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MK0431A vs. Pioglitazone in Patients With Type 2 Diabetes Mellitus (0431A-066)

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ClinicalTrials.gov Identifier: NCT00532935
Recruitment Status : Completed
First Posted : September 21, 2007
Results First Posted : October 18, 2010
Last Update Posted : June 9, 2017
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Type 2 Diabetes Mellitus
Interventions Drug: sitagliptin phosphate (+) metformin hydrochloride
Drug: Comparator: pioglitazone
Enrollment 517
Recruitment Details

First Patient In: 19-Mar-2008

Last Patient Last Visit: 23-Oct-2009

Seventy-four medical clinics worldwide (19 sites in the United States, 31 in Eastern Europe, and 24 in the rest of the world).

Pre-assignment Details

Patients 18-78 years old with Type 2 Diabetes Mellitus (T2DM), drug-naïve (off antihyperglycemic agent

[AHA] for at least 3 months prior to screening, and a maximum 4 weeks cumulative AHA therapy over the

previous 3 years), hemoglobin A1C 7.5 to 12% were eligible. Eligible patients underwent a 2-week placebo

run-in period prior to randomization.

Arm/Group Title Sitagliptin/Metformin Fixed-Dose Combination Pioglitazone
Hide Arm/Group Description The Sitagliptin/Metformin Fixed-Dose Combination (Sita/Met FDC) group includes data from patients randomized to receive treatment with oral tablets of Sita/Met FDC initiated at a dose of 50/500 mg twice a day (b.i.d). The dose was to have been up-titrated over 4 weeks to 50/1000 mg b.i.d. Patients were discontinued if they were considered clinically inappropriate for up-titration or could not be up-titrated or maintained on the up-titrated dose. The Pioglitazone group includes data from patients randomized to receive treatment with oral tablets of pioglitazone initiated at a dose of 30 mg once daily (q.d.). The dose was to have been up-titrated over 4 weeks to 45 mg q.d. Patients were discontinued if they were considered clinically inappropriate for up-titration or could not be up-titrated or maintained on the up-titrated dose.
Period Title: Overall Study
Started 261 [1] 256 [1]
Completed 210 204
Not Completed 51 52
Reason Not Completed
Adverse Event             11             12
Lack of Efficacy             0             3
Lost to Follow-up             10             6
Physician Decision             4             5
Pregnancy             1             0
Protocol Violation             4             2
Withdrawal by Subject             10             9
Protocol Specific Criteria             11             15
[1]
Excludes 1 patient who was randomized twice at different sites.
Arm/Group Title Sitagliptin/Metformin Fixed-Dose Combination Pioglitazone Total
Hide Arm/Group Description The Sitagliptin/Metformin Fixed-Dose Combination (Sita/Met FDC) group includes data from patients randomized to receive treatment with oral tablets of Sita/Met FDC initiated at a dose of 50/500 mg twice a day (b.i.d). The dose was to have been up-titrated over 4 weeks to 50/1000 mg b.i.d. Patients were discontinued if they were considered clinically inappropriate for up-titration or could not be up-titrated or maintained on the up-titrated dose. The Pioglitazone group includes data from patients randomized to receive treatment with oral tablets of pioglitazone initiated at a dose of 30 mg once daily (q.d.). The dose was to have been up-titrated over 4 weeks to 45 mg q.d. Patients were discontinued if they were considered clinically inappropriate for up-titration or could not be up-titrated or maintained on the up-titrated dose. Total of all reporting groups
Overall Number of Baseline Participants 261 256 517
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 261 participants 256 participants 517 participants
52.4  (10.7) 52.2  (11) 52.3  (10.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 261 participants 256 participants 517 participants
Female
118
  45.2%
122
  47.7%
240
  46.4%
Male
143
  54.8%
134
  52.3%
277
