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Trial record 20 of 119 for:    COP1

A Study in Subjects With Relapsing-Remitting Multiple Sclerosis (RRMS) to Assess the Efficacy, Safety and Tolerability of Glatiramer Acetate (GA) Injection 40 mg Administered Three Times a Week Compared to Placebo (GALA)

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ClinicalTrials.gov Identifier: NCT01067521
Recruitment Status : Completed
First Posted : February 11, 2010
Results First Posted : October 9, 2018
Last Update Posted : November 14, 2018
Sponsor:
Information provided by (Responsible Party):
Teva Pharmaceutical Industries ( Teva Pharmaceutical Industries, Ltd. )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Relapsing Remitting Multiple Sclerosis
Interventions Drug: Glatiramer acetate (GA)
Drug: Placebo
Enrollment 1404
Recruitment Details A total of 1524 subjects were screened in this study, and 120 (7.9%) subjects failed screening. Of these, 69 did not meet inclusion or exclusion criteria, 30 withdrew from the study and 21 failed screening for other reasons.
Pre-assignment Details 1404 subjects were enrolled and randomized in the placebo-controlled (PC) double-blind period. Participants were randomized 2:1 to the treatment arms.
Arm/Group Title Early Start: GA 40 mg / GA 40 mg Delayed Start: Placebo / GA 40 mg
Hide Arm/Group Description Participants were administered glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week for 12 months during the double-blind Placebo-Controlled Period, and then continued that treatment in the Open-label Period from Month 13 up to Year 6.5 until the study ended. Participants were administered placebo subcutaneous injections three times a week for 12 months during the double-blind Placebo-Controlled Period. Participants were then switched to glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week during the Open-Label Period from Month 13 up to Year 6.5 until the study ended.
Period Title: Double-Blind Placebo-Controlled Period
Started 943 461
Completed 859 430
Not Completed 84 31
Reason Not Completed
Death             0             1
Adverse Event             29             6
Withdrawal by Subject             34             17
Physician Decision             1             1
Refused to sign informed consent             4             1
Noncompliance with study drug             2             0
Protocol Violation             2             0
Pregnancy             7             4
Lost to Follow-up             5             1
Period Title: Open-Label Period
Started 834 [1] 419 [1]
Completed 580 261
Not Completed 254 158
Reason Not Completed
Death             3             1
Adverse Event             30             28
Withdrawal by Subject             160             88
Physician Decision             13             11
Non-compliance with study drug             5             0
Protocol Violation             3             0
Pregnancy             14             8
Teva requested subject to be withdrawn             5             2
Lost to Follow-up             21             20
[1]
Some participants did not continue into the open-label period.
Arm/Group Title Early Start: GA 40 mg / GA 40 mg Delayed Start: Placebo / GA 40 mg Total
Hide Arm/Group Description Participants were administered glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week for 12 months during the double-blind Placebo-Controlled Period, and then continued that treatment in the Open-label Period from Month 13 up to Year 6.5 until the study ended. Participants were administered placebo subcutaneous injections three times a week for 12 months during the double-blind Placebo-Controlled Period. Participants were then switched to glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week during the Open-Label Period from Month 13 up to Year 6.5 until the study ended. Total of all reporting groups
Overall Number of Baseline Participants 943 461 1404
Hide Baseline Analysis Population Description
Intent to treat (ITT) Analysis Set of Participants at the Placebo-Controlled Period Baseline
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 943 participants 461 participants 1404 participants
37.36  (9.401) 38.12  (9.222) 37.61  (9.346)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 943 participants 461 participants 1404 participants
Female
641
  68.0%
313
  67.9%
954
  67.9%
Male
302
  32.0%
148
  32.1%
450
  32.1%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 943 participants 461 participants 1404 participants
American Indian or Alaska Native
1
   0.1%
0
   0.0%
1
   0.1%
Asian
2
   0.2%
0
   0.0%
2
   0.1%
Black or African American
12
   1.3%
3
   0.7%
15
   1.1%
Other, not specified
12
   1.3%
3
   0.7%
15
   1.1%
White
916
  97.1%
455
  98.7%
1371
  97.6%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 943 participants 461 participants 1404 participants
Not Hispanic or Latino
934
  99.0%
460
  99.8%
1394
  99.3%
Hispanic or Latino
9
   1.0%
1
   0.2%
10
   0.7%
Body Mass Index (BMI)   [1] 
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 942 participants 461 participants 1403 participants
24.38  (4.709) 24.44  (4.804) 24.40  (4.739)
[1]
Measure Analysis Population Description: One participant in the Placebo arm was missing the BMI baseline measure.
Time from First Symptom  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 943 participants 461 participants 1404 participants
7.68  (6.748) 7.61  (6.360) 7.66  (6.621)
Time from Multiple Sclerosis (MS) Diagnosis  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 943 participants 461 participants 1404 participants
3.70  (4.982) 3.88  (4.744) 3.76  (4.904)
Number of T1 Gadolinium (Gd)-Enhanced Lesions per Participant at Baseline  
Mean (Standard Deviation)
Unit of measure:  Lesions
Number Analyzed 943 participants 461 participants 1404 participants
1.7  (4.70) 1.4  (3.69) 1.6  (4.39)
Number of T2 Lesions Per Participant at Baseline  
Mean (Standard Deviation)
Unit of measure:  Lesions
Number Analyzed 943 participants 461 participants 1404 participants
38.0  (26.34) 36.7  (26.68) 37.5  (26.45)
Sienax Normalized Brain Volume at Baseline   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  mL
Number Analyzed 942 participants 461 participants 1403 participants
1533.888  (110.6107) 1537.899  (110.7549) 1535.206  (110.6347)
[1]
Measure Description: Sienax estimates total brain tissue volume, from a single image, normalised for skull size.
