Trial Outcomes & Findings for Evaluate Early Glatiramer Acetate Treatment in Delaying Conversion to Clinically Definite Multiple Sclerosis of Subjects Presenting With Clinically Isolated Syndrome (NCT NCT00666224)

NCT ID: NCT00666224

Last Updated: 2012-06-25

Results Overview

Data from interim analysis with database lock on October 14, 2007. The time from randomization to conversion to CDMS as determined by the occurrence of a second clinical attack during the double-blind period. Poser criteria are: Two relapses and clinical evidence of two separate lesions; clinical evidence of one lesion and paraclinical evidence of another separate lesion. The two relapses must involve different parts of Central Nervous System and must be separated by a period of at least one month. Lesions are determined by Magnetic Resonance Imaging (MRI).

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 481 participants
• Primary outcome timeframe: up to 3 years
• Results posted on: 2012-06-25

Participant Flow

A clinically isolated syndrome (CIS) is a first neurological episode, lasting at least 24 hours, caused by inflammation/demyelination in one or more sites in the central nervous system (CNS.) Subjects were enrolled within 90 days of the event and randomized up to 32 days following screening.

Six-hundred and nineteen (619) subjects were screened for this study; 138 subjects were screening failures, including one subject, randomized in error. This subject, who had a relapse between screening visit and baseline, never received any treatment, and is considered a screening failure.

Participant milestones

Measure	Glatiramer Acetate Glatiramer acetate (GA) 20 mg once daily by subcutaneous injection during the double-blind period. Following a pre-planned interim analysis, the Data Monitoring Committee (DMC) recommended that the double blind period be closed and participants moved into the Open Label (OL) period. Participants in this treatment arm continued taking glatiramer acetate 20 mg once daily by subcutaneous injection during the open-label (OL) period.	Placebo (DB) to GA (OL) Placebo matching glatiramer acetate given once daily by subcutaneous injection during the double-blind period (DB). Following a pre-planned interim analysis, the Data Monitoring Committee (DMC) recommended that the double blind period be closed and participants moved into the Open Label (OL) period. Glatiramer acetate (GA) given 20 mg once daily by subcutaneous injection during the open-label period (OL).
Double-Blind STARTED	243	238
Double-Blind COMPLETED	198	211
Double-Blind NOT COMPLETED	45	27
Open-Label STARTED	198	211
Open-Label COMPLETED	163	126
Open-Label NOT COMPLETED	35	85

Reasons for withdrawal

Measure	Glatiramer Acetate Glatiramer acetate (GA) 20 mg once daily by subcutaneous injection during the double-blind period. Following a pre-planned interim analysis, the Data Monitoring Committee (DMC) recommended that the double blind period be closed and participants moved into the Open Label (OL) period. Participants in this treatment arm continued taking glatiramer acetate 20 mg once daily by subcutaneous injection during the open-label (OL) period.	Placebo (DB) to GA (OL) Placebo matching glatiramer acetate given once daily by subcutaneous injection during the double-blind period (DB). Following a pre-planned interim analysis, the Data Monitoring Committee (DMC) recommended that the double blind period be closed and participants moved into the Open Label (OL) period. Glatiramer acetate (GA) given 20 mg once daily by subcutaneous injection during the open-label period (OL).
Double-Blind Adverse Event	15	5
Double-Blind Lost to Follow-up	2	2
Double-Blind Withdrawal by Subject	18	14
Double-Blind Physician Decision	0	3
Double-Blind Sponsor decision	1	0
Double-Blind Pregnancy	3	2
Double-Blind Noncompliance	1	0
Double-Blind Death	1	0
Double-Blind Undefined/Unknown	4	1
Open-Label Adverse Event	8	43
Open-Label Lost to Follow-up	4	5
Open-Label Withdrawal by Subject	12	25
Open-Label Physician Decision	7	5
Open-Label Pregnancy	1	5
Open-Label Noncompliance	2	1
Open-Label Undefined/Unknown	1	1

