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

NCT03440112 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: HUM00360361-AR01NS099535
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

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.

Conditions

Parkinson Disease

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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.

  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)

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

Study Arms (4)

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.

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.

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.

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.

Drug: Placebo (Added 4/2020)

Interventions

Clarithromycin (Not used as of 4/2020) DRUG

Clarithromycin (generic) capsule 250mg each

Also known as: Biaxin

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

Placebo (Not used as of 4/2020) DRUG

Lactose in a gel capsule

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

Transdermal flumazenil (Added 4/2020) DRUG

Transdermal flumazenil 24mg/mL

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

Placebo (Added 4/2020) DRUG

Transdermal placebo

Also known as: Placebo cream

Placebo cream (added 4/2020)

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• PD with Dementia (PDD) or dementia with Lewy bodies (DLB).
• 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.

Sponsors & Collaborators

• Nicolaas Bohnen, MD, PhD: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator

Study Sites (1)

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

Ann Arbor, Michigan, 48106, United States

Location

MeSH Terms

Conditions

Parkinson Disease

Interventions

Clarithromycin

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals

Limitations and Caveats

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.

Results Point of Contact

• Title: Stiven Roytman
• Organization: University of Michigan

stivenr@med.umich.edu

7349988424

Study Officials

• Nicolaas I Bohnen, MD, PhD

  University of Michigan

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Participant, Investigator
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Radiology and Neurology

Study Record Dates

• First Submitted: January 26, 2018
• First Posted: February 20, 2018
• Study Start: January 29, 2018
• Primary Completion: December 8, 2021
• Study Completion: December 8, 2021
• Last Updated: January 10, 2023
• Results First Posted: January 10, 2023

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)