Parkinson Disease
Conditions
Keywords
Gait, Balance, GABA, Transdermal flumazenil (previously Clarithromycin changed 4/2020), PET Imaging, MRI, Mobility
Brief summary
The arm of this study evaluates possible GABA-A receptor target engagement effects of the FDA-approved medication, transdermal flumazenil (added 4/2020, replaced clarithromycin), in the setting of Parkinson's disease. Half of the subjects will receive transdermal flumazenil for 7-10 days, and half will receive a placebo. \[11C\]Flumazenil GABA-A receptor PET imaging will be used to assess target engagement effects. Note \[11C\]Flumazenil GABA-A receptor PET was not performed as part of the transdermal flumazenil study because of a Covid pandemic research amendment.
Detailed description
This study focuses on neurochemical changes in the brain that occur in Parkinson's disease. In particular we will be looking a neurotransmitter called GABA. In some Parkinson's disease patients we see too much GABA activity in the brain. This target engagement study examines the target engagement effect of GABA-A receptor modulation by transdermal flumazenil (previously clarithromycin). \[11C\]-flumazenil Positron Emission Tomography (PET) imaging results will be used to assess for possible GABA-A receptor target engagement effects of transdermal flumazenil (previously clarithromycin). Note \[11C\]Flumazenil GABA-A receptor PET was not performed as part of the transdermal flumazenil study because of a Covid pandemic research amendment.
Interventions
DRUGClarithromycin (Not used as of 4/2020)
Clarithromycin (generic) capsule 250mg each
DRUGPlacebo (Not used as of 4/2020)
Lactose in a gel capsule
DRUGTransdermal flumazenil (Added 4/2020)
Transdermal flumazenil 24mg/mL
DRUGPlacebo (Added 4/2020)
Transdermal placebo
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Nicolaas Bohnen, MD, PhD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Participant, Investigator
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
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 vascu¬lar dementia, normal pressure hydrocephalus, multiple system atrophy, corticobasal ganglionic dege¬neration, or toxic causes of parkinsonism. Prototypical cases have distincti¬ve 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 currently on benzodiazepine, GABAB-ergic medications (baclofen, tizanidine), modafinil, 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. History of transient ischemic attack (TIA) or stroke within the last year. 13. History of systemic lupus erythematosis. 14. Abnormal liver enzymes (AST or ALT) \> 3 times upper limit of normal. 15. History of atrial fibrillation. 16. History of retinal branch artery occlusion. 17. Active dermatitis inner forearms. 18. Any other medical history determined by investigators to preclude safe participation. Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Quantitative Biomechanics 1 (Clinical Motor Ratings MDS-UPDRS) | Day 1 (before treatment administration), day 7 (after 7 days of treatment), and day 14 (7 days of treatment discontinuation). | We will use the total Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III - motor scale rating scores to assess motor function. Scale from 0-132, higher scores indicate worse motor outcomes. Outcome measure was collected during dopaminergic medication ON state. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Quantitative Biomechanics 2 (MiniBESTest Dynamic Balance Scale Sensory Subscore) | Day 1 (before treatment administration), day 7 (after 7 days of treatment), and day 14 (7 days of treatment discontinuation). | MiniBEST sensory subscore measures an individual's ability to maintain balance under conditions of sensory constrain and unstable/inclined standing surface. It is is computed as a sum of MiniBEST items 7, 8, and 9.The score ranges from 0 to 6, with 0 indicating inability to balance under all of the condition, and 6 indicating no difficulty in maintaining balance under any of the conditions (lower score indicates worse balance). Outcome measure was collected during dopaminergic medication ON state. |
Countries
United States
Participant flow
Pre-assignment details
5 participants withdrew prior to assignment. 7 participants were recruited for clarithromycin sub-study, which was subsequently dropped in 04/2020 due to concerns related to increased risk of death among the elderly who were taking this antibiotic even for a short time. Only 3 of those participants were randomized and went through study procedures, but the randomization key was not broken so we have no way of knowing what group they were assigned to.
