Trial Outcomes & Findings for Open-Label Safety Study of ADS-5102 in PD Patients With LID (NCT NCT02202551)

NCT ID: NCT02202551

Last Updated: 2020-10-06

Results Overview

The primary objective of the study was to evaluate the safety and tolerability of ADS-5102 oral capsules, an extended release (ER) formulation of amantadine, administered at a dose of 340 mg once daily at bedtime for the treatment of levodopa-induced dyskinesia (LID) in subjects with Parkinson's disease (PD).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

223 participants

Primary outcome timeframe

Up to 101 weeks

Results posted on

2020-10-06

Participant Flow

Participant milestones

Participant milestones
Measure	Group 1a Subjects completed previous LID study and enrolled in ADS-AMT-PD302 study immediately. Subjects in Group 1A received ADS-5102 in the prior study.	Group 1P Subjects completed previous LID study and enrolled in ADS-AMT-PD302 study immediately. Subjects in Group 1P received placebo in the prior study	Group 2 Subjects in Group 2 completed previous LID study, enrolled ADS-AMT-PD302 after a time gap.	Group 3 Subjects were not in a previous Adamas LID study and had prior DBS (deep brain stimulation)
Overall Study STARTED	60	78	24	61
Overall Study COMPLETED	35	41	14	39
Overall Study NOT COMPLETED	25	37	10	22

Reasons for withdrawal

Reasons for withdrawal
Measure	Group 1a Subjects completed previous LID study and enrolled in ADS-AMT-PD302 study immediately. Subjects in Group 1A received ADS-5102 in the prior study.	Group 1P Subjects completed previous LID study and enrolled in ADS-AMT-PD302 study immediately. Subjects in Group 1P received placebo in the prior study	Group 2 Subjects in Group 2 completed previous LID study, enrolled ADS-AMT-PD302 after a time gap.	Group 3 Subjects were not in a previous Adamas LID study and had prior DBS (deep brain stimulation)
Overall Study Adverse Event	8	19	5	9
Overall Study Death	3	2	1	1
Overall Study Lost to Follow-up	0	1	0	1
Overall Study Needed to take excluded medication	0	2	0	1
Overall Study Subject moved away	0	1	0	0
Overall Study DBS surgery	3	0	0	0
Overall Study Dyskinesia upon taper	1	0	0	0
Overall Study Lack of Efficacy	0	1	0	0
Overall Study Physician Decision	1	0	0	0
Overall Study Site closure	3	0	0	1
Overall Study Unable to complete visits per protocol	1	0	0	0
Overall Study Worsening Dyskinesia	0	0	0	1
Overall Study Protocol Violation	0	1	0	0
Overall Study Sponsor's decision	2	0	0	0
Overall Study Subject unwilling to proceed	1	5	3	5
Overall Study Subject consent withdrawn	0	3	1	2
Overall Study eGFR<50mL/min/m2	2	2	0	1

