ADS-5102 for the Treatment of Levodopa Induced Dyskinesia (EASE LID Study)

• Sponsor: Adamas Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02136914
• Collaborator: (none)
• Enrollment: 126
• Locations: 46
• Arms: 2
• Duration (Months): 19
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a multi-center, randomized, double-blind, placebo-controlled, 2-arm, parallel group study to evaluate the efficacy and safety of ADS-5102 extended release (ER) capsules, an investigational formulation of amantadine, dosed once nightly at bedtime for the treatment of levodopa induced dyskinesia (LID) in subjects with Parkinson's disease (PD). The novel pharmacokinetic profile of ADS-5102 is expected to achieve i) maximal concentrations in the early morning through mid-day, when LID can be troublesome, and ii) lower concentrations in the evening, potentially reducing the negative impact of amantadine on sleep. This pharmacokinetic profile could enable higher doses to be tolerated with a once-nightly ER formulation than can be tolerated with an immediate-release formulation. The once-nightly dosing regimen may also provide enhanced convenience and compliance.

In a previous clinical study, ADS-5102 met its primary endpoint; LID was significantly reduced as measured by the change in UDysRS score over 8 weeks vs. placebo.

Condition or Disease	Intervention/Treatment	Phase
Dyskinesia; Levodopa Induced Dyskinesia (LID); Parkinson's Disease	Drug: ADS-5102; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 126 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of ADS-5102 (Amantadine HCl) Extended Release Capsules for the Treatment of Levodopa Induced Dyskinesia in Parkinson's Disease Patients (EASE LID Study)
• Study Start Date: May 1, 2014
• Actual Primary Completion Date: Dec 1, 2015
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ADS-5102 ADS-5102 (amantadine HCl extended release)	Drug: ADS-5102; Oral capsules to be administered once nightly at bedtime, for 25 weeks; Other Names: amantadine HCl extended release
Placebo Comparator: Placebo Placebo	Other: Placebo; Oral capsules to be administered once nightly at bedtime, for 25 weeks

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the Unified Dyskinesia Rating Scale (UDysRS) Score at Week 12 [Baseline to Week 12]

   The UDysRS is a dyskinesia rating scale from 0-104; it evaluates involuntary movements associated with PD. A higher score indicates more severe PD. The UDysRS was measured at Baseline and Weeks 2, 8, 12, 18, and 24.

Secondary Outcome Measures

1. Change From Baseline in the Unified Dyskinesia Rating Scale (UDysRS) Score at Week 24 [Baseline to Week 24]

   The UDysRS is a dyskinesia rating scale from 0-104; it evaluates involuntary movements associated with PD. A higher score indicates more severe PD. The UDysRS was measured at Baseline and Weeks 2, 8, 12, 18, and 24.

2. Change in the Standardized PD Home Diary (ON Time Without Troublesome Dyskinesia, ON Time With Troublesome Dyskinesia, OFF Time) [Baseline (BL) to Week 12 (W12) and Week 24 (W24)]

   A PD home diary was used to score 5 different conditions in 30-minute intervals: ASLEEP, OFF, ON (ie, had adequate control of PD symptoms) without dyskinesia, ON with non-troublesome dyskinesia, and ON with troublesome dyskinesia. The results were based on 2 consecutive 24-hour diaries taken prior to the day of randomization and prior to the Week 2, 8, 12, 18, and 24 visits.

3. Change in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Combined Score (Parts I, II, and III) [Baseline (BL) to Week 12 (W12) and Week 24 (W24)]

   The MDS-UPDRS Parts I, II, and III examined non-motor experiences of daily living, motor experiences of daily living, and motor examination, respectively. Each Part contains items or questions that were each rated on a scale from 0 (normal) to 4 (severe). The Combined Parts I, II, and III (representing the sum of the individual scores from Parts I, II, and III) has a scale range of 0-236. Higher scores, whether for individual Parts or the sum of the combined Parts, indicate more severe PD.

