Parkinson Disease
Conditions
Keywords
Gait, Balance, Flumazenil, PET Imaging, MRI, Mobility, Intravenous
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.
Interventions
DRUGFlumazenil
1mg in 10cc normal saline
DRUGPlacebo
10 cc normal saline
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to 99 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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. |
Countries
United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 18 |
| 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. | 10 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Visit 1 | Failed to complete dopaminergic PET scan | 1 | 0 |
| Visit 2 | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Sequence B - (Placebo at Visit 1) | Sequence A - (Flumazenil at Visit 1) | Total |
|---|---|---|---|
| Age, Continuous | 69.5 years STANDARD_DEVIATION 7.2 | 68.61 years STANDARD_DEVIATION 5.85 | 68.93 years STANDARD_DEVIATION 6.25 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 18 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Postural Instability and Gait Disorder score | 5.4 units on a scale STANDARD_DEVIATION 2.28 | 5.64 units on a scale STANDARD_DEVIATION 2.75 | 5.55 units on a scale STANDARD_DEVIATION 2.55 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 18 Participants | 27 Participants |
| Region of Enrollment United States | 10 Participants | 18 Participants | 28 Participants |
| Sex: Female, Male Female | 2 Participants | 5 Participants | 7 Participants |
| Sex: Female, Male Male | 8 Participants | 13 Participants | 21 Participants |
| Thalamic FMZ PET | 3.14 Parametric DVR STANDARD_DEVIATION 0.3 | 3.10 Parametric DVR STANDARD_DEVIATION 0.24 | 3.11 Parametric DVR STANDARD_DEVIATION 0.26 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 28 |
| other Total, other adverse events | 0 / 29 | 0 / 28 |
| serious Total, serious adverse events | 0 / 29 | 0 / 28 |
Outcome results
Primary
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.
Time frame: up to 3 hours (including pre and post infusion motor evaluation)
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | PIGD Score Change | -1.375 Change in PIGD Score | Standard Deviation 0.5175492 |
| Flumazenil | PIGD Score Change | -2.500 Change in PIGD Score | Standard Deviation 1.5165751 |
Comparison: 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.p-value: 2.9e-795% CI: [0.13, 1.07]Mixed Models Analysis
Primary
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).
Time frame: up to 3 hours (including pre and post infusion motor evaluation)
Population: MDS-UPDRS PIGD scores for the same set of 28 participants, recorded before and after treatment (placebo or flumazenil) administration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Postural Instability and Gait Disorder (PIGD) Score | Before Infusion | 4.625 score on a scale | Standard Deviation 2.36 |
| Placebo | Postural Instability and Gait Disorder (PIGD) Score | After Infusion | 4.23 score on a scale | Standard Deviation 2.15 |
| Flumazenil | Postural Instability and Gait Disorder (PIGD) Score | Before Infusion | 4.625 score on a scale | Standard Deviation 2.34 |
| Flumazenil | Postural Instability and Gait Disorder (PIGD) Score | After Infusion | 4.09 score on a scale | Standard Deviation 2 |
Comparison: Null hypothesis was no difference in PIGD score within participants before and after flumazenil infusion.p-value: 0.0407Paired-Sample Two-Tailed T-Test
Comparison: Null hypothesis is that there is no significant interaction between drug and time of administration (pre vs. post infusion).p-value: 0.103Repeated Measures ANCOVA