[2]
Measure Analysis Population Description: One participant in the GA40 mg ("Early Start') arm was missing the Sienax normalized brain volume baseline measure.
1.Primary Outcome
Title Total Number of Confirmed Relapses During the Placebo Controlled (PC) Treatment Period Estimated by Negative Binomial Regression
Hide Description Relapses were monitored throughout the study. During the PC Period, two neurologists/physicians assessed subjects’ general medical and neurological evaluations separately. A relapse was defined as the appearance of 1+ new neurological abnormalities or the reappearance of 1+ previously observed neurological abnormalities lasting >= 48 hours and immediately preceded by an improving neurological state of at >=30 days from onset of previous relapse. An event was counted as a relapse only when the subject's symptoms were accompanied by observed objective neurological changes, consistent with >= one of the following: - An increase of >= 0.5 in the Expanded Disability Status Scale (EDSS) score as compared to previous evaluation. - An increase of one grade in the actual score of >=2 of the 7 functional systems (FS), as compared to previous evaluation. - An increase of 2 grades in the actual score of one FS as compared to the previous evaluation. Adjusted mean values are displayed.
Time Frame Day 1 to 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
Intent To Treat (ITT) Analysis Population
Arm/Group Title Early Start: GA 40 mg / GA 40 mg Delayed Start: Placebo / GA 40 mg
Hide Arm/Group Description:
Participants were administered glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week for 12 months during the double-blind Placebo-Controlled Period, and then continued that treatment in the Open-label Period from Month 13 up to Year 6.5 until the study ended.
Participants were administered placebo subcutaneous injections three times a week for 12 months during the double-blind Placebo-Controlled Period. Participants were then switched to glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week during the Open-Label Period from Month 13 up to Year 6.5 until the study ended.
Overall Number of Participants Analyzed 943 461
Mean (Standard Error)
Unit of Measure: confirmed relapses
0.331  (0.028) 0.505  (0.049)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Early Start: GA 40 mg / GA 40 mg, Delayed Start: Placebo / GA 40 mg
Comments Relapses were estimated by a baseline-adjusted, Negative Binomial Regression with an “offset” based on the log of subject’s exposure to treatment. The model included the following covariates: - Baseline EDSS score. - Log of the prior 2-year number of relapses. - Volume of T2 lesions at baseliner. - Status of Gd-enhancing T1 activity at baseline (=0 no Gd-enhancing T1 at baseline; =1 at least one Gd-enhancing T1 at baseline). - CGR.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments The overall significance level for this study is 5%
Method Negative Binomial Regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.656
Confidence Interval (2-Sided) 95%
0.539 to 0.799
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.066
Estimation Comments GA 40 mg vs. placebo
2.Primary Outcome
Title Annualized Rate of Confirmed Relapses Comparing Early Starters to Delayed Starters Estimated by Negative Binomial Regression
Hide Description The annualized relapse rate (ARR) was calculated for the study by dividing the cumulative number of confirmed relapses by the number of person-years of exposure to treatment. The analysis of the annualized relapse rate is based on estimating a contrast (early start vs delayed start) derived from a baseline-adjusted, Negative Binomial Regression model to the number of confirmed relapses observed during study (post randomization) with an “offset” based on the log of exposure to treatment.
Time Frame Day 1 up to 6.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
ITT
Arm/Group Title Early Start: GA 40 mg / GA 40 mg Delayed Start: Placebo / GA 40 mg
Hide Arm/Group Description:
RParticipants were administered glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week for 12 months during the double-blind Placebo-Controlled Period, and then continued that treatment in the Open-label Period from Month 13 up to Year 6.5 until the study ended.
Participants were administered placebo subcutaneous injections three times a week for 12 months during the double-blind Placebo-Controlled Period. Participants were then switched to glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week during the Open-Label Period from Month 13 up to Year 6.5 until the study ended.
Overall Number of Participants Analyzed 943 461
Mean (Standard Error)
Unit of Measure: relapses per year
0.2621  (0.0189) 0.3146  (0.0279)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Early Start: GA 40 mg / GA 40 mg, Delayed Start: Placebo / GA 40 mg
Comments Entire Study The Negative Binomial Regression model covariates: • treatment group • PCBL (Placebo-Controlled Baseline) Kurtzke’s Expanded Disability Status Scale (EDSS) score as 1 degree of freedom variable • Log of the # of relapses in the 2 years prior to PCBL • Volume of T2 lesions at PCBL • Status of Gd-enhancing T1 lesion activity at PCBL (=0 if no Gd-enhancing T1 lesions at PCBL; =1 if at least one Gd-enhancing T1 lesion at PCBL) • Country or Geographical Region (CGR)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0409
Comments not adjusted for multiplicity
Method Negative Binomial Regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.8332
Confidence Interval (2-Sided) 95%
0.6995 to 0.9925
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.0744
Estimation Comments Early Start vs Delayed Start
3.Secondary Outcome
Title The Cumulative Number of New/Enlarging T2 Lesions Taken at Month 6 and Month 12 During the Placebo Controlled (PC) Treatment Period Estimated by Negative Binomial Regression
Hide Description T2 lesions are hyperintense brain lesions that show on magnetic resonance imaging (MRI) and are associated with multiple sclerosis. The cumulative number of T2 lesions at Months 6 and 12 that are new or enlarged as compared to the baseline MRI are offered. Note that the two timeframes (Months 6 and 12) are combined. Adjusted mean is based on negative binomial regression, adjusted for baseline number of T2 lesions and country or geographical region as covariates.
