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
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Merck Sharp & Dohme LLC
- Enrollment
- 64
- Primary Endpoint
- Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Fasting Glucose (IFG)
Study Overview
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).
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Investigator)
Eligibility Criteria
- Ages
- 35 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
Part I, Placebo-HCTZ
Placebo in Period 1 followed by HCTZ in Period 2
Intervention: Hydrochlorothiazide (HCTZ) (Drug)
Part I, HCTZ-Placebo
HCTZ in Period 1, followed by placebo in Period 2
Intervention: Hydrochlorothiazide (HCTZ) (Drug)
Part II, Placebo-ISMN
Placebo in Period 1, followed by ISMN in Period 2
Intervention: Isosorbide mononitrate (ISMN) (Drug)
Part II, ISMN-Placebo
ISMN in Period 1, followed by placebo in Period 2
Intervention: Isosorbide mononitrate (ISMN) (Drug)
Outcomes
Primary Outcomes
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
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
Time Frame: 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)
Time Frame: 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)
Time Frame: 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 Outcomes
- 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)
- 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)
- 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)