Participants by arm
| Arm | Count |
|---|---|
| Transdermal Flumazenil (Active) Added in April 2020. Subjects will take 18mg transdermal application every 3-4 hrs dispensed as 3 dispenser bottle clicks of 0.25 ml each, while awake for 3 days then if no side-effects subjects will increase to 36mg transdermal application every 3-4 hrs dispensed as 6 dispenser bottle clicks of 0.25 ml each, while awake. | 11 |
| Placebo Cream Added in April 2020. Placebo will be taken exactly as the transdermal flumazenil arm: Subjects will take 18mg transdermal application every 3-4 hrs dispensed as 3 dispenser bottle clicks of 0.25 ml each, while awake for 3 days then if no side-effects subjects will increase to 36mg transdermal application every 3-4 hrs dispensed as 6 dispenser bottle clicks of 0.25 ml each, while awake. | 11 |
| Oral Clarithromycin (Active or Placebo) Discontinued April 2020, study aborted. Subjects will take 250 mg twice daily by mouth for 3 days and then - if no side-effects - the dose will increased to 500 mg twice daily by mouth. | 3 |
| Total | 25 |
Baseline characteristics
| Characteristic | Total | Transdermal Flumazenil (Active) | Placebo Cream | Oral Clarithromycin (Active or Placebo) |
|---|---|---|---|---|
| Age, Continuous | 70.6 years STANDARD_DEVIATION 4.43 | 72.09 years STANDARD_DEVIATION 4.41 | 70.27 years STANDARD_DEVIATION 3.8 | 66.33 years STANDARD_DEVIATION 5.13 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 11 Participants | 11 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| MiniBEST Sensory Subscore | 5.6 units on a scale STANDARD_DEVIATION 0.82 | 5.27 units on a scale STANDARD_DEVIATION 1.1 | 5.81 units on a scale STANDARD_DEVIATION 0.4 | 6 units on a scale STANDARD_DEVIATION 0 |
| Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III | 43.5 units on a scale | 45 units on a scale | 41.5 units on a scale | 40.50 units on a scale |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 25 Participants | 11 Participants | 11 Participants | 3 Participants |
| Region of Enrollment United States | 25 participants | 11 participants | 11 participants | 3 participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 20 Participants | 8 Participants | 10 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 11 | 0 / 3 |
| other Total, other adverse events | 0 / 11 | 0 / 11 | 0 / 3 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 | 0 / 3 |
Outcome results
Primary
Change in Quantitative Biomechanics 1 (Clinical Motor Ratings MDS-UPDRS)
We will use the total Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III - motor scale rating scores to assess motor function. Scale from 0-132, higher scores indicate worse motor outcomes. Outcome measure was collected during dopaminergic medication ON state.
Time frame: Day 1 (before treatment administration), day 7 (after 7 days of treatment), and day 14 (7 days of treatment discontinuation).
Population: Parkinson's disease participants older than 50. Some, but not all, participants in the Clarithromycin arm were randomized, and only few completed study procedures because of premature termination of the trial due to an FDA safety risk warning of Clarithromycin, precluding any meaningful analysis. Consequently, this study arm was replaced by the transdermal Flumazenil arm.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Transdermal Flumazenil (Active) | Change in Quantitative Biomechanics 1 (Clinical Motor Ratings MDS-UPDRS) | Day 7 | 36.75 units on a scale |
| Transdermal Flumazenil (Active) | Change in Quantitative Biomechanics 1 (Clinical Motor Ratings MDS-UPDRS) | Day 1 | 38 units on a scale |
| Transdermal Flumazenil (Active) | Change in Quantitative Biomechanics 1 (Clinical Motor Ratings MDS-UPDRS) | Day 14 | 32.75 units on a scale |
| Placebo Cream | Change in Quantitative Biomechanics 1 (Clinical Motor Ratings MDS-UPDRS) | Day 7 | 31.50 units on a scale |
| Placebo Cream | Change in Quantitative Biomechanics 1 (Clinical Motor Ratings MDS-UPDRS) | Day 1 | 34 units on a scale |
| Placebo Cream | Change in Quantitative Biomechanics 1 (Clinical Motor Ratings MDS-UPDRS) | Day 14 | 34 units on a scale |
| Clarithromycin (Active or Placebo) | Change in Quantitative Biomechanics 1 (Clinical Motor Ratings MDS-UPDRS) | Day 1 | 28 units on a scale |
