Clincosm LogoSign in Get a demo

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

Sponsor
Reata Pharmaceuticals, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT02036970
Collaborator
(none)
166
Enrollment
32
Locations
10
Arms
48.5
Duration (Months)
5.2
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study assesses the safety and efficacy of bardoxolone methyl relative to placebo in patients with pulmonary hypertension to determine the recommended dose range, evaluate the change from baseline in 6-minute walk distance (6MWD) and determine the effect of Bardoxolone methyl in pulmonary hypertension associated with connective tissue disease, interstitial lung disease, and idiopathic etiologies, including subsets of patients with WHO Group III or WHO Group V PH following 16 weeks of study participation.

Condition or Disease Intervention/Treatment Phase
  • Drug: Bardoxolone methyl
  • Drug: Placebo
 Phase 2

Detailed Description

The molecular and pharmacological effects of bardoxolone methyl are broad through its induction of Nrf2 and suppression of NF-κB. Bardoxolone methyl may therefore address multiple facets of the pathophysiology of PH because it suppresses activation of proinflammatory mediators, enhances endothelial NO bioavailability, improves metabolic dysfunction, suppresses vascular proliferation, and prevents maladaptive remodeling. Furthermore, while existing therapies primarily target only smooth muscle cells, bardoxolone methyl targets multiple cell types relevant to PH, including endothelial cells, smooth muscle cells, and macrophages.

This is a two-part study.

Part 1: Part 1 of the study will include a dose-ranging phase and a dose-titration phase.

Part 2 (extension period): All patients from Part 1 who complete the 16-week treatment period as planned will be eligible to continue directly into the extension period to evaluate the intermediate and long-term safety and efficacy of bardoxolone methyl.

Study Design

Study Type:
Interventional
Actual Enrollment :
166 participants
Allocation:
Randomized
Intervention Model:
Sequential Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Dose-Ranging Study of the Efficacy and Safety of Bardoxolone Methyl in Patients With Pulmonary Hypertension
Study Start Date :
May 1, 2014
Actual Primary Completion Date :
Jan 19, 2018
Actual Study Completion Date :
May 16, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Part 1 Dose-Ranging Bardoxolone methyl 2.5 mg/Part 2: Open-Label

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)

Drug: Bardoxolone methyl
Other Names:
  • RTA 402 capsules

    		•
    Experimental: Part 1: Dose-Ranging Bardoxolone methyl 5 mg/Part 2: Open-Label

    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)

    Drug: Bardoxolone methyl
    Other Names:
  • RTA 402 capsules

    		•
    Experimental: Part 1: Dose-Ranging Bardoxolone methyl 10 mg/Part 2: Open-Label

    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)

    Drug: Bardoxolone methyl
    Other Names:
  • RTA 402 capsules

    		•
    Experimental: Part 1: Dose-Ranging Bardoxolone methyl 20 mg/Part 2: Open-Label

    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)

    Drug: Bardoxolone methyl
    Other Names:
  • RTA 402 capsules

    		•
    Placebo Comparator: Part 1: Dose-Ranging Placebo 2.5 mg/Part 2: Bardoxolone methyl 2.5 mg

    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)

    Drug: Bardoxolone methyl
    Other Names:
  • RTA 402 capsules

    • Drug: Placebo
    Placebo Comparator: Part 1: Dose-Ranging Placebo 5 mg/Part 2: Bardoxolone methyl 5 mg

    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)

    Drug: Bardoxolone methyl
    Other Names:
  • RTA 402 capsules

    • Drug: Placebo
    Placebo Comparator: Part 1: Dose-Ranging Placebo 10 mg/Part 2: Bardoxolone methyl 10 mg

    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)

    Drug: Bardoxolone methyl
    Other Names:
  • RTA 402 capsules

    • Drug: Placebo
    Placebo Comparator: Part 1: Dose-Ranging Placebo 20 mg/Part 2: Bardoxolone methyl 20 mg

    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)

    Drug: Bardoxolone methyl
    Other Names:
  • RTA 402 capsules

    • Drug: Placebo
    Experimental: Part 1: Dose Titration: Bardoxolone methyl 10 mg/Part 2: Bardoxolone methyl 10 mg

    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)

    Drug: Bardoxolone methyl
    Other Names:
  • RTA 402 capsules

    		•
    Placebo Comparator: Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone methyl 10 mg

    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

    Drug: Bardoxolone methyl
    Other Names:
  • RTA 402 capsules

    • Drug: Placebo

    Outcome Measures

    Primary Outcome Measures

    1. Change From Baseline Though Week 16 in 6-Minute Walk Distance (6MWD) for Bardoxolone Methyl Compared to Placebo [Baseline through Week 16]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 75 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. Adult male and female patients ≥ 18 to ≤ 75 years of age upon study consent;

    2. BMI > 18.5 kg/m²

    3. Symptomatic pulmonary hypertension WHO class II and III;

    4. WHO Group I, III, or V PH according to the following criteria:

    5. If diagnosed with WHO Group I PAH, then on of the following subtypes:

    • Idiopathic or heritable PAH;

    • PAH associated with connective tissue disease;

    • PAH associated with simple, congenital systemic-to-pulmonary shunts at least 1 year following shunt repair;

    • PAH associated with anorexigen or drug-induced toxicity;

    • PAH associated with human immunodeficiency virus (HIV); or

    1. If WHO Group III PH then primary diagnosis must be one of the following subtypes:

    • Connective tissue disease associated ILD (CTD-ILD);

