Diabetes Mellitus, Type 2
Conditions
Brief summary
This study will test the effectiveness and safety of treatment with MK-0893 in combination with other drugs commonly used to treat type 2 diabetes for a duration up to 13 weeks.
Interventions
DRUGMK-0893
Initial loading dose of 200 mg MK-0893 at randomization, followed by MK-0893 administered orally as 40 mg tablets daily throughout the double-blind treatment period (4 weeks).
DRUGSitagliptin
Sitagliptin Phosphate administered orally as 100 mg tablets daily before the morning meal throughout the double-blind treatment period (4 weeks).
DRUGMetformin
Metformin taken orally (500 mg tablets) over an initial 2-week titration period starting at 500 mg administered twice daily before the morning and evening meals, increasing to 1500 mg daily, and ending with 1000 mg twice daily. Metformin then administered throughout the double-blind treatment period (4 weeks).
DRUGPlacebo for MK-0893
Matching placebo for MK-0893 was orally administered for the loading dose (200 mg) and for the following daily treatment (40 mg) over the 4 week double blind treatment period.
Matching placebo for Sitagliptin (100 mg) administered orally as 100 mg tablets daily before the morning meal throughout the double-blind treatment period (4 weeks).
DRUGPlacebo for Metformin
Metformin-matched placebo taken orally (500 mg tablets) over an initial 2-week titration period starting at 500 mg administered twice daily before the morning and evening meals, increasing to 1500 mg daily, and ending with 1000 mg twice daily. Metformin-matched placebo then administered throughout the double-blind treatment period (4 weeks).
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Participants who have Type 2 Diabetes Mellitus, with suboptimal glucose control, while either not on AHA (antihyperglycemic agent) therapy or on monotherapy or on low-dose combination therapy
Exclusion criteria
* Participants have a history of Type 1 Diabetes Mellitus * Participants taking insulin or thiazolidinediones (TZDs: peroxisome proliferator-activated receptor \[PPAR\]-gamma agonists) * Participants who have a contraindication to metformin or sitagliptin
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline (BL) to Week 4 in 24-hour Weighted Mean Glucose (WMG) Levels | BL, 4 weeks (end of double-blind treatment period) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From BL to Week 4 in Fasting Plasma Glucose (FPG) | BL, 4 weeks (end of double-blind treatment period) | — |
| Change From BL to Week 4 in 2-hr Glucose Area Under The Curve (AUC) | BL, 4 weeks (end of double-blind treatment period) | — |
| Change From BL to Week 4 in the 2-Hour Total GLP-1 Total AUC | BL, 4 weeks (end of double-blind treatment period) | Glucagon-Like Peptide-1 (GLP-1) is an incretin hormone that acts as a potent insulin secretegogue in response to nutrient ingestion and stimulates glucose disposition. The total AUC of Total GLP-1 levels was calculated from blood sample data measured after the morning meal. |
| Change From BL to Week 4 in the 2-Hour Active GLP-1 Total AUC | BL, 4 weeks (end of double-blind treatment period) | GLP-1 is cleaved from proglucagon to form the active peptide GLP-1. The active form promotes suppression of glucagon secretion. The total AUC of Active GLP-1 levels was calculated from blood sample data measured after the morning meal. |
Participant flow
Pre-assignment details
Participants received matching placebos to MK-0893, Sitagliptin, and Metformin during a 2-week run-in period.
