MK0431 (Sitagliptin) and Metformin Co-Administration Factorial Study in Patients With Type 2 Diabetes Mellitus (0431-036)(COMPLETED)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT00103857
First received: February 15, 2005
Last updated: November 12, 2013
Last verified: November 2013
Results First Received: February 19, 2009  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Factorial Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Treatment
Condition: Type 2 Diabetes Mellitus
Interventions: Drug: Comparator: MK0431 50 mg b.i.d. (b.i.d. = twice daily)
Drug: Comparator: MK0431 100 mg q.d. (q.d. = once daily)
Drug: Comparator: Placebo (Phase A)/Metformin (Phase B)
Drug: Comparator: Metformin 500 mg b.i.d.
Drug: Comparator: Open-Label MK0431/Metformin 50/1000 mg b.i.d.
Drug: Comparator: Metformin 1000 mg b.i.d.

  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

First Patient In: 01-Apr-2005

Last Patient Last Visit: 29-Feb-2008

140 study centers worldwide


Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Patients 18-78 years with T2DM and an HbA1c 7.5-11% on diet/exercise were eligible for randomization into the 54-week (wk) base study. Patients with an HbA1c >11% or glucose >280 mg/dL were eligible to participate in the Open-label Cohort through Wk 24. Randomized patients who completed the base study were eligible to enter a 50-wk extension study.

