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This Was an Open-label, Single-arm Extension Study (CFTY720D2306E1) to a Double-blind, Randomized Multicenter, Placebo-controlled, Parallel-group Core Study (CFTY720D2306) in PPMS. (INFORMS)

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ClinicalTrials.gov Identifier: NCT00731692
Recruitment Status : Terminated (The extension study was terminated early after the results of the core study showed the study did not meet primary endpoint; confirmed disability progression)
First Posted : August 11, 2008
Results First Posted : June 14, 2017
Last Update Posted : June 14, 2017
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Primary Progressive Multiple Sclerosis
Interventions Drug: FTY720
Drug: Placebo
Enrollment 970
Recruitment Details Patients were randomized equally to receive either fingolimod or placebo. Patients initially randomized to fingolimod 1.25 mg/day or matching placebo groups switched in a blinded manner to fingolimod 0.5 mg/day or continued on placebo after amendment in Nov. 2009. Patients were randomized to receive either fingolimod 0.5 mg/day or placebo..
Pre-assignment Details Prior to protocol amendment 147 patients received 1.25mg of FTY720; post protocol amendment 5 not all 147 patients switched to 0.5mg FTY720, only 121 switched and their data is presented under the 0.5mg dose.
Arm/Group Title FTY720 1.25 mg to 0.5 mg FTY720 0.5 mg to 0.5 mg Placebo to -FTY 0.5 mg
Hide Arm/Group Description Cohort 1: fingolimod 1.25 group consists of patients who were initially randomized to fingolimod 1.25 mg and switched to fingolimod 0.5 mg after amendment Cohort 2: The 0.5 mg group consists of patients who were directly randomized to fingolimod 0.5 mg (i.e. AFTER the amendment) Cohort 1 and 2: Patients who started on placebo continued on placebo after re-randomization
Period Title: Core Study (36 Months)
Started 147 336 487
Safety Set (SAF) 0 336 487
Full Analysis Set (FAS) 0 336 487
Pharmacokinetic Analysis Set 102 249 0
Post Protocol Amendment 5 Switch 0 121 [1] 0
Completed 79 220 317
Not Completed 68 116 170
Reason Not Completed
Lack of Efficacy             11             23             64
Physician Decision             1             0             2
Death             2             1             2
Lost to Follow-up             1             3             3
Administrative             2             2             6
Abnormal Test Procedure Result             4             3             5
Protocol Violation             4             5             8
Abnormal Lab values             6             19             5
Adverse Event             25             28             29
Withdrawal by Subject             12             32             46
[1]
post protocol amendment 121 patients switch to 0.5 mg dose from 125mg dose
Period Title: Extension Phase
Started 74 196 301
Completed 0 0 0
Not Completed 74 196 301
Reason Not Completed
Admin Problems: Terminated # patients             69             189             277
Abnormal test procedure             0             0             1
Abnormal lab values             0             0             1
Lost to Follow-up             0             1             4
Withdrawal by Subject             4             5             3
Adverse Event             1             1             15
Arm/Group Title FTY720 1.25 mg to 0.5 mg FTY720 0.5 mg to 0.5 mg Placebo Total
Hide Arm/Group Description Cohort 1: fingolimod 1.25 group consists of patients who were initially randomized to fingolimod 1.25 mg and switched to fingolimod 0.5 mg after amendment Cohort 2: The 0.5 mg group consists of patients who were directly randomized to fingolimod 0.5 mg (i.e. AFTER the amendment) Cohort 1 and 2: Patients who started on placebo continued on placebo after re-randomization Total of all reporting groups
Overall Number of Baseline Participants 147 336 487 970
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 147 participants 336 participants 487 participants 970 participants
47.8  (8.47) 48.5  (8.59) 48.5  (8.31) 48.5  (8.42)
Age, Customized  
Measure Type: Number
Unit of measure:  Particpants
Number Analyzed 147 participants 336 participants 487 participants 970 participants
<=30 3 6 4 13
31 to 40 22 60 90 172
41 to 50 68 127 194 389
>50 54 143 199 396
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 147 participants 336 participants 487 participants 970 participants
Female
71
  48.3%
163
  48.5%
235
  48.3%
469
  48.4%
Male
76
  51.7%
173
  51.5%
252
  51.7%
501
  51.6%
1.Primary Outcome
Title Kaplan-Meier Estimate of the Risk of 3-month Confirmed Disability Progression Based on Composite Endpoint
Hide Description 3-month sustained increase from Baseline in EDSS (at least 1 point increase from Baseline for patients with a Baseline value of 5 or less or at least 0.5 point increase from Baseline for patients with a Baseline value of 5.5 or more) or 3-month sustained increase of at least 20% from BL in the time taken to complete the timed 25-foot walk test (25’ TWT); or 3-month sustained increase of at least 20% from BL in the time taken to complete the 9-HPT. The 25’ TWT is a quantitative measure of lower extremity function. The EDSS is a scale assessing neurologic impairment, including a series of scores in each of 8 functional systems: Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel and Bladder, Cerebral and Other functions. The score ranges from 0 (normal) to 10 (death due to MS)). The 9-hole peg test (9-HPT) is a quantitative measure of upper extremity (arm and hand) function.
Time Frame up to 36 months after the last patient was randomized
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) - The main efficacy analyses were performed using the FAS, in patients who were initially randomized to either FTY 0.5mg or to Placebo.