    • Idiopathic pulmonary fibrosis (IPF);

    • Nonspecific interstitial pneumonia (NSIP); or

    1. If WHO Group V PH then patient must be diagnosed with sarcoidosis;

    2. Had a diagnostic right heart catheterization performed and documented within 36 months prior to Day 1 that confirmed a diagnosis of PH

    3. If WHO Group I, has been receiving no more than three (3) FDA-approved disease-specific PAH therapies except for intravenous (iv) prostacyclin/prostacyclin analogues. PAH therapy must be at a stable dose for at least 90 days prior to Day 1;

    4. Has adequate kidney function defined as an estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) 4-variable formula;

    Exclusion Criteria:

    1. Participation in other interventional clinical studies involving pharmaceutical products being tested or used in a way different from the approved form or when used for an unapproved indication within 30 days prior to Day 1;

    2. Initiation of an exercise program for cardio-pulmonary rehabilitation within 3 months (90 days) prior to Day 1 or planned initiation during Part 1 of the study;

    3. Stopped receiving any PH chronic therapy within 60 days prior to Day 1;

    4. Requirement for receipt of intravenous inotropes within 30 days prior to Day 1;

    5. Has uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) > 160 mm Hg or sitting diastolic blood pressure > 100 mm Hg during Screening after a period of rest;

    6. Has systolic BP < 90 mm Hg during Screening after a period of rest;

    7. WHO Group III or V patients who at rest require supplemental oxygen at a rate of >4 L/min and have peripheral capillary oxygen saturation levels <92%;

    8. Has a history of clinically significant left-sided heart disease and/or clinically significant cardiac disease,including but not limited to any of the following:

    9. Congenital or acquired valvular disease if clinically significant apart from tricuspid valvular insufficiency due to pulmonary hypertension;

    10. Pericardial constriction;

    11. Restrictive or congestive cardiomyopathy;

    12. Left ventricular ejection fraction < 40% per echocardiogram (ECHO) within 60 days of Day 1;

    13. Any current or prior history of symptomatic coronary disease (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or anginal chest pain);

    14. Acutely decompensated heart failure within 30 days prior to Day 1, as per Investigator assessment;

    15. History of atrial septostomy within 180 days prior to Day 1;

    16. History of obstructive sleep apnea that is untreated;

    17. Has a history of portal hypertension or chronic liver disease, including hepatitis B and/or hepatitis C (with evidence of recent infection and/or active virus replication) defined as mild to severe hepatic impairment (Child-Pugh Class A-C);

    18. Serum aminotransferase (ALT or AST) levels > the upper limit of normal (ULN) at Screening;

    19. For patients with HIV-associated PAH, any of the following:

    20. Concomitant active opportunistic infections within 180 days prior to Screening;

    21. Detectable viral load within 90 days prior to Screening;

    22. Cluster designation (CD+) T-cell count < 200 mm3 within 90 days prior to Screening;

    23. Changes in antiretroviral regimen within 90 days prior to Screening;

    24. Using inhaled pentamidine

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Banner University Medical Center, Phoenix Advanced Lung Disease Institute Phoenix Arizona United States 85004
    2 Arizona Pulmonary Specialists Phoenix Arizona United States 85012
    3 Cedars Sinai Medical Center Beverly Hills California United States 90211
    4 VA Healthcare System of Greater Los Angeles Los Angeles California United States 90073
    5 University of California Davis Medical Center - Division of Pulmonary and Critical Care Sacramento California United States 95817
    6 Harbor - UCLA Medical Center Torrance California United States 90502
    7 University of Colorado Denver - Division of Pulmonary Sciences Aurora Colorado United States 80045
    8 South Denver Cardiology Associates, P.C Littleton Colorado United States 80120
    9 Georgetown University Medical Center - Department of Rheumatology Washington District of Columbia United States 20007
    10 Cleveland Clinic of Florida Weston Florida United States 33331
    11 University of Chicago Chicago Illinois United States 60637
    12 Maine Medical Center - Division of Pulmonary and Critical Care Medicine Portland Maine United States 04102
    13 Tufts Medical Center Boston Massachusetts United States 02111
    14 Brigham and Women's Hospital Boston Massachusetts United States 02115
    15 Boston University School of Medicine Boston Massachusetts United States 02118
    16 Winthrop University Hospital Mineola New York United States 11501
    17 Mount Sinai, Beth Israel Medical Center New York New York United States 10003
    18 Weill Cornell Medical Center New York New York United States 10021
    19 University of Rochester - University of Rochester Medical Center Rochester New York United States 14642
    20 The Lindner Clinical Trial Center Cincinnati Ohio United States 45219
    21 University of Cincinnati - Department of Internal Medicine Pulmonary, Critical Care & Sleep Medicine Cincinnati Ohio United States 45267
    22 The Ohio State University Wexner Medical Center Columbus Ohio United States 43210
    23 Oklahoma Heart Hospital Oklahoma City Oklahoma United States 73120
    24 University of Pittsburgh Medical Center Pittsburgh Pennsylvania United States 15213
    25 University of Texas Southwestern Medical Center Dallas Texas United States 75390
    26 BreatheAmerica El Paso, Inc. El Paso Texas United States 79912
    27 Houston Methodist Research Institute Houston Texas United States 77030
    28 The University of Texas - Health Science Center & Medical School at Houston Houston Texas United States 77030
    29 University of Texas Houston - Division of Rheumatology and Clinical Immunogenetics Houston Texas United States 77030
    30 University of Utah Salt Lake City Utah United States 84132
    31 University Clinic Carl Gustav Carus Dresden Germany 01304
    32 Universitaetsklinikum Hamburg-Eppendorf Hamburg Germany 20246

    Sponsors and Collaborators

    • Reata Pharmaceuticals, Inc.

