon		Israel	78278
286	Novartis Investigative Site	Haifa		Israel	3436212
287	Novartis Investigative Site	Ramat Gan		Israel	52621
288	Novartis Investigative Site	Sefad		Israel	13100
289	Novartis Investigative Site	Asti	AT	Italy	14100
290	Novartis Investigative Site	Acquaviva delle Fonti	BA	Italy	70021
291	Novartis Investigative Site	Bergamo	BG	Italy	24127
292	Novartis Investigative Site	Bologna	BO	Italy	40139
293	Novartis Investigative Site	Montichiari	BS	Italy	25018
294	Novartis Investigative Site	Cagliari	CA	Italy	09126
295	Novartis Investigative Site	Chieti	CH	Italy	66100
296	Novartis Investigative Site	Catania	CT	Italy	95122
297	Novartis Investigative Site	Catania	CT	Italy	95123
298	Novartis Investigative Site	Cona	FE	Italy	44100
299	Novartis Investigative Site	Foggia	FG	Italy	71100
300	Novartis Investigative Site	Firenze	FI	Italy	50134
301	Novartis Investigative Site	Genova	GE	Italy	16132
302	Novartis Investigative Site	Pozzilli	IS	Italy	86077
303	Novartis Investigative Site	Roma	Lazio	Italy	00168
304	Novartis Investigative Site	Milano	MI	Italy	20122
305	Novartis Investigative Site	Milano	MI	Italy	20132
306	Novartis Investigative Site	Palermo	PA	Italy	90146
307	Novartis Investigative Site	Fidenza	PR	Italy	43036
308	Novartis Investigative Site	Pavia	PV	Italy	27100
309	Novartis Investigative Site	Ravenna	RA	Italy	48100
310	Novartis Investigative Site	Roma	RM	Italy	00133
311	Novartis Investigative Site	Roma	RM	Italy	00135
312	Novartis Investigative Site	Roma	RM	Italy	00161
313	Novartis Investigative Site	Roma	RM	Italy	00189
314	Novartis Investigative Site	Siena	SI	Italy	53100
315	Novartis Investigative Site	Orbassano	TO	Italy	10043
316	Novartis Investigative Site	Udine	UD	Italy	33100
317	Novartis Investigative Site	Gallarate	VA	Italy	21013
318	Novartis Investigative Site	Vicenza	VI	Italy	36100
319	Novartis Investigative Site	Verona	VR	Italy	37134
320	Novartis Investigative Site	Viterbo	VT	Italy	01100
321	Novartis Investigative Site	Napoli		Italy	80131
322	Novartis Investigative Site	Napoli		Italy	80132
323	Novartis Investigative Site	Napoli		Italy	80138
324	Novartis Investigative Site	Irbid		Jordan	22110
325	Novartis Investigative Site	Gyeonggi do	Korea	Korea, Republic of	10408
326	Novartis Investigative Site	Seoul		Korea, Republic of	03722
327	Novartis Investigative Site	Seoul		Korea, Republic of	06351
328	Novartis Investigative Site	Kuala Lumpur	Wilayah Persekutuan	Malaysia	50586
329	Novartis Investigative Site	Kuala Lumpur		Malaysia	59100
330	Novartis Investigative Site	Breda	CK	Netherlands	4818
331	Novartis Investigative Site	Amsterdam		Netherlands	1061 AE
332	Novartis Investigative Site	Amsterdam		Netherlands	1081 HV
333	Novartis Investigative Site	Blaricum		Netherlands	1261 AN
334	Novartis Investigative Site	Enschede		Netherlands	7513 ER
335	Novartis Investigative Site	Gouda		Netherlands	2803 HH
336	Novartis Investigative Site	Nieuwegein		Netherlands
337	Novartis Investigative Site	Nijmegen		Netherlands	6525 GC
338	Novartis Investigative Site	Rotterdam		Netherlands	3015 CE
339	Novartis Investigative Site	Sittard-Geleen		Netherlands	6162 BG
340	Novartis Investigative Site	Tilburg		Netherlands	5022 GC
341	Novartis Investigative Site	Lillehammer		Norway	2629
342	Novartis Investigative Site	Molde		Norway	6412
343	Novartis Investigative Site	Stavanger		Norway	4068
344	Novartis Investigative Site	Panama City		Panama	0801
345	Novartis Investigative Site	Panama City		Panama
346	Novartis Investigative Site	La Perla	Callao	Peru	04
347	Novartis Investigative Site	Jesus Maria	Lima	Peru	11
348	Novartis Investigative Site	San Isidro	Lima	Peru	27
349	Novartis Investigative Site	Bialystok		Poland	15-276
350	Novartis Investigative Site	Bialystok		Poland	15-420
351	Novartis Investigative Site	Bydgoszcz		Poland	85 681
352	Novartis Investigative Site	Gdansk		Poland	80-803
353	Novartis Investigative Site	Katowice		Poland	40 571
354	Novartis Investigative Site	Katowice		Poland	40-648
355	Novartis Investigative Site	Lodz		Poland	90 324
356	Novartis Investigative Site	Poznan		Poland	60-355
357	Novartis Investigative Site	Warszawa		Poland	02-097
358	Novartis Investigative Site	Warszawa		Poland	02-507
359	Novartis Investigative Site	Warszawa		Poland	02-957
360	Novartis Investigative Site	Warszawa		Poland	04141
361	Novartis Investigative Site	Amadora		Portugal	2720-276
362	Novartis Investigative Site	Coimbra		Portugal	3000075
363	Novartis Investigative Site	Lisboa		Portugal	1150 314
364	Novartis Investigative Site	Porto		Portugal	4099-001
365	Novartis Investigative Site	Porto		Portugal	4200 319
366	Novartis Investigative Site	Setubal		Portugal	2910-446
367	Novartis Investigative Site	Bucharest		Romania	010825
368	Novartis Investigative Site	Bucharest		Romania	011461
369	Novartis Investigative Site	Bucharest		Romania	050098
370	Novartis Investigative Site	Craiova		Romania	200620
371	Novartis Investigative Site	Targu Mures		Romania	540136
372	Novartis Investigative Site	Samara	Samara Region	Russian Federation	443095
373	Novartis Investigative Site	Ekaterinburg		Russian Federation	620109
374	Novartis Investigative Site	Kazan		Russian Federation	420021
375	Novartis Investigative Site	Kazan		Russian Federation	420097
376	Novartis Investigative Site	Moscow		Russian Federation	101990
377	Novartis Investigative Site	Moscow		Russian Federation	121359
378	Novartis Investigative Site	Moscow		Russian Federation	125367
379	Novartis Investigative Site	Moscow		Russian Federation	127018
380	Novartis Investigative Site	Nizhny Novgorod		Russian Federation	603018
381	Novartis Investigative Site	Nizhny Novgorod		Russian Federation	603155
382	Novartis Investigative Site	Saint Petersburg		Russian Federation	194044
383	Novartis Investigative Site	Smolensk		Russian Federation	214019
384	Novartis Investigative Site	St. Petersburg		Russian Federation	194291
385	Novartis Investigative Site	St. Petersburg		Russian Federation	197376
386	Novartis Investigative Site	Bratislava	Slovak Republic	Slovakia	84103
387	Novartis Investigative Site	Bratislava		Slovakia	813 69
388	Novartis Investigative Site	Bratislava		Slovakia	826 06
389	Novartis Investigative Site	Martin		Slovakia	036 59
390	Novartis Investigative Site	Trnava		Slovakia	917 75
391	Novartis Investigative Site	Cape Town		South Africa	7925
392	Novartis Investigative Site	Durban		South Africa
393	Novartis Investigative Site	Rosebank		South Africa	2196
394	Novartis Investigative Site	Malaga	Andalucia	Spain	29010
395	Novartis Investigative Site	Sevilla	Andalucia	Spain	41009
396	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
397	Novartis Investigative Site	Barcelona	Catalunya	Spain	08036
398	Novartis Investigative Site	L Hospitalet De Llobregat	Catalunya	Spain	08907
399	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46010
400	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46026
401	Novartis Investigative Site	Santiago de Compostela	Galicia	Spain	15706
402	Novartis Investigative Site	Bilbao	Pais Vasco	Spain	48013
403	Novartis Investigative Site	San Sebastian	Pais Vasco	Spain	20080
404	Novartis Investigative Site	Barcelona		Spain	08041
405	Novartis Investigative Site	Madrid		Spain	28034
406	Novartis Investigative Site	Madrid		Spain	28040
407	Novartis Investigative Site	Madrid		Spain	28046
408	Novartis Investigative Site	Madrid		Spain	28222
409	Novartis Investigative Site	Santa Cruz de Tenerife		Spain	38009
410	Novartis Investigative Site	Goeteborg		Sweden	413 45
411	Novartis Investigative Site	Linkoping		Sweden	SE 581 85
412	Novartis Investigative Site	Stockholm		Sweden	102 35
413	Novartis Investigative Site	Stockholm		Sweden	14186
414	Novartis Investigative Site	Umea		Sweden	901 85
415	Novartis Investigative Site	Aarau		Switzerland	5001
416	Novartis Investigative Site	Basel		Switzerland	4031
417	Novartis Investigative Site	Carouge		Switzerland	1227
418	Novartis Investigative Site	Lausanne		Switzerland	1011
419	Novartis Investigative Site	Lugano		Switzerland	6900
420	Novartis Investigative Site	St Gallen		Switzerland	9007
421	Novartis Investigative Site	Zuerich		Switzerland	8091
422	Novartis Investigative Site	Istanbul	TUR	Turkey	34098
423	Novartis Investigative Site	Ankara		Turkey	06100
424	Novartis Investigative Site	Ankara		Turkey	06500
425	Novartis Investigative Site	Antalya		Turkey	07070
426	Novartis Investigative Site	Gaziantep		Turkey	27310
427	Novartis Investigative Site	Haseki / Istanbul		Turkey	34096
428	Novartis Investigative Site	Istanbul		Turkey	34093
429	Novartis Investigative Site	Istanbul		Turkey	34147
430	Novartis Investigative Site	Istanbul		Turkey	34722
431	Novartis Investigative Site	Izmir		Turkey	35040
432	Novartis Investigative Site	Izmir		Turkey	35340
433	Novartis Investigative Site	Mersin		Turkey	33079
434	Novartis Investigative Site	Samsun		Turkey	55139
435	Novartis Investigative Site	Trabzon		Turkey	61080
436	Novartis Investigative Site	Yenisehir / Izmir		Turkey
437	Novartis Investigative Site	Truro	Cornwall	United Kingdom	TR1 3LJ
438	Novartis Investigative Site	Brighton	East Sussex	United Kingdom	BN2 5BE
439	Novartis Investigative Site	Salford	Manchester	United Kingdom	M6 8HD
440	Novartis Investigative Site	Headington	Oxfordshire	United Kingdom	OX3 9DU
441	Novartis Investigative Site	Sheffield	South Yorkshire	United Kingdom	S10 2JF
442	Novartis Investigative Site	Stoke on Trent	Staffordshire	United Kingdom	ST46QG
443	Novartis Investigative Site	Birmingham		United Kingdom	B15 2TH
444	Novartis Investigative Site	Bristol		United Kingdom	BS10 5NB
445	Novartis Investigative Site	Dundee		United Kingdom	DD1 9SY
446	Novartis Investigative Site	Edinburgh		United Kingdom	EH4 2XU
447	Novartis Investigative Site	Essex		United Kingdom	RM7 0BE
448	Novartis Investigative Site	Great Yarmouth		United Kingdom	NR31 6LA
449	Novartis Investigative Site	Liverpool		United Kingdom	L9 7LJ
450	Novartis Investigative Site	London		United Kingdom	SE22 8PT
451	Novartis Investigative Site	London		United Kingdom	SW17 0QT
452	Novartis Investigative Site	London		United Kingdom	W8 6RF
453	Novartis Investigative Site	Middlesbrough		United Kingdom	TS4 3BW
454	Novartis Investigative Site	Newcastle Upon Tyne		United Kingdom	NE1 4LP
455	Novartis Investigative Site	Northampton		United Kingdom	NN1 5BD
456	Novartis Investigative Site	Nottingham		United Kingdom	NG7 2UH
457	Novartis Investigative Site	Poole		United Kingdom	BH15 2JB
458	Novartis Investigative Site	Swindon		United Kingdom	SN3 6BB

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Apr 1, 2016
• Statistical Analysis Plan - Nov 26, 2018

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01201356
• Other Study ID Numbers: CFTY720D2399; 2010-020515-37
• First Posted: Sep 14, 2010
• Last Update Posted: Apr 21, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Fingolimod; FTY720; Relapsing forms of MS; Multiple Sclerosis; Efficacy
• Additional relevant MeSH terms: Multiple Sclerosis; Sclerosis; Fingolimod Hydrochloride

Study Results

Participant Flow

Recruitment Details	This was an open-label, multi-center, single treatment arm design allowing patients participating in the fingolimod MS clinical development program to enroll in order to collect additional long-term safety, tolerability, efficacy, and health outcomes data.
Pre-assignment Detail	This study had two parts: Part 1, collecting long-term safety, tolerability, efficacy and health outcomes data until all Part 1 end of study (EOS) visits and last follow-up visit; Part 2, collecting limited safety and tolerability data, in a subset of patients who participated in Part 1, and other eligible patients from ongoing fingolimod trials.

Arm/Group Title	Fingolimod 0.5 mg/Day
Arm/Group Description	Open-label fingolimod 0.5 mg, taken orally once daily
Period Title: Overall Study
STARTED	4125
Safety Set	4083
Fingolimod Full Analysis Set	4046
COMPLETED	3481
NOT COMPLETED	644

Baseline Characteristics

Arm/Group Title	Fingolimod 0.5 mg/Day
Arm/Group Description	Open-label fingolimod 0.5 mg, taken orally once daily
Overall Participants	4125
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.8 (9.05)
Age, Customized (Number) [Number]
< 18 years	1 0%
18 - 30 years	951 23.1%
31 - 40 years	1497 36.3%
41 - 55 years	1605 38.9%
> 55 years	71 1.7%
Sex: Female, Male (Count of Participants)
Female	2933 71.1%
Male	1192 28.9%
Race/Ethnicity, Customized (Number) [Number]
Caucasian	3927 95.2%
Black	38 0.9%
Asian	35 0.8%
Native American	11 0.3%
Other	114 2.8%

