Type 2 Diabetes Mellitus
Conditions
Brief summary
A five-period crossover study to assess and compare the trough dipeptidyl peptidase IV (DPP-4) inhibition at 24-hours following the final morning dose for sitagliptin, saxagliptin and vildagliptin after 5 days of once daily dosing and vildagliptin after 5 days of twice daily dosing in participants with T2DM. The primary hypothesis is that following multiple daily dose administration to achieve steady-state drug concentrations, 100-mg sitagliptin will demonstrate greater DPP-4 inhibition at 24-hours after the final dose compared to 5-mg saxagliptin and 50-mg vildagliptin (once daily administration) in participants with T2DM. Each participant will receive all 5 treatments in randomized order. There will be a washout interval of at least 10 days between the last dose of study drug in one period and the first dose of study drug in the following period.
Interventions
Sitagliptin 100 mg: one sitagliptin 100 mg tablet once daily in the morning following a fast of at least approximately 8 hours on Days 1 through 5 in one out of five treatment periods.
DRUGSaxagliptin 5 mg
Saxagliptin 5 mg: one saxagliptin 5 mg tablet once daily in the morning following a fast of at least approximately 8 hours on Days 1 through 5 in one out of five treatment periods.
Vildagliptin 50 mg: one vildagliptin 50 mg tablet once daily in the morning following a fast of at least approximately 8 hours on Days 1 through 5 in one out of five treatment periods.
Vildagliptin 50 mg BID: one vildagliptin 50 mg tablet BID (twice daily), once in the morning following a fast of at least approximately 8 hours and once in the evening on Days 1 through 5 in one out of five treatment periods.
DRUGPlacebo
Placebo: one placebo for sitagliptin tablet once daily in the morning following a fast of at least approximately 8 hours on Days 1 through 5 in one out of five treatment periods.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* female participants of reproductive potential must not be pregnant and agree to use (and/or have their partner use) two acceptable methods of birth control beginning at least 2 weeks prior to administration of the first dose of study drug until at least 2 weeks after the last administration of study drug * has a body mass index between 18 and 43 kg/m\^2 inclusive * has a clinically confirmed diagnosis of T2DM * is not currently receiving any oral antihyperglycemic medications and has a screening visit hemoglobin A1c (HbA1c) between 6.5% and 10% inclusive * must not have been previously treated with a DPP-4 inhibitor or glucagon-like peptide-1 analogs within 12 weeks of prestudy visit * has fasting plasma or serum glucose (FPG) ≤200 mg/dL (11.1 mmol/L) at screening and randomization * is a non-smoker or has not used nicotine or nicotine-containing products for at least approximately the last 6 months * is willing to follow the American Heart Association weight maintaining diet and exercise program or equivalent beginning 2 weeks prior to administration of first dose of study drug and throughout the study until the poststudy visit * agrees to refrain from the consumption of grapefruit and grapefruit juice for at least 2 weeks prior to the start of the study and throughout the study * agrees to refrain from the consumption of all fruit juices periodically throughout the study
Exclusion criteria
* is mentally or legally incapacitated, has significant emotional problems at the time of prestudy visit or expected during the conduct of the study or has a history of a clinically significant psychiatric disorder over the last 5 years * has an estimated creatinine clearance of ≤60 mL/min * has a history of stroke, chronic seizures, or major neurological disorder * has a history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases (with the exception of stable thyroid disease, T2DM and typical associated diseases such as hypertension and hyperlipidemia) * must not have been previously treated with any regimen that includes insulin (injected or inhaled) for at least 3 months * has a history of type 1 diabetes mellitus and/or history of ketoacidosis, or C peptide ≤0.8 ng/mL (≤0.26 nmol/L); or secondary forms of diabetes, acute metabolic diabetic complications or evidence of significant diabetic complications (i.e. retinopathy, neuropathy, nephropathy) * has a history of neoplastic disease (including leukemia, lymphoma, malignant melanoma), or myeloproliferative disease * is on a weight loss program and is not in the maintenance phase, or participant has been treated with a weight loss medication within 8 weeks of screening * anticipates the use of any new medication(s), including prescription and non-prescription drugs or herbal remedies beginning approximately 2 weeks prior to administration of the initial dose of study drug and throughout the study until the poststudy visit * anticipates any change in dose of current stable medications * has donated or lost 1 unit of blood within 4 weeks of the prestudy visit * has had major surgery within 30 days prior to screening or has planned major surgery * has a history of uncontrolled hypertension * is taking a medication which is not permitted in the study to treat a co-morbid condition, including but not limited to cytochrome P450 3A4/5 inhibitors and inducers, P-glycoprotein 1 inhibitors, and human organic anion transporter 3 inhibitors * consumes excessive amounts of alcohol, coffee, tea, cola, or other caffeinated beverage daily * has a history of significant multiple and/or severe allergies, or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food * is currently a regular user (including recreational use) of any illicit drugs or has a history of drug (including alcohol) abuse within approximately the past 6 months * is a nursing mother
