We're building a better ClinicalTrials.gov. Check it out and tell us what you think!
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Bardoxolone Methyl Evaluation in Patients With Pulmonary Hypertension (PH) - LARIAT

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: NCT02036970
Recruitment Status : Completed
First Posted : January 15, 2014
Results First Posted : July 23, 2021
Last Update Posted : December 7, 2021
Sponsor:
Information provided by (Responsible Party):
Reata Pharmaceuticals, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Sequential Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Conditions Pulmonary Arterial Hypertension
Pulmonary Hypertension
Interstitial Lung Disease
Idiopathic Interstitial Pneumonia
Idiopathic Pulmonary Fibrosis
Sarcoidosis
Respiratory Bronchiolitis Associated Interstitial Lung Disease
Desquamative Interstitial Pneumonia
Cryptogenic Organizing Pneumonia
Acute Interstitial Pneumonitis
Idiopathic Lymphoid Interstitial Pneumonia
Idiopathic Pleuroparenchymal Fibroelastosis
Interventions Drug: Bardoxolone methyl
Drug: Placebo
Enrollment 166
Recruitment Details  
Pre-assignment Details Part 1: 16-week double-blind, randomized, placebo-controlled treatment period (Day 1 to Week 16). Part 2: Open-label extension period (Week 16 onwards). Part 2 is the extension period and patients were to stay until study drug became available through extended access program [Study 402-C-1602]. Each participant in Part 2 was also in Part 1.
Arm/Group Title Part 1: Dose-Ranging Bardoxolone Methyl 2.5 mg/Part 2: Open-Label Part 1: Dose-Ranging Bardoxolone Methyl 5 mg/Part 2: Open-Label Part 1: Dose-Ranging Bardoxolone Methyl 10 mg/Part 2: Open-Label Part 1: Dose-Ranging Bardoxolone Methyl 20 mg/Part 2: Open-Label Part 1: Dose-Ranging Placebo 2.5 mg/Part 2: Bardoxolone Methyl 2.5 mg Part 1: Dose-Ranging Placebo 5 mg/Part 2: Bardoxolone Methyl 5 mg Part 1: Dose-Ranging Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 1: Dose-Ranging Placebo 20 mg/Part 2: Bardoxolone Methyl 20 mg Part 1: Dose Titration: Bardoxolone Methyl 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg
Hide Arm/Group Description Participants received bardoxolone methyl 2.5 mg once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 continued to receive the same bardoxolone methyl 2.5 mg once-daily in Part 2 (Week 16 and onwards) Participants received bardoxolone methyl 5 mg once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 continued to receive the same bardoxolone methyl 5 mg once-daily in Part 2 (Week 16 and onwards) Participants received bardoxolone methyl 10 mg once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 continued to receive the same bardoxolone methyl 10 mg once-daily in Part 2 (Week 16 and onwards) Participants received bardoxolone methyl 20 mg once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 continued to receive the same bardoxolone methyl 20 mg once-daily in Part 2 (Week 16 and onwards) Participants received bardoxolone methyl 2.5 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 2.5 mg once-daily in Part 2 (Week 16 and onwards) Participants received bardoxolone methyl 5 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 5 mg once-daily in Part 2 (Week 16 and onwards) Participants received bardoxolone methyl 10 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 10 mg once-daily in Part 2 (Week 16 and onwards) Participants received bardoxolone methyl 20 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 20 mg once-daily in Part 2 (Week 16 and onwards) Participants in Part 1 started with bardoxolone methyl 5 mg once-daily from Day 1 and escalated to bardoxolone methyl 10 mg once-daily starting at Week 4 thru Week 16. Participants who continued to Part 2 continued to receive the same bardoxolone methyl dose once-daily in Part 2 (Week 16 and onwards) Participants in Part 1 received Placebo once-daily from Day 1 thru Week 16. Participants who continued to Part 2 initially received bardoxolone methyl 5 mg once-daily from Week 16 thru Week 20 and bardoxolone methyl 10 mg from week 20 onwards
Period Title: Part 1: Day 1 Through Week 16
Started 6 12 11 12 2 4 3 4 74 38
Cohort 1: PAH (BL 6MWD <= 450 Meters) 6 6 11 6 2 2 3 2 0 0
Cohort 2: PAH (BL 6MWD > 450 Meters) 0 6 0 6 0 2 0 2 0 0
Cohort 3a: PAH CTD 0 0 0 0 0 0 0 0 14 8
Cohort 3b: PAH Non-CTD 0 0 0 0 0 0 0 0 16 9
Cohort 4a: PH CTD-ILD 0 0 0 0 0 0 0 0 17 8
Cohort 4b: PH CTD-IPF 0 0 0 0 0 0 0 0 6 2
Cohort 4c: PH CTD-IIP 0 0 0 0 0 0 0 0 4 1
Cohort 4d: PH CTD-Sarcoidosis 0 0 0 0 0 0 0 0 17 1
Completed 5 12 7 9 1 3 3 3 66 33
Not Completed 1 0 4 3 1 1 0 1 8 5
Reason Not Completed
Adverse Event             0             0             3             2             0             1             0             1             3             1
Death             0             0             0             0             0             0             0             0             1             0
Protocol Violation             1             0             1             0             0             0             0             0             2             0
Withdrawal by Subject             0             0             0             0             1             0             0             0             2             4
Progressive Disease             0             0             0             1             0             0             0             0             0             0
Period Title: Part 2: Week 16 Onwards
Started 5 11 [1] 6 [1] 9 1 3 3 3 63 [2] 33
Cohort 1: PAH (BL 6MWD <= 450 Meters) 5 5 6 5 1 1 3 2 0 0
Cohort 2: PAH (BL 6MWD > 450 Meters) 0 6 0 4 0 2 0 1 0 0
Cohort 3a: PAH CTD 0 0 0 0 0 0 0 0 12 8
Cohort 3b: PAH Non-CTD 0 0 0 0 0 0 0 0 12 7
Cohort 4a: PH CTD-ILD 0 0 0 0 0 0 0 0 16 7
Cohort 4b: PH CTD-IPF 0 0 0 0 0 0 0 0 5 2
Cohort 4c: PH CTD-IIP 0 0 0 0 0 0 0 0 3 1
Cohort 4d: PH CTD-Sarcoidosis 0 0 0 0 0 0 0 0 15 8
Completed 5 6 3 7 0 3 2 2 54 28
Not Completed 0 5 3 2 1 0 1 1 9 5
Reason Not Completed
Adverse Event             0             2             1             1             1             0             1             0             6             3
Protocol Violation             0             0             0             0             0             0             0             1             0             0
Withdrawal by Subject             0             1             1             0             0             0             0             0             3             0
Progressive Disease             0             2             1             1             0             0             0             0             0             2
[1]
One patient who completed Part 1 elected not to continue to Part 2.
