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

Phase 1

Completed

• Conditions: Hypertension
• Interventions: Drug: Isosorbide mononitrate (ISMN); Drug: Hydrochlorothiazide (HCTZ)

• Registration Number: NCT00871871
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

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).

Detailed Description

Not available

Study Timeline

• Study Start: 2009-03
• Study First Submitted: 2009-03-27
• Study First Submitted QC: 2009-03-27
• Study First Posted: 2009-03-30
• Primary Completion: 2010-02
• Study Completion: 2010-03
• Results First Submitted: 2011-02-22
• Results First Submitted QC: 2011-08-17
• Results First Posted: 2011-09-22
• Status Verified: 2015-07
• Last Update Submitted: 2015-07-22
• Last Update Posted: 2015-07-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 64

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Part II, ISMN-Placebo	Isosorbide mononitrate (ISMN)	ISMN in Period 1, followed by placebo in Period 2
Part II, Placebo-ISMN	Isosorbide mononitrate (ISMN)	Placebo in Period 1, followed by ISMN in Period 2
Part I, HCTZ-Placebo	Hydrochlorothiazide (HCTZ)	HCTZ in Period 1, followed by placebo in Period 2
Part I, Placebo-HCTZ	Hydrochlorothiazide (HCTZ)	Placebo in Period 1 followed by HCTZ in Period 2

Primary Outcome Measures

Name	Time	Method
Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Fasting Glucose (IFG)	90 -120 minutes post-dose	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 II: Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady-state	90 -120 minutes post-dose	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.
Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Glucose Tolerance (IGT)	90 -120 minutes post-dose	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 Who Had Normal Glucose Tolerance (NGT)	90 -120 minutes post-dose	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.

Secondary Outcome Measures

Name	Time	Method
Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Impaired Glucose Tolerant (IGT)	90 -120 minutes post-dose	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)	90 -120 minutes post-dose	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)	90 -120 minutes post-dose	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.