CardioVOLT: Cardiovascular Outcomes of Low Testosterone

Sponsor

University of Colorado, Denver (Other)

Overall Status

Recruiting

CT.gov ID

NCT02758431

Collaborator

(none)

379

Enrollment

Location

Arms

Duration (Months)

4.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study plans to learn more about heart and vascular aging in men. In some men as they get older, testosterone levels fall below the normal range for young men. Also, as men get older cardiovascular health worsens. This can lead to high blood pressure and heart disease. In this study we want to find out what causes cardiovascular health to worsen in older men. Also we want to find out what happens when testosterone levels are lowered for a short time. Specifically, we want to see if the reduction in cardiovascular health in older men with low testosterone levels is because of damage to mitochondria. Mitochondria are the main power supply of the cells in our body. The results from this study will help to understand why cardiovascular health declines in older men with low testosterone levels compared to younger men and older men who have higher testosterone levels. Knowing this information will help to develop therapies to prevent heart disease in men.

Condition or Disease	Intervention/Treatment	Phase
Hypogonadism	Drug: Acyline Drug: Placebo Gel Drug: Placebo Tablet Drug: Testosterone Gel Drug: Arimidex	N/A

Detailed Description

Cardiovascular (CV) aging, featuring large artery stiffening, endothelial dysfunction, and impaired left ventricular (LV) diastolic function, is a major risk factor for the development of cardiovascular diseases (CVD). Male aging is associated with a gradual and variable decline in serum testosterone (T) and low T is associated with accelerated CV aging. The purpose of this research is to determine the key functional mechanisms underlying accelerated CV aging in older men with low T. The overall hypothesis is that mitochondrial dysfunction and oxidative stress are mechanisms underlying the apparent accelerated CV aging in older men with low T. To test this hypothesis Aim 1 will use cross-sectional comparisons of young and older men with normal T (≥400 ng/dl), and older men with chronically low T (<300 ng/dl). To better isolate the effects of low T from factors that change with aging and chronic low T, Aim 2 will expand on the cross-sectional comparisons by assessing measures of CV function, oxidative stress burden and mitochondrial function in older men with normal T before and after randomization to short-term (28 d) gonadal suppression (gonadotropin releasing hormone antagonist, GnRHant) + placebo (PL), GnRHant+T alone, or GnRHant+T+aromatase inhibitor (AI). AI will control for the effects of aromatization of T to estradiol (E2), and thereby isolate T effects while suppressing E2, a potent modulator of CV function. The results from this research should provide new mechanistic insight into the processes that mediate the impairment in CV function at the cellular and systemic level in older men with low T. These studies will lead to a better understanding of the independent role of T in age-related changes in CV function and the mechanisms of action, which will help guide future sex-specific therapies for the prevention of CVD.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

379 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Primary Purpose:

Other

Official Title:

Cardiovascular Consequences of Hypogonadism in Men

Study Start Date :

Feb 1, 2016

Anticipated Primary Completion Date :

Sep 1, 2022

Anticipated Study Completion Date :

Nov 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Group 1: Acyline plus placebo (No Testosterone Add-Back) Acyline plus placebo gel and placebo tablet.	Drug: Acyline Acyline 300ug/kg injection will be administered on Day 0 and on day 14 Other Names: Gonadotropin releasing hormone antagonist Drug: Placebo Gel Placebo gel packet applied daily for 28 days. Other Names: Placebo Drug: Placebo Tablet Placebo oral tablet taken daily for 28 days. Other Names: Placebo
Active Comparator: Group 2: Acyline plusTestosterone Acyline plus transdermal testosterone gel plus placebo tablet.	Drug: Acyline Acyline 300ug/kg injection will be administered on Day 0 and on day 14 Other Names: Gonadotropin releasing hormone antagonist Drug: Placebo Tablet Placebo oral tablet taken daily for 28 days. Other Names: Placebo Drug: Testosterone Gel Testosterone Gel applied daily for 28 days Other Names: Transdermal Testosterone Gel
Active Comparator: Group 3: Acyline plus Testosterone plus Arimidex) Acyline plus transdermal testosterone gel plus Aromatase inhibitor (Arimidex) oral.	Drug: Acyline Acyline 300ug/kg injection will be administered on Day 0 and on day 14 Other Names: Gonadotropin releasing hormone antagonist Drug: Testosterone Gel Testosterone Gel applied daily for 28 days Other Names: Transdermal Testosterone Gel Drug: Arimidex Arimidex Oral Tablet 1mg taken orally daily for 28 days Other Names: Aromatase inhibitor

Arm

Intervention/Treatment

Placebo Comparator: Group 1: Acyline plus placebo (No Testosterone Add-Back)

Acyline plus placebo gel and placebo tablet.

Drug: Acyline

Acyline 300ug/kg injection will be administered on Day 0 and on day 14

Other Names:

Gonadotropin releasing hormone antagonist

Drug: Placebo Gel

Placebo gel packet applied daily for 28 days.

Other Names:

Placebo

Drug: Placebo Tablet

Placebo oral tablet taken daily for 28 days.

Other Names:

Placebo

Active Comparator: Group 2: Acyline plusTestosterone

Acyline plus transdermal testosterone gel plus placebo tablet.

Drug: Acyline

Acyline 300ug/kg injection will be administered on Day 0 and on day 14

Other Names:

Gonadotropin releasing hormone antagonist

Drug: Placebo Tablet

Placebo oral tablet taken daily for 28 days.

