Parkinson DiseasePhase 1/2GABA-ANCT03440112

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

A Phase 1/2 study testing Clarithromycin (Not used as of 4/2020) and Transdermal flumazenil (Added 4/2020) in people with Parkinson Disease, run by Nicolaas Bohnen, MD, PhD at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 50 years and older
Conditions the study is for: Parkinson Disease
What is being tested?: Clarithromycin (Not used as of 4/2020) and Transdermal flumazenil (Added 4/2020)
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 34 participants
Where: 1 siteUnited States
Study dates: 29 Jan 2018to 8 Dec 2021
Phase: Phase 1/2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 50 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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

Who cannot join

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.

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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

Trial locations and contacts

1 site in 1 country.

United States1 site

University of Michigan Health System Functional Neuroimaging, Cognitive and Mobility Laboratory
Ann Arbor, Michigan, 48106

Other trials in United States

About this study

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

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.

Read the 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.

Conditions: Parkinson Disease
Being tested: Clarithromycin (Not used as of 4/2020), Placebo (Not used as of 4/2020), Transdermal flumazenil (Added 4/2020), Placebo (Added 4/2020)
Keywords: Gait, Balance, GABA, Transdermal flumazenil (previously Clarithromycin changed 4/2020), PET Imaging, MRI, Mobility
Medical subject headings: Parkinson Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Clarithromycin (Not used as of 4/2020)Drug
Also called Biaxin
Clarithromycin (generic) capsule 250mg each
Placebo (Not used as of 4/2020)Drug
Lactose in a gel capsule
Transdermal flumazenil (Added 4/2020)Drug
Transdermal flumazenil 24mg/mL
Placebo (Added 4/2020)Drug
Also called Placebo cream
Transdermal placebo

Study groups in NCT03440112
Study group	Role	What they receive
Clarithromycin (Not used anymore as of 4/2020; study aborted)	Active comparator	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. Receives: Drug: Clarithromycin (Not used as of 4/2020)
Placebo (Not used anymore as of 4/2020; study aborted)	Placebo comparator	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. Receives: Drug: Placebo (Not used as of 4/2020)
Transdermal flumazenil (added 4/2020 as safer alternative for clarithromycin)	Active comparator	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. Receives: Drug: Transdermal flumazenil (Added 4/2020)
Placebo cream (added 4/2020)	Placebo comparator	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. Receives: Drug: Placebo (Added 4/2020)

What is being measured

The primary outcome is the main question the study is designed to answer.

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

Secondary outcomes (1)

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

29 Jan 20188 Dec 2021

First posted20 Feb 2018
Study start29 Jan 2018
Primary completion8 Dec 2021
Study completion8 Dec 2021

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Other trials for Parkinson DiseaseStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1/2
Primary purpose: Other
Allocation: Randomised
Intervention model: Parallel groups
Masking: Triple blind
Who is masked: Participant, Care provider, Investigator
Enrolment: 34 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03440112
Sponsor's protocol ID: HUM00360361-A
Other IDs: R01NS099535
Acronym: GABA-A
Status last verified: Dec 2022
First submitted: 26 Jan 2018
Last updated: 10 Jan 2023
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: No

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Study at a glance

From the registry record, last updated by the sponsor on 10 Jan 2023. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Modulation of GABA-A Receptors and Axial Motor Impairments in Parkinson
ClinicalTrials.gov ID: NCT03440112
Acronym / sponsor ID: GABA-A / HUM00360361-A
Conditions: Parkinson Disease
Keywords: Gait, Balance, GABA, Transdermal flumazenil (previously Clarithromycin changed 4/2020), PET Imaging, MRI, Mobility
Phase: Phase 1/2
Study type: Interventional
Recruitment status: Completed
Enrolment: 34 participants (actual)
Lead sponsor: Nicolaas Bohnen, MD, PhDUniversity, hospital or other
Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
Study start: 29 Jan 2018 (actual)
Primary completion: 8 Dec 2021 (actual)
Study completion: 8 Dec 2021 (actual)
First posted: 20 Feb 2018 (actual)
Results: Posted 10 Jan 2023

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Other
Allocation: Randomised
Intervention model: Parallel groups
Masking: Triple blind (participant, care provider, investigator)
Number of arms: 4

Arm	Type	Receives
Clarithromycin (Not used anymore as of 4/2020; study aborted)	Active comparator	Drug: Clarithromycin (Not used 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.
Placebo (Not used anymore as of 4/2020; study aborted)	Placebo comparator	Drug: Placebo (Not used 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.
Transdermal flumazenil (added 4/2020 as safer alternative for clarithromycin)	Active comparator	Drug: 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.
Placebo cream (added 4/2020)	Placebo comparator	Drug: Placebo (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.

