A Study Comparing the Pharmacokinetic and Pharmacodynamic Profiles for Sitagliptin, Saxagliptin and Vildagliptin in Participants With Type 2 Diabetes Mellitus (T2DM) (MK-0431-142)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT01582308
First received: April 19, 2012
Last updated: December 4, 2013
Last verified: December 2013
Results First Received: December 4, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Pharmacokinetics/Dynamics Study;   Intervention Model: Crossover Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Type 2 Diabetes Mellitus
Interventions: Drug: Sitagliptin 100 mg
Drug: Saxagliptin 5 mg
Drug: Vildagliptin 50 mg
Drug: Vildagliptin 50 mg BID
Drug: Placebo

  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
Each treatment sequence started with 2 participants in Period 1. In addition, there were 2 replacement participants; in treatment sequence 5, a participant who discontinued after period 1 (placebo treatment) was replaced and in treatment sequence 7, a participant who discontinued during period 1 (saxagliptin treatment) was replaced.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
A washout period of at least 10 days occurred between each treatment period.

Reporting Groups
  Description
Treatment Sequence 1 Sitagliptin 100 mg in Period 1 followed by saxagliptin 5 mg in Period 2 followed by vildagliptin 50 mg BID in Period 3 followed by placebo in Period 4 followed by vildagliptin 50 mg in Period 5
Treatment Sequence 2 Saxagliptin 5 mg in Period 1 followed by vildagliptin 50 mg in Period 2 followed by placebo in Period 3 followed by sitagliptin 100 mg in Period 4 followed by vildagliptin 50 mg BID in Period 5
Treatment Sequence 3 Vildagliptin 50 mg in Period 1 followed by vildagliptin 50 mg BID in Period 2 followed by sitagliptin 100 mg in Period 3 followed by saxagliptin 5 mg in Period 4 followed by placebo in Period 5
Treatment Sequence 4 Vildagliptin 50 mg BID in Period 1 followed by placebo in Period 2 followed by saxagliptin 5 mg in Period 3 followed by vildagliptin 50 mg in Period 4 followed by sitagliptin 100 mg in Period 5
Treatment Sequence 5 Placebo in Period 1 followed by sitagliptin 100 mg in Period 2 followed by vildagliptin 50 mg in Period 3 followed by vildagliptin 50 mg BID in Period 4 followed by saxagliptin 5 mg in Period 5
Treatment Sequence 6 Sitagliptin 100 mg in Period 1 followed by vildagliptin 50 mg in Period 2 followed by saxagliptin 5 mg in Period 3 followed by placebo in Period 4 followed by vildagliptin 50 mg BID in Period 5
Treatment Sequence 7 Saxagliptin 5 mg in Period 1 followed by vildagliptin 50 mg BID in Period 2 followed by vildagliptin 50 mg in Period 3 followed by sitagliptin 100 mg in Period 4 followed by placebo in Period 5
Treatment Sequence 8 Vildagliptin 50 mg in Period 1 followed by placebo in Period 2 followed by vildagliptin 50 mg BID in Period 3 followed by saxagliptin 5 mg in Period 4 followed by sitagliptin 100 mg in Period 5
Treatment Sequence 9 Vildagliptin 50 mg BID in Period 1 followed by sitagliptin 100 mg in Period 2 followed by placebo in Period 3 followed by vildagliptin 50 mg in Period 4 followed by saxagliptin 5 mg in Period 5
Treatment Sequence 10 Placebo in Period 1 followed by saxagliptin 5 mg in Period 2 followed by sitagliptin 100 mg in Period 3 followed by vildagliptin 50 mg BID in Period 4 followed by vildagliptin 50 mg in Period 5

Participant Flow for 9 periods

Period 1:   Period 1
    Treatment Sequence 1     Treatment Sequence 2     Treatment Sequence 3     Treatment Sequence 4     Treatment Sequence 5     Treatment Sequence 6     Treatment Sequence 7     Treatment Sequence 8     Treatment Sequence 9     Treatment Sequence 10  
STARTED     2     2     2     2     3 [1]   2     3 [2]   2     2     2  
COMPLETED     2     2     2     2     3     2     2     2     2     2  
NOT COMPLETED     0     0     0     0     0     0     1     0     0     0  
Withdrawal by Subject                 0                 0                 0                 0                 0                 0                 1                 0                 0                 0  
[1] Includes replacement for a participant who discontinued after period 1
[2] Includes replacement for a participant who discontinued during period 1