Baseline Characteristics

Evaluate Early Glatiramer Acetate Treatment in Delaying Conversion to Clinically Definite Multiple Sclerosis of Subjects Presenting With Clinically Isolated Syndrome

Baseline characteristics by cohort

Measure	Glatiramer Acetate (Double-blind Period) n=243 Participants Glatiramer acetate 20 mg once daily by subcutaneous injection during the double-blind period.	Placebo (Double-blind Period) n=238 Participants Placebo matching GA once daily by subcutaneous injection during the double-blind period.	Total n=481 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	243 Participants n=5 Participants	238 Participants n=7 Participants	481 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age Continuous	31.5 years STANDARD_DEVIATION 6.9 • n=5 Participants	30.8 years STANDARD_DEVIATION 7.0 • n=7 Participants	31.2 years STANDARD_DEVIATION 6.9 • n=5 Participants
Sex: Female, Male Female	159 Participants n=5 Participants	163 Participants n=7 Participants	322 Participants n=5 Participants
Sex: Female, Male Male	84 Participants n=5 Participants	75 Participants n=7 Participants	159 Participants n=5 Participants
Race/Ethnicity, Customized Asian / Oriental	2 participants n=5 Participants	1 participants n=7 Participants	3 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants
Race/Ethnicity, Customized Caucasian	233 participants n=5 Participants	229 participants n=7 Participants	462 participants n=5 Participants
Race/Ethnicity, Customized Hispanic	3 participants n=5 Participants	2 participants n=7 Participants	5 participants n=5 Participants
Race/Ethnicity, Customized Other (not specified)	4 participants n=5 Participants	5 participants n=7 Participants	9 participants n=5 Participants
Region of Enrollment Argentina	7 participants n=5 Participants	6 participants n=7 Participants	13 participants n=5 Participants
Region of Enrollment Australia	7 participants n=5 Participants	6 participants n=7 Participants	13 participants n=5 Participants
Region of Enrollment Austria	5 participants n=5 Participants	6 participants n=7 Participants	11 participants n=5 Participants
Region of Enrollment Denmark	5 participants n=5 Participants	6 participants n=7 Participants	11 participants n=5 Participants
Region of Enrollment Finland	10 participants n=5 Participants	10 participants n=7 Participants	20 participants n=5 Participants
Region of Enrollment France	11 participants n=5 Participants	11 participants n=7 Participants	22 participants n=5 Participants
Region of Enrollment Germany	32 participants n=5 Participants	31 participants n=7 Participants	63 participants n=5 Participants
Region of Enrollment Hungary	16 participants n=5 Participants	15 participants n=7 Participants	31 participants n=5 Participants
Region of Enrollment Italy	56 participants n=5 Participants	57 participants n=7 Participants	113 participants n=5 Participants
Region of Enrollment New Zealand	4 participants n=5 Participants	3 participants n=7 Participants	7 participants n=5 Participants
Region of Enrollment Norway	2 participants n=5 Participants	2 participants n=7 Participants	4 participants n=5 Participants
Region of Enrollment Romania	28 participants n=5 Participants	30 participants n=7 Participants	58 participants n=5 Participants
Region of Enrollment Spain	23 participants n=5 Participants	22 participants n=7 Participants	45 participants n=5 Participants
Region of Enrollment Sweden	2 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants
Region of Enrollment United Kingdom	15 participants n=5 Participants	12 participants n=7 Participants	27 participants n=5 Participants
Region of Enrollment United States	20 participants n=5 Participants	21 participants n=7 Participants	41 participants n=5 Participants
Participants Who Used Corticosteroids for Initial Attack Used corticosteroids	149 participants n=5 Participants	159 participants n=7 Participants	308 participants n=5 Participants
Participants Who Used Corticosteroids for Initial Attack Did not use corticosteroids	94 participants n=5 Participants	79 participants n=7 Participants	173 participants n=5 Participants

PRIMARY outcome

Timeframe: up to 3 years

Population: Intent-to-Treat (ITT) analysis set. The ITT consists of all participants who have been randomized and received at least one dose of glatiramer acetate or placebo.

