Efficacy and Safety of Alogliptin Plus Metformin Compared to Glipizide Plus Metformin in Patients With Type 2 Diabetes Mellitus (ENDURE)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Takeda
ClinicalTrials.gov Identifier:
NCT00856284
First received: March 4, 2009
Last updated: September 25, 2013
Last verified: September 2013
Results First Received: September 25, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Treatment
Condition: Type 2 Diabetes Mellitus
Interventions: Drug: Alogliptin
Drug: Metformin
Drug: Glipizide

  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
Participants took part in the study at 310 study sites worldwide from 05 March 2009 to 17 October 2012.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants with type 2 diabetes mellitus experiencing inadequate glycemic control while on metformin therapy were enrolled equally in 1 of 3 treatment groups: alogliptin 12.5 mg once daily (QD), alogliptin 25 mg QD, and glipizide 5 mg QD.

Reporting Groups
  Description
Metformin + Alogliptin 12.5 mg Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.
Metformin + Alogliptin 25 mg Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.
Metformin + Glipizide Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.

Participant Flow:   Overall Study
    Metformin + Alogliptin 12.5 mg     Metformin + Alogliptin 25 mg     Metformin + Glipizide  
STARTED     880     885     874  
Received Study Drug     873     878     869  
COMPLETED     472     493     427  
NOT COMPLETED     408     392     447  
Hyperglycemic rescue                 231                 201                 235  
Adverse Event                 60                 74                 82  
Major protocol deviation                 24                 16                 15  
Lost to Follow-up                 20                 22                 28  
Voluntary withdrawal                 48                 52                 62  
Pregnancy                 1                 2                 0  
Investigator discretion                 9                 8                 10  
Other                 15                 17                 14  
Randomized in error                 0                 0                 1  



  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.
The Randomized Set included all enrolled subjects who were subsequently randomized.

Reporting Groups
  Description
Metformin + Alogliptin 12.5 mg Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.
Metformin + Alogliptin 25 mg Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.
Metformin + Glipizide Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.
Total Total of all reporting groups

Baseline Measures
    Metformin + Alogliptin 12.5 mg     Metformin + Alogliptin 25 mg     Metformin + Glipizide     Total  
Number of Participants  
[units: participants]
  880     885     874     2639  
Age  
[units: years]
Mean ± Standard Deviation
  55.2  ± 9.60     55.5  ± 9.81     55.4  ± 9.60     55.4  ± 9.67  
Age, Customized [1]
[units: participants]
       
<65 years     734     710     723     2167  
≥65 years     146     175     151     472  
≥75 years     13     17     15     45  
Gender  
[units: participants]
       
Female     461     433     433     1327  
Male     419     452     441     1312  
Race/Ethnicity, Customized  
[units: participants]
       
American Indian or Alaska Native     40     42     36     118  
Asian     191     207     203     601  
Black or African American     74     66     81     221  
Native Hawaiian or Other Pacific Islander     7     1     4     12  
White     557     555     533     1645  
Multiracial     11     14     17     42  
Race/Ethnicity, Customized  
[units: participants]
       
Hispanic or Latino     192     204     192     588  
Not Hispanic or Latino     688     681     682     2051  
Body Mass Index (BMI) [2]
[units: kg/m^2]
Mean ± Standard Deviation
  31.27  ± 5.417     31.27  ± 5.341     31.11  ± 5.320     31.22  ± 5.358  
Glycosylated hemoglobin (HbA1c) [3]
[units: percentage]
Mean ± Standard Deviation
  7.59  ± 0.599     7.61  ± 0.606     7.60  ± 0.617     7.60  ± 0.607  
Baseline HbA1c Category  
[units: participants]
       
<8.0%     615     620     613     1848  
≥8.0%     265     265     261     791  
Diabetes duration [4]
[units: years]
Mean ± Standard Deviation
  5.65  ± 5.324     5.42  ± 4.730     5.48  ± 4.884     5.52  ± 4.985  
Metformin dose  
[units: mg]
Mean ± Standard Deviation
  1825.2  ± 405.59     1837.2  ± 373.06     1823.4  ± 390.63     1828.6  ± 389.85  
Glomerular filtration rate [5]
[units: mL/min/1.73m^2]
Mean ± Standard Deviation
       
MDRD     83.04  ± 16.586     82.35  ± 16.199     82.28  ± 16.994     82.56  ± 16.591  
Cockcroft-Gault     109.3  ± 33.40     109.3  ± 32.85     108.0  ± 32.64     108.9  ± 32.96  
Smoking history  
[units: participants]
       
Never smoked     543     586     578     1707  
Current smoker     135     122     111     368  
Ex-smoker     202     177     185     564  
[1] Categories ≥65 years and ≥75 years are not mutually exclusive. Participants ≥75 years are counted in both categories.
[2] BMI data available for 879, 885 and 872 participants in each treatment arm, respectively.
[3] Mean HbA1c data includes 877, 883 and 870 participants in each treatment arm, respectively.
[4] Diabetes duration data available for 880, 884 and 874 participants in each treatment arm, respectively.
[5] Glomerular filtration rate (GFR) was calculated using the modification of diet in renal disease (MDRD) formula and the Cockcroft-Gault formula. Data include 877, 883 and 870 participants in each treatment arm, respectively.



