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Efficacy and Safety Study of Peginterferon Beta-1a in Participants With Relapsing Multiple Sclerosis (ADVANCE)

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ClinicalTrials.gov Identifier: NCT00906399
Recruitment Status : Completed
First Posted : May 21, 2009
Results First Posted : September 19, 2014
Last Update Posted : September 19, 2014
Sponsor:
Information provided by (Responsible Party):
Biogen

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Relapsing Multiple Sclerosis
Interventions Drug: BIIB017 (peginterferon beta-1a)
Drug: Placebo
Enrollment 1516
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Year 1: Placebo Year 1: Peginterferon Beta-1a Q4W Year 1: Peginterferon Beta-1a Q2W Year 2: Placebo Followed by Peginterferon Beta-1a Q4W Year 2: Placebo Followed by Peginterferon Beta-1a Q2W Year 2: Peginterferon Beta-1a Q4W Year 2: Peginterferon Beta-1a Q2W
Hide Arm/Group Description Placebo every 2 weeks for 48 weeks 125 µg peginterferon beta-1a subcutaneously every 4 weeks (Q4W) for 48 weeks. Participants received a placebo injection 2 weeks after each active injection (in order to maintain the blind with Q2W arm). 125 µg peginterferon beta-1a subcutaneously every 2 weeks (Q2W) for 48 weeks. Placebo every 2 weeks for 48 weeks followed by 125 µg peginterferon beta-1a subcutaneously every 4 weeks for 48 weeks. Participants received a placebo injection 2 weeks after each active injection (in order to maintain the blind with Q2W arm). Placebo every 2 weeks for 48 weeks followed by 125 µg peginterferon beta-1a subcutaneously every 2 weeks for 48 weeks. 125 µg peginterferon beta-1a subcutaneously every 4 weeks (Q4W) for 48 weeks. Participants received a placebo injection 2 weeks after each active injection (in order to maintain the blind with Q2W arm). 125 µg peginterferon beta-1a subcutaneously every 2 weeks (Q2W) for 48 weeks.
Period Title: Year 1
Started 500 501 515 0 0 0 0
Completed Year 1 Study Treatment 456 438 438 0 0 0 0
Completed 456 438 439 [1] 0 0 0 0
Not Completed 44 63 76 0 0 0 0
Reason Not Completed
Randomized But Not Treated             0             1             3             0             0             0             0
Adverse Event             4             22             24             0             0             0             0
Lost to Follow-up             4             4             2             0             0             0             0
Withdrawal by Subject             30             32             36             0             0             0             0
Physician Decision             0             1             3             0             0             0             0
Death             2             1             1             0             0             0             0
Not specified             4             2             7             0             0             0             0
[1]
1 participant discontinued treatment before end of study period but remained to complete follow-up.
Period Title: Year 2
Started 0 0 0 228 228 438 438
Completed Year 2 Study Treatment 0 0 0 200 196 391 411
Completed 0 0 0 198 193 391 409
Not Completed 0 0 0 30 35 47 29
Reason Not Completed
Adverse Event             0             0             0             9             8             11             6
Lost to Follow-up             0             0             0             1             4             2             4
Withdrawal by Subject             0             0             0             17             18             27             13
Physician Decision             0             0             0             0             2             6             3
Death             0             0             0             1             0             0             3
Not specified             0             0             0             2             3             1             0
Arm/Group Title Placebo Peginterferon Beta-1a Q4W Peginterferon Beta-1a Q2W Total
Hide Arm/Group Description Placebo every 2 weeks for 48 weeks 125 µg peginterferon beta-1a subcutaneously every 4 weeks (Q4W) for 48 weeks. Participants received a placebo injection 2 weeks after each active injection (in order to maintain the blind with Q2W arm). 125 µg peginterferon beta-1a subcutaneously every 2 weeks (Q2W) for 48 weeks Total of all reporting groups
Overall Number of Baseline Participants 500 500 512 1512
Hide Baseline Analysis Population Description
Intent-to-treat population: participants who were randomized and received at least 1 dose of study treatment (peginterferon beta-1a or placebo).
