FREEDOMS II: Efficacy and Safety of Fingolimod (FTY720) in Patients With Relapsing-remitting Multiple Sclerosis

• Sponsor: Novartis (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00355134
• Collaborator: (none)
• Enrollment: 1,083
• Locations: 113
• Arms: 3
• Duration (Months): 62
• Patients Per Site: 9.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study assessed the safety, tolerability and efficacy of two doses of oral fingolimod compared to placebo on efficacy parameters in patients with relapsing-remitting multiple sclerosis (RRMS).

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis	Drug: Fingolimod; Drug: Placebo	Phase 3

Detailed Description

This randomized, multicenter, parallel-group study consisted of 2 phases: a 24-month double-blind, randomized, multicenter, placebo-controlled, parallel-group study and an Extension phase which consisted of a dose-blinded period and an open-label period.

In the Core phase, patients were randomized to receive a fixed dose of fingolimod (0.5 mg/day), fingolimod (1.25 mg/day) or placebo for up to 24 months.

For the Extension phase, patients who were treated with fingolimod during the Core phase continued treatment at the assigned dose level, while those previously treated with placebo during the Core phase were re-randomized in a 1:1 ratio to receive one of the two doses of fingolimod (1.25 mg or 0.5 mg). All patients in the extension received blinded investigational drug: fingolimod 1.25 mg and 0.5 mg in capsules for oral administration once daily until the decision to discontinue the fingolimod 1.25 mg dose became effective and subsequently all patients were switched to open-label fingolimod 0.5 mg.

With the implementation of Amendment 11, the 1.25 mg dose was discontinued and all patients were switched to fingolimod 0.5 mg dose. With the implementation of Amendment 12, all patients treated with Placebo in the fingolimod Core phase were switched to treatment with 0.5 mg fingolimod per day. The Extension phase continued until all patients either discontinued or transferred to Study CFTY720D2399 (NCT01201356; initiated in September 2010).

Study Design

• Study Type: Interventional
• Actual Enrollment: 1083 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 24-month Double-blind, Randomized, Multicenter, Placebo-controlled, Parallel-group Study Comparing the Efficacy and Safety of 0.5 mg and 1.25 mg Fingolimod (FTY720) Administered Orally Once Daily Versus Placebo in Patients With Relapsing-remitting Multiple Sclerosis With Optional Extension Phase
• Study Start Date: Jun 1, 2006
• Actual Primary Completion Date: Jun 1, 2011
• Actual Study Completion Date: Aug 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fingolimod 1.25 mg Participants received 1.25 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 1.25 mg fingolimod orally once a day. Note: Upon implementation of a protocol amendment all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day.	Drug: Fingolimod; Fingolimod capsules for oral administration; Other Names: FTY720 Gilenya®
Experimental: Fingolimod 0.5 mg Participants received 0.5 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 0.5 mg fingolimod orally once a day.	Drug: Fingolimod; Fingolimod capsules for oral administration; Other Names: FTY720 Gilenya®
Experimental: Placebo Participants received placebo capsules orally once a day for up to 24 months during the core phase. In the Extension phase participants received either 1.25 or 0.5 mg fingolimod orally once a day. Note: Upon implementation of a protocol amendment all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking placebo were switched to 0.5 mg fingolimod orally once a day.	Drug: Placebo; Matching placebo capsules for oral administration.

Outcome Measures

Primary Outcome Measures

1. Aggregate Annualized Relapse Rate (ARR) Estimate up to Month 24 [24 months]

   ARR is the average number of relapses in a year calculated by negative binomial regression as the sum of confirmed relapses of all patients in the group divided by the sum of the number of days on study of all patients in the group and multiplied by 365.25. A relapse was 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 (<37.5C) or known infection. A relapse must be confirmed by the Independent Evaluating Physician (examining neurologist). ARR estimates were calculated from a negative binomial regression model adjusted for treatment, pooled center, number of relapses in the previous 2 years prior to enrollment, and Baseline expanded disability status scale (EDSS).

Secondary Outcome Measures

1. Aggregate Annualized Relapse Rate (ARR) Estimate up to End of Study [From Baseline until end of study (up to approximately 54 months).]

   ARR is the average number of relapses in a year calculated by negative binomial regression as the sum of confirmed relapses of all patients in the group divided by the sum of the number of days on study of all patients in the group and multiplied by 365.25. A relapse was 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 (<37.5C) or known infection. A relapse must be confirmed by the Independent Evaluating Physician (examining neurologist). ARR estimates were calculated from a negative binomial regression model adjusted for treatment, pooled center, number of relapses in the previous 2 years prior to enrollment, and Baseline expanded disability status scale (EDSS).

2. Percent Change From Baseline in Brain Volume [Baseline, Month 24 and end of study (up to approximately 54 months)]

   Brain volume was measured using magnetic resonance imaging (MRI). Change from Baseline in brain volume is expressed as a percentage of the Baseline brain volume.

3. Number of New or Newly Enlarged T2 Lesions [From Baseline until Month 48]

   Inflammatory disease activity was assessed by magnetic resonance imaging (MRI) measurement of the number of new or newly enlarged T2 lesions, by year.

4. Number of Gadolinium-enhanced T1 Lesions [Month 24 and end of study (up to approximately 54 months)]

   Inflammatory disease activity was assessed by magnetic resonance imaging (MRI) measurement of the number of gadolinium-enhanced T1 lesions.

5. Change From Baseline in Lesion Volume at Month 24 (Core Phase) [Baseline and Month 24]

   Change from Baseline in lesion volume was measured by MRI for T2 lesions and for T1 hypointense lesions.

6. Percentage of Participants Free of 3-month Confirmed Disability Progression at Month 24 and End of Study [24 months and end of study (up to approximately 54 months)]

   Disability progression was defined using the following criteria: One point increase from baseline in patients with Baseline Expanded Disability Status Scale (EDSS) score from 0 to 5.0; or half a point increase from Baseline in patients with Baseline EDSS score of 5.5 or above. A 3-month confirmed disability progression was defined as a 3-month sustained increase from Baseline in EDSS score. The EDSS quantifies disability in multiple sclerosis in 8 functional systems; the score ranges from 0 (normal) to 10 (death due to MS). Progression curves were generated by the Kaplan-Meier method.

7. Percentage of Participants Free of 6-month Confirmed Disability Progression at Month 24 and End of Study [24 months and end of study (up to approximately 54 months)]

   Disability progression was defined using the following criteria: One point increase from baseline in patients with Baseline Expanded Disability Status Scale (EDSS) score from 0 to 5.0; or half a point increase from Baseline in patients with Baseline EDSS score of 5.5 or above. A 6-month confirmed disability progression was defined as a 6-month sustained increase from Baseline in EDSS score. The EDSS quantifies disability in multiple sclerosis in 8 functional systems; the score ranges from 0 (normal) to 10 (death due to MS). Progression curves were generated by the Kaplan-Meier method.

