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

Phase 1

Completed

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

• Registration Number: NCT03440112
• Lead Sponsor: Nicolaas Bohnen, MD, PhD

Brief Summary

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

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 Timeline

• Study First Submitted: 2018-01-26
• Study Start: 2018-01-29
• Study First Submitted QC: 2018-02-13
• Study First Posted: 2018-02-20
• Primary Completion: 2021-12-08
• Study Completion: 2021-12-08
• Results First Submitted: 2022-09-15
• Status Verified: 2022-12
• Results First Submitted QC: 2022-12-15
• Last Update Submitted: 2022-12-15
• Results First Posted: 2023-01-10
• Last Update Posted: 2023-01-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 34

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Clarithromycin (Not used anymore as of 4/2020; study aborted)	Clarithromycin (Not used as of 4/2020)	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.
Placebo cream (added 4/2020)	Placebo (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.
Placebo (Not used anymore as of 4/2020; study aborted)	Placebo (Not used as of 4/2020)	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.
Transdermal flumazenil (added 4/2020 as safer alternative for clarithromycin)	Transdermal flumazenil (Added 4/2020)	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.

Primary Outcome Measures

Name	Time	Method
Change in Quantitative Biomechanics 1 (Clinical Motor Ratings MDS-UPDRS)	Day 1 (before treatment administration), day 7 (after 7 days of treatment), and day 14 (7 days of treatment discontinuation).	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.

Secondary Outcome Measures

Name	Time	Method
Change in Quantitative Biomechanics 2 (MiniBESTest Dynamic Balance Scale Sensory Subscore)	Day 1 (before treatment administration), day 7 (after 7 days of treatment), and day 14 (7 days of treatment discontinuation).	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.

Trial Locations

Locations (1)

University of Michigan Health System Functional Neuroimaging, Cognitive and Mobility Laboratory; 🇺🇸 Ann Arbor, Michigan, United States