CANagliflozin Treatment And Trial Analysis-Sulfonylurea (CANTATA-SU) SGLT2 Add-on to Metformin Versus Glimepiride

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:
NCT00968812
First received: August 28, 2009
Last updated: April 3, 2014
Last verified: April 2014
Results First Received: April 17, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Diabetes Mellitus, Type 2
Interventions: Drug: Glimepiride
Drug: Canagliflozin (JNJ-28431754)
Drug: Metformin

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This study evaluated the efficacy and safety of canagliflozin (JNJ-28431754) compared with glimepiride in participants with type 2 diabetes mellitus with inadequate glycemic control despite metformin treatment. The study was conducted between 28 August 2009 and 25 January 2013 and included 157 study centers in 19 countries worldwide.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
1,452 participants were randomly allocated to the 3 treatment arms. 1450 participants received at least 1 dose of study drug and were included in the modified intent-to-treat (mITT) analysis set and safety analysis set. Participant flow is presented for Baseline to Week 104.

Reporting Groups
  Description
Canagliflozin 100 mg: Baseline to Week 104 Each patient received 100 mg of canagliflozin (JNJ-28431754) once daily with protocol-specified doses of metformin for 104 weeks.
Canagliflozin 300 mg: Baseline to Week 104 Each patient received 300 mg of canagliflozin (JNJ-28431754) once daily with protocol-specified doses of metformin for 104 weeks.
Glimepiride: Baseline to Week 104 Each patient received glimepiride, at protocol-specified doses, once daily in combination with protocol-specified doses of metformin for 104 weeks.

Participant Flow:   Overall Study
    Canagliflozin 100 mg: Baseline to Week 104     Canagliflozin 300 mg: Baseline to Week 104     Glimepiride: Baseline to Week 104  
STARTED     483     485     482  
COMPLETED     343     323     314  
NOT COMPLETED     140     162     168  
Adverse Event                 30                 46                 33  
Death                 2                 2                 1  
Lack of Efficacy                 9                 7                 16  
Lost to Follow-up                 17                 12                 11  
Physician Decision                 8                 5                 9  
Protocol Violation                 7                 4                 3  
Withdrawal by Subject                 17                 23                 25  
Creatinine or eGFR withdrawal criteria                 9                 13                 7  
Noncompliance with study drug                 4                 1                 6  
Unable to take rescue therapy                 12                 12                 17  
Not specified                 25                 37                 40  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Canagliflozin 100 mg Each patient received 100 mg of canagliflozin (JNJ-28431754) once daily with protocol-specified doses of metformin for 104 weeks.
Canagliflozin 300 mg Each patient received 300 mg of canagliflozin (JNJ-28431754) once daily with protocol-specified doses of metformin for 104 weeks.
Glimepiride Each patient received glimepiride, at protocol-specified doses, once daily in combination with protocol-specified doses of metformin for 104 weeks.
Total Total of all reporting groups

Baseline Measures
    Canagliflozin 100 mg     Canagliflozin 300 mg     Glimepiride     Total  
Number of Participants  
[units: participants]
  483     485     482     1450  
Age  
[units: participants]
       
<=18 years     0     0     0     0  
Between 18 and 65 years     397     411     399     1207  
>=65 years     86     74     83     243  
Age  
[units: years]
Mean ± Standard Deviation
  56.4  ± 9.49     55.8  ± 9.17     56.3  ± 9.01     56.2  ± 9.22  
Gender  
[units: participants]
       
Female     231     244     219     694  
Male     252     241     263     756  
Region Enroll  
[units: participants]
       
ARGENTINA     18     18     18     54  
BULGARIA     7     7     7     21  
CANADA     19     20     19     58  
COSTA RICA     10     9     9     28  
DENMARK     24     25     25     74  
FINLAND     18     17     19     54  
GERMANY     6     7     6     19  
INDIA     55     55     56     166  
ISRAEL     14     15     14     43  
MEXICO     24     25     24     73  
NORWAY     9     9     9     27  
PHILIPPINES     14     13     13     40  
POLAND     14     15     15     44  
ROMANIA     43     43     44     130  
RUSSIAN FEDERATION     23     22     22     67  
SLOVAKIA     15     14     13     42  
SOUTH KOREA     31     32     31     94  
UKRAINE     22     22     22     66  
UNITED STATES     117     117     116     350  



  Outcome Measures
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1.  Primary:   Change in HbA1c From Baseline to Week 52   [ Time Frame: Day 1 (Baseline) and Week 52 ]

