Brain Bioenergetics in Parkinson's Disease and Response to Repeated Oral UDCA Treatment

NCT ID: NCT02967250

Last Updated: 2022-03-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 5 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-04-01
• Study Completion Date: 2022-02-28

Brief Summary

The objective of this study is to understand the bioenergetic impairments that underlie Parkinson's disease (PD) and evaluating treatments that may improve abnormal mitochondrial function that is present in PD. The hypothesis is that repeated oral dosing of UDCA will result in increased brain ATP levels in individuals with Parkinson's disease (PD). The specific aims are 1.) to measure plasma UDCA levels in individuals with PD at baseline and after four weeks of repeated high doses of oral UDCA (50mg/kg/day) and 2.) to measure cortical bioenergetic profile and ATPase activity (as ascertained through MRS) in those with PD at baseline and at four weeks after repeated high doses of oral UDCA (50mg/kg/day) simultaneously. Secondary aims are to characterize oral UDCA pharmacokinetics and develop a pharmacokinetic/pharmacodynamic model to characterize the relationship between peripheral measurements of UDCA (and associated conjugates) and peripheral measures and/or central (brain) bioenergetic measurements.

Detailed Description

The objective of this study is to understand the bioenergetic impairments that underlie Parkinson's disease (PD) and evaluating treatments that may improve abnormal mitochondrial function that is present in PD. High field - 7 tesla (T) - magnetic resonance spectroscopy (MRS) is able to non-invasively assess for changes in brain energetics and will be used to evaluate the effects that repeated oral doses of the mitochondrial enhancer ursodeoxycholic acid (UDCA) has on brain bioenergetics derived from MRS measurements. This study will combine results obtained using MRS brain scans along with peripheral measurements of bile acids (e.g., total UDCA). This research will require at least 2 visits: baseline evaluation and at approximately 6 weeks after subjects are on a stable oral dose for 4 weeks. Participants will provide their medical history during the first visit, and undergo a physical examination and rating scale each visit (duration: ~1 hour) as well as a brain MRI scan (1-1.5 hours). Blood will be obtained at both visits to monitor for adverse effects as well as to assess for changes in bile acids from orally administered UDCA. If additional funding is obtained we may have another visit added between the first and second assessments to obtain additional blood measurements and MRS data.

Since there is extensive animal and cell model data supporting the rationale for a therapeutic trial of UDCA in PD, and because MRS methods can non-invasively detect changes in brain chemistry we propose a study to evaluate the effects of a 4-6 weeks of high-dose oral UDCA on central (brain) and peripheral measures (through MRS and blood measurements, respectively) in individuals with PD and healthy controls. The hypothesis and specific aims are as follows:

Hypothesis: Repeated oral dosing of UDCA will result in increased brain ATP levels in individuals with Parkinson's disease (PD).

Specific Aims:

1. Measure plasma UDCA levels in individuals with PD at baseline and after four weeks of repeated high doses of oral UDCA (50mg/kg/day).

2. Measure cortical bioenergetic profile and ATPase activity (as ascertained through MRS) in those with PD at baseline and at four weeks after repeated high doses of oral UDCA (50mg/kg/day) simultaneously with Aim 1.

Secondary Aims:

1. Characterize oral UDCA pharmacokinetics

2. Develop a pharmacokinetic/pharmacodynamic model to characterize the relationship between peripheral measurements of UDCA (and associated conjugates) and peripheral measures and/or central (brain) bioenergetic measurements.

Conditions

Parkinson Disease

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Ursodeoxycholic acid treatment

Each subject will receive UDCA intervention for six weeks.

Group Type: EXPERIMENTAL

ursodeoxycholic acid

Intervention Type: DRUG

Subjects will be provided \~50mg/kg/day (based on the use of 250 and 500mg capsules) of UDCA to be divided into 3 equal daily doses and titrated up over \~2 weeks to a stable dose for 4 weeks.

Interventions

ursodeoxycholic acid

Subjects will be provided \~50mg/kg/day (based on the use of 250 and 500mg capsules) of UDCA to be divided into 3 equal daily doses and titrated up over \~2 weeks to a stable dose for 4 weeks.

Intervention Type: DRUG

Other Intervention Names

Ursodiol

Eligibility Criteria

Inclusion Criteria

1. All participants must be 18 years or older.

2. All enrollees must understand and cooperate with requirements of the study and be able to provide written informed consent

3. Individuals with medically stable mild to moderate Parkinson's disease or healthy controls (as determined by enrolling investigator)

4. All participants must not have taken UDCA for 4 weeks prior to the study.

5. Absence of dementia in all subjects, as determined by pre-scanning cognitive assessment.

Exclusion Criteria

1. Inability to undergo MRI scanning without sedation and other MRI counterindications, such as metal in the body.

2. Medically unstable conditions

3. Pregnant or lactating or those women of child-bearing age that are not using acceptable forms of contraception

4. Unable to adhere to study protocol as determined by the PI

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Minnesota

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Lisa Coles, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Minnesota

Paul Tuite, MD

Role: PRINCIPAL_INVESTIGATOR

University of Minnesota

Locations

Center for Magnetic Resonance Research

Minneapolis, Minnesota, United States

Countries

United States

Other Identifiers

NEUR-2016-18222

Identifier Type: -

Identifier Source: org_study_id