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

Sponsor

Nicolaas Bohnen, MD, PhD (Other)

Overall Status

Completed

CT.gov ID

NCT03440112

Collaborator

National Institute of Neurological Disorders and Stroke (NINDS) (NIH)

Enrollment

Location

Arms

46.3

Actual Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Parkinson Disease	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)	Phase 1/Phase 2

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).

Study Design

Study Type:

Interventional

Actual Enrollment :

27 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Masking Description:

Participant, Investigator

Primary Purpose:

Other

Official Title:

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

Actual Study Start Date :

Jan 29, 2018

Actual Primary Completion Date :

Dec 8, 2021

Actual Study Completion Date :

Dec 8, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Clarithromycin (Not used anymore 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.	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) 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) 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

Outcome Measures

Primary Outcome Measures

Change in quantitative biomechanics 1 [7-10 days]
We will use the total Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III - motor scale to assess motor functions before and after 7 days of transdermal flumazenil. Scale from 0-132, higher scores indicate worse motor outcomes.

Secondary Outcome Measures

Change in quantitative biomechanics 2 [7-10 days]
We will use the Postural Instability and Gait Disturbances - Unified Parkinson's Disease Rating Scale (PIGD-UPDRS) motor scale to assess axial motor functions before and after 7 days of transdermal flumazenil. Scale from 0-28, higher scores indicate worse motor outcomes.

Eligibility Criteria

Criteria

Ages Eligible for Study:

50 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Parkinson's disease (PD): PD diagnosis will follow the UK Parkinson's Disease Society Brain Bank Research Center (UKPDSBRC) clinical diagnostic criteria for PD.
Hoehn and Yahr stages 2-4
Absence of dementia confirmed by cognitive testing.
Abnormal 11C-Dihydrotetrabenazine ([11c]-DTBZ) PET study to demonstrate nigrostriatal dopaminergic denervation

Exclusion Criteria:

PD with Dementia (PDD) or dementia with Lewy bodies (DLB).
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.
Subjects currently on benzodiazepine, GABAB-ergic medications (baclofen, tizanidine), modafinil, neuroleptic, anticholinergic (trihexyphenidyl, benztropine), or cholinesterase inhibitor drugs.
Evidence of a mass lesion on structural brain imaging (MRI).
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.
Severe claustrophobia precluding MR or PET imaging.
Subjects limited by participation in research procedures involving ionizing radiation.
Pregnancy (urine or serum pregnancy test within 48 hours of each PET session) or breastfeeding.
History of seizures
Significant anxiety or history of panic disorder.
History of recent suicide attempt or overdose of tricyclic antidepressants or other medications.
History of transient ischemic attack (TIA) or stroke within the last year.
History of systemic lupus erythematosis.
Abnormal liver enzymes (AST or ALT) > 3 times upper limit of normal.
History of atrial fibrillation.
History of retinal branch artery occlusion.
Active dermatitis inner forearms.
Any other medical history determined by investigators to preclude safe participation.