Time Frame Baseline (Day -7), Month 6, Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
ITT. When a subject had both Month 6 and Month 12 scans missing, the subject was excluded from the analysis. When the Month 12 scan was missing, data from Month 6 was used and an offset of log (0.5) introduced. When the Month 6 scan was missing, data from Month 12 was used with an offset of 0.
Arm/Group Title Early Start: GA 40 mg / GA 40 mg Delayed Start: Placebo / GA 40 mg
Hide Arm/Group Description:
Participants were administered glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week for 12 months during the double-blind Placebo-Controlled Period, and then continued that treatment in the Open-label Period from Month 13 up to Year 6.5 until the study ended.
Participants were administered placebo subcutaneous injections three times a week for 12 months during the double-blind Placebo-Controlled Period. Participants were then switched to glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week during the Open-Label Period from Month 13 up to Year 6.5 until the study ended.
Overall Number of Participants Analyzed 884 441
Mean (Standard Error)
Unit of Measure: lesions
3.650  (0.259) 5.592  (0.490)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Early Start: GA 40 mg / GA 40 mg, Delayed Start: Placebo / GA 40 mg
Comments Negative binomial regression
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments The overall significance level for this study is 5%
Method Negative binomial regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.653
Confidence Interval (2-Sided) 95%
0.546 to 0.780
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.059
Estimation Comments GA 40 mg vs. placebo
4.Secondary Outcome
Title The Cumulative Number of Gadolinium (Gd)-Enhanced Lesions on T1-Weighted Images At Month 6 and Month 12 of the Placebo-Controlled (PC) Treatment Period Estimated by Negative Binomial Regression
Hide Description The cumulative number of gadolinium (Gd)-enhanced lesions on T1-weighted images at Months 6 and 12 as compared to the baseline MRI are offered. Note that the two timeframes (Months 6 and 12) are combined. Adjusted mean is based on negative binomial regression with an “offset” employing the log of the proportion of the number of the available post-baseline scans to adjust for missing MRI scans (if any), adjusted for baseline number of enhancing lesions on T1-weighted images and country or geographical region as covariates.
Time Frame Baseline (Day -7), Month 6, Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
ITT. When a subject had both Month 6 and Month 12 scans missing, the subject was excluded from the analysis.
Arm/Group Title Early Start: GA 40 mg / GA 40 mg Delayed Start: Placebo / GA 40 mg
Hide Arm/Group Description:
Participants were administered glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week for 12 months during the double-blind Placebo-Controlled Period, and then continued that treatment in the Open-label Period from Month 13 up to Year 6.5 until the study ended.
Participants were administered placebo subcutaneous injections three times a week for 12 months during the double-blind Placebo-Controlled Period. Participants were then switched to glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week during the Open-Label Period from Month 13 up to Year 6.5 until the study ended.
Overall Number of Participants Analyzed 884 441
Mean (Standard Error)
Unit of Measure: lesions
0.905  (0.087) 1.639  (0.194)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Early Start: GA 40 mg / GA 40 mg, Delayed Start: Placebo / GA 40 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments The overall significance level for this study is 5%
Method Negative Binomial Regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.552
Confidence Interval (2-Sided) 95%
0.436 to 0.699
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.066
Estimation Comments GA 40 mg vs. placebo
5.Secondary Outcome
Title Brain Atrophy As Defined by the Percent of Change in Normalized Brain Volume From Baseline to Month 12 During the Placebo Controlled (PC) Treatment Period
Hide Description

The analysis of brain atrophy as defined by the percentage change in normalized brain volume from baseline to Month 12 was based on the outcome of a contrast (GA 40 mg TIW vs. placebo) derived from a baseline-adjusted ANCOVA. In addition to the treatment group, the model included the following covariates: - SIENAX normalized brain volume at baseline. - The number of enhancing lesions on T1-weighted images at baseline. - country or geographical region.

Sienax estimates total brain tissue volume, from a single image, normalised for skull size.

Time Frame Baseline (Day -7), Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population of participants who had SIENEX brain volume estimates at both baseline and Month 12.
Arm/Group Title Early Start: GA 40 mg / GA 40 mg Delayed Start: Placebo / GA 40 mg
Hide Arm/Group Description:
Participants were administered glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week for 12 months during the double-blind Placebo-Controlled Period, and then continued that treatment in the Open-label Period from Month 13 up to Year 6.5 until the study ended.
Participants were administered placebo subcutaneous injections three times a week for 12 months during the double-blind Placebo-Controlled Period. Participants were then switched to glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week during the Open-Label Period from Month 13 up to Year 6.5 until the study ended.
