Type 2 Diabetes Mellitus (T2DM)
Conditions
Keywords
Type 2 Diabetes Mellitus (T2DM)
Brief summary
A clinical study to determine the safety, efficacy and mechanism of action of sitagliptin alone and in combination with pioglitazone, in patients with type 2 diabetes mellitus who have inadequate glycemic (blood sugar) control.
Interventions
sitagliptin phosphate 100 mg as oral tablets. Each patient will be administered 1 tablet once daily.
pioglitazone 30 mg will be supplied as oral tablets. Each patient will be administered 1 tablet once daily.
pioglitazone 30 mg placebos will be supplied as oral tablets. Each patient will be administered 1 tablet once daily.
sitagliptin phosphate 100 mg placebos will be supplied as oral tablets. Each patient will be administered 1 tablet once daily.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Patient has type 2 diabetes mellitus * Male * Female that is highly unlikely to become pregnant * Patient is not on an antihyperglycemic agent (AHA) (hemoglobin A1c \[A1C\] 7-10%) or on oral single AHA or low-dose combination therapy (A1C 6.5-9.0%)
Exclusion criteria
* Patient has a history of type 1 diabetes mellitus or a history of ketoacidosis * Patient has required insulin therapy within the past 12 weeks * Patient is on or has been taking a Peroxisome Proliferator-Activated Receptor-gamma (PPAR -gamma) agent (i.e. Thiazolidinediones \[TZDs\]) within the prior 12 weeks of the screening visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glucagon 3-hour Total Area Under the Curve (AUC) After 12 Weeks of Treatment | Baseline and 12 weeks | Glucagon concentration was measured at 9 points during an Meal Tolerance Test (MTT), at times -10, 0, 10, 20, 30, 60, 90, 120, and 180 minutes. Total AUC was calculated over 3 hours including all sample points starting from 0 minutes using the trapezoid method. The change from baseline reflects Week 12 total AUC minus the Week 0 total AUC. |
| Percent Change From Baseline in Index of Static Beta-cell Sensitivity to Glucose After 12 Weeks of Treatment | Baseline and 12 weeks | Static sensitivity is a measure of the effect of glucose on beta cell secretion and is the ratio between the insulin secretion rate and glucose concentration above the threshold level at steady state. Percent change from baseline was calculated as the difference between index of static sensitivities at Week 12 and at baseline with respect to the index of static sensitivity at baseline times 100. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glucose 5-hour Total AUC After 12 Weeks of Treatment | Baseline and 12 weeks | Glucose concentration was measured at 11 points during an Meal Tolerance Test (MTT), at times -10, 0, 10, 20, 30, 60, 90, 120, 180, 240, 300 minutes. Total AUC was calculated over 5 hours including all sample points starting from 0 minutes using the trapezoid method. The change from baseline reflects Week 12 total AUC minus the Week 0 total AUC. |
Participant flow
Recruitment details
First Patient In: 12-Sep-2007; Last Patient Last Visit: 24-Feb-2009 Forty-four medical clinics worldwide (17 in the United States, 20 in Europe, 4 in Australia, and 3 in Israel).
Pre-assignment details
Patients 30-65 years of age with type 2 diabetes mellitus (T2DM) with inadequate glycemic control (fasting plasma glucose \[FPG\] 130-260 mg/dL \[7.2-14.4 mmol/L\]) on diet and exercise alone were eligible for randomization.
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin 100 mg Includes patients receiving once-daily administration of sitagliptin 100 mg and matching placebo to pioglitazone 30 mg. | 52 |
| Pioglitazone 30 mg Includes patients receiving once-daily administration of pioglitazone 30 mg and matching placebo to sitagliptin 100 mg. | 54 |
| Sitagliptin 100 mg + Pioglitazone 30 mg Includes patients receiving once-daily administration of sitagliptin 100 mg and pioglitazone 30 mg. | 52 |
| Placebo Includes patients receiving once-daily administration of matching placebo to sitagliptin 100 mg and matching placebo to pioglitazone 30 mg. | 53 |
| Total | 211 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 1 | 2 |
| Overall Study | Lost to Follow-up | 0 | 2 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 0 | 3 | 2 |
Baseline characteristics
| Characteristic | Pioglitazone 30 mg | Sitagliptin 100 mg + Pioglitazone 30 mg | Sitagliptin 100 mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 53.4 years STANDARD_DEVIATION 7.8 | 53.3 years STANDARD_DEVIATION 8.6 | 54.6 years STANDARD_DEVIATION 7.6 | 53.3 years STANDARD_DEVIATION 7.7 | 53.6 years STANDARD_DEVIATION 7.9 |
| Glucose 5-hour (hr) Total area under the curve (AUC) | 1250.6 mg*hr/dL STANDARD_DEVIATION 349.6 | 1276.0 mg*hr/dL STANDARD_DEVIATION 348.5 | 1179.9 mg*hr/dL STANDARD_DEVIATION 322.8 | 1255.1 mg*hr/dL STANDARD_DEVIATION 290.9 | 1240.4 mg*hr/dL STANDARD_DEVIATION 328.4 |
| Hemoglobin A1c (HbA1c) | 7.9 Percent STANDARD_DEVIATION 0.9 | 7.9 Percent STANDARD_DEVIATION 0.9 | 7.7 Percent STANDARD_DEVIATION 0.8 | 8.0 Percent STANDARD_DEVIATION 1.1 | 7.9 Percent STANDARD_DEVIATION 1 |
| Race/Ethnicity, Customized Asian | 1 participants | 0 participants | 1 participants | 2 participants | 4 participants |
| Race/Ethnicity, Customized Black | 9 participants | 3 participants | 6 participants | 2 participants | 20 participants |
| Race/Ethnicity, Customized Other | 1 participants | 0 participants | 0 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized White | 43 participants | 49 participants | 45 participants | 48 participants | 185 participants |
| Sex: Female, Male Female | 31 Participants | 18 Participants | 24 Participants | 21 Participants | 94 Participants |
| Sex: Female, Male Male | 23 Participants | 34 Participants | 28 Participants | 32 Participants | 117 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 52 | 3 / 54 | 0 / 52 | 9 / 53 |
| serious Total, serious adverse events | 1 / 52 | 0 / 54 | 1 / 52 | 0 / 53 |
Outcome results
Primary
Change From Baseline in Glucagon 3-hour Total Area Under the Curve (AUC) After 12 Weeks of Treatment
Glucagon concentration was measured at 9 points during an Meal Tolerance Test (MTT), at times -10, 0, 10, 20, 30, 60, 90, 120, and 180 minutes. Total AUC was calculated over 3 hours including all sample points starting from 0 minutes using the trapezoid method. The change from baseline reflects Week 12 total AUC minus the Week 0 total AUC.
