Back to resultsCardiovascular Outcomes of Low Testosterone (CardioVOLT)
Primary Purpose
Hypogonadism
Status
Active
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Acyline
Placebo Gel
Placebo Tablet
Testosterone Gel
Arimidex
Sponsored by
About this trial
This is an interventional other trial for Hypogonadism focused on measuring testosterone
Eligibility Criteria
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).
Sites / Locations
- University of Colorado CCTSI CTRC
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Placebo Comparator
Active Comparator
Active Comparator
Arm Label
Group 1: Acyline plus placebo (No Testosterone Add-Back)
Group 2: Acyline plusTestosterone
Group 3: Acyline plus Testosterone plus Arimidex)
Arm Description
Acyline plus placebo gel and placebo tablet.
Acyline plus transdermal testosterone gel plus placebo tablet.
Acyline plus transdermal testosterone gel plus Aromatase inhibitor (Arimidex) oral.
Outcomes
Primary Outcome Measures
Endothelial function
Brachial artery flow-mediated dilation, and EndoPAT™
Carotid artery compliance
Carotid artery compliance and beta stiffness index
Arterial stiffness
Pulse-wave velocity
Left ventricular diastolic function
Measured via Cardiac Echo
Secondary Outcome Measures
NADPH oxidase
Oxidative stress marker measured in endothelial cells
Nitrotyrosine
Measured in endothelial cells
MnSOD
Mitochondrial superoxide dismutase measured in endothelial cells
eNOS
Endothelial nitric oxide synthase (eNOS) measured in endothelial cell
COX IV
Marker of mitochondrial function measured in PBMCs
Mitochondrial RCR
Mitochondrial respiration measured via Oroboros O2K
Full Information
NCT ID
NCT02758431
First Posted
April 20, 2016
Last Updated
June 5, 2023
Sponsor
University of Colorado, Denver
Collaborators
National Institute on Aging (NIA)
1. Study Identification
Unique Protocol Identification Number
NCT02758431
Brief Title
Cardiovascular Outcomes of Low Testosterone
Acronym
CardioVOLT
Official Title
Cardiovascular Consequences of Hypogonadism in Men
Study Type
Interventional
2. Study Status
Record Verification Date
June 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
July 1, 2016 (Actual)
Primary Completion Date
January 31, 2024 (Anticipated)
Study Completion Date
January 31, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Colorado, Denver
Collaborators
National Institute on Aging (NIA)
4. Oversight
Data Monitoring Committee
No
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypogonadism
Keywords
testosterone
7. Study Design
Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
379 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Group 1: Acyline plus placebo (No Testosterone Add-Back)
Arm Type
Placebo Comparator
Arm Description
Acyline plus placebo gel and placebo tablet.
Arm Title
Group 2: Acyline plusTestosterone
Arm Type
Active Comparator
Arm Description
Acyline plus transdermal testosterone gel plus placebo tablet.
Arm Title
Group 3: Acyline plus Testosterone plus Arimidex)
Arm Type
Active Comparator
Arm Description
Acyline plus transdermal testosterone gel plus Aromatase inhibitor (Arimidex) oral.
Intervention Type
Drug
Intervention Name(s)
Acyline
Other Intervention Name(s)
Gonadotropin releasing hormone antagonist
Intervention Description
Acyline 300ug/kg injection will be administered on Day 0 and on day 14
Intervention Type
Drug
Intervention Name(s)
Placebo Gel
Other Intervention Name(s)
Placebo
Intervention Description
Placebo gel packet applied daily for 28 days.
Intervention Type
Drug
Intervention Name(s)
Placebo Tablet
Other Intervention Name(s)
Placebo
Intervention Description
Placebo oral tablet taken daily for 28 days.
Intervention Type
Drug
Intervention Name(s)
Testosterone Gel
Other Intervention Name(s)
Transdermal Testosterone Gel
Intervention Description
Testosterone Gel applied daily for 28 days
Intervention Type
Drug
Intervention Name(s)
Arimidex
Other Intervention Name(s)
Aromatase inhibitor
Intervention Description
Arimidex Oral Tablet 1mg taken orally daily for 28 days
Primary Outcome Measure Information:
Title
Endothelial function
Description
Brachial artery flow-mediated dilation, and EndoPAT™
Time Frame
Change from baseline at 28 days
Title
Carotid artery compliance
Description
Carotid artery compliance and beta stiffness index
Time Frame
Change from baseline at 28 days
Title
Arterial stiffness
Description
Pulse-wave velocity
Time Frame
Change from baseline at 28 days
Title
Left ventricular diastolic function
Description
Measured via Cardiac Echo
Time Frame
Change from baseline at 28 days
Secondary Outcome Measure Information:
Title
NADPH oxidase
Description
Oxidative stress marker measured in endothelial cells
Time Frame
Change from baseline at 28 days
Title
Nitrotyrosine
Description
Measured in endothelial cells
Time Frame
Change from baseline at 28 days
Title
MnSOD
Description
Mitochondrial superoxide dismutase measured in endothelial cells
Time Frame
Change from baseline at 28 days
Title
eNOS
Description
Endothelial nitric oxide synthase (eNOS) measured in endothelial cell
Time Frame
Change from baseline at 28 days
Title
COX IV
Description
Marker of mitochondrial function measured in PBMCs
Time Frame
Change from baseline at 28 days
Title
Mitochondrial RCR
Description
Mitochondrial respiration measured via Oroboros O2K
Time Frame
Change from baseline at 28 days
Other Pre-specified Outcome Measures:
Title
Supine blood pressure
Description
On the cardiovascular testing days, supine blood pressure will be measured in triplicate.
Time Frame
Change from baseline at 28 days
Title
Body Composition
Description
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.
Time Frame
Baseline
Title
Plasma Lipid Concentrations
Description
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.
Time Frame
Baseline
Title
Glucose Concentrations
Description
Fasted glucose concentrations will be measured at screening and at each vascular test.
Time Frame
Change from baseline at 28 days
Title
Sex Hormones
Description
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.
Time Frame
Change from baseline at 28 days
Title
Endothelin-1 (ET-1)
Description
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.
Time Frame
Change from baseline at 28 days
Title
Physical Activity Levels
Description
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.
Time Frame
Change from baseline at 28 days
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kerrie Moreau, PhD
Organizational Affiliation
University of Colorado, Denver
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Colorado CCTSI CTRC
City
Denver
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Cardiovascular Outcomes of Low Testosterone
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