Outcome Measures

1. Primary Outcome

Title	Parts I and II: Number of Participants With Adverse Events, Serious Adverse Event, and Death
Description	Analysis of absolute and relative frequencies for Adverse Event (AE), Serious Adverse Event (SAE) and Deaths by primary System Organ Class (SOC) to demonstrate that Fingolimod 0.5 mg/day is safe in patients with relapsing forms of Multiple Sclerosis (MS) through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis performed.
Time Frame	Baseline (Part I) to Month 6 Follow-up (Part II), up to 8 years

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	Fingolimod 0.5 mg/Day
Arm/Group Description	Open-label fingolimod 0.5 mg, taken orally once daily
Measure Participants	4083
Adverse Event (AEs)	2125 51.5%
Serious Adverse Events (SAEs)	515 12.5%
Deaths	16 0.4%

2. Secondary Outcome

Title	Part I: Aggregate Annualized Relapse Rates (ARR) From First Dose of Fingolimod
Description	Annualized relapse rate (ARR) is defined as the number of all relapses (including both confirmed and unconfirmed relapses) experienced during a specific period of time adjusted to a one-year period. ARR is calculated as follows: (total number of all relapses) / (total number of days in the study for all patients for that specific period of time) x 365.25. Month 0 is the first dose of fingolimod study drug among all studies in which patient participated. Only descriptive analysis performed.
Time Frame	Month 0 (Core Baseline) to End of Follow-up Visit (an average of 162 months)

Outcome Measure Data

Analysis Population Description

Fingolimod full analysis set. Only participants with an observed value were considered for the analysis.

Arm/Group Title	Fingolimod 0.5 mg/Day
Arm/Group Description	Open-label fingolimod 0.5 mg, taken orally once daily
Measure Participants	4046
Month 0 to Month 6	0.325
Month 0 to Month 12	0.273
Month 0 to Month 24	0.237
Month 0 to Month 36	0.217
Month 0 to Month 48	0.208
Month 0 to Month 60	0.197
Month 0 to Month 72	0.190
Month 0 to Month 84	0.182
Month 0 to Month 96	0.177
Month 0 to Month 108	0.172
Month 0 to Month 120	0.170
Month 0 to Month 132	0.170
Month 0 to Month 144	0.169
Month 0 to Month 156	0.169
Month 0 to end of Study	0.166
Month 0 to end of Follow-up	0.169

3. Secondary Outcome

Title	Part I: Number of Participants With Relapses (Confirmed and Unconfirmed) From First Dose of Fingolimod
Description	A relapse is defined as the appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from 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. In Study Part One, a relapse must be confirmed by an Expanded Disability Status Scale (EDSS) certified Physician within 7 days of the onset of symptoms. A relapse is confirmed when it is accompanied by an increase of at least half a step (0.5) on the EDSS or an increase of 1 point on two different Functional Systems (FS) of the EDSS or 2 points on one of the FS (excluding Bowel/Bladder or Cerebral FS). Month 0 is the first dose of fingolimod study drug among all studies in which patient participated. Only descriptive analysis performed.
Time Frame	Month 0 (Core Baseline) to End of Follow-up Visit (an average of 162 months)

Outcome Measure Data

Analysis Population Description

Fingolimod full analysis set. Only participants with an observed value were considered for the analysis.

Arm/Group Title	Fingolimod 0.5 mg/Day
Arm/Group Description	Open-label fingolimod 0.5 mg, taken orally once daily
Measure Participants	4046
Month 0 to Month 6	655 15.9%
Month 0 to Month 12	992 24%
Month 0 to Month 24	1461 35.4%
Month 0 to Month 36	1794 43.5%
Month 0 to Month 48	2127 51.6%
Month 0 to Month 60	2383 57.8%
Month 0 to Month 72	2616 63.4%
Month 0 to Month 84	2793 67.7%
Month 0 to Month 96	2944 71.4%
Month 0 to Month 108	3036 73.6%
Month 0 to Month 120	3063 74.3%
Month 0 to Month 132	3072 74.5%
Month 0 to Month 144	3075 74.5%
Month 0 to Month 156	3079 74.6%
Month 0 to end of Study	2970 72%
Month 0 to end of Follow-up	3079 74.6%

4. Secondary Outcome

Title	Part I: Annualized Rates of New or Newly Enlarging T2 Lesions (ARneT2) Compared With First Dose of Fingolimod
Description	Annualized rate of new/newly enlarging T2 lesions (ARneT2) is defined as the number of new or newly enlarging T2 lesions experienced during a specific period of time adjusted to a one-year period. ARneT2 was calculated as follows: (total number of new/newly enlarging T2 lesions) / (total number of days in the study for all patients for that specific period of time) x 365.25.Month 0 is the first dose of fingolimod study drug among all studies in which patient participated. Only descriptive analysis performed.
Time Frame	Month 0 (Core Baseline) to End of Study (an average of Month 156)

Outcome Measure Data

Analysis Population Description

Fingolimod full analysis set. Only participants with an observed value were considered for the analysis.

Arm/Group Title	Fingolimod 0.5 mg/Day
Arm/Group Description	Open-label fingolimod 0.5 mg, taken orally once daily
Measure Participants	4046
Month 0 to Month 3	12.324
Month 0 to Month 6	2.073
Month 0 to Month 12	1.360
Month 0 to Month 24	1.042
Month 0 to Month 36	1.011
Month 0 to Month 48	1.008
Month 0 to Month 60	0.957
Month 0 to Month 72	0.963
Month 0 to Month 84	0.906
Month 0 to Month 96	0.813
Month 0 to Month 108	0.713
Month 0 to Month 120	0.702
Month 0 to Month 132	0.659
Month 0 to Month 144	0.681
Month 0 to Month 156	0.637
Month 0 to end of study	0.751

5. Secondary Outcome

Title	Part I: Change From First Dose of Fingolimod in Total T2 Lesions Volume
Description	Total volume of T2 lesions was summarized by presenting descriptive statistics for change from first dose of fingolimod baseline values by visit.
Time Frame	Month 3 to End of Study (Study Completion Visit)

Outcome Measure Data

Analysis Population Description

Fingolimod full analysis set. Only participants with an observed value were considered for the analysis.

Arm/Group Title	Fingolimod 0.5 mg/Day
Arm/Group Description	Open-label fingolimod 0.5 mg, taken orally once daily
Measure Participants	4046
T2 volume change at Month 3	-749.5 (5269.04)
T2 volume change at Month 6	-207.0 (1385.64)
T2 volume change at Month 12	-55.0 (1700.16)
T2 volume change at Month 24	16.2 (2009.87)
T2 volume change at Month 36	235.8 (2519.39)
T2 volume change at Month 48	875.1 (4145.99)
T2 volume change at Month 60	1546.3 (4556.51)
T2 volume change at Month 72	1719.2 (5184.27)
T2 volume change at Month 84	1635.8 (5075.13)
T2 volume change at Month 96	1303.9 (4712.78)
T2 volume change at Month 108	1562.0 (4654.67)
T2 volume change at Month 120	1393.1 (4908.76)
T2 volume change at Month 132	905.9 (3960.94)
T2 volume change at Month 144	702.7 (3765.80)
T2 volume change at Month 156	274.0 (5784.85)
T2 volume change at End of Study	1588.5 (5157.00)

6. Secondary Outcome

Title	Part I: Change From First Dose of Fingolimod in Total T1 Hypointense Lesions Volume
Description	T1 hypointense lesion (black hole) volume was summarized by presenting descriptive statistics for change from first dose of fingolimod baseline values by visit.
Time Frame	Month 3 to End of Study (Study Completion Visit)

Outcome Measure Data

Analysis Population Description

Fingolimod full analysis set. Only participants with an observed value were considered for the analysis.

