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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03440112
Recruitment Status : Recruiting
First Posted : February 20, 2018
Last Update Posted : July 5, 2019
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, clarithromycin, in the setting of Parkinson's disease. Two-thirds of the subjects will receive clarithromycin for 7-9 days, and 1/3 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 Drug: Placebo 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. There is emerging in vitro and in vivo evidence that clarithromycin, an FDA-approved and orally available macrolide antibiotic, can act as a negative allosteric modulator of brain GABA-A receptors. This target engagement study examines the target engagement effect of GABA-A receptor modulation by clarithromycin. [11C]-flumazenil Positron Emission Tomography (PET) imaging results will be used to assess for possible GABA-A receptor target engagement effects of 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
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
Clarithromycin (generic) capsule 250mg each
Other Name: Biaxin

Placebo Comparator: Placebo
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
Lactose in a gel capsule

Primary Outcome Measures :
  1. Change in [11-Carbon]-flumazenil ([11C]FMZ) PET Binding [ Time Frame: 7-9 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: 7-9 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.

Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 vascular dementia, normal pressure hydrocephalus, multiple system atrophy, corticobasal ganglionic degeneration, or toxic causes of parkinsonism. Prototypical cases have distinctive 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 on benzodiazepine, GABAB-ergic medications (baclofen, tizanidine), neuroleptic, anticholinergic (trihexphenidyl, 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. Any other medical history determined by investigators to preclude safe participation.

Exclusion criteria specific for clarithromycin arm of the study

  1. Allergy or hypersensitivity to clarithromycin, other macrolide antibiotics, or similar medicines such as azithromycin, erythromycin or telithromycin.
  2. History of significant atrial or ventricular arrhythmias.
  3. Significant liver or kidney disease.
  4. Corrected QT interval (QTc) prolongation.
  5. Subjects taking digoxin, colchicine, pimozide, cisapride, quetiapine, astemizole, terfenadine, ergotamine, or dihydroergotamine.

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 identifier (NCT number): NCT03440112

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Contact: Christine Minderovic, BS 734-998-8400
Contact: Catherine Dowling, MD 734-998-8400

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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   
Contact: Sarosh    734-998-8400   
Sponsors and Collaborators
Nicolaas Bohnen, MD, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
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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 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: July 5, 2019
Last Verified: July 2019
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:
PET Imaging
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
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