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 500 participants 500 participants 512 participants 1512 participants
36.3  (9.74) 36.4  (9.87) 36.9  (9.79) 36.5  (9.80)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 500 participants 500 participants 512 participants 1512 participants
Female
358
  71.6%
352
  70.4%
361
  70.5%
1071
  70.8%
Male
142
  28.4%
148
  29.6%
151
  29.5%
441
  29.2%
Expanded Disability Status Scale (EDSS)   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 500 participants 500 participants 512 participants 1512 participants
2.44  (1.180) 2.48  (1.244) 2.47  (1.255) 2.46  (1.226)
[1]
Measure Description: The EDSS measures the disability status of people with multiple sclerosis (MS) on a scale that ranges from 0 to 10. The range of main categories include 0 (normal neurologic exam), to 5 (ambulatory without aid or rest for 200 meters/disability severe enough to impair full daily activities), to 10 (death due to MS).
1.Primary Outcome
Title Annualized Relapse Rate (ARR) at 1 Year
Hide Description A relapse is defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting for at least 24 hours, and accompanied by new objective neurologic findings. Only relapses confirmed by an independent neurology evaluation committee (INEC) are included in the analysis. Data after participants switched to alternative multiple sclerosis (MS) medications are excluded. Data were analyzed using negative binomial regression, adjusted for baseline Expanded Disability Status Scale (EDSS) score (< 4 versus ≥ 4), baseline age (< 40 versus ≥ 40 years), and baseline relapse rate (number of relapses in 3 years prior to study entry divided by 3).
Time Frame 1 Year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat (ITT) population: participants who were randomized and received at least 1 dose of study treatment (peginterferon beta-1a or placebo).
Arm/Group Title Year 1: Placebo Year 1: Peginterferon Beta-1a Q4W Year 1: Peginterferon Beta-1a Q2W
Hide Arm/Group Description:
Placebo every 2 weeks for 48 weeks
125 µg peginterferon beta-1a subcutaneously every 4 weeks (Q4W) for 48 weeks. Participants received a placebo injection 2 weeks after each active injection (in order to maintain the blind with Q2W arm).
125 µg peginterferon beta-1a subcutaneously every 2 weeks (Q2W) for 48 weeks.
Overall Number of Participants Analyzed 500 500 512
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: relapses per person-years
0.397
(0.328 to 0.481)
0.288
(0.234 to 0.355)
0.256
(0.206 to 0.318)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Year 1: Placebo, Year 1: Peginterferon Beta-1a Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0114
Comments [Not Specified]
Method Negative Binomial Regression
Comments Based on negative binomial regression, with adjustment for baseline EDSS (< 4 versus ≥ 4), baseline relapse rate, age (< 40 versus ≥ 40 years).
Method of Estimation Estimation Parameter Rate Ratio
Estimated Value 0.725
Confidence Interval (2-Sided) 95%
0.565 to 0.930
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Year 1: Placebo, Year 1: Peginterferon Beta-1a Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0007
Comments [Not Specified]
Method Negative Binomial Regression
Comments Based on negative binomial regression, with adjustment for baseline EDSS (< 4 versus ≥ 4), baseline relapse rate, age (< 40 versus ≥ 40).
Method of Estimation Estimation Parameter Rate Ratio
Estimated Value 0.644
Confidence Interval (2-Sided) 95%
0.500 to 0.831
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Number of New Or Newly Enlarging T2 Hyperintense Lesions at 1 Year
Hide Description Number of new or newly enlarging T2 hyperintense lesions on brain magnetic resonance imaging (MRI) scans. Data observed after participants switched to alternative MS medications are excluded. Adjusted mean is based on negative binomial regression, adjusted for baseline number of T2 lesions.
Time Frame 1 Year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT population, with at least 1 post-baseline assessment. Missing data prior to alternative MS medications and visits after participants switched to alternative MS medications imputed based on previous visit data assuming the constant rate of lesion development or group mean at same visit.
Arm/Group Title Year 1: Placebo Year 1: Peginterferon Beta-1a Q4W Year 1: Peginterferon Beta-1a Q2W
Hide Arm/Group Description:
Placebo every 2 weeks for 48 weeks
125 µg peginterferon beta-1a subcutaneously every 4 weeks (Q4W) for 48 weeks. Participants received a placebo injection 2 weeks after each active injection (in order to maintain the blind with Q2W arm).
125 µg peginterferon beta-1a subcutaneously every 2 weeks (Q2W) for 48 weeks.
Overall Number of Participants Analyzed 476 462 457
Mean (95% Confidence Interval)
Unit of Measure: lesions
10.9
(9.6 to 12.5)
7.9
(6.9 to 9.0)
3.6
(3.1 to 4.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Year 1: Placebo, Year 1: Peginterferon Beta-1a Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0008
Comments [Not Specified]
Method Negative Binomial Regression
Comments Lesion mean ratio (95% CI) and p-value based on negative binomial regression, adjusted for baseline number of T2 lesions.