Period 2:   10-day Washout Following Period 1
    Treatment Sequence 1     Treatment Sequence 2     Treatment Sequence 3     Treatment Sequence 4     Treatment Sequence 5     Treatment Sequence 6     Treatment Sequence 7     Treatment Sequence 8     Treatment Sequence 9     Treatment Sequence 10  
STARTED     2     2     2     2     3     2     2     2     2     2  
COMPLETED     2     2     2     2     2     2     2     2     2     2  
NOT COMPLETED     0     0     0     0     1     0     0     0     0     0  
Physician Decision                 0                 0                 0                 0                 1                 0                 0                 0                 0                 0  

Period 3:   Period 2
    Treatment Sequence 1     Treatment Sequence 2     Treatment Sequence 3     Treatment Sequence 4     Treatment Sequence 5     Treatment Sequence 6     Treatment Sequence 7     Treatment Sequence 8     Treatment Sequence 9     Treatment Sequence 10  
STARTED     2     2     2     2     2     2     2     2     2     2  
COMPLETED     2     2     2     2     2     2     2     2     2     2  
NOT COMPLETED     0     0     0     0     0     0     0     0     0     0  

Period 4:   10-day Washout Following Period 2
    Treatment Sequence 1     Treatment Sequence 2     Treatment Sequence 3     Treatment Sequence 4     Treatment Sequence 5     Treatment Sequence 6     Treatment Sequence 7     Treatment Sequence 8     Treatment Sequence 9     Treatment Sequence 10  
STARTED     2     2     2     2     2     2     2     2     2     2  
COMPLETED     2     2     2     2     2     2     2     2     2     2  
NOT COMPLETED     0     0     0     0     0     0     0     0     0     0  

Period 5:   Period 3
    Treatment Sequence 1     Treatment Sequence 2     Treatment Sequence 3     Treatment Sequence 4     Treatment Sequence 5     Treatment Sequence 6     Treatment Sequence 7     Treatment Sequence 8     Treatment Sequence 9     Treatment Sequence 10  
STARTED     2     2     2     2     2     2     2     2     2     2  
COMPLETED     2     2     2     2     2     2     2     2     2     2  
NOT COMPLETED     0     0     0     0     0     0     0     0     0     0  

Period 6:   10-day Washout Following Period 3
    Treatment Sequence 1     Treatment Sequence 2     Treatment Sequence 3     Treatment Sequence 4     Treatment Sequence 5     Treatment Sequence 6     Treatment Sequence 7     Treatment Sequence 8     Treatment Sequence 9     Treatment Sequence 10  
STARTED     2     2     2     2     2     2     2     2     2     2  
COMPLETED     2     2     2     2     2     2     2     2     2     2  
NOT COMPLETED     0     0     0     0     0     0     0     0     0     0  

Period 7:   Period 4
    Treatment Sequence 1     Treatment Sequence 2     Treatment Sequence 3     Treatment Sequence 4     Treatment Sequence 5     Treatment Sequence 6     Treatment Sequence 7     Treatment Sequence 8     Treatment Sequence 9     Treatment Sequence 10  
STARTED     2     2     2     2     2     2     2     2     2     2  
COMPLETED     1     2     2     2     2     1     2     2     2     1  
NOT COMPLETED     1     0     0     0     0     1     0     0     0     1  
Physician Decision                 1                 0                 0                 0                 0                 1                 0                 0                 0                 1  

Period 8:   10-day Washout Following Period 4
    Treatment Sequence 1     Treatment Sequence 2     Treatment Sequence 3     Treatment Sequence 4     Treatment Sequence 5     Treatment Sequence 6     Treatment Sequence 7     Treatment Sequence 8     Treatment Sequence 9     Treatment Sequence 10  
STARTED     1     2     2     2     2     1     2     2     2     1  
COMPLETED     1     2     2     2     2     1     2     2     2     1  
NOT COMPLETED     0     0     0     0     0     0     0     0     0     0  

Period 9:   Period 5
    Treatment Sequence 1     Treatment Sequence 2     Treatment Sequence 3     Treatment Sequence 4     Treatment Sequence 5     Treatment Sequence 6     Treatment Sequence 7     Treatment Sequence 8     Treatment Sequence 9     Treatment Sequence 10  
STARTED     1     2     2     2     2     1     2     2     2     1  
COMPLETED     1     2     2     2     2     1     2     2     2     1  
NOT COMPLETED     0     0     0     0     0     0     0     0     0     0  



  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.
No text entered.