4. Clinician's Global Impression of Change (CGI-C) in Overall PD Symptoms [Baseline to Week 12 and Week 24]

   The CGI-C consisted of a single question that assessed the investigator's global impression of the subject's change from Baseline in overall PD symptoms, including but not limited to LID. The CGI-C required that the investigator rate the extent to which the subject's PD had improved or worsened (from marked worsening to marked improvement). The CGI-C was assessed at Baseline and Weeks 2, 8, 12, 18, and 24.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Signed a current IRB/REB/IEC-approved informed consent form

• Parkinson's disease, per UK Parkinson's Disease Society (UKPDS) Brain Bank Clinical Diagnostic Criteria

• On a stable regimen of antiparkinson's medications for at least 30 days prior to screening, including a levodopa preparation administered not less than three times daily, and willing to continue the same doses and regimens during study participation

• Following diary training, the subject is willing and able to understand and complete the 24-hour PD home diary (caregiver/study partner assistance allowed)

• Any other current and allowed prescription/non-prescription medications and/or nutritional supplements taken regularly must have been at a stable dose and regimen for at least 30 days prior to screening, and subject must be willing to continue the same doses and regimens during study participation (this criterion does not apply to medications that are being taken pre-study only on an as-needed basis)

Exclusion Criteria:

• History of neurosurgical intervention related to Parkinson's disease (e.g. deep brain stimulation)

• History of seizures within 2 years prior to screening

• History of stroke or transient ischemic attack (TIA) within 2 years prior to screening

• History of cancer within 5 years prior to screening, with the following exceptions: adequately treated non-melanomatous skin cancers, localized bladder cancer, non-metastatic prostate cancer or in situ cervical cancer

• Presence of cognitive impairment, as evidenced by a Mini-Mental Status Examination (MMSE) score of less than 24 during screening

• If female, is pregnant or lactating

• If a sexually active female, is not surgically sterile or at least 2 years post-menopausal, or does not agree to utilize an effective method of contraception from screening through at least 4 weeks after the completion of study treatment.

• Treatment with an investigational drug or device within 30 days prior to screening

• Treatment with an investigational biologic within 6 months prior to screening

• Current participation in another clinical trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States	35233
2		Phoenix	Arizona	United States	85013
3		Scottsdale	Arizona	United States	85259
4		Sun City	Arizona	United States	85351
5		Fountain Valley	California	United States	92708
6		Pasadena	California	United States	91105
7		Reseda	California	United States	91335
8		Sacramento	California	United States	95817
9		Torrance	California	United States	90505
10		Ventura	California	United States	93003
11		Aurora	Colorado	United States	80045
12		Manchester	Connecticut	United States	06040
13		Boca Raton	Florida	United States	33486
14		Gainesville	Florida	United States	32607
15		Naples	Florida	United States	34102
16		Port Charlotte	Florida	United States	33980
17		Sunrise	Florida	United States	33351
18		Tampa	Florida	United States	33613
19		Weston	Florida	United States	33331
20		Atlanta	Georgia	United States	30329
21		Chicago	Illinois	United States	60612
22		Des Moines	Iowa	United States	50309
23		Kansas City	Kansas	United States	66160
24		Bingham Farms	Michigan	United States	48025
25		West Bloomfield	Michigan	United States	48322
26		Golden Valley	Minnesota	United States	55427
27		Saint Louis	Missouri	United States	63110
28		Albany	New York	United States	12208
29		Commack	New York	United States	11725
30		New York	New York	United States	10003
31		New York	New York	United States	10016
32		New York	New York	United States	10029
33		Raleigh	North Carolina	United States	27607
34		Cincinnati	Ohio	United States	45219
35		Cleveland	Ohio	United States	44195
36		Toledo	Ohio	United States	43614
37		Tulsa	Oklahoma	United States	74136
38		Philadelphia	Pennsylvania	United States	19107
39		Dallas	Texas	United States	75390
40		Houston	Texas	United States	77030-1
41		Houston	Texas	United States	77030-2
42		Kirkland	Washington	United States	98034
43		Milwaukee	Wisconsin	United States	53233
44		Edmonton	Alberta	Canada	T6G 2B7
45		Toronto	Ontario	Canada	M5T 2S8
46		Regina	Saskatchewan	Canada	S4T 1A5

Sponsors and Collaborators

• Adamas Pharmaceuticals, Inc.