Method of Estimation Estimation Parameter Lesion Mean Ratio
Estimated Value 0.72
Confidence Interval (2-Sided) 95%
0.60 to 0.87
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Year 1: Placebo, Year 1: Peginterferon Beta-1a Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Negative Binomial Regression
Comments Lesion mean ratio (95% CI) and p-value based on negative binomial regression, adjusted for baseline number of T2 lesions.
Method of Estimation Estimation Parameter Lesion Mean Ratio
Estimated Value 0.33
Confidence Interval (2-Sided) 95%
0.27 to 0.40
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Proportion of Participants Relapsed at 1 Year
Hide Description A relapse is defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting for at least 24 hours, and accompanied by new objective neurologic findings. Only relapses confirmed by INEC were included in the analysis. Estimated proportion of participants relapsed is based on the Kaplan-Meier product limit method.
Time Frame Year 1
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT population: participants who were randomized and received at least 1 dose of study treatment (peginterferon beta-1a or placebo). Participants who did not experience a relapse prior to switching to alternative MS medications or withdrew from study were censored at the time of switch/withdrawal.
Arm/Group Title Year 1: Placebo Year 1: Peginterferon Beta-1a Q4W Year 1: Peginterferon Beta-1a Q2W
Hide Arm/Group Description:
Placebo every 2 weeks for 48 weeks
125 µg peginterferon beta-1a subcutaneously every 4 weeks (Q4W) for 48 weeks. Participants received a placebo injection 2 weeks after each active injection (in order to maintain the blind with Q2W arm).
125 µg peginterferon beta-1a subcutaneously every 2 weeks (Q2W) for 48 weeks.
Overall Number of Participants Analyzed 500 500 512
Measure Type: Number
Unit of Measure: proportion of participants
0.291 0.222 0.187
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Year 1: Placebo, Year 1: Peginterferon Beta-1a Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0200
Comments Based on Cox proportion hazards model, adjusted for baseline EDSS (< 4 versus ≥ 4), age (<40 versus ≥ 40 years), baseline relapse rate, and baseline Gd enhancing lesions (presence versus absence).
Method Cox Proportion Hazards model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.74
Confidence Interval (2-Sided) 95%
0.57 to 0.95
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Year 1: Placebo, Year 1: Peginterferon Beta-1a Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments Based on Cox proportion hazards model, adjusted for baseline EDSS (< 4 versus ≥ 4), age (<40 versus ≥ 40 years), baseline relapse rate, and baseline Gd enhancing lesions (presence versus absence).
Method Cox Proportion Hazards model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.61
Confidence Interval (2-Sided) 95%
0.47 to 0.80
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Estimated Proportion of Participants With Sustained Disability Progression at 1 Year
Hide Description Sustained disability progression is defined as: at least a 1.0 point increase on the EDSS from baseline EDSS ≥ 1.0 that is sustained for 12 weeks, or at least a 1.5 point increase on the EDSS from baseline EDSS = 0 that is sustained for 12 weeks. The EDSS measures the disability status of people with MS on a scale that ranges from 0 to 10. The range of main categories include 0 (normal neurologic examination), to 5 (ambulatory without aid or rest for 200 meters/disability severe enough to impair full daily activities), to 10 (death due to MS). Estimated proportion of participants with progression based on the Kaplan-Meier product limit method.
Time Frame 1 Year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT population: participants who were randomized and received at least 1 dose of study treatment (peginterferon beta-1a or placebo). Participants were censored at the time of withdrawal/switch if they withdrew from study or switched to alternative MS medication without a progression.
Arm/Group Title Year 1: Placebo Year 1: Peginterferon Beta-1a Q4W Year 1: Peginterferon Beta-1a Q2W
Hide Arm/Group Description:
Placebo every 2 weeks for 48 weeks
125 µg peginterferon beta-1a subcutaneously every 4 weeks (Q4W) for 48 weeks. Participants received a placebo injection 2 weeks after each active injection (in order to maintain the blind with Q2W arm).
125 µg peginterferon beta-1a subcutaneously every 2 weeks (Q2W) for 48 weeks.
Overall Number of Participants Analyzed 500 500 512
Measure Type: Number
Unit of Measure: proportion of participants
0.105 0.068 0.068
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Year 1: Placebo, Year 1: Peginterferon Beta-1a Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0380
Comments Based on Cox Proportional Hazards model, adjusted for baseline EDSS (< 4 versus ≥ 4) and age (< 40 versus ≥ 40 years).
