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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: August 17, 2015
Last verified: August 2015
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, 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
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

Participant Flow for 3 periods

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

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

Period 3:   Period I
    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   Period II, Exen + Met
STARTED   0   0   0   0   0 
COMPLETED   0   0   0   0   0 
NOT COMPLETED   0   0   0   0   0 



  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 
Overall Participants Analyzed 
[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
  Show All Outcome Measures

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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Time Frame No text entered.
Additional Description No text entered.

Reporting Groups
  Description
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
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

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