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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;   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
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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. ]
  Hide Outcome Measure 5

Measure Type Secondary
Measure Title Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5%
Measure Description The percentage of participants with HbA1c less than or equal to 6.5% at Weeks 26, 52, 78, and 104. Participants who did not complete the scheduled Week 104 visit were assessed based on their response at the time of discontinuation.
Time Frame Weeks 26, 52, 78, and 104.  
Safety Issue No  

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.
Full analysis set. Participants who did not complete the scheduled Week 26, Week 52, Week 78 or Week 104 visit were assessed based on their response at the time of discontinuation.

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.

Measured Values
    Metformin + Alogliptin 12.5 mg     Metformin + Alogliptin 25 mg     Metformin + Glipizide  
Number of Participants Analyzed  
[units: participants]
  873     878     869  
Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5%  
[units: percentage¬†of¬†participants]
     
Week 26     25.6     26.2     24.8  
Week 52     24.5     24.8     20.8  
Week 78     24.2     26.4     21.8  
Week 104     23.5     24.1     19.0  

No statistical analysis provided for Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5%



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


  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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