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

Primary Purpose

Parkinson Disease

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Clarithromycin (Not used as of 4/2020)

Placebo (Not used as of 4/2020)

Transdermal flumazenil (Added 4/2020)

Placebo (Added 4/2020)

About this trial

This is an interventional other trial for Parkinson Disease focused on measuring Gait, Balance, GABA, Transdermal flumazenil (previously Clarithromycin changed 4/2020), PET Imaging, MRI, Mobility

Eligibility Criteria

50 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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.

Additional Exclusion Criteria for Flumazenil sub-studies:

Allergy to flumazenil
Significant liver disease
History of alcohol or other substance abuse within past two years.
Subjects currently taking benzodiazepines

Sites / Locations

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

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Placebo Comparator

Active Comparator

Placebo Comparator

Arm Label

Clarithromycin (Not used anymore as of 4/2020; study aborted)

Placebo (Not used anymore as of 4/2020; study aborted)

Transdermal flumazenil (added 4/2020 as safer alternative for clarithromycin)

Placebo cream (added 4/2020)

Arm Description

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 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.

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.

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.

Outcomes

Primary Outcome Measures

Change in Quantitative Biomechanics 1 (Clinical Motor Ratings MDS-UPDRS)

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

Change in Quantitative Biomechanics 2 (MiniBESTest Dynamic Balance Scale Sensory Subscore)

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.

Full Information

NCT ID

NCT03440112

First Posted

January 26, 2018

Last Updated

December 15, 2022

Sponsor

Nicolaas Bohnen, MD, PhD

Collaborators

National Institute of Neurological Disorders and Stroke (NINDS)

1. Study Identification

Unique Protocol Identification Number

NCT03440112

Brief Title

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

Acronym

GABA-A

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

December 2022

Overall Recruitment Status

Completed

Study Start Date

January 29, 2018 (Actual)

Primary Completion Date

December 8, 2021 (Actual)

Study Completion Date

December 8, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Nicolaas Bohnen, MD, PhD

Collaborators

National Institute of Neurological Disorders and Stroke (NINDS)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Parkinson Disease

Keywords

Gait, Balance, GABA, Transdermal flumazenil (previously Clarithromycin changed 4/2020), PET Imaging, MRI, Mobility

7. Study Design

Primary Purpose

Other

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Masking Description

Participant, Investigator

Allocation

Randomized

Enrollment

34 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Clarithromycin (Not used anymore as of 4/2020; study aborted)

Arm Type

Active Comparator

Arm Description

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.

Arm Title

Placebo (Not used anymore as of 4/2020; study aborted)

Arm Type

Placebo Comparator

Arm Description

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.

Arm Title

Transdermal flumazenil (added 4/2020 as safer alternative for clarithromycin)

Arm Type

Active Comparator

Arm Description

Arm Title

Placebo cream (added 4/2020)

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Clarithromycin (Not used as of 4/2020)

Other Intervention Name(s)

Biaxin

Intervention Description

Clarithromycin (generic) capsule 250mg each

Intervention Type

Drug

Intervention Name(s)

Placebo (Not used as of 4/2020)

Intervention Description

Lactose in a gel capsule

Intervention Type

Drug

Intervention Name(s)

Transdermal flumazenil (Added 4/2020)

Intervention Description

Transdermal flumazenil 24mg/mL

Intervention Type

Drug

Intervention Name(s)

Placebo (Added 4/2020)

Other Intervention Name(s)

Placebo cream

Intervention Description

Transdermal placebo

Primary Outcome Measure Information:

Title

Change in Quantitative Biomechanics 1 (Clinical Motor Ratings MDS-UPDRS)

Description

Time Frame

Day 1 (before treatment administration), day 7 (after 7 days of treatment), and day 14 (7 days of treatment discontinuation).

Secondary Outcome Measure Information:

Title

Change in Quantitative Biomechanics 2 (MiniBESTest Dynamic Balance Scale Sensory Subscore)

Description

Time Frame

Day 1 (before treatment administration), day 7 (after 7 days of treatment), and day 14 (7 days of treatment discontinuation).

10. Eligibility

Sex

All

Minimum Age & Unit of Time

50 Years

Accepts Healthy Volunteers

Eligibility Criteria

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. Additional Exclusion Criteria for Flumazenil sub-studies: Allergy to flumazenil Significant liver disease History of alcohol or other substance abuse within past two years. Subjects currently taking benzodiazepines

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Nicolaas I Bohnen, MD, PhD

Organizational Affiliation

University of Michigan

Official's Role

Principal Investigator

Facility Information:

Facility Name

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

City

Ann Arbor

State/Province

Michigan

ZIP/Postal Code

48106

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

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

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