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The Efficacy, Safety, and Tolerability of Laquinimod in Participants With Relapsing Remitting Multiple Sclerosis (RRMS) (CONCERTO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01707992
Recruitment Status : Completed
First Posted : October 16, 2012
Results First Posted : March 13, 2019
Last Update Posted : March 13, 2019
Sponsor:
Information provided by (Responsible Party):
Teva Pharmaceutical Industries ( Teva Branded Pharmaceutical Products, R&D Inc. )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Multiple Sclerosis
Interventions Drug: Laquinimod
Drug: Placebo
Enrollment 2199
Recruitment Details  
Pre-assignment Details The study was conducted at 215 sites in 29 countries.
Arm/Group Title Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg Active Treatment Phase: Laquinimod 0.6 mg Active Treatment Phase: Laquinimod 1.2 mg Active Treatment Phase: Off Drug
Hide Arm/Group Description Participants received 2 capsules of placebo (matched to laquinimod 0.6 milligrams [mg]) once daily orally for up to 24 months. Participants received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for up to 24 months. Participants received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for up to 24 months. Participants who completed the placebo-controlled phase on placebo and on laquinimod 0.6 mg treatment group after 01 January 2016, received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for 24 months. Participants who completed the placebo-controlled phase on placebo and on laquinimod 1.2 mg treatment group prior to 01 January 2016, received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for 24 months. Participants who were discontinued from treatment with laquinimod 1.2 mg during the placebo-controlled phase due to sponsor decision after 01 January 2016 continued to the active-treatment phase off drug for 24 months.
Period Title: Placebo-Controlled Phase (24 Months)
Started 740 727 732 0 0 0
Completed 596 623 532 0 0 0
Not Completed 144 104 200 0 0 0
Reason Not Completed
Adverse Event             8             13             9             0             0             0
Lack of Efficacy             10             3             2             0             0             0
Withdrawal by Subject             88             68             154             0             0             0
Protocol Violation             1             0             0             0             0             0
Pregnancy             12             5             9             0             0             0
Lost to Follow-up             10             4             9             0             0             0
Death             2             1             1             0             0             0
Noncompliance with drug administration             2             1             6             0             0             0
Other than specified             11             9             10             0             0             0
Period Title: Active Treatment Phase (24 Months)
Started 0 0 0 891 504 215
Completed 0 0 0 7 10 0
Not Completed 0 0 0 884 494 215
Reason Not Completed
Adverse Event             0             0             0             4             1             0
Lack of Efficacy             0             0             0             3             1             2
Withdrawal by Subject             0             0             0             58             220             32
Pregnancy             0             0             0             2             5             2
Lost to Follow-up             0             0             0             5             11             1
Death             0             0             0             2             0             0
Other than specified             0             0             0             1             5             2
Noncompliance             0             0             0             0             4             2
Study terminated by sponsor             0             0             0             809             243             174
Participant withdrew per Sponsor request             0             0             0             0             4             0
Arm/Group Title Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg Total
Hide Arm/Group Description Participants received 2 capsules of placebo (matched to laquinimod 0.6 mg) once daily orally for up to 24 months. Participants received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for up to 24 months. Participants received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for up to 24 months. Total of all reporting groups
Overall Number of Baseline Participants 740 727 732 2199
Hide Baseline Analysis Population Description
Intent-to-treat (ITT) analysis set included all randomized participants.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 740 participants 727 participants 732 participants 2199 participants
35.9  (8.95) 36.8  (9.25) 36.1  (9.22) 36.3  (9.14)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 740 participants 727 participants 732 participants 2199 participants
Adults (18-64 years)
740
 100.0%
727
 100.0%
732
 100.0%
2199
 100.0%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 740 participants 727 participants 732 participants 2199 participants
Female
488
  65.9%
510
  70.2%
475
  64.9%
1473
  67.0%
Male
252
  34.1%
217
  29.8%
257
  35.1%
726
  33.0%
Race  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 740 participants 727 participants 732 participants 2199 participants
White
724
  97.8%
712
  97.9%
717
  98.0%
2153
  97.9%
Black
3
   0.4%
3
   0.4%
3
   0.4%
9
   0.4%
Asian
3
   0.4%
2
   0.3%
3
   0.4%
8
   0.4%
Other
10
   1.4%
8
   1.1%
9
   1.2%
27
   1.2%
Missing
0
   0.0%
2
   0.3%
0
   0.0%
2
   0.1%
Kurtzke’s Expanded Disability Status Scale (EDSS) Score   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 740 participants 727 participants 732 participants 2199 participants
Less than or equal to (<=) 4.0
653
  88.2%
635
  87.3%
644
  88.0%
1932
  87.9%
Greater than (>) 4.0
87
  11.8%
90
  12.4%
88
  12.0%
265
  12.1%
Missing
0
   0.0%
2
   0.3%
0
   0.0%
2
   0.1%
[1]
Measure Description: EDSS assesses disability in 8 functional systems with an overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis [MS]).
