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

• ClinicalTrials.gov Identifier: NCT03440112
• Recruitment Status: Recruiting
• First Posted: February 20, 2018
• Last Update Posted: July 1, 2021
• Sponsor: Nicolaas Bohnen, MD, PhD
• 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:

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 (Clinical Trial)
• Estimated Enrollment: 30 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: January 29, 2018
• Estimated Primary Completion Date: April 30, 2022
• Estimated Study Completion Date: April 30, 2022

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 Name: 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 Name: Placebo cream

Outcome Measures

Primary Outcome Measures :

1. Change in quantitative biomechanics 1 [ Time Frame: 7-10 days ]
   We will use the total MDS-UPDRS motor scale to assess motor functions before and after 7 days of transdermal flumazenil

Secondary Outcome Measures :

1. Change in quantitative biomechanics 2 [ Time Frame: 7-10 days ]
   We will use the PIGD-UPDRS motor scale to assess axial motor functions before and after 7 days of transdermal flumazenil

Eligibility Criteria

• Ages Eligible for Study: 50 Years and older (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 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

Contacts and Locations

Contacts

Contact: Nicolaas Bohnen; 734-998-8400; nbohnen@umich.edu

Contact: Sheryl Korsnes; 734-998-8400

Locations

United States, Michigan

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

Ann Arbor, Michigan, United States, 48106

Contact: Nicolaas Bohnen 734-998-8400 nbohnen@umich.edu

Contact: Sheryl Korsnes 734-998-8400

Sponsors and Collaborators

Nicolaas Bohnen, MD, PhD

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: NCT03440112
• Other Study ID Numbers: HUM00360361-A; R01NS099535 ( U.S. NIH Grant/Contract )
• First Posted: February 20, 2018
• Last Update Posted: July 1, 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; GABA; Transdermal flumazenil (previously Clarithromycin changed 4/2020); PET Imaging; MRI; Mobility

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; Clarithromycin; Flumazenil; Anti-Bacterial Agents; Anti-Infective Agents; Protein Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Antidotes; Protective Agents; Physiological Effects of Drugs; GABA Modulators; GABA Agents; Neurotransmitter Agents