[2]
Three patients who completed Part 1 elected not to continue to Part 2.
Arm/Group Title Part 1: Dose-Ranging Bardoxolone Methyl 2.5 mg/Part 2: Open-Label Part 1: Dose-Ranging Bardoxolone Methyl 5 mg/Part 2: Open-Label Part 1: Dose-Ranging Bardoxolone Methly 10 mg/Part 2: Open-Label Part 1: Dose-Ranging Bardoxolone Methyl 20 mg/Part 2: Open-Label Part 1: Dose-Ranging Placebo 2.5 mg/Part 2: Bardoxolone Methyl 2.5 mg Part 1: Dose-Ranging Placebo 5 mg/Part 2: Bardoxolone Methyl 5 mg Part 1: Dose-Ranging Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 1: Dose-Ranging Placebo 20 mg/Part 2: Bardoxolone Methyl 20 mg Part 1: Dose Titration: Bardoxolone Methyl 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg Total
Hide Arm/Group Description Part 1: Participants were randomized to receive bardoxolone methyl 2.5 mg once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and continued to receive the same bardoxolone methyl 2.5 mg once-daily from Week 16 onwards. Part 1: Participants were randomized to receive bardoxolone methyl 5 mg once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and continued to receive the same bardoxolone methyl 5 mg once-daily from Week 16 onwards. Part 1: Participants were randomized to receive bardoxolone methyl 10 mg once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 wer eligible to continue to the extension Part 2 and continued to receive the same bardoxolone methyl 10 mg once-daily from Week 16 onwards. Part 1: Participants were randomized to receive bardoxolone methyl 20 mg once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and continued to receive the same bardoxolone methyl 20 mg once-daily from Week 16 onwards. Part 1: Participants were randomized to receive bardoxolone methyl matching placebo 2.5 mg capsules once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and received bardoxolone methyl 2.5 mg once-daily from Week 16 and onwards. Part 1: Participants were randomized to receive bardoxolone methyl matching placebo 5 mg capsules once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and received bardoxolone methyl 5 mg once-daily from Week 16 and onwards. Part 1: Participants were randomized to receive bardoxolone methyl matching placebo 10 mg capsules once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and received bardoxolone methyl 10 mg once-daily from Week 16 and onwards. Part 1: Participants were randomized to receive bardoxolone methyl matching placebo 20 mg capsules once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and received bardoxolone methyl 20 mg once-daily from Week 16 and onwards. Part 1: Participants were randomized to receive bardoxolone methyl 10 mg capsules. Participants initially started with bardoxolone methyl 5 mg once-daily from Day 1 and titrated to bardoxolone methyl 10 mg once-daily starting at Week 4 up to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and received the same bardoxolone methyl dose once-daily from Week 16 and onwards. Part 1: Participants were randomized to receive bardoxolone methyl matching placebo 10 mg capsules once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and initially received bardoxolone methyl 5 mg once-daily from Week 16 thru Week 20 and bardoxolone methyl 10 mg from Week 20 and onwards. Total of all reporting groups
Overall Number of Baseline Participants 6 12 11 12 2 4 3 4 74 38 166
Hide Baseline Analysis Population Description
Intent-to-treat (ITT) population, which included all randomized patients.
Age, Continuous   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Part 1: 16-week double-blind, randomized, placebo-controlled treatment period (Day 1 to Week 16) Number Analyzed 6 participants 12 participants 11 participants 12 participants 2 participants 4 participants 3 participants 4 participants 74 participants 38 participants 166 participants
52.5  (7.15) 52.8  (14.84) 50.6  (16.33) 49.6  (13.06) 53  (15.56) 39.5  (11.27) 54.7  (.58) 51.3  (8.54) 56.4  (12.41) 55.6  (12.7) 54.3  (12.8)
Part 2: Open-label extension period (Week 16 and onwards) Number Analyzed 5 participants 11 participants 6 participants 9 participants 1 participants 3 participants 3 participants 3 participants 63 participants 33 participants 137 participants
54.6  (5.55) 53.4  (15.4) 59.2  (10.26) 51  (14.76) 64  (0) 40  (13.75) 54.7  (.58) 47.7  (5.69) 56.5  (12.23) 56.7  (12.44) 55.5  (12.38)
[1]
Measure Analysis Population Description: The number analyzed for Part 2 reflects the number of patients who began Part 2 of the study.
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Part 1: 16-week double-blind, randomized, placebo-controlled treatment period (Day 1 to Week 16) Number Analyzed 6 participants 12 participants 11 participants 12 participants 2 participants 4 participants 3 participants 4 participants 74 participants 38 participants 166 participants
Female
4
  66.7%
10
  83.3%
8
  72.7%
11
  91.7%
1
  50.0%
4
 100.0%
2
  66.7%
3
  75.0%
54
  73.0%
27
  71.1%
124
  74.7%
Male
2
  33.3%
2
  16.7%
3
  27.3%
1
   8.3%
1
  50.0%
0
   0.0%
1
  33.3%
1
  25.0%
20
  27.0%
11
  28.9%
42
  25.3%
Part 2: Open-label extension period (Week 16 and onwards) Number Analyzed 5 participants 11 participants 6 participants 9 participants 1 participants 3 participants 3 participants 3 participants 63 participants 33 participants 137 participants
Female
4
  80.0%
9
  81.8%
4
  66.7%
9
 100.0%
1
 100.0%
3
 100.0%
2
  66.7%
3
 100.0%
47
  74.6%
24
  72.7%
106
  77.4%
Male
1
  20.0%
2
  18.2%
2
  33.3%
0
   0.0%
0
   0.0%
0
   0.0%
1
  33.3%
0
   0.0%
16
  25.4%
9
  27.3%
31
  22.6%
[1]
Measure Analysis Population Description: The number analyzed for Part 2 reflects the number of patients who began Part 2 of the study.
