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

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

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.

Study Overview

• Status: Completed
• Conditions: Parkinson Disease
• Intervention / Treatment: Drug: Clarithromycin (Not used as of 4/2020); Drug: Placebo (Not used as of 4/2020); Drug: Transdermal flumazenil (Added 4/2020); Drug: Placebo (Added 4/2020)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • University of Michigan Health System Functional Neuroimaging, Cognitive and Mobility Laboratory

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Additional Exclusion Criteria for Flumazenil sub-studies:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Drug: Clarithromycin (Not used as of 4/2020); Clarithromycin (generic) capsule 250mg each; Other Names: Biaxin
Placebo Comparator: 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.	Drug: Placebo (Not used as of 4/2020); Lactose in a gel capsule
Active Comparator: 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.	Drug: Transdermal flumazenil (Added 4/2020); Transdermal flumazenil 24mg/mL
Placebo Comparator: 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.	Drug: Placebo (Added 4/2020); Transdermal placebo; Other Names: Placebo cream

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Quantitative Biomechanics 1 (Clinical Motor Ratings MDS-UPDRS)	We will use the total Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III - motor scale rating scores to assess motor function. Scale from 0-132, higher scores indicate worse motor outcomes. Outcome measure was collected during dopaminergic medication ON state.	Day 1 (before treatment administration), day 7 (after 7 days of treatment), and day 14 (7 days of treatment discontinuation).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Quantitative Biomechanics 2 (MiniBESTest Dynamic Balance Scale Sensory Subscore)	MiniBEST sensory subscore measures an individual's ability to maintain balance under conditions of sensory constrain and unstable/inclined standing surface. It is is computed as a sum of MiniBEST items 7, 8, and 9.The score ranges from 0 to 6, with 0 indicating inability to balance under all of the condition, and 6 indicating no difficulty in maintaining balance under any of the conditions (lower score indicates worse balance). Outcome measure was collected during dopaminergic medication ON state.	Day 1 (before treatment administration), day 7 (after 7 days of treatment), and day 14 (7 days of treatment discontinuation).

Collaborators and Investigators

• Sponsor: Nicolaas Bohnen, MD, PhD
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Nicolaas I Bohnen, MD, PhD, University of Michigan

Study record dates

Study Major Dates

• Study Start (Actual): January 29, 2018
• Primary Completion (Actual): December 8, 2021
• Study Completion (Actual): December 8, 2021

Study Registration Dates

• First Submitted: January 26, 2018
• First Submitted That Met QC Criteria: February 13, 2018
• First Posted (Actual): February 20, 2018

Study Record Updates

• Last Update Posted (Estimate): January 10, 2023
• Last Update Submitted That Met QC Criteria: December 15, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: MRI; Balance; Gait; PET Imaging; Mobility; GABA; Transdermal flumazenil (previously Clarithromycin changed 4/2020)
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Protective Agents; Anti-Bacterial Agents; GABA Modulators; GABA Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Protein Synthesis Inhibitors; Antidotes; Clarithromycin; Flumazenil
• Other Study ID Numbers: HUM00360361-A; R01NS099535 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No