Target Engagement of Terazosin in Healthy Adults

Study Overview
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Brief Summary
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The purpose of the study is to assess the target engagement of Terazosin (TZ) in a single cohort of 6 healthy adult participants. During the study participants will undergo PET/CT scans, 7-Tesla MRI scans, blood draws, and an optional lumbar puncture (LP.)

Detailed Description
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The study is a single center, 37-day, controlled pilot study to assess the target engagement of Terazosin (TZ) in a single cohort of 6 healthy adult participants (3 men and 3 women.) During the study participants will undergo PET/CT scans, 7-Tesla MRI scans, blood draws, and an optional lumbar puncture (LP.) Participants will have their baseline ATP levels measured (at 0mg TZ.) They will then take doses of TZ at 1mg and will increase their dose on a weekly basis by 1mg until they reach a total dose of 5mg. ATP levels will be assessed on study days 8 and 36. Participants interested in voluntarily donating a sample of cerebral spinal fluid will undergo an optional lumbar puncture on study day 37. The purpose of the study is to gain a better understanding of the mechanisms in which TZ acts in the brain. TZ was recently discovered to increase energy levels (in the form of ATP molecules) in the brain by enhancing glycolysis. By using different brain imaging techniques, blood assays and cerebral spinal fluid assays, the study will attempt to: 1) quantify the rate of glycolysis in the brain at different dosages of TZ, 2) quantify ATP levels in the brain at different dosages of TZ, 3) quantify ATP levels in blood at different dosages of TZ, and 4) assess the brain permeability of TZ. It is hoped that knowledge gained from the study will help guide future clinical trials using TZ for the treatment of various neurodegenerative diseases such as Parkinson's Disease.

Official Title
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Assessing Target Engagement of Terazosin in Healthy Adults

Conditions
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Healthy

Intervention / Treatment
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* Drug: Terazosin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy Men or women aged 60-90 Exclusion Criteria: History of stroke Ineligibility for MRI (e.g. soft tissue metallic implants, clips, cardiac pacemaker, cardiac defibrillator, internal pacing wires, metallic fragments, shrapnel, etc.) Current use of more than one of the following classes of medications: beta blockers, ace inhibitors, angiotensin receptor blockers, calcium channel blockers, or diuretics Use of any alpha blockers (terazosin, doxazosin, alfuzosin, prazosin, or tamsulosin) in the past year. Current use of the over-the-counter supplement yohimbe Orthostatic hypotension defined as symptomatic decrease in BP > 20mmHg systolic or > 10mmHg diastolic and HR increase < 20bpm on supine to sitting or standing. Alcohol and drug abuse Clinically significant traumatic brain injury History of Type I diabetes Uncontrolled Type II diabetes Other known medical or psychiatric comorbidity that in the investigator's opinion would compromise participation in the study or increase fall risk Use of investigational drugs within 30 days before screening History of hemodynamic instability For females: pregnancy or breastfeeding

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Interventional Model Description: Single group of healthy older adults
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Primary Cohort<br>Titrating doses of terazosin starting at 1mg daily and increasing to 5mg daily on a weekly basis for five weeks. | Drug: Terazosin<br>* Terazosin 1 mg oral capsule<br>* Other names: Hytrin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantification of glycolysis in the brain at baseline | Use of FDG PET to quantify glycolysis in the brain at baseline prior to initiation of terazosin | Study day 1 | 
| Change in glycolysis in the brain from baseline to 1 week (1mg of terazosin) | Use of FDG PET to determine how TZ quantitatively increases glycolysis as measured by FDG uptake from baseline to 1 week (Day 8/ 1mg TZ) | Study day 8 | 
| Change in glycolysis in the brain from baseline to 5 weeks (5mg of terazosin) | Use of FDG PET to determine how TZ quantitatively increases glycolysis as measured by FDG uptake from baseline to 5 weeks (Day 36/ 5mg TZ) | Study day 36 | 
| Quantification of ATP in brain at baseline | Use of Magnetic Resonance Spectroscopy (MRS) to quantify ATP in the brain at baseline prior to initiation of terazosin | Study day 1 | 
| Change in ATP in the brain from baseline to 1 week (1mg of terazosin) | Use of Magnetic Resonance Spectroscopy (MRS) determine how TZ quantitatively increases ATP as measured by MRS from baseline to 1 week (Day 8/ 1mg TZ) | Study day 8 | 
| Change in ATP in the brain from baseline to 5 weeks (5mg of terazosin) | Use of Magnetic Resonance Spectroscopy (MRS) determine how TZ quantitatively increases ATP as measured by MRS from baseline to 5 weeks (Day 36/ 5mg TZ) | Study day 36 | 
| Quantification of ATP in blood at baseline | Use of a novel assay to quantify ATP in the blood at baseline prior to initiation of terazosin | Study day 1 | 
| Change in ATP in the blood from baseline to 1 week (1mg of terazosin) | Use of a novel assay to determine how TZ quantitatively increases ATP in the blood from baseline to 1 week (Day 8/ 1mg TZ) | Study day 8 | 
| Change in ATP in the blood from baseline to 5 week (1mg of terazosin) | Use of a novel assay to determine how TZ quantitatively increases ATP in the blood from baseline to 5 weeks (Day 36/ 5mg TZ) | Study day 36 | 
| Quantification of TZ in Cerebrospinal Fluid | Participants will be given the option to undergo a lumbar puncture on Day 37 (5 mg TZ). Their blood will also be drawn to compare levels of TZ in the blood to levels detected in the CSF. | Study day 37 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability | We will assess patient-reported adverse events. | Ongoing (days 1 - 37) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Terazosin, Hytrin, Target engagement, Glycolysis, ATP