Participants by arm
| Arm | Count |
|---|---|
| MK-0893 + Sitagliptin Participants received an initial loading dose of 200 mg MK-0893 at randomization, followed by MK-0893 administered orally as 40 mg tablets daily throughout the double-blind treatment period. Sitagliptin was administered orally as 100 mg tablets daily before the morning meal throughout the double-blind treatment period. | 48 |
| MK-0893 + Metformin Participants received an initial loading dose of 200 mg MK-0893 at randomization, followed by MK-0893 orally (40 mg tablets) administered daily throughout the double-blind treatment period. Participants received Metformin orally (500 mg tablets) over an initial 2-week titration period starting at 500 mg administered twice daily before the morning and evening meals, increasing to 1500 mg daily, and ending with 1000 mg twice daily. Metformin was then administered throughout the double-blind treatment period. | 49 |
| Sitagliptin + Metformin Sitagliptin was administered orally as 100 mg tablets daily before the morning meal throughout the double-blind treatment period. Participants received Metformin orally (500 mg tablets) over an initial 2-week titration period starting at 500 mg administered twice daily before the morning and evening meals, increasing to 1500 mg daily, and ending with 1000 mg twice daily. Metformin was then administered throughout the double-blind treatment period. | 49 |
| Total | 146 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 2 | 2 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | MK-0893 + Sitagliptin | MK-0893 + Metformin | Sitagliptin + Metformin | Total |
|---|---|---|---|---|
| Age, Continuous | 53.6 years STANDARD_DEVIATION 8 | 52.0 years STANDARD_DEVIATION 9.7 | 53.8 years STANDARD_DEVIATION 8.7 | 53.2 years STANDARD_DEVIATION 8.8 |
| Gender Female | 16 Participants | 26 Participants | 15 Participants | 57 Participants |
| Gender Male | 32 Participants | 23 Participants | 34 Participants | 89 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 48 | 10 / 49 | 8 / 49 |
| serious Total, serious adverse events | 0 / 48 | 0 / 49 | 0 / 49 |
Outcome results
Primary
Change From Baseline (BL) to Week 4 in 24-hour Weighted Mean Glucose (WMG) Levels
Time frame: BL, 4 weeks (end of double-blind treatment period)
Population: Full Analysis Set Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MK-0893 + Sitagliptin | Change From Baseline (BL) to Week 4 in 24-hour Weighted Mean Glucose (WMG) Levels | -85.7 mg/dL | Standard Error 4.6 |
| MK-0893 + Metformin | Change From Baseline (BL) to Week 4 in 24-hour Weighted Mean Glucose (WMG) Levels | -117.4 mg/dL | Standard Error 4.6 |
| Sitagliptin + Metformin | Change From Baseline (BL) to Week 4 in 24-hour Weighted Mean Glucose (WMG) Levels | -99.6 mg/dL | Standard Error 4.6 |
Comparison: Hypothesis: After 4 weeks of treatment, MK-0893+sitagliptin provide greater reduction in 24-hour WMG than sitagliptin+metformin. Using a standard deviation (SD) of 23.5 mg/dL, a sample size of 40 participants per group had 80% power to detect a true difference of 15 mg/dL in the mean change from BL in 24-hour WMG between any 2 treatment groups for a two-sided test at alpha=0.05, with a half-width of 10.3 mg/dL around the 95% confidence interval (CI) for the between group difference.p-value: 0.00295% CI: [5.2, 22.7]Longitudinal Data Analysis
Comparison: Hypothesis: After 4 weeks of treatment, MK-0893+metformin provide greater reduction in 24-hour WMG than sitagliptin+metformin. Using a standard deviation (SD) of 23.5 mg/dL, a sample size of 40 participants per group had 80% power to detect a true difference of 15 mg/dL in the mean change from BL in 24-hour WMG between any 2 treatment groups for a two-sided test at alpha=0.05, with a half-width of 10.3 mg/dL around the 95% confidence interval for the between group difference.p-value: <0.00195% CI: [-26.5, -9.2]Longitudinal Data Analysis