| Clarithromycin (Active or Placebo) | Change in Quantitative Biomechanics 1 (Clinical Motor Ratings MDS-UPDRS) | Day 14 | 22 units on a scale |
| Clarithromycin (Active or Placebo) | Change in Quantitative Biomechanics 1 (Clinical Motor Ratings MDS-UPDRS) | Day 7 | 23.50 units on a scale |
Comparison: A pair of random-intercept mixed linear models was fitted, a visit model and an interaction model. Visit model included fixed effect of visit and a random intercept by participant. Interaction model adds an interaction by treatment term on top of the visit model. Null hypothesis is that visit by treatment interaction does not explain significant additional variance in clinical outcome scores. Likelihood ratio test comparing the interaction model to the visit model was used to derive a p-value.p-value: 0.391Mixed Models Analysis
Secondary
Change in Quantitative Biomechanics 2 (MiniBESTest Dynamic Balance Scale Sensory Subscore)
MiniBEST sensory subscore measures an individual's ability to maintain balance under conditions of sensory constrain and unstable/inclined standing surface. It is is computed as a sum of MiniBEST items 7, 8, and 9.The score ranges from 0 to 6, with 0 indicating inability to balance under all of the condition, and 6 indicating no difficulty in maintaining balance under any of the conditions (lower score indicates worse balance). Outcome measure was collected during dopaminergic medication ON state.
Time frame: Day 1 (before treatment administration), day 7 (after 7 days of treatment), and day 14 (7 days of treatment discontinuation).
Population: Parkinson's disease participants older than 50. Some, but not all, participants in the Clarithromycin arm were randomized, and only few completed study procedures (baseline visit only) because of premature termination of the trial due to an FDA safety risk warning of Clarithromycin, precluding any meaningful analysis. Consequently, this study arm was replaced by the transdermal Flumazenil arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Transdermal Flumazenil (Active) | Change in Quantitative Biomechanics 2 (MiniBESTest Dynamic Balance Scale Sensory Subscore) | Day 7 | 5.82 units on a scale | Standard Deviation 0.4 |
| Transdermal Flumazenil (Active) | Change in Quantitative Biomechanics 2 (MiniBESTest Dynamic Balance Scale Sensory Subscore) | Day 1 | 5.54 units on a scale | Standard Deviation 0.69 |
| Transdermal Flumazenil (Active) | Change in Quantitative Biomechanics 2 (MiniBESTest Dynamic Balance Scale Sensory Subscore) | Day 14 | 6 units on a scale | Standard Deviation 0 |
| Placebo Cream | Change in Quantitative Biomechanics 2 (MiniBESTest Dynamic Balance Scale Sensory Subscore) | Day 7 | 6 units on a scale | Standard Deviation 0 |
| Placebo Cream | Change in Quantitative Biomechanics 2 (MiniBESTest Dynamic Balance Scale Sensory Subscore) | Day 1 | 6 units on a scale | Standard Deviation 0 |
| Placebo Cream | Change in Quantitative Biomechanics 2 (MiniBESTest Dynamic Balance Scale Sensory Subscore) | Day 14 | 5.82 units on a scale | Standard Deviation 0.6 |
| Clarithromycin (Active or Placebo) | Change in Quantitative Biomechanics 2 (MiniBESTest Dynamic Balance Scale Sensory Subscore) | Day 1 | 6 units on a scale | Standard Deviation 0 |
| Clarithromycin (Active or Placebo) | Change in Quantitative Biomechanics 2 (MiniBESTest Dynamic Balance Scale Sensory Subscore) | Day 14 | 6 units on a scale | Standard Deviation 0 |
| Clarithromycin (Active or Placebo) | Change in Quantitative Biomechanics 2 (MiniBESTest Dynamic Balance Scale Sensory Subscore) | Day 7 | 5.67 units on a scale | Standard Deviation 0.58 |
Comparison: A pair of random-intercept mixed linear models was fitted, a visit model and an interaction model. Visit model included fixed effect of visit and a random intercept by participant. Interaction model adds an interaction by treatment term on top of the visit model. Null hypothesis is that visit by treatment interaction does not explain significant additional variance in clinical outcome scores. Likelihood ratio test comparing the interaction model to the visit model was used to derive a p-value.p-value: 0.02351Mixed Models Analysis