Overall Number of Participants Analyzed 840 423
Mean (Standard Error)
Unit of Measure: percentage change
-0.706  (0.037) -0.645  (0.047)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Early Start: GA 40 mg / GA 40 mg, Delayed Start: Placebo / GA 40 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2058
Comments The overall significance level for this study is 5%
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.061
Confidence Interval (2-Sided) 95%
-0.154 to 0.033
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.048
Estimation Comments GA 40 mg vs Placebo
6.Secondary Outcome
Title The Number of New/Enlarging T2 Lesions at Months 6, 12 and 36 Estimated by Negative Binomial Regression
Hide Description All data accumulated from screening, the PC Treatment period up to the end of the Open Label (OL) period are combined and referred to as the Long Term Period. T2 lesions are hyperintense brain lesions that show on magnetic resonance imaging (MRI) and are associated with multiple sclerosis. The number of T2 lesions at Months 6, 12 and 36 that are new or enlarged as compared to the baseline MRI are offered. Adjusted mean is based on negative binomial regression, adjusted for baseline number of T2 lesions and country or geographical region as covariates. An “offset” employing the log of the proportion of the number of the available post-placebo-controlled baseline (PCBL) scans was used to adjust for missing MRI scans.
Time Frame Baseline (Day -7), Month 6, Month 12, Month 36
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population of participants with MRIs at both baseline and the designated timeframes.
Arm/Group Title Early Start: GA 40 mg / GA 40 mg Delayed Start: Placebo / GA 40 mg
Hide Arm/Group Description:
Participants were administered glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week for 12 months during the double-blind Placebo-Controlled Period, and then continued that treatment in the Open-label Period from Month 13 up to Year 6.5 until the study ended.
Participants were administered placebo subcutaneous injections three times a week for 12 months during the double-blind Placebo-Controlled Period. Participants were then switched to glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week during the Open-Label Period from Month 13 up to Year 6.5 until the study ended.
Overall Number of Participants Analyzed 883 440
Mean (Standard Error)
Unit of Measure: lesions
Month 6 Number Analyzed 883 participants 440 participants
2.872  (0.214) 3.902  (0.43)
Month 12 Number Analyzed 854 participants 425 participants
4.484  (0.318) 7.086  (0.699)
Month 36 Number Analyzed 571 participants 263 participants
5.836  (0.41) 8.759  (0.82)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Early Start: GA 40 mg / GA 40 mg, Delayed Start: Placebo / GA 40 mg
Comments Month 6 Negative binomial regression
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0056
Comments not adjusted for multiplicity
Method Negative binomial regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.736
Confidence Interval (2-Sided) 95%
0.592 to 0.914
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.081
Estimation Comments Early Start vs Delayed Start
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Early Start: GA 40 mg / GA 40 mg, Delayed Start: Placebo / GA 40 mg
Comments Month 12 Negative binomial regression
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments not adjusted for multiplicity
Method Negative binomial regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.633
Confidence Interval (2-Sided) 95%
0.524 to 0.765
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.061
Estimation Comments Early Start vs Delayed Start
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Early Start: GA 40 mg / GA 40 mg, Delayed Start: Placebo / GA 40 mg
Comments Month 36 Negative binomial regression
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments not adjusted for multiplicity
Method Negative binomial regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.666
Confidence Interval (2-Sided) 95%
0.557 to 0.797
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.061
Estimation Comments Early Start vs Delayed Start
7.Secondary Outcome
Title The Cumulative Number of Gadolinium (Gd)-Enhanced Lesions on T1-Weighted Images At Months 6, 12 and 36 Estimated by Negative Binomial Regression
Hide Description All data accumulated from screening, the PC Treatment period up to the end of the Open Label (OL) period are combined and referred to as the Long Term Period. The cumulative number of gadolinium (Gd)-enhanced lesions on T1-weighted images at Months 6, 12 and 36 as compared to the baseline MRI are offered. Adjusted mean is based on negative binomial regression The model was fit using an autoregressive covariance structure. Covariates used: number of enhancing lesions on T1-weighted images at placebo-controlled baseline and country or geographical region. The cumulative number is derived from all the data points before it. For example, if the participant skipped one time point in between the baseline and 36 months, then it cannot be calculated.
Time Frame Baseline (Day -7), Month 6, Month 12, Month 36
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population of participants with MRIs at both baseline and the designated timeframes, inclusive of the proceeding post-baseline timeframes.
Arm/Group Title Early Start: GA 40 mg / GA 40 mg Delayed Start: Placebo / GA 40 mg
Hide Arm/Group Description:
Participants were administered glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week for 12 months during the double-blind Placebo-Controlled Period, and then continued that treatment in the Open-label Period from Month 13 up to Year 6.5 until the study ended.
Participants were administered placebo subcutaneous injections three times a week for 12 months during the double-blind Placebo-Controlled Period. Participants were then switched to glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week during the Open-Label Period from Month 13 up to Year 6.5 until the study ended.
