Target Engagement of Terazosin in Healthy Adults

Healthy Clinical Trial

Official title:

Assessing Target Engagement of Terazosin in Healthy Adults

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04551040
• Other study ID #: 202005461
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: March 26, 2021
• Est. completion date: June 30, 2024

Study information

• Verified date: December 2023
• Source: University of Iowa
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.)

Description:

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 18
• Est. completion date: June 30, 2024
• Est. primary completion date: March 1, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 60 Years to 90 Years

Eligibility

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

Related Conditions & MeSH terms

• Healthy

Intervention

Drug:
• Terazosin
Terazosin 1 mg oral capsule

Locations

Country	Name	City	State
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa

Sponsors (2)

Lead Sponsor	Collaborator
University of Iowa	Michael J. Fox Foundation for Parkinson's Research

Country where clinical trial is conducted

United States, 

References & Publications (13)

Blesa J, Phani S, Jackson-Lewis V, Przedborski S. Classic and new animal models of Parkinson's disease. J Biomed Biotechnol. 2012;2012:845618. doi: 10.1155/2012/845618. Epub 2012 Mar 28. — View Citation

Cai R, Zhang Y, Simmering JE, Schultz JL, Li Y, Fernandez-Carasa I, Consiglio A, Raya A, Polgreen PM, Narayanan NS, Yuan Y, Chen Z, Su W, Han Y, Zhao C, Gao L, Ji X, Welsh MJ, Liu L. Enhancing glycolysis attenuates Parkinson's disease progression in models and clinical databases. J Clin Invest. 2019 Oct 1;129(10):4539-4549. doi: 10.1172/JCI129987. — View Citation

Chen X, Zhao C, Li X, Wang T, Li Y, Cao C, Ding Y, Dong M, Finci L, Wang JH, Li X, Liu L. Terazosin activates Pgk1 and Hsp90 to promote stress resistance. Nat Chem Biol. 2015 Jan;11(1):19-25. doi: 10.1038/nchembio.1657. Epub 2014 Nov 10. — View Citation

Cunnane S, Nugent S, Roy M, Courchesne-Loyer A, Croteau E, Tremblay S, Castellano A, Pifferi F, Bocti C, Paquet N, Begdouri H, Bentourkia M, Turcotte E, Allard M, Barberger-Gateau P, Fulop T, Rapoport SI. Brain fuel metabolism, aging, and Alzheimer's disease. Nutrition. 2011 Jan;27(1):3-20. doi: 10.1016/j.nut.2010.07.021. Epub 2010 Oct 29. — View Citation

Hoegger MJ, Fischer AJ, McMenimen JD, Ostedgaard LS, Tucker AJ, Awadalla MA, Moninger TO, Michalski AS, Hoffman EA, Zabner J, Stoltz DA, Welsh MJ. Impaired mucus detachment disrupts mucociliary transport in a piglet model of cystic fibrosis. Science. 2014 Aug 15;345(6198):818-22. doi: 10.1126/science.1255825. — View Citation

Hoffe B, Holahan MR. The Use of Pigs as a Translational Model for Studying Neurodegenerative Diseases. Front Physiol. 2019 Jul 10;10:838. doi: 10.3389/fphys.2019.00838. eCollection 2019. — View Citation

Hoyer S. Brain glucose and energy metabolism during normal aging. Aging (Milano). 1990 Sep;2(3):245-58. doi: 10.1007/BF03323925. — View Citation

Hytrin (terazosin) [package insert]. Abbott Indistries, North Chicago, IL. 2001.

Matthews DC, Lerman H, Lukic A, Andrews RD, Mirelman A, Wernick MN, Giladi N, Strother SC, Evans KC, Cedarbaum JM, Even-Sapir E. FDG PET Parkinson's disease-related pattern as a biomarker for clinical trials in early stage disease. Neuroimage Clin. 2018 Aug 10;20:572-579. doi: 10.1016/j.nicl.2018.08.006. eCollection 2018. — View Citation

Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016 Mar;7(2):27-31. doi: 10.4103/0976-0105.177703. — View Citation

Patel A, Malinovska L, Saha S, Wang J, Alberti S, Krishnan Y, Hyman AA. ATP as a biological hydrotrope. Science. 2017 May 19;356(6339):753-756. doi: 10.1126/science.aaf6846. — View Citation

Rogers CS, Stoltz DA, Meyerholz DK, Ostedgaard LS, Rokhlina T, Taft PJ, Rogan MP, Pezzulo AA, Karp PH, Itani OA, Kabel AC, Wohlford-Lenane CL, Davis GJ, Hanfland RA, Smith TL, Samuel M, Wax D, Murphy CN, Rieke A, Whitworth K, Uc A, Starner TD, Brogden KA, Shilyansky J, McCray PB Jr, Zabner J, Prather RS, Welsh MJ. Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Science. 2008 Sep 26;321(5897):1837-41. doi: 10.1126/science.1163600. — View Citation

Schapira AH. Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurol. 2008 Jan;7(1):97-109. doi: 10.1016/S1474-4422(07)70327-7. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	Safety and Tolerability	We will assess patient-reported adverse events.	Ongoing (days 1 - 37)