Trial Outcomes & Findings for Modulation of GABA-A Receptors in Parkinson Disease-Transdermal Flumazenil Arm (NCT NCT03440112)

Last Updated: 2023-01-10

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

34 participants

Primary outcome timeframe

Day 1 (before treatment administration), day 7 (after 7 days of treatment), and day 14 (7 days of treatment discontinuation).

Results posted on

2023-01-10

Participant Flow

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.

Participant milestones

Participant milestones
Measure	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.	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.	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.
Overall Study STARTED	11	11	3
Overall Study COMPLETED	11	11	3
Overall Study NOT COMPLETED	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Modulation of GABA-A Receptors in Parkinson Disease-Transdermal Flumazenil Arm

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Transdermal Flumazenil (Active) n=11 Participants 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.	Placebo Cream n=11 Participants 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.	Oral Clarithromycin (Active or Placebo) n=3 Participants 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.	Total n=25 Participants Total of all reporting groups
Age, Continuous	72.09 years STANDARD_DEVIATION 4.41 • n=93 Participants	70.27 years STANDARD_DEVIATION 3.80 • n=4 Participants	66.33 years STANDARD_DEVIATION 5.13 • n=27 Participants	70.6 years STANDARD_DEVIATION 4.43 • n=483 Participants
Sex: Female, Male Female	3 Participants n=93 Participants	1 Participants n=4 Participants	1 Participants n=27 Participants	5 Participants n=483 Participants
Sex: Female, Male Male	8 Participants n=93 Participants	10 Participants n=4 Participants	2 Participants n=27 Participants	20 Participants n=483 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	11 Participants n=93 Participants	11 Participants n=4 Participants	3 Participants n=27 Participants	25 Participants n=483 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Asian	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Black or African American	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) White	11 Participants n=93 Participants	11 Participants n=4 Participants	3 Participants n=27 Participants	25 Participants n=483 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Region of Enrollment United States	11 participants n=93 Participants	11 participants n=4 Participants	3 participants n=27 Participants	25 participants n=483 Participants
MiniBEST Sensory Subscore	5.27 units on a scale STANDARD_DEVIATION 1.1 • n=93 Participants	5.81 units on a scale STANDARD_DEVIATION 0.40 • n=4 Participants	6 units on a scale STANDARD_DEVIATION 0 • n=27 Participants	5.6 units on a scale STANDARD_DEVIATION 0.82 • n=483 Participants
Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III	45 units on a scale n=93 Participants	41.5 units on a scale n=4 Participants	40.50 units on a scale n=27 Participants	43.5 units on a scale n=483 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Transdermal Flumazenil (Active) n=11 Participants 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.	Placebo Cream n=11 Participants 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.	Clarithromycin (Active or Placebo) n=3 Participants 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.
Change in Quantitative Biomechanics 1 (Clinical Motor Ratings MDS-UPDRS) Day 1	38 units on a scale Interval 27.5 to 44.5	34 units on a scale Interval 30.0 to 47.0	28 units on a scale Interval 25.5 to 33.0
Change in Quantitative Biomechanics 1 (Clinical Motor Ratings MDS-UPDRS) Day 7	36.75 units on a scale Interval 29.75 to 52.0	31.50 units on a scale Interval 25.375 to 43.375	23.50 units on a scale Interval 21.25 to 26.75
Change in Quantitative Biomechanics 1 (Clinical Motor Ratings MDS-UPDRS) Day 14	32.75 units on a scale Interval 26.375 to 47.375	34 units on a scale Interval 29.5 to 40.0	22 units on a scale Interval 19.5 to 23.0

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Transdermal Flumazenil (Active) n=11 Participants 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.	Placebo Cream n=11 Participants 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.	Clarithromycin (Active or Placebo) n=3 Participants 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.
Change in Quantitative Biomechanics 2 (MiniBESTest Dynamic Balance Scale Sensory Subscore) Day 14	6 units on a scale Standard Deviation 0	5.82 units on a scale Standard Deviation 0.60	6 units on a scale Standard Deviation 0
Change in Quantitative Biomechanics 2 (MiniBESTest Dynamic Balance Scale Sensory Subscore) Day 1	5.54 units on a scale Standard Deviation 0.69	6 units on a scale Standard Deviation 0	6 units on a scale Standard Deviation 0
Change in Quantitative Biomechanics 2 (MiniBESTest Dynamic Balance Scale Sensory Subscore) Day 7	5.82 units on a scale Standard Deviation 0.40	6 units on a scale Standard Deviation 0	5.67 units on a scale Standard Deviation 0.58

Adverse Events

Transdermal Flumazenil (Active)

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Placebo Cream

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Oral Clarithromycin (Dropped in 04/2020)

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Stiven Roytman

University of Michigan

Phone: 7349988424

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place