Arm/Group Title	Fingolimod 0.5 mg/Day
Arm/Group Description	Open-label fingolimod 0.5 mg, taken orally once daily
Measure Participants	4046
T1 volume change at Month 3	-519.8 (1339.62)
T1 volume change at Month 12	49.1 (718.77)
T1 volume change at Month 24	64.1 (786.02)
T1 volume change at Month 36	151.08 (1001.28)
T1 volume change at Month 48	524.8 (1706.26)
T1 volume change at Month 60	853.6 (1957.74)
T1 volume change at Month 72	975.7 (2637.67)
T1 volume change at Month 84	930.1 (2471.70)
T1 volume change at Month 96	753.4 (1845.63)
T1 volume change at Month 108	628.7 (1922.45)
T1 volume change at Month 120	817.3 (2198.58)
T1 volume change at Month 132	726.7 (NA)
T1 volume change at End of Study	800.6 (2247.27)

7. Secondary Outcome

Title	Part I: Percent Brain Volume Change (PBVC) Relative to First Dose of Fingolimod
Description	Descriptive statistics on percent brain volume change from first dose of fingolimod baseline were presented by visit. A negative change from baseline indicates improvement.
Time Frame	Month 3 to Month 156

Outcome Measure Data

Analysis Population Description

Fingolimod full analysis set. Only participants with an observed value were considered for the analysis.

Arm/Group Title	Fingolimod 0.5 mg/Day
Arm/Group Description	Open-label fingolimod 0.5 mg, taken orally once daily
Measure Participants	4046
Percent volume change at Month 3	-0.19 (0.660)
Percent volume change at Month 6	-0.20 (0.801)
Percent volume change at Month 12	-0.36 (0.901)
Percent volume change at Month 24	-0.74 (1.209)
Percent volume change at Month 36	-1.03 (1.541)
Percent volume change at Month 48	-1.44 (1.851)
Percent volume change at Month 60	-1.65 (2.196)
Percent volume change at Month 72	-2.02 (2.514)
Percent volume change at Month 84	-2.38 (2.638)
Percent volume change at Month 96	-2.41 (2.607)
Percent volume change at Month 108	-2.91 (2.863)
Percent volume change at Month 120	-3.42 (2.911)
Percent volume change at Month 132	-4.61 (2.511)
Percent volume change at Month 144	-4.21 (2.778)
Percent volume change at Month 156	-4.33 (3.146)

8. Secondary Outcome

Title	Part I: Annualized Rate of Brain Atrophy (ARBA) Relative to First Dose of Fingolimod
Description	The annualized rate of brain volume change is an "averaged annual percentage change" in brain volume. ARBA was calculated as: ARBA = [(SIENA/100+1) ^ (365.25/#days)-1]*100 where SIENA=(Vk/V0-1)*100 and Vk is the brain volume at time k, V0 is the brain volume at time 0 and k is the total number of days in the study for all patients for that specific period of time) × 365.25. Only descriptive analysis performed.
Time Frame	Month 3 to Month 156

Outcome Measure Data

Analysis Population Description

Fingolimod full analysis set. Only participants with an observed value were considered for the analysis.

Arm/Group Title	Fingolimod 0.5 mg/Day
Arm/Group Description	Open-label fingolimod 0.5 mg, taken orally once daily
Measure Participants	4046
Month 3	-0.73 (2.834)
Month 6	-0.39 (1.590)
Month 12	-0.35 (0.891)
Month 24	-0.37 (0.615)
Month 36	-0.35 (0.522)
Month 48	-0.37 (0.480)
Month 60	-0.34 (0.451)
Month 72	-0.35 (0.433)
Month 84	-0.35 (0.395)
Month 96	-0.31 (0.340)
Month 108	-0.33 (0.326)
Month 120	-0.36 (0.308)
Month 132	-0.43 (0.240)
Month 144	-0.36 (0.244)
Month 156	-0.35 (0.256)

9. Secondary Outcome

Title	Part I: Number of Participants With Confirmed 6-month Disability Progression After First Dose of Fingolimod
Description	Disability progression was defined based on an increase in the EDSS score by 1.5 point for patients with a first dose of fingolimod (FDF) baseline EDSS score of 0, 1 point for patients with FDF baseline EDSS of >=1 and <=5.5, and by 0.5 points for patients with an FDF baseline EDSS>5.5, confirmed after 6 months and all intermediate EDSS assessments. A 6-month confirmed disability progression was defined as a 6-month sustained increase from the reference (potential onset of progression) value in the EDSS scores. i.e., every EDSS score (scheduled or unscheduled) within a 6-month duration after the first progression should meet the progression criteria as specified above. The confirmation could only happen at a scheduled visit and in the absence of a relapse. Only descriptive analysis performed.
Time Frame	Month 12 to Month 156

Outcome Measure Data

Analysis Population Description

Fingolimod full analysis set

Arm/Group Title	Fingolimod 0.5 mg/Day
Arm/Group Description	Open-label fingolimod 0.5 mg, taken orally once daily
Measure Participants	4046
Month 12	212 5.1%
Month 24	336 8.1%
Month 36	434 10.5%
Month 48	519 12.6%
Month 60	590 14.3%
Month 72	659 16%
Month 84	714 17.3%
Month 96	753 18.3%
Month 108	767 18.6%
Month 120	772 18.7%
Month 132	775 18.8%
Month 144	776 18.8%
Month 156	777 18.8%

10. Secondary Outcome

Title	Part I: Number of Participants With Categorized Change From First Dose of Fingolimod in Expanded Disability Status Scale (EDSS) Overall Score
Description	The EDSS is a scale for assessing neurological impairment in MS (Kurtzke 1983) including (1) a series of scores in each of eight functional systems, and (2) the EDSS steps (ranging from 0 (normal) to 10 (death due to MS). The functional systems are Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel and Bladder, Cerebral and Other functions. Based on the assessment of each FS, the participant's overall score is categorized as Improvement, Stable or Deterioration. If baseline EDSS score is <=5, improvement is indicated by an EDSS score change of <= -1, stable is indicated by an EDSS score change of > -1 and <= 0.5, deterioration is indicated by an EDSS score change of > 0.5; if baseline EDSS score is > 5, improvement is indicated by an EDSS score change of <= -0.5, stable is indicated by an EDSS score change of > -0.5 and <= 0, deterioration is indicated by an EDSS score change of > 0. Only descriptive analysis performed.
Time Frame	Month 3 to Month 6 Follow-up

Outcome Measure Data

Analysis Population Description

Fingolimod full analysis set. Only participants with an observed value were considered for the analysis.