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 52   [ Time Frame: Baseline and Week 52 ]

2.  Primary:   Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 104   [ Time Frame: Baseline and Week 104 ]

3.  Secondary:   Change From Baseline in Glycosylated Hemoglobin at Other Time Points   [ Time Frame: Baseline and Weeks 4, 8, 12, 16, 20, 26, 39, 65, 78, and 91. ]

4.  Secondary:   Change From Baseline in Fasting Plasma Glucose Over Time   [ Time Frame: Baseline and Weeks 2, 4, 8, 12, 16, 20, 26, 39, 52, 65, 78, 91, and 104. ]

5.  Secondary:   Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5%   [ Time Frame: Weeks 26, 52, 78, and 104. ]

6.  Secondary:   Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0%   [ Time Frame: Weeks 26, 52, 78, and 104. ]

7.  Secondary:   Change From Baseline in Body Weight Over Time   [ Time Frame: Baseline and Weeks 12, 26, 39, 52, 65, 78, 91, and 104. ]


  Serious Adverse Events
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Time Frame Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks).
Additional Description At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Reporting Groups
  Description
Metformin + Alogliptin 12.5 mg Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.
Metformin + Alogliptin 25 mg Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.
Metformin + Glipizide Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.

Serious Adverse Events
    Metformin + Alogliptin 12.5 mg     Metformin + Alogliptin 25 mg     Metformin + Glipizide  
Total, serious adverse events        
# participants affected / at risk     86/873 (9.85%)     97/878 (11.05%)     81/869 (9.32%)  
Blood and lymphatic system disorders        
Anaemia † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Iron deficiency anaemia † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Cardiac disorders        
Coronary artery disease † 1      
# participants affected / at risk     5/873 (0.57%)     3/878 (0.34%)     2/869 (0.23%)  
Angina unstable † 1      
# participants affected / at risk     1/873 (0.11%)     4/878 (0.46%)     4/869 (0.46%)  
Acute myocardial infarction † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     5/869 (0.58%)  
Atrial fibrillation † 1      
# participants affected / at risk     1/873 (0.11%)     3/878 (0.34%)     2/869 (0.23%)  
Atrial flutter † 1      
# participants affected / at risk     2/873 (0.23%)     2/878 (0.23%)     1/869 (0.12%)  
Cardiac failure † 1      
# participants affected / at risk     0/873 (0.00%)     3/878 (0.34%)     1/869 (0.12%)  
Cardiac failure congestive † 1      
# participants affected / at risk     2/873 (0.23%)     1/878 (0.11%)     1/869 (0.12%)  
Myocardial infarction † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     3/869 (0.35%)  
Angina pectoris † 1      
# participants affected / at risk     0/873 (0.00%)     2/878 (0.23%)     1/869 (0.12%)  
Myocardial ischaemia † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     2/869 (0.23%)  
Atrioventricular block complete † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     1/869 (0.12%)  
Cardiomyopathy † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     1/869 (0.12%)  
Silent myocardial infarction † 1      
# participants affected / at risk     0/873 (0.00%)     2/878 (0.23%)     0/869 (0.00%)  
Acute coronary syndrome † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Arteriosclerosis coronary artery † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Atrioventricular block † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Atrioventricular block second degree † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Bradycardia † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Congestive cardiomyopathy † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Coronary artery occlusion † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Left ventricular failure † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Pericardial effusion † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Right ventricular failure † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Tachyarrhythmia † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Ear and labyrinth disorders        
Acute vestibular syndrome † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Vertigo † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Vertigo positional † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Endocrine disorders        
Primary hyperaldosteronism † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Eye disorders        
Cataract † 1      
# participants affected / at risk     1/873 (0.11%)     1/878 (0.11%)     1/869 (0.12%)  
Cataract nuclear † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Cataract subcapsular † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Iridocyclitis † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Retinal detachment † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Vision blurred † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Gastrointestinal disorders        
Colitis † 1      
# participants affected / at risk     2/873 (0.23%)     2/878 (0.23%)     0/869 (0.00%)  
Abdominal pain † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     2/869 (0.23%)  
Inguinal hernia † 1      
# participants affected / at risk     1/873 (0.11%)     1/878 (0.11%)     1/869 (0.12%)  
Nausea † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     1/869 (0.12%)  
Pancreatitis acute † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     1/869 (0.12%)  
Umbilical hernia † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     1/869 (0.12%)  
Anal fistula † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Colitis ischaemic † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Diarrhoea † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Diverticulum † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Dyspepsia † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Enterocolitis † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Gastritis † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Gastrointestinal haemorrhage † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Haematemesis † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Haemorrhoids † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Intestinal ischaemia † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Mallory-Weiss syndrome † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Pancreatitis † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Umbilical hernia, obstructive † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Upper gastrointestinal haemorrhage † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Vomiting † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
General disorders        
Non-cardiac chest pain † 1      