Arm/Group Title FTY720 0.5 mg to 0.5 mg Placebo
Hide Arm/Group Description:
Cohort 2: The 0.5 mg group consists of patients who were directly randomized to fingolimod 0.5 mg (i.e. AFTER the amendment)
Cohort 1 and 2: Patients who started on placebo continued on placebo after re-randomization
Overall Number of Participants Analyzed 336 487
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
77.2
(71.87 to 82.51)
80.3
(73.31 to 87.25)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FTY720 0.5 mg to 0.5 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.544
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.95
Confidence Interval (2-Sided) 95%
0.80 to 1.12
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Kaplan-Meier Estimate of the Risk of 3- Month Confirmed Disability Progression Based on Expanded Disability Status Scale (EDSS)
Hide Description The Expanded Disability Status Scale (EDSS) is a scale for assessing neurologic impairment in MS (Kurtzke 1983) and includes a series of scores in each of 8 functional systems and 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. Fatigue is not included in the Cerebral score of the EDSS. The score ranges from 0 (normal) to 10 (death due to MS)
Time Frame up to 36 months after the last patient was randomized
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) - The main efficacy analyses were performed using the FAS, in patients who were initially randomized to either FTY 0.5mg or to Placebo.
Arm/Group Title FTY720 0.5 mg to 0.5 mg Placebo
Hide Arm/Group Description:
Cohort 2: The 0.5 mg group consists of patients who were directly randomized to fingolimod 0.5 mg (i.e. AFTER the amendment)
Cohort 1 and 2: Patients who started on placebo continued on placebo after re-randomization
Overall Number of Participants Analyzed 336 487
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
54.3
(47.16 to 61.45)
58.7
(53.30 to 64.18)
3.Secondary Outcome
Title Percent Change From Baseline in Brain Volume at Month 36
Hide Description The percent change from Baseline in brain volume was analyzed using a random coefficients model. The model included: 1) fixed effects: treatment and region and 2) continuous covariates: time, number of Gd enhancing lesions at Baseline, Baseline T2 volume, and normalized brain volume at Baseline. Time as a continuous covariate allowed for the estimation of different slopes and intercepts among treatment groups.
Time Frame Baseline to month 36
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) - The main efficacy analyses were performed using the FAS, in patients who were initially randomized to either FTY 0.5mg or to Placebo. N= Total number of patients included in the analysis.
Arm/Group Title FTY720 0.5 mg to 0.5 mg Placebo
Hide Arm/Group Description:
Cohort 2: The 0.5 mg group consists of patients who were directly randomized to fingolimod 0.5 mg (i.e. AFTER the amendment)
Cohort 1 and 2: Patients who started on placebo continued on placebo after re-randomization
Overall Number of Participants Analyzed 293 421
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Percent Change
-1.49
(-1.64 to -1.35)
-1.53
(-1.65 to -1.41)
4.Secondary Outcome
Title Kaplan Meier Estimate -Percentage of Participants With 3- Month Confirmed Disability Progression Based on 9-HPT.
Hide Description The 9-HPT is a quantitative measure of upper extremity (arm and hand) function designed and validated for evaluation of MS patients. N= Total number of patients included in the analysis
Time Frame up to 36 months after the last patient was randomized
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) - The main efficacy analyses were performed using the FAS, in patients who were initially randomized to either FTY 0.5mg or to Placebo.
Arm/Group Title FTY720 0.5 mg to 0.5 mg Placebo
Hide Arm/Group Description:
Cohort 2: The 0.5 mg group consists of patients who were directly randomized to fingolimod 0.5 mg (i.e. AFTER the amendment)
Cohort 1 and 2: Patients who started on placebo continued on placebo after re-randomization
Overall Number of Participants Analyzed 147 133
Measure Type: Number
Unit of Measure: Percentge of Participants
25.0 24.9
5.Secondary Outcome
Title Kaplan Meier Estimate -Percentage of Participants With 3- Month Confirmed Disability Progression Based on 25' TWT.
Hide Description The 25' TWT is a quantitative measure of lower extremity function designed and validated for evaluation of MS patients. N= Total number of patients included in the analysis
Time Frame up to 36 months after the last patient was randomized
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) - The main efficacy analyses were performed using the FAS, in patients who were initially randomized to either FTY 0.5mg or to Placebo.
Arm/Group Title FTY720 0.5 mg to 0.5 mg Placebo
Hide Arm/Group Description:
Cohort 2: The 0.5 mg group consists of patients who were directly randomized to fingolimod 0.5 mg (i.e. AFTER the amendment)
Cohort 1 and 2: Patients who started on placebo continued on placebo after re-randomization
Overall Number of Participants Analyzed 147 133
Measure Type: Number
Unit of Measure: Percentage of Participants
54.8 56.7
6.Secondary Outcome
Title Number of New/Enlarging T2 Lesions Per Year Measured From Baseline to Month 36
Hide Description Inflammatory disease, as measured by number of new or newly-enlarging T2 lesions, was assessed by Magnetic resonance Imaging (MRI) scanning of the brain and full spinal cord. N= Total number of patients included in the analysis
Time Frame Baseline to 36 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) -The main efficacy analyses were performed using the FAS, in patients who were initially randomized to either FTY 0.5mg or to Placebo.
Arm/Group Title FTY720 0.5 mg to 0.5 mg Placebo
Hide Arm/Group Description:
Cohort 2: The 0.5 mg group consists of patients who were directly randomized to fingolimod 0.5 mg (i.e. AFTER the amendment)
Cohort 1 and 2: Patients who started on placebo continued on placebo after re-randomization
Overall Number of Participants Analyzed 298 421
Least Squares Mean (95% Confidence Interval)
Unit of Measure: T2 Lesions per year
0.13
(0.10 to 0.18)
0.50
(0.40 to 0.61)
7.Secondary Outcome
Title Number of Gd-enhancing Lesions at Month 36
Hide Description Inflammatory disease, as measured by number of T1 Gd-enhancing lesions, was assessed by MRI scanning of the brain and full spinal cord. N= Total number of patients included in the analysis
Time Frame Baseline to 36 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) - The main efficacy analyses were performed using the FAS, in patients who were initially randomized to either FTY 0.5mg or to Placebo.
