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

NCT03462641 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: HUM00130361R01NS099535
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

Brief Summary

This arm is a positron emission tomography (PET) biomechanistic GABA-A receptor target engagement study that includes detailed clinical and motor assessments before and after the i.v. administration of 1 mg flumazenil or placebo in Parkinson disease subjects. Each subject will receive 1mg flumazenil or placebo at two visits.

Conditions

Parkinson Disease

Keywords

Gait; Balance; Flumazenil; PET Imaging; MRI; Mobility; Intravenous

Outcome Measures

Primary Outcomes (2)

• Postural Instability and Gait Disorder (PIGD) Score

  Postural Instability and Gait Disorder (PIGD) score is a subscale score of MDS-UPDRS scale. It is computed as a sum of following MDS-UPDRS items: 3.10 Gait 3.11 Freezing of gait 3.12 Postural stability 3.13 Posture Minimal possible score is 0, maximal possible score is 16. Higher scores indicate greater severity of PIGD symptoms (worse outcome).

  up to 3 hours (including pre and post infusion motor evaluation)

• PIGD Score Change

  Difference in PIGD score from pre-infusion to post-infusion. Only observations where PIGD score change is less than 0 (decrease) are retained, as the hypothesis we are interested is whether the effect magnitude of flumazenil on PIGD score depends on baseline GABA-A receptor binding as assesed by FMZ PET.

  up to 3 hours (including pre and post infusion motor evaluation)

Study Arms (2)

Sequence A - (Flumazenil at Visit 1)

EXPERIMENTAL

A detailed 90 minute clinical assessment was conducted before and after treatment administration for each visit. Flumazenil 1mg in 10cc normal saline was given intravenously (iv) over 5-10 minutes on the first visit as treatment. 10 cc of normal saline placebo was given intravenously (iv) over 5-10 minutes on the second visit as treatment.

Drug: Flumazenil; Drug: Placebo

Sequence B - (Placebo at Visit 1)

EXPERIMENTAL

A detailed 90 minute clinical assessment was conducted before and after treatment administration for each visit. 10 cc of normal saline placebo was given intravenously (iv) over 5-10 minutes on the first visit as treatment. Flumazenil 1mg in 10cc normal saline was given intravenously (iv) over 5-10 minutes on the second visit as treatment.

Drug: Flumazenil; Drug: Placebo

Interventions

Flumazenil DRUG

1mg in 10cc normal saline

Sequence A - (Flumazenil at Visit 1); Sequence B - (Placebo at Visit 1)

Placebo DRUG

10 cc normal saline

Sequence A - (Flumazenil at Visit 1); Sequence B - (Placebo at Visit 1)

Eligibility Criteria

• Age: 50 Years - 99 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 on benzodiazepine, GABA-ergic medications (baclofen, tizanidine), 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
• Any other medical history determined by investigators to preclude safe participation.
• Allergy to flumazenil
• Significant liver disease
• History of alcohol or other substance abuse within past two years.
• History of regular benzodiazepine use within past year

Sponsors & Collaborators

• University of Michigan: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator

Study Sites (1)

University of Michigan Functional Neuroimaging, Cognitive and Mobility Laboratory

Ann Arbor, Michigan, 48106, United States

Location

MeSH Terms

Conditions

Parkinson Disease

Interventions

Flumazenil

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)

Benzodiazepinones; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

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

734 998-8400

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
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Radiology and Neurology

Study Record Dates

• First Submitted: March 6, 2018
• First Posted: March 12, 2018
• Study Start: March 9, 2018
• Primary Completion: June 4, 2021
• Study Completion: June 4, 2021
• Last Updated: September 27, 2022
• Results First Posted: June 29, 2022

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)