Data from interim analysis with database lock on October 14, 2007. The time from randomization to conversion to CDMS as determined by the occurrence of a second clinical attack during the double-blind period. Poser criteria are: Two relapses and clinical evidence of two separate lesions; clinical evidence of one lesion and paraclinical evidence of another separate lesion. The two relapses must involve different parts of Central Nervous System and must be separated by a period of at least one month. Lesions are determined by Magnetic Resonance Imaging (MRI).

Outcome measures

Measure	Glatiramer Acetate (Double-blind Period) n=243 Participants Glatiramer acetate 20 mg once daily by subcutaneous injection during the double-blind period.	Placebo (Double-blind Period) n=238 Participants Placebo matching GA once daily by subcutaneous injection during the double-blind period.
Time to Clinically Definite Multiple Sclerosis (CDMS) Conversion	657.85 days Standard Deviation 349.3	590.54 days Standard Deviation 340.2

PRIMARY outcome

Timeframe: up to 3 years

Population: Intent-to-Treat (ITT) analysis set. The ITT consists of all participants who have been randomized and received at least one dose of glatiramer acetate or placebo.

Data from interim analysis with database lock on October 14, 2007. Due to the number of participants in the glatiramer acetate group that converted to CDMS (see outcome #6), the 25th percentile was considered when running the Kaplan-Meier estimate for time to conversion to CDMS. Conversion to CDMS is determined by the occurrence of the second clinical attack.

Outcome measures

Measure	Glatiramer Acetate (Double-blind Period) n=243 Participants Glatiramer acetate 20 mg once daily by subcutaneous injection during the double-blind period.	Placebo (Double-blind Period) n=238 Participants Placebo matching GA once daily by subcutaneous injection during the double-blind period.
Twenty-fifth Percentile (25%) Kaplan-Meier Estimates for Time From Randomization to Conversion to Clinically Definite Multiple Sclerosis (CDMS) During the Double-blind Period	722 days Interval 505.0 to Not able to be estimated due to small numbers of participants converting to CDMS	336 days Interval 260.0 to 456.0

SECONDARY outcome

Timeframe: up to 3 years

Population: Intent-to-Treat (ITT) analysis set. The ITT consists of all participants who have been randomized and received at least one dose of glatiramer acetate or placebo.

Data from interim analysis with database lock on October 14, 2007. T2 lesions are brain lesions that show on magnetic resonance imaging (MRI) and are associated with multiple sclerosis. This outcome measures the number of new lesions at the last observed value. Last Observed Value (LOV) is defined as the last post baseline measurement taken on study drug but no more than 30 days after study drug cessation.

Outcome measures

Measure	Glatiramer Acetate (Double-blind Period) n=243 Participants Glatiramer acetate 20 mg once daily by subcutaneous injection during the double-blind period.	Placebo (Double-blind Period) n=238 Participants Placebo matching GA once daily by subcutaneous injection during the double-blind period.
Number of New T2 Brain Lesions Observed at the Last Observed Value (LOV) in the Double-blind Period	0.7 new T2 lesions Standard Deviation 1.7	1.8 new T2 lesions Standard Deviation 3.6

SECONDARY outcome

Timeframe: Day 0 (baseline), up to 3 years

Population: Intent to treat population for which data at both timepoints are available

Data from interim analysis with database lock on October 14, 2007. The difference in T2 brain lesion volume as observed in MRIs from baseline to the last observed value. Last Observed Value (LOV) is defined as the last post baseline measurement taken on study drug but no more than 30 days after study drug cessation.

Outcome measures

Measure	Glatiramer Acetate (Double-blind Period) n=218 Participants Glatiramer acetate 20 mg once daily by subcutaneous injection during the double-blind period.	Placebo (Double-blind Period) n=221 Participants Placebo matching GA once daily by subcutaneous injection during the double-blind period.
Change From Baseline to Last Observed Value (LOV) in T2 Brain Lesion Volume in the Double-blind Period	1.2 ml Standard Deviation 2.6	2.6 ml Standard Deviation 3.9

SECONDARY outcome

Timeframe: Day 0 (baseline), up to 3 years

Population: Intent to treat population of participants with both baseline and last observed values.