Method Cox Proportion Hazards model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.62
Confidence Interval (2-Sided) 95%
0.40 to 0.97
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Year 1: Placebo, Year 1: Peginterferon Beta-1a Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0383
Comments Based on Cox Proportional Hazards model, adjusted for baseline EDSS (< 4 versus ≥ 4) and age (< 40 versus ≥ 40 years).
Method Cox Proportion Hazards model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.62
Confidence Interval (2-Sided) 95%
0.40 to 0.97
Estimation Comments [Not Specified]
Time Frame Screening through Week 96 (treatment period), plus 4 weeks (±5 days) follow-up
Adverse Event Reporting Description One participant, randomized to placebo->Q4W, received one wrong dosing kit during Year 1, and was mistakenly distributed with one Q2W kit, therefore receiving study drug in Weeks 20 and 22 instead of placebo. For Year 1 safety tables, this participant was grouped with Q2W, and for Year 2 safety tables, this participant was grouped with Q4W.
 
Arm/Group Title Year 1: Placebo Year 1: Peginterferon Beta-1a Q4W Year 1: Peginterferon Beta-1a Q2W Year 2: Placebo Followed by Peginterferon Beta-1a Q4W Year 2: Placebo Followed by Peginterferon Beta-1a Q2W Year 2: Peginterferon Beta-1a Q4W Year 2: Peginterferon Beta-1a Q2W
Hide Arm/Group Description Placebo every 2 weeks for 48 weeks 125 µg peginterferon beta-1a subcutaneously every 4 weeks (Q4W) for 48 weeks. Participants received a placebo injection 2 weeks after each active injection (in order to maintain the blind with Q2W arm). 125 µg peginterferon beta-1a subcutaneously every 2 weeks (Q2W) for 48 weeks. Placebo every 2 weeks for 48 weeks followed by 125 µg peginterferon beta-1a subcutaneously every 4 weeks for 48 weeks. Participants received a placebo injection 2 weeks after each active injection (in order to maintain the blind with Q2W arm). Placebo every 2 weeks for 48 weeks followed by 125 µg peginterferon beta-1a subcutaneously every 2 weeks for 48 weeks. 125 µg peginterferon beta-1a subcutaneously every 4 weeks (Q4W) for 48 weeks. Participants received a placebo injection 2 weeks after each active injection (in order to maintain the blind with Q2W arm). 125 µg peginterferon beta-1a subcutaneously every 2 weeks (Q2W) for 48 weeks.
All-Cause Mortality
Year 1: Placebo Year 1: Peginterferon Beta-1a Q4W Year 1: Peginterferon Beta-1a Q2W Year 2: Placebo Followed by Peginterferon Beta-1a Q4W Year 2: Placebo Followed by Peginterferon Beta-1a Q2W Year 2: Peginterferon Beta-1a Q4W Year 2: Peginterferon Beta-1a Q2W
Affected / at Risk (%) 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
Year 1: Placebo Year 1: Peginterferon Beta-1a Q4W Year 1: Peginterferon Beta-1a Q2W Year 2: Placebo Followed by Peginterferon Beta-1a Q4W Year 2: Placebo Followed by Peginterferon Beta-1a Q2W Year 2: Peginterferon Beta-1a Q4W Year 2: Peginterferon Beta-1a Q2W
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   76/499 (15.23%)   70/500 (14.00%)   55/513 (10.72%)   42/227 (18.50%)   36/228 (15.79%)   67/439 (15.26%)   39/438 (8.90%) 
Blood and lymphatic system disorders               
Febrile Neutropenia  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Leukopenia  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Thrombocytopenia  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  1/227 (0.44%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Cardiac disorders               
Cardiac Failure Congestive  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Cardiopulmonary Failure  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  1/438 (0.23%) 
Myocardial Infarction  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Congenital, familial and genetic disorders               
Congenital Cystic Kidney Disease  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  1/438 (0.23%) 
Endocrine disorders               
Basedow's Disease  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Eye disorders               
Retinal Detachment  1  1/499 (0.20%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  1/228 (0.44%)  0/439 (0.00%)  0/438 (0.00%) 
Gastrointestinal disorders               
Inguinal Hernia  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Intestinal Obstruction  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Abdominal Distension  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  1/438 (0.23%) 
Constipation  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  1/438 (0.23%) 
Haemorrhoids  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  1/228 (0.44%)  0/439 (0.00%)  0/438 (0.00%) 
Intestinal Strangulation  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Proctalgia  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  1/438 (0.23%) 
General disorders               
