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

• Status: Completed
• Trial end date: 2021-06-04
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Michigan
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS)
• Treatments: Flumazenil

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