8. Percentage of Participants Relapse-free up to Month 24 [24 months]

   Estimates of the percentage of participants relapse-free at 24 months were generated from Kaplan-Meier curves of the time to first relapse. A relapse was 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 (<37.5C) or infection. A relapse was confirmed by an Independent Evaluating Physician.

9. Percentage of Participants Relapse-free up to End of Study [From Baseline until the end of study (up to approximately 54 months)]

   Estimates of the percentage of participants relapse-free at end of study were generated from Kaplan-Meier curves of the time to first relapse. A relapse was 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 (<37.5C) or infection. A relapse was confirmed by an Independent Evaluating Physician.

10. Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Z-score [Baseline, Month 24 and end of study (up to approximately 54 months)]

    The Multiple Sclerosis Functional Composite (MSFC) is a multidimensional clinical outcome measure that includes quantitative tests of leg function/ambulation (Timed 25-Foot Walk), arm function (9-Hole Peg Test), and cognitive function (Paced Auditory Serial Addition Test). The overall MSFC z-score as an average of the three standardized scores derived using baseline data pooled over each treatment arm as reference population. Higher scores reflect better neurological function and a positive change from Baseline indicates improvement.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male and female patients between ages 18-55 with a diagnosis of multiple sclerosis

• Patients with a relapsing-remitting disease course

• Patients with expanded disability status scale (EDSS) score of 0-5.5

Exclusion Criteria:

• Patients with other chronic disease of the immune system, malignancies, acute pulmonary disease, cardiac failure, etc.

• Pregnant or nursing women

For inclusion in the extension phase patients should complete the 24 month core study with or without 24 months on study drug. If a patient discontinued study drug during the core study due to an adverse event, serious adverse event, laboratory abnormality etc. they would be excluded from the Extension Phase.

Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama Birmingham	Birmingham	Alabama	United States	35249
2	North Central Neurology Associates, PC	Cullman	Alabama	United States	35058
3	University of South Alabama - Dept of Neurology	Mobile	Alabama	United States	36693
4	Barrow Neurology Clinic	Phoenix	Arizona	United States	85013
5	Research and Education Institute of Alta Bates Summit Medical Center	Berkeley	California	United States	94705
6	University of California - Irvine, Deptarment of Neurology	Irvine	California	United States	92697
7	Cedars Sinai Medical Center	Los Angeles	California	United States	90048
8	The Neurology Center	Oceanside	California	United States	92056
9	Neuro-Therapeutics, Inc.	Pasadena	California	United States	91105
10	UC Davis Medical Center	Sacramento	California	United States	95817
11	Multiple Sclerosis Center at UCSF	San Francisco	California	United States	94117
12	University of Colorado	Denver	Colorado	United States	80262
13	Associated Neurologists, PC	Danbury	Connecticut	United States	06810
14	Associated Neurologists of Southern CT, P.C.	Fairfield	Connecticut	United States	06824
15	Yale University - Yale Multiple Sclerosis Center	New Haven	Connecticut	United States	06510
16	Georgetown University Hospital - Dept of Neurology	Washington	District of Columbia	United States	20007
17	Sunrise Clinical Research, Inc.	Hollywood	Florida	United States	33021
18	University of Florida Health Sciences Center/Shands Jacksonville	Jacksonville	Florida	United States	32209
19	Neurology Associates, PA	Maitland	Florida	United States	32751
20	University of Miami, Department of Neurology	Miami	Florida	United States	33136
21	Neurological Associates	Pompano Beach	Florida	United States	33060
22	Roskamp Institute, Clinical Trials Division	Sarasota	Florida	United States	34243
23	Neurology Clinical Research, Inc	Sunrise	Florida	United States	33351
24	AMO Corporation	Tallahassee	Florida	United States	32308
25	Axiom Clinical Research of Florida	Tampa	Florida	United States	33609
26	The MS Center of Vero Beach	Vero Beach	Florida	United States	32960
27	MS Center of Atlanta	Atlanta	Georgia	United States	30327
28	Medical College of Georgia	Augusta	Georgia	United States	30912
29	Northwestern University Medical School - Dept of Neurology	Chicago	Illinois	United States	60611
30	Rush University Medical Center Department of Neurological Sciences	Chicago	Illinois	United States	60612
31	University of Chicago - Dept of Neurology	Chicago	Illinois	United States	60637
32	Alexian Brothers Neurosciences Research	Elk Grove Village	Illinois	United States	60007
33	South Suburban Neurology	Flossmoor	Illinois	United States	60402
34	Neurologic Associates, Ltd.	Palos Heights	Illinois	United States	60453
35	Fort Wayne Neurological Center	Fort Wayne	Indiana	United States	46805
36	Indiana University Medical Center	Indianapolis	Indiana	United States	46202
37	Ruan Neurology Clinical Research Center	Des Moines	Iowa	United States	50314
38	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
39	Mid America Neuroscience Institute	Lenexa	Kansas	United States	66214
40	Kentucky Research Associates	Louisville	Kentucky	United States	40202
41	University of Maryland	Baltimore	Maryland	United States	21201
42	Johns Hopkins MS Center	Baltimore	Maryland	United States	21287
43	Caritas St. Elizabeth's Medical Center	Brighton	Massachusetts	United States	02135
44	Newton Wesley Hospital	Newton	Massachusetts	United States	02462
45	Springfield Neurology	Springfield	Massachusetts	United States	01104
46	UMass Memorial Medical Center	Worchester	Massachusetts	United States	01605
47	University of Michigan Mulitiple Sclerosis Clinic	Ann Arbor	Michigan	United States	48109
48	Wayne State University MS Clinic	Detroit	Michigan	United States	48201
49	Henry Ford Hospital, Department of Neurology	Detroit	Michigan	United States	48202
50	Michigan State University MS Clinic	East Lansing	Michigan	United States	48824
51	Michigan Medical, P.C.	Grand Rapids	Michigan	United States	49525
52	Michigan Neurology Associates, PC	St. Clair Shores	Michigan	United States	48080
53	St. Luke's Hospital - Mid-America Brain and Stroke Institute	Kansas City	Missouri	United States	64111
54	The MS Center for Innovation in Care	St. Louis	Missouri	United States	63110
55	Institute for Neurosciences	Reno	Nevada	United States	85902
56	Multiple Sclerosis Center	Lebanon	New Hampshire	United States	03756
57	Gimbel Multiple Sclerosis Center at Holy Name Hospital	Teaneck	New Jersey	United States	07666
58	University of New Mexico Health Science Center	Albuquerque	New Mexico	United States	87131
59	Empire Neurology, PC	Latham	New York	United States	12110
60	NYU Hospital for Joint Diseases	New York	New York	United States	10003
61	Cornell University - NY Presbyterian Hospital	New York	New York	United States	10021
62	Mount Sinai School of Medicine	New York	New York	United States	10029
63	Island Neurological Associates, PC	Plainview	New York	United States	11803
64	University of Rochester Medical Center	Rochester	New York	United States	14642
65	Alpha Neurology	Staten Island	New York	United States	10306
66	SUNY Stony Brook	Stony Brook	New York	United States	11794
67	SUNY Upstate Medical University	Syracuse	New York	United States	13210
68	UNC - Chapel Hill Neuroscience Hospital	Chapel Hill	North Carolina	United States	27599
69	Duke University Medical Center	Durham	North Carolina	United States	27705
70	Raleigh Neurology Associates	Raleigh	North Carolina	United States	27607
71	Wake Forest University Baptist Medical Center	Winston-Salem	North Carolina	United States	27157
72	Neurology & Neuroscience Associates, Inc.	Akron	Ohio	United States	44302
73	Northern Ohio Neuroscience, LLC.	Bellevue	Ohio	United States	44811
74	NeuroCare Center, Inc	Canton	Ohio	United States	44718
75	River Hills Health Care	Cincinnati	Ohio	United States	45219
76	Ohio State University	Columbus	Ohio	United States	48221
77	University of Toledo Health Science Campus	Toledo	Ohio	United States	43614
78	Oak Clinic	Uniontown	Ohio	United States	44685
79	MS Center of Oklahoma, Mercy Neuroscience Institute	Oklahoma City	Oklahoma	United States	73120
80	Neurologial Associates of Tulsa	Tulsa	Oklahoma	United States	74137
81	Oregon Neurology	Tualatin	Oregon	United States	97062
82	University of Pennsylvania, Department of Neurology	Philadelphia	Pennsylvania	United States	19104
83	Thomas Jefferson University Hospital, Department of Neurology	Philadelphia	Pennsylvania	United States	19107
84	Allegheny Neurological Associates	Pittsburgh	Pennsylvania	United States	15212
85	University of Pittsburgh - Dept of Neurology	Pittsburgh	Pennsylvania	United States	15213
86	Absher Neurology	Greenville	South Carolina	United States	29615
87	Mountain Empire Neurological Associates, PC	Bristol	Tennessee	United States	37620
88	Advanced Neurosciences Institute	Nashville	Tennessee	United States	37205
89	Vanderbilt Stallworth Rehabilitation Hospital	Nashville	Tennessee	United States	37212
90	University of Texas - Houston Medical School	Houston	Texas	United States	77030
91	Investigational Site - Private Practice	Lubbock	Texas	United States	79410
92	Integra Clinical Research, LLC	San Antonio	Texas	United States	78231
93	Neurology Health Care Service - Fletcher Allen Hospital	Burlington	Vermont	United States	05401
94	University of Virginia - Fontaine Adult Neurology	Charlottesville	Virginia	United States	22903
95	Virginia Mason Multiple Sclerosis Center	Seattle	Washington	United States	98111
96	Seattle Neuroscience Institute at Swedish Medical Center	Seattle	Washington	United States	98122
97	University Health Associates - West Virgina University	Morgantown	West Virginia	United States	26506
98	Dean Foundation	Madison	Wisconsin	United States	53715
99	University of Wisconsin Medical School	Madison	Wisconsin	United States	53792
100	St. Luke's Medical Center	Milwaukee	Wisconsin	United States	53215
101	Novartis Investigative Site	North Gosford	New South Wales	Australia
102	Novartis Investigative Site	Vienna		Austria
103	Novartis Investigative Site	Ottawa	Ontario	Canada
104	Novartis Investigative Site	Greenfield Park	Quebec	Canada
105	Novartis Investigative Site	Bialystok		Poland
106	Novartis Investigative Site	Warsaw		Poland
107	Novartis Investigative Site	Warszawa		Poland
108	Novartis Investigative Site	Bucharest		Romania
109	Novartis Investigative Site	Targu Mures		Romania
110	Novartis Investigative Site	Istanbul		Turkey
111	Novartis Investigative Site	Izmir		Turkey
112	Novartis Investigative Site	Yenisehir/Izmir		Turkey
113	Novartis Investigative Site	Bristol		United Kingdom