Overall Number of Participants Analyzed 883 440
Mean (Standard Error)
Unit of Measure: lesions
Month 6 Number Analyzed 883 participants 440 participants
0.629  (0.072) 1.131  (9.186)
Month 12 Number Analyzed 854 participants 425 participants
1.054  (0.115) 2.051  (0.282)
Month 36 Number Analyzed 570 participants 263 participants
1.501  (0.168) 2.265  (0.278)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Early Start: GA 40 mg / GA 40 mg, Delayed Start: Placebo / GA 40 mg
Comments Month 6
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0005
Comments not adjusted for multiplicity
Method Negative Binomial Regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.556
Confidence Interval (2-Sided) 95%
0.4 to 0.773
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.093
Estimation Comments Early Start vs Delayed Start
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Early Start: GA 40 mg / GA 40 mg, Delayed Start: Placebo / GA 40 mg
Comments Month 12
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments not adjusted for multiplicity
Method Negative binomial regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.514
Confidence Interval (2-Sided) 95%
0.388 to 0.679
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.073
Estimation Comments Early Start vs Delayed Start
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Early Start: GA 40 mg / GA 40 mg, Delayed Start: Placebo / GA 40 mg
Comments Month 36
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0015
Comments not adjusted for multiplicity
Method Negative binomial regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.663
Confidence Interval (2-Sided) 95%
0.514 to 0.854
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.086
Estimation Comments Early Start vs Delayed Start
8.Secondary Outcome
Title Brain Atrophy As Defined by the Percent of Change in Brain Volume From Baseline to Months 6, 12 and 36 Estimated by a Mixed Model for Repeated Measures
Hide Description

The analysis of brain atrophy as defined by the percentage change in brain volume from baseline to Months 6, 12 and 36 was performed using mixed model for repeated measures (MMRM) with SIENAX normalized brain volume at baseline, number of Gd-enhancing lesions at baseline, and country or geographical region as fixed effects.

Sienax estimates total brain tissue volume, from a single image, normalised for skull size.

Time Frame Baseline (Day -7), Month 6, Month 12, Month 36
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population of participants with SIENEX brain scans at both baseline and the designated timeframes.
Arm/Group Title Early Start: GA 40 mg / GA 40 mg Delayed Start: Placebo / GA 40 mg
Hide Arm/Group Description:
Participants were administered glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week for 12 months during the double-blind Placebo-Controlled Period, and then continued that treatment in the Open-label Period from Month 13 up to Year 6.5 until the study ended.
Participants were administered placebo subcutaneous injections three times a week for 12 months during the double-blind Placebo-Controlled Period. Participants were then switched to glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week during the Open-Label Period from Month 13 up to Year 6.5 until the study ended.
Overall Number of Participants Analyzed 872 436
Mean (Standard Error)
Unit of Measure: percentage change
Month 6 Number Analyzed 872 participants 436 participants
-0.429  (0.032) -0.345  (0.04)
Month 12 Number Analyzed 846 participants 423 participants
-0.739  (0.035) -0.653  (0.046)
Month 36 Number Analyzed 543 participants 250 participants
-1.935  (0.063) -1.952  (0.09)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Early Start: GA 40 mg / GA 40 mg, Delayed Start: Placebo / GA 40 mg
Comments Month 6
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0425
Comments not adjusted for multiplicity
Method Mixed model for repeated measures (MMRM)
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.084
Confidence Interval (2-Sided) 95%
-0.166 to -0.003
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.041
Estimation Comments Early Start vs Delayed Start
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Early Start: GA 40 mg / GA 40 mg, Delayed Start: Placebo / GA 40 mg
Comments Month 12
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0844
Comments not adjusted for multiplicity
Method Mixed model for repeated measures (MMRM)
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.086
Confidence Interval (2-Sided) 95%
-0.184 to 0.012
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.05
Estimation Comments Early Start vs Delayed Start
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Early Start: GA 40 mg / GA 40 mg, Delayed Start: Placebo / GA 40 mg
Comments Month 36
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8701
Comments not adjusted for multiplicity
Method Mixed model for repeated measures (MMRM)
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.017
Confidence Interval (2-Sided) 95%
-0.91 to 0.225
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.106
Estimation Comments Early Start vs Delayed Start
9.Secondary Outcome
Title Participants With Treatment-Emergent Adverse Events (TEAEs)
Hide Description Adverse events (AEs) summarized in this table are those that began or worsened after treatment with study drug (treatment-emergent AEs). An adverse event was defined in the protocol as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily activities. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
Time Frame Early Start: Day 1 up to 6.5 years Delayed Start – Placebo: Day 1 up to Month 12 Delayed Start - GA: Month 13 up to 6.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Glatiramer Acetate (GA) - Treated Analysis Set The GA-Treated analysis set includes all subjects randomized into the study and treated with at least 1 dose of GA at any time during the study. Analyses includes data collected for these subjects from the first time GA was administered.
Arm/Group Title Early Start: GA 40 mg / GA 40 mg Delayed Start: GA 40 mg Delayed Start: Placebo
Hide Arm/Group Description:
Participants were administered glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week for 12 months during the double-blind Placebo-Controlled Period, and then continued that treatment in the Open-label Period from Month 13 up to Year 6.5 until the study ended
After completing the double-blind Placebo-Controlled Period, participants had the option of continuing in the study on glatiramer acetate (GA) 40 mg/ml by subcutaneous injection three times a week until the study ended. This 'Delayed Start' treatment began at Month 13 and continued until the study ended (up to about 6.5 years).
Participants were administered placebo subcutaneous injections three times a week from Day 1 to Month 12 during the double-blind Placebo-Controlled Period.