Baseline Characteristics

Open-Label Safety Study of ADS-5102 in PD Patients With LID

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Group 1a n=60 Participants Subjects completed previous LID study and enrolled in ADS-AMT-PD302 study immediately. Subjects in Group 1A received ADS-5102 in the prior study.	Group 1P n=78 Participants Subjects completed previous LID study and enrolled in ADS-AMT-PD302 study immediately. Subjects in Group 1P received placebo in the prior study	Group 2 n=24 Participants Subjects in Group 2 completed previous LID study, enrolled ADS-AMT-PD302 after a time gap.	Group 3 n=61 Participants Subjects were not in a previous Adamas LID study and had prior DBS (deep brain stimulation)	Total n=223 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants
Age, Categorical Between 18 and 65 years	28 Participants n=93 Participants	30 Participants n=4 Participants	12 Participants n=27 Participants	39 Participants n=483 Participants	109 Participants n=36 Participants
Age, Categorical >=65 years	32 Participants n=93 Participants	48 Participants n=4 Participants	12 Participants n=27 Participants	22 Participants n=483 Participants	114 Participants n=36 Participants
Age, Continuous	64.0 years STANDARD_DEVIATION 9.81 • n=93 Participants	65.9 years STANDARD_DEVIATION 8.80 • n=4 Participants	64.4 years STANDARD_DEVIATION 7.81 • n=27 Participants	60.2 years STANDARD_DEVIATION 9.20 • n=483 Participants	63.7 years STANDARD_DEVIATION 9.32 • n=36 Participants
Sex: Female, Male Female	26 Participants n=93 Participants	33 Participants n=4 Participants	13 Participants n=27 Participants	20 Participants n=483 Participants	92 Participants n=36 Participants
Sex: Female, Male Male	34 Participants n=93 Participants	45 Participants n=4 Participants	11 Participants n=27 Participants	41 Participants n=483 Participants	131 Participants n=36 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	0 Participants n=36 Participants
Race (NIH/OMB) Asian	2 Participants n=93 Participants	2 Participants n=4 Participants	0 Participants n=27 Participants	4 Participants n=483 Participants	8 Participants n=36 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	0 Participants n=36 Participants
Race (NIH/OMB) Black or African American	0 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants	1 Participants n=483 Participants	2 Participants n=36 Participants
Race (NIH/OMB) White	57 Participants n=93 Participants	74 Participants n=4 Participants	23 Participants n=27 Participants	54 Participants n=483 Participants	208 Participants n=36 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	0 Participants n=36 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=93 Participants	2 Participants n=4 Participants	0 Participants n=27 Participants	2 Participants n=483 Participants	5 Participants n=36 Participants