Reporting Groups
  Description
Sitagliptin 100 mg q.d. The Sitagliptin 100 mg q.d. (q.d. = once daily) group includes data from patients randomized to receive treatment with two 50 mg oral tablets of sitagliptin once daily for up to 104 weeks (including the 54-week base study [24-week, placebo-controlled Phase A and 30-week, active-controlled Phase B] and 50-week extension study). Note: In this double-blind, double-dummy study, randomized patients in the base study received a total of 7 tablets (active or placebo) per day administered in the specified tablet images as follows: sitagliptin 50 mg 2 tablets in the morning and 1 tablet in the evening, metformin 500 mg 2 tablets b.i.d. (b.i.d. = twice daily). In the extension study, patients received a total of 7 tablets (active or placebo) per day. Tablets in the image of sitagliptin (active or placebo) were administered as sitagliptin 100 mg 1 tablet in the morning and sitagliptin 50 mg 1 tablet b.i.d. Metformin administration occurred in the same manner as specified in the base study.
Metformin 500 mg b.i.d. The Metformin 500 mg b.i.d. (b.i.d. = twice daily) group includes data from patients randomized to receive treatment with oral tablets of metformin 500 mg b.i.d. Treatment was administered as 500 mg q.d. (q.d. = once daily) beginning at randomization/Day 1 and increased after 1 week to a stable dose of 500 mg b.i.d. Patients in this group continued to take metformin 500 mg b.i.d for the remainder of the treatment period of up to 104 weeks (including the 54-week base study [24-week, placebo-controlled Phase A and 30-week, active-controlled Phase B] and 50-week extension study).
Metformin 1000 mg b.i.d. The Metformin 1000 mg b.i.d. (b.i.d. = twice daily) group includes data from patients randomized to receive treatment with oral tablets of metformin 1000 mg b.i.d. Treatment was administered as 500 mg q.d. (q.d. = once daily) beginning at randomization/Day 1 and increased over 4 weeks by increments of 500 mg per week to a stable dose of 1000 mg b.i.d. Patients in this group continued to take metformin 1000 mg b.i.d for the remainder of the treatment period of up to 104 weeks (including the 54-week base study [24-week, placebo-controlled Phase A and 30-week, active-controlled Phase B] and 50-week extension study).
Sitagliptin 50 mg b.i.d. + Metformin 500 mg b.i.d. The Sitagliptin 50 mg b.i.d. + Metformin 500 mg b.i.d. (b.i.d. = twice daily) group includes data from patients randomized to receive treatment with oral tablets of sitagliptin 50 mg b.i.d + metformin 500 mg b.i.d. Treatment was co-administered as sitagliptin 50 mg q.d. (q.d. = once daily) and metformin 500 mg q.d. beginning at randomization/Day 1; after 1-week, the dose of sitagliptin was increased to 50 mg b.i.d. and the dose of metformin was increased to 500 mg b.i.d. Patients in this group continued to take sitagliptin 50 mg b.i.d. and metformin 500 mg b.i.d for the remainder of the treatment period of up to 104 weeks (including the 54-week base study [24-week, placebo-controlled Phase A and 30-week, active-controlled Phase B] and 50-week extension study).
Sitagliptin 50 mg b.i.d + Metformin 1000 mg b.i.d. The Sitagliptin 50 mg b.i.d + Metformin 1000 mg b.i.d. (b.i.d. = twice daily) group includes data from patients randomized to receive treatment with oral tablets of sitagliptin 50 mg b.i.d + metformin 1000 mg b.i.d. Treatment was co-administered as sitagliptin 50 mg q.d. (q.d. = once daily) and metformin 500 mg q.d. beginning at randomization/Day 1; the dose of sitagliptin was increased after 1-week to 50 mg b.i.d and the dose of metformin was increased over 4 weeks by increments of 500 mg per week to 1000 mg b.i.d. Patients in this group continued to take sitagliptin 50 mg b.i.d. and metformin 1000 mg b.i.d for the remainder of the treatment period of up to 104 weeks (including the 54-week base study [24-week, placebo-controlled Phase A and 30-week, active-controlled Phase B] and 50-week extension study).
Placebo/Metformin 1000 mg b.i.d. The Placebo/Metformin 1000 mg b.i.d. group (b.i.d. = twice daily) includes data from patients randomized to receive the sequence of treatment with oral tablets of placebo (randomization/Day 1 through Week 24) followed by metformin. Beginning at Week 24, patients were switched in a blinded manner to active treatment with metformin administered as 500 mg q.d. (q.d. = once daily) increased over 4 weeks by increments of 500 mg per week to a stable dose of 1000 mg b.i.d. Patients in this group continued to take metformin 1000 mg b.i.d for the remainder of the up to 30-week Phase B base study treatment period and during the extension study of up to 50 weeks.
Sitagliptin 50 mg b.i.d + Metformin 1000 mg b.i.d. OLC The Sitagliptin 50 mg b.i.d + Metformin 1000 mg b.i.d. (b.i.d. = twice daily) OLC (Open-label Cohort) includes data from non-randomized patients assigned to receive treatment with open-label, oral tablets of sitagliptin and metformin. Treatment was co-administered as sitagliptin 50 mg q.d. (q.d. = once daily) and metformin 500 mg q.d. beginning on Day 1. The dose of sitagliptin was increased after 1-week to 50 mg b.i.d and the dose of metformin was increased over 4 weeks by increments of 500 mg per week to 1000 mg b.i.d. Patients continued to take open-label sitagliptin 50 mg b.i.d. and metformin 1000 mg b.i.d for the remainder of the Phase A treatment period of up to 24 weeks. Results presented for the OLC are through Week 24. Patients in the OLC completed the study at Week 24.

Participant Flow for 2 periods

Period 1:   54-Week Base Study
    Sitagliptin 100 mg q.d.     Metformin 500 mg b.i.d.     Metformin 1000 mg b.i.d.     Sitagliptin 50 mg b.i.d. + Metformin 500 mg b.i.d.     Sitagliptin 50 mg b.i.d + Metformin 1000 mg b.i.d.     Placebo/Metformin 1000 mg b.i.d.     Sitagliptin 50 mg b.i.d + Metformin 1000 mg b.i.d. OLC  
STARTED     179     182     182     190     182     176     117 [1]
COMPLETED     122     126     135     148     141     115     79  
NOT COMPLETED     57     56     47     42     41     61     38  
Adverse Event                 12                 9                 11                 6                 5                 11                 3  
Death                 0                 0                 0                 0                 1                 1                 0  
Lack of Efficacy                 11                 14                 8                 4                 3                 14                 19  
Lost to Follow-up                 5                 4                 7                 5                 10                 9                 3  
Physician Decision                 1                 1                 0                 0                 1                 0                 0  
Pregnancy                 1                 0                 0                 0                 1                 0                 1  
Protocol Violation                 6                 4                 2                 4                 0                 3                 3  
Withdrawal by Subject                 17                 16                 16                 15                 10                 15                 4  
protocol discontinuation criteria                 2                 5                 2                 6                 5                 3                 5  
patient moved                 0                 1                 1                 2                 3                 1                 0  
non-compliance with study procedures                 1                 2                 0                 0                 0                 2                 0  
patient incarcerated                 0                 0                 0                 0                 1                 1                 0  
laboratory reporting error                 0                 0                 0                 0                 1                 0                 0  
site error                 0                 0                 0                 0                 0                 1                 0  
patient intolerance to rescue therapy                 1                 0                 0                 0                 0                 0                 0  
[1] Results for the OLC are through Week 24. Results for the 6 randomized groups are through Week 54.