# participants affected / at risk     3/873 (0.34%)     4/878 (0.46%)     3/869 (0.35%)  
Chest pain † 1      
# participants affected / at risk     0/873 (0.00%)     2/878 (0.23%)     0/869 (0.00%)  
Hernia † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Sudden death † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Hepatobiliary disorders        
Cholecystitis † 1      
# participants affected / at risk     1/873 (0.11%)     1/878 (0.11%)     1/869 (0.12%)  
Cholecystitis acute † 1      
# participants affected / at risk     0/873 (0.00%)     3/878 (0.34%)     0/869 (0.00%)  
Cholelithiasis † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     1/869 (0.12%)  
Bile duct stone † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Drug-induced liver injury † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Immune system disorders        
Anaphylactic reaction † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Infections and infestations        
Cellulitis † 1      
# participants affected / at risk     3/873 (0.34%)     1/878 (0.11%)     3/869 (0.35%)  
Pneumonia † 1      
# participants affected / at risk     1/873 (0.11%)     2/878 (0.23%)     2/869 (0.23%)  
Gastroenteritis † 1      
# participants affected / at risk     2/873 (0.23%)     2/878 (0.23%)     0/869 (0.00%)  
Dengue fever † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     2/869 (0.23%)  
Diverticulitis † 1      
# participants affected / at risk     1/873 (0.11%)     1/878 (0.11%)     1/869 (0.12%)  
Hepatitis viral † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     2/869 (0.23%)  
Urinary tract infection † 1      
# participants affected / at risk     1/873 (0.11%)     1/878 (0.11%)     1/869 (0.12%)  
Urosepsis † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     1/869 (0.12%)  
Abdominal abscess † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Abscess limb † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Acute sinusitis † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Amoebiasis † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Appendicitis † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Bronchitis † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Cystitis † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Gangrene † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Gastroenteritis salmonella † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Lobar pneumonia † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Malaria † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Osteomyelitis † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Pneumocystis jiroveci pneumonia † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Scrotal abscess † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Sepsis † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Septic shock † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Staphylococcal infection † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Injury, poisoning and procedural complications        
Ankle fracture † 1      
# participants affected / at risk     1/873 (0.11%)     2/878 (0.23%)     1/869 (0.12%)  
Fall † 1      
# participants affected / at risk     2/873 (0.23%)     0/878 (0.00%)     0/869 (0.00%)  
Joint injury † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     2/869 (0.23%)  
Road traffic accident † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     1/869 (0.12%)  
Comminuted fracture † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Craniocerebral injury † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Facial bones fracture † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Femur fracture † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Incisional hernia † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Joint dislocation † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Ligament rupture † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Lower limb fracture † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Patella fracture † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Peripheral nerve injury † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Tendon rupture † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Tibia fracture † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Metabolism and nutrition disorders        
Dehydration † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Diabetic ketoacidosis † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Hypoglycaemia † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Musculoskeletal and connective tissue disorders        
Osteoarthritis † 1      
# participants affected / at risk     2/873 (0.23%)     3/878 (0.34%)     4/869 (0.46%)  
Musculoskeletal chest pain † 1      
# participants affected / at risk     1/873 (0.11%)     2/878 (0.23%)     1/869 (0.12%)  
Intervertebral disc protrusion † 1      
# participants affected / at risk     1/873 (0.11%)     1/878 (0.11%)     0/869 (0.00%)  
Muscle haemorrhage † 1      
# participants affected / at risk     2/873 (0.23%)     0/878 (0.00%)     0/869 (0.00%)  
Spinal osteoarthritis † 1      
# participants affected / at risk     1/873 (0.11%)     1/878 (0.11%)     0/869 (0.00%)  
Arthralgia † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Back pain † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Bursitis † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Haemarthrosis † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Myalgia intercostal † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Polymyositis † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Spinal column stenosis † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)        
Breast cancer † 1      
# participants affected / at risk     2/873 (0.23%)     0/878 (0.00%)     1/869 (0.12%)  
Basal cell carcinoma † 1      
# participants affected / at risk     1/873 (0.11%)     1/878 (0.11%)     0/869 (0.00%)  
Uterine leiomyoma † 1      
# participants affected / at risk     2/873 (0.23%)     0/878 (0.00%)     0/869 (0.00%)  
Adenocarcinoma † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Bladder transitional cell carcinoma † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Colon adenoma † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Colon cancer † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Colon cancer stage 0 † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Endometrial cancer † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Gastrointestinal tract adenoma † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Lipoma † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Lung adenocarcinoma † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Non-Hodgkin's lymphoma † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Non-small cell lung cancer stage IIIB † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Ovarian adenoma † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Ovarian cancer † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Rectal cancer metastatic † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Renal oncocytoma † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Small cell lung cancer stage unspecified † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Squamous cell carcinoma of skin † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Nervous system disorders        
