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

Primary Purpose

Parkinson Disease

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Flumazenil
Placebo
Sponsored by
University of Michigan
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Parkinson Disease focused on measuring Gait, Balance, Flumazenil, PET Imaging, MRI, Mobility, Intravenous

Eligibility Criteria

50 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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, GABA-ergic medications (baclofen, tizanidine), neuroleptic, anticholinergic (trihexyphenidyl, 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.
  13. Allergy to flumazenil
  14. Significant liver disease
  15. History of alcohol or other substance abuse within past two years.
  16. History of regular benzodiazepine use within past year

Sites / Locations

  • University of Michigan Functional Neuroimaging, Cognitive and Mobility Laboratory

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Sequence A - (Flumazenil at Visit 1)

Sequence B - (Placebo at Visit 1)

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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).
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.

Secondary Outcome Measures

Full Information

First Posted
March 6, 2018
Last Updated
September 15, 2022
Sponsor
University of Michigan
Collaborators
National Institute of Neurological Disorders and Stroke (NINDS)
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1. Study Identification

Unique Protocol Identification Number
NCT03462641
Brief Title
Modulation of GABA-A Receptors in Parkinson Disease-Flumazenil Arm
Official Title
Modulation of GABA-A Receptors and Axial Motor Impairments in Parkinson Disease-Flumazenil Arm
Study Type
Interventional

2. Study Status

Record Verification Date
September 2022
Overall Recruitment Status
Completed
Study Start Date
March 9, 2018 (Actual)
Primary Completion Date
June 4, 2021 (Actual)
Study Completion Date
June 4, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Michigan
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
No
Data Monitoring Committee
Yes

5. Study Description

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.
Detailed Description
This biomechanistic GABA-A receptor target engagement study includes clinical and motor assessments before and at various time points up to approximately 90 minutes after the i.v. administration of 1 mg flumazenil and placebo in Parkinson disease subjects. Thirty Parkinson disease subjects with disease severity (Hoehn and Yahr) stages 2-4 will be recruited. Baseline [11C]FMZ and vesicular monoamine transporter type 2 (VMAT2) [11C]DTBZ brain PET imaging will be performed prior to drug administration to assess for GABA-A receptor availability and the integrity of nigrostriatal dopaminergic nerve terminals, respectively.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Parkinson Disease
Keywords
Gait, Balance, Flumazenil, PET Imaging, MRI, Mobility, Intravenous

7. Study Design

Primary Purpose
Other
Study Phase
Phase 1, Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
36 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Sequence A - (Flumazenil at Visit 1)
Arm Type
Experimental
Arm Description
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.
Arm Title
Sequence B - (Placebo at Visit 1)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Flumazenil
Intervention Description
1mg in 10cc normal saline
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
10 cc normal saline
Primary Outcome Measure Information:
Title
Postural Instability and Gait Disorder (PIGD) Score
Description
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).
Time Frame
up to 3 hours (including pre and post infusion motor evaluation)
Title
PIGD Score Change
Description
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.
Time Frame
up to 3 hours (including pre and post infusion motor evaluation)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
50 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
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 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. 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
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 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
No

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

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