Multiple Dose Effects of Hydrochlorothiazide and Isosorbide Mononitrate on Glucose Homeostasis (MK-0000-117)(Completed)

A Randomized, Double-Blind, Placebo-Controlled, 2-Part Study to Evaluate the Multiple Dose Effects of Hydrochlorothiazide and Isosorbide Mononitrate on Glucose Homeostasis in Obese Patients With Hypertension

This study will measure and compare changes in insulin production and sensitivity using the hyperglycemic clamp technique in obese patients with impaired glucose tolerance and hypertension treated with placebo, isosorbide mononitrate (ISMN) or hydrochlorothiazide (HCTZ).

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: Hydrochlorothiazide (HCTZ); Drug: Comparator: Placebo to HCTZ; Drug: Isosorbide mononitrate (ISMN); Drug: Comparator: Placebo to ISMN

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Female participants must be post-menopausal
• Body Mass Index (BMI) of at least 29 kg/m^2
• Weight has been stable over the past 3 months
• Has never been treated for hypertension or is diagnosed with hypertension taking up to 2 anti-hypertensive medications
• Willing to stop hypertension treatment for 14 days prior to randomization and throughout the study
• Does not have a history of diabetes
• In good health with the exception of hypertension
• No history of abnormal heart rhythms
• Part I only: willing to comply with high potassium/low sodium diet for the duration of the study
• Willing to avoid strenuous physical activity during the study
• Nonsmoker and/or has not used nicotine for at least 3 months and agrees to refrain from use of tobacco-containing products throughout the study
• Agrees to refrain from consuming alcohol and caffeine during in-patient periods and to limit consumption at all other times during the study
• Agrees not to consume grapefruit, grapefruit products, and citrus, apple, and pineapple juices 2 weeks prior to administration of the first dose of study drug

Exclusion Criteria:

• History of any illness that may make their participation in the study unsafe or confuse the study results
• Taking spironolactone or eplerenone
• Cannot refrain from using any prescription or non-prescription drugs during the study
• On a weight loss program and is not in the maintenance phase
• Started a weight loss drug within 8 weeks of the first study visit
• Consumes excessive amounts of alcohol or caffeine
• Has had major surgery, donated or lost 1 unit of blood within 4 weeks of the first study visit
• History of multiple and/or severe allergies to drugs or food
• Is dehydrated

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part I, Placebo-HCTZ; Placebo in Period 1 followed by HCTZ in Period 2	Drug: Hydrochlorothiazide (HCTZ); HCTZ 50 mg (two 25 mg capsules) once daily for 4 weeks per treatment period.; Other Names: HCTZ; Drug: Comparator: Placebo to HCTZ; Placebo to HCTZ two 0 mg capsules once daily for 4 weeks per treatment period
Experimental: Part I, HCTZ-Placebo; HCTZ in Period 1, followed by placebo in Period 2	Drug: Hydrochlorothiazide (HCTZ); HCTZ 50 mg (two 25 mg capsules) once daily for 4 weeks per treatment period.; Other Names: HCTZ; Drug: Comparator: Placebo to HCTZ; Placebo to HCTZ two 0 mg capsules once daily for 4 weeks per treatment period
Experimental: Part II, Placebo-ISMN; Placebo in Period 1, followed by ISMN in Period 2	Drug: Isosorbide mononitrate (ISMN); ISMN 60 mg extended release capsule once daily for 4 weeks per treatment period; Drug: Comparator: Placebo to ISMN; Placebo to ISMN 0 mg capsule once daily for 4 weeks per treatment period
Experimental: Part II, ISMN-Placebo; ISMN in Period 1, followed by placebo in Period 2	Drug: Isosorbide mononitrate (ISMN); ISMN 60 mg extended release capsule once daily for 4 weeks per treatment period; Drug: Comparator: Placebo to ISMN; Placebo to ISMN 0 mg capsule once daily for 4 weeks per treatment period

