Modulation of GABA-A Receptors in Parkinson Disease-Flumazenil Arm

NCT ID: NCT03462641

Last Updated: 2022-09-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 36 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-03-09
• Study Completion Date: 2021-06-04

Brief Summary

This arm is a positron emission tomography (PET) biomechanistic GABA-A receptor target engagement study that includes detailed clinical and motor assessments before and after the i.v. administration of 1 mg flumazenil or placebo in Parkinson disease subjects. Each subject will receive 1mg flumazenil or placebo at two visits.

Detailed Description

This biomechanistic GABA-A receptor target engagement study includes clinical and motor assessments before and at various time points up to approximately 90 minutes after the i.v. administration of 1 mg flumazenil and placebo in Parkinson disease subjects. Thirty Parkinson disease subjects with disease severity (Hoehn and Yahr) stages 2-4 will be recruited. Baseline [11C]FMZ and vesicular monoamine transporter type 2 (VMAT2) [11C]DTBZ brain PET imaging will be performed prior to drug administration to assess for GABA-A receptor availability and the integrity of nigrostriatal dopaminergic nerve terminals, respectively.

Conditions

Parkinson Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: OTHER
• Blinding Strategy: TRIPLE

Study Groups

Sequence A - (Flumazenil at Visit 1)

A detailed 90 minute clinical assessment was conducted before and after treatment administration for each visit. Flumazenil 1mg in 10cc normal saline was given intravenously (iv) over 5-10 minutes on the first visit as treatment. 10 cc of normal saline placebo was given intravenously (iv) over 5-10 minutes on the second visit as treatment.

Group Type: EXPERIMENTAL

Flumazenil

Intervention Type: DRUG

1mg in 10cc normal saline

Placebo

Intervention Type: DRUG

10 cc normal saline

Sequence B - (Placebo at Visit 1)

A detailed 90 minute clinical assessment was conducted before and after treatment administration for each visit. 10 cc of normal saline placebo was given intravenously (iv) over 5-10 minutes on the first visit as treatment. Flumazenil 1mg in 10cc normal saline was given intravenously (iv) over 5-10 minutes on the second visit as treatment.

Group Type: EXPERIMENTAL

Flumazenil

Intervention Type: DRUG

1mg in 10cc normal saline

Placebo

Intervention Type: DRUG

10 cc normal saline

Interventions

Flumazenil

1mg in 10cc normal saline

Intervention Type: DRUG

Placebo

10 cc normal saline

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Parkinson's disease (PD): PD diagnosis will follow the UK Parkinson's Disease Society Brain Bank Research Center (UKPDSBRC) clinical diagnostic criteria for PD.

2. Hoehn and Yahr stages 2-4

3. Absence of dementia confirmed by cognitive testing.

4. Abnormal 11C-Dihydrotetrabenazine ([11C]-DTBZ) PET study to demonstrate nigrostriatal dopaminergic denervation.

Exclusion Criteria

1. PD with Dementia (PDD) or dementia with Lewy bodies (DLB).

2. Other disorders which may resemble PD, such as vascular dementia, normal pressure hydrocephalus, multiple system atrophy, corticobasal ganglionic degeneration, or toxic causes of parkinsonism. Prototypical cases have distinctive clinical profiles, like early and severe dysautonomia or appendicular apraxia, which may differentiate them from idiopathic PD. The use of the UKPDSBRC clinical diagnostic criteria for PD will mitigate the inclusion of subjects with atypical parkinsonism.

3. Subjects on benzodiazepine, GABA-ergic medications (baclofen, tizanidine), neuroleptic, anticholinergic (trihexyphenidyl, benztropine), or cholinesterase inhibitor drugs.

4. Evidence of a mass lesion on structural brain imaging (MRI).

5. Participants in whom MRI is contraindicated including, but not limited to, those with a pacemaker, presence of metallic fragments near the eyes or spinal cord, chest, or cochlear implant.

6. Severe claustrophobia precluding MR or PET imaging.

7. Subjects limited by participation in research procedures involving ionizing radiation.

8. Pregnancy (urine or serum pregnancy test within 48 hours of each PET session) or breastfeeding.

9. History of seizures

10. Significant anxiety or history of panic disorder.

11. History of recent suicide attempt or overdose of tricyclic antidepressants or other medications

12. Any other medical history determined by investigators to preclude safe participation.

13. Allergy to flumazenil

14. Significant liver disease

15. History of alcohol or other substance abuse within past two years.

16. History of regular benzodiazepine use within past year

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Neurological Disorders and Stroke (NINDS)

NIH

Sponsor Role: collaborator

University of Michigan

OTHER

Sponsor Role: lead

Responsible Party

Nicolaas Bohnen, MD, PhD

Professor of Radiology and Neurology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Nicolaas I Bohnen, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Michigan

Locations

University of Michigan Functional Neuroimaging, Cognitive and Mobility Laboratory

Ann Arbor, Michigan, United States

Countries

United States

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

R01NS099535

Identifier Type: NIH

Identifier Source: secondary_id

View Link

HUM00130361

Identifier Type: -

Identifier Source: org_study_id