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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT01582308
First received: April 19, 2012
Last updated: June 2, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Type 2 Diabetes Mellitus
Drug: Sitagliptin 100 mg
Drug: Saxagliptin 5 mg
Drug: Vildagliptin 50 mg
Drug: Vildagliptin 50 mg BID
Drug: Placebo
Phase 1

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

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • Percent Inhibition of Dipeptidyl Peptidase IV (DPP-4) Activity at Trough [ Time Frame: 24 hours following the final morning dose on Day 5 ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • Pharmacokinetic Analysis: Area Under the Curve 0-24 Hours (AUC 0-24hr) [ 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 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Predose (0 hours) and 0.5, 1, 2, 4, 8 and 12 hours after the morning dose on Day 5 ] [ Designated as safety issue: No ]
    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) [ 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 ] [ Designated as safety issue: No ]
    Measurement of the peak plasma drug concentration following the Day 5 morning dose.

  • Pharmacokinetic Analysis: Time to the Peak Plasma Drug Concentration (Tmax) [ 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 ] [ Designated as safety issue: No ]
    Measurement of the time to the peak plasma drug concentration following the Day 5 morning dose.


Enrollment: 22
Study Start Date: June 2012
Study Completion Date: December 2012
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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
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.
Other Name: Januvia™
Drug: 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.
Other Name: Onglyza™
Drug: 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.
Other Name: Galvus™
Drug: 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.
Other Name: Galvus™
Drug: 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.
Experimental: Treatment Sequence 2
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
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.
Other Name: Januvia™
Drug: 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.
Other Name: Onglyza™
Drug: 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.
Other Name: Galvus™
Drug: 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.
Other Name: Galvus™
Drug: 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.
Experimental: 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
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.
Other Name: Januvia™
Drug: 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.
Other Name: Onglyza™
Drug: 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.
Other Name: Galvus™
Drug: 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.
Other Name: Galvus™
Drug: 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.
Experimental: 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
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.
Other Name: Januvia™
Drug: 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.
Other Name: Onglyza™
Drug: 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.
Other Name: Galvus™
Drug: 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.
Other Name: Galvus™
Drug: 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.
Experimental: 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
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.
Other Name: Januvia™
Drug: 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.
Other Name: Onglyza™
Drug: 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.
Other Name: Galvus™
Drug: 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.
Other Name: Galvus™
Drug: 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.
Experimental: 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
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.
Other Name: Januvia™
Drug: 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.
Other Name: Onglyza™
Drug: 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.
Other Name: Galvus™
Drug: 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.
Other Name: Galvus™
Drug: 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.
Experimental: 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
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.
Other Name: Januvia™
Drug: 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.
Other Name: Onglyza™
Drug: 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.
Other Name: Galvus™
Drug: 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.
Other Name: Galvus™
Drug: 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.
Experimental: 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
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.
Other Name: Januvia™
Drug: 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.
Other Name: Onglyza™
Drug: 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.
Other Name: Galvus™
Drug: 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.
Other Name: Galvus™
Drug: 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.
Experimental: 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
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.
Other Name: Januvia™
Drug: 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.
Other Name: Onglyza™
Drug: 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.
Other Name: Galvus™
Drug: 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.
Other Name: Galvus™
Drug: 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.
Experimental: 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
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.
Other Name: Januvia™
Drug: 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.
Other Name: Onglyza™
Drug: 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.
Other Name: Galvus™
Drug: 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.
Other Name: Galvus™
Drug: 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.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

No Contacts or Locations Provided
  More Information

Publications:
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01582308     History of Changes
Other Study ID Numbers: 0431-142, 2011-005567-25
Study First Received: April 19, 2012
Results First Received: December 4, 2013
Last Updated: June 2, 2014
Health Authority: Moldova: Medicines Agency

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Endocrine System Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Saxagliptin
Sitagliptin
Vildagliptin
Dipeptidyl-Peptidase IV Inhibitors
Enzyme Inhibitors
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Hypoglycemic Agents
Incretins
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protease Inhibitors

ClinicalTrials.gov processed this record on November 27, 2014