Secondary
Change From BL to Week 4 in 2-hr Glucose Area Under The Curve (AUC)
Time frame: BL, 4 weeks (end of double-blind treatment period)
Population: Full Analysis Set Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MK-0893 + Sitagliptin | Change From BL to Week 4 in 2-hr Glucose Area Under The Curve (AUC) | -187.7 mg.h/dL | Standard Error 11.4 |
| MK-0893 + Metformin | Change From BL to Week 4 in 2-hr Glucose Area Under The Curve (AUC) | -254.9 mg.h/dL | Standard Error 11.1 |
| Sitagliptin + Metformin | Change From BL to Week 4 in 2-hr Glucose Area Under The Curve (AUC) | -210.3 mg.h/dL | Standard Error 11.4 |
Comparison: Hypothesis: After 4 weeks of treatment, MK-0893+sitagliptin provide greater reduction in 2-hr Glucose AUC than sitagliptin+metformin. Using a SD of 23.5 mg/dL, a sample size of 40 participants per group had 80% power to detect a true difference of 15 mg/dL in the mean change from BL in 2-Hour Glucose Total AUC between any 2 treatment groups for a two-sided test at alpha=0.05, with a half-width of 10.3 mg/dL around the 95% confidence interval for the between group difference.p-value: 0.05695% CI: [-0.6, 45.8]Longitudinal Data Analysis
Comparison: Hypothesis: After 4 weeks of treatment, MK-0893+metformin provide greater reduction in 2-hr Glucose AUC than sitagliptin+metformin. Using a SD of 23.5 mg/dL, a sample size of 40 participants per group had 80% power to detect a true difference of 15 mg/dL in the mean change from BL in 2-Hour Glucose Total AUC between any 2 treatment groups for a two-sided test at alpha=0.05, with a half-width of 10.3 mg/dL around the 95% confidence interval for the between group difference.p-value: <0.00195% CI: [-67.3, -21.8]Longitudinal Data Analysis
Secondary
Change From BL to Week 4 in Fasting Plasma Glucose (FPG)
Time frame: BL, 4 weeks (end of double-blind treatment period)
Population: Full Analysis Set Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MK-0893 + Sitagliptin | Change From BL to Week 4 in Fasting Plasma Glucose (FPG) | -73.7 mg/dL | Standard Error 4.4 |
| MK-0893 + Metformin | Change From BL to Week 4 in Fasting Plasma Glucose (FPG) | -101.9 mg/dL | Standard Error 4.3 |
| Sitagliptin + Metformin | Change From BL to Week 4 in Fasting Plasma Glucose (FPG) | -82.8 mg/dL | Standard Error 4.3 |
Comparison: Hypothesis: After 4 weeks of treatment, MK-0893+sitagliptin provide greater reduction in 24-hour FPG than sitagliptin+metformin. Using a standard deviation (SD) of 23.5 mg/dL, a sample size of 40 participants per group had 80% power to detect a true difference of 15 mg/dL in the mean change from BL in 24-hour FPG between any 2 treatment groups for a two-sided test at alpha=0.05, with a half-width of 10.3 mg/dL around the 95% confidence interval for the between group difference.p-value: 0.0595% CI: [0, 18.2]Longitudinal Data Analysis
Comparison: Hypothesis: After 4 weeks of treatment, MK-0893+metformin provide greater reduction in 24-hour FPG than sitagliptin+metformin. Using a standard deviation (SD) of 23.5 mg/dL, a sample size of 40 participants per group had 80% power to detect a true difference of 15 mg/dL in the mean change from BL in 24-hour FPG between any 2 treatment groups for a two-sided test at alpha=0.05, with a half-width of 10.3 mg/dL around the 95% confidence interval for the between group difference.p-value: <0.00195% CI: [-28, -10.1]Longitudinal Data Analysis
Secondary
Change From BL to Week 4 in the 2-Hour Active GLP-1 Total AUC
GLP-1 is cleaved from proglucagon to form the active peptide GLP-1. The active form promotes suppression of glucagon secretion. The total AUC of Active GLP-1 levels was calculated from blood sample data measured after the morning meal.