Other Names:

Placebo

Drug: Testosterone Gel

Testosterone Gel applied daily for 28 days

Other Names:

Transdermal Testosterone Gel

Active Comparator: Group 3: Acyline plus Testosterone plus Arimidex)

Acyline plus transdermal testosterone gel plus Aromatase inhibitor (Arimidex) oral.

Drug: Acyline

Acyline 300ug/kg injection will be administered on Day 0 and on day 14

Other Names:

Gonadotropin releasing hormone antagonist

Drug: Testosterone Gel

Testosterone Gel applied daily for 28 days

Other Names:

Transdermal Testosterone Gel

Drug: Arimidex

Arimidex Oral Tablet 1mg taken orally daily for 28 days

Other Names:

Aromatase inhibitor

Outcome Measures

Primary Outcome Measures

Endothelial function [Change from baseline at 28 days]
Brachial artery flow-mediated dilation, and EndoPAT™
Carotid artery compliance [Change from baseline at 28 days]
Carotid artery compliance and beta stiffness index
Arterial stiffness [Change from baseline at 28 days]
Pulse-wave velocity
Left ventricular diastolic function [Change from baseline at 28 days]
Measured via Cardiac Echo

Secondary Outcome Measures

NADPH oxidase [Change from baseline at 28 days]
Oxidative stress marker measured in endothelial cells
Nitrotyrosine [Change from baseline at 28 days]
Measured in endothelial cells
MnSOD [Change from baseline at 28 days]
Mitochondrial superoxide dismutase measured in endothelial cells
eNOS [Change from baseline at 28 days]
Endothelial nitric oxide synthase (eNOS) measured in endothelial cell
COX IV [Change from baseline at 28 days]
Marker of mitochondrial function measured in PBMCs
Mitochondrial RCR [Change from baseline at 28 days]
Mitochondrial respiration measured via Oroboros O2K

Other Outcome Measures

Supine blood pressure [Change from baseline at 28 days]
On the cardiovascular testing days, supine blood pressure will be measured in triplicate.
Body Composition [Baseline]
Whole body and regional body composition will be determined using dual energy x-ray absorptiometry for subject characteristics and for the determination of fat-free mass for the AA dose preparation.
Plasma Lipid Concentrations [Baseline]
Plasma lipid concentrations, including total-cholesterol (C) and triglycerides (TG) will be determined at baseline. The rationale for making these measurements is for screening criteria, subject characteristics, and because they may correlate with CV function.
Glucose Concentrations [Change from baseline at 28 days]
Fasted glucose concentrations will be measured at screening and at each vascular test.
Sex Hormones [Change from baseline at 28 days]
Serum concentrations of total testosterone (T), estradiol, albumin, sex hormone binding globulin (SHBG), luteinizing hormone and follicle stimulating hormone will be measured to document changes in hormone concentrations and free T will be calculated using the known affinity constants of T for SHBG and for albumin. Additional measures of T will be measured after 60 days if testosterone has not returned to baseline. The 60 day plus measures are for safety.
Endothelin-1 (ET-1) [Change from baseline at 28 days]
Plasma ET-1 will be measured because it is a potent vasoconstrictor and has complex interactions with NO. Specifically, ET-1 synthesis is under tonic inhibition by NO.
Physical Activity Levels [Change from baseline at 28 days]
To document the habitual physical activity status at baseline and the last week of respective interventions, daily energy expenditure will be estimated using ActivPal monitors.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Men aged 18-40 years and 50-75 years
Chronically low testosterone group will have testosterone concentrations <300 ng/dl, and young and older normal testosterone groups will have testosterone levels 400-1000 ng/dl
No use of sex hormones for at least 1 year
Body mass index <40 kg/m2
Nonsmokers
Resting blood pressure <160/90 mmHg
Fasting plasma glucose <126 mg/dL
Healthy, as determined by medical history, physical examination, standard blood chemistries (chemistry panel, complete blood clot and circulating thyroid levels) and a graded exercise stress test with monitoring of blood pressure and electrocardiogram (ECG)
Sedentary or recreationally active (< 3 days/wk of vigorous aerobic exercise)
No use of medications that might influence cardiovascular function including anti-hypertensive, lipid lowering medications, and corticosteroids
No use of vitamin supplements or anti-inflammatory medications, or willing to stop 1 month prior and throughout the study.

Exclusion Criteria:

Contraindications to:
Gonadotropin releasing hormone (GnRH) antagonist
Testosterone gel and aromatase inhibitor including hypersensitivity to Acyline, Androgel®, Arimidex®
Extrinsic peptide hormones, mannitol, GnRH or any other GnRH analogs
History of or active prostate or breast cancer or other sex hormone-dependent neoplasms
Pre-existing or active cardiac, renal or hepatic disease
History of stomach ulcer or bleeding
History of epilepsy or other seizure disorder
Diabetes
Active infection
Disease that affects the nervous system
Abnormal resting ECG

Additionally, men participating in the gonadal suppression intervention study will do so with the understanding that they will be randomly assigned to study groups that involve either GnRH antagonist plus testosterone gel plus placebo tablet (33% chance), GnRH antagonist plus testosterone gel plus aromatase inhibitor tablet (33% chance) or GnRH antagonist plus placebo gel plus placebo tablet (33% chance).