    Investigators

    None specified.

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Reata Pharmaceuticals, Inc.
    ClinicalTrials.gov Identifier:
    NCT02036970
    Other Study ID Numbers:
    • RTA 402-C-1302
    First Posted:
    Jan 15, 2014
    Last Update Posted:
    Dec 7, 2021
    Last Verified:
    Nov 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Keywords provided by Reata Pharmaceuticals, Inc.
    Pulmonary Arterial Hypertension
    PAH
    Bardoxolone methyl
    6-minute walk distance
    CDDO-me
    RTA 402
    Pulmonary Hypertension
    Interstitial Lung Disease
    Idiopathic Interstitial Pneumonia
    Idiopathic Pulmonary Fibrosis
    Sarcoidosis
    Respiratory Bronchiolitis Associated ILD
    Desquamative Interstitial Pneumonia
    Cryptogenic Organizing Pneumonia
    Acute Interstitial Pneumonitis
    Idiopathic Lymphoid Interstitial Pneumonia
    Idiopathic Pleuroparenchymal Fibroelastosis
    Additional relevant MeSH terms:
    Pneumonia
    Bronchiolitis
    Lung Diseases
    Hypertension, Pulmonary
    Pulmonary Arterial Hypertension
    Pulmonary Fibrosis
    Idiopathic Pulmonary Fibrosis
    Lung Diseases, Interstitial
    Idiopathic Interstitial Pneumonias
    Hamman-Rich Syndrome
    Cryptogenic Organizing Pneumonia
    Hypertension
    Sarcoidosis
    Fibrosis

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail 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
    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
    Period Title: Part 1: Day 1 Through Week 16
    STARTED 5 11 6 9 1 3 3 3 63 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

    Baseline Characteristics

    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
    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 Participants 6 12 11 12 2 4 3 4 74 38 166
    Age (years) [Mean (Standard Deviation) ]
    Part 1: 16-week double-blind, randomized, placebo-controlled treatment period (Day 1 to Week 16)
    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)
    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)
    Sex: Female, Male (Count of Participants)
    Female
    4
    66.7%
    10
    83.3%
    8
    72.7%
    11
    91.7%
    1
    50%
    4
    100%
    2
    66.7%
    3
    75%
    54
    73%
    27
    71.1%
    124
    74.7%
    Male
    2
    33.3%
    2
    16.7%
    3
    27.3%
    1
    8.3%
    1
    50%
    0
    0%
    1
    33.3%
    1
    25%
    20
    27%
    11
    28.9%
    42
    25.3%
    Female
    4
    66.7%
    9
    75%
    4
    36.4%
    9
    75%
    1
    50%
    3
    75%
    2
    66.7%
    3
    75%
    47
    63.5%
    24
    63.2%
    106
    63.9%
    Male
    1
    16.7%
    2
    16.7%
    2
    18.2%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    0
    0%
    16
    21.6%
    9
    23.7%
    31
    18.7%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    2
    33.3%
    3
    25%
    0
    0%
    1
    8.3%
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    12
    16.2%
    7
    18.4%
    26
    15.7%
    Not Hispanic or Latino
    4
    66.7%
    9
    75%
    11
    100%
    11
    91.7%
    2
    100%
    3
    75%
    3
    100%
    4
    100%
    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%
    Hispanic or Latino
    2
    33.3%
    2
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    10
    13.5%
    7
    18.4%
    21
    12.7%
    Not Hispanic or Latino
    3
    50%
    9
    75%
    6
    54.5%
    9
    75%
    1
    50%
    3
    75%
    3
    100%
    3
    75%
    53
    71.6%
    26
    68.4%
    116
    69.9%
    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%
    Race (NIH/OMB) (Count of 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%
    Asian
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    2.7%
    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%
    1
    2.6%
    1
    0.6%
    Black or African American
    0
    0%
    1
    8.3%
    1
    9.1%
    0
    0%
    0
    0%
    3
    75%
    0
    0%
    0
    0%
    17
    23%
    9
    23.7%
    31
    18.7%
    White
    6
    100%
    11
    91.7%
    9
    81.8%
    12
    100%
    2
    100%
    1
    25%
    3
    100%
    4
    100%
    54
    73%
    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%
    Unknown or Not Reported
    0
    0%
    0
    0%
    1
    9.1%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.4%
    0
    0%
    2
    1.2%
    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%
    Asian
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.4%
    0
    0%
    1
    0.6%
    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%
    Black or African American
    0
    0%
    1
    8.3%
    0
    0%
    0
    0%
    0
    0%
    3
    75%
    0
    0%
    0
    0%
    14
    18.9%
    5
    13.2%
    23
    13.9%
    White
    5
    83.3%
    10
    83.3%
    5
    45.5%
    9
    75%
    1
    50%
    0
    0%
    3
    100%
    3
    75%
    47
    63.5%
    28
    73.7%
    111
    66.9%
    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%
    Unknown or Not Reported
    0
    0%
    0
    0%
    1
    9.1%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.4%
    0
    0%
    2
    1.2%
    6-Minute Walk Test (6MWT) (meters) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [meters]
    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)