Arm/Group Title FTY720 0.5 mg to 0.5 mg Placebo
Hide Arm/Group Description:
Cohort 2: The 0.5 mg group consists of patients who were directly randomized to fingolimod 0.5 mg (i.e. AFTER the amendment)
Cohort 1 and 2: Patients who started on placebo continued on placebo after re-randomization
Overall Number of Participants Analyzed 223 320
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Gd-enhanced lesions per patient per scan
0.05
(0.02 to 0.09)
0.21
(0.15 to 0.30)
8.Secondary Outcome
Title Percent Change in Total T2 Lesion Volume From Baseline to Month 36
Hide Description Inflammatory disease as measured by percent change in total T2 lesion volume (mm3) was assessed by MRI. N= Total number of patients included in the analysis
Time Frame Baseline to month 36
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) - The main efficacy analyses were performed using the FAS, in patients who were initially randomized to either FTY 0.5mg or to Placebo.
Arm/Group Title FTY720 0.5 mg to 0.5 mg Placebo
Hide Arm/Group Description:
Cohort 2: The 0.5 mg group consists of patients who were directly randomized to fingolimod 0.5 mg (i.e. AFTER the amendment)
Cohort 1 and 2: Patients who started on placebo continued on placebo after re-randomization
Overall Number of Participants Analyzed 224 326
Mean (Standard Deviation)
Unit of Measure: Percent Change
-9.2  (30.55) 8.9  (44.13)
9.Secondary Outcome
Title Change From Baseline in the Patient Reported Indices in Multiple Sclerosis (PRIMUS-QoL Score)
Hide Description The quality of life scale contains 22 items. Each item will be given a score of 1 or 0. A score of 1 (or 0) indicates the presence (or absence) of the symptom or adverse quality of life. All 22 item scores will be summed to obtain a total score ranging from 0 (good) to 22 (poor), which is the PRIMUS QoL scale score
Time Frame Baseline, 36 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) - The main efficacy analyses were performed using the FAS, in patients who were initially randomized to either FTY 0.5mg or to Placebo. Only subjects with a value at both baseline and at month 36 are included.
Arm/Group Title FTY720 1.25 mg to 0.5 mg FTY720 0.5 mg to 0.5 mg Placebo
Hide Arm/Group Description:
Cohort 1: fingolimod 1.25 group consists of patients who were initially randomized to fingolimod 1.25 mg and switched to fingolimod 0.5 mg after amendment
Cohort 2: The 0.5 mg group consists of patients who were directly randomized to fingolimod 0.5 mg (i.e. AFTER the amendment)
Cohort 1 and 2: Patients who started on placebo continued on placebo after re-randomization
Overall Number of Participants Analyzed 66 150 230
Mean (Standard Deviation)
Unit of Measure: Score on a scale
0.2424  (4.18444) 0.5921  (4.77704) 0.9597  (4.38578)
10.Secondary Outcome
Title Change From Baseline in PRIMUS-Activities
Hide Description The activities subscale of PRIMUS contains 15 items and each item is given a score of 0 (able to do on own without difficulties), 1 (able to do on own with difficulties), or 2 (unable to do on own). All 15 items were summed to obtain a total score ranging from 0 (good) to 30 (poor).
Time Frame Baseline, 36 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) - The main efficacy analyses were performed using the FAS, in patients who were initially randomized to either FTY 0.5mg or to Placebo. Only subjects with a value at both baseline and at month 36 are included.
Arm/Group Title FTY720 1.25 mg to 0.5 mg FTY720 0.5 mg to 0.5 mg Placebo
Hide Arm/Group Description:
Cohort 1: fingolimod 1.25 group consists of patients who were initially randomized to fingolimod 1.25 mg and switched to fingolimod 0.5 mg after amendment
Cohort 2: The 0.5 mg group consists of patients who were directly randomized to fingolimod 0.5 mg (i.e. AFTER the amendment)
Cohort 1 and 2: Patients who started on placebo continued on placebo after re-randomization
Overall Number of Participants Analyzed 68 153 237
Mean (Standard Deviation)
Unit of Measure: Score on a scale
3.5504  (7.05241) 2.6324  (6.22256) 2.8830  (6.76499)
11.Secondary Outcome
Title Change From Baseline in Unidimensional Fatigue Impact (U-FIS) Score
Hide Description Unidimensional Fatigue Impact Scale (U-FIS), contains 22 patient-reported items that assess the impact of fatigue on cognitive, physical, and psychosocial functioning. Responses formed a single unidimensional scale measuring fatigue impact. The U-FIS was calculated and analyzed according to the U-FIS scoring manual. The U-FIS scale contains 22 items with 5 possible outcomes for each item. Two response categories (about half the time and a lot of the time) were combined into 1 category to obtain 4 possible outcomes: 0 (never), 1 (a little of the time), 2 (about half the time/a lot of the time), and 3 (all the time). The 22 condensed item scores were summed to obtain a total score ranging from 0 (no fatigue) to 66 (severe fatigue impact).
Time Frame Baseline, 36 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) - The main efficacy analyses were performed using the FAS, in patients who were initially randomized to either FTY 0.5mg or to Placebo. Only subjects with a value at both baseline and at month 36 are included.
Arm/Group Title FTY720 1.25 mg to 0.5 mg FTY720 0.5 mg to 0.5 mg Placebo
Hide Arm/Group Description:
Cohort 1: fingolimod 1.25 group consists of patients who were initially randomized to fingolimod 1.25 mg and switched to fingolimod 0.5 mg after amendment
Cohort 2: The 0.5 mg group consists of patients who were directly randomized to fingolimod 0.5 mg (i.e. AFTER the amendment)
Cohort 1 and 2: Patients who started on placebo continued on placebo after re-randomization
Overall Number of Participants Analyzed 70 154 241
Mean (Standard Deviation)
Unit of Measure: Score on a scale
1.3197  (12.44042) 2.8451  (14.04769) 3.1394  (12.20929)
12.Secondary Outcome
Title Change From Baseline in European Quality of Life – 5 Dimensions (EQ-5D Score)
Hide Description EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state (confined to bed). Scoring formula developed by EuroQoL Group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state.
