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

• Sponsor: University of Michigan (Other)
• Overall Status: Completed
• CT.gov ID: NCT03462641
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS) (NIH)
• Enrollment: 36
• Location: 1
• Arms: 2
• Actual Duration (Months): 38.9
• Patients Per Site Per Month: 0.9

Study Details

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.

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.

Study Design

• Study Type: Interventional
• 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: Mar 9, 2018
• Actual Primary Completion Date: Jun 4, 2021
• Actual Study Completion Date: Jun 4, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Postural Instability and Gait Disorder (PIGD) Score [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 [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	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

• Principal Investigator: Nicolaas I Bohnen, MD, PhD, University of Michigan

Study Documents (Full-Text)

• Study Protocol - Dec 14, 2020
• Statistical Analysis Plan - May 31, 2022

More Information

Publications

None provided.

• Responsible Party: Nicolaas Bohnen, MD, PhD, Professor of Radiology and Neurology, University of Michigan
• ClinicalTrials.gov Identifier: NCT03462641
• Other Study ID Numbers: HUM00130361; R01NS099535
• First Posted: Mar 12, 2018
• Last Update Posted: Jun 29, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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, Professor of Radiology and Neurology, University of Michigan: Gait; Balance; Flumazenil; PET Imaging; MRI; Mobility; Intravenous
• Additional relevant MeSH terms: Parkinson Disease; Flumazenil

Study Results

Participant Flow

Pre-assignment Detail	Of the 36 people who consented, six were not actually randomized. One participant passed away for reasons unrelated to the study prior to assignment. One participant failed to complete the required dopaminergic PET scan. Two participants failed to show dopaminergic denervation on their PET scan, which was one of the exclusion criteria. Two participants withdrew prior to screening.

Arm/Group Title	Sequence A - (Flumazenil at Visit 1)	Sequence B - (Placebo at Visit 1)
Arm/Group 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.
Period Title: Visit 1
STARTED	19	11
Actually Received Drug or Placebo	18	11
COMPLETED	18	11
NOT COMPLETED	1	0
Period Title: Visit 1
STARTED	18	11
Actually Received Drug or Placebo	18	10
COMPLETED	18	10
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Sequence A - (Flumazenil at Visit 1)	Sequence B - (Placebo at Visit 1)	Total
Arm/Group 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.	Total of all reporting groups
Overall Participants	18	10	28
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	68.61 (5.85)	69.5 (7.20)	68.93 (6.25)
Sex: Female, Male (Count of Participants)
Female	5 27.8%	2 20%	7 25%
Male	13 72.2%	8 80%	21 75%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	18 100%	10 100%	28 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	1 10%	1 3.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	18 100%	9 90%	27 96.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	18 100%	10 100%	28 100%
Postural Instability and Gait Disorder score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	5.64 (2.75)	5.4 (2.28)	5.55 (2.55)
Thalamic FMZ PET (Parametric DVR) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Parametric DVR]	3.10 (0.24)	3.14 (0.30)	3.11 (0.26)

Outcome Measures

1. Primary Outcome

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)

Outcome Measure Data

Analysis Population Description

MDS-UPDRS PIGD scores for the same set of 28 participants, recorded before and after treatment (placebo or flumazenil) administration.

Arm/Group Title	Placebo	Flumazenil
Arm/Group Description	MDS-UPDRS PIGD score before treatment administration on the day when placebo was given.	MDS-UPDRS PIGD score before treatment administration on the day when flumazenil was given.
Measure Participants	28	28
Before Infusion	4.625 (2.36)	4.625 (2.34)
After Infusion	4.23 (2.15)	4.09 (2.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Flumazenil
	Comments	Null hypothesis was no difference in PIGD score within participants before and after flumazenil infusion.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0407
	Comments	Alpha was set to 0.05.
	Method	Paired-Sample Two-Tailed T-Test
	Comments
Method of Estimation	Estimation Parameter	t-value
	Estimated Value	-2.15
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 1.32
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Flumazenil
	Comments	Null hypothesis is that there is no significant interaction between drug and time of administration (pre vs. post infusion).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.103
	Comments	P value is given for the Drug*Time term, which represents interaction between time relative to administration (before infusion vs after infusion) and treatment administered (placebo vs flumazenil). Alpha was set to 0.05.
	Method	Repeated Measures ANCOVA
	Comments
Method of Estimation	Estimation Parameter	F-value
	Estimated Value	2.861
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

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)

Outcome Measure Data

Analysis Population Description

A subset of participants assigned to each sequence which showed a decrease in PIGD score from pre-infusion to post-infusion for placebo or flumazenil treatment. A total of 12 participants are included in this analysis, with some of them showing response in both placebo and flumazenil condition and others in one of the two.

Arm/Group Title	Placebo Responders	Flumazenil Responders
Arm/Group Description	A subset of participants that showed a decreased PIGD score in response to placebo treatment.	A subset of participants that showed a decreased PIGD score in response to flumazenil treatment.
Measure Participants	8	6
Mean (Standard Deviation) [Change in PIGD Score]	-1.375 (0.5175492)	-2.500 (1.5165751)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	A pair of maximum likelihood mixed linear models were estimated. The first was a random intercept model that merely accounted for individual differences in PIGD score before infusion. The second was an interaction model, that added an interaction term between baseline FMZ PET binding and PIGD score change from pre to post infusion. The interaction model was compared against the random intercept model to determine significance of the interaction using likelihood ratio goodness of fit test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.00000029
	Comments	P value presented is for model comparison between interaction model and random intercept model.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Standardized β Coefficient
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95%; 0.13 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	up to 3 hours (including pre and post infusion motor evaluation)
Arm/Group Title	Placebo Treatment		Flumazenil Treatment
Arm/Group Description	10 cc of normal saline placebo was given intravenously (iv) over 5-10 minutes. 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. 10 cc of normal saline placebo was given intravenously (iv) over 5-10 minutes. A detailed 90 minute clinical assessment was conducted before and after treatment administration for each visit.
All Cause Mortality
	Placebo Treatment		Flumazenil Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		0/28 (0%)
Serious Adverse Events
	Placebo Treatment		Flumazenil Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		0/28 (0%)
Other (Not Including Serious) Adverse Events
	Placebo Treatment		Flumazenil Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		0/28 (0%)

Limitations/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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.