Normalized Brain Volume   [1] 
Mean (Standard Deviation)
Unit of measure:  Milliliters (mL)
Number Analyzed 737 participants 722 participants 728 participants 2187 participants
1437.2  (93.37) 1433.0  (92.49) 1434.4  (93.41) 1434.9  (93.07)
[1]
Measure Analysis Population Description: This characteristic was analyzed for a total of 2187 participants (Placebo [737], Laquinimod 0.6 mg [722], and Laquinimod 1.2 mg [728])
1.Primary Outcome
Title Placebo-Controlled Phase: Time to Confirmed Disease Progression (CDP) Confirmed After At Least 3 Months (Number of Participants With CDP After At Least 3 Months)
Hide Description Time to CDP was defined as the time to a sustained increase in Kurtzke’s Expanded Disability Status Scale (EDSS) score of at least 1 point if baseline EDSS score was less than or equal to 5.0, or at least 0.5 point if the baseline EDSS score was 5.5, over a period of at least three months. EDSS assesses disability in 8 functional systems with an overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis [MS]). Data is presented as distribution of CDP (number of participants with CDP) sustained for 3 months.
Time Frame Baseline to Month 24
Hide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all randomized participants.
Arm/Group Title Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg
Hide Arm/Group Description:
Participants received 2 capsules of placebo (matched to laquinimod 0.6 mg) once daily orally for up to 24 months.
Participants received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for up to 24 months.
Participants received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for up to 24 months.
Overall Number of Participants Analyzed 740 727 732
Measure Type: Count of Participants
Unit of Measure: Participants
73
   9.9%
66
   9.1%
69
   9.4%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo-Controlled Phase: Placebo, Placebo-Controlled Phase: Laquinimod 0.6 mg
Comments The primary analysis for the comparison between laquinimod 0.6 mg versus placebo was conducted using the baseline adjusted Cox proportional hazards model. Categorical EDSS at baseline (less than or equal to [<=] 4 or greater than [>] 4), country/geographical region (CGR), categorical age at baseline (<=38 or >38), and T2 volume at baseline were included as covariates in the model.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value = 0.7057
Comments Threshold for significance at 0.05 level.
Method Cox proportional hazards model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.937
Confidence Interval (2-Sided) 95%
0.668 to 1.313
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Placebo-Controlled Phase: Percent Change From Baseline in Brain Volume at Month 15
Hide Description Brain atrophy was defined by the percent change in brain volume from baseline to Month 15. For participants who prematurely discontinued treatment or completed the placebo-controlled phase before Month 15, the last available measurement was used, provided it was performed at least 9 months following the initiation of study drug.
Time Frame Baseline, Month 15
Hide Outcome Measure Data
Hide Analysis Population Description
The modified intent-to-treat 1 (mITT1) analysis set included data from all randomized participants at the Month 15 visit. Here, 'Overall number of participants analyzed' = Participants evaluable for this outcome measure.
Arm/Group Title Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg
Hide Arm/Group Description:
Participants received 2 capsules of placebo (matched to laquinimod 0.6 mg) once daily orally for up to 24 months.
Participants received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for up to 24 months.
Participants received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for up to 24 months.
Overall Number of Participants Analyzed 619 636 616
Mean (Standard Deviation)
Unit of Measure: percent change
-0.8  (1.02) -0.4  (1.01) -0.4  (1.05)
3.Secondary Outcome
Title Placebo-Controlled Phase: Time to First Confirmed Relapse (Number of Participants With Confirmed Relapse)
Hide Description Relapse was defined as appearance of one or more new neurological abnormalities or reappearance or worsening of one or more previously observed neurological abnormalities, lasting for at least 48 hours (in absence of fever or any infection) and immediately preceded by an improving neurological state of at least 30 days from onset of previous relapse. An event was counted as a relapse only when the participant’s symptoms were accompanied by observed objective neurological changes, consistent with an increase of at least 0.5 in EDSS; or one grade in score of 2 or more of 7 Functional Systems (FS) (excluding changes in bowel or bladder function or cognition); or 2 grades in score of one of the FS as compared to previous evaluation. EDSS assesses disability in 8 FS with an overall score ranging from 0 (normal) to 10 (death due to MS). Data is presented as distribution of relapsing participants (number of participants with confirmed relapse).
Time Frame Baseline to Month 24
Hide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all randomized participants.
Arm/Group Title Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg
Hide Arm/Group Description:
Participants received 2 capsules of placebo (matched to laquinimod 0.6 mg) once daily orally for up to 24 months.
Participants received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for up to 24 months.
Participants received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for up to 24 months.
Overall Number of Participants Analyzed 740 727 732
Measure Type: Count of Participants
Unit of Measure: Participants
332
  44.9%
269
  37.0%
222
  30.3%
4.Secondary Outcome
Title Placebo-Controlled Phase: Time to CDP Confirmed After At Least 6 Months (Number of Participants With CDP After At Least 6 Months)
Hide Description Time to CDP was defined as the time to a sustained increase in Kurtzke’s EDSS score of at least 1 point if baseline EDSS score was less than or equal to 5.0, or at least 0.5 point if the baseline EDSS score was 5.5, over a period of at least 6 months. EDSS assesses disability in 8 functional systems with an overall score ranging from 0 (normal) to 10 (death due to MS). Data is presented as distribution of CDP (number of participants with CDP) sustained for 6 months.