Ethnicity (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Part 1: 16-week double-blind, randomized, placebo-controlled treatment period (Day 1 to Week 16) Number Analyzed 6 participants 12 participants 11 participants 12 participants 2 participants 4 participants 3 participants 4 participants 74 participants 38 participants 166 participants
Hispanic or Latino
2
  33.3%
3
  25.0%
0
   0.0%
1
   8.3%
0
   0.0%
1
  25.0%
0
   0.0%
0
   0.0%
12
  16.2%
7
  18.4%
26
  15.7%
Not Hispanic or Latino
4
  66.7%
9
  75.0%
11
 100.0%
11
  91.7%
2
 100.0%
3
  75.0%
3
 100.0%
4
 100.0%
62
  83.8%
31
  81.6%
140
  84.3%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Part 2: Open-label extension period (Week 16 and onwards) Number Analyzed 5 participants 11 participants 6 participants 9 participants 1 participants 3 participants 3 participants 3 participants 63 participants 33 participants 137 participants
Hispanic or Latino
2
  40.0%
2
  18.2%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
10
  15.9%
7
  21.2%
21
  15.3%
Not Hispanic or Latino
3
  60.0%
9
  81.8%
6
 100.0%
9
 100.0%
1
 100.0%
3
 100.0%
3
 100.0%
3
 100.0%
53
  84.1%
26
  78.8%
116
  84.7%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
[1]
Measure Analysis Population Description: The number analyzed for Part 2 reflects the number of patients who began Part 2 of the study.
Race (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Part 1: 16-week double-blind, randomized, placebo-controlled treatment period (Day 1 to Week 16) Number Analyzed 6 participants 12 participants 11 participants 12 participants 2 participants 4 participants 3 participants 4 participants 74 participants 38 participants 166 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
2
   2.7%
0
   0.0%
2
   1.2%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   2.6%
1
   0.6%
Black or African American
0
   0.0%
1
   8.3%
1
   9.1%
0
   0.0%
0
   0.0%
3
  75.0%
0
   0.0%
0
   0.0%
17
  23.0%
9
  23.7%
31
  18.7%
White
6
 100.0%
11
  91.7%
9
  81.8%
12
 100.0%
2
 100.0%
1
  25.0%
3
 100.0%
4
 100.0%
54
  73.0%
28
  73.7%
130
  78.3%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
1
   9.1%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   1.4%
0
   0.0%
2
   1.2%
Part 2: Open-label extension period (Week 16 and onwards) Number Analyzed 5 participants 11 participants 6 participants 9 participants 1 participants 3 participants 3 participants 3 participants 63 participants 33 participants 137 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   1.6%
0
   0.0%
1
   0.7%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
1
   9.1%
0
   0.0%
0
   0.0%
0
   0.0%
3
 100.0%
0
   0.0%
0
   0.0%
14
  22.2%
5
  15.2%
23
  16.8%
White
5
 100.0%
10
  90.9%
5
  83.3%
9
 100.0%
1
 100.0%
0
   0.0%
3
 100.0%
3
 100.0%
47
  74.6%
28
  84.8%
111
  81.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
1
  16.7%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   1.6%
0
   0.0%
2
   1.5%
[1]
Measure Analysis Population Description: The number analyzed for Part 2 reflects the number of patients who began Part 2 of the study.
6-Minute Walk Test (6MWT)   [1] 
Mean (Standard Deviation)
Unit of measure:  Meters
Number Analyzed 6 participants 12 participants 11 participants 12 participants 2 participants 4 participants 3 participants 4 participants 74 participants 38 participants 166 participants
412  (19.7) 425.8  (81) 385.7  (55.45) 454.5  (93.01) 358  (96.17) 418.9  (71.18) 367  (46.02) 449.3  (84.64) 380.8  (96.46) 395.2  (84.99) 396.2  (88.32)
[1]
Measure Analysis Population Description: Modified Intent-to-treat (mITT) population, which included all randomized patients who received at least 28 doses of study treatment, did not undergo heart or lung transplantation during the treatment period, and performed at least one-post baseline 6MWT assessment. Only Part 1 patients are included since the primary outcome is the change from baseline in 6MWD through Week 16.
1.Primary Outcome
Title Change From Baseline Though Week 16 in 6-Minute Walk Distance (6MWD) for Bardoxolone Methyl Compared to Placebo
Hide Description Overall treatment effect in exercise capacity, as measured by the total distance walked in 6 minutes (6MWD) mean change from baseline though Week 16. A lower 6MWD reflects greater severity thus, a positive change from baseline suggests an improvement.
Time Frame Baseline through Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
mITT population included all randomized patients receiving at least 28 doses of study treatment, did not undergo heart or lung transplantation during the treatment period, and performed at least one-post baseline 6MWD assessment. Only Part 1 patients are included since the primary outcome is the change from baseline in 6MWD through Week 16. Primary outcome assessed for subgroups of participants with PAH from Cohorts 1, 2 and 3 of the study and participants with PH, Cohort 4 of the study.
Arm/Group Title Part 1: Dose-Ranging Bardoxolone Methyl 2.5 mg/Part 2: Open-Label Part 1: Dose-Ranging Bardoxolone Methyl 5 mg/Part 2: Open-Label Part 1: Dose-Ranging Bardoxolone Methyl 10 mg/Part 2: Open-Label Part 1: Dose-Ranging Bardoxolone Methyl 20 mg/Part 2: Open-Label Part 1: Dose-Ranging Placebo 2.5 mg/Part 2: Bardoxolone Methyl 2.5 mg Part 1: Dose-Ranging Placebo 5 mg/Part 2: Bardoxolone Methyl 5 mg Part 1: Dose-Ranging Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 1: Dose-Ranging Placebo 20 mg/Part 2: Bardoxolone Methyl 20 mg Part 1: Dose Titration: Bardoxolone Methyl 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg
Hide Arm/Group Description:
Part 1: Participants were randomized to receive bardoxolone methyl 2.5 mg once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and continued to receive the same bardoxolone methyl 2.5 mg once-daily from Week 16 onwards.
Part 1: Participants were randomized to receive bardoxolone methyl 5 mg once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and continued to receive the same bardoxolone methyl 5 mg once-daily from Week 16 onwards.
Part 1: Participants were randomized to receive bardoxolone methyl 10 mg once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 wer eligible to continue to the extension Part 2 and continued to receive the same bardoxolone methyl 10 mg once-daily from Week 16 onwards.
Part 1: Participants were randomized to receive bardoxolone methyl 20 mg once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and continued to receive the same bardoxolone methyl 20 mg once-daily from Week 16 onwards.