2.  Secondary:   Percentage of Patients Experiencing at Least 1 Hypoglycemic Event From Baseline to Week 52   [ Time Frame: Day 1 (Baseline) and Week 52 ]

3.  Secondary:   Percent Change in Body Weight From Baseline to Week 52   [ Time Frame: Day 1 (Baseline) and Week 52 ]

4.  Secondary:   Change in HbA1c From Baseline to Week 104   [ Time Frame: Baseline, Week 104 ]
Results not yet posted.   Anticipated Posting Date:   01/2014   Safety Issue:   No


  Serious Adverse Events
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Time Frame Adverse event data were collected for the duration of the study (104 weeks).
Additional Description

The total number of adverse events listed in the "Other (non-Serious) Adverse Events" table are based upon a cut-off of greater than or equal to 5 percent of patients experiencing the adverse event in any treatment arm.

MEDDRA 14.1 used for Week 52 / MEDDRA 15.0 for Week 104 results.


Reporting Groups
  Description
Canagliflozin 100 mg: Baseline to Week 52 Each patient received 100 mg of canagliflozin (JNJ-28431754) once daily with protocol-specified doses of metformin for 104 weeks. Data are presented for Baseline to Week 52.
Canagliflozin 300 mg: Baseline to Week 52 Each patient received 300 mg of canagliflozin (JNJ-28431754) once daily with protocol-specified doses of metformin for 104 weeks. Data are presented for Baseline to Week 52.
Glimepiride: Baseline to Week 52 Each patient received glimepiride, at protocol-specified doses, once daily in combination with protocol-specified doses of metformin for 104 weeks. Data are presented for Baseline to Week 52.
Canagliflozin 100 mg: Baseline to Week 104 Each patient received 100 mg of canagliflozin (JNJ-28431754) once daily with protocol-specified doses of metformin for 104 weeks. Data are presented for Baseline to Week 104.
Canagliflozin 300 mg: Baseline to Week 104 Each patient received 300 mg of canagliflozin (JNJ-28431754) once daily with protocol-specified doses of metformin for 104 weeks. Data are presented for Baseline to Week 104.
Glimepiride: Baseline to Week 104 Each patient received glimepiride, at protocol-specified doses, once daily in combination with protocol-specified doses of metformin for 104 weeks. Data are presented for Baseline to Week 104.