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Glucose Tolerance (IGT)	Steady state was defined as 90-120 minutes post-dose. IGT was defined as a 2 hour plasma glucose >= 140 and <= 199 mg/dL during a 75g oral glucose tolerance test at screening.	90 -120 minutes post-dose
Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Fasting Glucose (IFG)	Steady state was defined as 90-120 minutes post-dose. IFG was defined as fasting plasma glucose (FPG) between 100 and 125 mg/dL at screening.	90 -120 minutes post-dose
Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants Who Had Normal Glucose Tolerance (NGT)	Steady state was defined as 90-120 minutes post-dose. NGT participants (FPG <100 mg/dL & 2 hour plasma glucose (PG) <140 mg/dL during a 75g oral glucose tolerance test (OGTT) at screening) were neither Impaired Glucose Tolerant (IGT) nor Impaired Fasting Glucose (IFG). IGT was defined as a 2 hour plasma glucose >= 140 and <= 199 mg/dL during a 75g oral glucose tolerance test at screening. IFG was defined as FPG between 100 and 125 mg/dL at screening.	90 -120 minutes post-dose
Part II: Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady-state	Steady state was defined as 90-120 minutes post-dose. The ratio was the quantity of glucose disposed by the body per kg body weight per minute at steady state divided by the approximate steady state plasma insulin concentration. The approximate steady state plasma insulin concentration was estimated by the time-weighted average of the insulin concentration measured at 10 minute intervals in which time = 90, 100, 110, and 120 minutes.	90 -120 minutes post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Impaired Glucose Tolerant (IGT)	Steady state was defined as 90-120 minutes post-dose. The ratio was the quantity of glucose disposed by the body per kg body weight per minute at steady state divided by the approximate steady state plasma insulin concentration. The approximate steady state plasma insulin concentration was estimated by the time-weighted average of the insulin concentration measured at 10 minute intervals in which time = 90, 100, 110, and 120 minutes. IGT was defined as a 2 hour plasma glucose >= 140 and <= 199 mg/dL during a 75g oral glucose tolerance test at screening.	90 -120 minutes post-dose
Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Impaired Fasting Glucose (IFG)	Steady state was defined as 90-120 minutes post-dose. The ratio was the quantity of glucose disposed by the body per kg body weight per minute at steady state divided by the approximate steady state plasma insulin concentration. The approximate steady state plasma insulin concentration was estimated by the time-weighted average of the insulin concentration measured at 10 minute intervals in which time = 90, 100, 110, and 120 minutes. IFG was defined as fasting plasma glucose (FPG) between 100 and 125 mg/dL at screening.	90 -120 minutes post-dose
Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Normal Glucose Tolerant (NGT)	Steady state was defined as 90-120 minutes post-dose. The ratio was the measure of the quantity of glucose disposed per unit of plasma insulin concentration (PIC). Approximate PIC was estimated by the time-weighted average of the insulin concentration measured at 10 minute intervals, time = 90, 100, 110, and 120 minutes. NGT participants (FPG <100 mg/dL & 2 hour PG <140 mg/dL during a 75g OGTT at screening) were neither IGT nor IFG at screening. IGT - defined as a 2 hour PG >= 140 and <= 199 mg/dL during a 75g OGTT at screening. IFG - defined as FPG between 100 and 125 mg/dL at screening.	90 -120 minutes post-dose

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start: March 1, 2009
• Primary Completion (Actual): February 1, 2010
• Study Completion (Actual): March 1, 2010

Study Registration Dates

• First Submitted: March 27, 2009
• First Submitted That Met QC Criteria: March 27, 2009
• First Posted (Estimate): March 30, 2009

Study Record Updates

• Last Update Posted (Estimate): July 28, 2015
• Last Update Submitted That Met QC Criteria: July 22, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics, Osmotic; Diuretics; Sodium Chloride Symporter Inhibitors; Nitric Oxide Donors; Hydrochlorothiazide; Isosorbide; Isosorbide Dinitrate; Isosorbide-5-mononitrate
• Other Study ID Numbers: 0000-117; 2009_567

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No