Part 1: Participants were randomized to receive bardoxolone methyl matching placebo 2.5 mg capsules once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and received bardoxolone methyl 2.5 mg once-daily from Week 16 and onwards.
Part 1: Participants were randomized to receive bardoxolone methyl matching placebo 5 mg capsules once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and received bardoxolone methyl 5 mg once-daily from Week 16 and onwards.
Part 1: Participants were randomized to receive bardoxolone methyl matching placebo 10 mg capsules once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and received bardoxolone methyl 10 mg once-daily from Week 16 and onwards.
Part 1: Participants were randomized to receive bardoxolone methyl matching placebo 20 mg capsules once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and received bardoxolone methyl 20 mg once-daily from Week 16 and onwards.
Part 1: Participants were randomized to receive bardoxolone methyl 10 mg capsules. Participants initially started with bardoxolone methyl 5 mg once-daily from Day 1 and titrated to bardoxolone methyl 10 mg once-daily starting at Week 4 up to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and received the same bardoxolone methyl dose once-daily from Week 16 and onwards.
Part 1: Participants were randomized to receive bardoxolone methyl matching placebo 10 mg capsules once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and initially received bardoxolone methyl 5 mg once-daily from Week 16 thru Week 20 and bardoxolone methyl 10 mg from Week 20 and onwards.
Overall Number of Participants Analyzed 6 12 9 10 2 4 3 4 70 38
Mean (Standard Deviation)
Unit of Measure: meters
Change from Baseline though Week 16 for participants with PAH Number Analyzed 6 participants 12 participants 9 participants 10 participants 2 participants 4 participants 3 participants 4 participants 29 participants 17 participants
32.5  (29.14) 24  (30.08) 3.4  (31.28) -3.2  (39.53) 20.3  (13.08) 24.6  (59.4) 23.8  (34.54) -21.8  (4.17) 13.9  (41.15) 19.4  (21.06)
Change from Baseline though Week 16 for participants with PH Number Analyzed 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 41 participants 21 participants
7.6  (32.01) 10.8  (32.01)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 1: Dose-Ranging Bardoxolone Methyl 2.5 mg/Part 2: Open-Label, Part 1: Dose-Ranging Bardoxolone Methyl 5 mg/Part 2: Open-Label, Part 1: Dose-Ranging Bardoxolone Methyl 10 mg/Part 2: Open-Label, Part 1: Dose-Ranging Bardoxolone Methyl 20 mg/Part 2: Open-Label, Part 1: Dose-Ranging Placebo 2.5 mg/Part 2: Bardoxolone Methyl 2.5 mg, Part 1: Dose-Ranging Placebo 5 mg/Part 2: Bardoxolone Methyl 5 mg, Part 1: Dose-Ranging Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg, Part 1: Dose-Ranging Placebo 20 mg/Part 2: Bardoxolone Methyl 20 mg, Part 1: Dose Titration: Bardoxolone Methyl 10 mg/Part 2: Bardoxolone Methyl 10 mg, Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg
Comments Overall treatment effect in participants with PAH. Mean overall treatment effect across all visits for change from baseline in 6MWD was estimated and compared with placebo through 16 weeks of treatment using mixed-model repeated measures (MMRM), with treatment group, visit, and the interaction between treatment and visit as fixed factors. A compound symmetry covariance matrix was assumed. Data from Wks 4, 8, 12, and 16 used in the model with the change from baseline at Wk16 as primary endpoint.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8133
Comments The p-value comparison is for the difference in the change in 6WMD from baseline at Week 16 for bardoxolone methyl relative to placebo in participants with pulmonary arterial hypertension (PAH).
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -1.74
Confidence Interval (2-Sided) 95%
-16.22 to 12.74
Estimation Comments Mean difference (Net) = Bardoxolone methyl - Placebo.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Part 1: Dose Titration: Bardoxolone Methyl 10 mg/Part 2: Bardoxolone Methyl 10 mg, Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg
Comments Overall treatment effect in participants with PH. Mean overall treatment effect across all visits for change from baseline in 6MWD was estimated & compared with placebo through 16 wks of treatment using mixed-model repeated measures (MMRM), with treatment group, visit, and the interaction between treatment & visit as fixed factors. Compound symmetry covariance matrix was assumed. Data from Wks 4, 8, 12, and 16 were used in the model with the change from baseline at Wk 16 as the primary endpoint
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.759
Comments The p-value comparison is for the difference in the change in 6WMD from baseline at Week 16 for bardoxolone methyl relative to placebo in participants with pulmonary hypertension (PH)
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -3.17
Confidence Interval (2-Sided) 95%
-23.54 to 17.20
Estimation Comments Mean difference (Net) = Bardoxolone methyl - Placebo.
Time Frame Part 1: 16-week double-blind, randomized, placebo-controlled treatment period (Day 1 to Week 16). Part 2: Open-label extension period (Week 16 onwards). Part 2 is the extension period and patients were to stay until study drug became available through extended access program [Study 402-C-1602].
