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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03462641
Recruitment Status : Completed
First Posted : March 12, 2018
Results First Posted : June 29, 2022
Last Update Posted : September 27, 2022
Sponsor:
Collaborator:
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Nicolaas Bohnen, MD, PhD, University of Michigan

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.

Condition or disease Intervention/treatment Phase
Parkinson Disease Drug: Flumazenil Drug: Placebo Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 36 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Other
Official Title: Modulation of GABA-A Receptors and Axial Motor Impairments in Parkinson Disease-Flumazenil Arm
Actual Study Start Date : March 9, 2018
Actual Primary Completion Date : June 4, 2021
Actual Study Completion Date : June 4, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Flumazenil

Arm Intervention/treatment
Experimental: Sequence A - (Flumazenil at Visit 1)
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
1mg in 10cc normal saline

Drug: Placebo
10 cc normal saline

Experimental: Sequence B - (Placebo at Visit 1)
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
1mg in 10cc normal saline

Drug: Placebo
10 cc normal saline




Primary Outcome Measures :
  1. Postural Instability and Gait Disorder (PIGD) Score [ Time Frame: up to 3 hours (including pre and post infusion motor evaluation) ]

    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).


  2. PIGD Score Change [ Time Frame: up to 3 hours (including pre and post infusion motor evaluation) ]
    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.



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Ages Eligible for Study:   50 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03462641


Locations
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United States, Michigan
University of Michigan Functional Neuroimaging, Cognitive and Mobility Laboratory
Ann Arbor, Michigan, United States, 48106
Sponsors and Collaborators
University of Michigan
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
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Principal Investigator: Nicolaas I Bohnen, MD, PhD University of Michigan
  Study Documents (Full-Text)

Documents provided by Nicolaas Bohnen, MD, PhD, University of Michigan:
Study Protocol  [PDF] December 14, 2020
Statistical Analysis Plan  [PDF] May 31, 2022

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Responsible Party: Nicolaas Bohnen, MD, PhD, Professor of Radiology and Neurology, University of Michigan
ClinicalTrials.gov Identifier: NCT03462641    
Other Study ID Numbers: HUM00130361
R01NS099535 ( U.S. NIH Grant/Contract )
First Posted: March 12, 2018    Key Record Dates
Results First Posted: June 29, 2022
Last Update Posted: September 27, 2022
Last Verified: September 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Nicolaas Bohnen, MD, PhD, University of Michigan:
Gait
Balance
Flumazenil
PET Imaging
MRI
Mobility
Intravenous
Additional relevant MeSH terms:
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Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Synucleinopathies
Neurodegenerative Diseases
Flumazenil
Antidotes
Protective Agents
Physiological Effects of Drugs
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action