Contributions to Hypertension With Androgen Deprivation Therapy (ARCH)

Autonomic and Renal Contributions to Hypertension With Androgen Deprivation Therapy

This study plans to learn more about contributors to high blood pressure in men who undergo androgen deprivation therapy (ADT) to treat prostate cancer. Prostate cancer is the most common non-skin cancer in men, affecting approximately 1 in 8 American men and its primary treatment is through the use of ADT. However, ADT increases the likelihood of developing heart disease including high blood pressure. This study will determine if dysfunction of the nervous system and/or kidneys occurs in men undergoing ADT, as these systems play a significant role in control of blood pressure. The results from this study will help us understand the ways in which ADT contributes to heart disease and help us develop therapies to prevent heart disease in prostate cancer survivors.

Study Overview

• Status: Recruiting
• Conditions: Hypertension; Prostate Cancer; Autonomic Dysfunction; Androgen Deprivation Therapy; Renal Disease
• Intervention / Treatment: Drug: Gonadotropin-Releasing Hormone Agonist; Drug: Androgen receptor inhibitor; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 228
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Matthew Babcock, PhD; Phone Number: 303-724-1401; Email: matthew.babcock@cuanschutz.edu

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • UCHealth University of Colorado Hospital
      • Contact: Matthew Babcock, PhD; Phone Number: 720-848-6470; Email: matthew.babcock@cuanschutz.edu
      • Principal Investigator: Matthew Babcock, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• -age 40+ years;
• resting blood pressure <140/90 mmHg;
• fasted blood glucose <126 mg/dL;
• testosterone ≥400 ng/dL;
• sedentary to recreationally active;
• nonsmokers;
• healthy as determined by medical history, physical exam, blood and urine chemistries and resting and exercise ECG during a physician supervised graded exercise treadmill test OR recent diagnosis of non-metastatic prostate cancer with plans to undergo androgen deprivation therapy;
• PSA <4.00 ng/dL if in the non-cancer group;
• Gleason Score ≤7 if in the prostate cancer group;
• no use of medications that might influence cardiovascular function (e.g., antihypertensives, lipid-lowering medications);
• willing and able to be on GnRHagonist and AR inhibitor;
• not taking antioxidant vitamins, corticosteroids, or anti-inflammatory medications, or willing to stop use for four weeks prior to the start of the study;
• not using exogenous sex hormones for at least one year

Exclusion Criteria:

• -acute liver disease;
• chronic kidney disease, serum creatinine >1.3 mg/dL, macroalbuminuria >300 mg/g of proteinuria
• pre-existing or active cardiac, renal or hepatic disease, epilepsy or other seizure disorder;
• diabetes, active or chronic infection, disease that affects the nervous system;
• Gleason Score ≥8;
• thyroid dysfunction, defined as ultrasensitive TSH <0.5 or >5.0 mU/L, volunteers with abnormal TSH values will be re-considered for participation after follow-up evaluation by the PCP with initiation or adjustment of thyroid hormone replacement;
• tobacco use within the previous 12 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Prostate Cancer; Men undergoing androgen deprivation therapy via gonadotropin releasing hormone agonist plus androgen receptor inhibitor for the treatment of prostate cancer	Drug: Gonadotropin-Releasing Hormone Agonist; 8 weeks of GnRH agonist; Other Names: Leuprolide; Goserelin; Drug: Androgen receptor inhibitor; 2 weeks of AR Inhibitor; Other Names: Bicalutamide; Enzalutamide; Flutamide
Active Comparator: Healthy + ADT; Healthy men undergoing gonadal suppression via gonadotropin releasing hormone agonist plus androgen receptor inhibitor for 9 weeks	Drug: Gonadotropin-Releasing Hormone Agonist; 8 weeks of GnRH agonist; Other Names: Leuprolide; Goserelin; Drug: Androgen receptor inhibitor; 2 weeks of AR Inhibitor; Other Names: Bicalutamide; Enzalutamide; Flutamide
Placebo Comparator: Healthy + Placebo; Healthy men undergoing placebo for 9 weeks.	Drug: Placebo; Placebo tablet and injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Cardiovagal Baroreflex Sensitivity	The change in cardiovagal baroreflex sensitivity will be assessed the modified Oxford procedure	Before and after 9 weeks of androgen deprivation therapy or placebo
Change in blood pressure reactivity to the cold pressor test	The change in blood pressure will be assessed from quiet rest to sympathetic activation using the cold pressor test	Before and after 9 weeks of androgen deprivation therapy or placebo
Change in exercise pressor reflex	The change in blood pressure will be assessed from quiet rest to isometric handgrip exercise	Before and after 9 weeks of androgen deprivation therapy or placebo
Change in ambulatory blood pressure variability	Ambulatory blood pressure variability will be determined from 24-hour ambulatory blood pressure monitoring.	Before and after 9 weeks of androgen deprivation therapy or placebo
Change in beat-to-beat blood pressure variability	Beat-to-beat blood pressure variability will be using finger photoplethysmography measured in the laboratory.	Before and after 9 weeks of androgen deprivation therapy or placebo
Change in renal vascular resistance	Renal blood flow will be determined using ultrasound and blood pressure will be determined using finger photoplethysmography. These measures will be used to estimate renal vascular resistance.	Before and after 9 weeks of androgen deprivation therapy or placebo
Change in Renal dysfunction biomarkers	Neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule (KIM)-1, interleukin (IL)-18, and vanin-1 will be quantified in urine using commercially available assay kits. Concentrations will be normalized to urinary flow rate.	Before and after 9 weeks of androgen deprivation therapy or placebo