Time Frame Baseline, 36 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) - The main efficacy analyses were performed using the FAS, in patients who were initially randomized to either FTY 0.5mg or to Placebo. Only subjects with a value at both baseline and at month 36 are included.
Arm/Group Title FTY720 1.25 mg to 0.5 mg FTY720 0.5 mg to 0.5 mg Placebo
Hide Arm/Group Description:
Cohort 1: fingolimod 1.25 group consists of patients who were initially randomized to fingolimod 1.25 mg and switched to fingolimod 0.5 mg after amendment
Cohort 2: The 0.5 mg group consists of patients who were directly randomized to fingolimod 0.5 mg (i.e. AFTER the amendment)
Cohort 1 and 2: Patients who started on placebo continued on placebo after re-randomization
Overall Number of Participants Analyzed 99 213 320
Mean (Standard Deviation)
Unit of Measure: Score on a scale
-0.0332  (0.19420) -0.0475  (0.26099) -0.0539  (0.22383)
13.Secondary Outcome
Title Change From Baseline in Multiple Sclerosis Walking Scale (MSWS-12 Score)
Hide Description The Multiple Sclerosis Walking Scaleis a patient reported measure of walking quality (Hobart et al 2003), consisting of 12 items asking patients to rate the impact of MS upon their walking ability. Responses were captured on a 3-point scale ranging from 1 (Not at all) to 3 (A lot) for items 1 to 3 and on a 5-point scale ranging from 1 (not limited) to 5 (extremely) for items 4 to 12. All 12 item scores were summed to obtain a total score ranging from 12 (good) to 54 (poor) which is the MSWS-12 scale score. The total score was transformed to a 0 to 100 scale score. The MSWS-12 scale score will be transformed to a 0-100 scale score before any summaries or statistical analyses are performed. The transformed score is obtained by subtracting 12 and divided by 42 and multiplying by 100 (i.e., transformed scale score = (raw scale score- 12)/42*100).
Time Frame Baseline, 36 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) - The main efficacy analyses were performed using the FAS, in patients who were initially randomized to either FTY 0.5mg or to Placebo. Only subjects with a value at both baseline and at month 36 are included.
Arm/Group Title FTY720 1.25 mg to 0.5 mg FTY720 0.5 mg to 0.5 mg Placebo
Hide Arm/Group Description:
Cohort 1: fingolimod 1.25 group consists of patients who were initially randomized to fingolimod 1.25 mg and switched to fingolimod 0.5 mg after amendment
Cohort 2: The 0.5 mg group consists of patients who were directly randomized to fingolimod 0.5 mg (i.e. AFTER the amendment)
Cohort 1 and 2: Patients who started on placebo continued on placebo after re-randomization
Overall Number of Participants Analyzed 75 182 261
Mean (Standard Deviation)
Unit of Measure: Score on a scale
6.4444  (23.81568) 5.5616  (24.59030) 9.5899  (23.98316)
14.Secondary Outcome
Title Blood Concentrations of Fingolimod and Fingolimod-phosphate
Hide Description

Concentrations of fingolimod and fingolimod-phosphate in whole blood were determined by validated liquid chromatography methods with tandem mass spectrometry. The lower limits of quantification were 0.08 ng/ml for fingolimod and 0.1 ng/ml for fingolimod-phosphate.

Venous blood samples were collected for the analysis.

Time Frame Month 3 up to 36 months
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Hide Analysis Population Description
Full analysis set (FAS) -The main efficacy analyses were performed using the FAS, in patients who were initially randomized to either FTY 0.5mg or to Placebo. (N). Only participants (n) who provided one or more evaluable blood concentration were included in the pharmacokinetic analysis population. Analysis include 147 patients (cohort 1)
Arm/Group Title FTY720 1.25 mg to 0.5 mg FTY720 1.25mg to 0.5 mg FTY720 0.5 mg to 0.5 mg
Hide Arm/Group Description:
Cohort 1: fingolimod 1.25 group consists of patients who were initially randomized to fingolimod 1.25 mg and switched to fingolimod 0.5 mg after amendment
fingolimod 1.25mg/0.5 mg group consists of patients who were initially randomized to fingolimod 1.25 mg and switched to fingolimod 0.5 mg
Cohort 2: The 0.5 mg group consists of patients who were directly randomized to fingolimod 0.5 mg (i.e. AFTER the amendment)
Overall Number of Participants Analyzed 102 102 249
Mean (Standard Deviation)
Unit of Measure: ng/ml
Month 3 Fingolimod (n=64, 179) 6.04  (3.11) NA [1]   (NA) 2.58  (1.34)
Month 12 Fingolimod (n=23, 161) 6.24  (2.21) 2.87  (1.70) 2.55  (1.37)
Month 18 Fingolimod (n=71,155) NA [2]   (NA) 2.44  (1.15) 2.59  (1.44)
Month 24 Fingolimod (n=67, 160) NA [2]   (NA) 2.41  (1.30) 2.64  (1.50)
Month 30 Fingolimod (n=62, 158) NA [2]   (NA) 2.52  (1.28) 2.60  (1.33)
Month 36 Fingolimod (n=55, 118) NA [2]   (NA) 2.44  (1.08) 2.63  (1.38)
End of treatment Fingolimod (n=32, 115) NA [2]   (NA) 2.02  (1.10) 2.57  (1.51)
Month 3 Fingolimod-Phosphate (n=64, 179) 3.20  (1.73) NA [1]   (NA) 1.40  (0.747)
Month 12 Fingolimod-Phosphate (n=23, 161) 3.21  (1.16) 1.54  (0.871) 1.43  (0.805)
Month 18 Fingolimod-Phosphate (n=71,155) NA [2]   (NA) 1.34  (0.630) 1.41  (0.758)
Month 24 Fingolimod-Phosphate (n=67, 160) NA [2]   (NA) 1.35  (0.765) 1.44  (0.790)
Month 30 Fingolimod-Phosphate (n=62, 158) NA [2]   (NA) 1.32  (0.676) 1.48  (0.759)
Month 36 Fingolimod-Phosphate (n=55, 118) NA [2]   (NA) 1.32  (0.591) 1.51  (0.765)
End of treatment Fingolimod-Phosphate (n=32, 115 NA [2]   (NA) 1.19  (0.618) 1.50  (0.900)
[1]
No evaluable blood concentration available
[2]
Patients switched to 0.5mg. No evaluable blood concentration available
15.Secondary Outcome
Title Change in MSFC Z-score and Subscale Scores From Baseline to Month 36
Hide 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 to Month 36
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) - The main efficacy analyses were performed using the FAS
Arm/Group Title FTY720 0.5 mg Placebo
Hide Arm/Group Description:
Cohort 2: The 0.5 mg group consists of patients who were directly randomized to fingolimod 0.5 mg (i.e. AFTER the amendment)
Cohort 1 and 2: Patients who started on placebo continued on placebo after re-randomization
Overall Number of Participants Analyzed 193 279
Mean (Standard Deviation)
Unit of Measure: Z-scores
-0.189  (0.6980) -0.212  (0.8468)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Core: FTY720 1.25 mg Core: FTY720 0.5 mg Core: Placebo Extension: FTY1.25-0.5 Extension: FTY0.5-0.5 Extension: Placebo-FTY0.5
Hide Arm/Group Description Patients who received FTY720 1.25 mg during core Patients who received FTY720 0.5 mg during core Patients who received Placebo during core Patients who received FTY20 1.25 mg in core and received 0.5 mg of FTY during Extension Patients who received FTY20 0.5 mg in core and received 0.5 mg of FTY during Extension Patients who received Placebo in core and received 0.5 mg of FTY during Extension
All-Cause Mortality
Core: FTY720 1.25 mg Core: FTY720 0.5 mg Core: Placebo Extension: FTY1.25-0.5 Extension: FTY0.5-0.5 Extension: Placebo-FTY0.5