    Outcome Measures

    1. Primary Outcome
    Title Change From Baseline Though Week 16 in 6-Minute Walk Distance (6MWD) for Bardoxolone Methyl Compared to Placebo
    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

    Outcome Measure Data

    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
    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.
    Measure Participants 6 12 9 10 2 4 3 4 70 38
    Change from Baseline though Week 16 for participants with PAH
    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
    7.6
    (32.01)
    10.8
    (32.01)
    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
    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
    Method of Estimation Estimation Parameter Mean Difference (Net)
    Estimated Value -1.74
    Confidence Interval (2-Sided) 95%
    -16.22 to 12.74
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference (Net) = Bardoxolone methyl - Placebo.
    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
    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
    Method of Estimation Estimation Parameter Mean Difference (Net)
    Estimated Value -3.17
    Confidence Interval (2-Sided) 95%
    -23.54 to 17.20
    Parameter Dispersion Type:
    Value:
    Estimation Comments Mean difference (Net) = Bardoxolone methyl - Placebo.

    Adverse Events

    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
    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
    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 (%) # 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 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 Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    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 (%) # 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 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 Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 2/12 (16.7%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/4 (25%) 7/74 (9.5%) 2/38 (5.3%) 2/5 (40%) 5/11 (45.5%) 3/6 (50%) 6/9 (66.7%) 0/1 (0%) 1/3 (33.3%) 2/3 (66.7%) 1/3 (33.3%) 9/63 (14.3%) 9/33 (27.3%)
    Blood and lymphatic system disorders
    Anaemia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Cardiac disorders
    Acute right ventricular failure 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Atrial fibrillation 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Cardiac failure acute 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Cardiac tamponade 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Coronary artery disease 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Pericardial effusion 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Right ventricular failure 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Ventricular arrhythmia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Gastrointestinal disorders
    Abdominal pain 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Ascites 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Gastric ulcer 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Gastrointestinal haemorrhage 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Small intestinal obstruction 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    General disorders
    General physical health deterioration 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Non-cardiac chest pain 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Infections and infestations
    Bronchitis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Campylobacter gastroenteritis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Cellulitis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Diarrhoea infectious 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Escherichia urinary tract infection 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Influenza 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Lung infection 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Pneumonia 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 1/33 (3%)
    Salpingitis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Urinary tract infection enterococcal 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Urosepsis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Viral upper respiratory tract infection 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Injury, poisoning and procedural complications
    Hip fracture 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 1/5 (20%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Pneumothorax traumatic 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Subdural haematoma 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Wound 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Investigations
    International normalised ratio increased 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Metabolism and nutrition disorders
    Dehydration 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Fluid overload 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/4 (25%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Musculoskeletal and connective tissue disorders
    Back pain 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Muscular weakness 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/4 (25%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Osteoarthritis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 1/5 (20%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Pain in extremity 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/4 (25%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/63 (0%) 0/33 (0%)
    Systemic lupus erythematosus 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Nervous system disorders
    Dizziness 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Embolic stroke 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 1/5 (20%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Syncope 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Transient ischaemic attack 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Psychiatric disorders
    Delirium 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/63 (0%) 0/33 (0%)
    Renal and urinary disorders
    Nephrolithiasis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Renal failure acute 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Reproductive system and breast disorders
    Haemorrhagic ovarian cyst 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Hypoxia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Pleural effusion 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Pleuritic pain 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Pulmonary arterial hypertension 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Pulmonary embolism 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Pulmonary fibrosis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Pulmonary hypertension 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Vascular disorders
    Hypertensive crisis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Hypotension 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Raynaud's phenomenon 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Other (Not Including 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 (%) # 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 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 Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 5/6 (83.3%) 11/12 (91.7%) 10/11 (90.9%) 12/12 (100%) 2/2 (100%) 4/4 (100%) 3/3 (100%) 4/4 (100%) 64/74 (86.5%) 33/38 (86.8%) 5/5 (100%) 11/11 (100%) 6/6 (100%) 8/9 (88.9%) 1/1 (100%) 2/3 (66.7%) 3/3 (100%) 3/3 (100%) 50/63 (79.4%) 30/33 (90.9%)
    Blood and lymphatic system disorders
    Anaemia 1/6 (16.7%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 1/5 (20%) 1/11 (9.1%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 3/63 (4.8%) 0/33 (0%)
    Coagulopathy 1/6 (16.7%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Iron deficiency anaemia 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 1/9 (11.1%) 0/1 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Pancytopenia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Splenic vein thrombosis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Splenomegaly 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Thrombocytopenia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 1/33 (3%)
    Cardiac disorders
