A Phase 1/2 interventional study of Clarithromycin (Not used as of 4/2020) and Placebo (Not used as of 4/2020) in Parkinson Disease, sponsored by Nicolaas Bohnen, MD, PhD. Completed at 1 site in United States. Open to participants aged 50 Years and older. Per ClinicalTrials.gov, last updated 2023-01-10.
Sponsored by Nicolaas Bohnen, MD, PhD · Phase 1/2, Interventional, and Other
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.
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.
Exclusion Criteria:
Additional Exclusion Criteria for Flumazenil sub-studies:
Clarithromycin 250mg (1 capsule) will be taken orally twice a day for 3 days and if tolerated will be increased to 500mg (2 capsules) orally twice a day for 4-6 days.
Drug: Clarithromycin (Not used as of 4/2020)
Placebo will be taken exactly as the clarithromycin arm: 1 capsule orally twice a day for 3 days and if tolerated will be increased to 2 capsules orally twice a day for 4-6 days.
Drug: Placebo (Not used as of 4/2020)
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.
Drug: Transdermal flumazenil (Added 4/2020)
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.
Drug: Placebo (Added 4/2020)
Clarithromycin (generic) capsule 250mg each
Also known as: Biaxin
Lactose in a gel capsule
Transdermal flumazenil 24mg/mL
Transdermal placebo
Also known as: Placebo cream
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).
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).
| Milestone | Transdermal Flumazenil (Active) | Placebo Cream | Oral Clarithromycin (Dropped in 04/2020) |
|---|---|---|---|
| Started | 11 | 11 | 3 |
| Completed | 11 | 11 | 3 |
| Not completed | 0 | 0 | 0 |
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.
| units on a scale | Transdermal Flumazenil (Active) | Placebo Cream | Clarithromycin (Active or Placebo) |
|---|---|---|---|
| Day 1 | 38 (27.5 to 44.5) | 34 (30 to 47) | 28 (25.50 to 33.00) |
| Day 7 | 36.75 (29.75 to 52) | 31.50 (25.375 to 43.375) | 23.50 (21.25 to 26.75) |
| Day 14 | 32.75 (26.375 to 47.375) | 34 (29.5 to 40) | 22 (19.5 to 23.0) |
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.
| units on a scale | Transdermal Flumazenil (Active) | Placebo Cream | Clarithromycin (Active or Placebo) |
|---|---|---|---|
| Day 1 | 5.54 ± 0.69 | 6 ± 0 | 6 ± 0 |
| Day 7 | 5.82 ± 0.40 | 6 ± 0 | 5.67 ± 0.58 |
| Day 14 | 6 ± 0 | 5.82 ± 0.60 | 6 ± 0 |
Collected over Up to 14 days.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Transdermal Flumazenil (Active) | 0/11 (0%) | 0/11 (0%) | 0/11 (0%) |
| Placebo Cream | 0/11 (0%) | 0/11 (0%) | 0/11 (0%) |
| Oral Clarithromycin (Dropped in 04/2020) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) |
Parkinson's disease patients age 50 years or older. 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.
| Age, Continuous(years) | Transdermal Flumazenil (Active) | Placebo Cream | Oral Clarithromycin (Active or Placebo) | Total |
|---|---|---|---|---|
| Mean | 72.09 ± 4.41 | 70.27 ± 3.80 | 66.33 ± 5.13 | 70.6 ± 4.43 |
| Sex: Female, Male(Participants) | Transdermal Flumazenil (Active) | Placebo Cream | Oral Clarithromycin (Active or Placebo) | Total |
|---|---|---|---|---|
| Female | 3 | 1 | 1 | 5 |
| Male | 8 | 10 | 2 | 20 |
| Ethnicity (NIH/OMB)(Participants) | Transdermal Flumazenil (Active) | Placebo Cream | Oral Clarithromycin (Active or Placebo) | Total |
|---|---|---|---|---|
| Hispanic or Latino | 0 | 0 | 0 | 0 |
| Not Hispanic or Latino | 11 | 11 | 3 | 25 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Transdermal Flumazenil (Active) | Placebo Cream | Oral Clarithromycin (Active or Placebo) | Total |
|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 | 0 |
| White | 11 | 11 | 3 | 25 |
| More than one race | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 |
| Region of Enrollment(participants) | Transdermal Flumazenil (Active) | Placebo Cream | Oral Clarithromycin (Active or Placebo) | Total |
|---|---|---|---|---|
| United States | 11 | 11 | 3 | 25 |
| MiniBEST Sensory Subscore(units on a scale) | Transdermal Flumazenil (Active) | Placebo Cream | Oral Clarithromycin (Active or Placebo) | Total |
|---|---|---|---|---|
| Mean | 5.27 ± 1.1 | 5.81 ± 0.40 | 6 ± 0 | 5.6 ± 0.82 |
| Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III(units on a scale) | Transdermal Flumazenil (Active) | Placebo Cream | Oral Clarithromycin (Active or Placebo) | Total |
|---|---|---|---|---|
| Median | 45 (38.5 to 57) | 41.5 (37 to 49.25) | 40.50 (33.00 to 45.25) | 43.5 (36.00 to 51.50) |
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Nicolaas Bohnen, MD, PhD