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| ID | Type | Description | Link |
|---|---|---|---|
| 2011-005567-25 | EudraCT Number |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment Sequence 1 | Experimental | 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 |
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| Treatment Sequence 2 | Experimental | 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 |
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| Treatment Sequence 3 | Experimental | 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 |
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| Treatment Sequence 4 | Experimental | 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 |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sitagliptin 100 mg | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 24 hours following the final morning dose on Day 5 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24163113 | Result | Tatosian DA, Guo Y, Schaeffer AK, Gaibu N, Popa S, Stoch A, Langdon RB, Kauh EA. Dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes treated with saxagliptin, sitagliptin, or vildagliptin. Diabetes Ther. 2013 Dec;4(2):431-42. doi: 10.1007/s13300-013-0045-8. Epub 2013 Oct 26. |
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A washout period of at least 10 days occurred between each treatment period.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| FG001 | Treatment Sequence 2 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Period 1 |
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| Treatment Sequence 5 | Experimental | 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 |
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| Treatment Sequence 6 | Experimental | 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 |
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| Treatment Sequence 7 | Experimental | 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 |
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| Treatment Sequence 8 | Experimental | 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 |
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| Treatment Sequence 9 | Experimental | 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 |
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| Treatment Sequence 10 | Experimental | 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 |
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| Saxagliptin 5 mg | Drug | 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. |
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| Vildagliptin 50 mg | Drug | 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. |
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| Vildagliptin 50 mg BID | Drug | 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. |
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| Placebo | Drug | 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. |
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| 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. | Predose (0 hours) and 0.5, 1, 2, 4, 8 and 12 hours after the morning dose on Day 5 |
| Pharmacokinetic Analysis: Peak Plasma Drug Concentration (Cmax) | Measurement of the peak plasma drug concentration following the Day 5 morning dose. | 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 |
| 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. | 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 |
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 |
| FG002 | 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 |
| FG003 | 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 |
| FG004 | 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 |
| FG005 | 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 |
| FG006 | 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 |
| FG007 | 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 |
| FG008 | 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 |
| FG009 | 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 |
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| NOT COMPLETED |
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| 10-day Washout Following Period 1 |
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| Period 2 |
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| 10-day Washout Following Period 2 |
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| Period 3 |
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| 10-day Washout Following Period 3 |
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| Period 4 |
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| 10-day Washout Following Period 4 |
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| Period 5 |
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| ID | Title | Description |
|---|---|---|
| BG000 | All Enrolled Participants |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||||
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| Age, Categorical | Count of Participants | Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| 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. | All participants who had at least at least one measurement. | Posted | Least Squares Mean | 95% Confidence Interval | Percent inhibition | 24 hours following the final morning dose on Day 5 |
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| 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. | All participants who had at least at least one measurement. | Posted | Geometric Mean | Geometric Coefficient of Variation | nM*hr | 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 |
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| 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | nM*hr | Predose (0 hours) and 0.5, 1, 2, 4, 8 and 12 hours after the morning dose on Day 5 |
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| Secondary | Pharmacokinetic Analysis: Peak Plasma Drug Concentration (Cmax) | Measurement of the peak plasma drug concentration following the Day 5 morning dose. | All participants who had at least at least one measurement. | Posted | Geometric Mean | Geometric Coefficient of Variation | nM | 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 |
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| 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. | All participants who had at least at least one measurement. | Posted | Median | Full Range | hr | 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 |
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Through approximately 14 days following the last dose of study drug in Period 5
Of the 22 participants, 5 participants discontinued therapy and did not complete all 5 periods of the study.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Sitagliptin 100 mg | Sitagliptin 100 mg daily for 5 days | 0 | 20 | 1 | 20 | ||
| EG001 | Saxagliptin 5 mg | Saxagliptin 5 mg daily for 5 days | 0 | 21 | 4 | 21 | ||
| EG002 | Vildagliptin 50 mg | Vildagliptin 50 mg daily for 5 days | 0 | 18 | 1 | 18 | ||
| EG003 | Vildagliptin 50 mg BID | Vildagliptin 50 mg twice daily for 5 days | 0 | 19 | 1 | 19 | ||
| EG004 | Placebo | Placebo to sitagliptin daily for 5 days | 0 | 21 | 0 | 21 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Influenza | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 15.1 | Systematic Assessment |
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The Sponsor must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Senior Vice President, Global Clinical Development | Merck Sharp & Dohme Corp. | 1-800-672-6372 | ClinicalTrialsDisclosure@merck.com |
| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
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| ID | Term |
|---|---|
| D000068900 | Sitagliptin Phosphate |
| C502994 | saxagliptin |
| D000077597 | Vildagliptin |
| C494814 | BID protein, human |
| ID | Term |
|---|---|
| D014230 | Triazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011719 | Pyrazines |
| D009570 | Nitriles |
| D009930 | Organic Chemicals |
| D011759 | Pyrrolidines |
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Analysis model included fixed effects terms for treatment and period. |
| Linear mixed effects model |
| <.001 |
P-value of between-treatment comparison of percent inhibition of DPP-4 activity. |
| Least squares mean difference |
| 62.86 |
| 2-Sided |
| 90 |
| 58.21 |
| 67.74 |
| Superiority or Other |
| Analysis model included fixed effects terms for treatment and period. | Linear mixed effects model | 0.128 | P-value of between-treatment comparison of percent inhibition of DPP-4 activity. | Least squares mean difference | 1.11 | 2-Sided | 90 | -0.10 | 2.33 | Superiority or Other |
| Analysis model included fixed effects terms for treatment and period. | Linear mixed effects model | <.001 | P-value of between-treatment comparison of percent inhibition of DPP-4 activity. | Least squares mean difference | 88.24 | 2-Sided | 90 | 85.77 | 90.76 | Superiority or Other |
| Analysis model included fixed effects terms for treatment and period. | Linear mixed effects model | <.001 | P-value of between-treatment comparison of percent inhibition of DPP-4 activity. | Least squares mean difference | 44.62 | 2-Sided | 90 | 34.51 | 55.23 | Superiority or Other |
| Analysis model included fixed effects terms for treatment and period. | Linear mixed effects model | <.001 | P-value of between-treatment comparison of percent inhibition of DPP-4 activity. | Least squares mean difference | -17.13 | 2-Sided | 90 | -21.21 | -13.25 | Superiority or Other |
| Analysis model included fixed effects terms for treatment and period. | Linear mixed effects model | <.001 | P-value of between-treatment comparison of percent inhibition of DPP-4 activity. | Least squares mean difference | 70.00 | 2-Sided | 90 | 58.46 | 82.20 | Superiority or Other |
| Analysis model included fixed effects terms for treatment and period. | Linear mixed effects model | <.001 | P-value of between-treatment comparison of percent inhibition of DPP-4 activity. | Least squares mean difference | -61.75 | 2-Sided | 90 | -68.76 | -55.18 | Superiority or Other |
| Analysis model included fixed effects terms for treatment and period. | Linear mixed effects model | <.001 | P-value of between-treatment comparison of percent inhibition of DPP-4 activity. | Least squares mean difference | 25.38 | 2-Sided | 90 | 15.37 | 35.48 | Superiority or Other |
| Analysis model included fixed effects terms for treatment and period. | Linear mixed effects model | <.001 | P-value of between-treatment comparison of percent inhibition of DPP-4 activity. | Least squares mean difference | 87.13 | 2-Sided | 90 | 80.06 | 94.61 | Superiority or Other |
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