Clinical trial NCT03462641
Conditions: Parkinson Disease
Keywords: Gait Balance Flumazenil PET Imaging MRI Mobility Intravenous
Sponsor: University of Michigan
Start date: 2018-03-09; Completion date: 2021-06-04
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

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.

Arms: arm 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. arm 2: 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.
Interventions: intervention 1: Flumazenil intervention 2: Placebo
Intervention descriptions: intervention 1: 1mg in 10cc normal saline intervention 2: 10 cc normal saline

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
Protocol Synopsis  
Modulation of GABA-A Receptors in Parkinson Disease-Flumazenil Arm  
NCT03462641  
12/14/2020  
 


Axial motor impairments represent a significant cause of disability in Parkinson disease (PD), 
which is mainly explained by a lack of efficacy of dopaminergic treatments of these symptoms. 
Treatment approaches to reduce balance problems and falls have been recently identified as the 
number 1 research priority in PD. Postural instability and gait difficulties (PIGD) motor features 
are mediated by widespread neural networks that extend well beyond the nigrostriatal system. 
There is increasing interest in dysfunction of non-dopaminergic neurotransmitters to better 
understand the complexity of the multisystem nature of mobility impairments in PD. Flumazenil 
is a short-acting intravenously administered modulator of the γ-aminobutyric acid-A (GABA-A) 
receptor benzodiazepine binding site, which has shown to rapidly improve motor impairments in 
PD. Based upon current basal ganglion models in PD, flumazenil could normalize neuronal 
signaling of hyperGABA-ergic activity in PD.  
We have preliminary data that reduced cerebral GABAA receptor availability (likely reflecting 
increased synaptic or extracellular GABA-ergic activity) as determined by [11C]flumazenil PET 
imaging has most robust association with axial compared to other cardinal motor impairments in 
PD. Although flumazenil therapy has been shown to improve motor symptoms in PD, its 
practical limitation is that it can only be effectively and reliably given intravenously. The 
overarching goal of this project is to perform biomechanistic GABAA receptor target 
engagement studies to investigate the effects of GABAA receptor modulation to motor 
impairments in PD, including PIGD features using i.v. flumazenil vs placebo in a cross-over 
study design to be correlated to pretreatment C11-flumazenil PET thalamic binding. Our main 
hypothesis is that negative allosteric modulation of cerebral GABAA receptor activity improves 
dopamine-resistant PIGD features. 

SAP_001.pdf: 
 
 
 
 
 
 
Statistical Analysis Plan 
Modulation of GABA-A Receptors in Parkinson Disease-Flumazenil Arm  
NCT03462641  
05/31/2022  
 


In this proposal, the investigators present data suggesting that flumazenil (FMZ) administration 
leads to a decrease in postural instability and gait disorder (PIGD) symptoms of Parkinson’s 
Disease (PD). Further association is made between treatment effectiveness and GABA-A receptor 
FMZ PET thalamic binding at baseline.  
  
Study participants were pseudo-randomly assigned into A and B sequences, and came in for two 
visits, with sequence A participants receiving FMZ infusion on the first visit and sequence B 
participants receiving saline infusion (placebo) on the first visit. The other treatment was given 
on the subsequent day for participants in both sequences. Detailed motor examination including 
modified UPDRS was conducted on both days prior to infusion and at 60-90 minutes 
postinjection. UPDRS PIGD motor subscale score was computed as our primary outcome 
measure. FMZ PET imaging was done to collect data for the test of interaction between treatment 
and GABA-A receptor availability.  
  
A paired samples t-test was conducted for each participant’s pre and post infusion PIGD score for 
the flumazenil pharmacological injection treatment only to test whether FMZ pharmacological 
injection appears to have any effect on PIGD score in a univariate comparison. A repeated 
measures ANOVA model was used to test the significance of interaction between treatment 
(FMZ pharmacological injection vs. placebo) and time of administration (pre-infusion vs. post-
infusion), with additional three-way interaction term between treatment, time of administration, 
and sequence (A vs B) included to account for potential confounding effect of sequence. Lastly, a 
mixed linear model comparison was conducted between the random intercept model and FMZ 
PET by treatment interaction model, to test the hypothesis that the effect of flumazenil 
pharmacological i.v. treatment on change in PIGD scores depends on baseline GABA-A FMZ 
PET receptor availability in the thalamus. Bilaterally averaged thalamic FMZ PET distribution 
volume ratio (DVR) by treatment (FMZ pharmacological therapy injection vs placebo) was used 
for the interaction term, and difference between PIGD scores (post – pre) infusion were used as a 
response variable for that model.