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in sympathetic baroreflex sensitivity	Changes in muscle sympathetic nerve activity in response to changes in blood pressure will be assessed using the modified Oxford procedure	Before and after 9 weeks of androgen deprivation therapy or placebo
Change in Sympathetic reactivity	The change in muscle sympathetic nerve activity will be assessed from quiet rest to sympathetic activation using the cold pressor test.	Before and after 9 weeks of androgen deprivation therapy or placebo
Change in glomerular filtration rate	Glomerular filtration rate and renal plasma flow will be calculated by iohexol (Omnipaque 300, GE Healthcare) clearance technique. Plasma and urine iohexol and p-aminohippurate clearance will be measured on a High-Performance Liquid Chromatography (HPLC, Waters, Milford, MA).	Before and after 9 weeks of androgen deprivation therapy or placebo
Change in renal plasma flow	Renal plasma flow will be calculated by p-aminohippurate (Basic Pharma) clearance techniques. Plasma and urine p-aminohippurate clearance will be measured on a High-Performance Liquid Chromatography (HPLC, Waters, Milford, MA).	Before and after 9 weeks of androgen deprivation therapy or placebo

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Inflammation	Proteomic analysis of inflammatory cascade proteins will be quantified in plasma samples.	Before and after 9 weeks of androgen deprivation therapy or placebo
Change in Oxidative stress	Whole blood reactive oxygen species will be measured in from venous blood samples using electron paramagnetic resonance spectroscopy	Before and after 9 weeks of androgen deprivation therapy or placebo
Change in Body composition	Descriptive variable total body fat mass (for screening and to document any changes with the intervention)	Before and after 9 weeks of androgen deprivation therapy or placebo

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Investigators: Principal Investigator: Matthew Babcock, PhD, University of Colorado - Anschutz Medical Campus

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2023
• Primary Completion (Estimated): March 31, 2028
• Study Completion (Estimated): March 31, 2028

Study Registration Dates

• First Submitted: January 10, 2023
• First Submitted That Met QC Criteria: January 18, 2023
• First Posted (Actual): January 26, 2023

Study Record Updates

• Last Update Posted (Estimated): November 17, 2023
• Last Update Submitted That Met QC Criteria: November 14, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Nervous System Diseases; Hypertension; Primary Dysautonomias; Autonomic Nervous System Diseases; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Reproductive Control Agents; Fertility Agents, Female; Fertility Agents; Androgen Antagonists; Leuprolide; Goserelin; Hormones; Bicalutamide; Androgens; Flutamide; Androgen Receptor Antagonists
• Other Study ID Numbers: 22-2201.cc

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No