Time Frame Baseline to Month 24
Hide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all randomized participants.
Arm/Group Title Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg
Hide Arm/Group Description:
Participants received 2 capsules of placebo (matched to laquinimod 0.6 mg) once daily orally for up to 24 months.
Participants received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for up to 24 months.
Participants received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for up to 24 months.
Overall Number of Participants Analyzed 740 727 732
Measure Type: Count of Participants
Unit of Measure: Participants
49
   6.6%
49
   6.7%
51
   7.0%
5.Secondary Outcome
Title Placebo-Controlled Phase: Time to CDP Confirmed After At Least 9 Months (Number of Participants With Confirmed Relapse After At Least 9 Months)
Hide Description Time to CDP was defined as the time to a sustained increase in Kurtzke’s EDSS score of at least 1 point if baseline EDSS score was less than or equal to 5.0, or at least 0.5 point if the baseline EDSS score was 5.5, over a period of at least 9 months. EDSS assesses disability in 8 functional systems with an overall score ranging from 0 (normal) to 10 (death due to MS). Data is presented as distribution of CDP (number of participants with CDP) sustained for 9 months.
Time Frame Baseline to Month 24
Hide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all randomized participants.
Arm/Group Title Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg
Hide Arm/Group Description:
Participants received 2 capsules of placebo (matched to laquinimod 0.6 mg) once daily orally for up to 24 months.
Participants received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for up to 24 months.
Participants received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for up to 24 months.
Overall Number of Participants Analyzed 740 727 732
Measure Type: Count of Participants
Unit of Measure: Participants
38
   5.1%
38
   5.2%
39
   5.3%
6.Other Pre-specified Outcome
Title Placebo-Controlled Phase: Number of Participants With Adverse Events (AEs)
Hide Description An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs.
Time Frame Baseline up to Month 24
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set included all participants who were randomized and received at least one dose of study drug.
Arm/Group Title Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg
Hide Arm/Group Description:
Participants received 2 capsules of placebo (matched to laquinimod 0.6 mg) once daily orally for up to 24 months.
Participants received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for up to 24 months.
Participants received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for up to 24 months.
Overall Number of Participants Analyzed 740 727 732
Measure Type: Count of Participants
Unit of Measure: Participants
546
  73.8%
565
  77.7%
575
  78.6%
7.Other Pre-specified Outcome
Title Active-Treatment Phase: Number of Participants With AEs
Hide Description An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs.
Time Frame Baseline (Month 0 of active-treatment phase/Month 24 of placebo-controlled phase) up to Month 24 of active-treatment phase
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set in active-treatment phase included all participants who completed placebo-controlled phase on treatment and continued to either of the 2 laquinimod treatments during active-treatment phase.
Arm/Group Title Active Treatment Phase: Laquinimod 0.6 mg Active Treatment Phase: Laquinimod 1.2 mg
Hide Arm/Group Description:
Participants who completed the placebo-controlled phase on placebo and on laquinimod 0.6 mg treatment group after 01 January 2016, received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for 24 months.
Participants who completed the placebo-controlled phase on placebo and on laquinimod 1.2 mg treatment group prior to 01 January 2016, received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for 24 months.
Overall Number of Participants Analyzed 891 504
Measure Type: Count of Participants
Unit of Measure: Participants
442
  49.6%
241
  47.8%
8.Other Pre-specified Outcome
Title Placebo-Controlled Phase: Number of Participants With Clinically Significant Vital Signs Abnormalities
Hide Description Clinically significant vital signs abnormalities included: Pulse rate: greater than or equal to (>=) 120 beats per minute (bpm) and increase from baseline of >=30 bpm, <=45 bpm and decrease from baseline of >=30 bpm; Systolic blood pressure: >=180 millimeters of mercury (mmHg) and increase from baseline of >=30 mmHg, <=90 and decrease from baseline of >=30 mmHg; Diastolic blood pressure: >=100 mmHg and increase from baseline of >=20 mmHg, <=50 mmHg and decrease from baseline of >=20 mmHg.
Time Frame Baseline up to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set included all participants who were randomized and received at least one dose of study drug.
Arm/Group Title Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg
Hide Arm/Group Description:
Participants received 2 capsules of placebo (matched to laquinimod 0.6 mg) once daily orally for up to 24 months.
Participants received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for up to 24 months.
Participants received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for up to 24 months.
Overall Number of Participants Analyzed 740 727 732
Measure Type: Count of Participants
Unit of Measure: Participants
21
   2.8%
21
   2.9%
29
   4.0%
9.Other Pre-specified Outcome
Title Active-Treatment Phase: Number of Participants With Clinically Significant Vital Signs Abnormalities
Hide Description Clinically significant vital signs abnormalities included: Pulse rate: >=120 bpm and increase from baseline of >=30 bpm, <=45 bpm and decrease from baseline of >=30 bpm; Systolic blood pressure: >=180 mmHg and increase from baseline of >=30 mmHg, <=90 and decrease from baseline of >=30 mmHg; Diastolic blood pressure: >=100 mmHg and increase from baseline of >=20 mmHg, <=50 mmHg and decrease from baseline of >=20 mmHg.