    Angina pectoris 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Atrial fibrillation 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Atrial flutter 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Cardiac discomfort 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Palpitations 0/6 (0%) 0/12 (0%) 0/11 (0%) 2/12 (16.7%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 2/74 (2.7%) 0/38 (0%) 1/5 (20%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 1/1 (100%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Pericardial effusion 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/63 (3.2%) 0/33 (0%)
    Pericarditis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 1/33 (3%)
    Postural orthostatic tachycardia syndrome 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Right ventricular failure 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Supraventricular extrasystoles 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Tachycardia 0/6 (0%) 2/12 (16.7%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 2/74 (2.7%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Congenital, familial and genetic disorders
    Arteriovenous malformation 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Ear and labyrinth disorders
    Deafness 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Deafness bilateral 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Meniere's disease 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Tympanic membrane perforation 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Vertigo 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Eye disorders
    Cataract 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Conjunctival hyperaemia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Keratitis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Ocular hyperaemia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Periorbital oedema 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Retinal tear 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Scleral disorder 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Vision blurred 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 1/33 (3%)
    Gastrointestinal disorders
    Abdominal discomfort 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Abdominal distension 0/6 (0%) 1/12 (8.3%) 2/11 (18.2%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 1/4 (25%) 1/74 (1.4%) 1/38 (2.6%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Abdominal pain 0/6 (0%) 1/12 (8.3%) 1/11 (9.1%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 4/74 (5.4%) 0/38 (0%) 0/5 (0%) 3/11 (27.3%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 3/63 (4.8%) 2/33 (6.1%)
    Abdominal pain lower 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Colonic polyp 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Constipation 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 3/74 (4.1%) 3/38 (7.9%) 1/5 (20%) 3/11 (27.3%) 0/6 (0%) 2/9 (22.2%) 0/1 (0%) 1/3 (33.3%) 1/3 (33.3%) 0/3 (0%) 4/63 (6.3%) 1/33 (3%)
    Dental caries 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Diarrhoea 0/6 (0%) 2/12 (16.7%) 2/11 (18.2%) 2/12 (16.7%) 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 10/74 (13.5%) 3/38 (7.9%) 2/5 (40%) 2/11 (18.2%) 0/6 (0%) 1/9 (11.1%) 1/1 (100%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/63 (1.6%) 7/33 (21.2%)
    Diverticulum 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Dry mouth 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 2/74 (2.7%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Duodenitis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Dyspepsia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/63 (0%) 0/33 (0%)
    Flatulence 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Frequent bowel movements 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 1/5 (20%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Gastritis 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Gastrooesophageal reflux disease 1/6 (16.7%) 0/12 (0%) 0/11 (0%) 2/12 (16.7%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 5/74 (6.8%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 2/33 (6.1%)
    Gingivitis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Haematochezia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 2/38 (5.3%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Haemorrhoids 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Hiatus hernia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Ileus 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Impaired gastric emptying 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Lip dry 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/63 (0%) 0/33 (0%)
    Lower gastrointestinal haemorrhage 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Nausea 0/6 (0%) 1/12 (8.3%) 1/11 (9.1%) 4/12 (33.3%) 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 10/74 (13.5%) 6/38 (15.8%) 3/5 (60%) 4/11 (36.4%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 1/3 (33.3%) 2/63 (3.2%) 3/33 (9.1%)
    Oesophageal spasm 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Painful defaecation 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Rectal haemorrhage 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 2/33 (6.1%)
    Retching 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Salivary gland enlargement 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Toothache 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Vomiting 0/6 (0%) 1/12 (8.3%) 1/11 (9.1%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 2/74 (2.7%) 1/38 (2.6%) 2/5 (40%) 0/11 (0%) 0/6 (0%) 2/9 (22.2%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/63 (1.6%) 1/33 (3%)
    General disorders
    Asthenia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/4 (25%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Chest discomfort 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Chills 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Fatigue 0/6 (0%) 1/12 (8.3%) 1/11 (9.1%) 2/12 (16.7%) 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 7/74 (9.5%) 4/38 (10.5%) 0/5 (0%) 0/11 (0%) 3/6 (50%) 1/9 (11.1%) 1/1 (100%) 1/3 (33.3%) 1/3 (33.3%) 0/3 (0%) 4/63 (6.3%) 4/33 (12.1%)
    Generalised oedema 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Implant site haematoma 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Irritability 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Malaise 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Non-cardiac chest pain 1/6 (16.7%) 0/12 (0%) 1/11 (9.1%) 1/12 (8.3%) 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 3/74 (4.1%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 1/3 (33.3%) 1/3 (33.3%) 0/3 (0%) 4/63 (6.3%) 0/33 (0%)
    Oedema 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Oedema peripheral 0/6 (0%) 3/12 (25%) 1/11 (9.1%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 3/74 (4.1%) 5/38 (13.2%) 2/5 (40%) 3/11 (27.3%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 4/63 (6.3%) 3/33 (9.1%)
    Pain 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 2/12 (16.7%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 2/33 (6.1%)
    Pyrexia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 2/74 (2.7%) 2/38 (5.3%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 2/33 (6.1%)
    Vessel puncture site haematoma 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Vessel puncture site pain 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Vessel puncture site swelling 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Hepatobiliary disorders
    Cholelithiasis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Gallbladder disorder 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Gallbladder polyp 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Hepatic cirrhosis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Hepatic cyst 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Immune system disorders
    Drug hypersensitivity 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Seasonal allergy 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Infections and infestations
    Acute sinusitis 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Breast abscess 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Bronchitis 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 2/74 (2.7%) 1/38 (2.6%) 2/5 (40%) 1/11 (9.1%) 0/6 (0%) 2/9 (22.2%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Candidiasis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Cellulitis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/63 (3.2%) 0/33 (0%)