Investigators

• Study Director: Clinical Trials Director, Adamas Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Adamas Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02136914
• Other Study ID Numbers: ADS-AMT-PD301
• First Posted: May 13, 2014
• Last Update Posted: Feb 6, 2018
• Last Verified: Jan 1, 2018

• Keywords provided by Adamas Pharmaceuticals, Inc.: Levodopa Induced Dyskinesia; LID; Parkinsonism
• Additional relevant MeSH terms: Parkinson Disease; Dyskinesias; Amantadine

Study Results

Participant Flow

Recruitment Details	126 Participants with Parkinson's disease (PD) and Levodopa-induced Dyskinesia (LID) were randomized at 41 study sites in the United States and Canada. The first subject was randomized on 20 May 2014 and the last subject completed on 18 November 2015.
Pre-assignment Detail	All randomized subjects who received ≥ 1 dose of study drug (123) were included in the Safety Analysis Population (60 placebo, 63 ADS-5102); all randomized subjects who received ≥ 1 dose of study drug and provided ≥ 1 postbaseline efficacy assessment (121) were included in the Modified Intent-to-Treat (MITT) population (58 placebo, 63 ADS-5102).

Arm/Group Title	Placebo	ADS-5102 (340 mg)
Arm/Group Description	Placebo: oral capsules administered once nightly at bedtime for 25 weeks	340 mg dose of ADS-5102 (amantadine hydrochloride [HCl] extended release): oral capsules administered once nightly at bedtime for 25 weeks
Period Title: Overall Study
STARTED	63	63
Received Study Drug	60	63
COMPLETED	42	42
NOT COMPLETED	21	21

Baseline Characteristics

Arm/Group Title	Placebo	ADS-5102 (340 mg)	Total
Arm/Group Description	Placebo: oral capsules administered once nightly at bedtime for 25 weeks	340 mg dose of ADS-5102 (amantadine HCl extended release): oral capsules administered once nightly at bedtime for 25 weeks	Total of all reporting groups
Overall Participants	60	63	123
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	27 45%	32 50.8%	59 48%
>=65 years	33 55%	31 49.2%	64 52%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.6 (8.59)	63.9 (9.43)	64.7 (9.04)
Sex: Female, Male (Count of Participants)
Female	23 38.3%	28 44.4%	51 41.5%
Male	37 61.7%	35 55.6%	72 58.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 15%	3 4.8%	12 9.8%
Not Hispanic or Latino	51 85%	60 95.2%	111 90.2%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	3 5%	2 3.2%	5 4.1%
Native Hawaiian or Other Pacific Islander	0 0%	1 1.6%	1 0.8%
Black or African American	1 1.7%	0 0%	1 0.8%
White	53 88.3%	60 95.2%	113 91.9%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	3 5%	0 0%	3 2.4%
Unified Dyskinesia Rating Scale (UDysRS) (units on a scale) [Mean (Standard Deviation) ]
Total Score	38.2 (11.20)	40.9 (13.34)	39.6 (12.37)
Total Objective Score (Parts III, IV)	15.3 (6.66)	16.4 (7.72)	15.9 (7.21)
PD Home Diary (hours) [Mean (Standard Deviation) ]
Asleep	8.02 (1.446)	7.78 (1.732)	7.90 (1.597)
Off	2.94 (2.105)	3.16 (2.372)	3.05 (2.239)
ON without Troublesome Dyskinesia	8.59 (2.815)	8.34 (3.466)	8.46 (3.155)
ON with Troublesome Dyskinesia	4.46 (1.933)	4.72 (2.537)	4.59 (2.257)
Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) (units on a scale) [Mean (Standard Deviation) ]
Part I	11.5 (4.17)	12.5 (6.18)	12.0 (5.31)
Part II	15.8 (5.80)	15.7 (6.77)	15.8 (6.29)
Part III	24.6 (12.10)	25.9 (14.49)	25.3 (13.34)
Combined Parts I, II, and III	51.9 (16.95)	54.2 (20.37)	53.1 (18.75)
Part IV	11.3 (2.36)	11.8 (2.95)	11.6 (2.68)
Part IV, Item 4.1	2.4 (0.82)	2.6 (0.94)	2.5 (0.89)
Part IV, Item 4.2	2.5 (0.54)	2.6 (0.56)	2.5 (0.55)
Time Since PD Diagnosis (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	8.85 (3.911)	9.45 (4.372)	9.16 (4.148)
Duration of Levodopa Treatment (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	6.82 (3.346)	7.82 (3.719)	7.33 (3.563)
Duration of LID (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	3.21 (2.491)	4.05 (3.085)	3.64 (2.831)
Hoehn and Yahr Stage (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	2.3 (0.56)	2.2 (0.54)	2.3 (0.55)
Subjects taking Antiparkinson Medication (Count of Participants)
Levodopa (Sinemet or Stalevo)	60 100%	63 100%	123 100%
Dopamine Agonist	34 56.7%	29 46%	63 51.2%
MAO Inhibitors	24 40%	26 41.3%	50 40.7%
COMT Inhibitor	9 15%	7 11.1%	16 13%
Anticholinergics	3 5%	2 3.2%	5 4.1%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Unified Dyskinesia Rating Scale (UDysRS) Score at Week 12
Description	The UDysRS is a dyskinesia rating scale from 0-104; it evaluates involuntary movements associated with PD. A higher score indicates more severe PD. The UDysRS was measured at Baseline and Weeks 2, 8, 12, 18, and 24.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