Period 2:   50-Week Extension Study
    Sitagliptin 100 mg q.d.     Metformin 500 mg b.i.d.     Metformin 1000 mg b.i.d.     Sitagliptin 50 mg b.i.d. + Metformin 500 mg b.i.d.     Sitagliptin 50 mg b.i.d + Metformin 1000 mg b.i.d.     Placebo/Metformin 1000 mg b.i.d.     Sitagliptin 50 mg b.i.d + Metformin 1000 mg b.i.d. OLC  
STARTED     103 [1]   107 [1]   121 [2]   134 [2]   122 [1]   98 [3]   0  
COMPLETED     65     80     95     98     101     78     0  
NOT COMPLETED     38     27     26     36     21     20     0  
Adverse Event                 2                 3                 2                 0                 1                 1                 0  
Death                 0                 0                 0                 1                 0                 1                 0  
Lack of Efficacy                 26                 15                 13                 16                 8                 8                 0  
Lost to Follow-up                 4                 0                 1                 4                 3                 3                 0  
Physician Decision                 0                 1                 1                 0                 0                 0                 0  
Pregnancy                 0                 0                 1                 0                 1                 0                 0  
Protocol Violation                 1                 1                 1                 2                 0                 1                 0  
Withdrawal by Subject                 2                 5                 2                 8                 3                 3                 0  
protocol discontinuation criteria                 2                 2                 3                 2                 3                 3                 0  
non-compliance with study procedures                 1                 0                 0                 1                 1                 0                 0  
patient moved                 0                 0                 1                 2                 0                 0                 0  
patient scheduled for elective surgery                 0                 0                 1                 0                 0                 0                 0  
reason unspecified                 0                 0                 0                 0                 1                 0                 0  
[1] 19 randomized patients completed Period 1 but did not enter Period 2.
[2] 14 randomized patients completed Period 1 but did not enter Period 2.
[3] 17 randomized patients completed Period 1 but did not enter Period 2.