Arm/Group Title	Fingolimod 0.5 mg/Day
Arm/Group Description	Open-label fingolimod 0.5 mg, taken orally once daily
Measure Participants	4046
Improvement	374 9.1%
Stable	3126 75.8%
Deterioration	269 6.5%
Improvement	508 12.3%
Stable	2900 70.3%
Deterioration	340 8.2%
Improvement	482 11.7%
Stable	2425 58.8%
Deterioration	304 7.4%
Improvement	422 10.2%
Stable	1930 46.8%
Deterioration	322 7.8%
Improvement	405 9.8%
Stable	1764 42.8%
Deterioration	285 6.9%
Improvement	345 8.4%
Stable	1361 33%
Deterioration	271 6.6%
Improvement	376 9.1%
Stable	1524 36.9%
Deterioration	287 7%
Improvement	320 7.8%
Stable	1299 31.5%
Deterioration	294 7.1%
Improvement	313 7.6%
Stable	1271 30.8%
Deterioration	270 6.5%
Improvement	305 7.4%
Stable	1204 29.2%
Deterioration	287 7%
Improvement	326 7.9%
Stable	1172 28.4%
Deterioration	292 7.1%
Improvement	309 7.5%
Stable	1065 25.8%
Deterioration	288 7%
Improvement	284 6.9%
Stable	1015 24.6%
Deterioration	276 6.7%
Improvement	282 6.8%
Stable	948 23%
Deterioration	287 7%
Improvement	244 5.9%
Stable	875 21.2%
Deterioration	263 6.4%
Improvement	250 6.1%
Stable	838 20.3%
Deterioration	264 6.4%
Improvement	244 5.9%
Stable	784 19%
Deterioration	247 6%
Improvement	256 6.2%
Stable	788 19.1%
Deterioration	251 6.1%
Improvement	201 4.9%
Stable	694 16.8%
Deterioration	245 5.9%
Improvement	175 4.2%
Stable	577 14%
Deterioration	234 5.7%
Improvement	182 4.4%
Stable	540 13.1%
Deterioration	191 4.6%
Improvement	165 4%
Stable	499 12.1%
Deterioration	216 5.2%
Improvement	156 3.8%
Stable	503 12.2%
Deterioration	193 4.7%
Improvement	143 3.5%
Stable	440 10.7%
Deterioration	206 5%
Improvement	156 3.8%
Stable	437 10.6%
Deterioration	201 4.9%
Improvement	136 3.3%
Stable	398 9.6%
Deterioration	226 5.5%
Improvement	150 3.6%
Stable	456 11.1%
Deterioration	217 5.3%
Improvement	132 3.2%
Stable	407 9.9%
Deterioration	207 5%
Improvement	147 3.6%
Stable	450 10.9%
Deterioration	227 5.5%
Improvement	120 2.9%
Stable	413 10%
Deterioration	204 4.9%
Improvement	143 3.5%
Stable	386 9.4%
Deterioration	187 4.5%
Improvement	117 2.8%
Stable	375 9.1%
Deterioration	186 4.5%
Improvement	110 2.7%
Stable	325 7.9%
Deterioration	159 3.9%
Improvement	94 2.3%
Stable	283 6.9%
Deterioration	154 3.7%
Improvement	103 2.5%
Stable	261 6.3%
Deterioration	131 3.2%
Improvement	87 2.1%
Stable	287 7%
Deterioration	138 3.3%
Improvement	74 1.8%
Stable	198 4.8%
Deterioration	101 2.4%
Improvement	45 1.1%
Stable	181 4.4%
Deterioration	79 1.9%
Improvement	31 0.8%
Stable	94 2.3%
Deterioration	52 1.3%
Improvement	19 0.5%
Stable	88 2.1%
Deterioration	42 1%
Improvement	9 0.2%
Stable	36 0.9%
Deterioration	21 0.5%
Improvement	14 0.3%
Stable	45 1.1%
Deterioration	26 0.6%
Improvement	6 0.1%
Stable	18 0.4%
Deterioration	12 0.3%
Improvement	11 0.3%
Stable	36 0.9%
Deterioration	21 0.5%
Improvement	5 0.1%
Stable	19 0.5%
Deterioration	12 0.3%
Improvement	10 0.2%
Stable	39 0.9%
Deterioration	18 0.4%
Improvement	6 0.1%
Stable	18 0.4%
Deterioration	12 0.3%
Improvement	7 0.2%
Stable	30 0.7%
Deterioration	19 0.5%
Improvement	6 0.1%
Stable	21 0.5%
Deterioration	15 0.4%
Improvement	7 0.2%
Stable	22 0.5%
Deterioration	15 0.4%
Improvement	8 0.2%
Stable	16 0.4%
Deterioration	8 0.2%
Improvement	3 0.1%
Stable	9 0.2%
Deterioration	5 0.1%
Improvement	1 0%
Stable	2 0%
Deterioration	6 0.1%
Improvement	0 0%
Stable	1 0%
Deterioration	1 0%
Improvement	610 14.8%
Stable	2419 58.6%
Deterioration	785 19%
Improvement	203 4.9%
Stable	907 22%
Deterioration	381 9.2%
Improvement	29 0.7%
Stable	111 2.7%
Deterioration	88 2.1%

11. Secondary Outcome

Title	Part I: Change From First Dose of Fingolimod in Expanded Disability Status Scale (EDSS)
Description	The EDSS is a scale for assessing neurological impairment in MS (Kurtzke 1983) including (1) a series of scores in each of eight functional systems, and (2) the EDSS steps (ranging from 0 (normal) to 10 (death due to MS). The functional systems are Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel and Bladder, Cerebral and Other functions. Based on the assessment of each FS, the participant's overall score is determined between 0 to 10. A negative change from baseline indicates improvement. Only descriptive analysis performed.
Time Frame	Month 0 (Core Baseline) to End of Follow-up Visit (an average of 162 months)

Outcome Measure Data

Analysis Population Description

Fingolimod full analysis set. Only participants with an observed value were considered for the analysis.

Arm/Group Title	Fingolimod 0.5 mg/Day
Arm/Group Description	Open-label fingolimod 0.5 mg, taken orally once daily
Measure Participants	4046
Baseline (BL)	2.39 (1.452)
Change from BL at Month 3	-0.06 (0.638)
Change from BL at Month 6	-0.07 (0.716)
Change from BL at Month 9	-0.09 (0.750)
Change from BL at Month 12	-0.07 (0.815)
Change from BL at Month 15	-0.08 (0.814)
Change from BL at Month 18	-0.05 (0.890)
Change from BL at Month 21	-0.08 (0.876)
Change from BL at Month 24	-0.01 (0.916)
Change from BL at Month 27	-0.03 (0.932)
Change from BL at Month 30	-0.00 (0.935)
Change from BL at Month 33	-0.02 (0.951)
Change from BL at Month 36	0.01 (0.997)
Change from BL at Month 39	0.02 (0.963)
Change from BL at Month 42	0.04 (1.015)
Change from BL at Month 45	0.06 (1.006)
Change from BL at Month 48	0.06 (1.063)
Change from BL at Month 51	0.06 (1.071)
Change from BL at Month 54	0.04 (1.120)
Change from BL at Month 57	0.09 (1.077)
Change from BL at Month 60	0.17 (1.144)
Change from BL at Month 63	0.08 (1.123)
Change from BL at Month 66	0.15 (1.220)
Change from BL at Month 69	0.14 (1.116)
Change from BL at Month 72	0.22 (1.205)
Change from BL at Month 75	0.13 (1.159)
Change from BL at Month 78	0.28 (1.259)
Change from BL at Month 81	0.18 (1.158)
Change from BL at Month 84	0.25 (1.236)
Change from BL at Month 87	0.24 (1.206)
Change from BL at Month 90	0.29 (1.282)
Change from BL at Month 93	0.18 (1.219)
Change from BL at Month 96	0.31 (1.355)
Change from BL at Month 99	0.18 (1.220)
Change from BL at Month 102	0.30 (1.332)
Change from BL at Month 105	0.21 (1.320)
Change from BL at Month 108	0.28 (1.270)
Change from BL at Month 111	0.24 (1.343)
Change from BL at Month 114	0.30 (1.258)
Change from BL at Month 117	0.35 (1.389)
Change from BL at Month 120	0.40 (1.271)
Change from BL at Month 123	0.60 (1.302)
Change from BL at Month 126	0.38 (1.441)
Change from BL at Month 129	0.40 (1.448)
Change from BL at Month 132	0.40 (1.450)
Change from BL at Month 135	0.51 (1.519)
Change from BL at Month 138	0.42 (1.527)
Change from BL at Month 141	0.54 (1.509)
Change from BL at Month 144	0.60 (1.553)
Change from BL at Month 147	0.67 (1.640)
Change from BL at Month 150	0.44 (1.483)
Change from BL at Month 153	0.23 (1.534)
Change from BL at Month 156	0.26 (1.427)
Change from BL at Month 159	1.17 (1.369)
Change from BL at Month 162	0.75 (1.061)
Change from BL at End of study	0.14 (1.108)
Change from BL at Month 3 follow-up	0.29 (1.248)
Change from BL at Month 6 follow-up	0.56 (1.487)

