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

Sponsor:	Merck
Information provided by:	Merck
ClinicalTrials.gov Identifier:	NCT00871871

Purpose

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).

Condition	Intervention	Phase
Hypertension	Drug: Hydrochlorothiazide (HCTZ) Drug: Comparator: Placebo to HCTZ Drug: Isosorbide mononitrate (ISMN) Drug: Comparator: Placebo to ISMN	Phase I

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Pharmacodynamics Study Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment
Official Title:	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

Resource links provided by NLM:

MedlinePlus related topics: Diabetes Medicines High Blood Pressure Obesity

Drug Information available for: Hydrochlorothiazide Isosorbide-5-mononitrate Isosorbide dinitrate Isosorbide

U.S. FDA Resources

Further study details as provided by Merck:

Primary Outcome Measures:

Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Glucose Tolerance (IGT) [ Time Frame: 90 -120 minutes post-dose ] [ Designated as safety issue: No ]
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.
Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Fasting Glucose (IFG) [ Time Frame: 90 -120 minutes post-dose ] [ Designated as safety issue: No ]
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.
Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants Who Had Normal Glucose Tolerance (NGT) [ Time Frame: 90 -120 minutes post-dose ] [ Designated as safety issue: No ]
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.
Part II: Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady-state [ Time Frame: 90 -120 minutes post-dose ] [ Designated as safety issue: No ]
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.

Secondary Outcome Measures:

Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Impaired Glucose Tolerant (IGT) [ Time Frame: 90 -120 minutes post-dose ] [ Designated as safety issue: No ]
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.
Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Impaired Fasting Glucose (IFG) [ Time Frame: 90 -120 minutes post-dose ] [ Designated as safety issue: No ]
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.
Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Normal Glucose Tolerant (NGT) [ Time Frame: 90 -120 minutes post-dose ] [ Designated as safety issue: No ]
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.

Enrollment:	64
Study Start Date:	March 2009
Study Completion Date:	March 2010
Primary Completion Date:	February 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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 Name: 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 Name: 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

Eligibility

Ages Eligible for Study:	35 Years to 75 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00871871

Sponsors and Collaborators

Merck

Investigators

Study Director:

Medical Monitor

Merck

More Information

No publications provided

Responsible Party:	Vice President, Late Stage Development Group Leader, Merck Sharp & Dohme Corp
ClinicalTrials.gov Identifier:	NCT00871871 History of Changes
Other Study ID Numbers:	MK-0000-117, 2009_567
Study First Received:	March 27, 2009
Results First Received:	February 22, 2011
Last Updated:	August 17, 2011
Health Authority:	South Africa: Medicines Control Council

Additional relevant MeSH terms:

Hypertension
Vascular Diseases
Cardiovascular Diseases
Hydrochlorothiazide
Isosorbide
Isosorbide Dinitrate
Isosorbide-5-mononitrate
Diuretics
Natriuretic Agents
Physiological Effects of Drugs

Pharmacologic Actions
Sodium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Diuretics, Osmotic
Vasodilator Agents
Nitric Oxide Donors

ClinicalTrials.gov processed this record on February 09, 2012