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

Merck Sharp & Dohme (MSD)

Status and phase: Completed; Phase 1

Conditions: Type 2 Diabetes Mellitus

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

Study type: Interventional

Funder types: Industry

Identifiers

NCT01582308

2011-005567-25 (EudraCT Number)

0431-142

Details and patient eligibility

About

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.

Enrollment: 22 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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22 participants in 10 patient groups

Treatment Sequence 1

Experimental group

Description:

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

Treatment:

Drug: Placebo

Drug: Vildagliptin 50 mg BID

Drug: Vildagliptin 50 mg

Drug: Sitagliptin 100 mg

Drug: Saxagliptin 5 mg

Treatment Sequence 2

Experimental group

Description:

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

Treatment:

Drug: Placebo

Drug: Vildagliptin 50 mg BID

Drug: Vildagliptin 50 mg

Drug: Sitagliptin 100 mg

Drug: Saxagliptin 5 mg

Treatment Sequence 3

Experimental group

Description:

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

Treatment:

Drug: Placebo

Drug: Vildagliptin 50 mg BID

Drug: Vildagliptin 50 mg

Drug: Sitagliptin 100 mg

Drug: Saxagliptin 5 mg

Treatment Sequence 4

Experimental group

Description:

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

Treatment:

Drug: Placebo

Drug: Vildagliptin 50 mg BID

Drug: Vildagliptin 50 mg

Drug: Sitagliptin 100 mg

Drug: Saxagliptin 5 mg

Treatment Sequence 5

Experimental group

Description:

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

Treatment:

Drug: Placebo

Drug: Vildagliptin 50 mg BID

Drug: Vildagliptin 50 mg

Drug: Sitagliptin 100 mg

Drug: Saxagliptin 5 mg

Treatment Sequence 6

Experimental group

Description:

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

Treatment:

Drug: Placebo

Drug: Vildagliptin 50 mg BID

Drug: Vildagliptin 50 mg

Drug: Sitagliptin 100 mg

Drug: Saxagliptin 5 mg

Treatment Sequence 7

Experimental group

Description:

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

Treatment:

Drug: Placebo

Drug: Vildagliptin 50 mg BID

Drug: Vildagliptin 50 mg

Drug: Sitagliptin 100 mg

Drug: Saxagliptin 5 mg

Treatment Sequence 8

Experimental group

Description:

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

Treatment:

Drug: Placebo

Drug: Vildagliptin 50 mg BID

Drug: Vildagliptin 50 mg

Drug: Sitagliptin 100 mg

Drug: Saxagliptin 5 mg

Treatment Sequence 9

Experimental group

Description:

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

Treatment:

Drug: Placebo

Drug: Vildagliptin 50 mg BID

Drug: Vildagliptin 50 mg

Drug: Sitagliptin 100 mg

Drug: Saxagliptin 5 mg

Treatment Sequence 10

Experimental group

Description:

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

Treatment:

Drug: Placebo

Drug: Vildagliptin 50 mg BID

Drug: Vildagliptin 50 mg

Drug: Sitagliptin 100 mg

Drug: Saxagliptin 5 mg