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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 
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. ]
  Hide Outcome Measure 7

Measure Type Secondary
Measure Title Change From Baseline in Body Weight Over Time
Measure Description LS Means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and Baseline weight and Baseline metformin dose as covariates.
Time Frame Baseline and Weeks 12, 26, 39, 52, 65, 78, 91, 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, LOCF was used.

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 
Participants Analyzed 
[Units: Participants]
 867   868   861 
Change From Baseline in Body Weight Over Time 
[Units: Kg]
Least Squares Mean (Standard Error)
     
Week 12   -0.51  (0.076)   -0.53  (0.076)   0.71  (0.077) 
Week 26   -0.65  (0.101)   -0.71  (0.101)   0.86  (0.101) 
Week 39   -0.60  (0.109)   -0.86  (0.109)   0.97  (0.110) 
Week 52   -0.63  (0.117)   -0.90  (0.117)   0.89  (0.117) 
Week 65   -0.70  (0.122)   -0.92  (0.122)   0.87  (0.123) 
Week 78   -0.78  (0.124)   -0.94  (0.124)   0.88  (0.125) 
Week 91   -0.67  (0.127)   -0.88  (0.127)   0.89  (0.127) 
Week 104   -0.68  (0.127)   -0.89  (0.127)   0.95  (0.127) 

No statistical analysis provided for Change From Baseline in Body Weight Over Time




  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.


  More Information
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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



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
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Thailand: Ministry of Public Health
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