Sponsors and Collaborators

• Novartis

Investigators

• Study Chair: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Fingolimod clinical trials information website

Publications

None provided.

• Responsible Party: Novartis
• ClinicalTrials.gov Identifier: NCT00355134
• Other Study ID Numbers: CFTY720D2309; NCT00774670
• First Posted: Jul 21, 2006
• Last Update Posted: Aug 7, 2012
• Last Verified: Aug 1, 2012

• Keywords provided by Novartis: fingolimod; FTY720; relapsing-remitting multiple sclerosis; MS; RRMS
• Additional relevant MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Fingolimod Hydrochloride

Study Results

Participant Flow

Pre-assignment Detail	Patients were randomized to receive fingolimod 0.5 mg, 1.25 mg or placebo for up to 24 months. Upon entry into the Extension phase, patients treated with fingolimod 0.5 mg or 1.25 mg during the Core phase continued treatment at the same dose, those previously treated with placebo were re-randomized in to receive one of the two doses of fingolimod.

Arm/Group Title	Fingolimod 1.25 mg	Fingolimod 0.5 mg	Placebo (Core)	Extension: Fingolimod 1.25 mg	Extension: Fingolimod 0.5 mg
Arm/Group Description	Participants received 1.25 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 1.25 mg fingolimod orally. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day.	Participants received 0.5 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 0.5 mg fingolimod orally once a day.	Participants received placebo capsules orally once a day for up to 24 months during the core phase. Upon implementation of a protocol amendment, all patients taking placebo were switched to 0.5 mg fingolimod orally once a day.	Participants who had received placebo in the Core phase and then received 1.25 mg fingolimod orally once a day in the Extension phase. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day.	Participants who had received placebo in the Core phase and then received 0.5 mg fingolimod orally once a day in the Extension phase.
Period Title: Core Phase
STARTED	370	358	355	0	0
COMPLETED	251	272	255	0	0
NOT COMPLETED	119	86	100	0	0
Period Title: Core Phase
STARTED	203	217	0	105	107
COMPLETED	172	180	0	89	88
NOT COMPLETED	31	37	0	16	19