Who may qualify

Ages: 50 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (4 listed)

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

Key exclusion criteria (23 listed)

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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Clarithromycin (Not used as of 4/2020)Also: BiaxinClarithromycin (generic) capsule 250mg each	Drug	Clarithromycin (Not used anymore as of 4/2020; study aborted)
Placebo (Not used as of 4/2020)Lactose in a gel capsule	Drug	Placebo (Not used anymore as of 4/2020; study aborted)
Transdermal flumazenil (Added 4/2020)Transdermal flumazenil 24mg/mL	Drug	Transdermal flumazenil (added 4/2020 as safer alternative for clarithromycin)
Placebo (Added 4/2020)Also: Placebo creamTransdermal placebo	Drug	Placebo cream (added 4/2020)

Primary outcome

Change in Quantitative Biomechanics 1 (Clinical Motor Ratings MDS-UPDRS)
Time frame: Day 1 (before treatment administration), day 7 (after 7 days of treatment), and day 14 (7 days of treatment discontinuation).
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.

1 secondary outcome

Change in Quantitative Biomechanics 2 (MiniBESTest Dynamic Balance Scale Sensory Subscore)
Time frame: Day 1 (before treatment administration), day 7 (after 7 days of treatment), and day 14 (7 days of treatment discontinuation).

Results and safety

Results posted to the registry on 10 Jan 2023, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Transdermal Flumazenil (Active)	11	11
Placebo Cream	11	11
Oral Clarithromycin (Dropped in 04/2020)	3	3

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

Time frame: Day 1 (before treatment administration), day 7 (after 7 days of treatment), and day 14 (7 days of treatment discontinuation).. Median (Inter-Quartile Range). Unit: units on a scale

Measure	Transdermal Flumazenil (Active) n = 11	Placebo Cream n = 11	Clarithromycin (Active or Placebo) n = 3
Day 1	38 (27.5 to 44.5)	34 (30 to 47)	28 (25.50 to 33.00)
Day 7	36.75 (29.75 to 52)	31.50 (25.375 to 43.375)	23.50 (21.25 to 26.75)
Day 14	32.75 (26.375 to 47.375)	34 (29.5 to 40)	22 (19.5 to 23.0)

Transdermal Flumazenil (Active) vs Placebo Cream: Chi-Squared: 3.0039, p = 0.391, Mixed Models Analysis

Population analysed: Parkinson's disease participants older than 50. Some, but not all, participants in the Clarithromycin arm were randomized, and only few completed study procedures because of premature termination of the trial due to an FDA safety risk warning of Clarithromycin, precluding any meaningful analysis. Consequently, this study arm was replaced by the transdermal Flumazenil arm.

1 secondary outcome is reported in the full results.

Adverse events

Time frame: Up to 14 days.. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Transdermal Flumazenil (Active)	0 of 11 (0%)	0 of 11 (0%)	0 of 11
Placebo Cream	0 of 11 (0%)	0 of 11 (0%)	0 of 11
Oral Clarithromycin (Dropped in 04/2020)	0 of 3 (0%)	0 of 3 (0%)	0 of 3

Limitations and caveats (from the sponsor): Our participants were predominantly male, which is often the case with Parkinson's disease (PD) patient population since PD is known to affect males at a greater rate. This means that our findings may not generalize as well to population of female PD patients.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 10 Jan 2023.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Individual participant dataSharing planned: No

Related trials for Parkinson Disease

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Nicolaas I Bohnen, MD, PhD principal investigator

University of Michigan

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Jan 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 10 Jan 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Quantitative Biomechanics 1 (Clinical Motor Ratings MDS-UPDRS) (time frame: Day 1 (before treatment administration), day 7 (after 7 days of treatment), and day 14 (7 days of treatment discontinuation).). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03440112.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jan 2023.