Effects of Sitagliptin on Endothelial Function in Type 2 Diabetes on Background Metformin Therapy

Diabetes Clinical Trial

Official title:

A Randomized, Crossover Design Study of Acute and Chronic Effects of Sitagliptin on Endothelial Function in Humans With Type 2 Diabetes on Background Metformin

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01859793
• Other study ID #: Merck-50600
• Status: Active, not recruiting
• Phase: Phase 4
• First received: May 17, 2013
• Last updated: October 9, 2015
• Start date: June 2013
• Est. completion date: June 2016

Study information

• Verified date: October 2015
• Source: Medical College of Wisconsin
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The study is being performed to determine whether sitagliptin, a dipeptidyl peptidase-4 inhibitor, both acutely and chronically improves blood vessel function. Patients with type 2 diabetes who are on metformin will be enrolled in this study for up to 22 weeks in this double blinded cross over study where they will receive a sitagliptin pill once a day for 8 weeks and during a separate 8 weeks receive a matching placebo pill. The treatment periods are divided by a 4 week period. Blood vessel function will be measured by ultrasound before and after a single dose of sitagliptin and placebo, as well as after 8 weeks of treatment with each. Blood will also be taken to measure blood markers of inflammation at each time the ultrasounds are performed.

Description:

We plan to recruit 38 patients with T2DM for this single center, double blind randomized, interventional crossover trial comparing sitagliptin (100 mg/day) to matching placebo. We have chosen placebo over a comparator for this study as our goal is to determine whether sitagliptin both improves glycemic control and endothelial function, properties not shared by other popular classes of agents like sulfonylureas. Subjects will be randomized with a 1:1 allocation ratio to either sitagliptin 1st or placebo 1st.

The study have 5 total visits. Subjects who pass a phone screen will be invited to a screening visit for study eligibility (Visit 1) Informed consent will be reviewed; a unique study number will be assigned once written informed consent is obtained (no subject will be assigned more than 1 allocation number); relevant participant medical history will be recorded including currently prescribed medications; anthropometric measurements will be taken (height, weight, and waist circumference in metric units) and blood pressure will be recorded (measured in triplicate and averaged). Subjects will be allowed to take their blood pressure medication on the morning of their screening visit, but not the mornings of any of the other study visits to limit the acute influence of these medications on endothelial function. If the potential participant qualifies for the study, he/she will be randomized either to receive sitagliptin 1st (100 mg/day) or matching placebo. Prior to receiving either of set of pills, subjects will return to the study center within approximately 1-2 weeks of the screening visit to undergo initial tests of endothelial function and receive their pills. Prior to all study visits except screening, subjects will also be asked to refrain from any vigorous physical activity (no weight lifting, jogging or any activity vigorous than walking) 24 hours to reduce the risk of fasting hypoglycemia during the study visits. Subjects will also be asked to fast for 6-8 hours prior to the visit to limit the acute dietary influences on vascular endothelial function. At Visit 2, endothelial function will determined by brachial artery reactivity testing prior to and following a single dose of 100 mg of sitagliptin or matching placebo depending on the arm to which the subject was randomized. Blood samples will also be taken at this visit for systemic measurements of endothelial cell activation/inflammation (VCAM-1 and ICAM-1) prior to and 2 hours following acute drug administration. These will be measured at the indicated time points using commercially available kits.

Endothelial function, like the blood samples, will be measured just prior to medication administration and then 2 hours following medication administration by brachial artery reactivity testing as described in Section D.3. The 2 hour time from was chose in given the plasma levels of sitagliptin appear to peak 2 hours following dose administration.32 At the end of this visit, subjects will be given a 9 week supply of the study pills (sitagliptin or matching placebo) as dispensed by the Froedtert Hospital Investigational Pharmacy, and scheduled to return for Visit 3 approximately 8 weeks following Visit 2. Subjects will be asked to not take any study medication for the 24 hours prior to Visit 3. At Visit 3, subjects will undergo repeat testing of endothelial function. Following this study visit, subjects will remain off study pills until they return for Visit 4 approximately 4 weeks following Visit 3. Visit 4 repeats Visit 2 except subjects will receive the set of pills to which they had been randomized to receive second. Subjects will return to the study center for Visit 5 approximately 8 weeks after Visit 4. Visit 5 is identical to Visit 3. Subject adherence will be determined by pill counts performed by MCW Translational Research Unit nursing staff who will perform all pill accounting. All medication dispensation will be handled by the Froedtert Hospital Investigational Drug Pharmacy.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 38
• Est. completion date: June 2016
• Est. primary completion date: January 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 21 Years to 70 Years

Eligibility

Inclusion Criteria:

1. Adult age 21-70 years of age.

2. Diagnosis of type 2 diabetes by a physician as defined by the American Diabetes Association standard criteria: 1) Fasting Plasma glucose at or above 126 mg/dL 2) a two-hour value in an oral glucose tolerance test at or above 200 mg/dL, or 3) a random plasma glucose concentration 200 mg/dL in the presence of symptoms, or 4) glycosylated hemoglobin greater than or equal to 6.5%.

3. On stable metformin therapy for at least 6 weeks prior to enrollment.

4. Glycosylated Hemoglobin =6.2% and = 9.5%.

Exclusion Criteria:

1. History of stroke, peripheral arterial disease, or coronary artery disease (as defined by the presence of at least one coronary stenosis = 50% on angiography or by confirmed history of myocardial infarction by standard criteria.)

2. Evidence of other evident major illness including chronic renal insufficiency (creatinine clearance less than 60 mL/min),chronic liver disease (AST or ALT greater than 2.5 x normal), or cancer currently undergoing systemic therapy or had systemic therapy for cancer within 1 year of enrollment.

3. Pregnancy as determined by urinary beta-HCG test

4. Illicit drug use (heroin, cocaine etc) in the past 1 year.

5. Alcohol abuse, defined as the equivalent of 14 beers/week for a man or 7 beers/week for a woman

6. History of allergy to DPP-4 inhibitors at the time of screening/enrollment

7. Prior history of pancreatitis

8. Patients currently on insulin or sulfonylurea therapy.

9. Patients currently on digoxin.

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Atherosclerosis
• Diabetes

Intervention

Drug:
• sitagliptin
100 mg pill, administered once/day orally
• Placebo

Locations

Country	Name	City	State
United States	Medical College of Wisconsin	Milwaukee	Wisconsin

Sponsors (2)

Lead Sponsor	Collaborator
Medical College of Wisconsin	Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Brachial Artery Flow Mediated Dilation	A measurement of endothelial function in humans	Change before and after 8 weeks after daily dosing	No
Secondary	Circulating inflammatory markers ICAM-1 and VCAM-1		Change before and after 8 weeks after daily dosing of medication	No
Secondary	Circulating inflammatory markers ICAM-1 and VCAM-1		Change before and after 2 hours a single dose of medication	No