Reporting Groups
  Description
All Enrolled Participants No text entered.

Baseline Measures
    All Enrolled Participants  
Number of Participants  
[units: participants]
  22  
Age  
[units: Participants]
 
<=18 years     0  
Between 18 and 65 years     22  
>=65 years     0  
Gender  
[units: Participants]
 
Female     12  
Male     10  



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Percent Inhibition of Dipeptidyl Peptidase IV (DPP-4) Activity at Trough   [ Time Frame: 24 hours following the final morning dose on Day 5 ]
  Hide Outcome Measure 1

Measure Type Primary
Measure Title Percent Inhibition of Dipeptidyl Peptidase IV (DPP-4) Activity at Trough
Measure Description Percent inhibition of DPP-4 activity at 24 hours after the Day 5 morning dose (i.e., at trough) was determined by analysis of blood samples collected from the study participants.
Time Frame 24 hours following the final morning dose on Day 5  
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.
All participants who had at least at least one measurement.

Reporting Groups
  Description
Sitagliptin 100 mg Sitagliptin 100 mg daily for 5 days
Saxagliptin 5 mg Saxagliptin 5 mg daily for 5 days
Vildagliptin 50 mg Vildagliptin 50 mg daily for 5 days
Vildagliptin 50 mg BID Vildagliptin 50 mg twice daily for 5 days
Placebo Placebo to sitagliptin daily for 5 days

Measured Values
    Sitagliptin 100 mg     Saxagliptin 5 mg     Vildagliptin 50 mg     Vildagliptin 50 mg BID     Placebo  
Number of Participants Analyzed  
[units: participants]
  17     20     18     17     17  
Percent Inhibition of Dipeptidyl Peptidase IV (DPP-4) Activity at Trough  
[units: Percent inhibition]
Least Squares Mean ( 95% Confidence Interval )
  91.73  
  ( 91.37 to 92.08 )  
  73.50  
  ( 66.56 to 79.00 )  
  28.88  
  ( 17.90 to 38.38 )  
  90.63  
  ( 88.93 to 92.06 )  
  3.49  
  ( -0.66 to 7.48 )  