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Sitagliptin 100 mg q.d. The Sitagliptin 100 mg q.d. (q.d. = once daily) group includes data from patients randomized to receive treatment with two 50 mg oral tablets of sitagliptin once daily for up to 104 weeks (including the 54-week base study [24-week, placebo-controlled Phase A and 30-week, active-controlled Phase B] and 50-week extension study). Note: In this double-blind, double-dummy study, randomized patients in the base study received a total of 7 tablets (active or placebo) per day administered in the specified tablet images as follows: sitagliptin 50 mg 2 tablets in the morning and 1 tablet in the evening, metformin 500 mg 2 tablets b.i.d. (b.i.d. = twice daily). In the extension study, patients received a total of 7 tablets (active or placebo) per day. Tablets in the image of sitagliptin (active or placebo) were administered as sitagliptin 100 mg 1 tablet in the morning and sitagliptin 50 mg 1 tablet b.i.d. Metformin administration occurred in the same manner as specified in the base study.
Metformin 500 mg b.i.d. The Metformin 500 mg b.i.d. (b.i.d. = twice daily) group includes data from patients randomized to receive treatment with oral tablets of metformin 500 mg b.i.d. Treatment was administered as 500 mg q.d. (q.d. = once daily) beginning at randomization/Day 1 and increased after 1 week to a stable dose of 500 mg b.i.d. Patients in this group continued to take metformin 500 mg b.i.d for the remainder of the treatment period of up to 104 weeks (including the 54-week base study [24-week, placebo-controlled Phase A and 30-week, active-controlled Phase B] and 50-week extension study).
Metformin 1000 mg b.i.d. The Metformin 1000 mg b.i.d. (b.i.d. = twice daily) group includes data from patients randomized to receive treatment with oral tablets of metformin 1000 mg b.i.d. Treatment was administered as 500 mg q.d. (q.d. = once daily) beginning at randomization/Day 1 and increased over 4 weeks by increments of 500 mg per week to a stable dose of 1000 mg b.i.d. Patients in this group continued to take metformin 1000 mg b.i.d for the remainder of the treatment period of up to 104 weeks (including the 54-week base study [24-week, placebo-controlled Phase A and 30-week, active-controlled Phase B] and 50-week extension study).
Sitagliptin 50 mg b.i.d. + Metformin 500 mg b.i.d. The Sitagliptin 50 mg b.i.d. + Metformin 500 mg b.i.d. (b.i.d. = twice daily) group includes data from patients randomized to receive treatment with oral tablets of sitagliptin 50 mg b.i.d + metformin 500 mg b.i.d. Treatment was co-administered as sitagliptin 50 mg q.d. (q.d. = once daily) and metformin 500 mg q.d. beginning at randomization/Day 1; after 1-week, the dose of sitagliptin was increased to 50 mg b.i.d. and the dose of metformin was increased to 500 mg b.i.d. Patients in this group continued to take sitagliptin 50 mg b.i.d. and metformin 500 mg b.i.d for the remainder of the treatment period of up to 104 weeks (including the 54-week base study [24-week, placebo-controlled Phase A and 30-week, active-controlled Phase B] and 50-week extension study).
Sitagliptin 50 mg b.i.d + Metformin 1000 mg b.i.d. The Sitagliptin 50 mg b.i.d + Metformin 1000 mg b.i.d. (b.i.d. = twice daily) group includes data from patients randomized to receive treatment with oral tablets of sitagliptin 50 mg b.i.d + metformin 1000 mg b.i.d. Treatment was co-administered as sitagliptin 50 mg q.d. (q.d. = once daily) and metformin 500 mg q.d. beginning at randomization/Day 1; the dose of sitagliptin was increased after 1-week to 50 mg b.i.d and the dose of metformin was increased over 4 weeks by increments of 500 mg per week to 1000 mg b.i.d. Patients in this group continued to take sitagliptin 50 mg b.i.d. and metformin 1000 mg b.i.d for the remainder of the treatment period of up to 104 weeks (including the 54-week base study [24-week, placebo-controlled Phase A and 30-week, active-controlled Phase B] and 50-week extension study).
Placebo/Metformin 1000 mg b.i.d. The Placebo/Metformin 1000 mg b.i.d. group (b.i.d. = twice daily) includes data from patients randomized to receive the sequence of treatment with oral tablets of placebo (randomization/Day 1 through Week 24) followed by metformin. Beginning at Week 24, patients were switched in a blinded manner to active treatment with metformin administered as 500 mg q.d. (q.d. = once daily) increased over 4 weeks by increments of 500 mg per week to a stable dose of 1000 mg b.i.d. Patients in this group continued to take metformin 1000 mg b.i.d for the remainder of the up to 30-week Phase B base study treatment period and during the extension study of up to 50 weeks.
Sitagliptin 50 mg b.i.d + Metformin 1000 mg b.i.d. OLC The Sitagliptin 50 mg b.i.d + Metformin 1000 mg b.i.d. (b.i.d. = twice daily) OLC (Open-label Cohort) includes data from non-randomized patients assigned to receive treatment with open-label, oral tablets of sitagliptin and metformin. Treatment was co-administered as sitagliptin 50 mg q.d. (q.d. = once daily) and metformin 500 mg q.d. beginning on Day 1. The dose of sitagliptin was increased after 1-week to 50 mg b.i.d and the dose of metformin was increased over 4 weeks by increments of 500 mg per week to 1000 mg b.i.d. Patients continued to take open-label sitagliptin 50 mg b.i.d. and metformin 1000 mg b.i.d for the remainder of the Phase A treatment period of up to 24 weeks. Results presented for the OLC are through Week 24. Patients in the OLC completed the study at Week 24.
Total Total of all reporting groups