Body Mass Index	25.86 kg/m^2 STANDARD_DEVIATION 25.42 • n=93 Participants	25.72 kg/m^2 STANDARD_DEVIATION 24.63 • n=4 Participants	25.26 kg/m^2 STANDARD_DEVIATION 23.24 • n=27 Participants	27.29 kg/m^2 STANDARD_DEVIATION 4.891 • n=483 Participants	26.14 kg/m^2 STANDARD_DEVIATION 5.220 • n=36 Participants
eGFR	88.7 mL/min/1.73 m^2 STANDARD_DEVIATION 24.31 • n=93 Participants	92.2 mL/min/1.73 m^2 STANDARD_DEVIATION 19.64 • n=4 Participants	96.3 mL/min/1.73 m^2 STANDARD_DEVIATION 20.54 • n=27 Participants	92.1 mL/min/1.73 m^2 STANDARD_DEVIATION 19.95 • n=483 Participants	91.6 mL/min/1.73 m^2 STANDARD_DEVIATION 21.16 • n=36 Participants

PRIMARY outcome

Timeframe: Up to 101 weeks

Outcome measures

Outcome measures
Measure	Group 1a n=60 Participants Subjects completed previous LID study and enrolled in ADS-AMT-PD302 study immediately. Subjects in Group 1A received ADS-5102 in the prior study.	Group 1P n=78 Participants Subjects completed previous LID study and enrolled in ADS-AMT-PD302 study immediately. Subjects in Group 1P received placebo in the prior study	Group 2 n=24 Participants Subjects in Group 2 completed previous LID study, enrolled ADS-AMT-PD302 after a time gap.	Group 3 n=61 Participants Subjects were not in a previous Adamas LID study and had prior DBS (deep brain stimulation)
Number of Participants With Reported AEs and Safety-Related Study Drug Discontinuations AE	57 Participants	70 Participants	23 Participants	55 Participants
Number of Participants With Reported AEs and Safety-Related Study Drug Discontinuations Study drug-related AE	31 Participants	45 Participants	16 Participants	32 Participants
Number of Participants With Reported AEs and Safety-Related Study Drug Discontinuations SAEs	16 Participants	21 Participants	6 Participants	17 Participants
Number of Participants With Reported AEs and Safety-Related Study Drug Discontinuations Permanent discontinuation due to AE	12 Participants	21 Participants	6 Participants	10 Participants
Number of Participants With Reported AEs and Safety-Related Study Drug Discontinuations Permanent discontinuation due to drug-related AE	4 Participants	15 Participants	4 Participants	8 Participants
Number of Participants With Reported AEs and Safety-Related Study Drug Discontinuations Mild AEs	12 Participants	13 Participants	3 Participants	11 Participants
Number of Participants With Reported AEs and Safety-Related Study Drug Discontinuations Moderate AEs	25 Participants	36 Participants	13 Participants	26 Participants
Number of Participants With Reported AEs and Safety-Related Study Drug Discontinuations Mild drug-related AE	16 Participants	15 Participants	3 Participants	5 Participants
Number of Participants With Reported AEs and Safety-Related Study Drug Discontinuations Severe drug-related AE	3 Participants	7 Participants	1 Participants	5 Participants
Number of Participants With Reported AEs and Safety-Related Study Drug Discontinuations Moderate drug-related AE	12 Participants	23 Participants	12 Participants	22 Participants