Baseline Characteristics

Arm/Group Title	Fingolimod 1.25 mg	Fingolimod 0.5 mg	Placebo (Core)	Extension: Fingolimod 1.25 mg	Extension: Fingolimod 0.5 mg	Total
Arm/Group Description	Participants received 1.25 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 1.25 mg fingolimod orally. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day.	Participants received 0.5 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 0.5 mg fingolimod orally once a day.	Participants received placebo capsules orally once a day for up to 24 months during the core phase. Upon implementation of a protocol amendment, all patients taking placebo were switched to 0.5 mg fingolimod orally once a day.	Participants who had received placebo in the Core phase and then received 1.25 mg fingolimod orally once a day in the Extension phase. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day.	Participants who had received placebo in the Core phase and then received 0.5 mg fingolimod orally once a day in the Extension phase.	Total of all reporting groups
Overall Participants	370	358	355	105	107	1295
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.9 (8.90)	40.6 (8.39)	40.1 (8.42)	NA (NA)	NA (NA)	40.5 (8.58)
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.6 (8.71)	40.8 (7.96)	NA (NA)	39.8 (8.32)	41.1 (8.11)	40.6 (8.28)
Gender (participants) [Number]
Female	281 75.9%	275 76.8%	288 81.1%	0 0%	0 0%	844 65.2%
Male	89 24.1%	83 23.2%	67 18.9%	0 0%	0 0%	239 18.5%
Gender (participants) [Number]
Female	148 40%	160 44.7%	0 0%	88 83.8%	85 79.4%	481 37.1%
Male	55 14.9%	57 15.9%	0 0%	17 16.2%	22 20.6%	151 11.7%

Outcome Measures

1. Primary Outcome

Title	Aggregate Annualized Relapse Rate (ARR) Estimate up to Month 24
Description	ARR is the average number of relapses in a year calculated by negative binomial regression as the sum of confirmed relapses of all patients in the group divided by the sum of the number of days on study of all patients in the group and multiplied by 365.25. A relapse was 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 (<37.5C) or known infection. A relapse must be confirmed by the Independent Evaluating Physician (examining neurologist). ARR estimates were calculated from a negative binomial regression model adjusted for treatment, pooled center, number of relapses in the previous 2 years prior to enrollment, and Baseline expanded disability status scale (EDSS).
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

Full analysis set, including all patients who were randomized and took at least one dose of study drug.

Arm/Group Title	Fingolimod 1.25 mg	Fingolimod 0.5 mg	Placebo
Arm/Group Description	Participants received 1.25 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 1.25 mg fingolimod orally. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day.	Participants received 0.5 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 0.5 mg fingolimod orally once a day.	Participants received placebo capsules orally once a day for up to 24 months during the core phase. In the Extension phase participants received either 1.25 or 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking placebo were switched to 0.5 mg fingolimod orally once a day.
Measure Participants	370	358	355
Number (95% Confidence Interval) [relapses per year]	0.203	0.208	0.403

2. Secondary Outcome

Title	Aggregate Annualized Relapse Rate (ARR) Estimate up to End of Study
Description	ARR is the average number of relapses in a year calculated by negative binomial regression as the sum of confirmed relapses of all patients in the group divided by the sum of the number of days on study of all patients in the group and multiplied by 365.25. A relapse was 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 (<37.5C) or known infection. A relapse must be confirmed by the Independent Evaluating Physician (examining neurologist). ARR estimates were calculated from a negative binomial regression model adjusted for treatment, pooled center, number of relapses in the previous 2 years prior to enrollment, and Baseline expanded disability status scale (EDSS).
Time Frame	From Baseline until end of study (up to approximately 54 months).

Outcome Measure Data

Analysis Population Description

Core intent-to-treat (ITT) population: All patients who were randomized in the Core phase and received at least one dose of Core phase drug.

Arm/Group Title	Fingolimod 1.25 mg	Fingolimod 0.5 mg	Placebo
Arm/Group Description	Participants received 1.25 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 1.25 mg fingolimod orally. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day.	Participants received 0.5 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 0.5 mg fingolimod orally once a day.	Participants received placebo capsules orally once a day for up to 24 months during the core phase. In the Extension phase participants received either 1.25 or 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking placebo were switched to 0.5 mg fingolimod orally once a day.
Measure Participants	370	358	355
Number (95% Confidence Interval) [relapses per year]	0.180	0.192	0.363

3. Secondary Outcome

Title	Percent Change From Baseline in Brain Volume
Description	Brain volume was measured using magnetic resonance imaging (MRI). Change from Baseline in brain volume is expressed as a percentage of the Baseline brain volume.
Time Frame	Baseline, Month 24 and end of study (up to approximately 54 months)

Outcome Measure Data

Analysis Population Description

Core intent-to-treat (ITT) population: All patients who were randomized in the Core phase and received at least one dose of Core phase drug. Patients were grouped according to the assigned treatment. "N" indicates the number of participants with data available for the specified time period.

Arm/Group Title	Fingolimod 1.25 mg	Fingolimod 0.5 mg	Placebo
Arm/Group Description	Participants received 1.25 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 1.25 mg fingolimod orally. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day.	Participants received 0.5 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 0.5 mg fingolimod orally once a day.	Participants received placebo capsules orally once a day for up to 24 months during the core phase. In the Extension phase participants received either 1.25 or 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking placebo were switched to 0.5 mg fingolimod orally once a day.
Measure Participants	370	358	355
Month 24 [N=247; 266; 249]	-0.595 (1.3897)	-0.858 (1.2215)	-1.279 (1.5028)
End of study [N=178; 187; 182]	-1.130 (1.6380)	-1.266 (1.6941)	-1.694 (1.9567)

4. Secondary Outcome

Title	Number of New or Newly Enlarged T2 Lesions
Description	Inflammatory disease activity was assessed by magnetic resonance imaging (MRI) measurement of the number of new or newly enlarged T2 lesions, by year.
Time Frame	From Baseline until Month 48

Outcome Measure Data

Analysis Population Description

Core intent-to-treat (ITT) population: All patients who were randomized in the Core phase and received at least one dose of Core phase drug. Patients were grouped according to the assigned treatment. "N" indicates the number of participants with MRI data available for the specified time period.

Arm/Group Title	Fingolimod 1.25 mg	Fingolimod 0.5 mg	Placebo
Arm/Group Description	Participants received 1.25 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 1.25 mg fingolimod orally. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day.	Participants received 0.5 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 0.5 mg fingolimod orally once a day.	Participants received placebo capsules orally once a day for up to 24 months during the core phase. In the Extension phase participants received either 1.25 or 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking placebo were switched to 0.5 mg fingolimod orally once a day.
Measure Participants	370	358	355
Core Phase (Month 0 to 24) [N=245; 264; 251]	1.6 (5.41)	2.3 (7.26)	8.9 (13.86)
Month 24 to 36 [N=103; 111; 102]	0.63 (2.856)	0.45 (1.360)	0.63 (1.455)
Month 36 to 48 [N=24; 15; 15]	0.13 (0.448)	0.07 (0.258)	2.53 (8.741)

5. Secondary Outcome

Title	Number of Gadolinium-enhanced T1 Lesions
Description	Inflammatory disease activity was assessed by magnetic resonance imaging (MRI) measurement of the number of gadolinium-enhanced T1 lesions.
Time Frame	Month 24 and end of study (up to approximately 54 months)

Outcome Measure Data

Analysis Population Description

Core intent-to-treat (ITT) population: All patients who were randomized in the Core phase and received at least one dose of Core phase drug. "N" indicates the number of participants with evaluable MRI data for the specified time point.