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Core: FTY720 1.25 mg Core: FTY720 0.5 mg Core: Placebo Extension: FTY1.25-0.5 Extension: FTY0.5-0.5 Extension: Placebo-FTY0.5
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   38/147 (25.85%)   84/336 (25.00%)   117/487 (24.02%)   7/74 (9.46%)   10/196 (5.10%)   37/301 (12.29%) 
Blood and lymphatic system disorders             
Anaemia macrocytic  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Lymphadenopathy  1  1/147 (0.68%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  1/196 (0.51%)  0/301 (0.00%) 
Cardiac disorders             
Angina pectoris  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Arrhythmia  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Atrial fibrillation  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Atrioventricular block  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Atrioventricular block complete  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Atrioventricular block first degree  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Atrioventricular block second degree  1  1/147 (0.68%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Bradycardia  1  2/147 (1.36%)  2/336 (0.60%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Coronary artery disease  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Myocardial infarction  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Myocardial ischaemia  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Pericarditis  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Sinus bradycardia  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Tachycardia paroxysmal  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Endocrine disorders             
Hypothyroidism  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Eye disorders             
Amblyopia strabismic  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Angle closure glaucoma  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Cataract cortical  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Chorioretinopathy  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Cystoid macular oedema  1  0/147 (0.00%)  1/336 (0.30%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Diplopia  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Intraocular haematoma  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Macular oedema  1  1/147 (0.68%)  4/336 (1.19%)  4/487 (0.82%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Myopia  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Optic atrophy  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Retinal detachment  1  0/147 (0.00%)  1/336 (0.30%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Retinal tear  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Gastrointestinal disorders             
Abdominal pain  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Abdominal pain lower  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Anal polyp  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Colitis ulcerative  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Constipation  1  0/147 (0.00%)  2/336 (0.60%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Faecaloma  1  0/147 (0.00%)  1/336 (0.30%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Gastric ulcer  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Inguinal hernia  1  1/147 (0.68%)  0/336 (0.00%)  2/487 (0.41%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Intestinal obstruction  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Nausea  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Obstruction gastric  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Pancreatitis  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Pancreatitis acute  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Upper gastrointestinal haemorrhage  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
General disorders             
Asthenia  1  1/147 (0.68%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Chest discomfort  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Device dislocation  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Device occlusion  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Drug ineffective  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Fatigue  1  0/147 (0.00%)  1/336 (0.30%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Gait disturbance  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
General physical health deterioration  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Non-cardiac chest pain  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Pyrexia  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Hepatobiliary disorders             
Cholecystitis  1  1/147 (0.68%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Cholecystitis acute  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Cholelithiasis  1  0/147 (0.00%)  1/336 (0.30%)  3/487 (0.62%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Cholelithiasis obstructive  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Infections and infestations             
Appendicitis  1  1/147 (0.68%)  0/336 (0.00%)  2/487 (0.41%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Bacterial infection  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Blister infected  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Bronchitis viral  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Bronchopneumonia  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Bursitis infective  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  1/74 (1.35%)  0/196 (0.00%)  0/301 (0.00%) 
Cellulitis  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  1/74 (1.35%)  0/196 (0.00%)  0/301 (0.00%) 
Cystitis  1  1/147 (0.68%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  1/196 (0.51%)  0/301 (0.00%) 
Dengue fever  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Diverticulitis  1  0/147 (0.00%)  0/336 (0.00%)  2/487 (0.41%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Enterocolitis bacterial  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Epididymitis  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Gastroenteritis  1  0/147 (0.00%)  2/336 (0.60%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
H1N1 influenza  1  0/147 (0.00%)  0/336 (0.00%)  2/487 (0.41%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Herpes zoster  1  1/147 (0.68%)  2/336 (0.60%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Herpes zoster infection neurological  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Herpes zoster meningomyelitis  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Incision site infection  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Infection  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Infectious pleural effusion  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Influenza  1  0/147 (0.00%)  3/336 (0.89%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Meningitis  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Myelitis  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Ophthalmic herpes simplex  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Peritonitis  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Pneumonia  1  2/147 (1.36%)  4/336 (1.19%)  2/487 (0.41%)  1/74 (1.35%)  0/196 (0.00%)  1/301 (0.33%) 