Time Frame Baseline (Month 0 of active-treatment phase/Month 24 of placebo-controlled phase) up to Month 24 of active-treatment phase
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set in active-treatment phase included all participants who completed placebo-controlled phase on treatment and continued to either of the 2 laquinimod treatments during active-treatment phase.
Arm/Group Title Active Treatment Phase: Laquinimod 0.6 mg Active Treatment Phase: Laquinimod 1.2 mg
Hide Arm/Group Description:
Participants who completed the placebo-controlled phase on placebo and on laquinimod 0.6 mg treatment group after 01 January 2016, received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for 24 months.
Participants who completed the placebo-controlled phase on placebo and on laquinimod 1.2 mg treatment group prior to 01 January 2016, received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for 24 months.
Overall Number of Participants Analyzed 891 504
Measure Type: Count of Participants
Unit of Measure: Participants
17
   1.9%
7
   1.4%
10.Other Pre-specified Outcome
Title Placebo-Controlled Phase: Number of Participants With Shift From Baseline to Endpoint in Electrocardiogram (ECG) Parameters
Hide Description ECG parameters included: PR interval, QRS interval, QT interval corrected using the Fridericia formula (QTcF) and QT interval corrected using the Bazett's formula (QTcB). Shifts represented as Baseline - endpoint value (last observed post-baseline value). Abnormal NCS indicated an abnormal but not clinically significant finding. Abnormal CS indicated an abnormal and clinically significant finding.
Time Frame Baseline, Endpoint (Month 24)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set included all participants who were randomized and received at least one dose of study drug. Here, 'Overall number of participants analyzed=participants evaluable for this outcome measure.
Arm/Group Title Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg
Hide Arm/Group Description:
Participants received 2 capsules of placebo (matched to laquinimod 0.6 mg) once daily orally for up to 24 months.
Participants received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for up to 24 months.
Participants received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for up to 24 months.
Overall Number of Participants Analyzed 734 723 724
Measure Type: Count of Participants
Unit of Measure: Participants
Normal - Normal
463
  63.1%
467
  64.6%
470
  64.9%
Normal - Abnormal NCS
139
  18.9%
124
  17.2%
126
  17.4%
Normal - Abnormal CS
0
   0.0%
6
   0.8%
5
   0.7%
Abnormal NCS - Normal
32
   4.4%
27
   3.7%
28
   3.9%
Abnormal NCS - Abnormal NCS
98
  13.4%
96
  13.3%
90
  12.4%
Abnormal NCS - Abnormal CS
1
   0.1%
1
   0.1%
2
   0.3%
Abnormal CS - Normal
0
   0.0%
1
   0.1%
0
   0.0%
Abnormal CS - Abnormal NCS
0
   0.0%
0
   0.0%
0
   0.0%
Abnormal CS - Abnormal CS
1
   0.1%
1
   0.1%
3
   0.4%
11.Other Pre-specified Outcome
Title Active Treatment Phase: Number of Participants With Shift From Baseline to Endpoint in ECG Parameters
Hide Description ECG parameters included: PR interval, QRS interval, QTcF and QTcB. Shifts represented as Baseline - endpoint value (last observed post-baseline value). Abnormal NCS indicated an abnormal but not clinically significant finding. Abnormal CS indicated an abnormal and clinically significant finding.
Time Frame Baseline (Month 0 of active-treatment phase/Month 24 of placebo-controlled phase), endpoint (Month 24 of active-treatment phase)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set in active-treatment phase included all participants who completed placebo-controlled phase on treatment and continued to either of the 2 laquinimod treatments during active-treatment phase and had ECG shift from baseline data available.
Arm/Group Title Active Treatment Phase: Laquinimod 0.6 mg Active Treatment Phase: Laquinimod 1.2 mg
Hide Arm/Group Description:
Participants who completed the placebo-controlled phase on placebo and on laquinimod 0.6 mg treatment group after 01 January 2016, received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for 24 months.
Participants who completed the placebo-controlled phase on placebo and on laquinimod 1.2 mg treatment group prior to 01 January 2016, received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for 24 months.