Overall Number of Participants Analyzed 943 419 461
Measure Type: Count of Participants
Unit of Measure: Participants
Any TEAE
777
  82.4%
322
  76.8%
284
  61.6%
Severity of TEAEs: Mild
698
  74.0%
283
  67.5%
247
  53.6%
Severity of TEAEs: Moderate
441
  46.8%
168
  40.1%
101
  21.9%
Severity of TEAEs: Severe
95
  10.1%
24
   5.7%
16
   3.5%
Treatment-related TEAEs
501
  53.1%
189
  45.1%
73
  15.8%
Serious TEAEs
117
  12.4%
36
   8.6%
21
   4.6%
Deaths
3
   0.3%
1
   0.2%
1
   0.2%
TEAEs leading to treatment discontinuation
63
   6.7%
28
   6.7%
6
   1.3%
Time Frame Delayed Start (GA 40 mg): Month 13 up to 6.5 years Delayed Start (Placebo): Day 1 to Month 12 Early Start: (GA 40 mg/ GA 40 mg) Day 1 up to 6.5 years
Adverse Event Reporting Description

Death details:

Delayed Start (GA 40 mg): caused by subarachnoid hemorrhage and brain edema 1027 days after the first dose of GA.

Delayed Start (Placebo): cardiopulmonary failure

Early Start: Three deaths due to acute cardiac failure, cardio-respiratory arrest, and cardiac arrest occurring 488, 1283 and 1682 days after first dose of GA respectively.

 
Arm/Group Title Delayed Start: GA 40 mg Delayed Start: Placebo Early Start: GA 40 mg / GA 40 mg
Hide Arm/Group Description After completing the double-blind Placebo-Controlled Period, participants had the option of continuing in the study on glatiramer acetate (GA) 40 mg/ml by subcutaneous injection three times a week until the study ended. This 'Delayed Start' treatment started at Month 13 and continued until the study ended (up to about 6.5 years). Participants were administered placebo subcutaneous injections three times a week from Day 1 to Month 12 during the double-blind Placebo-Controlled Period. Participants were administered glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week for 12 months during the double-blind Placebo-Controlled Period, and then continued that treatment in the Open-label Period from Month 13 up to Year 6.5 until the study ended
All-Cause Mortality
Delayed Start: GA 40 mg Delayed Start: Placebo Early Start: GA 40 mg / GA 40 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/419 (0.24%)      1/461 (0.22%)      3/943 (0.32%)    
Show Serious Adverse Events Hide Serious Adverse Events
Delayed Start: GA 40 mg Delayed Start: Placebo Early Start: GA 40 mg / GA 40 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   36/419 (8.59%)      21/461 (4.56%)      117/943 (12.41%)    
Blood and lymphatic system disorders       
Anaemia  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Iron deficiency anaemia  1  1/419 (0.24%)  1 0/461 (0.00%)  0 1/943 (0.11%)  1
Cardiac disorders       
Angina pectoris  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Angina unstable  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Cardiac arrest  1  0/419 (0.00%)  0 1/461 (0.22%)  1 1/943 (0.11%)  1
Cardiac failure acute  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Cardio-respiratory arrest  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Cardiopulmonary failure  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Ischaemic cardiomyopathy  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Myocardial infarction  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Myocardial ischaemia  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Palpitations  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  2
Tachycardia  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Congenital, familial and genetic disorders       
Congenital hydronephrosis  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Ear and labyrinth disorders       
Hypoacusis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Vertigo positional  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Eye disorders       
Cataract  1  1/419 (0.24%)  1 0/461 (0.00%)  0 2/943 (0.21%)  4
Glaucoma  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Iridocyclitis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  3
Macular oedema  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Gastrointestinal disorders       
Abdominal hernia  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Abdominal pain  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Anal fistula  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Chronic gastritis  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Colitis  1  1/419 (0.24%)  1 0/461 (0.00%)  0 1/943 (0.11%)  1
Constipation  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Diarrhoea  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Gastric ulcer haemorrhage  1  1/419 (0.24%)  1 0/461 (0.00%)  0 1/943 (0.11%)  2
Gastroduodenitis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Haemorrhoids thrombosed  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Inguinal hernia  1  0/419 (0.00%)  0 0/461 (0.00%)  0 2/943 (0.21%)  2
Nausea  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Pancreatitis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Pancreatitis chronic  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Proctitis  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Swollen tongue  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Upper gastrointestinal haemorrhage  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Vomiting  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
General disorders       
Asthenia  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Chest pain  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Chills  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Feeling hot  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Immediate post-injection reaction  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Injection site erythema  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Injection site swelling  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Oedema  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Pyrexia  1  1/419 (0.24%)  1 0/461 (0.00%)  0 1/943 (0.11%)  1
Hepatobiliary disorders       
Cholecystitis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Cholecystitis acute  1  0/419 (0.00%)  0 0/461 (0.00%)  0 2/943 (0.21%)  2
Cholecystitis chronic  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Cholelithiasis  1  1/419 (0.24%)  1 1/461 (0.22%)  1 3/943 (0.32%)  3
Drug-induced liver injury  1  0/419 (0.00%)  0 0/461 (0.00%)  0 2/943 (0.21%)  2
Gallbladder polyp  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Hepatitis toxic  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Jaundice cholestatic  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Immune system disorders       
Anaphylactic reaction  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Anaphylactic shock  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Drug hypersensitivity  1  2/419 (0.48%)  3 0/461 (0.00%)  0 1/943 (0.11%)  2
Infections and infestations       
Appendiceal abscess  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Appendicitis  1  1/419 (0.24%)  1 0/461 (0.00%)  0 1/943 (0.11%)  1
Appendicitis perforated  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Bone tuberculosis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Bronchitis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 2/943 (0.21%)  2