  53.6%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 261 participants 256 participants 517 participants
White 168 167 335
Black 6 5 11
American Indian 2 0 2
Asian 58 55 113
Multi-racial 27 29 56
Hemoglobin A1C (A1C)  
Mean (Standard Deviation)
Unit of measure:  Percent of glycosylated hemoglobin (A1C)
Number Analyzed 261 participants 256 participants 517 participants
9.0  (1.3) 8.9  (1.3) 8.9  (1.3)
Fasting Plasma Glucose (FPG)  
Mean (Standard Deviation)
Unit of measure:  mg/dL
Number Analyzed 261 participants 256 participants 517 participants
190.6  (53.4) 188.9  (57.1) 189.8  (55.2)
2-Hour Post-Meal Glucose (2-HR PMG)  
Mean (Standard Deviation)
Unit of measure:  mg/dL
Number Analyzed 261 participants 256 participants 517 participants
273.7  (84.8) 278.8  (86.4) 276.2  (85.5)
1.Primary Outcome
Title Change From Baseline in A1C at Week 32
Hide Description A1C is measured as a percent. Thus this change from baseline reflects the Week 32 A1C percent minus the baseline A1C percent
Time Frame Baseline and Week 32
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) included all patients who received at least one dose of double-blind study drug and had both a baseline value and ≥ 1 post-baseline value for this outcome. For FAS patients with no data at Week 32, the last non-baseline observed measurement was carried forward to Week 32.
Arm/Group Title Sitagliptin/Metformin Fixed-Dose Combination Pioglitazone
Hide Arm/Group Description:
The Sitagliptin/Metformin Fixed-Dose Combination (Sita/Met FDC) group includes data from patients randomized to receive treatment with oral tablets of Sita/Met FDC initiated at a dose of 50/500 mg twice a day (b.i.d). The dose was to have been up-titrated over 4 weeks to 50/1000 mg b.i.d. Patients were discontinued if they were considered clinically inappropriate for up-titration or could not be up-titrated or maintained on the up-titrated dose.
The Pioglitazone group includes data from patients randomized to receive treatment with oral tablets of pioglitazone initiated at a dose of 30 mg once daily (q.d.). The dose was to have been up-titrated over 4 weeks to 45 mg q.d. Patients were discontinued if they were considered clinically inappropriate for up-titration or could not be up-titrated or maintained on the up-titrated dose.
Overall Number of Participants Analyzed 253 246
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Percent of glycosylated hemoglobin (A1C)
-1.86
(-2.00 to -1.73)
-1.39
(-1.53 to -1.26)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sitagliptin/Metformin Fixed-Dose Combination, Pioglitazone
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments ANCOVA model included a term for treatment and a covariate for the baseline A1C value.
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.47
Confidence Interval (2-Sided) 95%
-0.66 to -0.28
Parameter Dispersion
Type: Standard Deviation
Value: 1.10
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change From Baseline in Fasting Plasma Glucose (FPG) at Week 1
Hide Description Change from baseline reflects the Week 1 FPG minus the baseline FPG. At Week 1, the dose was 50/500 mg b.i.d. for Sita/Met FDC and 30 mg q.d. for pioglitazone
Time Frame Baseline and Week 1
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) included all patients who received at least one dose of double-blind study drug and had both a baseline value and ≥ 1 post-baseline value for this outcome.
Arm/Group Title Sitagliptin/Metformin Fixed-Dose Combination Pioglitazone
Hide Arm/Group Description:
The Sitagliptin/Metformin Fixed-Dose Combination (Sita/Met FDC) group includes data from patients randomized to receive treatment with oral tablets of Sita/Met FDC initiated at a dose of 50/500 mg twice a day (b.i.d). The dose was to have been up-titrated over 4 weeks to 50/1000 mg b.i.d. Patients were discontinued if they were considered clinically inappropriate for up-titration or could not be up-titrated or maintained on the up-titrated dose.
