Exenatide Versus Glimepiride in Patients With Type 2 Diabetes

This study has been completed.
Sponsor:
Collaborator:
Eli Lilly and Company
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT00359762
First received: July 31, 2006
Last updated: June 6, 2014
Last verified: June 2014
Results First Received: March 29, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Type 2 Diabetes Mellitus
Interventions: Drug: exenatide
Drug: glimepiride

  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
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Patients meeting defined failure of HbA1c control (primary endpoint) in Study Period II were eligible for entry to Study Period III

Reporting Groups
  Description
Period II, Exen + Met Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Period II, Glim + Met Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin
Period III, Exen + Met + Glim - Randomized Glimepiride once daily, started at 1 mg dose and titrated up to maintenance doses, was added to Exenatide 10 mcg twice daily subcutaneously injected and daily oral Metformin in Period III
Period III, Exen + Met + Pio or Rosi - Randomized Oral Rosiglitazone or Pioglitazone once or twice daily, started 15 mg per day, was added to Exenatide 10 mcg twice daily subcutaneously injected and daily oral Metformin in Period III
Period III, Glim + Met + Exen - Not Randomized Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for the first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period III) was added to oral Glimepiride once daily and daily oral Metformin in Period III

Participant Flow for 2 periods

Period 1:   Period II
    Period II, Exen + Met     Period II, Glim + Met     Period III, Exen + Met + Glim - Randomized     Period III, Exen + Met + Pio or Rosi - Randomized     Period III, Glim + Met + Exen - Not Randomized  
STARTED     515     514     0     0     0  
Intent to Treat (ITT) Safety Population     511     508     0     0     0  
ITT Efficacy Population     490     487     0     0     0  
Met Primary Endpoint     203     262     0     0     0  
Without Treatment Failure     138     124     0     0     0  
COMPLETED     341     386     0     0     0  
NOT COMPLETED     174     128     0     0     0  
Adverse Event                 49                 17                 0                 0                 0  
Protocol Violation                 11                 18                 0                 0                 0  
Physician Decision                 23                 17                 0                 0                 0  
Death                 4                 2                 0                 0                 0  
Lack of Efficacy                 8                 11                 0                 0                 0  
Lost to follow up                 5                 5                 0                 0                 0  
Entry Criteria Not Met                 4                 8                 0                 0                 0  
Subject Decision                 70                 50                 0                 0                 0  

Period 2:   Period III
    Period II, Exen + Met     Period II, Glim + Met     Period III, Exen + Met + Glim - Randomized     Period III, Exen + Met + Pio or Rosi - Randomized     Period III, Glim + Met + Exen - Not Randomized  
STARTED     0     0     77     77     166  
Extension ITT Safety Population     0     0     74     76     166  
Extension ITT Efficacy Population     0     0     73     75     164  
COMPLETED     0     0     48     47     101  
NOT COMPLETED     0     0     29     30     65  
Protocol Violation                 0                 0                 5                 3                 8  
Adverse Event                 0                 0                 3                 4                 10  
Physician Decision                 0                 0                 5                 9                 15  
Lack of Efficacy                 0                 0                 7                 5                 9  
Lost to follow up                 0                 0                 1                 1                 2  
Entry Criteria Not Met                 0                 0                 1                 0                 1  
Subject Decision                 0                 0                 7                 8                 20  



  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
Exen + Met Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Glim + Met Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin
Total Total of all reporting groups

Baseline Measures
    Exen + Met     Glim + Met     Total  
Number of Participants  
[units: participants]
  490     487     977  
Age  
[units: participants]
     
<=18 years     0     0     0  
Between 18 and 65 years     388     389     777  
>=65 years     102     98     200  
Age  
[units: years]
Mean ± Standard Deviation
  56.1  ± 10.03     56.8  ± 9.14     56.4  ± 9.60  
Gender  
[units: participants]
     
