A Study Comparing the Pharmacokinetic and Pharmacodynamic Profiles for Sitagliptin, Saxagliptin and Vildagliptin in Participants With Type 2 Diabetes Mellitus (T2DM) (MK-0431-142)

NCT01582308 | Completed Phase 1 Results

• 2 other identifiers: 0431-1422011-005567-25
• Study Type: interventional
• Target: 22
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Type 2 Diabetes Mellitus

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (4)

• 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

• 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

• 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

• 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

Study Arms (10)

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

Drug: Sitagliptin 100 mg; Drug: Saxagliptin 5 mg; Drug: Vildagliptin 50 mg; Drug: Vildagliptin 50 mg BID; Drug: Placebo

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

Drug: Sitagliptin 100 mg; Drug: Saxagliptin 5 mg; Drug: Vildagliptin 50 mg; Drug: Vildagliptin 50 mg BID; Drug: Placebo

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

Drug: Sitagliptin 100 mg; Drug: Saxagliptin 5 mg; Drug: Vildagliptin 50 mg; Drug: Vildagliptin 50 mg BID; Drug: Placebo

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

Drug: Sitagliptin 100 mg; Drug: Saxagliptin 5 mg; Drug: Vildagliptin 50 mg; Drug: Vildagliptin 50 mg BID; Drug: Placebo

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

Drug: Sitagliptin 100 mg; Drug: Saxagliptin 5 mg; Drug: Vildagliptin 50 mg; Drug: Vildagliptin 50 mg BID; Drug: Placebo

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

Drug: Sitagliptin 100 mg; Drug: Saxagliptin 5 mg; Drug: Vildagliptin 50 mg; Drug: Vildagliptin 50 mg BID; Drug: Placebo

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

Drug: Sitagliptin 100 mg; Drug: Saxagliptin 5 mg; Drug: Vildagliptin 50 mg; Drug: Vildagliptin 50 mg BID; Drug: Placebo

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

Drug: Sitagliptin 100 mg; Drug: Saxagliptin 5 mg; Drug: Vildagliptin 50 mg; Drug: Vildagliptin 50 mg BID; Drug: Placebo

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

Drug: Sitagliptin 100 mg; Drug: Saxagliptin 5 mg; Drug: Vildagliptin 50 mg; Drug: Vildagliptin 50 mg BID; Drug: Placebo

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

Drug: Sitagliptin 100 mg; Drug: Saxagliptin 5 mg; Drug: Vildagliptin 50 mg; Drug: Vildagliptin 50 mg BID; Drug: Placebo

Interventions

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.

Also known as: Januvia™

Treatment Sequence 1; Treatment Sequence 10; Treatment Sequence 2; Treatment Sequence 3; Treatment Sequence 4; Treatment Sequence 5; Treatment Sequence 6; Treatment Sequence 7; Treatment Sequence 8; Treatment Sequence 9

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.

Also known as: Onglyza™

Treatment Sequence 1; Treatment Sequence 10; Treatment Sequence 2; Treatment Sequence 3; Treatment Sequence 4; Treatment Sequence 5; Treatment Sequence 6; Treatment Sequence 7; Treatment Sequence 8; Treatment Sequence 9

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.

Also known as: Galvus™

Treatment Sequence 1; Treatment Sequence 10; Treatment Sequence 2; Treatment Sequence 3; Treatment Sequence 4; Treatment Sequence 5; Treatment Sequence 6; Treatment Sequence 7; Treatment Sequence 8; Treatment Sequence 9

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.

Also known as: Galvus™

Treatment Sequence 1; Treatment Sequence 10; Treatment Sequence 2; Treatment Sequence 3; Treatment Sequence 4; Treatment Sequence 5; Treatment Sequence 6; Treatment Sequence 7; Treatment Sequence 8; Treatment Sequence 9

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.

Treatment Sequence 1; Treatment Sequence 10; Treatment Sequence 2; Treatment Sequence 3; Treatment Sequence 4; Treatment Sequence 5; Treatment Sequence 6; Treatment Sequence 7; Treatment Sequence 8; Treatment Sequence 9

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (1)

• 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.

  PMID: 24163113 RESULT

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Sitagliptin Phosphate; saxagliptin; Vildagliptin; BID protein, human

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrazines; Nitriles; Organic Chemicals; Pyrrolidines

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 19, 2012
• First Posted: April 20, 2012
• Study Start: June 21, 2012
• Primary Completion: December 4, 2012
• Study Completion: December 14, 2012
• Last Updated: May 30, 2017
• Results First Posted: January 22, 2014

Record last verified: 2017-04

Data Sharing

• IPD Sharing: Will share