Trial Outcomes & Findings for Modulation of GABA-A Receptors in Parkinson Disease-Flumazenil Arm (NCT NCT03462641)

Last Updated: 2022-09-27

Results Overview

Postural Instability and Gait Disorder (PIGD) score is a subscale score of MDS-UPDRS scale. It is computed as a sum of following MDS-UPDRS items: 3.10 Gait 3.11 Freezing of gait 3.12 Postural stability 3.13 Posture Minimal possible score is 0, maximal possible score is 16. Higher scores indicate greater severity of PIGD symptoms (worse outcome).

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

36 participants

Primary outcome timeframe

up to 3 hours (including pre and post infusion motor evaluation)

Results posted on

2022-09-27

Participant Flow

Of the 36 people who consented, six were not actually randomized. One participant passed away for reasons unrelated to the study prior to assignment. One participant failed to complete the required dopaminergic PET scan. Two participants failed to show dopaminergic denervation on their PET scan, which was one of the exclusion criteria. Two participants withdrew prior to screening.

Participant milestones

Participant milestones
Measure	Sequence A - (Flumazenil at Visit 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.	Sequence B - (Placebo at Visit 1) 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.
Visit 1 STARTED	19	11
Visit 1 Actually Received Drug or Placebo	18	11
Visit 1 COMPLETED	18	11
Visit 1 NOT COMPLETED	1	0
Visit 2 STARTED	18	11
Visit 2 Actually Received Drug or Placebo	18	10
Visit 2 COMPLETED	18	10
Visit 2 NOT COMPLETED	0	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Sequence A - (Flumazenil at Visit 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.	Sequence B - (Placebo at Visit 1) 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.
Visit 1 Failed to complete dopaminergic PET scan	1	0
Visit 2 Withdrawal by Subject	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Sequence A - (Flumazenil at Visit 1) n=18 Participants 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.	Sequence B - (Placebo at Visit 1) n=10 Participants 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.	Total n=28 Participants Total of all reporting groups
Age, Continuous	68.61 years STANDARD_DEVIATION 5.85 • n=5 Participants	69.5 years STANDARD_DEVIATION 7.20 • n=7 Participants	68.93 years STANDARD_DEVIATION 6.25 • n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants	2 Participants n=7 Participants	7 Participants n=5 Participants
Sex: Female, Male Male	13 Participants n=5 Participants	8 Participants n=7 Participants	21 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	18 Participants n=5 Participants	10 Participants n=7 Participants	28 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	18 Participants n=5 Participants	9 Participants n=7 Participants	27 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	18 Participants n=5 Participants	10 Participants n=7 Participants	28 Participants n=5 Participants
Postural Instability and Gait Disorder score	5.64 units on a scale STANDARD_DEVIATION 2.75 • n=5 Participants	5.4 units on a scale STANDARD_DEVIATION 2.28 • n=7 Participants	5.55 units on a scale STANDARD_DEVIATION 2.55 • n=5 Participants
Thalamic FMZ PET	3.10 Parametric DVR STANDARD_DEVIATION 0.24 • n=5 Participants	3.14 Parametric DVR STANDARD_DEVIATION 0.30 • n=7 Participants	3.11 Parametric DVR STANDARD_DEVIATION 0.26 • n=5 Participants

PRIMARY outcome

Timeframe: up to 3 hours (including pre and post infusion motor evaluation)

Population: MDS-UPDRS PIGD scores for the same set of 28 participants, recorded before and after treatment (placebo or flumazenil) administration.

Outcome measures

Outcome measures
Measure	Placebo n=28 Participants MDS-UPDRS PIGD score before treatment administration on the day when placebo was given.	Flumazenil n=28 Participants MDS-UPDRS PIGD score before treatment administration on the day when flumazenil was given.
Postural Instability and Gait Disorder (PIGD) Score Before Infusion	4.625 score on a scale Standard Deviation 2.36	4.625 score on a scale Standard Deviation 2.34
Postural Instability and Gait Disorder (PIGD) Score After Infusion	4.23 score on a scale Standard Deviation 2.15	4.09 score on a scale Standard Deviation 2.00

PRIMARY outcome

Timeframe: up to 3 hours (including pre and post infusion motor evaluation)

Population: A subset of participants assigned to each sequence which showed a decrease in PIGD score from pre-infusion to post-infusion for placebo or flumazenil treatment. A total of 12 participants are included in this analysis, with some of them showing response in both placebo and flumazenil condition and others in one of the two.

Difference in PIGD score from pre-infusion to post-infusion. Only observations where PIGD score change is less than 0 (decrease) are retained, as the hypothesis we are interested is whether the effect magnitude of flumazenil on PIGD score depends on baseline GABA-A receptor binding as assesed by FMZ PET.

Outcome measures

Outcome measures
Measure	Placebo n=8 Participants MDS-UPDRS PIGD score before treatment administration on the day when placebo was given.	Flumazenil n=6 Participants MDS-UPDRS PIGD score before treatment administration on the day when flumazenil was given.
PIGD Score Change	-1.375 Change in PIGD Score Standard Deviation 0.5175492	-2.500 Change in PIGD Score Standard Deviation 1.5165751

Adverse Events

Placebo Treatment

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Flumazenil Treatment

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: 734 998-8400

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place