Female     218     235     453  
Male     272     252     524  
Glycosylated hemoglobin (HbA1c)  
[units: percentage of total hemoglobin]
Mean ± Standard Deviation
  7.4  ± 0.69     7.4  ± 0.71     7.4  ± 0.70  
Weight  
[units: kg]
Mean ± Standard Deviation
  92.8  ± 16.70     91.1  ± 14.78     92.0  ± 15.78  



  Outcome Measures
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1.  Primary:   Number of Patients With Treatment Failure   [ Time Frame: Baseline to end of Period II (up to 4.5 years) ]

2.  Primary:   Time to Treatment Failure   [ Time Frame: Baseline to end of Period II (up to 4.5 years) ]

3.  Secondary:   Homeostasis Model Assessment of Beta-cell Function (HOMA-B) at Year 3   [ Time Frame: Year 3 in Period II ]

4.  Secondary:   Change in HOMA-B From Baseline to Endpoint   [ Time Frame: Baseline, end of Period II (up to 4.5 years) ]

5.  Secondary:   Fasting Proinsulin/Insulin Ratio at Year 3   [ Time Frame: Year 3 in Period II ]

6.  Secondary:   Change in Fasting Proinsulin/Insulin Ratio From Baseline to Endpoint.   [ Time Frame: Baseline, end of Period II (up to 4.5 years) ]

7.  Secondary:   Ratio of the 30 Minute Increment in Plasma Insulin Concentration and the 30 Minute Increment in Plasma Glucose During the Oral Glucose Tolerance Test (DI30/DG30 Ratio) at Year 3   [ Time Frame: Year 3 in Period II ]

8.  Secondary:   Change in DI30/DG30 Ratio From Baseline to Endpoint   [ Time Frame: Baseline, end of Period II (up to 4.5 years) ]

9.  Secondary:   Disposition Index at Year 3   [ Time Frame: Year 3 in Period II ]

10.  Secondary:   Change in Disposition Index From Baseline to Endpoint   [ Time Frame: Baseline, end of Period II (up to 4.5 years) ]

11.  Secondary:   Change in HbA1c From Baseline to Year 3   [ Time Frame: Baseline, Year 3 in Period II ]

12.  Secondary:   Change in HbA1c From Baseline to Endpoint   [ Time Frame: Baseline, end of Period II (up to 4.5 years) ]

13.  Secondary:   Fasting Plasma Glucose at Year 3   [ Time Frame: Year 3 in Period II ]

14.  Secondary:   Change in Fasting Plasma Glucose From Baseline to Endpoint   [ Time Frame: Baseline, end of Period II (up to 4.5 years) ]

15.  Secondary:   Postprandial (2 Hours) Plasma Glucose at Year 3   [ Time Frame: Year 3 in Period II ]

16.  Secondary:   Change in Postprandial (2 Hours) Plasma Glucose From Baseline to Endpoint   [ Time Frame: Baseline, end of Period II (up to 4.5 years) ]

17.  Secondary:   Change in Body Weight From Baseline to Year 3   [ Time Frame: Baseline, Year 3 in Period II ]

18.  Secondary:   Systolic Blood Pressure at Year 3   [ Time Frame: Year 3 in Period II ]

19.  Secondary:   Diastolic Blood Pressure at Year 3   [ Time Frame: Year 3 in Period II ]

20.  Secondary:   Heart Rate at Year 3   [ Time Frame: Year 3 in Period II ]

21.  Secondary:   Triglycerides at Year 3   [ Time Frame: Year 3 in Period II ]

22.  Secondary:   Total Cholesterol at Year 3   [ Time Frame: Year 3 in Period II ]

23.  Secondary:   High-density Lipoprotein (HDL) Cholesterol at Year 3   [ Time Frame: Year 3 in Period II ]

24.  Secondary:   Hypoglycemia Rate Per Year   [ Time Frame: Baseline to end of Period II (up to 4.5 years) ]

25.  Secondary:   Change in HbA1c From Baseline to Year 2 for Patients Randomized at Entry in Period III   [ Time Frame: Baseline in Period III, Year 2 in Period III ]

26.  Secondary:   Change in HbA1c From Baseline to Year 2 for Patients Not Randomized at Entry in Period III   [ Time Frame: Baseline in Period III, Year 2 in Period III ]

27.  Secondary:   Hypoglycemia Rate Per Year in Period III   [ Time Frame: Start of Period III to end of study ]


  Serious Adverse Events
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Additional Description No text entered.