Death  1  1/499 (0.20%)  0/500 (0.00%)  1/513 (0.19%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  1/438 (0.23%) 
Injection Site Reaction  1  0/499 (0.00%)  0/500 (0.00%)  1/513 (0.19%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Irritability  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Chest Pain  1  1/499 (0.20%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Gait Disturbance  1  1/499 (0.20%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Hyperpyrexia  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  1/228 (0.44%)  0/439 (0.00%)  0/438 (0.00%) 
Hepatobiliary disorders               
Acute Hepatic Failure  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Bile Duct Stone  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Cholecystitis Acute  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  1/227 (0.44%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Cholelithiasis  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  1/228 (0.44%)  0/439 (0.00%)  0/438 (0.00%) 
Drug-Induced Liver Injury  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  1/228 (0.44%)  0/439 (0.00%)  0/438 (0.00%) 
Hepatic Function Abnormal  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Hepatitis Toxic  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  1/438 (0.23%) 
Immune system disorders               
Anaphylactic Reaction  1  0/499 (0.00%)  0/500 (0.00%)  1/513 (0.19%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Hypersensitivity  1  0/499 (0.00%)  0/500 (0.00%)  1/513 (0.19%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Sarcoidosis  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Infections and infestations               
Dengue Fever  1  0/499 (0.00%)  1/500 (0.20%)  1/513 (0.19%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Pneumonia  1  1/499 (0.20%)  2/500 (0.40%)  0/513 (0.00%)  1/227 (0.44%)  0/228 (0.00%)  0/439 (0.00%)  1/438 (0.23%) 
Urinary Tract Infection  1  1/499 (0.20%)  2/500 (0.40%)  0/513 (0.00%)  3/227 (1.32%)  1/228 (0.44%)  1/439 (0.23%)  1/438 (0.23%) 
Erysipelas  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Sepsis  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  1/227 (0.44%)  1/228 (0.44%)  0/439 (0.00%)  1/438 (0.23%) 
Septic Shock  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Upper Respiratory Tract Infection  1  0/499 (0.00%)  0/500 (0.00%)  1/513 (0.19%)  0/227 (0.00%)  1/228 (0.44%)  0/439 (0.00%)  0/438 (0.00%) 
Urosepsis  1  0/499 (0.00%)  0/500 (0.00%)  1/513 (0.19%)  0/227 (0.00%)  1/228 (0.44%)  0/439 (0.00%)  0/438 (0.00%) 
Acute Sinusitis  1  1/499 (0.20%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Appendicitis  1  1/499 (0.20%)  0/500 (0.00%)  0/513 (0.00%)  1/227 (0.44%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Cervicitis  1  1/499 (0.20%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Gastroenteritis Viral  1  1/499 (0.20%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Subcutaneous Abscess  1  1/499 (0.20%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Tonsillitis  1  1/499 (0.20%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Cystitis  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  1/438 (0.23%) 
Infected Skin Ulcer  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  1/227 (0.44%)  1/228 (0.44%)  0/439 (0.00%)  0/438 (0.00%) 
Lower Respiratory Tract Infection  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  1/228 (0.44%)  0/439 (0.00%)  1/438 (0.23%) 
Bacterial Diarrhoea  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  1/228 (0.44%)  0/439 (0.00%)  0/438 (0.00%) 
Cellulitis  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Cellulitis Gangrenous  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  1/438 (0.23%) 
Chronic Sinusitis  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Endometritis  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Myometritis  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  1/438 (0.23%) 
Pelvic Inflammatory Disease  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Pyelonephritis Chronic  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  1/228 (0.44%)  0/439 (0.00%)  0/438 (0.00%) 
Salpingo-Oophoritis  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  1/227 (0.44%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Typhoid Fever  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  1/438 (0.23%) 
Viral Pharyngitis  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  1/438 (0.23%) 
Viral Tracheitis  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  1/438 (0.23%) 
Injury, poisoning and procedural complications               
Ankle Fracture  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  1/438 (0.23%) 
Facial Bones Fracture  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Road Traffic Accident  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Avulsion Fracture  1  1/499 (0.20%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Fall  1  1/499 (0.20%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  2/439 (0.46%)  1/438 (0.23%) 