Statistical Analysis 1 for Percent Inhibition of Dipeptidyl Peptidase IV (DPP-4) Activity at Trough
Groups [1] Sitagliptin 100 mg vs. Saxagliptin 5 mg
Method [2] Linear mixed effects model
P Value [3] <.001
Least squares mean difference [4] 18.24
90% Confidence Interval ( 14.97 to 21.67 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis model included fixed effects terms for treatment and period.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value of between-treatment comparison of percent inhibition of DPP-4 activity.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Percent Inhibition of Dipeptidyl Peptidase IV (DPP-4) Activity at Trough
Groups [1] Sitagliptin 100 mg vs. Vildagliptin 50 mg
Method [2] Linear mixed effects model
P Value [3] <.001
Least squares mean difference [4] 62.86
90% Confidence Interval ( 58.21 to 67.74 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis model included fixed effects terms for treatment and period.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value of between-treatment comparison of percent inhibition of DPP-4 activity.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 3 for Percent Inhibition of Dipeptidyl Peptidase IV (DPP-4) Activity at Trough
Groups [1] Sitagliptin 100 mg vs. Vildagliptin 50 mg BID
Method [2] Linear mixed effects model
P Value [3] 0.128
Least squares mean difference [4] 1.11
90% Confidence Interval ( -0.10 to 2.33 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis model included fixed effects terms for treatment and period.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value of between-treatment comparison of percent inhibition of DPP-4 activity.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 4 for Percent Inhibition of Dipeptidyl Peptidase IV (DPP-4) Activity at Trough
Groups [1] Sitagliptin 100 mg vs. Placebo
Method [2] Linear mixed effects model
P Value [3] <.001
Least squares mean difference [4] 88.24
90% Confidence Interval ( 85.77 to 90.76 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis model included fixed effects terms for treatment and period.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value of between-treatment comparison of percent inhibition of DPP-4 activity.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 5 for Percent Inhibition of Dipeptidyl Peptidase IV (DPP-4) Activity at Trough
Groups [1] Saxagliptin 5 mg vs. Vildagliptin 50 mg
Method [2] Linear mixed effects model
P Value [3] <.001
Least squares mean difference [4] 44.62
90% Confidence Interval ( 34.51 to 55.23 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis model included fixed effects terms for treatment and period.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value of between-treatment comparison of percent inhibition of DPP-4 activity.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 6 for Percent Inhibition of Dipeptidyl Peptidase IV (DPP-4) Activity at Trough
Groups [1] Saxagliptin 5 mg vs. Vildagliptin 50 mg BID
Method [2] Linear mixed effects model
P Value [3] <.001
Least squares mean difference [4] -17.13
90% Confidence Interval ( -21.21 to -13.25 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis model included fixed effects terms for treatment and period.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value of between-treatment comparison of percent inhibition of DPP-4 activity.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 7 for Percent Inhibition of Dipeptidyl Peptidase IV (DPP-4) Activity at Trough
Groups [1] Saxagliptin 5 mg vs. Placebo
Method [2] Linear mixed effects model
P Value [3] <.001
Least squares mean difference [4] 70.00
90% Confidence Interval ( 58.46 to 82.20 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis model included fixed effects terms for treatment and period.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value of between-treatment comparison of percent inhibition of DPP-4 activity.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 8 for Percent Inhibition of Dipeptidyl Peptidase IV (DPP-4) Activity at Trough
Groups [1] Vildagliptin 50 mg vs. Vildagliptin 50 mg BID
Method [2] Linear mixed effects model
P Value [3] <.001
Least squares mean difference [4] -61.75
90% Confidence Interval ( -68.76 to -55.18 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis model included fixed effects terms for treatment and period.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value of between-treatment comparison of percent inhibition of DPP-4 activity.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 9 for Percent Inhibition of Dipeptidyl Peptidase IV (DPP-4) Activity at Trough
Groups [1] Vildagliptin 50 mg vs. Placebo
Method [2] Linear mixed effects model
P Value [3] <.001
Least squares mean difference [4] 25.38
90% Confidence Interval ( 15.37 to 35.48 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis model included fixed effects terms for treatment and period.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value of between-treatment comparison of percent inhibition of DPP-4 activity.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 10 for Percent Inhibition of Dipeptidyl Peptidase IV (DPP-4) Activity at Trough
Groups [1] Vildagliptin 50 mg BID vs. Placebo
Method [2] Linear mixed effects model
P Value [3] <.001
Least squares mean difference [4] 87.13
90% Confidence Interval ( 80.06 to 94.61 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis model included fixed effects terms for treatment and period.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value of between-treatment comparison of percent inhibition of DPP-4 activity.
[4] Other relevant estimation information:
  No text entered.



2.  Secondary:   Pharmacokinetic Analysis: Area Under the Curve 0-24 Hours (AUC 0-24hr)   [ Time Frame: Predose (0 Hours) and 0.5, 1, 2, 4, 8, 12, 13 (vildagliptin 50 mg BID only), 14 (vildagliptin 50 mg BID only), 16, 20 and 24 hours after the morning dose on Day 5 ]

3.  Secondary:   Pharmacokinetic Analysis: Area Under the Curve 0-12 Hours (AUC 0-12hr) for Vildagliptin 50 mg BID   [ Time Frame: Predose (0 hours) and 0.5, 1, 2, 4, 8 and 12 hours after the morning dose on Day 5 ]

4.  Secondary:   Pharmacokinetic Analysis: Peak Plasma Drug Concentration (Cmax)   [ Time Frame: Predose (0 hours) and 0.5, 1, 2, 4, 8, 12, 13 (vildagliptin 50 mg BID only), 14 (vildagliptin 50 mg BID only), 16, 20, 24, 36, 48 and 96 hours after the morning dose on Day 5 ]

5.  Secondary:   Pharmacokinetic Analysis: Time to the Peak Plasma Drug Concentration (Tmax)   [ Time Frame: Predose (0 hours) and 0.5, 1, 2, 4, 8, 12, 13 (vildagliptin 50 mg BID only), 14 (vildagliptin 50 mg BID only), 16, 20, 24, 36, 48 and 96 hours after the morning dose on Day 5 ]


  Serious Adverse Events


  Other Adverse Events


  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.


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
No text entered.  


Results Point of Contact:  
Name/Title: Senior Vice President, Global Clinical Development
Organization: Merck Sharp & Dohme Corp
phone: 1-800-672-6372
e-mail: ClinicalTrialsDisclosure@merck.com


No publications provided


Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01582308     History of Changes
Other Study ID Numbers: 0431-142, 2011-005567-25
Study First Received: April 19, 2012
Results First Received: December 4, 2013
Last Updated: December 4, 2013
Health Authority: Moldova: Medicines Agency