Reporting Groups
  Description
Period II, Exen + Met Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin
Period II, Glim + Met Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin
Period III, Exen + Met + Glim - Randomized Glimepiride once daily, started at 1 mg dose and titrated up to maintenance doses, was added to Exenatide 10 mcg twice daily subcutaneously injected and daily oral Metformin in Period III
Period III, Exen + Met + Pio or Rosi - Randomized Oral Rosiglitazone or Pioglitazone once or twice daily, started 15 mg per day, was added to Exenatide 10 mcg twice daily subcutaneously injected and daily oral Metformin in Period III
Period III, Glim + Met + Exen - Not Randomized Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for the first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period III) was added to oral Glimepiride once daily and daily oral Metformin in Period III

Serious Adverse Events
    Period II, Exen + Met     Period II, Glim + Met     Period III, Exen + Met + Glim - Randomized     Period III, Exen + Met + Pio or Rosi - Randomized     Period III, Glim + Met + Exen - Not Randomized  
Total, serious adverse events            
# participants affected / at risk     73/511 (14.29%)     68/508 (13.39%)     7/74 (9.46%)     13/76 (17.11%)     19/166 (11.45%)  
Blood and lymphatic system disorders            
Anaemia * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Cardiac disorders            
Atrial fibrillation * 1          
# participants affected / at risk     2/511 (0.39%)     2/508 (0.39%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Ischaemic cardiomyopathy * 1          
# participants affected / at risk     2/511 (0.39%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Tachyarrhythmia * 1          
# participants affected / at risk     2/511 (0.39%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Acute coronary syndrome * 1          
# participants affected / at risk     1/511 (0.20%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     1/166 (0.60%)  
Angina pectoris * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Atrial flutter * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Cardiac failure * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Myocardial infarction * 1          
# participants affected / at risk     1/511 (0.20%)     2/508 (0.39%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Palpitations * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Acute myocardial infarction * 1          
# participants affected / at risk     0/511 (0.00%)     2/508 (0.39%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Angina unstable * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     0/74 (0.00%)     1/76 (1.32%)     2/166 (1.20%)  
Cardiac disorder * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Coronary artery disease * 1          
# participants affected / at risk     0/511 (0.00%)     3/508 (0.59%)     1/74 (1.35%)     0/76 (0.00%)     1/166 (0.60%)  
Myocardial ischaemia * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     1/166 (0.60%)  
Pericarditis * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Congenital, familial and genetic disorders            
Haemophilia A with anti factor VIII * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Dermoid cyst * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Endocrine disorders            
Goitre * 1          
# participants affected / at risk     0/511 (0.00%)     3/508 (0.59%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Eye disorders            
Angle closure glaucoma * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Macular oedema * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     0/74 (0.00%)     1/76 (1.32%)     0/166 (0.00%)  
Gastrointestinal disorders            
Abdominal pain * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     1/76 (1.32%)     0/166 (0.00%)  
Anal fissure * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Colonic polyp * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Constipation * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Faecaloma * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Inguinal hernia * 1          
# participants affected / at risk     1/511 (0.20%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Umbilical hernia * 1          
# participants affected / at risk     1/511 (0.20%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Abdominal adhesions * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Abdominal hernia * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Acute abdomen * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Diverticulum intestinal * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Dyspepsia * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Gastritis * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     1/166 (0.60%)  
Gastrointestinal inflammation * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Haemorrhoids * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     1/166 (0.60%)  
Pancreatitis * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     1/166 (0.60%)  
General disorders            
Chest pain * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     1/76 (1.32%)     0/166 (0.00%)  
Sudden cardiac death * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Non-cardiac chest pain * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     1/166 (0.60%)  
Hepatobiliary disorders            
Cholelithiasis * 1          
# participants affected / at risk     2/511 (0.39%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     1/166 (0.60%)  
Cholecystitis * 1          
# participants affected / at risk     1/511 (0.20%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Infections and infestations            
Erysipelas * 1          