Meniscus Lesion  1  1/499 (0.20%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  1/438 (0.23%) 
Multiple Injuries  1  1/499 (0.20%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Tibia Fracture  1  1/499 (0.20%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Concussion  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Craniocerebral Injury  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  1/438 (0.23%) 
Radius Fracture  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Subdural Haematoma  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  1/227 (0.44%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Investigations               
Transaminases Increased  1  0/499 (0.00%)  0/500 (0.00%)  1/513 (0.19%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Alanine Aminotransferase Increased  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  1/438 (0.23%) 
Haemoglobin Decreased  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  1/228 (0.44%)  0/439 (0.00%)  0/438 (0.00%) 
Metabolism and nutrition disorders               
Malnutrition  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Musculoskeletal and connective tissue disorders               
Intervertebral Disc Disorder  1  0/499 (0.00%)  1/500 (0.20%)  1/513 (0.19%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Muscular Weakness  1  1/499 (0.20%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Patellofemoral Pain Syndrome  1  0/499 (0.00%)  0/500 (0.00%)  1/513 (0.19%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Haemarthrosis  1  1/499 (0.20%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Osteoporosis  1  1/499 (0.20%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Intervertebral Disc Protrusion  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  1/228 (0.44%)  1/439 (0.23%)  0/438 (0.00%) 
Osteonecrosis  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  1/227 (0.44%)  0/228 (0.00%)  0/439 (0.00%)  1/438 (0.23%) 
Back Pain  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  1/227 (0.44%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Bursitis  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  1/227 (0.44%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Enthesopathy  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  1/227 (0.44%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Sacroilitis  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  1/227 (0.44%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)               
Benign Vulval Neoplasm  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Breast Cancer  1  0/499 (0.00%)  0/500 (0.00%)  1/513 (0.19%)  0/227 (0.00%)  1/228 (0.44%)  0/439 (0.00%)  0/438 (0.00%) 
Cervix Carcinoma  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Uterine Leiomyoma  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Lip And/Or Oral Cavity Cancer  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  1/227 (0.44%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Nervous system disorders               
Multiple Sclerosis Relapse  1  57/499 (11.42%)  47/500 (9.40%)  34/513 (6.63%)  27/227 (11.89%)  21/228 (9.21%)  45/439 (10.25%)  25/438 (5.71%) 
Multiple Sclerosis  1  0/499 (0.00%)  1/500 (0.20%)  1/513 (0.19%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Carpal Tunnel Syndrome  1  0/499 (0.00%)  0/500 (0.00%)  1/513 (0.19%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Cerebral Ischaemia  1  0/499 (0.00%)  0/500 (0.00%)  1/513 (0.19%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Cerebrovascular Insufficiency  1  0/499 (0.00%)  0/500 (0.00%)  1/513 (0.19%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Monoparesis  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Neuritis Cranial  1  0/499 (0.00%)  0/500 (0.00%)  1/513 (0.19%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Neuromyelitis Optica  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Paraesthesia  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Partial Seizures  1  0/499 (0.00%)  0/500 (0.00%)  1/513 (0.19%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Partial Seizures With Secondary Generalization  1  0/499 (0.00%)  0/500 (0.00%)  1/513 (0.19%)  1/227 (0.44%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Sciatica  1  0/499 (0.00%)  0/500 (0.00%)  1/513 (0.19%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Uhthoff's Phenomenon  1  0/499 (0.00%)  0/500 (0.00%)  1/513 (0.19%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Ataxia  1  1/499 (0.20%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Neuralgia  1  1/499 (0.20%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Subarachnoid Haemorrhage  1  1/499 (0.20%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Bulbar Palsy  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  1/227 (0.44%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Complex Partial Seizures  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  1/228 (0.44%)  0/439 (0.00%)  0/438 (0.00%) 