SECONDARY outcome

Timeframe: Up to 101 weeks. MDS-UPDRS was performed at the following visits: Screening, Week 8, Week 16, Week 28, Week 40, Week 52, Week 64, Week 76, Week 88, Week 100 (or ET).

To evaluate clinical progression of PD as assessed by the MDS-UPDRS, combined score, Parts I, II, and III. Part I - non-motor experiences of daily living; Part II - motor experiences of daily living; Part III - motor examination. Parts I and II each contain 13 questions measured on a 5-point scale (0-4). Part III contains 18 objective rater assessments of the motor signs of PD measured on a 5-point scale (0-4). Total range for combined score (Part I-III) is = 0-176. Generally for MDS-UPDRS scores and sub-scores, the lower the score, the better. Parts I, II, and III are summed to make the total score.

Outcome measures

Outcome measures
Measure	Group 1a n=60 Participants Subjects completed previous LID study and enrolled in ADS-AMT-PD302 study immediately. Subjects in Group 1A received ADS-5102 in the prior study.	Group 1P n=77 Participants Subjects completed previous LID study and enrolled in ADS-AMT-PD302 study immediately. Subjects in Group 1P received placebo in the prior study	Group 2 n=24 Participants Subjects in Group 2 completed previous LID study, enrolled ADS-AMT-PD302 after a time gap.	Group 3 n=60 Participants Subjects were not in a previous Adamas LID study and had prior DBS (deep brain stimulation)
Change From Baseline in Movement Disorder's Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) (Parts I-III Combined Scores) Baseline	41.8 units on a scale Standard Deviation 18.43	45.6 units on a scale Standard Deviation 19.24	52.8 units on a scale Standard Deviation 23.06	52.4 units on a scale Standard Deviation 16.55
Change From Baseline in Movement Disorder's Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) (Parts I-III Combined Scores) Change from Baseline at Week 8	1.2 units on a scale Standard Deviation 10.03	-2.8 units on a scale Standard Deviation 14.11	0.8 units on a scale Standard Deviation 12.00	-5.3 units on a scale Standard Deviation 10.74
Change From Baseline in Movement Disorder's Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) (Parts I-III Combined Scores) Change from Baseline at Week 16	1.6 units on a scale Standard Deviation 13.41	-1.4 units on a scale Standard Deviation 16.22	5.7 units on a scale Standard Deviation 15.53	-5.2 units on a scale Standard Deviation 11.33
Change From Baseline in Movement Disorder's Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) (Parts I-III Combined Scores) Change from Baseline at Week 28	4.8 units on a scale Standard Deviation 10.04	1.5 units on a scale Standard Deviation 12.49	6.5 units on a scale Standard Deviation 14.18	-5.3 units on a scale Standard Deviation 12.99
Change From Baseline in Movement Disorder's Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) (Parts I-III Combined Scores) Change from Baseline at Week 40	7.5 units on a scale Standard Deviation 15.43	-0.4 units on a scale Standard Deviation 15.20	1.6 units on a scale Standard Deviation 18.29	-4.8 units on a scale Standard Deviation 12.49
Change From Baseline in Movement Disorder's Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) (Parts I-III Combined Scores) Change from Baseline at Week 52	13.2 units on a scale Standard Deviation 16.78	2.6 units on a scale Standard Deviation 14.57	6.1 units on a scale Standard Deviation 18.34	-4.6 units on a scale Standard Deviation 15.60
Change From Baseline in Movement Disorder's Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) (Parts I-III Combined Scores) Change from Baseline at Week 64	8.8 units on a scale Standard Deviation 14.83	2.6 units on a scale Standard Deviation 14.57	6.1 units on a scale Standard Deviation 18.34	-4.6 units on a scale Standard Deviation 15.60
Change From Baseline in Movement Disorder's Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) (Parts I-III Combined Scores) Change from Baseline at Week 76	11.7 units on a scale Standard Deviation 19.58	7.3 units on a scale Standard Deviation 19.18	9.4 units on a scale Standard Deviation 19.10	-4.9 units on a scale Standard Deviation 13.83
Change From Baseline in Movement Disorder's Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) (Parts I-III Combined Scores) Change from Baseline at Week 88	11.3 units on a scale Standard Deviation 16.65	3.7 units on a scale Standard Deviation 13.80	6.4 units on a scale Standard Deviation 22.65	0.9 units on a scale Standard Deviation 16.18
Change From Baseline in Movement Disorder's Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) (Parts I-III Combined Scores) Change from Baseline at Week 100	11.4 units on a scale Standard Deviation 15.66	3.7 units on a scale Standard Deviation 15.29	6.5 units on a scale Standard Deviation 16.46	4.1 units on a scale Standard Deviation 17.48