# participants affected / at risk     2/511 (0.39%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Abscess * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Abscess limb * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Cellulitis * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Gastroenteritis norovirus * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
HIV infection * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Helicobacter gastritis * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Influenza * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Pneumonia * 1          
# participants affected / at risk     1/511 (0.20%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Sinusitis * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Viral labyrinthitis * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Anal abscess * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     0/74 (0.00%)     1/76 (1.32%)     0/166 (0.00%)  
Appendicitis * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Bronchitis * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Gastroenteritis * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Infected epidermal cyst * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Intervertebral discitis * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Localised infection * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Osteomyelitis * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Postoperative wound infection * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Staphylococcal sepsis * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Subcutaneous abscess * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Injury, poisoning and procedural complications            
Fall * 1          
# participants affected / at risk     3/511 (0.59%)     2/508 (0.39%)     0/74 (0.00%)     0/76 (0.00%)     1/166 (0.60%)  
Lower limb fracture * 1          
# participants affected / at risk     2/511 (0.39%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Brain contusion * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Contusion * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Femoral neck fracture * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Injury * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Limb crushing injury * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Pubis fracture * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Radius fracture * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Road traffic accident * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Sternal fracture * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Subdural haemorrhage * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Tendon rupture * 1          
# participants affected / at risk     1/511 (0.20%)     3/508 (0.59%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Accident * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Clavicle fracture * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Fibula fracture * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Foot fracture * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     1/166 (0.60%)  
Meniscus lesion * 1          
# participants affected / at risk     0/511 (0.00%)     4/508 (0.79%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Pelvic fracture * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Post procedural haematoma * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Sports injury * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Upper limb fracture * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Ureteric injury * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Metabolism and nutrition disorders            
Hypoglycaemia * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     1/74 (1.35%)     0/76 (0.00%)     0/166 (0.00%)  
Hypokalaemia * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     1/74 (1.35%)     0/76 (0.00%)     0/166 (0.00%)  
Obesity * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     0/74 (0.00%)     1/76 (1.32%)     0/166 (0.00%)  
Musculoskeletal and connective tissue disorders            
Osteoarthritis * 1          
# participants affected / at risk     2/511 (0.39%)     4/508 (0.79%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Spinal column stenosis * 1          
# participants affected / at risk     2/511 (0.39%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Cervical spinal stenosis * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Intervertebral disc degeneration * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Pain in extremity * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Periarthritis * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     1/76 (1.32%)     1/166 (0.60%)  
Arthralgia * 1          
# participants affected / at risk     0/511 (0.00%)     2/508 (0.39%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Bursitis * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     0/74 (0.00%)     1/76 (1.32%)     0/166 (0.00%)  
Chondropathy * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Exostosis * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     0/74 (0.00%)     1/76 (1.32%)     0/166 (0.00%)  
Foot deformity * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     1/76 (1.32%)     0/166 (0.00%)  
Intervertebral disc protrusion * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     0/74 (0.00%)     1/76 (1.32%)     0/166 (0.00%)  
Joint effusion * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Knee deformity * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Osteitis * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)            
Breast cancer * 1          
# participants affected / at risk     3/511 (0.59%)     1/508 (0.20%)     0/74 (0.00%)     1/76 (1.32%)     1/166 (0.60%)  
Prostate cancer * 1          
# participants affected / at risk     2/511 (0.39%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Basal cell carcinoma * 1          
# participants affected / at risk     1/511 (0.20%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     1/166 (0.60%)  
Colon cancer * 1          