Extrapyramidal Disorder  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  1/227 (0.44%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Grand Mal Convulsion  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  1/227 (0.44%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Paraparesis  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  1/438 (0.23%) 
Syncope  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Trigeminal Neuralgia  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  1/227 (0.44%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Pregnancy, puerperium and perinatal conditions               
Abortion Incomplete  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Abortion Spontaneous  1  0/499 (0.00%)  0/500 (0.00%)  1/513 (0.19%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Ectopic Pregnancy  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Psychiatric disorders               
Depression  1  0/499 (0.00%)  0/500 (0.00%)  1/513 (0.19%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  1/438 (0.23%) 
Personality Disorder  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Suicidal Ideation  1  1/499 (0.20%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Conversion Disorder  1  1/499 (0.20%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Schizophrenia  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Renal and urinary disorders               
Hydronephrosis  1  0/499 (0.00%)  0/500 (0.00%)  1/513 (0.19%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Micturition Disorder  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Urinary Incontinence  1  0/499 (0.00%)  0/500 (0.00%)  1/513 (0.19%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Reproductive system and breast disorders               
Endometrial Hyperplasia  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Cervical Dysplasia  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Ectropion Of Cervix  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Endometriosis  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  1/438 (0.23%) 
Epididymal Cyst  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  1/227 (0.44%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Pelvic Adhesions  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Uterine Cervical Erosion  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  1/228 (0.44%)  0/439 (0.00%)  0/438 (0.00%) 
Respiratory, thoracic and mediastinal disorders               
Asthma  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Organising Pneumonia  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Pulmonary Embolism  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Skin and subcutaneous tissue disorders               
Decubitus Ulcer  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Dermatitis  1  0/499 (0.00%)  0/500 (0.00%)  1/513 (0.19%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Angioedema  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  1/228 (0.44%)  0/439 (0.00%)  1/438 (0.23%) 
Urticaria  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  1/228 (0.44%)  0/439 (0.00%)  0/438 (0.00%) 
Vascular disorders               
Deep Vein Thrombosis  1  0/499 (0.00%)  1/500 (0.20%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  1/439 (0.23%)  0/438 (0.00%) 
Venous Thrombosis Limb  1  1/499 (0.20%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Hypertensive Crisis  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  1/227 (0.44%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Shock  1  0/499 (0.00%)  0/500 (0.00%)  0/513 (0.00%)  0/227 (0.00%)  1/228 (0.44%)  0/439 (0.00%)  0/438 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (15.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Year 1: Placebo Year 1: Peginterferon Beta-1a Q4W Year 1: Peginterferon Beta-1a Q2W Year 2: Placebo Followed by Peginterferon Beta-1a Q4W Year 2: Placebo Followed by Peginterferon Beta-1a Q2W Year 2: Peginterferon Beta-1a Q4W Year 2: Peginterferon Beta-1a Q2W
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   378/499 (75.75%)   466/500 (93.20%)   472/513 (92.01%)   190/227 (83.70%)   206/228 (90.35%)   373/439 (84.97%)   367/438 (83.79%) 
Ear and labyrinth disorders               
Vertigo  1  43/499 (8.62%)  32/500 (6.40%)  27/513 (5.26%)  9/227 (3.96%)  11/228 (4.82%)  17/439 (3.87%)  14/438 (3.20%) 
Gastrointestinal disorders               
Nausea  1  31/499 (6.21%)  43/500 (8.60%)  45/513 (8.77%)  9/227 (3.96%)  14/228 (6.14%)  16/439 (3.64%)  27/438 (6.16%) 