MITT population

Arm/Group Title	Placebo	ADS-5102 (340 mg)
Arm/Group Description	Placebo: oral capsules administered once nightly at bedtime for 25 weeks	340 mg dose of ADS-5102 (amantadine HCl extended release): oral capsules administered once nightly at bedtime for 25 weeks
Measure Participants	58	63
Least Squares Mean (Standard Error) [units on a scale]	-8.0 (1.64)	-15.9 (1.62)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADS-5102 (340 mg)
	Comments	46 subjects per treatment arm provided 90% power using a 2-sided test at 5% significance.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0009
	Comments
	Method	Linear Mixed Model w/ Repeated Measures
	Comments	Change from baseline is a dependent variable, treatment group is a factor, and the baseline value is a covariate.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-7.9
	Confidence Interval	(2-Sided) 95%; -12.5 to -3.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.30
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in the Unified Dyskinesia Rating Scale (UDysRS) Score at Week 24
Description	The UDysRS is a dyskinesia rating scale from 0-104; it evaluates involuntary movements associated with PD. A higher score indicates more severe PD. The UDysRS was measured at Baseline and Weeks 2, 8, 12, 18, and 24.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

MITT population

Arm/Group Title	Placebo	ADS-5102 (340 mg)
Arm/Group Description	Placebo: oral capsules administered once nightly at bedtime for 25 weeks	340 mg dose of ADS-5102 (amantadine HCl extended release): oral capsules administered once nightly at bedtime for 25 weeks
Measure Participants	58	63
Least Squares Mean (Standard Error) [units on a scale]	-6.3 (1.94)	-15.6 (1.87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADS-5102 (340 mg)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0008
	Comments
	Method	Linear Mixed Model w/ Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-9.3
	Confidence Interval	(2-Sided) 95%; -14.7 to -4.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.70
	Estimation Comments

3. Secondary Outcome

Title	Change in the Standardized PD Home Diary (ON Time Without Troublesome Dyskinesia, ON Time With Troublesome Dyskinesia, OFF Time)
Description	A PD home diary was used to score 5 different conditions in 30-minute intervals: ASLEEP, OFF, ON (ie, had adequate control of PD symptoms) without dyskinesia, ON with non-troublesome dyskinesia, and ON with troublesome dyskinesia. The results were based on 2 consecutive 24-hour diaries taken prior to the day of randomization and prior to the Week 2, 8, 12, 18, and 24 visits.
Time Frame	Baseline (BL) to Week 12 (W12) and Week 24 (W24)