Baseline Measures
    Sitagliptin 100 mg q.d.     Metformin 500 mg b.i.d.     Metformin 1000 mg b.i.d.     Sitagliptin 50 mg b.i.d. + Metformin 500 mg b.i.d.     Sitagliptin 50 mg b.i.d + Metformin 1000 mg b.i.d.     Placebo/Metformin 1000 mg b.i.d.     Sitagliptin 50 mg b.i.d + Metformin 1000 mg b.i.d. OLC     Total  
Number of Participants  
[units: participants]
  179     182     182     190     182     176     117     1208  
Age  
[units: years]
Mean ± Standard Deviation
  53.3  ± 10.2     53.4  ± 10.2     53.2  ± 9.6     54.1  ± 10.0     53.3  ± 9.6     53.6  ± 10.0     52.6  ± 10.0     53.4  ± 9.9  
Gender  
[units: participants]
               
Female     86     93     100     85     105     83     50     602  
Male     93     89     82     105     77     93     67     606  
Race/Ethnicity, Customized  
[units: participants]
               
White     93     87     106     102     95     81     44     608  
Black     11     12     9     13     14     17     9     85  
Hispanic     52     55     39     55     49     47     54     351  
Asian     6     14     10     9     11     12     1     63  
Other     17     14     18     11     13     19     9     101  
HbA1c (Hemoglobin A1c)  
[units: Percent]
Mean ± Standard Deviation
  8.9  ± 1.0     8.9  ± 1.0     8.7  ± 0.9     8.8  ± 1.0     8.7  ± 0.9     8.7  ± 1.0     11.2  ± 1.2     9.0  ± 1.2  



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Change From Baseline in HbA1c (Hemoglobin A1C) at Week 24   [ Time Frame: Week 24 ]

2.  Secondary:   Change From Baseline in FPG (Fasting Plasma Glucose) at Week 24   [ Time Frame: Week 24 ]

3.  Secondary:   Change From Baseline in 2-Hour PMG (Post-Meal Glucose) at Week 24   [ Time Frame: Week 24 ]

4.  Secondary:   Change From Baseline in HbA1c (Hemoglobin A1C) at Week 54   [ Time Frame: Week 54 ]

5.  Secondary:   Change From Baseline in FPG (Fasting Plasma Glucose) at Week 54   [ Time Frame: Week 54 ]

6.  Secondary:   Change From Baseline in 2-Hour PMG (Post-Meal Glucose) at Week 54   [ Time Frame: Week 54 ]

7.  Secondary:   Change From Baseline in HbA1c (Hemoglobin A1C) at Week 104   [ Time Frame: Week 104 ]

8.  Secondary:   Change From Baseline in FPG (Fasting Plasma Glucose) at Week 104   [ Time Frame: Week 104 ]

9.  Secondary:   Change From Baseline in 2-Hour PMG (Post-Meal Glucose) at Week 104   [ Time Frame: Week 104 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

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
Non-serious adverse experience results represent those events included in the primary safety analysis for this study (i.e., events that occurred prior to the initiation of glycemic rescue therapy).


  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: Senior Vice President, Clinical and Quantitative Sciences
Organization: Merck Sharp & Dohme Corp
phone: 1-800-672-6372


Publications:

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT00103857     History of Changes
Other Study ID Numbers: 0431-036, MK0431-036, 2005_003
Study First Received: February 15, 2005
Results First Received: February 19, 2009
Last Updated: November 12, 2013
Health Authority: United States: Food and Drug Administration