    Clostridial infection 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Conjunctivitis bacterial 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Conjunctivitis infective 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/63 (0%) 0/33 (0%)
    Ear infection 0/6 (0%) 0/12 (0%) 1/11 (9.1%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 2/6 (33.3%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 2/33 (6.1%)
    Folliculitis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Gastroenteritis 1/6 (16.7%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 2/74 (2.7%) 1/38 (2.6%) 1/5 (20%) 2/11 (18.2%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/63 (0%) 1/33 (3%)
    Gastrointestinal infection 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Helicobacter gastritis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Helicobacter infection 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Herpes zoster 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 2/74 (2.7%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 1/33 (3%)
    Hordeolum 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Infected cyst 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Influenza 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 1/5 (20%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Laryngitis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/63 (0%) 0/33 (0%)
    Lower respiratory tract infection 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 2/33 (6.1%)
    Lung infection 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Nasopharyngitis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 1/4 (25%) 2/3 (66.7%) 0/4 (0%) 7/74 (9.5%) 3/38 (7.9%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 1/3 (33.3%) 1/63 (1.6%) 2/33 (6.1%)
    Oesophageal candidiasis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Oral herpes 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/63 (0%) 0/33 (0%)
    Otitis externa 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Otitis media 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Pharyngitis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/63 (3.2%) 1/33 (3%)
    Pneumonia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 2/11 (18.2%) 0/6 (0%) 2/9 (22.2%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 1/33 (3%)
    Pyelonephritis acute 1/6 (16.7%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Respiratory tract infection 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 2/33 (6.1%)
    Rhinitis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Sinusitis 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 4/74 (5.4%) 0/38 (0%) 1/5 (20%) 1/11 (9.1%) 1/6 (16.7%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 4/63 (6.3%) 2/33 (6.1%)
    Tooth abscess 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/4 (25%) 2/74 (2.7%) 1/38 (2.6%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 1/33 (3%)
    Upper respiratory tract infection 2/6 (33.3%) 2/12 (16.7%) 2/11 (18.2%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 10/74 (13.5%) 7/38 (18.4%) 2/5 (40%) 4/11 (36.4%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 1/3 (33.3%) 12/63 (19%) 9/33 (27.3%)
    Urinary tract infection 0/6 (0%) 1/12 (8.3%) 1/11 (9.1%) 3/12 (25%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/4 (25%) 5/74 (6.8%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 2/3 (66.7%) 4/63 (6.3%) 2/33 (6.1%)
    Urinary tract infection bacterial 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Viral infection 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Viral upper respiratory tract infection 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Vulvovaginal mycotic infection 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Injury, poisoning and procedural complications
    Contusion 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 1/2 (50%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 3/74 (4.1%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 1/33 (3%)
    Foot fracture 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Hip fracture 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 1/5 (20%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Joint dislocation 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Joint injury 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Laceration 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 3/63 (4.8%) 0/33 (0%)
    Ligament sprain 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/63 (3.2%) 0/33 (0%)
    Limb injury 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Muscle injury 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Procedural pain 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 1/5 (20%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Radius fracture 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Rib fracture 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Upper limb fracture 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Wound haemorrhage 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Investigations
    Alanine aminotransferase increased 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 5/74 (6.8%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 1/1 (100%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/63 (1.6%) 2/33 (6.1%)
    Aspartate aminotransferase increased 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 4/74 (5.4%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 1/1 (100%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 1/33 (3%)
    Blood bicarbonate decreased 0/6 (0%) 0/12 (0%) 1/11 (9.1%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Blood bilirubin increased 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Blood creatine phosphokinase increased 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Blood creatinine increased 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/63 (3.2%) 0/33 (0%)
    Blood phosphorus decreased 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Blood potassium decreased 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Blood urine present 1/6 (16.7%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Brain natriuretic peptide increased 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 3/74 (4.1%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 3/63 (4.8%) 3/33 (9.1%)
    Cardiac murmur 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Cardiac output increased 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 1/5 (20%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Electrocardiogram QT prolonged 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Electrocardiogram abnormal 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Gamma-glutamyltransferase increased 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 3/74 (4.1%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Heart rate increased 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Hepatic enzyme increased 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 1/5 (20%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    International normalised ratio increased 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Liver function test abnormal 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 2/74 (2.7%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 2/33 (6.1%)
    N-terminal prohormone brain natriuretic peptide increased 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 2/74 (2.7%) 2/38 (5.3%) 1/5 (20%) 2/11 (18.2%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 4/63 (6.3%) 2/33 (6.1%)
    Oxygen saturation decreased 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 1/11 (9.1%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Platelet count decreased 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Pulmonary arterial pressure increased 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Serum ferritin decreased 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Venous pressure jugular increased 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 1/5 (20%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/63 (3.2%) 0/33 (0%)
    Vital capacity abnormal 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Weight decreased 0/6 (0%) 0/12 (0%) 0/11 (0%) 2/12 (16.7%) 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 3/74 (4.1%) 1/38 (2.6%) 0/5 (0%) 1/11 (9.1%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/63 (1.6%) 2/33 (6.1%)
