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Cardiovascular Outcomes of Low Testosterone (CardioVOLT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02758431
Recruitment Status : Recruiting
First Posted : May 2, 2016
Last Update Posted : September 27, 2019
Sponsor:
Information provided by (Responsible Party):
University of Colorado, Denver

Tracking Information
First Submitted Date  ICMJE April 20, 2016
First Posted Date  ICMJE May 2, 2016
Last Update Posted Date September 27, 2019
Study Start Date  ICMJE February 2016
Estimated Primary Completion Date January 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 29, 2016)
  • Endothelial function [ Time Frame: Change from baseline at 28 days ]
    Brachial artery flow-mediated dilation, and EndoPAT™
  • Carotid artery compliance [ Time Frame: Change from baseline at 28 days ]
    Carotid artery compliance and beta stiffness index
  • Carotid artery compliance [ Time Frame: Change from baseline at 28 days ]
    Pulse-wave velocity
  • Left ventricular diastolic function [ Time Frame: Change from baseline at 28 days ]
    Measured via Cardiac Echo
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 29, 2016)
  • Oxidant burden/defense [ Time Frame: Change from baseline at 28 days ]
    Measured in the blood, endothelial cell and peripheral blood mononuclear cells (PBMCs). Example - oxidized LDL, isoprostanes, nitrotyrosine, 5- (and 6-)-chloromethyl-2', 7'-dichlorodihydrofluorescein diacetate (DCF).
  • Quantification of dichlorodihydrofluorescein diacetate (DCF) [ Time Frame: Change from baseline at 28 days ]
    Measured in the blood, endothelial cell and peripheral blood mononuclear cells (PBMCs). Example - oxidized LDL, isoprostanes, nitrotyrosine, 5- (and 6-)-chloromethyl-2', 7'-dichlorodihydrofluorescein diacetate (DCF).
  • Quantification of dihydroethidium [ Time Frame: Change from baseline at 28 days ]
    Measured in the blood, endothelial cell and peripheral blood mononuclear cells (PBMCs). Example - oxidized LDL, isoprostanes, nitrotyrosine, 5- (and 6-)-chloromethyl-2', 7'-dichlorodihydrofluorescein diacetate (DCF).
  • Quantification of nitrotyrosine [ Time Frame: Change from baseline at 28 days ]
    Measured in the blood, endothelial cell and peripheral blood mononuclear cells (PBMCs). Example - oxidized LDL, isoprostanes, nitrotyrosine, 5- (and 6-)-chloromethyl-2', 7'-dichlorodihydrofluorescein diacetate (DCF).
  • Assessment of peripheral blood mononuclear cells (PBMC) [ Time Frame: Change from baseline at 28 days ]
    Measured in the blood, endothelial cell and peripheral blood mononuclear cells (PBMCs). Example - oxidized LDL, isoprostanes, nitrotyrosine, 5- (and 6-)-chloromethyl-2', 7'-dichlorodihydrofluorescein diacetate (DCF).
  • Assessment of arteriole protein expression of candidate antioxidant genes [ Time Frame: Change from baseline at 28 days ]
    Measured in the blood, endothelial cell and peripheral blood mononuclear cells (PBMCs). Example - oxidized LDL, isoprostanes, nitrotyrosine, 5- (and 6-)-chloromethyl-2', 7'-dichlorodihydrofluorescein diacetate (DCF).
  • Assessment of Arterial and venous endothelial cells [ Time Frame: Change from baseline at 28 days ]
    Measured in the blood, endothelial cell and peripheral blood mononuclear cells (PBMCs). Example - oxidized LDL, isoprostanes, nitrotyrosine, 5- (and 6-)-chloromethyl-2', 7'-dichlorodihydrofluorescein diacetate (DCF).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: April 29, 2016)
  • Microvessel endothelial function [ Time Frame: Change from baseline at 28 days ]
    Subcutaneous adipose biopsy samples will be obtained under local anesthesia. Arterioles will be dissected free from the surrounding fat and will be pre-contracted with 3 μm phenylephrine and exposed to increasing doses of acetylcholine (Ach) alone and co-incubation with the nitric oxide synthase inhibitor L-NG-Nitroarginine methyl ester (L-NAME). To assess whether endothelial dysfunction is related to mitochondrial oxidative stress, arterioles will be exposed to both Mito-TEMPOL (1 mmol/L), and MitoQ for 30 minutes (with adequate wash-out between measures) and Ach-induced vasodilation will be reassessed.
  • Change in Blood pressure [ Time Frame: Change from baseline at 28 days ]
    For subject blood pressure screening, sitting measurements (Dinamap) will be performed under fasted conditions in the morning on at least two separate days that are one week apart. On the cardiovascular testing days, supine blood pressure will be measured in triplicate.
  • Evaluation of Body Composition [ Time Frame: 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.
  • Evaluation of Plasma Lipid Concentrations [ Time Frame: 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.
  • Evaluation of Lipoprotein Concentrations [ Time Frame: Baseline ]
    Plasma lipoprotein concentrations, including low-density lipoprotein (LDL)-C and high-density lipoprotein (HDL)-C, 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.
  • Change in Sex Hormones [ Time Frame: 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.
  • Change in Endothelin-1 (ET-1) [ Time Frame: 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.
  • Symptom Questionnaires [ Time Frame: Change from baseline at 28 days ]