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Part 1 Period of Part 1: Dose-Ranging Bardoxolone Methyl 2.5 mg/Part 2: Open-Label Part 1 Period of Part 1: Dose-Ranging Bardoxolone Methyl 5 mg/Part 2: Open-Label Part 1 Period of Part 1: Dose-Ranging Bardoxolone Methyl 10 mg/Part 2: Open-Label Part 1 Period of Part 1: Dose-Ranging Bardoxolone Methyl 20 mg/Part 2: Open-Label Part 1 Period of Part 1: Dose-Ranging Placebo 2.5 mg/Part 2: Bardoxolone Methyl 2.5 mg Part 1 Period of Part 1: Dose-Ranging Placebo 5 mg/Part 2: Bardoxolone Methyl 5 mg Part 1 Period of Part 1: Dose-Ranging Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 1 Period of Part 1: Dose-Ranging Placebo 20 mg/Part 2: Bardoxolone Methyl 20 mg Part 1 Period of Part 1: Dose Titration: Bardoxolone Methyl 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 1 Period of Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 2 Period of Part 1: Dose-Ranging Bardoxolone Methyl 2.5 mg/Part 2: Open-Label Part 2 Period of Part 1: Dose-Ranging Bardoxolone Methyl 5 mg/Part 2: Open-Label Part 2 Period of Part 1: Dose-Ranging Bardoxolone Methyl 10 mg/Part 2: Open-Label Part 2 Period of Part 1: Dose-Ranging Bardoxolone Methyl 20 mg/Part 2: Open-Label Part 2 Period of Part 1: Dose-Ranging Placebo 2.5 mg/Part 2: Bardoxolone Methyl 2.5 mg Part 2 Period of Part 1: Dose-Ranging Placebo 5 mg/Part 2: Bardoxolone Methyl 5 mg Part 2 Period of Part 1: Dose-Ranging Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 2 Period of Part 1: Dose-Ranging Placebo 20 mg/Part 2: Bardoxolone Methyl 20 mg Part 2 Period of Part 1: Dose Titration: Bardoxolone Methyl 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 2 Period of Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg
Hide Arm/Group Description Part 1: Participants were randomized to receive bardoxolone methyl 2.5 mg once-daily from Day 1 to Week 16. Part 1: Participants were randomized to receive bardoxolone methyl 5 mg once-daily from Day 1 to Week 16. Part 1: Participants were randomized to receive bardoxolone methyl 10 mg once-daily from Day 1 to Week 16. Part 1: Participants were randomized to receive bardoxolone methyl 20 mg once-daily from Day 1 to Week 16. Part 1: Participants were randomized to receive bardoxolone methyl matching placebo 2.5 mg capsules once-daily from Day 1 to Week 16. Part 1: Participants were randomized to receive bardoxolone methyl matching placebo 5 mg capsules once-daily from Day 1 to Week 16. Part 1: Participants were randomized to receive bardoxolone methyl matching placebo 10 mg capsules once-daily from Day 1 to Week 16. Part 1: Participants were randomized to receive bardoxolone methyl matching placebo 20 mg capsules once-daily from Day 1 to Week 16. Part 1: Participants were randomized to receive bardoxolone methyl 10 mg capsules. Participants initially started with bardoxolone methyl 5 mg once-daily from Day 1 and titrated to bardoxolone methyl 10 mg once-daily starting at Week 4 up to Week 16. Part 1: Participants were randomized to receive bardoxolone methyl matching placebo 10 mg capsules once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment receiving bardoxolone methyl 2.5 mg once daily in Part 1 were eligible to continue to the extension Part 2 and continued to receive the same bardoxolone methyl 2.5 mg once-daily from Week 16 onwards. Part 2: Participants who completed treatment receiving bardoxolone methyl 5 mg once daily in Part 1 were eligible to continue to the extension Part 2 and continued to receive the same bardoxolone methyl 5 mg once-daily from Week 16 onwards. Part 2: Participants who completed treatment receiving bardoxolone methyl 10 mg once daily in Part 1 were eligible to continue to the extension Part 2 and continued to receive the same bardoxolone methyl 10 mg once-daily from Week 16 onwards. Part 2: Participants who completed treatment receiving bardoxolone methyl 20 mg once daily in Part 1 were eligible to continue to the extension Part 2 and continued to receive the same bardoxolone methyl 20 mg once-daily from Week 16 onwards. Part 2: Participants who completed bardoxolone methyl matching placebo 2.5 mg capsules once-daily treatment in Part 1 were eligible to continue to the extension Part 2 and received bardoxolone methyl 2.5 mg once-daily from Week 16 and onwards. Part 2: Participants who completed bardoxolone methyl matching placebo 5 mg capsules once-daily treatment in Part 1 were eligible to continue to the extension Part 2 and received bardoxolone methyl 5 mg once-daily from Week 16 and onwards. Part 2: Participants who completed bardoxolone methyl matching placebo 10 mg capsules once-daily treatment in Part 1 were eligible to continue to the extension Part 2 and received bardoxolone methyl 10 mg once-daily from Week 16 and onwards. Part 2: Participants who completed bardoxolone methyl matching placebo 20 mg capsules once-daily treatment in Part 1 were eligible to continue to the extension Part 2 and received bardoxolone methyl 20 mg once-daily from Week 16 and onwards. Part 2: Participants who completed treatment titrated to 10 mg bardoxolone methyl in Part 1 were eligible to continue to the extension Part 2 and received bardoxolone methyl 10 mg once-daily from Week 16 and onwards. Part 2: Participants who completed bardoxolone methyl matching placebo 10 mg capsules once-daily treatment in Part 1 were eligible to continue to the extension Part 2 and initially received bardoxolone methyl 5 mg once-daily from Week 16 thru Week 20 and bardoxolone methyl 10 mg from Week 20 and onwards.
All-Cause Mortality
Part 1 Period of Part 1: Dose-Ranging Bardoxolone Methyl 2.5 mg/Part 2: Open-Label Part 1 Period of Part 1: Dose-Ranging Bardoxolone Methyl 5 mg/Part 2: Open-Label Part 1 Period of Part 1: Dose-Ranging Bardoxolone Methyl 10 mg/Part 2: Open-Label Part 1 Period of Part 1: Dose-Ranging Bardoxolone Methyl 20 mg/Part 2: Open-Label Part 1 Period of Part 1: Dose-Ranging Placebo 2.5 mg/Part 2: Bardoxolone Methyl 2.5 mg Part 1 Period of Part 1: Dose-Ranging Placebo 5 mg/Part 2: Bardoxolone Methyl 5 mg Part 1 Period of Part 1: Dose-Ranging Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 1 Period of Part 1: Dose-Ranging Placebo 20 mg/Part 2: Bardoxolone Methyl 20 mg Part 1 Period of Part 1: Dose Titration: Bardoxolone Methyl 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 1 Period of Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 2 Period of Part 1: Dose-Ranging Bardoxolone Methyl 2.5 mg/Part 2: Open-Label Part 2 Period of Part 1: Dose-Ranging Bardoxolone Methyl 5 mg/Part 2: Open-Label Part 2 Period of Part 1: Dose-Ranging Bardoxolone Methyl 10 mg/Part 2: Open-Label Part 2 Period of Part 1: Dose-Ranging Bardoxolone Methyl 20 mg/Part 2: Open-Label Part 2 Period of Part 1: Dose-Ranging Placebo 2.5 mg/Part 2: Bardoxolone Methyl 2.5 mg Part 2 Period of Part 1: Dose-Ranging Placebo 5 mg/Part 2: Bardoxolone Methyl 5 mg Part 2 Period of Part 1: Dose-Ranging Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 2 Period of Part 1: Dose-Ranging Placebo 20 mg/Part 2: Bardoxolone Methyl 20 mg Part 2 Period of Part 1: Dose Titration: Bardoxolone Methyl 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 2 Period of Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone Methyl 10 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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) 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   0/6 (0.00%)   0/12 (0.00%)   0/11 (0.00%)   0/12 (0.00%)   0/2 (0.00%)   0/4 (0.00%)   0/3 (0.00%)   0/4 (0.00%)   1/74 (1.35%)   0/38 (0.00%)   0/5 (0.00%)   0/11 (0.00%)   0/6 (0.00%)   0/9 (0.00%)   0/1 (0.00%)   0/3 (0.00%)   0/3 (0.00%)   0/3 (0.00%)   0/63 (0.00%)   0/33 (0.00%) 
Hide Serious Adverse Events