Arm/Group Title	Fingolimod 1.25 mg	Fingolimod 0.5 mg	Placebo
Arm/Group Description	Participants received 1.25 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 1.25 mg fingolimod orally. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day.	Participants received 0.5 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 0.5 mg fingolimod orally once a day.	Participants received placebo capsules orally once a day for up to 24 months during the core phase. In the Extension phase participants received either 1.25 or 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking placebo were switched to 0.5 mg fingolimod orally once a day.
Measure Participants	370	358	355
Core Phase (Month 24) [N=251; 269; 256]	0.24 (2.395)	0.37 (1.841)	1.22 (2.967)
End of Extension study [N=184; 194; 184]	0.46 (2.381)	0.09 (0.308)	0.45 (3.618)

6. Secondary Outcome

Title	Change From Baseline in Lesion Volume at Month 24 (Core Phase)
Description	Change from Baseline in lesion volume was measured by MRI for T2 lesions and for T1 hypointense lesions.
Time Frame	Baseline and Month 24

Outcome Measure Data

Analysis Population Description

Full analysis set for whom data were available. N=the number of patients with non-missing baseline and post-baseline values.

Arm/Group Title	Fingolimod 1.25 mg	Fingolimod 0.5 mg	Placebo
Arm/Group Description	Participants received 1.25 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 1.25 mg fingolimod orally. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day.	Participants received 0.5 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 0.5 mg fingolimod orally once a day.	Participants received placebo capsules orally once a day for up to 24 months during the core phase. In the Extension phase participants received either 1.25 or 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking placebo were switched to 0.5 mg fingolimod orally once a day.
Measure Participants	370	358	355
T2 lesions [N=248, 266, 251]	-436.92 (1557.820)	-223.27 (1405.459)	541.83 (2830.868)
T1 hypointense lesions [N=247, 266, 248]	-99.13 (391.210)	-111.28 (530.961)	-37.68 (671.708)

7. Secondary Outcome

Title	Percentage of Participants Free of 3-month Confirmed Disability Progression at Month 24 and End of Study
Description	Disability progression was defined using the following criteria: One point increase from baseline in patients with Baseline Expanded Disability Status Scale (EDSS) score from 0 to 5.0; or half a point increase from Baseline in patients with Baseline EDSS score of 5.5 or above. A 3-month confirmed disability progression was defined as a 3-month sustained increase from Baseline in EDSS score. The EDSS quantifies disability in multiple sclerosis in 8 functional systems; the score ranges from 0 (normal) to 10 (death due to MS). Progression curves were generated by the Kaplan-Meier method.
Time Frame	24 months and end of study (up to approximately 54 months)

Outcome Measure Data

Analysis Population Description

Core intent-to-treat (ITT) population: All patients who were randomized in the Core phase and received at least one dose of Core phase drug.

Arm/Group Title	Fingolimod 1.25 mg	Fingolimod 0.5 mg	Placebo
Arm/Group Description	Participants received 1.25 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 1.25 mg fingolimod orally. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day.	Participants received 0.5 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 0.5 mg fingolimod orally once a day.	Participants received placebo capsules orally once a day for up to 24 months during the core phase. In the Extension phase participants received either 1.25 or 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking placebo were switched to 0.5 mg fingolimod orally once a day.
Measure Participants	370	358	355
At month 24	78.3 21.2%	74.7 20.9%	71.0 20%
At end of study	66.64 18%	58.89 16.4%	63.51 17.9%

8. Secondary Outcome

Title	Percentage of Participants Free of 6-month Confirmed Disability Progression at Month 24 and End of Study
Description	Disability progression was defined using the following criteria: One point increase from baseline in patients with Baseline Expanded Disability Status Scale (EDSS) score from 0 to 5.0; or half a point increase from Baseline in patients with Baseline EDSS score of 5.5 or above. A 6-month confirmed disability progression was defined as a 6-month sustained increase from Baseline in EDSS score. The EDSS quantifies disability in multiple sclerosis in 8 functional systems; the score ranges from 0 (normal) to 10 (death due to MS). Progression curves were generated by the Kaplan-Meier method.
Time Frame	24 months and end of study (up to approximately 54 months)

Outcome Measure Data

Analysis Population Description

Core intent-to-treat (ITT) population: All patients who were randomized in the Core phase and received at least one dose of Core phase drug.

Arm/Group Title	Fingolimod 1.25 mg	Fingolimod 0.5 mg	Placebo
Arm/Group Description	Participants received 1.25 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 1.25 mg fingolimod orally. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day.	Participants received 0.5 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 0.5 mg fingolimod orally once a day.	Participants received placebo capsules orally once a day for up to 24 months during the core phase. In the Extension phase participants received either 1.25 or 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking placebo were switched to 0.5 mg fingolimod orally once a day.
Measure Participants	370	358	355
At Month 24	86.9 23.5%	86.2 24.1%	82.2 23.2%
At end of study	79.92 21.6%	74.89 20.9%	75.03 21.1%

9. Secondary Outcome

Title	Percentage of Participants Relapse-free up to Month 24
Description	Estimates of the percentage of participants relapse-free at 24 months were generated from Kaplan-Meier curves of the time to first relapse. A relapse was 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 (<37.5C) or infection. A relapse was confirmed by an Independent Evaluating Physician.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Fingolimod 1.25 mg	Fingolimod 0.5 mg	Placebo
Arm/Group Description	Participants received 1.25 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 1.25 mg fingolimod orally. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day.	Participants received 0.5 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 0.5 mg fingolimod orally once a day.	Participants received placebo capsules orally once a day for up to 24 months during the core phase. In the Extension phase participants received either 1.25 or 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking placebo were switched to 0.5 mg fingolimod orally once a day.
Measure Participants	370	358	355
Number (95% Confidence Interval) [percentage of participants]	73.2 19.8%	71.5 20%	52.7 14.8%

10. Secondary Outcome

Title	Percentage of Participants Relapse-free up to End of Study
Description	Estimates of the percentage of participants relapse-free at end of study were generated from Kaplan-Meier curves of the time to first relapse. A relapse was 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 (<37.5C) or infection. A relapse was confirmed by an Independent Evaluating Physician.
Time Frame	From Baseline until the end of study (up to approximately 54 months)

Outcome Measure Data

Analysis Population Description

Core intent-to-treat (ITT) population: All patients who were randomized in the Core phase and received at least one dose of Core phase drug.