Vomiting  1  11/499 (2.20%)  37/500 (7.40%)  26/513 (5.07%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Diarrhoea  1  23/499 (4.61%)  22/500 (4.40%)  18/513 (3.51%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
General disorders               
Injection Site Erythema  1  33/499 (6.61%)  282/500 (56.40%)  315/513 (61.40%)  119/227 (52.42%)  135/228 (59.21%)  211/439 (48.06%)  212/438 (48.40%) 
Influenza Like Illness  1  63/499 (12.63%)  234/500 (46.80%)  238/513 (46.39%)  95/227 (41.85%)  106/228 (46.49%)  199/439 (45.33%)  192/438 (43.84%) 
Pyrexia  1  75/499 (15.03%)  218/500 (43.60%)  227/513 (44.25%)  66/227 (29.07%)  66/228 (28.95%)  138/439 (31.44%)  136/438 (31.05%) 
Chills  1  23/499 (4.61%)  92/500 (18.40%)  88/513 (17.15%)  28/227 (12.33%)  29/228 (12.72%)  52/439 (11.85%)  41/438 (9.36%) 
Injection Site Pain  1  15/499 (3.01%)  67/500 (13.40%)  78/513 (15.20%)  25/227 (11.01%)  25/228 (10.96%)  32/439 (7.29%)  45/438 (10.27%) 
Asthenia  1  38/499 (7.62%)  70/500 (14.00%)  68/513 (13.26%)  24/227 (10.57%)  10/228 (4.39%)  39/439 (8.88%)  40/438 (9.13%) 
Injection Site Pruritus  1  6/499 (1.20%)  56/500 (11.20%)  70/513 (13.65%)  17/227 (7.49%)  26/228 (11.40%)  24/439 (5.47%)  47/438 (10.73%) 
Fatigue  1  49/499 (9.82%)  55/500 (11.00%)  52/513 (10.14%)  10/227 (4.41%)  21/228 (9.21%)  26/439 (5.92%)  32/438 (7.31%) 
Pain  1  16/499 (3.21%)  29/500 (5.80%)  25/513 (4.87%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Hyperthermia  1  5/499 (1.00%)  26/500 (5.20%)  22/513 (4.29%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Infections and infestations               
Nasopharyngitis  1  77/499 (15.43%)  69/500 (13.80%)  54/513 (10.53%)  22/227 (9.69%)  17/228 (7.46%)  45/439 (10.25%)  47/438 (10.73%) 
Urinary Tract Infection  1  20/499 (4.01%)  28/500 (5.60%)  28/513 (5.46%)  10/227 (4.41%)  11/228 (4.82%)  31/439 (7.06%)  29/438 (6.62%) 
Upper Respiratory Tract Infection  1  27/499 (5.41%)  16/500 (3.20%)  28/513 (5.46%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Investigations               
Body Temperature Increased  1  14/499 (2.81%)  33/500 (6.60%)  31/513 (6.04%)  5/227 (2.20%)  10/228 (4.39%)  19/439 (4.33%)  24/438 (5.48%) 
Alanine Aminotransferase Increased  1  13/499 (2.61%)  19/500 (3.80%)  29/513 (5.65%)  13/227 (5.73%)  14/228 (6.14%)  17/439 (3.87%)  13/438 (2.97%) 
Musculoskeletal and connective tissue disorders               
Myalgia  1  30/499 (6.01%)  97/500 (19.40%)  99/513 (19.30%)  27/227 (11.89%)  27/228 (11.84%)  60/439 (13.67%)  58/438 (13.24%) 
Back Pain  1  57/499 (11.42%)  64/500 (12.80%)  62/513 (12.09%)  11/227 (4.85%)  19/228 (8.33%)  31/439 (7.06%)  32/438 (7.31%) 
Arthralgia  1  35/499 (7.01%)  54/500 (10.80%)  58/513 (11.31%)  23/227 (10.13%)  14/228 (6.14%)  33/439 (7.52%)  33/438 (7.53%) 
Pain In Extremity  1  48/499 (9.62%)  53/500 (10.60%)  44/513 (8.58%)  10/227 (4.41%)  14/228 (6.14%)  23/439 (5.24%)  31/438 (7.08%) 
Muscular Weakness  1  18/499 (3.61%)  23/500 (4.60%)  22/513 (4.29%)  12/227 (5.29%)  12/228 (5.26%)  18/439 (4.10%)  13/438 (2.97%) 
Nervous system disorders               
Headache  1  165/499 (33.07%)  206/500 (41.20%)  225/513 (43.86%)  70/227 (30.84%)  64/228 (28.07%)  122/439 (27.79%)  126/438 (28.77%) 
Multiple Sclerosis Relapse  1  154/499 (30.86%)  111/500 (22.20%)  90/513 (17.54%)  50/227 (22.03%)  52/228 (22.81%)  95/439 (21.64%)  63/438 (14.38%) 
Dizziness  1  30/499 (6.01%)  22/500 (4.40%)  35/513 (6.82%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Paraesthesia  1  23/499 (4.61%)  22/500 (4.40%)  26/513 (5.07%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Hypoaesthesia  1  30/499 (6.01%)  29/500 (5.80%)  17/513 (3.31%)  13/227 (5.73%)  11/228 (4.82%)  10/439 (2.28%)  11/438 (2.51%) 
Psychiatric disorders               
Depression  1  21/499 (4.21%)  25/500 (5.00%)  22/513 (4.29%)  6/227 (2.64%)  13/228 (5.70%)  18/439 (4.10%)  17/438 (3.88%) 
Insomnia  1  19/499 (3.81%)  18/500 (3.60%)  28/513 (5.46%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Respiratory, thoracic and mediastinal disorders               
Oropharyngeal Pain  1  31/499 (6.21%)  26/500 (5.20%)  34/513 (6.63%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Cough  1  28/499 (5.61%)  26/500 (5.20%)  21/513 (4.09%)  0/227 (0.00%)  0/228 (0.00%)  0/439 (0.00%)  0/438 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (15.0)
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.
Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.
Results Point of Contact
Name/Title: Biogen Idec Study Medical Director
Organization: Biogen Idec
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Biogen
ClinicalTrials.gov Identifier: NCT00906399     History of Changes
Other Study ID Numbers: 105MS301
2008-006333-27 ( EudraCT Number )
First Submitted: May 20, 2009
First Posted: May 21, 2009
Results First Submitted: July 28, 2014
Results First Posted: September 19, 2014
Last Update Posted: September 19, 2014