Overall Number of Participants Analyzed 888 501
Measure Type: Count of Participants
Unit of Measure: Participants
Normal – Normal
641
  72.2%
353
  70.5%
Normal - Abnormal NCS
137
  15.4%
80
  16.0%
Normal - Abnormal CS
7
   0.8%
5
   1.0%
Abnormal NCS – Normal
18
   2.0%
17
   3.4%
Abnormal NCS - Abnormal NCS
81
   9.1%
45
   9.0%
Abnormal NCS - Abnormal CS
4
   0.5%
0
   0.0%
Abnormal CS – Normal
0
   0.0%
0
   0.0%
Abnormal CS - Abnormal NCS
0
   0.0%
0
   0.0%
Abnormal CS - Abnormal CS
0
   0.0%
1
   0.2%
12.Other Pre-specified Outcome
Title Placebo-Controlled Phase: Number of Participants With Potentially Clinically Significant Abnormal Serum Chemistry
Hide Description Potentially clinically significant serum chemistry abnormalities included: Glucose <=3 and >=13.88 millimoles per liter (mmol/L); Alanine aminotransferase (ALT) (in units per liter [U/L]), aspartate aminotransferase (AST) (in U/L), alkaline phosphatase (in U/L), gamma-glutamyltransferase (GGT) (in U/L), creatine phosphokinase (CPK) (in U/L), C-reactive protein (CRP) (in milligrams per liter [mg/L]), pancreatic amylase (in U/L)>=3 * upper limit of normal (ULN); Fibrinogen >=6 grams per liter (gm/L); Sodium <=130 and >=150 mmol/L; Potassium <=3.2 and >=5.5 mmol/L; Calcium <=1.87 and >=2.75 mmol/L; Phosphate <=0.65 and >=1.61 mmol/L.
Time Frame Baseline up to Month 24
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set included all participants who were randomized and received at least one dose of study drug. Here, 'Overall number of participants analyzed'=participants evaluable for this outcome measure.
Arm/Group Title Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg
Hide Arm/Group Description:
Participants received 2 capsules of placebo (matched to laquinimod 0.6 mg) once daily orally for up to 24 months.
Participants received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for up to 24 months.
Participants received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for up to 24 months.
Overall Number of Participants Analyzed 736 723 724
Measure Type: Count of Participants
Unit of Measure: Participants
157
  21.3%
165
  22.8%
187
  25.8%
13.Other Pre-specified Outcome
Title Active Treatment Phase: Number of Participants With Potentially Clinically Significant Abnormal Serum Chemistry
Hide Description Potentially clinically significant serum chemistry abnormalities included: Glucose <=3 and >=13.88 mmol/L; ALT (in U/L), AST (in U/L), alkaline phosphatase (in U/L), GGT (in U/L), CPK (in U/L), CRP (in mg/L), pancreatic amylase (in U/L)>=3 * ULN; Fibrinogen >=6 gm/L; Sodium <=130 and >=150 mmol/L; Potassium <=3.2 and >=5.5 mmol/L; Calcium <=1.87 and >=2.75 mmol/L; Phosphate <=0.65 and >=1.61 mmol/L; Blood urea nitrogen (in mmol/L); Total bilirubin >=28 micromols per liter (micromols/L); Creatinine >=117 micromols/L; Albumin <=25 gm/L.
Time Frame Baseline (Month 0 of active-treatment phase/Month 24 of placebo-controlled phase) up to Month 24 of active-treatment phase
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set in active-treatment phase included all participants who completed placebo-controlled phase on treatment and continued to either of the 2 laquinimod treatments during active-treatment phase.
Arm/Group Title Active Treatment Phase: Laquinimod 0.6 mg Active Treatment Phase: Laquinimod 1.2 mg
Hide Arm/Group Description:
Participants who completed the placebo-controlled phase on placebo and on laquinimod 0.6 mg treatment group after 01 January 2016, received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for 24 months.
Participants who completed the placebo-controlled phase on placebo and on laquinimod 1.2 mg treatment group prior to 01 January 2016, received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for 24 months.
Overall Number of Participants Analyzed 891 504
Measure Type: Count of Participants
Unit of Measure: Participants
887
  99.6%
501
  99.4%
14.Other Pre-specified Outcome
Title Placebo-Controlled Phase: Number of Participants With Potentially Clinically Significant Abnormal Hematology Values
Hide Description Potentially clinically significant hematological abnormalities included: Hemoglobin <=11.5 grams per deciliter (gm/dL) in males and <=10 gm/dL in females; White blood cells (WBCs) count <=2.5 and >=21*10^9 per liter (L); Absolute neutrophil count (ANC) <=1.49*10^9 per L; Platelet count <=100 and >=600*10^9 per L.
Time Frame Baseline up to Month 24
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set included all participants who were randomized and received at least one dose of study drug. Here, 'Overall number of participants analyzed'=participants evaluable for this outcome measure.
Arm/Group Title Placebo-Controlled Phase: Placebo Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg
Hide Arm/Group Description:
Participants received 2 capsules of placebo (matched to laquinimod 0.6 mg) once daily orally for up to 24 months.
Participants received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for up to 24 months.
Participants received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for up to 24 months.
Overall Number of Participants Analyzed 735 723 723
Measure Type: Count of Participants
Unit of Measure: Participants
71
   9.7%
78
  10.8%
83
  11.5%
15.Other Pre-specified Outcome
Title Active Treatment Phase: Number of Participants With Potentially Clinically Significant Abnormal Hematology Values
Hide Description Potentially clinically significant hematological abnormalities included: Hemoglobin <=11.5, >=20 gm/dL in males, and <=10, >=18.5 gm/dL in females; WBCs count <=2.5 and >=21*10^9 per L; ANC <=1.49*10^9 per L; Platelet count <=100 and >=600*10^9 per L.