Arm/Group Title	Fingolimod 1.25 mg	Fingolimod 0.5 mg	Placebo
Arm/Group Description	Participants received 1.25 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 1.25 mg fingolimod orally. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day.	Participants received 0.5 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 0.5 mg fingolimod orally once a day.	Participants received placebo capsules orally once a day for up to 24 months during the core phase. In the Extension phase participants received either 1.25 or 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking placebo were switched to 0.5 mg fingolimod orally once a day.
Measure Participants	370	358	355
Number (95% Confidence Interval) [percentage of participants]	63.88 17.3%	66.57 18.6%	49.12 13.8%

11. Secondary Outcome

Title	Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Z-score
Description	The Multiple Sclerosis Functional Composite (MSFC) is a multidimensional clinical outcome measure that includes quantitative tests of leg function/ambulation (Timed 25-Foot Walk), arm function (9-Hole Peg Test), and cognitive function (Paced Auditory Serial Addition Test). The overall MSFC z-score as an average of the three standardized scores derived using baseline data pooled over each treatment arm as reference population. Higher scores reflect better neurological function and a positive change from Baseline indicates improvement.
Time Frame	Baseline, Month 24 and end of study (up to approximately 54 months)

Outcome Measure Data

Analysis Population Description

Core intent-to-treat (ITT) population: All patients who were randomized in the Core phase and received at least one dose of Core phase drug. "N" indicates the number of participants with non-missing data at each time point.

Arm/Group Title	Fingolimod 1.25 mg	Fingolimod 0.5 mg	Placebo
Arm/Group Description	Participants received 1.25 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 1.25 mg fingolimod orally. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day.	Participants received 0.5 mg fingolimod orally once a day for up to 24 months during the core phase. In the Extension phase participants continued to receive 0.5 mg fingolimod orally once a day.	Participants received placebo capsules orally once a day for up to 24 months during the core phase. In the Extension phase participants received either 1.25 or 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day. Upon implementation of a protocol amendment, all patients taking placebo were switched to 0.5 mg fingolimod orally once a day.
Measure Participants	370	358	355
Month 24 [N=250; 271; 258]	-0.08 (0.916)	0.00 (0.600)	-0.07 (0.540)
End of Study [N=174; 187; 184]	0.011 (0.3499)	-0.091 (0.8770)	0.019 (0.6304)