The Pioglitazone group includes data from patients randomized to receive treatment with oral tablets of pioglitazone initiated at a dose of 30 mg once daily (q.d.). The dose was to have been up-titrated over 4 weeks to 45 mg q.d. Patients were discontinued if they were considered clinically inappropriate for up-titration or could not be up-titrated or maintained on the up-titrated dose.
Overall Number of Participants Analyzed 250 242
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mg/dL
-40.5
(-44.1 to -36.9)
-13.0
(-16.6 to -9.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sitagliptin/Metformin Fixed-Dose Combination, Pioglitazone
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments ANCOVA model included a term for treatment and a covariate for the baseline FPG value.
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -27.6
Confidence Interval (2-Sided) 95%
-32.7 to -22.4
Parameter Dispersion
Type: Standard Deviation
Value: 29.1
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change From Baseline in 2-hour Post-Meal Glucose (PMG) at Week 32
Hide Description Change from baseline reflects the Week 32 2-hour PMG minus the baseline 2-hour PMG
Time Frame Baseline and Week 32
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) included all patients who received at least one dose of double-blind study drug and had both a baseline value and ≥ 1 post-baseline value for this outcome. For FAS patients with no data at Week 32, the last non-baseline observed measurement was carried forward to Week 32.
Arm/Group Title Sitagliptin/Metformin Fixed-Dose Combination Pioglitazone
Hide Arm/Group Description:
The Sitagliptin/Metformin Fixed-Dose Combination (Sita/Met FDC) group includes data from patients randomized to receive treatment with oral tablets of Sita/Met FDC initiated at a dose of 50/500 mg twice a day (b.i.d). The dose was to have been up-titrated over 4 weeks to 50/1000 mg b.i.d. Patients were discontinued if they were considered clinically inappropriate for up-titration or could not be up-titrated or maintained on the up-titrated dose.
The Pioglitazone group includes data from patients randomized to receive treatment with oral tablets of pioglitazone initiated at a dose of 30 mg once daily (q.d.). The dose was to have been up-titrated over 4 weeks to 45 mg q.d. Patients were discontinued if they were considered clinically inappropriate for up-titration or could not be up-titrated or maintained on the up-titrated dose.
Overall Number of Participants Analyzed 192 198
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mg/dL
-102.2
(-110.7 to -93.8)
-82.0
(-90.4 to -73.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sitagliptin/Metformin Fixed-Dose Combination, Pioglitazone
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments ANCOVA model included a term for treatment and a covariate for the baseline 2-hour PMG value.
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -20.2
Confidence Interval (2-Sided) 95%
-32.1 to -8.3
Parameter Dispersion
Type: Standard Deviation
Value: 59.7
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Change From Baseline in FPG at Week 32
Hide Description Change from baseline reflects the Week 32 FPG minus the baseline FPG
Time Frame Baseline and Week 32
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) included all patients who received at least one dose of double-blind study drug and had both a baseline value and ≥ 1 post-baseline value for this outcome. For FAS patients with no data at Week 32, the last non-baseline observed measurement was carried forward to Week 32.
Arm/Group Title Sitagliptin/Metformin Fixed-Dose Combination Pioglitazone
Hide Arm/Group Description:
The Sitagliptin/Metformin Fixed-Dose Combination (Sita/Met FDC) group includes data from patients randomized to receive treatment with oral tablets of Sita/Met FDC initiated at a dose of 50/500 mg twice a day (b.i.d). The dose was to have been up-titrated over 4 weeks to 50/1000 mg b.i.d. Patients were discontinued if they were considered clinically inappropriate for up-titration or could not be up-titrated or maintained on the up-titrated dose.
