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| ID | Type | Description | Link |
|---|---|---|---|
| R01NS099535 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Neurological Disorders and Stroke (NINDS) | NIH |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Clarithromycin (Not used anymore as of 4/2020; study aborted) | Active Comparator | 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. |
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| Placebo (Not used anymore as of 4/2020; study aborted) | Placebo Comparator | 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. |
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| Transdermal flumazenil (added 4/2020 as safer alternative for clarithromycin) | Active Comparator | 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. |
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| Placebo cream (added 4/2020) | Placebo Comparator | 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Clarithromycin (Not used as of 4/2020) | Drug | Clarithromycin (generic) capsule 250mg each |
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| Measure | Description | Time Frame |
|---|---|---|
| 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. | Day 1 (before treatment administration), day 7 (after 7 days of treatment), and day 14 (7 days of treatment discontinuation). |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
Additional Exclusion Criteria for Flumazenil sub-studies:
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| Name | Affiliation | Role |
|---|---|---|
| Nicolaas I Bohnen, MD, PhD | University of Michigan | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Michigan Health System Functional Neuroimaging, Cognitive and Mobility Laboratory | Ann Arbor | Michigan | 48106 | United States |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Transdermal Flumazenil (Active) | 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. |
| FG001 | Placebo Cream | 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. |
| FG002 | Oral Clarithromycin (Dropped in 04/2020) | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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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.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Median | Inter-Quartile Range | units on a scale | Day 1 (before treatment administration), day 7 (after 7 days of treatment), and day 14 (7 days of treatment discontinuation). |
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Up to 14 days.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Transdermal Flumazenil (Active) | 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. |
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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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Stiven Roytman | University of Michigan | 7349988424 | stivenr@med.umich.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Dec 14, 2020 | Oct 25, 2022 | Prot_003.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Sep 12, 2022 | Oct 25, 2022 | SAP_004.pdf |
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| ID | Term |
|---|---|
| D010300 | Parkinson Disease |
| ID | Term |
|---|---|
| D020734 | Parkinsonian Disorders |
| D001480 | Basal Ganglia Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| D017291 | Clarithromycin |
| ID | Term |
|---|---|
| D004917 | Erythromycin |
| D018942 | Macrolides |
| D061065 | Polyketides |
| D007783 | Lactones |
| D009930 |
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Participant, Investigator
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| Placebo (Not used as of 4/2020) | Drug | Lactose in a gel capsule |
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| Transdermal flumazenil (Added 4/2020) | Drug | Transdermal flumazenil 24mg/mL |
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| Placebo (Added 4/2020) | Drug | Transdermal placebo |
|
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| Day 1 (before treatment administration), day 7 (after 7 days of treatment), and day 14 (7 days of treatment discontinuation). |
| BG001 |
| 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. |
| BG002 | 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. |
| BG003 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| MiniBEST 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). Baseline measure was collected during pre-clinical screening visit in dopaminergic medication OFF state. | Mean | Standard Deviation | units on a scale |
|
| Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III | We will use the total Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III - motor scale to assess motor function. Scale from 0-132, higher scores indicate worse motor outcomes. Baseline measure was collected during pre-clinical screening visit in dopaminergic medication OFF state. | Median | Inter-Quartile Range | units on a scale |
|
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. |
| OG001 | Placebo Cream | 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. |
| OG002 | Clarithromycin (Active or Placebo) | Discontinued April 2020. 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. |
|
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| 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. | 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. | Posted | Mean | Standard Deviation | units on a scale | Day 1 (before treatment administration), day 7 (after 7 days of treatment), and day 14 (7 days of treatment discontinuation). |
|
|
|
|
| 0 |
| 11 |
| 0 |
| 11 |
| 0 |
| 11 |
| EG001 | Placebo Cream | 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. | 0 | 11 | 0 | 11 | 0 | 11 |
| EG002 | Oral Clarithromycin (Dropped in 04/2020) | 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. | 0 | 3 | 0 | 3 | 0 | 3 |
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| D009422 | Nervous System Diseases |
| D009069 | Movement Disorders |
| D000080874 | Synucleinopathies |
| D019636 | Neurodegenerative Diseases |
| Organic Chemicals |
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| Day 14 |
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