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

Parkinson Disease Clinical Trial

Official title:

Modulation of GABA-A Receptors and Axial Motor Impairments in Parkinson Disease-Flumazenil Arm

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03462641
• Other study ID #: HUM00130361
• Secondary ID: R01NS099535
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: March 9, 2018
• Est. completion date: June 4, 2021

Study information

• Verified date: September 2022
• Source: University of Michigan
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: June 4, 2021
• Est. primary completion date: June 4, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years to 99 Years

Eligibility

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

Related Conditions & MeSH terms

• Parkinson Disease

Intervention

Drug:
• Flumazenil
1mg in 10cc normal saline
• Placebo
10 cc normal saline

Locations

Country	Name	City	State
United States	University of Michigan Functional Neuroimaging, Cognitive and Mobility Laboratory	Ann Arbor	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
University of Michigan	National Institute of Neurological Disorders and Stroke (NINDS)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Postural Instability and Gait Disorder (PIGD) Score	Postural Instability and Gait Disorder (PIGD) score is a subscale score of MDS-UPDRS scale.; It is computed as a sum of following MDS-UPDRS items: 3.10 Gait; 3.11 Freezing of gait; 3.12 Postural stability; 3.13 Posture; Minimal possible score is 0, maximal possible score is 16. Higher scores indicate greater severity of PIGD symptoms (worse outcome).	up to 3 hours (including pre and post infusion motor evaluation)
Primary	PIGD Score Change	Difference in PIGD score from pre-infusion to post-infusion. Only observations where PIGD score change is less than 0 (decrease) are retained, as the hypothesis we are interested is whether the effect magnitude of flumazenil on PIGD score depends on baseline GABA-A receptor binding as assesed by FMZ PET.	up to 3 hours (including pre and post infusion motor evaluation)