Outcome Measure Data

Analysis Population Description

MITT population

Arm/Group Title	Placebo	ADS-5102 (340 mg)
Arm/Group Description	Placebo: oral capsules administered once nightly at bedtime for 25 weeks	340 mg dose of ADS-5102 (amantadine HCl extended release): oral capsules administered once nightly at bedtime for 25 weeks
Measure Participants	58	63
Change in ON time w/o troublesome dyskinesia (W12)	0.82 (0.432)	3.56 (0.434)
Change in ON time w/o troublesome dyskinesia (W24)	1.37 (0.456)	3.59 (0.440)
Change in OFF time (W12)	0.32 (0.263)	-0.59 (0.265)
Change in OFF time (W24)	0.22 (0.282)	-0.58 (0.268)
Change in ON time w/ troublesome dyskinesia (W12)	-1.58 (0.358)	-3.12 (0.359)
Change in ON time w/ troublesome dyskinesia (W24)	-1.86 (0.380)	-3.31 (0.363)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADS-5102 (340 mg)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Change from Baseline in ON time without troublesome dyskinesia at Week 12.
	Method	Linear Mixed Model w/ Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	2.74
	Confidence Interval	(2-Sided) 95%; 1.53 to 3.96
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.612
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ADS-5102 (340 mg)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0007
	Comments	Change from Baseline in ON time without troublesome dyskinesia at Week 24.
	Method	Linear Mixed Model w/ Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	2.22
	Confidence Interval	(2-Sided) 95%; 0.96 to 3.47
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.634
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	ADS-5102 (340 mg)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0171
	Comments	Change from Baseline in OFF time at Week 12.
	Method	Linear Mixed Model w/ Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.90
	Confidence Interval	(2-Sided) 95%; -1.64 to -0.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.373
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	ADS-5102 (340 mg)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0406
	Comments	Change from Baseline in OFF time at Week 24.
	Method	Linear Mixed Model w/ Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.81
	Confidence Interval	(2-Sided) 95%; -1.58 to -0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.389
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	ADS-5102 (340 mg)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0031
	Comments	Change from Baseline in ON time with troublesome dyskinesia at Week 12.
	Method	Linear Mixed Model w/ Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-1.54
	Confidence Interval	(2-Sided) 95%; -2.55 to -0.53
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.508
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	ADS-5102 (340 mg)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0072
	Comments	Change from Baseline in ON time with troublesome dyskinesia at Week 24.
	Method	Linear Mixed Model w/ Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-1.45
	Confidence Interval	(2-Sided) 95%; -2.49 to -0.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.526
	Estimation Comments

4. Secondary Outcome

Title	Change in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Combined Score (Parts I, II, and III)
Description	The MDS-UPDRS Parts I, II, and III examined non-motor experiences of daily living, motor experiences of daily living, and motor examination, respectively. Each Part contains items or questions that were each rated on a scale from 0 (normal) to 4 (severe). The Combined Parts I, II, and III (representing the sum of the individual scores from Parts I, II, and III) has a scale range of 0-236. Higher scores, whether for individual Parts or the sum of the combined Parts, indicate more severe PD.
Time Frame	Baseline (BL) to Week 12 (W12) and Week 24 (W24)

Outcome Measure Data

Analysis Population Description

MITT population

Arm/Group Title	Placebo	ADS-5102 (340 mg)
Arm/Group Description	Placebo: oral capsules administered once nightly at bedtime for 25 weeks	340 mg dose of ADS-5102 (amantadine HCl extended release): oral capsules administered once nightly at bedtime for 25 weeks
Measure Participants	58	63
Change from BL at Week 12	-4.0 (1.96)	-5.2 (1.92)
Change from BL at Week 24	-3.5 (2.60)	-1.3 (2.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADS-5102 (340 mg)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6833
	Comments	Change from Baseline in MDS-UPDRS at Week 12.
	Method	Linear Mixed Model w/ Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-1.1
	Confidence Interval	(2-Sided) 95%; -6.6 to 4.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.74
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ADS-5102 (340 mg)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5557
	Comments	Change from Baseline in MDS-UPDRS at Week 24.
	Method	Linear Mixed Model w/ Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	2.1
	Confidence Interval	(2-Sided) 95%; -5.0 to 9.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.58
	Estimation Comments