Burn infection  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Cellulitis  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Diverticulitis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Gallbladder empyema  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Gastroenteritis  1  1/419 (0.24%)  1 0/461 (0.00%)  0 1/943 (0.11%)  1
Gastroenteritis rotavirus  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Helicobacter infection  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Hepatitis B  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Influenza  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Injection site abscess  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Latent tuberculosis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Nail infection  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Ophthalmic herpes zoster  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Peritonitis  1  2/419 (0.48%)  2 0/461 (0.00%)  0 0/943 (0.00%)  0
Pneumonia  1  0/419 (0.00%)  0 0/461 (0.00%)  0 4/943 (0.42%)  4
Pyelonephritis  1  0/419 (0.00%)  0 2/461 (0.43%)  2 0/943 (0.00%)  0
Pyelonephritis acute  1  1/419 (0.24%)  1 0/461 (0.00%)  0 1/943 (0.11%)  1
Pyelonephritis chronic  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Salpingitis  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Sepsis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Sinusitis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 2/943 (0.21%)  2
Staphylococcal sepsis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Urinary tract infection  1  0/419 (0.00%)  0 0/461 (0.00%)  0 3/943 (0.32%)  3
Urosepsis  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Vestibular neuronitis  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Viral infection  1  0/419 (0.00%)  0 0/461 (0.00%)  0 2/943 (0.21%)  2
Injury, poisoning and procedural complications       
Ankle fracture  1  0/419 (0.00%)  0 0/461 (0.00%)  0 2/943 (0.21%)  2
Brain contusion  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Burns second degree  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Clavicle fracture  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Contusion  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Craniocerebral injury  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Extradural haematoma  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Face injury  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Fall  1  0/419 (0.00%)  0 0/461 (0.00%)  0 2/943 (0.21%)  2
Femur fracture  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Foot fracture  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Forearm fracture  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Fractured skull depressed  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Head injury  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Laceration  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Meniscus injury  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Multiple injuries  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Radius fracture  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Road traffic accident  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Skull fracture  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Spinal compression fracture  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Tendon injury  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Thermal burn  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Tibia fracture  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Investigations       
Blood pressure increased  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Body temperature increased  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Catheterisation cardiac  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Weight decreased  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Metabolism and nutrition disorders       
Diabetes mellitus  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Electrolyte imbalance  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Hypokalaemia  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Type 2 diabetes mellitus  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Musculoskeletal and connective tissue disorders       
Back pain  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Chondropathy  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Exostosis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Foot deformity  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Intervertebral disc disorder  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Intervertebral disc protrusion  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Myositis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  4
Osteoarthritis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Osteonecrosis  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Spondylitis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Spondylolisthesis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  2
Synovitis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Anaplastic astrocytoma  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Astrocytoma  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Basal cell carcinoma  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Breast neoplasm  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Follicular thyroid cancer  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Intraductal papilloma of breast  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Invasive ductal breast carcinoma  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Leiomyoma  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Oesophageal carcinoma  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Renal cell carcinoma  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Seminoma  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Thyroid cancer  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Uterine leiomyoma  1  2/419 (0.48%)  2 0/461 (0.00%)  0 4/943 (0.42%)  4
Nervous system disorders       
Apallic syndrome  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Brain oedema  1  1/419 (0.24%)  1 0/461 (0.00%)  0 1/943 (0.11%)  1
Carpal tunnel syndrome  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Cerebral haemorrhage  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Epilepsy  1  0/419 (0.00%)  0 0/461 (0.00%)  0 3/943 (0.32%)  3
Haemorrhage intracranial  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Idiopathic generalised epilepsy  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Ischaemic stroke  1  0/419 (0.00%)  0 0/461 (0.00%)  0 3/943 (0.32%)  3
Loss of consciousness  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Lumbar radiculopathy  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  2
Lumbosacral radiculopathy  1  0/419 (0.00%)  0 0/461 (0.00%)  0 2/943 (0.21%)  2
Multiple sclerosis relapse  1  2/419 (0.48%)  3 1/461 (0.22%)  1 5/943 (0.53%)  5
Optic neuritis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Sciatica  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Seizure  1  0/419 (0.00%)  0 0/461 (0.00%)  0 2/943 (0.21%)  2
Status epilepticus  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  3