Part 1 Period of Part 1: Dose-Ranging Bardoxolone Methyl 2.5 mg/Part 2: Open-Label Part 1 Period of Part 1: Dose-Ranging Bardoxolone Methyl 5 mg/Part 2: Open-Label Part 1 Period of Part 1: Dose-Ranging Bardoxolone Methyl 10 mg/Part 2: Open-Label Part 1 Period of Part 1: Dose-Ranging Bardoxolone Methyl 20 mg/Part 2: Open-Label Part 1 Period of Part 1: Dose-Ranging Placebo 2.5 mg/Part 2: Bardoxolone Methyl 2.5 mg Part 1 Period of Part 1: Dose-Ranging Placebo 5 mg/Part 2: Bardoxolone Methyl 5 mg Part 1 Period of Part 1: Dose-Ranging Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 1 Period of Part 1: Dose-Ranging Placebo 20 mg/Part 2: Bardoxolone Methyl 20 mg Part 1 Period of Part 1: Dose Titration: Bardoxolone Methyl 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 1 Period of Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 2 Period of Part 1: Dose-Ranging Bardoxolone Methyl 2.5 mg/Part 2: Open-Label Part 2 Period of Part 1: Dose-Ranging Bardoxolone Methyl 5 mg/Part 2: Open-Label Part 2 Period of Part 1: Dose-Ranging Bardoxolone Methyl 10 mg/Part 2: Open-Label Part 2 Period of Part 1: Dose-Ranging Bardoxolone Methyl 20 mg/Part 2: Open-Label Part 2 Period of Part 1: Dose-Ranging Placebo 2.5 mg/Part 2: Bardoxolone Methyl 2.5 mg Part 2 Period of Part 1: Dose-Ranging Placebo 5 mg/Part 2: Bardoxolone Methyl 5 mg Part 2 Period of Part 1: Dose-Ranging Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 2 Period of Part 1: Dose-Ranging Placebo 20 mg/Part 2: Bardoxolone Methyl 20 mg Part 2 Period of Part 1: Dose Titration: Bardoxolone Methyl 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 2 Period of Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone Methyl 10 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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) 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   0/6 (0.00%)   1/12 (8.33%)   0/11 (0.00%)   2/12 (16.67%)   0/2 (0.00%)   0/4 (0.00%)   0/3 (0.00%)   1/4 (25.00%)   7/74 (9.46%)   2/38 (5.26%)   2/5 (40.00%)   5/11 (45.45%)   3/6 (50.00%)   6/9 (66.67%)   0/1 (0.00%)   1/3 (33.33%)   2/3 (66.67%)   1/3 (33.33%)   9/63 (14.29%)   9/33 (27.27%) 
Blood and lymphatic system disorders                                         
Anaemia  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Cardiac disorders                                         
Acute right ventricular failure  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Atrial fibrillation  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/74 (1.35%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Cardiac failure acute  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
Cardiac tamponade  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
Coronary artery disease  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Pericardial effusion  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Right ventricular failure  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
Ventricular arrhythmia  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/74 (1.35%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Gastrointestinal disorders                                         
Abdominal pain  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Ascites  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Gastric ulcer  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Gastrointestinal haemorrhage  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Small intestinal obstruction  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
General disorders                                         
General physical health deterioration  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Non-cardiac chest pain  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/74 (1.35%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Infections and infestations                                         
Bronchitis  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Campylobacter gastroenteritis  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Cellulitis  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/74 (1.35%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Diarrhoea infectious  1  0/6 (0.00%)  1/12 (8.33%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Escherichia urinary tract infection  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
Influenza  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  1/38 (2.63%)  0/5 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Lung infection  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  1/38 (2.63%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Pneumonia  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  1/12 (8.33%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  1/38 (2.63%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  1/33 (3.03%) 
Salpingitis  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
Urinary tract infection enterococcal  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
Urosepsis  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Viral upper respiratory tract infection  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Injury, poisoning and procedural complications                                         
Hip fracture  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  1/5 (20.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Pneumothorax traumatic  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Subdural haematoma  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Wound  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
Investigations                                         
International normalised ratio increased  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
Metabolism and nutrition disorders                                         
Dehydration  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Fluid overload  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
Musculoskeletal and connective tissue disorders                                         
Back pain  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
Muscular weakness  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Osteoarthritis  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  1/5 (20.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Pain in extremity  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/63 (0.00%)  0/33 (0.00%) 
Systemic lupus erythematosus  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                                         
Basal cell carcinoma  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/74 (1.35%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Nervous system disorders                                         
Dizziness  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/1 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Embolic stroke  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  1/5 (20.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Syncope  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Transient ischaemic attack  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Psychiatric disorders                                         
Delirium  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/63 (0.00%)  0/33 (0.00%) 
Renal and urinary disorders                                         
Nephrolithiasis  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Renal failure acute  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Reproductive system and breast disorders                                         
Haemorrhagic ovarian cyst  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
Respiratory, thoracic and mediastinal disorders                                         
Acute respiratory failure  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Hypoxia  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/74 (1.35%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Pleural effusion  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/74 (1.35%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Pleuritic pain  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
Pulmonary arterial hypertension  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  1/12 (8.33%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Pulmonary embolism  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
Pulmonary fibrosis  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Pulmonary hypertension  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  1/6 (16.67%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Vascular disorders                                         