Pulmonary sepsis  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Pyelonephritis  1  0/147 (0.00%)  0/336 (0.00%)  3/487 (0.62%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Pyelonephritis acute  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Respiratory tract infection  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Septic shock  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Serratia sepsis  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Subcutaneous abscess  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  1/74 (1.35%)  0/196 (0.00%)  0/301 (0.00%) 
Systemic mycosis  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Tonsillitis  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Tracheobronchitis  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Upper respiratory tract infection  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Urinary tract infection  1  2/147 (1.36%)  8/336 (2.38%)  12/487 (2.46%)  1/74 (1.35%)  0/196 (0.00%)  4/301 (1.33%) 
Urinary tract infection bacterial  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Urosepsis  1  1/147 (0.68%)  0/336 (0.00%)  2/487 (0.41%)  0/74 (0.00%)  1/196 (0.51%)  0/301 (0.00%) 
Viral infection  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Viral upper respiratory tract infection  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Injury, poisoning and procedural complications             
Accidental overdose  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Alcohol poisoning  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Ankle fracture  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  1/196 (0.51%)  0/301 (0.00%) 
Clavicle fracture  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Concussion  1  1/147 (0.68%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Facial bones fracture  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  1/196 (0.51%)  0/301 (0.00%) 
Fall  1  3/147 (2.04%)  1/336 (0.30%)  3/487 (0.62%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Femoral neck fracture  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Femur fracture  1  1/147 (0.68%)  1/336 (0.30%)  3/487 (0.62%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Fibula fracture  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Foot fracture  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Fracture displacement  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Hand fracture  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Head injury  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Hip fracture  1  0/147 (0.00%)  1/336 (0.30%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Humerus fracture  1  1/147 (0.68%)  0/336 (0.00%)  2/487 (0.41%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Joint dislocation  1  1/147 (0.68%)  0/336 (0.00%)  2/487 (0.41%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Laceration  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Limb traumatic amputation  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Lumbar vertebral fracture  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Meniscus injury  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Overdose  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Pneumothorax traumatic  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Post procedural complication  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Post procedural haematoma  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Post procedural haemorrhage  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Radius fracture  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Rib fracture  1  1/147 (0.68%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Road traffic accident  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Skull fracture  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Subdural haematoma  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Thermal burn  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Tibia fracture  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Traumatic renal injury  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Upper limb fracture  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Wound  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Wound dehiscence  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Wrist fracture  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Investigations             
Alanine aminotransferase increased  1  0/147 (0.00%)  0/336 (0.00%)  2/487 (0.41%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Aspartate aminotransferase increased  1  0/147 (0.00%)  0/336 (0.00%)  2/487 (0.41%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Blood pressure increased  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Foetal heart rate abnormal  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
International normalised ratio decreased  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Lymphocyte count decreased  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  1/74 (1.35%)  0/196 (0.00%)  0/301 (0.00%) 
Troponin increased  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Weight decreased  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Metabolism and nutrition disorders             
Dehydration  1  0/147 (0.00%)  1/336 (0.30%)  2/487 (0.41%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Hypokalaemia  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Polydipsia  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Musculoskeletal and connective tissue disorders             
Arthralgia  1  0/147 (0.00%)  1/336 (0.30%)  2/487 (0.41%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Back pain  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  2/301 (0.66%) 
Bone swelling  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Bursitis  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  1/74 (1.35%)  0/196 (0.00%)  0/301 (0.00%) 
Intervertebral disc disorder  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Joint swelling  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Mobility decreased  1  0/147 (0.00%)  0/336 (0.00%)  2/487 (0.41%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Muscular weakness  1  0/147 (0.00%)  0/336 (0.00%)  2/487 (0.41%)  1/74 (1.35%)  0/196 (0.00%)  2/301 (0.66%) 
Osteoarthritis  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Osteopenia  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Pain in extremity  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Rhabdomyolysis  1  0/147 (0.00%)  0/336 (0.00%)  2/487 (0.41%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Sjogren's syndrome  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Spinal column stenosis  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Tendon disorder  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