Subarachnoid haemorrhage  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Syncope  1  0/419 (0.00%)  0 1/461 (0.22%)  1 1/943 (0.11%)  1
Trigeminal neuralgia  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Pregnancy, puerperium and perinatal conditions       
Abortion incomplete  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Abortion spontaneous  1  1/419 (0.24%)  1 1/461 (0.22%)  1 1/943 (0.11%)  1
Abortion threatened  1  0/419 (0.00%)  0 1/461 (0.22%)  1 1/943 (0.11%)  1
Psychiatric disorders       
Anxiety  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Bipolar I disorder  1  2/419 (0.48%)  2 0/461 (0.00%)  0 0/943 (0.00%)  0
Depression  1  1/419 (0.24%)  1 0/461 (0.00%)  0 1/943 (0.11%)  1
Suicidal ideation  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Renal and urinary disorders       
Anuria  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Hydronephrosis  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Nephrolithiasis  1  0/419 (0.00%)  0 2/461 (0.43%)  2 2/943 (0.21%)  2
Perinephritis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Renal colic  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Renal cyst  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Renal failure  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Stress urinary incontinence  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Ureterolithiasis  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Urinary incontinence  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  2
Reproductive system and breast disorders       
Adenomyosis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Benign prostatic hyperplasia  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Breast disorder  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Cervical dysplasia  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Endometrial hyperplasia  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Fibrocystic breast disease  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Metrorrhagia  1  0/419 (0.00%)  0 1/461 (0.22%)  1 2/943 (0.21%)  2
Oligomenorrhoea  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Ovarian cyst  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Uterine cervical erosion  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Uterine polyp  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Dyspnoea  1  2/419 (0.48%)  2 0/461 (0.00%)  0 0/943 (0.00%)  0
Lung infiltration  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Pharyngeal oedema  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Pulmonary embolism  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Respiratory arrest  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Respiratory failure  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Skin and subcutaneous tissue disorders       
Angioedema  1  0/419 (0.00%)  0 0/461 (0.00%)  0 2/943 (0.21%)  2
Erythema  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Hyperkeratosis  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Panniculitis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Pruritus  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Psoriasis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Rash  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Urticaria  1  1/419 (0.24%)  1 1/461 (0.22%)  1 1/943 (0.11%)  1
Surgical and medical procedures       
Appendicectomy  1  1/419 (0.24%)  1 0/461 (0.00%)  0 1/943 (0.11%)  1
Breast conserving surgery  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  2
Cataract operation  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Cervix operation  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Hip arthroplasty  1  2/419 (0.48%)  3 0/461 (0.00%)  0 0/943 (0.00%)  0
Hysterectomy  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Inguinal hernia repair  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Mammoplasty  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Nephrectomy  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Spinal operation  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Thyroidectomy  1  1/419 (0.24%)  1 0/461 (0.00%)  0 0/943 (0.00%)  0
Toe amputation  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Tonsillectomy  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Ureteric calculus removal  1  0/419 (0.00%)  0 1/461 (0.22%)  1 0/943 (0.00%)  0
Vascular disorders       
Aortic dissection  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Deep vein thrombosis  1  0/419 (0.00%)  0 0/461 (0.00%)  0 2/943 (0.21%)  2
Hypertension  1  1/419 (0.24%)  1 0/461 (0.00%)  0 1/943 (0.11%)  1
Peripheral venous disease  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
Thrombophlebitis superficial  1  0/419 (0.00%)  0 0/461 (0.00%)  0 1/943 (0.11%)  1
1
Term from vocabulary, MedDRA (19.0)
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Delayed Start: GA 40 mg Delayed Start: Placebo Early Start: GA 40 mg / GA 40 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   238/419 (56.80%)      167/461 (36.23%)      609/943 (64.58%)    
General disorders       
Injection site erythema  1  107/419 (25.54%)  122 8/461 (1.74%)  10 243/943 (25.77%)  391
Injection site pain  1  55/419 (13.13%)  61 10/461 (2.17%)  10 115/943 (12.20%)  138
Injection site pruritus  1  23/419 (5.49%)  24 2/461 (0.43%)  2 68/943 (7.21%)  95
Injection site swelling  1  23/419 (5.49%)  23 3/461 (0.65%)  5 50/943 (5.30%)  95
Infections and infestations       
Bronchitis  1  20/419 (4.77%)  25 7/461 (1.52%)  9 50/943 (5.30%)  65
Influenza  1  25/419 (5.97%)  33 17/461 (3.69%)  22 67/943 (7.10%)  103
Nasopharyngitis  1  56/419 (13.37%)  98 39/461 (8.46%)  47 167/943 (17.71%)  346
Upper respiratory tract infection  1  32/419 (7.64%)  54 25/461 (5.42%)  30 98/943 (10.39%)  158
Urinary tract infection  1  36/419 (8.59%)  50 22/461 (4.77%)  24 103/943 (10.92%)  165
Musculoskeletal and connective tissue disorders       
Back pain  1  33/419 (7.88%)  45 20/461 (4.34%)  26 98/943 (10.39%)  150
Nervous system disorders       
Headache  1  39/419 (9.31%)  83 55/461 (11.93%)  71 132/943 (14.00%)  316
Multiple sclerosis relapse  1  10/419 (2.39%)  12 7/461 (1.52%)  9 48/943 (5.09%)  63
1
Term from vocabulary, MedDRA (19.0)
Indicates events were collected by systematic assessment
Analyses of Open-Label Period data are not adjusted for multiplicity and therefore do not control for type one statistical error.
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.
Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor’s review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor’s designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Director, Clinical Research
Organization: Teva Branded Pharmaceutical Products, R&D Inc
Phone: 001-215-591-3000
EMail: info.era-clinical@teva.de
Layout table for additonal information
Responsible Party: Teva Pharmaceutical Industries ( Teva Pharmaceutical Industries, Ltd. )
ClinicalTrials.gov Identifier: NCT01067521     History of Changes
Other Study ID Numbers: MS-GA-301
2009-018084-27 ( EudraCT Number )
First Submitted: February 10, 2010
First Posted: February 11, 2010
Results First Submitted: July 17, 2018
Results First Posted: October 9, 2018
Last Update Posted: November 14, 2018