Data from interim analysis with database lock on October 14, 2007. Brain volume was measured annually by magnetic resonance imaging (MRI) during the Double-blind period. Brain atrophy was measured by comparing the change in brain volume from baseline to the Last Observed Value (LOV). LOV is defined as the last post baseline measurement taken on study drug but no more than 30 days after study drug cessation. SIENA is a fully automated method of analyzing longitudinal brain change.

Outcome measures

Measure	Glatiramer Acetate (Double-blind Period) n=191 Participants Glatiramer acetate 20 mg once daily by subcutaneous injection during the double-blind period.	Placebo (Double-blind Period) n=174 Participants Placebo matching GA once daily by subcutaneous injection during the double-blind period.
Percentage Change in Brain Volume From Baseline to the Last Observed Value (LOV) During the Double-blind Period Using the Structural Image Evaluation of Normalized Atrophy (SIENA) Technique	-0.3 percent change Standard Deviation 0.6	-0.4 percent change Standard Deviation 0.7

SECONDARY outcome

Timeframe: up to 3 years

Population: Intent-to-Treat (ITT) analysis set.

Data from interim analysis with database lock on October 14, 2007. Conversion to CDMS as determined by the occurrence of a second clinical attack during the double-blind period. Poser criteria are: Two relapses and clinical evidence of two separate lesions; clinical evidence of one lesion and paraclinical evidence of another separate lesion. The two relapses must involve different parts of Central Nervous System and must be separated by a period of at least one month. Lesions are determined by Magnetic Resonance Imaging (MRI).

Outcome measures

Measure	Glatiramer Acetate (Double-blind Period) n=243 Participants Glatiramer acetate 20 mg once daily by subcutaneous injection during the double-blind period.	Placebo (Double-blind Period) n=238 Participants Placebo matching GA once daily by subcutaneous injection during the double-blind period.
Percentage of Participants Who Converted to Clinically Definite Multiple Sclerosis (CDMS) During the Double-blind Period	24.7 percentage of total participants	42.9 percentage of total participants

Adverse Events

Placebo (Double-blind Period)

Serious events: 19 serious events

Other events: 165 other events

Deaths: 0 deaths

Glatiramer Acetate (Double-blind Period)

Serious events: 11 serious events

Other events: 191 other events

Deaths: 0 deaths

Glatiramer Acetate (Entire Study)