Adverse Events

Time Frame	Adverse events were collected from first dose of study treatment in Study Part I until end of study treatment in Study Part II plus 6 weeks post treatment, up to a maximum duration of 8 years.
Arm/Group Title	Fingolimod 0.5 mg/Day
Arm/Group Description	Open-label fingolimod 0.5 mg, taken orally once daily
All Cause Mortality
	Fingolimod 0.5 mg/Day
	Affected / at Risk (%)	# Events
Total	16/4083 (0.4%)
Serious Adverse Events
	Fingolimod 0.5 mg/Day
	Affected / at Risk (%)	# Events
Total	515/4083 (12.6%)
Blood and lymphatic system disorders
Anaemia	3/4083 (0.1%)
Immune thrombocytopenic purpura	1/4083 (0%)
Iron deficiency anaemia	1/4083 (0%)
Leukopenia	1/4083 (0%)
Lymphadenopathy	1/4083 (0%)
Lymphopenia	1/4083 (0%)
Thrombocytopenia	1/4083 (0%)
Cardiac disorders
Angina pectoris	3/4083 (0.1%)
Atrial fibrillation	6/4083 (0.1%)
Atrioventricular block first degree	1/4083 (0%)
Bradycardia	1/4083 (0%)
Cardiac arrest	1/4083 (0%)
Cardiac failure	1/4083 (0%)
Cardio-respiratory arrest	1/4083 (0%)
Cardiopulmonary failure	1/4083 (0%)
Cardiovascular insufficiency	1/4083 (0%)
Cyanosis	1/4083 (0%)
Myocardial infarction	4/4083 (0.1%)
Pericarditis	1/4083 (0%)
Supraventricular tachycardia	1/4083 (0%)
Ventricular extrasystoles	1/4083 (0%)
Ventricular tachycardia	1/4083 (0%)
Congenital, familial and genetic disorders
Atrial septal defect	3/4083 (0.1%)
Bicuspid aortic valve	1/4083 (0%)
Congenital cytomegalovirus infection	1/4083 (0%)
Congenital knee dislocation	1/4083 (0%)
Ear and labyrinth disorders
Vertigo	4/4083 (0.1%)
Endocrine disorders
Hyperprolactinaemia	1/4083 (0%)
Thyroid mass	1/4083 (0%)
Eye disorders
Photophobia	1/4083 (0%)
Retinal detachment	2/4083 (0%)
Retinal haemorrhage	1/4083 (0%)
Retinal vein thrombosis	1/4083 (0%)
Gastrointestinal disorders
Abdominal adhesions	1/4083 (0%)
Abdominal hernia	2/4083 (0%)
Abdominal pain	4/4083 (0.1%)
Abdominal pain lower	2/4083 (0%)
Anal fissure	4/4083 (0.1%)
Barrett's oesophagus	1/4083 (0%)
Colitis	1/4083 (0%)
Crohn's disease	1/4083 (0%)
Diarrhoea	1/4083 (0%)
Duodenal ulcer	1/4083 (0%)
Duodenal ulcer perforation	1/4083 (0%)
Enterocolitis	2/4083 (0%)
Flatulence	1/4083 (0%)
Food poisoning	1/4083 (0%)
Gastric disorder	1/4083 (0%)
Gastric ulcer	1/4083 (0%)
Gastritis	2/4083 (0%)
Gastrooesophageal reflux disease	1/4083 (0%)
Haematochezia	1/4083 (0%)
Haemorrhoids	2/4083 (0%)
Inguinal hernia	3/4083 (0.1%)
Irritable bowel syndrome	2/4083 (0%)
Large intestine polyp	1/4083 (0%)
Nausea	2/4083 (0%)
Proctalgia	1/4083 (0%)
Proctitis	1/4083 (0%)
Rectal haemorrhage	2/4083 (0%)
Rectal polyp	1/4083 (0%)
Umbilical hernia	1/4083 (0%)
Vomiting	3/4083 (0.1%)
General disorders
Death	2/4083 (0%)
Death neonatal	1/4083 (0%)
Fat tissue increased	1/4083 (0%)
Fatigue	5/4083 (0.1%)
Gait disturbance	2/4083 (0%)
Hernia	1/4083 (0%)
Hypothermia	2/4083 (0%)
Influenza like illness	1/4083 (0%)
Multiple organ dysfunction syndrome	1/4083 (0%)
Non-cardiac chest pain	2/4083 (0%)
Peripheral swelling	1/4083 (0%)
Pyrexia	5/4083 (0.1%)
Vascular stent stenosis	1/4083 (0%)
Hepatobiliary disorders
Biliary colic	5/4083 (0.1%)
Biliary cyst	1/4083 (0%)
Biliary dyskinesia	1/4083 (0%)
Cholangitis acute	1/4083 (0%)
Cholecystitis	4/4083 (0.1%)
Cholecystitis chronic	3/4083 (0.1%)
Cholelithiasis	10/4083 (0.2%)
Drug-induced liver injury	2/4083 (0%)
Hepatitis acute	1/4083 (0%)
Liver disorder	1/4083 (0%)
Immune system disorders
Haemophagocytic lymphohistiocytosis	1/4083 (0%)
Immunodeficiency	1/4083 (0%)
Infections and infestations
Abdominal abscess	1/4083 (0%)
Abdominal sepsis	1/4083 (0%)
Appendicitis	10/4083 (0.2%)
Appendicitis perforated	2/4083 (0%)
Bartholin's abscess	1/4083 (0%)
Bronchitis	1/4083 (0%)
Cellulitis	6/4083 (0.1%)
Cystitis	1/4083 (0%)
Dermatitis infected	1/4083 (0%)
Diverticulitis	1/4083 (0%)
Epididymitis	2/4083 (0%)
Furuncle	1/4083 (0%)
Gastroenteritis	1/4083 (0%)
Gastroenteritis viral	1/4083 (0%)
Gastrointestinal infection	1/4083 (0%)
Groin abscess	1/4083 (0%)
Helicobacter infection	1/4083 (0%)
Hepatitis A	1/4083 (0%)
Hepatitis C	2/4083 (0%)
Hepatitis E	1/4083 (0%)
Herpes simplex encephalitis	1/4083 (0%)
Herpes zoster	9/4083 (0.2%)
Herpes zoster infection neurological	1/4083 (0%)
Histoplasmosis	1/4083 (0%)
Infected dermal cyst	2/4083 (0%)
Infection	1/4083 (0%)
Influenza	2/4083 (0%)
Injection site abscess	1/4083 (0%)
Intervertebral discitis	1/4083 (0%)
Lower respiratory tract infection	1/4083 (0%)
Lung infection	1/4083 (0%)
Lymphangitis	1/4083 (0%)
Mastoiditis	1/4083 (0%)
Meningitis cryptococcal	1/4083 (0%)
Meningoencephalitis herpetic	1/4083 (0%)
Orchitis	2/4083 (0%)
Pelvic inflammatory disease	1/4083 (0%)
Peritonsillar abscess	1/4083 (0%)
Pilonidal cyst	1/4083 (0%)
Pneumonia	14/4083 (0.3%)
Pneumonia bacterial	1/4083 (0%)
