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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Hypertension

Intervention / Treatment
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* Drug: Hydrochlorothiazide (HCTZ)
* Drug: Comparator: Placebo to HCTZ
* Drug: Isosorbide mononitrate (ISMN)
* Drug: Comparator: Placebo to ISMN


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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 |