The Pioglitazone group includes data from patients randomized to receive treatment with oral tablets of pioglitazone initiated at a dose of 30 mg once daily (q.d.). The dose was to have been up-titrated over 4 weeks to 45 mg q.d. Patients were discontinued if they were considered clinically inappropriate for up-titration or could not be up-titrated or maintained on the up-titrated dose.
Overall Number of Participants Analyzed 258 250
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mg/dL
-56.0
(-60.9 to -51.0)
-44.0
(-49.1 to -39.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sitagliptin/Metformin Fixed-Dose Combination, Pioglitazone
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments ANCOVA model included a term for treatment and a covariate for the baseline FPG value.
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -11.9
Confidence Interval (2-Sided) 95%
-19.0 to -4.9
Parameter Dispersion
Type: Standard Deviation
Value: 40.3
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Percent of Participants With A1C <7.0% at Week 32
Hide Description [Not Specified]
Time Frame Week 32
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) included all patients who received at least one dose of double-blind study drug and had both a baseline value and ≥ 1 post-baseline value for this outcome. For FAS patients with no data at Week 32, the last non-baseline observed measurement was carried forward to Week 32.
Arm/Group Title Sitagliptin/Metformin Fixed-Dose Combination Pioglitazone
Hide Arm/Group Description:
The Sitagliptin/Metformin Fixed-Dose Combination (Sita/Met FDC) group includes data from patients randomized to receive treatment with oral tablets of Sita/Met FDC initiated at a dose of 50/500 mg twice a day (b.i.d). The dose was to have been up-titrated over 4 weeks to 50/1000 mg b.i.d. Patients were discontinued if they were considered clinically inappropriate for up-titration or could not be up-titrated or maintained on the up-titrated dose.
The Pioglitazone group includes data from patients randomized to receive treatment with oral tablets of pioglitazone initiated at a dose of 30 mg once daily (q.d.). The dose was to have been up-titrated over 4 weeks to 45 mg q.d. Patients were discontinued if they were considered clinically inappropriate for up-titration or could not be up-titrated or maintained on the up-titrated dose.
Overall Number of Participants Analyzed 253 246
Measure Type: Number
Unit of Measure: Percent Participants
57.3 43.5
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sitagliptin/Metformin Fixed-Dose Combination, Pioglitazone
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments Based on a test of the odds ratio = 1, comparing the odds of having A1C <7.0% at Week 32 in the Sitagliptin/Metformin 50/1000 mg b.i.d. group vs. the Pioglitazone 45 mg q.d. group.
Method Regression, Logistic
Comments logistic regression model included a term for treatment and a covariate for the baseline A1C value.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.0
Confidence Interval (2-Sided) 95%
1.3 to 2.8
Estimation Comments This parameter estimate and 95% confidence interval correspond to the odds of having A1C <7.0% at Week 32 in the Sitagliptin/Metformin 50/1000 mg b.i.d. group vs. the Pioglitazone 45 mg q.d. group.
Time Frame Week 0 through Week 32
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Sitagliptin/Metformin Fixed-Dose Combination Pioglitazone
Hide Arm/Group Description The Sitagliptin/Metformin Fixed-Dose Combination (Sita/Met FDC) group includes data from patients randomized to receive treatment with oral tablets of Sita/Met FDC initiated at a dose of 50/500 mg twice a day (b.i.d). The dose was to have been up-titrated over 4 weeks to 50/1000 mg b.i.d. Patients were discontinued if they were considered clinically inappropriate for up-titration or could not be up-titrated or maintained on the up-titrated dose. The Pioglitazone group includes data from patients randomized to receive treatment with oral tablets of pioglitazone initiated at a dose of 30 mg once daily (q.d.). The dose was to have been up-titrated over 4 weeks to 45 mg q.d. Patients were discontinued if they were considered clinically inappropriate for up-titration or could not be up-titrated or maintained on the up-titrated dose.
