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

Type 2 Diabetes Mellitus Clinical Trial

Official title:

A Study to Assess and Compare the Pharmacokinetic and Pharmacodynamic Profiles for Sitagliptin, Saxagliptin and Vildagliptin in Patients With Type 2 Diabetes Mellitus

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01582308
• Other study ID #: 0431-142
• Secondary ID: 2011-005567-25
• Status: Completed
• Phase: Phase 1
• First received: April 19, 2012
• Last updated: April 1, 2015
• Start date: June 2012
• Est. completion date: December 2012

Study information

• Verified date: April 2015
• Source: Merck Sharp & Dohme Corp.
• Contact: n/a
• Is FDA regulated: No
• Health authority: Moldova: Medicines Agency
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 22
• Est. completion date: December 2012
• Est. primary completion date: December 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Type 2 Diabetes Mellitus

Intervention

Drug:
• Sitagliptin 100 mg
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.
• Saxagliptin 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
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
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.
• Placebo
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.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme Corp.

References & 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/s — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	24 hours following the final morning dose on Day 5	No
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.	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	No
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.	Predose (0 hours) and 0.5, 1, 2, 4, 8 and 12 hours after the morning dose on Day 5	No
Secondary	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	No
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.	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	No