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Inhibition of Dipeptidyl Peptidase IV (DPP-4) Activity at Trough | 24 hours following the final morning dose on Day 5 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Analysis: Area Under the Curve 0-24 Hours (AUC 0-24hr) | 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 | AUC 0-24hr is the area under the plasma drug concentration-time curve calculated for the 24 hour interval after the Day 5 morning dose. |
| Pharmacokinetic Analysis: Area Under the Curve 0-12 Hours (AUC 0-12hr) for Vildagliptin 50 mg BID | Predose (0 hours) and 0.5, 1, 2, 4, 8 and 12 hours after the morning dose on Day 5 | AUC 0-12hr is the area under the plasma drug concentration-time curve calculated for the 12 hour interval after the Day 5 morning dose for the vildagliptin 50 mg BID dose only. |
| Pharmacokinetic Analysis: Peak Plasma Drug Concentration (Cmax) | 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 | Measurement of the peak plasma drug concentration following the Day 5 morning dose. |
| Pharmacokinetic Analysis: Time to the Peak Plasma Drug Concentration (Tmax) | 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 | Measurement of the time to the peak plasma drug concentration following the Day 5 morning dose. |
Participant flow
Recruitment details
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
A washout period of at least 10 days occurred between each treatment period.
Participants by arm
| Arm | Count |
|---|---|
| All Enrolled Participants | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 10-day Washout Following Period 1 | Physician Decision | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Period 1 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Period 4 | Physician Decision | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | All Enrolled Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 20 | 4 / 21 | 1 / 18 | 1 / 19 | 0 / 21 |
| serious Total, serious adverse events | 0 / 20 | 0 / 21 | 0 / 18 | 0 / 19 | 0 / 21 |
Outcome results
Primary
Percent Inhibition of Dipeptidyl Peptidase IV (DPP-4) Activity at Trough
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
Population: All participants who had at least at least one measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin 100 mg | Percent Inhibition of Dipeptidyl Peptidase IV (DPP-4) Activity at Trough | 91.73 Percent inhibition |
| Saxagliptin 5 mg | Percent Inhibition of Dipeptidyl Peptidase IV (DPP-4) Activity at Trough | 73.50 Percent inhibition |
| Vildagliptin 50 mg | Percent Inhibition of Dipeptidyl Peptidase IV (DPP-4) Activity at Trough | 28.88 Percent inhibition |
| Vildagliptin 50 mg BID | Percent Inhibition of Dipeptidyl Peptidase IV (DPP-4) Activity at Trough | 90.63 Percent inhibition |
| Placebo | Percent Inhibition of Dipeptidyl Peptidase IV (DPP-4) Activity at Trough | 3.49 Percent inhibition |
Comparison: Analysis model included fixed effects terms for treatment and period.p-value: <0.00190% CI: [14.97, 21.67]Linear mixed effects model
Comparison: Analysis model included fixed effects terms for treatment and period.p-value: <0.00190% CI: [58.21, 67.74]Linear mixed effects model
Comparison: Analysis model included fixed effects terms for treatment and period.p-value: 0.12890% CI: [-0.1, 2.33]Linear mixed effects model
Comparison: Analysis model included fixed effects terms for treatment and period.p-value: <0.00190% CI: [85.77, 90.76]Linear mixed effects model
Comparison: Analysis model included fixed effects terms for treatment and period.p-value: <0.00190% CI: [34.51, 55.23]Linear mixed effects model
Comparison: Analysis model included fixed effects terms for treatment and period.p-value: <0.00190% CI: [-21.21, -13.25]Linear mixed effects model
Comparison: Analysis model included fixed effects terms for treatment and period.p-value: <0.00190% CI: [58.46, 82.2]Linear mixed effects model
Comparison: Analysis model included fixed effects terms for treatment and period.p-value: <0.00190% CI: [-68.76, -55.18]Linear mixed effects model
Comparison: Analysis model included fixed effects terms for treatment and period.p-value: <0.00190% CI: [15.37, 35.48]Linear mixed effects model
Comparison: Analysis model included fixed effects terms for treatment and period.p-value: <0.00190% CI: [80.06, 94.61]Linear mixed effects model
Secondary
Pharmacokinetic Analysis: Area Under the Curve 0-12 Hours (AUC 0-12hr) for Vildagliptin 50 mg BID
AUC 0-12hr is the area under the plasma drug concentration-time curve calculated for the 12 hour interval after the Day 5 morning dose for the vildagliptin 50 mg BID dose only.