Time Frame Baseline (Month 0 of active-treatment phase/Month 24 of placebo-controlled phase) up to Month 24 of active-treatment phase
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set in active-treatment phase included all participants who completed placebo-controlled phase on treatment and continued to either of the 2 laquinimod treatments during active-treatment phase.
Arm/Group Title Active Treatment Phase: Laquinimod 0.6 mg Active Treatment Phase: Laquinimod 1.2 mg
Hide Arm/Group Description:
Participants who completed the placebo-controlled phase on placebo and on laquinimod 0.6 mg treatment group after 01 January 2016, received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for 24 months.
Participants who completed the placebo-controlled phase on placebo and on laquinimod 1.2 mg treatment group prior to 01 January 2016, received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for 24 months.
Overall Number of Participants Analyzed 891 504
Measure Type: Count of Participants
Unit of Measure: Participants
886
  99.4%
499
  99.0%
Time Frame Adverse events were collected for the procedure and at each follow-up visit at 2 weeks, 6 weeks, 12 weeks, 24 weeks, and 52 weeks post-treatment.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg Placebo-Controlled Phase: Placebo Active Treatment Phase: Early Laquinimod 0.6 mg Active Treatment Phase: Early Laquinimod 1.2 mg Active Treatment Phase: Off Drug Active Treatment Phase: From Placebo to Laquinimod 0.6 mg Active Treatment Phase: From Placebo to Laquinimod 1.2 mg
Hide Arm/Group Description Participants received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for up to 24 months. Participants received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for up to 24 months. Participants received 2 capsules of placebo (matched to laquinimod 0.6 mg) once daily orally for up to 24 months. Participants who completed the placebo-controlled phase on laquinimod 0.6 mg treatment group after 01 January 2016, received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for 24 months. Participants who completed the placebo-controlled phase on laquinimod 1.2 mg treatment group prior to 01 January 2016, received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for 24 months. Participants who were discontinued from treatment with laquinimod 1.2 mg during the placebo-controlled phase due to sponsor decision after 01 January 2016, continued to the active-treatment phase off drug for 24 months. Participants who completed the placebo-controlled phase on placebo treatment group after 01 January 2016, received 1 capsule of laquinimod 0.6 mg and 1 capsule of matching placebo once daily orally for 24 months. Participants who completed the placebo-controlled phase on placebo treatment group prior to 01 January 2016, received laquinimod 1.2 mg (2 capsules of laquinimod 0.6 mg each) once daily orally for 24 months.
All-Cause Mortality
Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg Placebo-Controlled Phase: Placebo Active Treatment Phase: Early Laquinimod 0.6 mg Active Treatment Phase: Early Laquinimod 1.2 mg Active Treatment Phase: Off Drug Active Treatment Phase: From Placebo to Laquinimod 0.6 mg Active Treatment Phase: From Placebo to Laquinimod 1.2 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/727 (0.14%)      1/732 (0.14%)      2/740 (0.27%)      2/580 (0.34%)      0/268 (0.00%)      0/215 (0.00%)      0/311 (0.00%)      0/236 (0.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
Placebo-Controlled Phase: Laquinimod 0.6 mg Placebo-Controlled Phase: Laquinimod 1.2 mg Placebo-Controlled Phase: Placebo Active Treatment Phase: Early Laquinimod 0.6 mg Active Treatment Phase: Early Laquinimod 1.2 mg Active Treatment Phase: Off Drug Active Treatment Phase: From Placebo to Laquinimod 0.6 mg Active Treatment Phase: From Placebo to Laquinimod 1.2 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   57/727 (7.84%)      49/732 (6.69%)      43/740 (5.81%)      24/580 (4.14%)      10/268 (3.73%)      5/215 (2.33%)      5/311 (1.61%)      9/236 (3.81%)    
Blood and lymphatic system disorders                 
Hypochromic anaemia  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Immune thrombocytopenic purpura  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Iron deficiency anaemia  1  1/727 (0.14%)  1 0/732 (0.00%)  0 2/740 (0.27%)  2 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 1/236 (0.42%)  1
Lymphadenitis  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 1/268 (0.37%)  1 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Thrombocytopenia  1  1/727 (0.14%)  1 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Cardiac disorders                 
Acute myocardial infarction  1  0/727 (0.00%)  0 4/732 (0.55%)  4 0/740 (0.00%)  0 1/580 (0.17%)  1 1/268 (0.37%)  1 1/215 (0.47%)  1 0/311 (0.00%)  0 0/236 (0.00%)  0
Angina pectoris  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 1/236 (0.42%)  1
Arteriosclerosis coronary artery  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Atrial fibrillation  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Cardiogenic shock  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Cardiovascular insufficiency  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Coronary artery occlusion  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 1/215 (0.47%)  1 0/311 (0.00%)  0 0/236 (0.00%)  0
Coronary artery stenosis  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Myocardial infarction  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 2/580 (0.34%)  2 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Myocardial ischaemia  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Ear and labyrinth disorders                 
Vertigo  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Gastrointestinal disorders                 
Abdominal pain  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 1/236 (0.42%)  1
Coeliac disease  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Colitis  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 1/236 (0.42%)  1
Duodenal perforation  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 1/236 (0.42%)  1
Enteritis  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Gastric polyps  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Gastritis  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Gastritis erosive  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Gastrointestinal inflammation  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Gastrooesophageal reflux disease  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Inguinal hernia  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Pancreatic necrosis  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 1/268 (0.37%)  1 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Pancreatitis  1  0/727 (0.00%)  0 4/732 (0.55%)  4 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Pancreatitis acute  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Pancreatitis chronic  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Periodontal inflammation  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Peritoneal adhesions  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Peritoneal haemorrhage  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Autoimmune pancreatitis  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Ileus  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
General disorders                 
Asthenia  1  0/727 (0.00%)  0 1/732 (0.14%)  2 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Fatigue  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Gait disturbance  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Non-cardiac chest pain  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Pyrexia  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Strangulated hernia  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 1/268 (0.37%)  1 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Hepatobiliary disorders                 