    Weight increased 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 2/4 (50%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    White blood cell count increased 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 3/63 (4.8%) 0/33 (0%)
    Metabolism and nutrition disorders
    Decreased appetite 1/6 (16.7%) 0/12 (0%) 3/11 (27.3%) 5/12 (41.7%) 1/2 (50%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 7/74 (9.5%) 1/38 (2.6%) 1/5 (20%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 3/63 (4.8%) 6/33 (18.2%)
    Dyslipidaemia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 1/5 (20%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Fluid overload 0/6 (0%) 0/12 (0%) 1/11 (9.1%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/4 (25%) 0/74 (0%) 2/38 (5.3%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 2/9 (22.2%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 3/63 (4.8%) 0/33 (0%)
    Fluid retention 0/6 (0%) 0/12 (0%) 1/11 (9.1%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/4 (25%) 1/74 (1.4%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Folate deficiency 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 1/33 (3%)
    Glucose tolerance impaired 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Gout 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Hyperalbuminaemia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Hypercholesterolaemia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Hypokalaemia 1/6 (16.7%) 2/12 (16.7%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 2/5 (40%) 2/11 (18.2%) 0/6 (0%) 2/9 (22.2%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/63 (1.6%) 1/33 (3%)
    Hypomagnesaemia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Iron deficiency 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 2/33 (6.1%)
    Lactic acidosis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Lactose intolerance 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Metabolic acidosis 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Vitamin B12 deficiency 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 1/6 (16.7%) 1/12 (8.3%) 1/11 (9.1%) 1/12 (8.3%) 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 3/74 (4.1%) 1/38 (2.6%) 2/5 (40%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 2/3 (66.7%) 0/3 (0%) 4/63 (6.3%) 0/33 (0%)
    Arthritis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Arthropathy 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Back pain 0/6 (0%) 3/12 (25%) 0/11 (0%) 2/12 (16.7%) 1/2 (50%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 4/74 (5.4%) 4/38 (10.5%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 1/33 (3%)
    Bone pain 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Bursitis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Chondrocalcinosis pyrophosphate 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Clubbing 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Exostosis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Fibromyalgia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 1/5 (20%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Foot deformity 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 1/5 (20%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Intervertebral disc degeneration 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/4 (25%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Intervertebral disc protrusion 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Joint swelling 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 1/5 (20%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Muscle spasms 1/6 (16.7%) 0/12 (0%) 3/11 (27.3%) 3/12 (25%) 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 11/74 (14.9%) 2/38 (5.3%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 2/3 (66.7%) 0/3 (0%) 5/63 (7.9%) 5/33 (15.2%)
    Musculoskeletal chest pain 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Musculoskeletal discomfort 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 1/5 (20%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Musculoskeletal pain 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Myalgia 0/6 (0%) 2/12 (16.7%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 1/74 (1.4%) 1/38 (2.6%) 2/5 (40%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Neck pain 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 1/2 (50%) 0/4 (0%) 0/3 (0%) 1/4 (25%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Pain in extremity 0/6 (0%) 2/12 (16.7%) 1/11 (9.1%) 3/12 (25%) 0/2 (0%) 0/4 (0%) 1/3 (33.3%) 0/4 (0%) 2/74 (2.7%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 2/3 (66.7%) 0/3 (0%) 0/3 (0%) 3/63 (4.8%) 1/33 (3%)
    Pain in jaw 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 2/5 (40%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Plantar fasciitis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Rheumatoid arthritis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Scleroderma 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Temporomandibular joint syndrome 1/6 (16.7%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Colon cancer 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Squamous cell carcinoma 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Squamous cell carcinoma of skin 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Uterine leiomyoma 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Nervous system disorders
    Ageusia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Burning sensation 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 1/1 (100%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Central nervous system lesion 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Dizziness 0/6 (0%) 1/12 (8.3%) 1/11 (9.1%) 2/12 (16.7%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/4 (25%) 4/74 (5.4%) 3/38 (7.9%) 1/5 (20%) 1/11 (9.1%) 1/6 (16.7%) 1/9 (11.1%) 1/1 (100%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Dizziness exertional 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Dysgeusia 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 2/74 (2.7%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Headache 0/6 (0%) 2/12 (16.7%) 3/11 (27.3%) 5/12 (41.7%) 1/2 (50%) 1/4 (25%) 1/3 (33.3%) 1/4 (25%) 8/74 (10.8%) 7/38 (18.4%) 3/5 (60%) 0/11 (0%) 2/6 (33.3%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 2/3 (66.7%) 0/3 (0%) 2/63 (3.2%) 3/33 (9.1%)
    Memory impairment 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Migraine 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Multiple sclerosis 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Occipital neuralgia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Paraesthesia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 1/1 (100%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Presyncope 0/6 (0%) 0/12 (0%) 1/11 (9.1%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Sciatica 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Somnolence 0/6 (0%) 0/12 (0%) 0/11 (0%) 2/12 (16.7%) 1/2 (50%) 0/4 (0%) 0/3 (0%) 1/4 (25%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Spinal claudication 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 1/4 (25%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Syncope 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 2/4 (50%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 2/38 (5.3%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Tremor 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 1/1 (100%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Psychiatric disorders
    Anxiety 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 2/74 (2.7%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 1/33 (3%)
    Attention deficit/hyperactivity disorder 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 1/1 (100%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Confusional state 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Depression 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Hallucination 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Insomnia 1/6 (16.7%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 1/38 (2.6%) 1/5 (20%) 1/11 (9.1%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Libido decreased 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Renal and urinary disorders