Adverse Events

Time Frame	Duration of treatment was up to 24 months during the Core phase, and dependent on the length of patient participation during the Extension phase (up to approximately 54 months overall duration of treatment).
Arm/Group Title	Core: Fingolimod 1.25 mg		Core: Fingolimod 0.5 mg		Core: Placebo		Extension: Fingolimod 1.25 mg		Extension: Fingolimod 0.5 mg
Arm/Group Description	Participants received 1.25 mg fingolimod orally once a day for up to 24 months during the core phase. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day.		Participants received 0.5 mg fingolimod orally once a day for up to 24 months during the core phase.		Participants received placebo capsules orally once a day for up to 24 months during the core phase. Upon implementation of a protocol amendment, all patients taking placebo were switched to 0.5 mg fingolimod orally once a day.		Participants received 1.25 mg fingolimod orally once a day in the Extension phase. Upon implementation of a protocol amendment, all patients taking 1.25 mg fingolimod were switched to 0.5 mg fingolimod orally once a day.		Participants received 0.5 mg fingolimod orally once a day in the Extension phase.
All Cause Mortality
	Core: Fingolimod 1.25 mg		Core: Fingolimod 0.5 mg		Core: Placebo		Extension: Fingolimod 1.25 mg		Extension: Fingolimod 0.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Core: Fingolimod 1.25 mg		Core: Fingolimod 0.5 mg		Core: Placebo		Extension: Fingolimod 1.25 mg		Extension: Fingolimod 0.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	53/370 (14.3%)		53/358 (14.8%)		45/355 (12.7%)		27/308 (8.8%)		21/324 (6.5%)
Blood and lymphatic system disorders
Idiopathic thrombocytopenic purpura	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Leukopenia	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Lymphopenia	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		1/308 (0.3%)		1/324 (0.3%)
Cardiac disorders
Acute coronary syndrome	0/370 (0%)		0/358 (0%)		0/355 (0%)		1/308 (0.3%)		0/324 (0%)
Acute myocardial infarction	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		1/308 (0.3%)		0/324 (0%)
Angina pectoris	1/370 (0.3%)		0/358 (0%)		2/355 (0.6%)		1/308 (0.3%)		0/324 (0%)
Atrial fibrillation	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Atrioventricular block	2/370 (0.5%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Atrioventricular block first degree	0/370 (0%)		0/358 (0%)		0/355 (0%)		1/308 (0.3%)		0/324 (0%)
Atrioventricular block second degree	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		1/308 (0.3%)		0/324 (0%)
Bradycardia	6/370 (1.6%)		0/358 (0%)		1/355 (0.3%)		2/308 (0.6%)		0/324 (0%)
Cardiac flutter	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Coronary artery disease	0/370 (0%)		0/358 (0%)		0/355 (0%)		1/308 (0.3%)		0/324 (0%)
Mitral valve incompetence	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Palpitations	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Pericarditis	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Tricuspid valve incompetence	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Ventricular tachycardia	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Endocrine disorders
Diabetes insipidus	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Hyperthyroidism	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Eye disorders
Macular oedema	2/370 (0.5%)		1/358 (0.3%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Retinal detachment	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		1/324 (0.3%)
Gastrointestinal disorders
Abdominal hernia	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Abdominal mass	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Abdominal pain	1/370 (0.3%)		2/358 (0.6%)		2/355 (0.6%)		0/308 (0%)		0/324 (0%)
Abdominal pain lower	0/370 (0%)		1/358 (0.3%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Caecitis	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Constipation	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Diarrhoea	0/370 (0%)		1/358 (0.3%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Gastric disorder	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Hiatus hernia	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Intestinal obstruction	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Large intestine perforation	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Vomiting	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
General disorders
Asthenia	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Chest discomfort	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Chest pain	1/370 (0.3%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		1/324 (0.3%)
Fatigue	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Non-cardiac chest pain	0/370 (0%)		2/358 (0.6%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Pelvic mass	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Pyrexia	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Hepatobiliary disorders
Bile duct stone	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Cholecystitis	2/370 (0.5%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Cholelithiasis	0/370 (0%)		1/358 (0.3%)		2/355 (0.6%)		0/308 (0%)		1/324 (0.3%)
Jaundice	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Immune system disorders
Drug hypersensitivity	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Infections and infestations
Acute sinusitis	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Appendicitis	0/370 (0%)		2/358 (0.6%)		1/355 (0.3%)		1/308 (0.3%)		0/324 (0%)
Bartholin's abscess	0/370 (0%)		0/358 (0%)		0/355 (0%)		1/308 (0.3%)		0/324 (0%)
Bronchitis	0/370 (0%)		1/358 (0.3%)		1/355 (0.3%)		0/308 (0%)		1/324 (0.3%)
Cellulitis	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Diverticulitis	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Encephalitis herpes	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Gastritis viral	0/370 (0%)		0/358 (0%)		0/355 (0%)		1/308 (0.3%)		0/324 (0%)
Gastroenteritis	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		1/308 (0.3%)		0/324 (0%)
Gastroenteritis viral	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Hepatitis C	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Herpes zoster	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Herpes zoster disseminated	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Kidney infection	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Labyrinthitis	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Lower respiratory tract infection fungal	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Lyme disease	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Mastoiditis	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Otitis media	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Pneumonia	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		1/324 (0.3%)
Post procedural infection	0/370 (0%)		0/358 (0%)		0/355 (0%)		1/308 (0.3%)		0/324 (0%)
Pyelonephritis	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Sinusitis	0/370 (0%)		2/358 (0.6%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Staphylococcal abscess	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Staphylococcal infection	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Urinary tract infection	0/370 (0%)		1/358 (0.3%)		1/355 (0.3%)		1/308 (0.3%)		0/324 (0%)
Vulvitis	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Injury, poisoning and procedural complications
Ankle fracture	1/370 (0.3%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Drug exposure during pregnancy	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Injury	0/370 (0%)		0/358 (0%)		0/355 (0%)		1/308 (0.3%)		0/324 (0%)
Joint dislocation	0/370 (0%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		1/324 (0.3%)
Laceration	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Lower limb fracture	0/370 (0%)		0/358 (0%)		0/355 (0%)		1/308 (0.3%)		1/324 (0.3%)
Overdose	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		1/324 (0.3%)
Post procedural haemorrhage	0/370 (0%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		1/324 (0.3%)
Toxicity to various agents	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Investigations
Alanine aminotransferase increased	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Hepatic enzyme increased	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Metabolism and nutrition disorders
Dehydration	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		1/324 (0.3%)
Hypokalaemia	0/370 (0%)		1/358 (0.3%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Hyponatraemia	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		1/308 (0.3%)		0/324 (0%)
Hypophosphataemia	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Metabolic acidosis	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Back pain	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Intervertebral disc degeneration	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Intervertebral disc protrusion	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Mobility decreased	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Morphoea	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Musculoskeletal chest pain	0/370 (0%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		1/324 (0.3%)
Myalgia	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Neck pain	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		1/308 (0.3%)		0/324 (0%)
Spinal column stenosis	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Spinal osteoarthritis	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Astrocytoma	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Basal cell carcinoma	6/370 (1.6%)		9/358 (2.5%)		2/355 (0.6%)		0/308 (0%)		1/324 (0.3%)
Breast cancer	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		1/308 (0.3%)		1/324 (0.3%)