Serious events: 44 serious events

Other events: 352 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo (Double-blind Period) n=238 participants at risk Placebo matching GA once daily by subcutaneous injection during the double-blind period.	Glatiramer Acetate (Double-blind Period) n=243 participants at risk Glatiramer acetate 20 mg once daily by subcutaneous injection during the double-blind period. This subset of the GA treatment experience allows for comparison to the Placebo Double-blind Period data.	Glatiramer Acetate (Entire Study) n=454 participants at risk Glatiramer acetate (GA) 20 mg once daily by subcutaneous injection. GA adverse experiences from both the double-blind and open-label periods are combined in this column.
Cardiac disorders Atrial fibrillation	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Cardiac disorders Palpitations	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Congenital, familial and genetic disorders Hydrocele	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Ear and labyrinth disorders Deafness	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Ear and labyrinth disorders Vertigo	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Gastrointestinal disorders Abdominal pain	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Gastrointestinal disorders Abdominal tenderness	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.41% 1/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Gastrointestinal disorders Haematemesis	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
General disorders Chest pain	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.44% 2/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
General disorders Chills	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
General disorders Feeling Hot	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Hepatobiliary disorders Cholecystitis	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Immune system disorders Anaphylactic Reaction	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.88% 4/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Immune system disorders Anaphylactic shock	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Immune system disorders Drug hypersensitivity	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Immune system disorders Hypersensitivity	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.41% 1/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.44% 2/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Infections and infestations Appendicitis	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Infections and infestations Gastroenteritis viral	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Infections and infestations Sinusitis	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Injury, poisoning and procedural complications Ankle fracture	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Injury, poisoning and procedural complications Avulsion fracture	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Injury, poisoning and procedural complications Contusion	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Injury, poisoning and procedural complications Fall	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Injury, poisoning and procedural complications Femoral neck fracture	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.41% 1/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Injury, poisoning and procedural complications Lumbar vertebral fracture	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Injury, poisoning and procedural complications Multiple drug overdose	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Injury, poisoning and procedural complications Post procedural haemorrhage	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Injury, poisoning and procedural complications Renal injury	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Investigations Hepatic enzyme increased	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.44% 2/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Investigations Platelet count decreased	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.41% 1/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Investigations Transaminases increased	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Investigations Visual field tests abnormal	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.41% 1/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Musculoskeletal and connective tissue disorders Fistula	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder transitional cell carcinoma	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cholesteatoma	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.41% 1/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rectal neoplasm	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine leiomyoma	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Nervous system disorders Amnesia	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Nervous system disorders Aphasia	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Nervous system disorders Cluster headache	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Nervous system disorders Dizziness	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Nervous system disorders Facial palsy	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Nervous system disorders Intracranial venous sinus thrombosis	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Nervous system disorders Multiple sclerosis relapse	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Nervous system disorders Syncope	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Pregnancy, puerperium and perinatal conditions Abortion spontaneous	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Pregnancy, puerperium and perinatal conditions Imminent abortion	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Psychiatric disorders Anxiety	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Psychiatric disorders Completed suicide	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.41% 1/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Psychiatric disorders Depression	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Psychiatric disorders Suicide attempt	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Renal and urinary disorders Nephrolithiasis	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.41% 1/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Renal and urinary disorders Renal colic	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Respiratory, thoracic and mediastinal disorders Asthma	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.44% 2/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Skin and subcutaneous tissue disorders Dermatitis allergic	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Skin and subcutaneous tissue disorders Urticaria	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.41% 1/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.44% 2/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Surgical and medical procedures Abortion induced	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Surgical and medical procedures Anal fissure excision	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Surgical and medical procedures Appendicectomy	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Surgical and medical procedures Bladder neoplasm surgery	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Surgical and medical procedures Breast reconstruction	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Surgical and medical procedures Cholecystectomy	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.41% 1/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.44% 2/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Surgical and medical procedures Cholesteatoma removal	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.41% 1/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Surgical and medical procedures Endometrial ablation	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Surgical and medical procedures Haemorrhoid operation	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Surgical and medical procedures Lipoma excision	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Surgical and medical procedures Nail operation	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Surgical and medical procedures Resection of rectum	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Surgical and medical procedures Skin neoplasm excision	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.41% 1/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Surgical and medical procedures Tonsillectomy	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Vascular disorders Flushing	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Vascular disorders Varicose vein	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.00% 0/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	0.22% 1/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).