SECONDARY outcome

Timeframe: 100 Weeks. MDS-UPDRS was performed at the following visits: Screening, Week 8, Week 16, Week 28, Week 40, Week 52, Week 64, Week 76, Week 88, Week 100 (or ET).

This component (Questions 4.1 - 4.6) includes time spent with dyskinesia, functional impact of dyskinesia, time spent in OFF state, functional impact of fluctuations, complexity of motor fluctuations, painful OFF-state dystonia. Questions 4.1-4.6 are summed to make the Part IV score. Generally for MDS-UPDRS scores and sub-scores, the lower the score, the better. Total range for Part IV is = 0-24

Outcome measures

Outcome measures
Measure	Group 1a n=60 Participants Subjects completed previous LID study and enrolled in ADS-AMT-PD302 study immediately. Subjects in Group 1A received ADS-5102 in the prior study.	Group 1P n=77 Participants Subjects completed previous LID study and enrolled in ADS-AMT-PD302 study immediately. Subjects in Group 1P received placebo in the prior study	Group 2 n=24 Participants Subjects in Group 2 completed previous LID study, enrolled ADS-AMT-PD302 after a time gap.	Group 3 n=60 Participants Subjects were not in a previous Adamas LID study and had prior DBS (deep brain stimulation)
Change From Baseline in Movement Disorder's Society - Unified Parkinson's Disease Rating Scale MDS-UPDRS (Part IV - Motor Complications) Baseline	6.5 units on a scale Standard Deviation 3.38	9.6 units on a scale Standard Deviation 3.07	9.8 units on a scale Standard Deviation 3.92	10.4 units on a scale Standard Deviation 2.77
Change From Baseline in Movement Disorder's Society - Unified Parkinson's Disease Rating Scale MDS-UPDRS (Part IV - Motor Complications) Change in Baseline from Week 8	-0.2 units on a scale Standard Deviation 3.21	-3.4 units on a scale Standard Deviation 3.27	-3.6 units on a scale Standard Deviation 4.16	-4.0 units on a scale Standard Deviation 4.20
Change From Baseline in Movement Disorder's Society - Unified Parkinson's Disease Rating Scale MDS-UPDRS (Part IV - Motor Complications) Change in Baseline from Week 16	-0.8 units on a scale Standard Deviation 3.61	-3.2 units on a scale Standard Deviation 3.61	-1.1 units on a scale Standard Deviation 5.03	-3.9 units on a scale Standard Deviation 3.68
Change From Baseline in Movement Disorder's Society - Unified Parkinson's Disease Rating Scale MDS-UPDRS (Part IV - Motor Complications) Change from Baseline at Week 28	-0.3 units on a scale Standard Deviation 3.61	-3.3 units on a scale Standard Deviation 3.12	-1.4 units on a scale Standard Deviation 3.84	-4.4 units on a scale Standard Deviation 3.79
Change From Baseline in Movement Disorder's Society - Unified Parkinson's Disease Rating Scale MDS-UPDRS (Part IV - Motor Complications) Change from Baseline at Week 40	0.0 units on a scale Standard Deviation 3.95	-2.8 units on a scale Standard Deviation 3.39	-2.9 units on a scale Standard Deviation 4.81	-4.7 units on a scale Standard Deviation 4.06
Change From Baseline in Movement Disorder's Society - Unified Parkinson's Disease Rating Scale MDS-UPDRS (Part IV - Motor Complications) Change from Baseline at Week 52	0.2 units on a scale Standard Deviation 3.64	-2.9 units on a scale Standard Deviation 3.56	-2.5 units on a scale Standard Deviation 4.40	-3.6 units on a scale Standard Deviation 3.62
Change From Baseline in Movement Disorder's Society - Unified Parkinson's Disease Rating Scale MDS-UPDRS (Part IV - Motor Complications) Change from Baseline at Week 64	0.4 units on a scale Standard Deviation 3.82	-3.3 units on a scale Standard Deviation 3.42	-1.9 units on a scale Standard Deviation 4.32	-2.5 units on a scale Standard Deviation 4.22
Change From Baseline in Movement Disorder's Society - Unified Parkinson's Disease Rating Scale MDS-UPDRS (Part IV - Motor Complications) Change from Baseline at Week 76	0.9 units on a scale Standard Deviation 4.20	-2.9 units on a scale Standard Deviation 3.67	-2.7 units on a scale Standard Deviation 3.90	-3.7 units on a scale Standard Deviation 3.68
Change From Baseline in Movement Disorder's Society - Unified Parkinson's Disease Rating Scale MDS-UPDRS (Part IV - Motor Complications) Change from Baseline at Week 88	0.4 units on a scale Standard Deviation 3.77	-2.8 units on a scale Standard Deviation 3.60	-3.7 units on a scale Standard Deviation 4.69	-4.3 units on a scale Standard Deviation 3.55
Change From Baseline in Movement Disorder's Society - Unified Parkinson's Disease Rating Scale MDS-UPDRS (Part IV - Motor Complications) Change from Baseline at Week 100	0.4 units on a scale Standard Deviation 3.28	-2.4 units on a scale Standard Deviation 4.19	-3.6 units on a scale Standard Deviation 3.66	-3.6 units on a scale Standard Deviation 3.94

Adverse Events

Group 1a

Serious events: 16 serious events

Other events: 47 other events

Deaths: 4 deaths

Group 1P

Serious events: 21 serious events

Other events: 61 other events

Deaths: 2 deaths

Group 2

Serious events: 6 serious events

Other events: 21 other events

Deaths: 2 deaths

Group 3

Serious events: 17 serious events

Other events: 45 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Additional Information

Reed Johnson

Adamas Pharmaceuticals, Inc.