Cholecystitis  1  0/727 (0.00%)  0 3/732 (0.41%)  3 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Cholecystitis acute  1  2/727 (0.28%)  2 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Cholecystitis chronic  1  2/727 (0.28%)  2 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Cholelithiasis  1  1/727 (0.14%)  1 0/732 (0.00%)  0 2/740 (0.27%)  2 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Cholelithiasis obstructive  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Cholestasis  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Drug-induced liver injury  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Hepatitis cholestatic  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Hepatotoxicity  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Hepatitis toxic  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Immune system disorders                 
Drug hypersensitivity  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 1/311 (0.32%)  1 0/236 (0.00%)  0
Sarcoidosis  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Infections and infestations                 
Abscess oral  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Appendicitis  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 1/236 (0.42%)  1
Bronchitis  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Cholecystitis infective  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Chronic sinusitis  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 1/268 (0.37%)  1 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Chronic tonsillitis  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Endometritis  1  1/727 (0.14%)  1 0/732 (0.00%)  0 2/740 (0.27%)  2 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Enterovirus infection  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Erysipelas  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Helicobacter gastritis  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Hepatitis B  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Herpes zoster oticus  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Infected dermal cyst  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 1/311 (0.32%)  1 0/236 (0.00%)  0
Ovarian abscess  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Peritonitis  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 1/268 (0.37%)  1 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Pilonidal cyst  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Pneumonia  1  2/727 (0.28%)  2 2/732 (0.27%)  2 1/740 (0.14%)  1 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Pneumonia bacterial  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Pyelonephritis  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Pyelonephritis acute  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Pyelonephritis chronic  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Salpingitis  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Salpingo-oophoritis  1  2/727 (0.28%)  2 0/732 (0.00%)  0 2/740 (0.27%)  2 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Sepsis  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 1/268 (0.37%)  1 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Sinusitis  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Urinary bladder abscess  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Urinary tract infection  1  1/727 (0.14%)  1 1/732 (0.14%)  1 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Uterine infection  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Hepatitis viral  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Tuberculosis  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Injury, poisoning and procedural complications                 
Ankle fracture  1  0/727 (0.00%)  0 2/732 (0.27%)  2 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 1/311 (0.32%)  1 0/236 (0.00%)  0
Bone contusion  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Brain contusion  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 1/268 (0.37%)  1 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Cartilage injury  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Craniocerebral injury  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 1/268 (0.37%)  1 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Fall  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Femoral neck fracture  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 1/311 (0.32%)  1 0/236 (0.00%)  0
Femur fracture  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Head injury  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Humerus fracture  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Jaw fracture  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Meniscus injury  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 1/236 (0.42%)  1
Multiple injuries  1  1/727 (0.14%)  1 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Poisoning deliberate  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Postoperative adhesion  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Pubis fracture  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Radius fracture  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Road traffic accident  1  2/727 (0.28%)  2 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Skull fracture  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 1/268 (0.37%)  1 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Skull fractured base  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 1/268 (0.37%)  1 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Subdural haematoma  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 1/268 (0.37%)  1 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Thermal burn  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Thoracic vertebral fracture  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Toxicity to various agents  1  1/727 (0.14%)  1 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Traumatic liver injury  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Ulna fracture  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Upper limb fracture  1  1/727 (0.14%)  1 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Intentional overdose  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Investigations                 
Alpha 1 foetoprotein abnormal  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 1/236 (0.42%)  1
Blood creatine phosphokinase increased  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 1/215 (0.47%)  1 0/311 (0.00%)  0 0/236 (0.00%)  0
Hepatic enzyme increased  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Nuclear magnetic resonance imaging brain abnormal  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Troponin increased  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Metabolism and nutrition disorders                 
Diabetes mellitus  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Diabetes mellitus inadequate control  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Diabetic ketoacidosis  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Metabolic disorder  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Type 1 diabetes mellitus  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Musculoskeletal and connective tissue disorders                 
Ankylosing spondylitis  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Cervical spinal stenosis  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Femoroacetabular impingement  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Intervertebral disc protrusion  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 1/268 (0.37%)  1 0/215 (0.00%)  0 0/311 (0.00%)  0 1/236 (0.42%)  1