Hypertensive crisis  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Hypotension  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Raynaud's phenomenon  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
1
Term from vocabulary, MedDRA (15.0)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
Part 1 Period of Part 1: Dose-Ranging Bardoxolone Methyl 2.5 mg/Part 2: Open-Label Part 1 Period of Part 1: Dose-Ranging Bardoxolone Methyl 5 mg/Part 2: Open-Label Part 1 Period of Part 1: Dose-Ranging Bardoxolone Methyl 10 mg/Part 2: Open-Label Part 1 Period of Part 1: Dose-Ranging Bardoxolone Methyl 20 mg/Part 2: Open-Label Part 1 Period of Part 1: Dose-Ranging Placebo 2.5 mg/Part 2: Bardoxolone Methyl 2.5 mg Part 1 Period of Part 1: Dose-Ranging Placebo 5 mg/Part 2: Bardoxolone Methyl 5 mg Part 1 Period of Part 1: Dose-Ranging Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 1 Period of Part 1: Dose-Ranging Placebo 20 mg/Part 2: Bardoxolone Methyl 20 mg Part 1 Period of Part 1: Dose Titration: Bardoxolone Methyl 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 1 Period of Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 2 Period of Part 1: Dose-Ranging Bardoxolone Methyl 2.5 mg/Part 2: Open-Label Part 2 Period of Part 1: Dose-Ranging Bardoxolone Methyl 5 mg/Part 2: Open-Label Part 2 Period of Part 1: Dose-Ranging Bardoxolone Methyl 10 mg/Part 2: Open-Label Part 2 Period of Part 1: Dose-Ranging Bardoxolone Methyl 20 mg/Part 2: Open-Label Part 2 Period of Part 1: Dose-Ranging Placebo 2.5 mg/Part 2: Bardoxolone Methyl 2.5 mg Part 2 Period of Part 1: Dose-Ranging Placebo 5 mg/Part 2: Bardoxolone Methyl 5 mg Part 2 Period of Part 1: Dose-Ranging Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 2 Period of Part 1: Dose-Ranging Placebo 20 mg/Part 2: Bardoxolone Methyl 20 mg Part 2 Period of Part 1: Dose Titration: Bardoxolone Methyl 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 2 Period of Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone Methyl 10 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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) 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   5/6 (83.33%)   11/12 (91.67%)   10/11 (90.91%)   12/12 (100.00%)   2/2 (100.00%)   4/4 (100.00%)   3/3 (100.00%)   4/4 (100.00%)   64/74 (86.49%)   33/38 (86.84%)   5/5 (100.00%)   11/11 (100.00%)   6/6 (100.00%)   8/9 (88.89%)   1/1 (100.00%)   2/3 (66.67%)   3/3 (100.00%)   3/3 (100.00%)   50/63 (79.37%)   30/33 (90.91%) 
Blood and lymphatic system disorders                                         
Anaemia  1  1/6 (16.67%)  1/12 (8.33%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/74 (1.35%)  0/38 (0.00%)  1/5 (20.00%)  1/11 (9.09%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  3/63 (4.76%)  0/33 (0.00%) 
Coagulopathy  1  1/6 (16.67%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Iron deficiency anaemia  1  0/6 (0.00%)  1/12 (8.33%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  1/9 (11.11%)  0/1 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
Pancytopenia  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Splenic vein thrombosis  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Splenomegaly  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Thrombocytopenia  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/74 (1.35%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  1/33 (3.03%) 
Cardiac disorders                                         
Angina pectoris  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Atrial fibrillation  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/74 (1.35%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
Atrial flutter  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Cardiac discomfort  1  0/6 (0.00%)  1/12 (8.33%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/74 (1.35%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Palpitations  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  2/12 (16.67%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  2/74 (2.70%)  0/38 (0.00%)  1/5 (20.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  1/1 (100.00%)  1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Pericardial effusion  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/63 (3.17%)  0/33 (0.00%) 
Pericarditis  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  1/33 (3.03%) 
Postural orthostatic tachycardia syndrome  1  0/6 (0.00%)  1/12 (8.33%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Right ventricular failure  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Supraventricular extrasystoles  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  1/38 (2.63%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Tachycardia  1  0/6 (0.00%)  2/12 (16.67%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  2/74 (2.70%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Congenital, familial and genetic disorders                                         
Arteriovenous malformation  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Ear and labyrinth disorders                                         
Deafness  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Deafness bilateral  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Meniere's disease  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Tympanic membrane perforation  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Vertigo  1  0/6 (0.00%)  1/12 (8.33%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/74 (1.35%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Eye disorders                                         
Cataract  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  1/12 (8.33%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  1/38 (2.63%)  0/5 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
Conjunctival hyperaemia  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Keratitis  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Ocular hyperaemia  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  1/3 (33.33%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Periorbital oedema  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  1/38 (2.63%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Retinal tear  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  1/38 (2.63%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Scleral disorder  1  0/6 (0.00%)  1/12 (8.33%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Vision blurred  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  1/12 (8.33%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  1/38 (2.63%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  1/33 (3.03%) 
Gastrointestinal disorders                                         
Abdominal discomfort  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Abdominal distension  1  0/6 (0.00%)  1/12 (8.33%)  2/11 (18.18%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  1/3 (33.33%)  1/4 (25.00%)  1/74 (1.35%)  1/38 (2.63%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Abdominal pain  1  0/6 (0.00%)  1/12 (8.33%)  1/11 (9.09%)  1/12 (8.33%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  4/74 (5.41%)  0/38 (0.00%)  0/5 (0.00%)  3/11 (27.27%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  3/63 (4.76%)  2/33 (6.06%) 
Abdominal pain lower  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Colonic polyp  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Constipation  1  0/6 (0.00%)  1/12 (8.33%)  0/11 (0.00%)  1/12 (8.33%)  0/2 (0.00%)  1/4 (25.00%)  0/3 (0.00%)  0/4 (0.00%)  3/74 (4.05%)  3/38 (7.89%)  1/5 (20.00%)  3/11 (27.27%)  0/6 (0.00%)  2/9 (22.22%)  0/1 (0.00%)  1/3 (33.33%)  1/3 (33.33%)  0/3 (0.00%)  4/63 (6.35%)  1/33 (3.03%) 
Dental caries  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  1/38 (2.63%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Diarrhoea  1  0/6 (0.00%)  2/12 (16.67%)  2/11 (18.18%)  2/12 (16.67%)  0/2 (0.00%)  1/4 (25.00%)  0/3 (0.00%)  0/4 (0.00%)  10/74 (13.51%)  3/38 (7.89%)  2/5 (40.00%)  2/11 (18.18%)  0/6 (0.00%)  1/9 (11.11%)  1/1 (100.00%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  1/63 (1.59%)  7/33 (21.21%) 
Diverticulum  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Dry mouth  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  2/74 (2.70%)  1/38 (2.63%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
