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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;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Participant, Investigator);   Primary Purpose: Treatment
Condition: Type 2 Diabetes Mellitus
Interventions: Drug: Alogliptin
Drug: Metformin
Drug: Glipizide

  Participant Flow
  Hide Participant Flow

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 
Overall Participants Analyzed 
[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 
[1] Categories ≥65 years and ≥75 years are not mutually exclusive. Participants ≥75 years are counted in both categories.
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) [1] 
[Units: Kg/m^2]
Mean (Standard Deviation)
 31.27  (5.417)   31.27  (5.341)   31.11  (5.320)   31.22  (5.358) 
[1] BMI data available for 879, 885 and 872 participants in each treatment arm, respectively.
Glycosylated hemoglobin (HbA1c) [1] 
[Units: Percentage]
Mean (Standard Deviation)
 7.59  (0.599)   7.61  (0.606)   7.60  (0.617)   7.60  (0.607) 
[1] Mean HbA1c data includes 877, 883 and 870 participants in each treatment arm, respectively.
Baseline HbA1c Category 
[Units: Participants]
       
<8.0%   615   620   613   1848 
≥8.0%   265   265   261   791 
Diabetes duration [1] 
[Units: Years]
Mean (Standard Deviation)
 5.65  (5.324)   5.42  (4.730)   5.48  (4.884)   5.52  (4.985) 
[1] Diabetes duration data available for 880, 884 and 874 participants in each treatment arm, respectively.
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 [1] 
[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) 
[1] 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.
Smoking history 
[Units: Participants]
       
Never smoked   543   586   578   1707 
Current smoker   135   122   111   368 
Ex-smoker   202   177   185   564 


  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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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Medical Director, Clinical Science
Organization: Takeda
phone: 800-778-2860
e-mail: clinicaltrialregistry@tpna.com


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT00856284     History of Changes
Other Study ID Numbers: SYR-322_305
2008-007444-34 ( Registry Identifier: EudraCT )
U1111-1111-7397 ( Registry Identifier: WHO )
HKCTR-862 ( Registry Identifier: HKUCTR )
DOH-27-0709-2825 ( Registry Identifier: SANCTR )
09/H0703/66 ( Registry Identifier: NRES )
NMRR-09-203-3590 ( Registry Identifier: NMRR )
Study First Received: March 4, 2009
Results First Received: September 25, 2013
Last Updated: September 25, 2013