Time frame: Predose (0 hours) and 0.5, 1, 2, 4, 8 and 12 hours after the morning dose on Day 5
Population: All participants who had at least at least one measurement. This outcome measure is for the vildagliptin 50 mg BID dose only; therefore, results are only presented for vildagliptin 50 mg BID dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin 100 mg | Pharmacokinetic Analysis: Area Under the Curve 0-12 Hours (AUC 0-12hr) for Vildagliptin 50 mg BID | 3720 nM*hr | Geometric Coefficient of Variation 28.9 |
Secondary
Pharmacokinetic Analysis: Area Under the Curve 0-24 Hours (AUC 0-24hr)
AUC 0-24hr is the area under the plasma drug concentration-time curve calculated for the 24 hour interval after the Day 5 morning dose.
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
Population: All participants who had at least at least one measurement.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin 100 mg | Pharmacokinetic Analysis: Area Under the Curve 0-24 Hours (AUC 0-24hr) | 7070 nM*hr | Geometric Coefficient of Variation 25.1 |
| Saxagliptin 5 mg | Pharmacokinetic Analysis: Area Under the Curve 0-24 Hours (AUC 0-24hr) | 370 nM*hr | Geometric Coefficient of Variation 25 |
| Vildagliptin 50 mg | Pharmacokinetic Analysis: Area Under the Curve 0-24 Hours (AUC 0-24hr) | 3100 nM*hr | Geometric Coefficient of Variation 27 |
| Vildagliptin 50 mg BID | Pharmacokinetic Analysis: Area Under the Curve 0-24 Hours (AUC 0-24hr) | 6600 nM*hr | Geometric Coefficient of Variation 26.3 |
Secondary
Pharmacokinetic Analysis: Peak Plasma Drug Concentration (Cmax)
Measurement of the peak plasma drug concentration following the Day 5 morning dose.
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
Population: All participants who had at least at least one measurement.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin 100 mg | Pharmacokinetic Analysis: Peak Plasma Drug Concentration (Cmax) | 724 nM | Geometric Coefficient of Variation 31.3 |
| Saxagliptin 5 mg | Pharmacokinetic Analysis: Peak Plasma Drug Concentration (Cmax) | 88.8 nM | Geometric Coefficient of Variation 25.2 |
| Vildagliptin 50 mg | Pharmacokinetic Analysis: Peak Plasma Drug Concentration (Cmax) | 586 nM | Geometric Coefficient of Variation 37 |
| Vildagliptin 50 mg BID | Pharmacokinetic Analysis: Peak Plasma Drug Concentration (Cmax) | 759 nM | Geometric Coefficient of Variation 34.7 |
Secondary
Pharmacokinetic Analysis: Time to the Peak Plasma Drug Concentration (Tmax)
Measurement of the time to the peak plasma drug concentration following the Day 5 morning dose.
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
Population: All participants who had at least at least one measurement.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sitagliptin 100 mg | Pharmacokinetic Analysis: Time to the Peak Plasma Drug Concentration (Tmax) | 4 hr |
| Saxagliptin 5 mg | Pharmacokinetic Analysis: Time to the Peak Plasma Drug Concentration (Tmax) | 1 hr |
| Vildagliptin 50 mg | Pharmacokinetic Analysis: Time to the Peak Plasma Drug Concentration (Tmax) | 1 hr |
| Vildagliptin 50 mg BID | Pharmacokinetic Analysis: Time to the Peak Plasma Drug Concentration (Tmax) | 1 hr |