Basal cell carcinoma  1  1/147 (0.68%)  11/336 (3.27%)  9/487 (1.85%)  1/74 (1.35%)  2/196 (1.02%)  1/301 (0.33%) 
Breast cancer  1  2/147 (1.36%)  1/336 (0.30%)  0/487 (0.00%)  1/74 (1.35%)  0/196 (0.00%)  0/301 (0.00%) 
Dysplastic naevus  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Fibrous histiocytoma  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Invasive ductal breast carcinoma  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Invasive lobular breast carcinoma  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Lung neoplasm malignant  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Lymphocytic leukaemia  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Malignant melanoma  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Malignant melanoma in situ  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Medullary thyroid cancer  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Melanocytic naevus  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Metastases to bone  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Metastases to central nervous system  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Metastases to kidney  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Metastases to liver  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Non-Hodgkin's lymphoma  1  1/147 (0.68%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Osteoma  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Ovarian cancer metastatic  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Prostate cancer  1  0/147 (0.00%)  1/336 (0.30%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Small cell lung cancer metastatic  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Squamous cell carcinoma of skin  1  0/147 (0.00%)  6/336 (1.79%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Uterine leiomyoma  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Nervous system disorders             
Aphasia  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Arachnoiditis  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Brain oedema  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Central nervous system lesion  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Cerebrovascular accident  1  0/147 (0.00%)  0/336 (0.00%)  2/487 (0.41%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Cerebrovascular disorder  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  1/74 (1.35%)  0/196 (0.00%)  1/301 (0.33%) 
Generalised tonic-clonic seizure  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Monoparesis  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Multiple sclerosis  1  2/147 (1.36%)  3/336 (0.89%)  5/487 (1.03%)  0/74 (0.00%)  0/196 (0.00%)  2/301 (0.66%) 
Multiple sclerosis relapse  1  0/147 (0.00%)  1/336 (0.30%)  5/487 (1.03%)  0/74 (0.00%)  0/196 (0.00%)  2/301 (0.66%) 
Muscle spasticity  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Myelitis transverse  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Neuralgia  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Nystagmus  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Optic neuritis  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Paraparesis  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Peroneal nerve palsy  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Presyncope  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Primary progressive multiple sclerosis  1  1/147 (0.68%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Progressive multiple sclerosis  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  1/196 (0.51%)  0/301 (0.00%) 
Quadriparesis  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Sciatica  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Seizure  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  1/196 (0.51%)  0/301 (0.00%) 
Status epilepticus  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Syncope  1  0/147 (0.00%)  0/336 (0.00%)  2/487 (0.41%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Transient ischaemic attack  1  0/147 (0.00%)  1/336 (0.30%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Trigeminal neuralgia  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Uhthoff's phenomenon  1  2/147 (1.36%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
VIIth nerve paralysis  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Psychiatric disorders             
Adjustment disorder  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Aggression  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Depression  1  0/147 (0.00%)  0/336 (0.00%)  2/487 (0.41%)  0/74 (0.00%)  1/196 (0.51%)  0/301 (0.00%) 
Depressive symptom  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Mania  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Mood swings  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Panic attack  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Psychotic disorder  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Suicidal ideation  1  0/147 (0.00%)  1/336 (0.30%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Renal and urinary disorders             
Acute kidney injury  1  0/147 (0.00%)  1/336 (0.30%)  2/487 (0.41%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Bladder neck sclerosis  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Haematuria  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Nephrogenic diabetes insipidus  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Nephrolithiasis  1  1/147 (0.68%)  2/336 (0.60%)  1/487 (0.21%)  0/74 (0.00%)  1/196 (0.51%)  0/301 (0.00%) 
Neurogenic bladder  1  1/147 (0.68%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Polyuria  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Renal failure  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Urethral obstruction  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  1/196 (0.51%)  0/301 (0.00%) 
Urinary incontinence  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Urinary retention  1  0/147 (0.00%)  2/336 (0.60%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Reproductive system and breast disorders             
Adenomyosis  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Adnexal torsion  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Benign prostatic hyperplasia  1  0/147 (0.00%)  1/336 (0.30%)  2/487 (0.41%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Breast mass  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Endometriosis  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Prostatitis  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Prostatomegaly  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Respiratory, thoracic and mediastinal disorders             