Time frame: Baseline and 12 weeks
Population: The Full Analysis Set (FAS) included all patients with a baseline value and ≥1 post-baseline value for this outcome. For FAS patients with no data at Week 12, the last observed measurement was carried forward to Week 12.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin 100 mg | Change From Baseline in Glucagon 3-hour Total Area Under the Curve (AUC) After 12 Weeks of Treatment | -17.2 pg*hr/mL |
| Pioglitazone 30 mg | Change From Baseline in Glucagon 3-hour Total Area Under the Curve (AUC) After 12 Weeks of Treatment | -4.9 pg*hr/mL |
| Sitagliptin 100 mg + Pioglitazone 30 mg | Change From Baseline in Glucagon 3-hour Total Area Under the Curve (AUC) After 12 Weeks of Treatment | -29.8 pg*hr/mL |
| Placebo | Change From Baseline in Glucagon 3-hour Total Area Under the Curve (AUC) After 12 Weeks of Treatment | 12.5 pg*hr/mL |
p-value: 0.00295% CI: [-48.7, -10.6]ANCOVA
Primary
Percent Change From Baseline in Index of Static Beta-cell Sensitivity to Glucose After 12 Weeks of Treatment
Static sensitivity is a measure of the effect of glucose on beta cell secretion and is the ratio between the insulin secretion rate and glucose concentration above the threshold level at steady state. Percent change from baseline was calculated as the difference between index of static sensitivities at Week 12 and at baseline with respect to the index of static sensitivity at baseline times 100.
Time frame: Baseline and 12 weeks
Population: The Full Analysis Set (FAS) included all patients with a baseline value and ≥1 post-baseline value for this outcome. For FAS patients with no data at Week 12, the last observed measurement was carried forward to Week 12.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin 100 mg | Percent Change From Baseline in Index of Static Beta-cell Sensitivity to Glucose After 12 Weeks of Treatment | 71.5 Percent Change |
| Pioglitazone 30 mg | Percent Change From Baseline in Index of Static Beta-cell Sensitivity to Glucose After 12 Weeks of Treatment | 27.0 Percent Change |
| Sitagliptin 100 mg + Pioglitazone 30 mg | Percent Change From Baseline in Index of Static Beta-cell Sensitivity to Glucose After 12 Weeks of Treatment | 125.2 Percent Change |
| Placebo | Percent Change From Baseline in Index of Static Beta-cell Sensitivity to Glucose After 12 Weeks of Treatment | -2.3 Percent Change |
p-value: <0.00195% CI: [44.2, 104.4]ANCOVA
Secondary
Change From Baseline in Glucose 5-hour Total AUC After 12 Weeks of Treatment
Glucose concentration was measured at 11 points during an Meal Tolerance Test (MTT), at times -10, 0, 10, 20, 30, 60, 90, 120, 180, 240, 300 minutes. Total AUC was calculated over 5 hours including all sample points starting from 0 minutes using the trapezoid method. The change from baseline reflects Week 12 total AUC minus the Week 0 total AUC.
Time frame: Baseline and 12 weeks
Population: The Full Analysis Set (FAS) included all patients with a baseline value and ≥1 post-baseline value for this outcome. For FAS patients with no data at Week 12, the last observed measurement was carried forward to Week 12.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin 100 mg | Change From Baseline in Glucose 5-hour Total AUC After 12 Weeks of Treatment | -209.8 mg*hr/dL |
| Pioglitazone 30 mg | Change From Baseline in Glucose 5-hour Total AUC After 12 Weeks of Treatment | -245.6 mg*hr/dL |
| Sitagliptin 100 mg + Pioglitazone 30 mg | Change From Baseline in Glucose 5-hour Total AUC After 12 Weeks of Treatment | -389.2 mg*hr/dL |
| Placebo | Change From Baseline in Glucose 5-hour Total AUC After 12 Weeks of Treatment | 18.6 mg*hr/dL |
p-value: <0.00195% CI: [-513.4, -302.1]ANCOVA