Phone: 510-450-3500

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Group 1a n=60 participants at risk Subjects completed previous LID study and enrolled in ADS-AMT-PD302 study immediately. Subjects in Group 1A received ADS-5102 in the prior study.	Group 1P n=78 participants at risk Subjects completed previous LID study and enrolled in ADS-AMT-PD302 study immediately. Subjects in Group 1P received placebo in the prior study	Group 2 n=24 participants at risk Subjects in Group 2 completed previous LID study, enrolled ADS-AMT-PD302 after a time gap.	Group 3 n=61 participants at risk Subjects were not in a previous Adamas LID study and had prior DBS (deep brain stimulation)
Gastrointestinal disorders Nausea	11.7% 7/60 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	10.3% 8/78 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	25.0% 6/24 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	1.6% 1/61 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).
Psychiatric disorders Insomnia	13.3% 8/60 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	6.4% 5/78 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	16.7% 4/24 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	6.6% 4/61 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).
Skin and subcutaneous tissue disorders Livedo reticularis	10.0% 6/60 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	6.4% 5/78 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	12.5% 3/24 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	9.8% 6/61 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).
Nervous system disorders On and off phenomenon	11.7% 7/60 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	5.1% 4/78 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	16.7% 4/24 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	4.9% 3/61 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).
Gastrointestinal disorders Dry mouth	6.7% 4/60 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	7.7% 6/78 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	16.7% 4/24 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	4.9% 3/61 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).
Musculoskeletal and connective tissue disorders Back pain	6.7% 4/60 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	6.4% 5/78 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	8.3% 2/24 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	6.6% 4/61 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).
Psychiatric disorders Depression	6.7% 4/60 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	6.4% 5/78 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	8.3% 2/24 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	6.6% 4/61 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).
Nervous system disorders Parkinson's disease	5.0% 3/60 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	6.4% 5/78 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	4.2% 1/24 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	9.8% 6/61 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).
Psychiatric disorders Anxiety	5.0% 3/60 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	7.7% 6/78 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	4.2% 1/24 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	6.6% 4/61 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).
Psychiatric disorders Abnormal dreams	8.3% 5/60 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	5.1% 4/78 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	8.3% 2/24 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	3.3% 2/61 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).
Infections and infestations Nasopharyngitis	6.7% 4/60 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	5.1% 4/78 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	4.2% 1/24 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	6.6% 4/61 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).
Musculoskeletal and connective tissue disorders Arthralgia	8.3% 5/60 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	6.4% 5/78 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	4.2% 1/24 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	1.6% 1/61 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).
Cardiac disorders Hypertension	3.3% 2/60 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	7.7% 6/78 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	0.00% 0/24 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	6.6% 4/61 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).
Infections and infestations Upper respiratory tract infection	6.7% 4/60 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	3.8% 3/78 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	12.5% 3/24 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	3.3% 2/61 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).
Injury, poisoning and procedural complications Fall	21.7% 13/60 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	37.2% 29/78 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	33.3% 8/24 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	37.7% 23/61 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).
Psychiatric disorders Hallucination (pooled)	25.0% 15/60 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	30.8% 24/78 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	20.8% 5/24 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	16.4% 10/61 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).
Psychiatric disorders Hallucination, visual	23.3% 14/60 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	30.8% 24/78 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	16.7% 4/24 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	16.4% 10/61 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).
General disorders Edema peripheral	16.7% 10/60 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	15.4% 12/78 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	8.3% 2/24 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	19.7% 12/61 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).
Gastrointestinal disorders Constipation	15.0% 9/60 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	15.4% 12/78 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	25.0% 6/24 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	4.9% 3/61 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).
Infections and infestations Urinary tract infection	11.7% 7/60 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	10.3% 8/78 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	12.5% 3/24 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	8.2% 5/61 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).
Nervous system disorders Dizziness	6.7% 4/60 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	12.8% 10/78 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	20.8% 5/24 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).	4.9% 3/61 • 100 weeks Safety was assessed through adverse events (AEs), physical examinations, vital signs, and laboratory parameters (hematology, serum chemistry, urinalysis, and pregnancy testing, if appropriate).