    Internally developed symptom questionnaires will be obtained at baseline and following the 28 day intervention. The internally developed symptom questionnaire asks questions about potential side effects of the medications (e.g., injection site reaction, headache, nausea, hot flushes, breast tenderness, joint and/or back pain, bloating, acne, redness/skin irritation from gel, impotence, decreased libido and trouble concentration). This questionnaire will also be asked at day 14 of the intervention and 30 days following the intervention.
  • Changes in prostate specific antigen (PSA) [ Time Frame: Baseline, 14 days, 28 days, 60 days ]
    Safety monitoring will include assessment of PSA and American Urological Association (AUA) score.
  • Changes in Hematocrit (HCT) [ Time Frame: Baseline, 14 days, 28 days, 60 days ]
    Safety monitoring will include assessment of HCT, HCT will also be measured at 14 days and 1 month following completion of study.
  • Changes in liver enzymes (alanine amino transferase and aspartate amino transferase) [ Time Frame: Baseline, 14 days, 28 days, 60 days ]
    Safety monitoring will include liver enzymes at baseline and 4 weeks. Liver enzymes will also be measured at 14 days and 1 month following completion of study.
  • Dietary Analysis and Estimation of Physical Activity Levels [ Time Frame: Baseline ]
    Because marked changes in diet over the intervention/control period could influence outcomes, dietary composition and caloric intake will be determined from 3-day food intake records. This information will be used to construct dietary meals for the subjects to consume for two days prior to the main experiments at baseline and at follow-up. To document the habitual physical activity status of our subjects at baseline and the last week of respective interventions, daily energy expenditure will be estimated using ActivPal monitors.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Cardiovascular Outcomes of Low Testosterone
Official Title  ICMJE Cardiovascular Consequences of Hypogonadism in Men
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Other
Condition  ICMJE Hypogonadism
Intervention  ICMJE
  • Drug: Acyline
    Acyline 300ug/kg injection will be administered on Day 0 and on day 14
    Other Name: Gonadotropin releasing hormone antagonist
  • Drug: Placebo Gel
    Placebo gel packet applied daily for 28 days.
    Other Name: Placebo
  • Drug: Placebo Tablet
    Placebo oral tablet taken daily for 28 days.
    Other Name: Placebo
  • Drug: Testosterone Gel
    Testosterone Gel applied daily for 28 days
    Other Name: Transdermal Testosterone Gel
  • Drug: Arimidex
    Arimidex Oral Tablet 1mg taken orally daily for 28 days
    Other Name: Aromatase inhibitor
Study Arms  ICMJE
  • Placebo Comparator: Group 1: Acyline plus placebo (No Testosterone Add-Back)
    Acyline plus placebo gel and placebo tablet.
    Interventions:
    • Drug: Acyline
    • Drug: Placebo Gel
    • Drug: Placebo Tablet
  • Active Comparator: Group 2: Acyline plusTestosterone
    Acyline plus transdermal testosterone gel plus placebo tablet.
    Interventions:
    • Drug: Acyline
    • Drug: Placebo Tablet
    • Drug: Testosterone Gel
  • Active Comparator: Group 3: Acyline plus Testosterone plus Arimidex)
    Acyline plus transdermal testosterone gel plus Aromatase inhibitor (Arimidex) oral.
    Interventions:
    • Drug: Acyline
    • Drug: Testosterone Gel
    • Drug: Arimidex
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 29, 2016)
379
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2021
Estimated Primary Completion Date January 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Men aged 18-40 years and 50-75 years
  2. 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
  3. No use of sex hormones for at least 1 year
  4. Body mass index <35 kg/m2
  5. Nonsmokers
  6. Resting blood pressure <160/90 mmHg
  7. Fasting plasma glucose <126 mg/dL
  8. 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)
  9. Sedentary or recreationally active (< 3 days/wk of vigorous aerobic exercise)
  10. No use of medications that might influence cardiovascular function including anti-hypertensive, lipid lowering medications, and corticosteroids
  11. No use of vitamin supplements or anti-inflammatory medications, or willing to stop 1 month prior and throughout the study.

Exclusion Criteria:

  1. Contraindications to:

    1. Gonadotropin releasing hormone (GnRH) antagonist
    2. Testosterone gel and aromatase inhibitor including hypersensitivity to Acyline, Androgel®, Arimidex®
    3. Extrinsic peptide hormones, mannitol, GnRH or any other GnRH analogs
  2. History of or active prostate or breast cancer or other sex hormone-dependent neoplasms
  3. Pre-existing or active cardiac, renal or hepatic disease
  4. History of stomach ulcer or bleeding
  5. History of epilepsy or other seizure disorder
  6. Diabetes
  7. Active infection
  8. Disease that affects the nervous system
  9. 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).

Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Kerrie Moreau, PhD 303-724-1914 kerrie.moreau@ucdenver.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02758431
Other Study ID Numbers  ICMJE 15-1162
UL1TR001082 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of Colorado, Denver
Study Sponsor  ICMJE University of Colorado, Denver
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Kerrie Moreau, PhD University of Colorado, Denver
PRS Account University of Colorado, Denver
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP