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

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ClinicalTrials.gov Identifier: NCT03440112
Recruitment Status : Recruiting
First Posted : February 20, 2018
Last Update Posted : June 11, 2020
Sponsor:
Collaborator:
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Nicolaas Bohnen, MD, PhD, University of Michigan

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).

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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 : November 15, 2021
Estimated Study Completion Date : November 15, 2021

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. Change in [11-Carbon]-flumazenil ([11C]FMZ) PET Binding [ Time Frame: 7-10 days ]
    We will use brain PET imaging to assess quantitative changes in GABA-A receptors before and after the administration of clarithromycin in Parkinson disease subjects


Secondary Outcome Measures :
  1. Change in quantitative biomechanics [ Time Frame: 7-10 days ]
    We will use the PIGD-UPDRS motor scale to assess axial motor functions before and after 7 days of clarithromycin and correlate this with the [11C]FMZ PET binding study.



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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03440112


Contacts
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Contact: Christine Minderovic, BS 734-998-8400 cmindero@umich.edu
Contact: Cyrus Sarosh, MS 734-998-8400 csarosh@med.umich.edu

Locations
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United States, Michigan
University of Michigan Health System Functional Neuroimaging, Cognitive and Mobility Laboratory Recruiting
Ann Arbor, Michigan, United States, 48106
Contact: Muller    734-998-8400    mtmuller@umich.edu   
Contact: Sarosh    734-998-8400    csarosh@umich.edu   
Sponsors and Collaborators
Nicolaas Bohnen, MD, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
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Principal Investigator: Nicolaas I Bohnen, MD, PhD University of Michigan
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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    Key Record Dates
Last Update Posted: June 11, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
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