All-Cause Mortality
Sitagliptin/Metformin Fixed-Dose Combination Pioglitazone
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Sitagliptin/Metformin Fixed-Dose Combination Pioglitazone
Affected / at Risk (%) Affected / at Risk (%)
Total   11/261 (4.21%)   8/256 (3.13%) 
Eye disorders     
Conjunctivitis allergic * 1  1/261 (0.38%)  0/256 (0.00%) 
Ulcerative keratitis * 1  1/261 (0.38%)  0/256 (0.00%) 
Gastrointestinal disorders     
Pancreatitis * 1  1/261 (0.38%)  0/256 (0.00%) 
Upper gastrointestinal haemorrhage * 1  0/261 (0.00%)  1/256 (0.39%) 
Hepatobiliary disorders     
Cholecystitis * 1  1/261 (0.38%)  0/256 (0.00%) 
Cholelithiasis * 1  3/261 (1.15%)  0/256 (0.00%) 
Hepatitis * 1  1/261 (0.38%)  0/256 (0.00%) 
Infections and infestations     
Pharyngitis * 1  0/261 (0.00%)  1/256 (0.39%) 
Pneumonia * 1  0/261 (0.00%)  1/256 (0.39%) 
Injury, poisoning and procedural complications     
Femur fracture * 1  1/261 (0.38%)  0/256 (0.00%) 
Musculoskeletal and connective tissue disorders     
Intervertebral disc protrusion * 1  1/261 (0.38%)  0/256 (0.00%) 
Musculoskeletal chest pain * 1  0/261 (0.00%)  1/256 (0.39%) 
Osteoarthritis * 1  0/261 (0.00%)  1/256 (0.39%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Basal cell carcinoma * 1  0/261 (0.00%)  1/256 (0.39%) 
Colon cancer * 1  1/261 (0.38%)  0/256 (0.00%) 
Renal cancer * 1  1/261 (0.38%)  0/256 (0.00%) 
Nervous system disorders     
Brain stem infarction * 1  1/261 (0.38%)  0/256 (0.00%) 
Transient ischaemic attack * 1  1/261 (0.38%)  0/256 (0.00%) 
Pregnancy, puerperium and perinatal conditions     
Abortion spontaneous complete * 1  1/261 (0.38%)  0/256 (0.00%) 
Renal and urinary disorders     
Urine flow decreased * 1  0/261 (0.00%)  1/256 (0.39%) 
Respiratory, thoracic and mediastinal disorders     
Chronic obstructive pulmonary disease * 1  1/261 (0.38%)  1/256 (0.39%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (12.1)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Sitagliptin/Metformin Fixed-Dose Combination Pioglitazone
Affected / at Risk (%) Affected / at Risk (%)
Total   94/261 (36.02%)   68/256 (26.56%) 
Gastrointestinal disorders     
Diarrhoea * 1  40/261 (15.33%)  11/256 (4.30%) 
Dyspepsia * 1  13/261 (4.98%)  2/256 (0.78%) 
General disorders     
Oedema peripheral * 1  3/261 (1.15%)  18/256 (7.03%) 
Infections and infestations     
Nasopharyngitis * 1  10/261 (3.83%)  16/256 (6.25%) 
Upper respiratory tract infection * 1  13/261 (4.98%)  17/256 (6.64%) 
Metabolism and nutrition disorders     
Hypoglycaemia * 1  22/261 (8.43%)  11/256 (4.30%) 
Nervous system disorders     
Headache * 1  20/261 (7.66%)  7/256 (2.73%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (12.1)
Unknown to the Sponsor and the investigators, two patients in the study were randomized twice (each at two different sites). Data for these patients were deemed unreliable and excluded from all analyses (efficacy and safety).
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.
Merck agreements may vary with individual investigators, but will not prohibit any investigator from publishing. Merck supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Results Point of Contact
Name/Title: Senior Vice President, Global Clinical Development
Organization: Merck Sharp & Dohme Corp
Phone: 1-800-672-6372
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT00532935     History of Changes
Other Study ID Numbers: 0431A-066
2007_510
First Submitted: September 19, 2007
First Posted: September 21, 2007
Results First Submitted: September 23, 2010
Results First Posted: October 18, 2010
Last Update Posted: June 9, 2017