Cerebrovascular accident † 1      
# participants affected / at risk     1/873 (0.11%)     1/878 (0.11%)     3/869 (0.35%)  
Syncope † 1      
# participants affected / at risk     2/873 (0.23%)     0/878 (0.00%)     1/869 (0.12%)  
Dizziness † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     1/869 (0.12%)  
Epilepsy † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     1/869 (0.12%)  
Headache † 1      
# participants affected / at risk     1/873 (0.11%)     1/878 (0.11%)     0/869 (0.00%)  
Ischaemic stroke † 1      
# participants affected / at risk     1/873 (0.11%)     1/878 (0.11%)     0/869 (0.00%)  
Transient ischaemic attack † 1      
# participants affected / at risk     0/873 (0.00%)     2/878 (0.23%)     0/869 (0.00%)  
Carotid artery stenosis † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Cerebral infarction † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Haemorrhagic stroke † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Intercostal neuralgia † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Neuralgia † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Parkinsonism † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Presyncope † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Radiculopathy † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Tension headache † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
VIIth nerve paralysis † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
VIth nerve paralysis † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Vertebrobasilar insufficiency † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Pregnancy, puerperium and perinatal conditions        
Abortion † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Psychiatric disorders        
Bipolar disorder † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     1/869 (0.12%)  
Alcohol withdrawal syndrome † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Depressed mood † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Depression † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Schizophrenia † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Renal and urinary disorders        
Renal failure acute † 1      
# participants affected / at risk     1/873 (0.11%)     2/878 (0.23%)     3/869 (0.35%)  
Nephrolithiasis † 1      
# participants affected / at risk     2/873 (0.23%)     2/878 (0.23%)     0/869 (0.00%)  
Renal colic † 1      
# participants affected / at risk     1/873 (0.11%)     1/878 (0.11%)     1/869 (0.12%)  
Calculus urinary † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Diabetic nephropathy † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Urinary retention † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Reproductive system and breast disorders        
Benign prostatic hyperplasia † 1      
# participants affected / at risk     1/873 (0.11%)     1/878 (0.11%)     0/869 (0.00%)  
Adenomyosis † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Cervical dysplasia † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Cervix disorder † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Cystocele † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Dysmenorrhoea † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Epididymitis † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Metrorrhagia † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Ovarian cyst † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Rectocele † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Uterine prolapse † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Uterovaginal prolapse † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Respiratory, thoracic and mediastinal disorders        
Chronic obstructive pulmonary disease † 1      
# participants affected / at risk     2/873 (0.23%)     0/878 (0.00%)     1/869 (0.12%)  
Pulmonary embolism † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     1/869 (0.12%)  
Acute pulmonary oedema † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Asthma † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Dyspnoea † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Emphysema † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Granulomatous pneumonitis † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Interstitial lung disease † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Pleuritic pain † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Pulmonary oedema † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Respiratory failure † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Skin and subcutaneous tissue disorders        
Rash maculo-papular † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Vascular disorders        
Hypertension † 1      
# participants affected / at risk     1/873 (0.11%)     3/878 (0.34%)     0/869 (0.00%)  
Hypertensive crisis † 1      
# participants affected / at risk     0/873 (0.00%)     2/878 (0.23%)     1/869 (0.12%)  
Deep vein thrombosis † 1      
# participants affected / at risk     1/873 (0.11%)     1/878 (0.11%)     0/869 (0.00%)  
Aortic aneurysm † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Arterial thrombosis limb † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Embolism † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Femoral artery occlusion † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Iliac artery occlusion † 1      
# participants affected / at risk     0/873 (0.00%)     1/878 (0.11%)     0/869 (0.00%)  
Orthostatic hypotension † 1      
# participants affected / at risk     0/873 (0.00%)     0/878 (0.00%)     1/869 (0.12%)  
Peripheral arterial occlusive disease † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Thrombophlebitis † 1      
# participants affected / at risk     1/873 (0.11%)     0/878 (0.00%)     0/869 (0.00%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 15.0




  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
The Week 52 results summarized in herein differ from the Week 52 results summarized in an interim analysis, because the per protocol set (PPS) defined for the final analysis included fewer subjects than the PPS defined for the interim analysis.


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