Pulmonary tuberculosis	1/4083 (0%)
Pyelitis	1/4083 (0%)
Pyelonephritis	2/4083 (0%)
Renal abscess	1/4083 (0%)
Respiratory tract infection	1/4083 (0%)
Salpingitis	1/4083 (0%)
Salpingo-oophoritis	1/4083 (0%)
Sepsis	1/4083 (0%)
Sinusitis	2/4083 (0%)
Spermatic cord funiculitis	1/4083 (0%)
Staphylococcal infection	2/4083 (0%)
Subcutaneous abscess	1/4083 (0%)
Upper respiratory tract infection	2/4083 (0%)
Urinary tract infection	14/4083 (0.3%)
Urinary tract infection enterococcal	1/4083 (0%)
Urosepsis	1/4083 (0%)
Viraemia	1/4083 (0%)
Viral diarrhoea	1/4083 (0%)
Viral infection	2/4083 (0%)
Vulval abscess	1/4083 (0%)
Injury, poisoning and procedural complications
Alcohol poisoning	1/4083 (0%)
Ankle fracture	6/4083 (0.1%)
Arthropod bite	1/4083 (0%)
Chest injury	1/4083 (0%)
Clavicle fracture	1/4083 (0%)
Concussion	1/4083 (0%)
Craniocerebral injury	1/4083 (0%)
Facial bones fracture	1/4083 (0%)
Fall	1/4083 (0%)
Femoral neck fracture	2/4083 (0%)
Femur fracture	1/4083 (0%)
Fibula fracture	2/4083 (0%)
Foot fracture	2/4083 (0%)
Head injury	1/4083 (0%)
Hip fracture	2/4083 (0%)
Humerus fracture	2/4083 (0%)
Joint injury	1/4083 (0%)
Kidney contusion	1/4083 (0%)
Ligament rupture	2/4083 (0%)
Lower limb fracture	2/4083 (0%)
Meniscus injury	2/4083 (0%)
Multiple injuries	1/4083 (0%)
Muscle injury	1/4083 (0%)
Near drowning	1/4083 (0%)
Patella fracture	1/4083 (0%)
Pelvic fracture	1/4083 (0%)
Pubis fracture	1/4083 (0%)
Radius fracture	1/4083 (0%)
Rib fracture	2/4083 (0%)
Road traffic accident	5/4083 (0.1%)
Skull fracture	1/4083 (0%)
Spinal fracture	1/4083 (0%)
Splenic rupture	1/4083 (0%)
Tibia fracture	4/4083 (0.1%)
Traumatic haematoma	1/4083 (0%)
Traumatic spinal cord compression	1/4083 (0%)
Ulna fracture	3/4083 (0.1%)
Ulnar nerve injury	1/4083 (0%)
Upper limb fracture	1/4083 (0%)
Vaginal laceration	1/4083 (0%)
Wrist fracture	2/4083 (0%)
Investigations
Hepatic enzyme increased	1/4083 (0%)
Lymphocyte count decreased	1/4083 (0%)
Weight decreased	2/4083 (0%)
Metabolism and nutrition disorders
Dehydration	2/4083 (0%)
Hyperamylasaemia	1/4083 (0%)
Obesity	1/4083 (0%)
Musculoskeletal and connective tissue disorders
Amyotrophy	1/4083 (0%)
Arthralgia	2/4083 (0%)
Back pain	7/4083 (0.2%)
Bursitis	1/4083 (0%)
Chondromalacia	1/4083 (0%)
Chondropathy	1/4083 (0%)
Compartment syndrome	1/4083 (0%)
Foot deformity	1/4083 (0%)
Intervertebral disc protrusion	8/4083 (0.2%)
Jaw disorder	1/4083 (0%)
Joint instability	1/4083 (0%)
Joint swelling	1/4083 (0%)
Lateral patellar compression syndrome	1/4083 (0%)
Mobility decreased	1/4083 (0%)
Muscular weakness	3/4083 (0.1%)
Osteoarthritis	6/4083 (0.1%)
Osteonecrosis	2/4083 (0%)
Pain in extremity	1/4083 (0%)
Rhabdomyolysis	1/4083 (0%)
Rotator cuff syndrome	1/4083 (0%)
Spinal column stenosis	1/4083 (0%)
Synovial cyst	1/4083 (0%)
Torticollis	1/4083 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	3/4083 (0.1%)
B-cell lymphoma	1/4083 (0%)
Basal cell carcinoma	30/4083 (0.7%)
Benign hydatidiform mole	1/4083 (0%)
Benign neoplasm of thyroid gland	1/4083 (0%)
Benign ovarian tumour	1/4083 (0%)
Bladder cancer	1/4083 (0%)
Bone giant cell tumour	1/4083 (0%)
Bowen's disease	3/4083 (0.1%)
Brain neoplasm benign	1/4083 (0%)
Breast cancer	11/4083 (0.3%)
Cervix carcinoma	1/4083 (0%)
Colon cancer	1/4083 (0%)
Colon cancer metastatic	1/4083 (0%)
Desmoid tumour	1/4083 (0%)
Extranodal marginal zone B-cell lymphoma (MALT type)	1/4083 (0%)
Fibroadenoma of breast	1/4083 (0%)
Gastrointestinal neoplasm	1/4083 (0%)
Intraductal proliferative breast lesion	1/4083 (0%)
Invasive lobular breast carcinoma	2/4083 (0%)
Laryngeal squamous cell carcinoma	1/4083 (0%)
Leiomyoma	1/4083 (0%)
Lung adenocarcinoma	1/4083 (0%)
Malignant melanoma	3/4083 (0.1%)
Melanocytic naevus	1/4083 (0%)
Meningioma	1/4083 (0%)
Metastases to lymph nodes	1/4083 (0%)
Metastases to spine	1/4083 (0%)
Neoplasm	1/4083 (0%)
Non-Hodgkin's lymphoma	1/4083 (0%)
Ovarian adenoma	1/4083 (0%)
Ovarian cancer metastatic	1/4083 (0%)
Pancreatic carcinoma	1/4083 (0%)
Papilloma	1/4083 (0%)
Phyllodes tumour	1/4083 (0%)
Prostate cancer	3/4083 (0.1%)
Rectal cancer	1/4083 (0%)
Renal cancer	3/4083 (0.1%)
Renal cell carcinoma	1/4083 (0%)
Seminoma	1/4083 (0%)
Small cell lung cancer	1/4083 (0%)
Squamous cell carcinoma	9/4083 (0.2%)
Squamous cell carcinoma of lung	1/4083 (0%)
Squamous cell carcinoma of skin	3/4083 (0.1%)
Thyroid adenoma	1/4083 (0%)
Uterine cancer	1/4083 (0%)
Uterine leiomyoma	10/4083 (0.2%)
Nervous system disorders
Altered state of consciousness	2/4083 (0%)
Brain hypoxia	1/4083 (0%)
Carotid artery occlusion	1/4083 (0%)
Cauda equina syndrome	1/4083 (0%)
Central nervous system lesion	1/4083 (0%)
Cerebellar infarction	1/4083 (0%)
Cerebral infarction	1/4083 (0%)
Cerebral venous thrombosis	1/4083 (0%)