Colon cancer	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Dysplastic naevus	0/370 (0%)		0/358 (0%)		0/355 (0%)		1/308 (0.3%)		0/324 (0%)
Endometrial cancer	0/370 (0%)		0/358 (0%)		0/355 (0%)		1/308 (0.3%)		0/324 (0%)
Ependymoma	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Hair follicle tumour benign	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Malignant melanoma in situ	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Melanocytic naevus	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		1/324 (0.3%)
Parathyroid tumour benign	0/370 (0%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		1/324 (0.3%)
Sarcoma of skin	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Squamous cell carcinoma	3/370 (0.8%)		1/358 (0.3%)		2/355 (0.6%)		1/308 (0.3%)		1/324 (0.3%)
Squamous cell carcinoma of skin	0/370 (0%)		0/358 (0%)		0/355 (0%)		1/308 (0.3%)		0/324 (0%)
T-cell lymphoma	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Thyroid adenoma	0/370 (0%)		0/358 (0%)		0/355 (0%)		1/308 (0.3%)		0/324 (0%)
Thyroid cancer	0/370 (0%)		1/358 (0.3%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Uterine leiomyoma	1/370 (0.3%)		0/358 (0%)		2/355 (0.6%)		1/308 (0.3%)		0/324 (0%)
Nervous system disorders
Akathisia	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Convulsion	0/370 (0%)		3/358 (0.8%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Encephalitis	0/370 (0%)		1/358 (0.3%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Encephalopathy	2/370 (0.5%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Grand mal convulsion	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Haemorrhagic stroke	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Headache	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		1/308 (0.3%)		0/324 (0%)
Intracranial aneurysm	0/370 (0%)		0/358 (0%)		0/355 (0%)		1/308 (0.3%)		0/324 (0%)
Migraine	1/370 (0.3%)		1/358 (0.3%)		2/355 (0.6%)		1/308 (0.3%)		0/324 (0%)
Multiple sclerosis relapse	2/370 (0.5%)		1/358 (0.3%)		3/355 (0.8%)		2/308 (0.6%)		5/324 (1.5%)
Optic neuritis	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Sciatica	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Simple partial seizures	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Status epilepticus	1/370 (0.3%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Syncope	2/370 (0.5%)		2/358 (0.6%)		1/355 (0.3%)		1/308 (0.3%)		1/324 (0.3%)
Transient ischaemic attack	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Abortion spontaneous	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		1/308 (0.3%)		0/324 (0%)
Ectopic pregnancy	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Psychiatric disorders
Acute psychosis	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Aggression	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Anxiety	1/370 (0.3%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Confusional state	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Depression	1/370 (0.3%)		0/358 (0%)		2/355 (0.6%)		0/308 (0%)		0/324 (0%)
Drug dependence	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Frustration	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Hallucination	0/370 (0%)		0/358 (0%)		0/355 (0%)		1/308 (0.3%)		0/324 (0%)
Major depression	0/370 (0%)		1/358 (0.3%)		3/355 (0.8%)		0/308 (0%)		0/324 (0%)
Mania	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Mental disorder	0/370 (0%)		0/358 (0%)		2/355 (0.6%)		0/308 (0%)		0/324 (0%)
Mental status changes	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Paranoia	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Suicidal behaviour	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Suicidal ideation	1/370 (0.3%)		0/358 (0%)		1/355 (0.3%)		1/308 (0.3%)		0/324 (0%)
Renal and urinary disorders
Chromaturia	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Nephrolithiasis	0/370 (0%)		3/358 (0.8%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Renal colic	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Reproductive system and breast disorders
Adenomyosis	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Cervical cyst	0/370 (0%)		0/358 (0%)		0/355 (0%)		1/308 (0.3%)		0/324 (0%)
Cervical dysplasia	0/370 (0%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		1/324 (0.3%)
Cystocele	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Haemorrhagic ovarian cyst	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Menorrhagia	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		1/308 (0.3%)		0/324 (0%)
Ovarian cyst	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Pelvic pain	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Rectocele	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Uterine prolapse	0/370 (0%)		0/358 (0%)		2/355 (0.6%)		0/308 (0%)		0/324 (0%)
Uterovaginal prolapse	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Vaginal haemorrhage	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Bronchospasm	0/370 (0%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Dyspnoea	1/370 (0.3%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Pulmonary embolism	1/370 (0.3%)		1/358 (0.3%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Wheezing	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Skin and subcutaneous tissue disorders
Urticaria	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Surgical and medical procedures
Abortion induced	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		1/308 (0.3%)		0/324 (0%)
Vascular disorders
Aortic dissection	0/370 (0%)		0/358 (0%)		1/355 (0.3%)		0/308 (0%)		0/324 (0%)
Embolism	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Haemorrhage	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Hypertension	1/370 (0.3%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		0/324 (0%)
Orthostatic hypotension	0/370 (0%)		0/358 (0%)		0/355 (0%)		0/308 (0%)		1/324 (0.3%)
Other (Not Including Serious) Adverse Events
	Core: Fingolimod 1.25 mg		Core: Fingolimod 0.5 mg		Core: Placebo		Extension: Fingolimod 1.25 mg		Extension: Fingolimod 0.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	335/370 (90.5%)		320/358 (89.4%)		305/355 (85.9%)		216/308 (70.1%)		223/324 (68.8%)
Blood and lymphatic system disorders
Lymphopenia	36/370 (9.7%)		26/358 (7.3%)		0/355 (0%)		25/308 (8.1%)		19/324 (5.9%)
Eye disorders
Vision blurred	8/370 (2.2%)		18/358 (5%)		12/355 (3.4%)		4/308 (1.3%)		8/324 (2.5%)
Gastrointestinal disorders
Abdominal pain upper	9/370 (2.4%)		18/358 (5%)		7/355 (2%)		3/308 (1%)		2/324 (0.6%)
Diarrhoea	52/370 (14.1%)		48/358 (13.4%)		43/355 (12.1%)		13/308 (4.2%)		16/324 (4.9%)
Dyspepsia	18/370 (4.9%)		12/358 (3.4%)		18/355 (5.1%)		4/308 (1.3%)		3/324 (0.9%)
Nausea	57/370 (15.4%)		63/358 (17.6%)		54/355 (15.2%)		13/308 (4.2%)		14/324 (4.3%)
Vomiting	29/370 (7.8%)		21/358 (5.9%)		27/355 (7.6%)		6/308 (1.9%)		8/324 (2.5%)
General disorders
Fatigue	29/370 (7.8%)		22/358 (6.1%)		25/355 (7%)		12/308 (3.9%)		3/324 (0.9%)
Pain	21/370 (5.7%)		10/358 (2.8%)		15/355 (4.2%)		8/308 (2.6%)		7/324 (2.2%)
Pyrexia	16/370 (4.3%)		14/358 (3.9%)		20/355 (5.6%)		2/308 (0.6%)		5/324 (1.5%)
Infections and infestations
Bronchitis	34/370 (9.2%)		29/358 (8.1%)		20/355 (5.6%)		18/308 (5.8%)		19/324 (5.9%)
Influenza	26/370 (7%)		34/358 (9.5%)		24/355 (6.8%)		11/308 (3.6%)		11/324 (3.4%)
Nasopharyngitis	88/370 (23.8%)		84/358 (23.5%)		85/355 (23.9%)		50/308 (16.2%)		52/324 (16%)
Sinusitis	45/370 (12.2%)		55/358 (15.4%)		45/355 (12.7%)		31/308 (10.1%)		27/324 (8.3%)
Upper respiratory tract infection	92/370 (24.9%)		87/358 (24.3%)		86/355 (24.2%)		49/308 (15.9%)		40/324 (12.3%)
Urinary tract infection	45/370 (12.2%)		47/358 (13.1%)		54/355 (15.2%)		23/308 (7.5%)		24/324 (7.4%)
Injury, poisoning and procedural complications
Fall	16/370 (4.3%)		22/358 (6.1%)		16/355 (4.5%)		14/308 (4.5%)		11/324 (3.4%)
Investigations
Alanine aminotransferase increased	35/370 (9.5%)		29/358 (8.1%)		6/355 (1.7%)		4/308 (1.3%)		13/324 (4%)
Gamma-glutamyltransferase increased	21/370 (5.7%)		23/358 (6.4%)		2/355 (0.6%)		2/308 (0.6%)		8/324 (2.5%)
Lymphocyte count decreased	20/370 (5.4%)		13/358 (3.6%)		0/355 (0%)		16/308 (5.2%)		20/324 (6.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	36/370 (9.7%)		30/358 (8.4%)		38/355 (10.7%)		15/308 (4.9%)		10/324 (3.1%)
Back pain	34/370 (9.2%)		29/358 (8.1%)		39/355 (11%)		20/308 (6.5%)		17/324 (5.2%)
Neck pain	21/370 (5.7%)		14/358 (3.9%)		16/355 (4.5%)		5/308 (1.6%)		7/324 (2.2%)
Pain in extremity	36/370 (9.7%)		44/358 (12.3%)		27/355 (7.6%)		20/308 (6.5%)		8/324 (2.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus	33/370 (8.9%)		38/358 (10.6%)		44/355 (12.4%)		18/308 (5.8%)		21/324 (6.5%)
Nervous system disorders
Dizziness	53/370 (14.3%)		38/358 (10.6%)		43/355 (12.1%)		10/308 (3.2%)		11/324 (3.4%)
Headache	81/370 (21.9%)		83/358 (23.2%)		76/355 (21.4%)		25/308 (8.1%)		29/324 (9%)
Migraine	15/370 (4.1%)		24/358 (6.7%)		19/355 (5.4%)		2/308 (0.6%)		8/324 (2.5%)
Paraesthesia	14/370 (3.8%)		19/358 (5.3%)		18/355 (5.1%)		5/308 (1.6%)		5/324 (1.5%)
Psychiatric disorders
Anxiety	18/370 (4.9%)		18/358 (5%)		17/355 (4.8%)		5/308 (1.6%)		5/324 (1.5%)
Depression	34/370 (9.2%)		29/358 (8.1%)		32/355 (9%)		11/308 (3.6%)		13/324 (4%)
Insomnia	24/370 (6.5%)		31/358 (8.7%)		24/355 (6.8%)		2/308 (0.6%)		6/324 (1.9%)
Respiratory, thoracic and mediastinal disorders
Cough	51/370 (13.8%)		52/358 (14.5%)		53/355 (14.9%)		23/308 (7.5%)		24/324 (7.4%)
Dyspnoea	46/370 (12.4%)		34/358 (9.5%)		33/355 (9.3%)		6/308 (1.9%)		6/324 (1.9%)
Nasal congestion	23/370 (6.2%)		17/358 (4.7%)		21/355 (5.9%)		7/308 (2.3%)		6/324 (1.9%)
Oropharyngeal pain	25/370 (6.8%)		29/358 (8.1%)		32/355 (9%)		12/308 (3.9%)		9/324 (2.8%)
Skin and subcutaneous tissue disorders
Rash	21/370 (5.7%)		22/358 (6.1%)		24/355 (6.8%)		14/308 (4.5%)		12/324 (3.7%)
Vascular disorders
Hypertension	46/370 (12.4%)		32/358 (8.9%)		11/355 (3.1%)		11/308 (3.6%)		6/324 (1.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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