Other adverse events

Measure	Placebo (Double-blind Period) n=238 participants at risk Placebo matching GA once daily by subcutaneous injection during the double-blind period.	Glatiramer Acetate (Double-blind Period) n=243 participants at risk Glatiramer acetate 20 mg once daily by subcutaneous injection during the double-blind period. This subset of the GA treatment experience allows for comparison to the Placebo Double-blind Period data.	Glatiramer Acetate (Entire Study) n=454 participants at risk Glatiramer acetate (GA) 20 mg once daily by subcutaneous injection. GA adverse experiences from both the double-blind and open-label periods are combined in this column.
Blood and lymphatic system disorders Lymphadenopathy	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	5.3% 13/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	6.2% 28/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Cardiac disorders Tachycardia	0.00% 0/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	4.1% 10/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	5.5% 25/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Gastrointestinal disorders Diarrhoea	4.2% 10/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	4.5% 11/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	5.7% 26/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Gastrointestinal disorders Nausea	5.0% 12/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	7.4% 18/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	7.5% 34/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Gastrointestinal disorders Vomiting	2.1% 5/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	6.2% 15/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	6.4% 29/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
General disorders Chest discomfort	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	5.3% 13/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	5.5% 25/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
General disorders Fatigue	9.2% 22/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	10.7% 26/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	8.8% 40/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
General disorders Injection site erythema	6.3% 15/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	29.6% 72/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	30.8% 140/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
General disorders Injection site haematoma	9.2% 22/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	6.6% 16/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	4.8% 22/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
General disorders Injection site induration	1.3% 3/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	10.3% 25/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	9.9% 45/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
General disorders Injection site pain	7.6% 18/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	22.2% 54/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	23.1% 105/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
General disorders Injection site pruritus	1.7% 4/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	12.8% 31/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	12.8% 58/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
General disorders Injection site reaction	2.1% 5/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	10.3% 25/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	9.0% 41/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
General disorders Injection site swelling	2.5% 6/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	9.9% 24/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	11.7% 53/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
General disorders Pyrexia	6.7% 16/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	5.3% 13/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	6.8% 31/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Infections and infestations Bronchitis	3.4% 8/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	4.9% 12/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	6.2% 28/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Infections and infestations Influenza	14.3% 34/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	11.1% 27/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	12.1% 55/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Infections and infestations Nasopharyngitis	20.6% 49/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	19.8% 48/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	20.7% 94/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Infections and infestations Pharyngitis	8.0% 19/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	7.0% 17/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	7.0% 32/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Infections and infestations Rhinitis	3.4% 8/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	5.8% 14/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	5.1% 23/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Infections and infestations Sinusitis	5.0% 12/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	6.2% 15/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	6.6% 30/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Infections and infestations Tonsillitis	2.9% 7/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	4.5% 11/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	5.1% 23/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Infections and infestations Upper respiratory tract infection	6.7% 16/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	9.1% 22/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	9.0% 41/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Infections and infestations Urinary tract infection	4.6% 11/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	4.1% 10/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	7.3% 33/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Musculoskeletal and connective tissue disorders Arthralgia	3.4% 8/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	3.7% 9/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	6.4% 29/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Musculoskeletal and connective tissue disorders Back pain	8.0% 19/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	10.3% 25/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	10.4% 47/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Musculoskeletal and connective tissue disorders Pain in extremity	7.1% 17/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	5.3% 13/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	6.2% 28/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Nervous system disorders Headache	18.1% 43/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	22.2% 54/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	17.6% 80/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Nervous system disorders Paraesthesia	7.6% 18/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	8.6% 21/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	8.1% 37/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Psychiatric disorders Anxiety	5.0% 12/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	6.2% 15/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	6.6% 30/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Psychiatric disorders Depression	5.9% 14/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	7.0% 17/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	7.7% 35/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Respiratory, thoracic and mediastinal disorders Cough	5.9% 14/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	7.8% 19/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	6.6% 30/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.3% 3/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	7.4% 18/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	10.6% 48/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Skin and subcutaneous tissue disorders Erythema	1.7% 4/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	4.5% 11/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	6.2% 28/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).
Vascular disorders Flushing	0.42% 1/238 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	6.2% 15/243 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).	6.8% 31/454 • The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).

Additional Information

Yossi Gilgun, PhD, Global Clinical Leader

Teva Pharmaceutical Industries, Ltd.

Phone: 972-9-863-1491

Email: yossi.gilgun@teva.co.il

Results disclosure agreements

• Principal investigator is a sponsor employee Should the investigator wish to publish the results of this study, he/she agrees to provide Teva with a manuscript for review 60 days prior to submission for publication. Teva retains the right to delete confidential information and to object to suggest publication and/or its timing (at the Company's sole discretion). If Teva chooses to publish this study a copy will be provided to the investigator at least 30 days prior to the expected date of submission to the intended publisher.
• Publication restrictions are in place

Restriction type: OTHER