Serious Adverse Events
    Canagliflozin 100 mg: Baseline to Week 52     Canagliflozin 300 mg: Baseline to Week 52     Glimepiride: Baseline to Week 52     Canagliflozin 100 mg: Baseline to Week 104     Canagliflozin 300 mg: Baseline to Week 104     Glimepiride: Baseline to Week 104  
Total, serious adverse events              
# participants affected / at risk     24/483 (4.97%)     26/485 (5.36%)     39/482 (8.09%)     47/483 (9.73%)     47/485 (9.69%)     69/482 (14.32%)  
Blood and lymphatic system disorders              
Anaemia * 1            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Cardiac disorders              
Acute coronary syndrome * 1            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Angina pectoris * 1            
# participants affected / at risk     1/483 (0.21%)     2/485 (0.41%)     2/482 (0.41%)     3/483 (0.62%)     2/485 (0.41%)     3/482 (0.62%)  
Angina unstable * 1            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     1/482 (0.21%)     1/483 (0.21%)     1/485 (0.21%)     2/482 (0.41%)  
Aortic valve incompetence * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Atrial fibrillation * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     2/482 (0.41%)  
Bundle branch block left * 1            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Cardiac arrest * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Cardiomyopathy * 1            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Coronary artery disease * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     1/483 (0.21%)     0/485 (0.00%)     2/482 (0.41%)  
Diabetic cardiomyopathy * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Mitral valve incompetence * 1            
# participants affected / at risk     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Myocardial infarction * 1            
# participants affected / at risk     1/483 (0.21%)     1/485 (0.21%)     0/482 (0.00%)     2/483 (0.41%)     1/485 (0.21%)     1/482 (0.21%)  
Myocardial ischaemia * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Pericardial effusion * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Tachycardia * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Ventricular arrhythmia * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Acute myocardial infarction * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     2/482 (0.41%)  
Cardiac failure * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Coronary artery occlusion * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Congenital, familial and genetic disorders              
Arnold-Chiari malformation * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Philmosis * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Eye disorders              
Angle closure glaucoma * 1            
# participants affected / at risk     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Cataract * 1            
# participants affected / at risk     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     2/482 (0.41%)  
Diabetic retinopathy * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Vitreous haemorrhage * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Gastrointestinal disorders              
Abdominal pain * 1            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Duodenal ulcer * 1            
# participants affected / at risk     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Duodenitis * 1            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Inguinal hernia * 1            
# participants affected / at risk     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     1/485 (0.21%)     0/482 (0.00%)  
Pancreatitis * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     1/485 (0.21%)     1/482 (0.21%)  
Small intestinal perforation * 1 [4]            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)  
Umbilical hernia * 1            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Abdominal strangulated herina * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Gastrointestinal haemorrhage * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Pancreatitis acute * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Pancreatitis chronic * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
General disorders              
Asthenia * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Non-cardiac chest pain * 1            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     2/482 (0.41%)     0/483 (0.00%)     2/485 (0.41%)     3/482 (0.62%)  
Oedema peripheral * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Cyst * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Hepatobiliary disorders              
Cholecystitis acute * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     1/485 (0.21%)     1/482 (0.21%)  
Cholelithiasis * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     3/482 (0.62%)     0/483 (0.00%)     0/485 (0.00%)     4/482 (0.83%)  
Hepatic cyst * 1            
# participants affected / at risk     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Cholecystitis chronic * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     2/483 (0.41%)     0/485 (0.00%)     0/482 (0.00%)  
Infections and infestations              
Appendicitis * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     2/482 (0.41%)     0/483 (0.00%)     0/485 (0.00%)     2/482 (0.41%)  
Endometritis * 1            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Gastroenteritis * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Localised infection * 1 [5]            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Lobar pneumonia * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Lower respiratory tract infection * 1            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Lung infection * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Pneumonia * 1            
# participants affected / at risk     1/483 (0.21%)     1/485 (0.21%)     2/482 (0.41%)     1/483 (0.21%)     2/485 (0.41%)     2/482 (0.41%)  
Postoperative wound infection * 1            
# participants affected / at risk     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Respiratory tract infection viral * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Staphylococcal infection * 1            
# participants affected / at risk     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Urinary tract infection * 1            
# participants affected / at risk     1/483 (0.21%)     1/485 (0.21%)     0/482 (0.00%)     1/483 (0.21%)     2/485 (0.41%)     1/482 (0.21%)  
Herpes zoster * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Orchitis * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Pyelonephritis * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Upper respiratory tract infection * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Sepsis * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Infection * 1 [5]            
# participants affected / at risk     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)  
Injury, poisoning and procedural complications              
Eye injury * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Fall * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Femoral neck fracture * 1            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Foot fracture * 1            
# participants affected / at risk     1/483 (0.21%)     0/485 (0.00%)     1/482 (0.21%)     1/483 (0.21%)     0/485 (0.00%)     1/482 (0.21%)  
Incisional hernia * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Injury * 1            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Ligament sprain * 1            
# participants affected / at risk     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)     2/483 (0.41%)     0/485 (0.00%)     0/482 (0.00%)  
Lower limb fracture * 1            
# participants affected / at risk     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Meniscus lesion * 1            
# participants affected / at risk     2/483 (0.41%)     0/485 (0.00%)     0/482 (0.00%)     2/483 (0.41%)     0/485 (0.00%)     0/482 (0.00%)  
Muscle injury * 1            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Muscle rupture * 1            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Overdose * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Road traffic accident * 1            
# participants affected / at risk     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     1/485 (0.21%)     0/482 (0.00%)  
Skull fracture * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Subdural haematoma * 1            
# participants affected / at risk     1/483 (0.21%)     0/485 (0.00%)     1/482 (0.21%)     1/483 (0.21%)     0/485 (0.00%)     1/482 (0.21%)  
Toxicity to various agents * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Ulna fracture * 1            