Duodenitis  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Dyspepsia  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/74 (1.35%)  1/38 (2.63%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/63 (0.00%)  0/33 (0.00%) 
Flatulence  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  1/4 (25.00%)  0/3 (0.00%)  0/4 (0.00%)  1/74 (1.35%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Frequent bowel movements  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  1/5 (20.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Gastritis  1  0/6 (0.00%)  1/12 (8.33%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Gastrooesophageal reflux disease  1  1/6 (16.67%)  0/12 (0.00%)  0/11 (0.00%)  2/12 (16.67%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  5/74 (6.76%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  2/33 (6.06%) 
Gingivitis  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  1/38 (2.63%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Haematochezia  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  2/38 (5.26%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Haemorrhoids  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  1/38 (2.63%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Hiatus hernia  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Ileus  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Impaired gastric emptying  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Lip dry  1  0/6 (0.00%)  1/12 (8.33%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/63 (0.00%)  0/33 (0.00%) 
Lower gastrointestinal haemorrhage  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Nausea  1  0/6 (0.00%)  1/12 (8.33%)  1/11 (9.09%)  4/12 (33.33%)  0/2 (0.00%)  1/4 (25.00%)  0/3 (0.00%)  0/4 (0.00%)  10/74 (13.51%)  6/38 (15.79%)  3/5 (60.00%)  4/11 (36.36%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  1/3 (33.33%)  2/63 (3.17%)  3/33 (9.09%) 
Oesophageal spasm  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Painful defaecation  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  1/38 (2.63%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Rectal haemorrhage  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  2/33 (6.06%) 
Retching  1  0/6 (0.00%)  1/12 (8.33%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Salivary gland enlargement  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Toothache  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/74 (1.35%)  1/38 (2.63%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
Vomiting  1  0/6 (0.00%)  1/12 (8.33%)  1/11 (9.09%)  1/12 (8.33%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  2/74 (2.70%)  1/38 (2.63%)  2/5 (40.00%)  0/11 (0.00%)  0/6 (0.00%)  2/9 (22.22%)  0/1 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  1/63 (1.59%)  1/33 (3.03%) 
General disorders                                         
Asthenia  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  1/4 (25.00%)  0/74 (0.00%)  1/38 (2.63%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Chest discomfort  1  0/6 (0.00%)  1/12 (8.33%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Chills  1  0/6 (0.00%)  1/12 (8.33%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Fatigue  1  0/6 (0.00%)  1/12 (8.33%)  1/11 (9.09%)  2/12 (16.67%)  0/2 (0.00%)  0/4 (0.00%)  1/3 (33.33%)  0/4 (0.00%)  7/74 (9.46%)  4/38 (10.53%)  0/5 (0.00%)  0/11 (0.00%)  3/6 (50.00%)  1/9 (11.11%)  1/1 (100.00%)  1/3 (33.33%)  1/3 (33.33%)  0/3 (0.00%)  4/63 (6.35%)  4/33 (12.12%) 
Generalised oedema  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  1/38 (2.63%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
Implant site haematoma  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  1/12 (8.33%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Irritability  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  1/12 (8.33%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Malaise  1  0/6 (0.00%)  1/12 (8.33%)  0/11 (0.00%)  1/12 (8.33%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
Non-cardiac chest pain  1  1/6 (16.67%)  0/12 (0.00%)  1/11 (9.09%)  1/12 (8.33%)  0/2 (0.00%)  1/4 (25.00%)  0/3 (0.00%)  0/4 (0.00%)  3/74 (4.05%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  1/3 (33.33%)  1/3 (33.33%)  0/3 (0.00%)  4/63 (6.35%)  0/33 (0.00%) 
Oedema  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Oedema peripheral  1  0/6 (0.00%)  3/12 (25.00%)  1/11 (9.09%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  1/3 (33.33%)  0/4 (0.00%)  3/74 (4.05%)  5/38 (13.16%)  2/5 (40.00%)  3/11 (27.27%)  1/6 (16.67%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  4/63 (6.35%)  3/33 (9.09%) 
Pain  1  0/6 (0.00%)  1/12 (8.33%)  0/11 (0.00%)  2/12 (16.67%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/74 (1.35%)  1/38 (2.63%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  2/33 (6.06%) 
Pyrexia  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  2/74 (2.70%)  2/38 (5.26%)  0/5 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  2/33 (6.06%) 
Vessel puncture site haematoma  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Vessel puncture site pain  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  1/12 (8.33%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Vessel puncture site swelling  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  1/12 (8.33%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Hepatobiliary disorders                                         
Cholelithiasis  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Gallbladder disorder  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Gallbladder polyp  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  1/12 (8.33%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Hepatic cirrhosis  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Hepatic cyst  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Immune system disorders                                         
Drug hypersensitivity  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/74 (1.35%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Seasonal allergy  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  1/12 (8.33%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
Infections and infestations                                         
Acute sinusitis  1  0/6 (0.00%)  1/12 (8.33%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Breast abscess  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Bronchitis  1  0/6 (0.00%)  1/12 (8.33%)  0/11 (0.00%)  1/12 (8.33%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  2/74 (2.70%)  1/38 (2.63%)  2/5 (40.00%)  1/11 (9.09%)  0/6 (0.00%)  2/9 (22.22%)  0/1 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  1/63 (1.59%)  0/33 (0.00%) 
Candidiasis  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Cellulitis  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/74 (1.35%)  1/38 (2.63%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/63 (3.17%)  0/33 (0.00%) 
Clostridial infection  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  1/38 (2.63%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  1/33 (3.03%) 
Conjunctivitis bacterial  1  0/6 (0.00%)  1/12 (8.33%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Conjunctivitis infective  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  1/74 (1.35%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/63 (0.00%)  0/33 (0.00%) 
Ear infection  1  0/6 (0.00%)  0/12 (0.00%)  1/11 (9.09%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  2/6 (33.33%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  2/33 (6.06%) 
Folliculitis  1  0/6 (0.00%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  0/74 (0.00%)  0/38 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/63 (0.00%)  0/33 (0.00%) 
Gastroenteritis  1  1/6 (16.67%)  0/12 (0.00%)  0/11 (0.00%)  0/12 (0.00%)  0/2 (0.00%)  0/4 (0.00%)  0/3 (0.00%)  0/4 (0.00%)  2/74 (2.70%)  1/38 (2.63%)  1/5 (20.00%)  2/11 (18.18%)  0/6 (0.00%)  0/9 (0.00%)  0/1 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/63 (0.00%)  1/33 (3.03%) 
Gastrointestinal infection  1