Musculoskeletal chest pain  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Neck pain  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Osteoarthritis  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Osteonecrosis  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Pain in extremity  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Spinal osteoarthritis  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 1/236 (0.42%)  1
Spinal pain  1  1/727 (0.14%)  2 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                 
Basal cell carcinoma  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Benign breast neoplasm  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Benign neoplasm of adrenal gland  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Chronic lymphocytic leukaemia  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 1/268 (0.37%)  1 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Clear cell renal cell carcinoma  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Fibroadenoma of breast  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Haemangioma  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Metastases to central nervous system  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 1/215 (0.47%)  1 0/311 (0.00%)  0 0/236 (0.00%)  0
Metastases to chest wall  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 1/215 (0.47%)  1 0/311 (0.00%)  0 0/236 (0.00%)  0
Papilloma  1  1/727 (0.14%)  1 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Salivary gland adenoma  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Thyroid cancer  1  1/727 (0.14%)  1 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Uterine leiomyoma  1  5/727 (0.69%)  5 0/732 (0.00%)  0 2/740 (0.27%)  2 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Bone sarcoma  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Nervous system disorders                 
Altered state of consciousness  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Coma  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Diabetic neuropathy  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Haemorrhagic stroke  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 1/215 (0.47%)  1 0/311 (0.00%)  0 0/236 (0.00%)  0
Headache  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Ischaemic stroke  1  0/727 (0.00%)  0 1/732 (0.14%)  1 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Multiple sclerosis  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Multiple sclerosis relapse  1  2/727 (0.28%)  2 1/732 (0.14%)  1 7/740 (0.95%)  7 2/580 (0.34%)  2 1/268 (0.37%)  1 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Neurological decompensation  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Neuromyelitis optica spectrum disorder  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Psychomotor hyperactivity  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Seizure  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Syncope  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Trigeminal neuralgia  1  1/727 (0.14%)  1 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Status epilepticus  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Pregnancy, puerperium and perinatal conditions                 
Abortion spontaneous  1  1/727 (0.14%)  1 0/732 (0.00%)  0 2/740 (0.27%)  2 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Foetal growth abnormality  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 1/236 (0.42%)  1
Unintended pregnancy  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 1/236 (0.42%)  1
Abortion  1  0/727 (0.00%)  0 2/732 (0.27%)  2 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Abortion missed  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Abortion threatened  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Psychiatric disorders                 
Acute psychosis  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Affective disorder  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Confusional state  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Major depression  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Persecutory delusion  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Personality change due to a general medical condition  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Psychotic disorder  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Schizophrenia  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Suicidal ideation  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Completed suicide  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Suicide attempt  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Renal and urinary disorders                 
Nephrolithiasis  1  1/727 (0.14%)  1 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Hydronephrosis  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Reproductive system and breast disorders                 
Acquired hydrocele  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 1/268 (0.37%)  1 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Adnexal torsion  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Cervix disorder  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Fallopian tube cyst  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Menometrorrhagia  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Metrorrhagia  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Ovarian cyst  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 1/311 (0.32%)  1 0/236 (0.00%)  0
Ovarian haemorrhage  1  1/727 (0.14%)  2 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Polycystic ovaries  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Respiratory, thoracic and mediastinal disorders                 
Acute respiratory failure  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Interstitial lung disease  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 1/236 (0.42%)  1
Lung disorder  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Nasal septum deviation  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Pleurisy  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Pneumothorax spontaneous  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Vasomotor rhinitis  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Bronchiectasis  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Skin and subcutaneous tissue disorders                 
Urticaria  1  2/727 (0.28%)  2 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Surgical and medical procedures                 
Hospitalisation  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 1/215 (0.47%)  1 0/311 (0.00%)  0 0/236 (0.00%)  0
Vascular disorders                 
Deep vein thrombosis  1  0/727 (0.00%)  0 1/732 (0.14%)  1 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Embolism arterial  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Hypertension  1  0/727 (0.00%)  0 0/732 (0.00%)  0 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Orthostatic hypotension  1  0/727 (0.00%)  0 0/732 (0.00%)  0 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Thrombophlebitis  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 1/580 (0.17%)  1 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Varicose vein  1  0/727 (0.00%)  0 1/732 (0.14%)  1 1/740 (0.14%)  1 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Vasculitis  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0
Venous thrombosis limb  1  1/727 (0.14%)  1 0/732 (0.00%)  0 0/740 (0.00%)  0 0/580 (0.00%)  0 0/268 (0.00%)  0 0/215 (0.00%)  0 0/311 (0.00%)  0 0/236 (0.00%)  0