# participants affected / at risk     1/511 (0.20%)     2/508 (0.39%)     0/74 (0.00%)     0/76 (0.00%)     1/166 (0.60%)  
Colorectal cancer * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Gallbladder cancer * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Glioblastoma * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Lung squamous cell carcinoma stage unspecified * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Rectal cancer * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Uterine leiomyoma * 1          
# participants affected / at risk     1/511 (0.20%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Bladder cancer * 1          
# participants affected / at risk     0/511 (0.00%)     2/508 (0.39%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Bladder neoplasm * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Breast cancer metastatic * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Endometrial cancer * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     1/74 (1.35%)     0/76 (0.00%)     0/166 (0.00%)  
Gastric neoplasm * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     1/74 (1.35%)     0/76 (0.00%)     0/166 (0.00%)  
Metastases to bone * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Metastases to liver * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Rectosigmoid cancer * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Renal neoplasm * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     0/74 (0.00%)     1/76 (1.32%)     0/166 (0.00%)  
Small cell lung cancer stage unspecified * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Uterine cancer * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Nervous system disorders            
Cerebrovascular accident * 1          
# participants affected / at risk     2/511 (0.39%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Syncope * 1          
# participants affected / at risk     2/511 (0.39%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Carotid arteriosclerosis * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Encephalitis * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Ischaemic stroke * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Radiculopathy * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Sciatica * 1          
# participants affected / at risk     1/511 (0.20%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Transient ischaemic attack * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Carpal tunnel syndrome * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Nervous system disorder * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     1/166 (0.60%)  
Transient global amnesia * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Psychiatric disorders            
Depression * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Mental disorder * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     1/166 (0.60%)  
Mood altered * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Renal and urinary disorders            
Nephrolithiasis * 1          
# participants affected / at risk     3/511 (0.59%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Renal colic * 1          
# participants affected / at risk     2/511 (0.39%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Cystitis haemorrhagic * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Renal failure acute * 1          
# participants affected / at risk     1/511 (0.20%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Calculus ureteric * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     1/74 (1.35%)     0/76 (0.00%)     0/166 (0.00%)  
Nocturia * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     1/166 (0.60%)  
Urinary bladder polyp * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Urinary tract inflammation * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Reproductive system and breast disorders            
Uterine cervical erosion * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Endometrial hyperplasia * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     0/74 (0.00%)     1/76 (1.32%)     0/166 (0.00%)  
Endometrial hypertrophy * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Metrorrhagia * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Ovarian cyst * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Uterine polyp * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Respiratory, thoracic and mediastinal disorders            
Sleep apnoea syndrome * 1          
# participants affected / at risk     2/511 (0.39%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Bullous lung disease * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Chronic obstructive pulmonary disease * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     1/74 (1.35%)     0/76 (0.00%)     0/166 (0.00%)  
Pulmonary embolism * 1          
# participants affected / at risk     1/511 (0.20%)     2/508 (0.39%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Asthma * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     1/166 (0.60%)  
Skin and subcutaneous tissue disorders            
Skin ulcer * 1          
# participants affected / at risk     0/511 (0.00%)     1/508 (0.20%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Vascular disorders            
Deep vein thrombosis * 1          
# participants affected / at risk     1/511 (0.20%)     0/508 (0.00%)     0/74 (0.00%)     0/76 (0.00%)     0/166 (0.00%)  
Hypertension * 1          
# participants affected / at risk     0/511 (0.00%)     0/508 (0.00%)     0/74 (0.00%)     1/76 (1.32%)     0/166 (0.00%)  
* Events were collected by non-systematic assessment
1 Term from vocabulary, MedDRA 13.1




  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
Only patients who reached primary endpoint 12 months or more before the projected end of the study could enter period III.


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