# participants affected / at risk     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Wrist fracture * 1            
# participants affected / at risk     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Chemical poisoning * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Clavicle fracture * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     1/485 (0.21%)     0/482 (0.00%)  
Concussion * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Contusion * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Femur fracture * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Head injury * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Heat exhaustion * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Humerus fracture * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Joint dislocation * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Procedural complication * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Procedural nausea * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Investigations              
Blood creatinine increased * 1            
# participants affected / at risk     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Electrocardiogram T wave biphasic * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Metabolism and nutrition disorders              
Dehydration * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Diabetes mellitus inadequate control * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Hyperglycaemia * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Obesity * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Musculoskeletal and connective tissue disorders              
Intervertebral disc protrusion * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Musculoskeletal pain * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Pain in extremity * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Spinal column stenosis * 1            
# participants affected / at risk     1/483 (0.21%)     0/485 (0.00%)     1/482 (0.21%)     2/483 (0.41%)     0/485 (0.00%)     1/482 (0.21%)  
Arthritis * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Osteoarthritis * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Polyarthritis * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)              
Endometrial cancer * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Renal cancer stage I * 1            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Squamous cell carcinoma of the cervix * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Uterine leiomyoma * 1            
# participants affected / at risk     0/483 (0.00%)     2/485 (0.41%)     0/482 (0.00%)     0/483 (0.00%)     3/485 (0.62%)     0/482 (0.00%)  
Breast cancer stage I * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Colon cancer * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Gastrointestinal tract adenoma * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Hepatic neoplasm * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Lung neoplasm * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Oesophageal carcinoma * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Prostate cancer * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     1/482 (0.21%)  
Nervous system disorders              
Carotid arterial embolus * 1            
# participants affected / at risk     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Cerebral infarction * 1            
# participants affected / at risk     1/483 (0.21%)     1/485 (0.21%)     0/482 (0.00%)     1/483 (0.21%)     1/485 (0.21%)     0/482 (0.00%)  
Cerebrovascular accident * 1            
# participants affected / at risk     2/483 (0.41%)     1/485 (0.21%)     0/482 (0.00%)     2/483 (0.41%)     1/485 (0.21%)     2/482 (0.41%)  
Hemiplegic migraine * 1 [6]            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)  
Vertebrobasilar insufficiency * 1            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Complex regional pain syndrome * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Dizziness * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Haemorrhage intracranial * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Hemiparesis * 1 [6]            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Syncope * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Transient ischaemic attack * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     1/485 (0.21%)     1/482 (0.21%)  
Psychiatric disorders              
Confusional state * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Stress * 1 [7]            
# participants affected / at risk     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)  
Anxiety * 1 [7]            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Renal and urinary disorders              
Incontinence * 1            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Calculus ureteric * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Nephrolithiasis * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Renal failure acute * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Urethral stenosis * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Urinary retention * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Reproductive system and breast disorders              
Dysfunctional uterine bleeding * 1            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Menstrual disorder * 1            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Benign prostatic hyperplasia * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     1/482 (0.21%)  
Prostatitis * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Prostatomegaly * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Respiratory, thoracic and mediastinal disorders              
Allergic bronchitis * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Chronic obstructive pulmonary disease * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     2/482 (0.41%)     0/483 (0.00%)     0/485 (0.00%)     2/482 (0.41%)  
Dyspnoea * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     2/482 (0.41%)     0/483 (0.00%)     0/485 (0.00%)     2/482 (0.41%)  
Interstitial lung disease * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Pulmonary oedema * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Pulmonary embolism * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Skin and subcutaneous tissue disorders              
Urticaria * 1            
# participants affected / at risk     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Diabetic foot * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     1/485 (0.21%)     0/482 (0.00%)  
Social circumstances              
Familial risk factor * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/482 (0.00%)  
Surgical and medical procedures              
Small bowel perforation * 1 [8]            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
Vascular disorders              
Deep vein thrombosis * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Haematoma * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Hypertension * 1            
# participants affected / at risk     0/483 (0.00%)     1/485 (0.21%)     1/482 (0.21%)     1/483 (0.21%)     1/485 (0.21%)     1/482 (0.21%)  
Hypertensive crisis * 2            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)     0/483 (0.00%)     0/485 (0.00%)     1/482 (0.21%)  
Intermittent claudication * 1            
# participants affected / at risk     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)     1/483 (0.21%)     0/485 (0.00%)     0/482 (0.00%)  
Hypotension * 1            
# participants affected / at risk     0/483 (0.00%)     0/485 (0.00%)     0/482 (0.00%)     0/483 (0.00%)     1/485 (0.21%)     0/482 (0.00%)  
* Events were collected by non-systematic assessment
1 Term from vocabulary, MEDDRA 14.1 / 15.0
2 Term from vocabulary, MEDDRA 14.1
[4] This event was re-coded as "Small bowel perforation"; it was subsequently re-mapped to the "Surgical and medical procedures".
[5] In the Week 52 study report, this event was coded as "infection"; it was subsequently re-coded in the Week 104 study report as "localised infection".
[6] In the Week 52 study report, this event was coded as "Hemiplegic migraine"; it was subsequently re-coded in the Week 104 study report as "Hemiparesis".
[7] In the Week 52 study report, this event was coded as "stress"; it was subsequently re-coded in the Week 104 study report as "anxiety".
[8] In Week 52 study report this event was coded as "small intestinal perforation" and was mapped under "Gastrointestinal disorders ".




  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No notable study limitations were identified by the Sponsor.


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