Time frame: BL, 4 weeks (end of double-blind treatment period)
Population: Full Analysis Set Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MK-0893 + Sitagliptin | Change From BL to Week 4 in the 2-Hour Active GLP-1 Total AUC | 11.0 pmole*h/L | Standard Error 1.1 |
| MK-0893 + Metformin | Change From BL to Week 4 in the 2-Hour Active GLP-1 Total AUC | 6.3 pmole*h/L | Standard Error 1.1 |
| Sitagliptin + Metformin | Change From BL to Week 4 in the 2-Hour Active GLP-1 Total AUC | 17.6 pmole*h/L | Standard Error 1.1 |
Comparison: Hypothesis: After 4 weeks of treatment, MK-0893+sitagliptin provide greater reduction in 2-Hour Active GLP-1 Total AUC than sitagliptin+metformin. Using a SD of 23.5 mg/dL, a sample size of 40 participants/group had 80% power to detect a true difference of 15 mg/dL in the mean change from BL in 2-Hour Active GLP-1 Total AUC between any 2 treatment groups for a 2-sided test at alpha=0.05, with a half-width of 10.3 mg/dL around the 95% CI for the between group differencep-value: <0.00195% CI: [-9.5, -3.8]Longitudinal Data Analysis
Comparison: Hypothesis: After 4 weeks of treatment, MK-0893+metformin provide greater reduction in 2-Hour Active GLP-1 Total AUC than sitagliptin+metformin. Using a SD of 23.5 mg/dL, a sample size of 40 participants/group had 80% power to detect a true difference of 15 mg/dL in the mean change from BL in 2-Hour Active GLP-1 Total AUC between any 2 treatment groups for a 2-sided test at alpha=0.05, with a half-width of 10.3 mg/dL around the 95% CI for the between group difference.p-value: <0.00195% CI: [-14.1, -8.5]Longitudinal Data Analysis
Secondary
Change From BL to Week 4 in the 2-Hour Total GLP-1 Total AUC
Glucagon-Like Peptide-1 (GLP-1) is an incretin hormone that acts as a potent insulin secretegogue in response to nutrient ingestion and stimulates glucose disposition. The total AUC of Total GLP-1 levels was calculated from blood sample data measured after the morning meal.
Time frame: BL, 4 weeks (end of double-blind treatment period)
Population: Full Analysis Set Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MK-0893 + Sitagliptin | Change From BL to Week 4 in the 2-Hour Total GLP-1 Total AUC | 7.4 pmol*h/L | Standard Error 1 |
| MK-0893 + Metformin | Change From BL to Week 4 in the 2-Hour Total GLP-1 Total AUC | 16.4 pmol*h/L | Standard Error 1 |
| Sitagliptin + Metformin | Change From BL to Week 4 in the 2-Hour Total GLP-1 Total AUC | 3.2 pmol*h/L | Standard Error 1 |
Comparison: Hypothesis: After 4 weeks of treatment, MK-0893+sitagliptin provide greater reduction in 2-Hour Total GLP-1 Total AUC than sitagliptin+metformin. Using a SD of 23.5 mg/dL, a sample size of 40 participants/group had 80% power to detect a true difference of 15 mg/dL in the mean change from BL in 2-Hour Total GLP-1 Total AUC between any 2 treatment groups for a 2-sided test at alpha=0.05, with a half-width of 10.3 mg/dL around the 95% CI for the between group difference.p-value: 0.00195% CI: [1.7, 6.7]Longitudinal Data Analysis
Comparison: Hypothesis: After 4 weeks of treatment, MK-0893+metformin provide greater reduction in 2-Hour Total GLP-1 Total AUC than sitagliptin+metformin. Using a SD of 23.5 mg/dL, a sample size of 40 participants/group had 80% power to detect a true difference of 15 mg/dL in the mean change from BL in 2-Hour Total GLP-1 Total AUC between any 2 treatment groups for a 2-sided test at alpha=0.05, with a half-width of 10.3 mg/dL around the 95% CI for the between group difference.p-value: <0.00195% CI: [10.7, 15.7]Longitudinal Data Analysis