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

• ClinicalTrials.gov Identifier: NCT03462641
• Recruitment Status: Completed
• First Posted: March 12, 2018
• Last Update Posted: June 29, 2021
• Sponsor: University of Michigan
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS)
• Information provided by (Responsible Party): Nicolaas Bohnen, MD, PhD, University of Michigan

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Parkinson Disease	Drug: Flumazenil; Drug: Placebo	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 26 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Other
• Official Title: Modulation of GABA-A Receptors and Axial Motor Impairments in Parkinson Disease-Flumazenil Arm
• Actual Study Start Date: March 9, 2018
• Actual Primary Completion Date: June 4, 2021
• Actual Study Completion Date: June 4, 2021

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Flumazenil; Flumazenil 1mg in 10cc normal saline will be given intravenously (iv) over 5-10 minutes and a detailed clinical assessment will follow for the next 90 minutes.	Drug: Flumazenil; 1mg in 10cc normal saline
Placebo Comparator: Placebo; 10 cc of normal saline placebo will be given intravenously (iv) over 5-10 minutes and a detailed clinical assessment will follow for the next 90 minutes.	Drug: Placebo; 10 cc normal saline

Outcome Measures

Primary Outcome Measures :

1. Change in quantitative biomechanics [ Time Frame: up to 3 hours (including pre- and post-infusion motor testing) ]
   We will use the PIGD-UPDRS motor scale to assess axial motor functions before and after 1mg flumazenil iv and correlate this with the [11-Carbon]-flumazenil ([11C]FMZ) PET binding.

Eligibility Criteria

• Ages Eligible for Study: 50 Years to 99 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Michigan

University of Michigan Functional Neuroimaging, Cognitive and Mobility Laboratory

Ann Arbor, Michigan, United States, 48106

Sponsors and Collaborators

University of Michigan

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Nicolaas I Bohnen, MD, PhD; University of Michigan

More Information

• Responsible Party: Nicolaas Bohnen, MD, PhD, Professor of Radiology and Neurology, University of Michigan
• ClinicalTrials.gov Identifier: NCT03462641
• Other Study ID Numbers: HUM00130361; R01NS099535 ( U.S. NIH Grant/Contract )
• First Posted: March 12, 2018
• Last Update Posted: June 29, 2021
• Last Verified: June 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Nicolaas Bohnen, MD, PhD, University of Michigan:

Gait; Balance; Flumazenil; PET Imaging; MRI; Mobility; Intravenous

Additional relevant MeSH terms:

Parkinson Disease; Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Flumazenil; Antidotes; Protective Agents; Physiological Effects of Drugs; GABA Modulators; GABA Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action