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

NCT ID: NCT03440112

Last Updated: 2023-01-10

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1/PHASE2

Total Enrollment

34 participants

Study Classification

INTERVENTIONAL

Study Start Date

2018-01-29

Study Completion Date

2021-12-08

Brief Summary

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The arm of this study evaluates possible GABA-A receptor target engagement effects of the FDA-approved medication, transdermal flumazenil (added 4/2020, replaced clarithromycin), in the setting of Parkinson's disease. Half of the subjects will receive transdermal flumazenil for 7-10 days, and half will receive a placebo. \[11C\]Flumazenil GABA-A receptor PET imaging will be used to assess target engagement effects. Note \[11C\]Flumazenil GABA-A receptor PET was not performed as part of the transdermal flumazenil study because of a Covid pandemic research amendment.

Detailed Description

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This study focuses on neurochemical changes in the brain that occur in Parkinson's disease. In particular we will be looking a neurotransmitter called GABA. In some Parkinson's disease patients we see too much GABA activity in the brain. This target engagement study examines the target engagement effect of GABA-A receptor modulation by transdermal flumazenil (previously clarithromycin). \[11C\]-flumazenil Positron Emission Tomography (PET) imaging results will be used to assess for possible GABA-A receptor target engagement effects of transdermal flumazenil (previously clarithromycin). Note \[11C\]Flumazenil GABA-A receptor PET was not performed as part of the transdermal flumazenil study because of a Covid pandemic research amendment.

Conditions

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Parkinson Disease

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

OTHER

Blinding Strategy

TRIPLE

Participants Caregivers Investigators
Participant, Investigator

Study Groups

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Clarithromycin (Not used anymore as of 4/2020; study aborted)

Clarithromycin 250mg (1 capsule) will be taken orally twice a day for 3 days and if tolerated will be increased to 500mg (2 capsules) orally twice a day for 4-6 days.

Group Type ACTIVE_COMPARATOR

Clarithromycin (Not used as of 4/2020)

Intervention Type DRUG

Clarithromycin (generic) capsule 250mg each

Placebo (Not used anymore as of 4/2020; study aborted)

Placebo will be taken exactly as the clarithromycin arm: 1 capsule orally twice a day for 3 days and if tolerated will be increased to 2 capsules orally twice a day for 4-6 days.

Group Type PLACEBO_COMPARATOR

Placebo (Not used as of 4/2020)

Intervention Type DRUG

Lactose in a gel capsule

Transdermal flumazenil (added 4/2020 as safer alternative for clarithromycin)

Added in April 2020. Subjects will take 18mg transdermal application every 3-4 hrs dispensed as 3 dispenser bottle clicks of 0.25 ml each, while awake for 3 days then if no side-effects subjects will increase to 36mg transdermal application every 3-4 hrs dispensed as 6 dispenser bottle clicks of 0.25 ml each, while awake.

Group Type ACTIVE_COMPARATOR

Transdermal flumazenil (Added 4/2020)

Intervention Type DRUG

Transdermal flumazenil 24mg/mL

Placebo cream (added 4/2020)

Added in April 2020. Placebo will be taken exactly as the transdermal flumazenil arm: Subjects will take 18mg transdermal application every 3-4 hrs dispensed as 3 dispenser bottle clicks of 0.25 ml each, while awake for 3 days then if no side-effects subjects will increase to 36mg transdermal application every 3-4 hrs dispensed as 6 dispenser bottle clicks of 0.25 ml each, while awake.

Group Type PLACEBO_COMPARATOR

Placebo (Added 4/2020)

Intervention Type DRUG

Transdermal placebo

Interventions

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Placebo (Not used as of 4/2020)

Lactose in a gel capsule

Intervention Type DRUG

Transdermal flumazenil (Added 4/2020)

Transdermal flumazenil 24mg/mL

Intervention Type DRUG

Placebo (Added 4/2020)

Transdermal placebo

Intervention Type DRUG

Clarithromycin (Not used as of 4/2020)

Clarithromycin (generic) capsule 250mg each

Intervention Type DRUG

Other Intervention Names

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Biaxin Placebo cream

Eligibility Criteria

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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 vascu¬lar dementia, normal pressure hydrocephalus, multiple system atrophy, corticobasal ganglionic dege¬neration, or toxic causes of parkinsonism. Prototypical cases have distincti¬ve 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 currently on benzodiazepine, GABAB-ergic medications (baclofen, tizanidine), modafinil, 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. History of transient ischemic attack (TIA) or stroke within the last year.
13. History of systemic lupus erythematosis.
14. Abnormal liver enzymes (AST or ALT) \> 3 times upper limit of normal.
15. History of atrial fibrillation.
16. History of retinal branch artery occlusion.
17. Active dermatitis inner forearms.
18. Any other medical history determined by investigators to preclude safe participation.


1. Allergy to flumazenil
2. Significant liver disease
3. History of alcohol or other substance abuse within past two years.
4. Subjects currently taking benzodiazepines
Minimum Eligible Age

50 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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National Institute of Neurological Disorders and Stroke (NINDS)

NIH

Sponsor Role collaborator

Nicolaas Bohnen, MD, PhD

OTHER

Sponsor Role lead

Responsible Party

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Nicolaas Bohnen, MD, PhD

Professor of Radiology and Neurology

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

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Nicolaas I Bohnen, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Michigan

Locations

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University of Michigan Health System Functional Neuroimaging, Cognitive and Mobility Laboratory

Ann Arbor, Michigan, United States

Site Status

Countries

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United States

Provided Documents

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Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

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R01NS099535

Identifier Type: NIH

Identifier Source: secondary_id

View Link

HUM00360361-A

Identifier Type: -

Identifier Source: org_study_id

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