Asthma  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Bronchopneumopathy  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Dyspnoea  1  0/147 (0.00%)  2/336 (0.60%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Haemothorax  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Nasal obstruction  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Pneumonia aspiration  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Pneumothorax  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Pulmonary embolism  1  1/147 (0.68%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Respiratory arrest  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Sleep apnoea syndrome  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Skin and subcutaneous tissue disorders             
Actinic keratosis  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Alopecia  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Decubitus ulcer  1  1/147 (0.68%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Jessner's lymphocytic infiltration  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Lentigo  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Social circumstances             
Activities of daily living impaired  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Poor personal hygiene  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Vascular disorders             
Aneurysm  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Arterial spasm  1  0/147 (0.00%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Deep vein thrombosis  1  1/147 (0.68%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Femoral artery occlusion  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Hypotension  1  1/147 (0.68%)  0/336 (0.00%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Orthostatic hypotension  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Peripheral venous disease  1  0/147 (0.00%)  4/336 (1.19%)  2/487 (0.41%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Raynaud's phenomenon  1  0/147 (0.00%)  1/336 (0.30%)  0/487 (0.00%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Venous thrombosis  1  0/147 (0.00%)  0/336 (0.00%)  1/487 (0.21%)  0/74 (0.00%)  0/196 (0.00%)  0/301 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Core: FTY720 1.25 mg Core: FTY720 0.5 mg Core: Placebo Extension: FTY1.25-0.5 Extension: FTY0.5-0.5 Extension: Placebo-FTY0.5
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   132/147 (89.80%)   278/336 (82.74%)   406/487 (83.37%)   43/74 (58.11%)   70/196 (35.71%)   138/301 (45.85%) 
Blood and lymphatic system disorders             
Lymphopenia  1  13/147 (8.84%)  19/336 (5.65%)  0/487 (0.00%)  4/74 (5.41%)  7/196 (3.57%)  11/301 (3.65%) 
Gastrointestinal disorders             
Abdominal pain upper  1  3/147 (2.04%)  17/336 (5.06%)  12/487 (2.46%)  0/74 (0.00%)  1/196 (0.51%)  2/301 (0.66%) 
Constipation  1  10/147 (6.80%)  27/336 (8.04%)  35/487 (7.19%)  0/74 (0.00%)  2/196 (1.02%)  6/301 (1.99%) 
Diarrhoea  1  13/147 (8.84%)  15/336 (4.46%)  18/487 (3.70%)  1/74 (1.35%)  3/196 (1.53%)  1/301 (0.33%) 
Nausea  1  14/147 (9.52%)  21/336 (6.25%)  19/487 (3.90%)  2/74 (2.70%)  1/196 (0.51%)  4/301 (1.33%) 
General disorders             
Fatigue  1  16/147 (10.88%)  24/336 (7.14%)  43/487 (8.83%)  0/74 (0.00%)  1/196 (0.51%)  9/301 (2.99%) 
Gait disturbance  1  10/147 (6.80%)  15/336 (4.46%)  24/487 (4.93%)  0/74 (0.00%)  1/196 (0.51%)  0/301 (0.00%) 
Pyrexia  1  8/147 (5.44%)  18/336 (5.36%)  20/487 (4.11%)  3/74 (4.05%)  0/196 (0.00%)  4/301 (1.33%) 
Infections and infestations             
Bronchitis  1  10/147 (6.80%)  16/336 (4.76%)  21/487 (4.31%)  3/74 (4.05%)  2/196 (1.02%)  1/301 (0.33%) 
Cystitis  1  10/147 (6.80%)  9/336 (2.68%)  17/487 (3.49%)  0/74 (0.00%)  0/196 (0.00%)  2/301 (0.66%) 
Gastroenteritis  1  10/147 (6.80%)  12/336 (3.57%)  22/487 (4.52%)  0/74 (0.00%)  3/196 (1.53%)  3/301 (1.00%) 
Influenza  1  14/147 (9.52%)  26/336 (7.74%)  43/487 (8.83%)  3/74 (4.05%)  4/196 (2.04%)  9/301 (2.99%) 
Nasopharyngitis  1  40/147 (27.21%)  78/336 (23.21%)  135/487 (27.72%)  9/74 (12.16%)  10/196 (5.10%)  23/301 (7.64%) 
Upper respiratory tract infection  1  21/147 (14.29%)  37/336 (11.01%)  57/487 (11.70%)  6/74 (8.11%)  6/196 (3.06%)  14/301 (4.65%) 
Urinary tract infection  1  21/147 (14.29%)  47/336 (13.99%)  75/487 (15.40%)  4/74 (5.41%)  11/196 (5.61%)  25/301 (8.31%) 
Injury, poisoning and procedural complications             
Fall  1  31/147 (21.09%)  47/336 (13.99%)  91/487 (18.69%)  6/74 (8.11%)  5/196 (2.55%)  13/301 (4.32%) 
Investigations             
Alanine aminotransferase increased  1  17/147 (11.56%)  39/336 (11.61%)  7/487 (1.44%)  0/74 (0.00%)  1/196 (0.51%)  6/301 (1.99%) 
Blood cholesterol increased  1  8/147 (5.44%)  15/336 (4.46%)  16/487 (3.29%)  0/74 (0.00%)  1/196 (0.51%)  3/301 (1.00%) 
Gamma-glutamyltransferase increased  1  19/147 (12.93%)  31/336 (9.23%)  3/487 (0.62%)  0/74 (0.00%)  3/196 (1.53%)  5/301 (1.66%) 
Metabolism and nutrition disorders             
Hypercholesterolaemia  1  10/147 (6.80%)  13/336 (3.87%)  19/487 (3.90%)  4/74 (5.41%)  4/196 (2.04%)  5/301 (1.66%) 
Musculoskeletal and connective tissue disorders             
Arthralgia  1  13/147 (8.84%)  30/336 (8.93%)  48/487 (9.86%)  3/74 (4.05%)  3/196 (1.53%)  8/301 (2.66%) 
Back pain  1  16/147 (10.88%)  36/336 (10.71%)  75/487 (15.40%)  5/74 (6.76%)  5/196 (2.55%)  10/301 (3.32%) 
Pain in extremity  1  9/147 (6.12%)  21/336 (6.25%)  35/487 (7.19%)  3/74 (4.05%)  3/196 (1.53%)  3/301 (1.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
Melanocytic naevus  1  21/147 (14.29%)  16/336 (4.76%)  31/487 (6.37%)  4/74 (5.41%)  3/196 (1.53%)  9/301 (2.99%) 
Seborrhoeic keratosis  1  10/147 (6.80%)  12/336 (3.57%)  14/487 (2.87%)  1/74 (1.35%)  3/196 (1.53%)  4/301 (1.33%) 
Nervous system disorders             
Dizziness  1  10/147 (6.80%)  19/336 (5.65%)  29/487 (5.95%)  2/74 (2.70%)  0/196 (0.00%)  2/301 (0.66%) 
Headache  1  28/147 (19.05%)  56/336 (16.67%)  77/487 (15.81%)  3/74 (4.05%)  3/196 (1.53%)  13/301 (4.32%) 
Psychiatric disorders             
Depression  1  11/147 (7.48%)  15/336 (4.46%)  37/487 (7.60%)  2/74 (2.70%)  2/196 (1.02%)  4/301 (1.33%) 
Insomnia  1  8/147 (5.44%)  12/336 (3.57%)  29/487 (5.95%)  1/74 (1.35%)  4/196 (2.04%)  7/301 (2.33%) 
Respiratory, thoracic and mediastinal disorders             
Cough  1  8/147 (5.44%)  28/336 (8.33%)  34/487 (6.98%)  2/74 (2.70%)  1/196 (0.51%)  4/301 (1.33%) 
Dyspnoea  1  8/147 (5.44%)  14/336 (4.17%)  16/487 (3.29%)  0/74 (0.00%)  0/196 (0.00%)  1/301 (0.33%) 
Skin and subcutaneous tissue disorders             
Eczema  1  8/147 (5.44%)  15/336 (4.46%)  19/487 (3.90%)  2/74 (2.70%)  1/196 (0.51%)  6/301 (1.99%) 
Vascular disorders             
Hypertension  1  23/147 (15.65%)  43/336 (12.80%)  28/487 (5.75%)  2/74 (2.70%)  5/196 (2.55%)  18/301 (5.98%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety
Results Point of Contact
Name/Title: Study Director
Organization: Novartis Pharmaceuticals
Phone: 862-778-8300
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00731692     History of Changes
Obsolete Identifiers: NCT01779934
Other Study ID Numbers: CFTY720D2306
2007-002627-32 ( EudraCT Number )
First Submitted: August 7, 2008
First Posted: August 11, 2008
Results First Submitted: December 16, 2015
Results First Posted: June 14, 2017
Last Update Posted: June 14, 2017