Cerebrovascular accident	1/4083 (0%)
Coma	1/4083 (0%)
Demyelination	1/4083 (0%)
Dizziness	1/4083 (0%)
Epilepsy	8/4083 (0.2%)
Facial spasm	1/4083 (0%)
Fine motor skill dysfunction	1/4083 (0%)
Focal dyscognitive seizures	1/4083 (0%)
Generalised tonic-clonic seizure	1/4083 (0%)
Headache	4/4083 (0.1%)
Hemianopia homonymous	1/4083 (0%)
Hemiparesis	1/4083 (0%)
Hyperaesthesia	1/4083 (0%)
Hypoaesthesia	1/4083 (0%)
Intracranial aneurysm	1/4083 (0%)
Ischaemic stroke	3/4083 (0.1%)
Lacunar infarction	1/4083 (0%)
Loss of consciousness	2/4083 (0%)
Migraine	2/4083 (0%)
Multiple sclerosis	3/4083 (0.1%)
Multiple sclerosis relapse	34/4083 (0.8%)
Muscle spasticity	1/4083 (0%)
Myelitis transverse	2/4083 (0%)
Neuralgia	2/4083 (0%)
Optic neuritis	3/4083 (0.1%)
Paraesthesia	2/4083 (0%)
Partial seizures	1/4083 (0%)
Presyncope	2/4083 (0%)
Sciatica	1/4083 (0%)
Secondary progressive multiple sclerosis	2/4083 (0%)
Seizure	3/4083 (0.1%)
Spinal cord compression	1/4083 (0%)
Status epilepticus	1/4083 (0%)
Subarachnoid haemorrhage	3/4083 (0.1%)
Syncope	4/4083 (0.1%)
Tension headache	1/4083 (0%)
Thrombotic stroke	1/4083 (0%)
Transient ischaemic attack	3/4083 (0.1%)
Trigeminal neuralgia	3/4083 (0.1%)
Uhthoff's phenomenon	1/4083 (0%)
Ulnar nerve palsy	1/4083 (0%)
Wernicke's encephalopathy	1/4083 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion	1/4083 (0%)
Abortion spontaneous	10/4083 (0.2%)
Ectopic pregnancy	1/4083 (0%)
Hyperemesis gravidarum	1/4083 (0%)
Product Issues
Device dislocation	1/4083 (0%)
Psychiatric disorders
Acute stress disorder	1/4083 (0%)
Adjustment disorder with depressed mood	2/4083 (0%)
Aggression	1/4083 (0%)
Anxiety	1/4083 (0%)
Bipolar I disorder	2/4083 (0%)
Completed suicide	3/4083 (0.1%)
Confusional state	2/4083 (0%)
Depression	9/4083 (0.2%)
Drug dependence	1/4083 (0%)
Eating disorder	1/4083 (0%)
Major depression	2/4083 (0%)
Mania	3/4083 (0.1%)
Mental disorder	2/4083 (0%)
Panic attack	2/4083 (0%)
Persecutory delusion	1/4083 (0%)
Personality change	1/4083 (0%)
Personality change due to a general medical condition	1/4083 (0%)
Psychogenic seizure	1/4083 (0%)
Psychotic disorder	1/4083 (0%)
Somatic symptom disorder	1/4083 (0%)
Stress	1/4083 (0%)
Suicidal ideation	5/4083 (0.1%)
Suicide attempt	3/4083 (0.1%)
Renal and urinary disorders
Acute kidney injury	2/4083 (0%)
Calculus urinary	1/4083 (0%)
Hydronephrosis	1/4083 (0%)
Nephrolithiasis	3/4083 (0.1%)
Renal haemorrhage	1/4083 (0%)
Urinary incontinence	2/4083 (0%)
Urinary retention	2/4083 (0%)
Reproductive system and breast disorders
Adnexa uteri cyst	1/4083 (0%)
Benign prostatic hyperplasia	1/4083 (0%)
Breast calcifications	1/4083 (0%)
Cervical dysplasia	7/4083 (0.2%)
Dysfunctional uterine bleeding	1/4083 (0%)
Endometriosis	1/4083 (0%)
Gynaecomastia	1/4083 (0%)
Metrorrhagia	3/4083 (0.1%)
Ovarian cyst	4/4083 (0.1%)
Postmenopausal haemorrhage	1/4083 (0%)
Uterine cyst	1/4083 (0%)
Uterine haemorrhage	3/4083 (0.1%)
Uterine polyp	4/4083 (0.1%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/4083 (0%)
Aspiration	1/4083 (0%)
Asthma	1/4083 (0%)
Cough	1/4083 (0%)
Dyspnoea	1/4083 (0%)
Epistaxis	1/4083 (0%)
Haemothorax	1/4083 (0%)
Nasal polyps	1/4083 (0%)
Pneumothorax	1/4083 (0%)
Pulmonary embolism	5/4083 (0.1%)
Skin and subcutaneous tissue disorders
Alopecia	1/4083 (0%)
Dermatitis	1/4083 (0%)
Dermatitis contact	1/4083 (0%)
Erythema	1/4083 (0%)
Erythema annulare	1/4083 (0%)
Rash	1/4083 (0%)
Skin erosion	1/4083 (0%)
Surgical and medical procedures
Abortion induced	1/4083 (0%)
Vascular disorders
Aneurysm	1/4083 (0%)
Aortic aneurysm	1/4083 (0%)
Deep vein thrombosis	4/4083 (0.1%)
Hypertension	2/4083 (0%)
Hypertensive crisis	1/4083 (0%)
Hypoperfusion	1/4083 (0%)
Peripheral artery thrombosis	1/4083 (0%)
Peripheral venous disease	2/4083 (0%)
Phlebitis	1/4083 (0%)
Shock haemorrhagic	1/4083 (0%)
Vasculitis	1/4083 (0%)
Venous stenosis	1/4083 (0%)
Other (Not Including Serious) Adverse Events
	Fingolimod 0.5 mg/Day
	Affected / at Risk (%)	# Events
Total	2125/4083 (52%)
Blood and lymphatic system disorders
Lymphopenia	219/4083 (5.4%)
General disorders
Fatigue	232/4083 (5.7%)
Infections and infestations
Bronchitis	214/4083 (5.2%)
Influenza	275/4083 (6.7%)
Nasopharyngitis	706/4083 (17.3%)
Upper respiratory tract infection	346/4083 (8.5%)
Urinary tract infection	335/4083 (8.2%)
Metabolism and nutrition disorders
Hypercholesterolaemia	212/4083 (5.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	208/4083 (5.1%)
Back pain	279/4083 (6.8%)
Nervous system disorders
Headache	348/4083 (8.5%)
Psychiatric disorders
Depression	205/4083 (5%)
Vascular disorders
Hypertension	243/4083 (6%)

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 (ie, data from all sites) in the clinical trial.