    Cystitis noninfective 1/6 (16.7%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Dysuria 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Pollakiuria 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Renal failure acute 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Urinary retention 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Reproductive system and breast disorders
    Benign prostatic hyperplasia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 1/5 (20%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Breast mass 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Dysmenorrhoea 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Menorrhagia 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Menstrual disorder 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/63 (0%) 0/33 (0%)
    Menstruation irregular 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Ovarian cyst 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Vaginal disorder 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 1/5 (20%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Vaginal haemorrhage 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Respiratory, thoracic and mediastinal disorders
    Asthma 1/6 (16.7%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 1/5 (20%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Bronchial hyperreactivity 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Cough 1/6 (16.7%) 1/12 (8.3%) 2/11 (18.2%) 1/12 (8.3%) 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 4/74 (5.4%) 4/38 (10.5%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 5/63 (7.9%) 4/33 (12.1%)
    Dyspnoea 1/6 (16.7%) 2/12 (16.7%) 3/11 (27.3%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 8/74 (10.8%) 1/38 (2.6%) 1/5 (20%) 2/11 (18.2%) 1/6 (16.7%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 5/63 (7.9%) 4/33 (12.1%)
    Dyspnoea exertional 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 2/74 (2.7%) 1/38 (2.6%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Dyspnoea paroxysmal nocturnal 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Epistaxis 1/6 (16.7%) 1/12 (8.3%) 1/11 (9.1%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 2/74 (2.7%) 2/38 (5.3%) 1/5 (20%) 0/11 (0%) 4/6 (66.7%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/63 (1.6%) 1/33 (3%)
    Hypoxia 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 1/5 (20%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Increased upper airway secretion 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Mediastinal mass 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Nasal congestion 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 3/33 (9.1%)
    Nasal dryness 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/63 (0%) 0/33 (0%)
    Nasal septum perforation 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Oropharyngeal pain 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 2/4 (50%) 0/3 (0%) 0/4 (0%) 3/74 (4.1%) 1/38 (2.6%) 0/5 (0%) 1/11 (9.1%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/63 (1.6%) 2/33 (6.1%)
    Pharyngeal lesion 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Pleural effusion 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Productive cough 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 3/63 (4.8%) 1/33 (3%)
    Pulmonary arterial hypertension 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Pulmonary congestion 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 1/5 (20%) 0/11 (0%) 1/6 (16.7%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Pulmonary fibrosis 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Pulmonary hypertension 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 1/33 (3%)
    Rales 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 2/74 (2.7%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 1/33 (3%)
    Rhinalgia 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Rhinorrhoea 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Sinus congestion 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 1/4 (25%) 0/3 (0%) 0/4 (0%) 2/74 (2.7%) 3/38 (7.9%) 1/5 (20%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Sleep apnoea syndrome 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Upper-airway cough syndrome 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Wheezing 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Skin and subcutaneous tissue disorders
    Alopecia 0/6 (0%) 2/12 (16.7%) 1/11 (9.1%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 0/38 (0%) 1/5 (20%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Dermal cyst 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Digital ulcer 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Dry skin 0/6 (0%) 0/12 (0%) 1/11 (9.1%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Erythema 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 1/5 (20%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Hyperhidrosis 0/6 (0%) 0/12 (0%) 1/11 (9.1%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Hyperkeratosis 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Increased tendency to bruise 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 2/74 (2.7%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Pruritus 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 2/74 (2.7%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Psoriasis 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Rash 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Rash generalised 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/63 (0%) 0/33 (0%)
    Rash papular 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 1/74 (1.4%) 2/38 (5.3%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Rash pruritic 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Skin haemorrhage 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Skin irritation 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Skin lesion 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/63 (1.6%) 0/33 (0%)
    Skin ulcer 1/6 (16.7%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 1/5 (20%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Subcutaneous nodule 1/6 (16.7%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Urticaria 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Social circumstances
    Menopause 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Vascular disorders
    Flushing 0/6 (0%) 1/12 (8.3%) 0/11 (0%) 2/12 (16.7%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 1/9 (11.1%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Hot flush 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 1/38 (2.6%) 0/5 (0%) 0/11 (0%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 2/33 (6.1%)
    Hypertension 0/6 (0%) 0/12 (0%) 1/11 (9.1%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 2/74 (2.7%) 0/38 (0%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Hypotension 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 2/38 (5.3%) 0/5 (0%) 0/11 (0%) 1/6 (16.7%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/63 (0%) 1/33 (3%)
    Orthostatic hypotension 0/6 (0%) 0/12 (0%) 0/11 (0%) 1/12 (8.3%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)
    Thrombophlebitis superficial 0/6 (0%) 0/12 (0%) 0/11 (0%) 0/12 (0%) 0/2 (0%) 0/4 (0%) 0/3 (0%) 0/4 (0%) 0/74 (0%) 0/38 (0%) 0/5 (0%) 1/11 (9.1%) 0/6 (0%) 0/9 (0%) 0/1 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/63 (0%) 0/33 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Sponsor can review results communications prior to public release and can embargo communications regarding trial results for up to a period that is more than 60 days but less than or equal to 180 days. Sponsor can require changes to the results communication where confidential information that would put Sponsor at a competitive disadvantage occurs. PI may publish results after a multi-investigator publication or 12 months following completion of the trial, whichever is earlier.

    Results Point of Contact

    Name/Title Kris Loerwald
    Organization Reata Pharmaceuticals, Inc.
    Phone +1 972-865-2219
    Email MedicalAffairs-Team@reatapharma.com
    Responsible Party:
    Reata Pharmaceuticals, Inc.
    ClinicalTrials.gov Identifier:
    NCT02036970
    Other Study ID Numbers:
    • RTA 402-C-1302
    First Posted:
    Jan 15, 2014
    Last Update Posted:
    Dec 7, 2021
    Last Verified:
    Nov 1, 2021