5. Secondary Outcome

Title	Clinician's Global Impression of Change (CGI-C) in Overall PD Symptoms
Description	The CGI-C consisted of a single question that assessed the investigator's global impression of the subject's change from Baseline in overall PD symptoms, including but not limited to LID. The CGI-C required that the investigator rate the extent to which the subject's PD had improved or worsened (from marked worsening to marked improvement). The CGI-C was assessed at Baseline and Weeks 2, 8, 12, 18, and 24.
Time Frame	Baseline to Week 12 and Week 24

Outcome Measure Data

Analysis Population Description

MITT population

Arm/Group Title	Placebo	ADS-5102 (340 mg)
Arm/Group Description	Placebo: oral capsules administered once nightly at bedtime for 25 weeks	340 mg dose of ADS-5102 (amantadine HCl extended release): oral capsules administered once nightly at bedtime for 25 weeks
Measure Participants	58	63
Marked Improvement	2 3.3%	18 28.6%
Moderate Improvement	9 15%	20 31.7%
Minimal Improvement	10 16.7%	13 20.6%
No Change	25 41.7%	9 14.3%
Minimal Worsening	10 16.7%	2 3.2%
Moderate Worsening	2 3.3%	0 0%
Marked Worsening	0 0%	1 1.6%
Marked Improvement	5 8.3%	14 22.2%
Moderate Improvement	10 16.7%	17 27%
Minimal Improvement	12 20%	12 19%
No Change	17 28.3%	7 11.1%
Minimal Worsening	6 10%	5 7.9%
Moderate Worsening	4 6.7%	5 7.9%
Marked Worsening	0 0%	2 3.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADS-5102 (340 mg)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Baseline to Week 12
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ADS-5102 (340 mg)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1071
	Comments	Baseline to Week 24
	Method	Cochran-Mantel-Haenszel
	Comments

Adverse Events

Time Frame	Baseline through Week 25
Arm/Group Title	Placebo		ADS-5102 (340 mg)
Arm/Group Description	Placebo: oral capsules administered once nightly at bedtime for 25 weeks		340 mg dose of ADS-5102 (amantadine HCl extended release): oral capsules administered once nightly at bedtime for 25 weeks
All Cause Mortality
	Placebo		ADS-5102 (340 mg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/60 (0%)		1/63 (1.6%)
Serious Adverse Events
	Placebo		ADS-5102 (340 mg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/60 (5%)		7/63 (11.1%)
Gastrointestinal disorders
Small intestinal obstruction	0/60 (0%)	0	1/63 (1.6%)	1
Constipation	0/60 (0%)	0	1/63 (1.6%)	1
Infections and infestations
Cellulitis	1/60 (1.7%)	1	1/63 (1.6%)	1
Injury, poisoning and procedural complications
Hip fracture	2/60 (3.3%)	2	1/63 (1.6%)	1
Humerus fracture	0/60 (0%)	0	1/63 (1.6%)	1
Subdural haematoma	0/60 (0%)	0	1/63 (1.6%)	1
Musculoskeletal and connective tissue disorders
Muscular weakness	0/60 (0%)	0	1/63 (1.6%)	1
Nervous system disorders
Presyncope	0/60 (0%)	0	1/63 (1.6%)	1
ON and OFF phenomenon	0/60 (0%)	0	1/63 (1.6%)	1
Encephalopathy	0/60 (0%)	0	1/63 (1.6%)	1
Other (Not Including Serious) Adverse Events
	Placebo		ADS-5102 (340 mg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	36/60 (60%)		56/63 (88.9%)
Gastrointestinal disorders
Dry mouth	0/60 (0%)		11/63 (17.5%)
Constipation	3/60 (5%)		9/63 (14.3%)
General disorders
Oedema peripheral	0/60 (0%)		15/63 (23.8%)
Infections and infestations
Urinary tract infection	5/60 (8.3%)		7/63 (11.1%)
Nasopharyngitis	3/60 (5%)		1/63 (1.6%)
Injury, poisoning and procedural complications
Fall	5/60 (8.3%)		10/63 (15.9%)
Contusion	1/60 (1.7%)		6/63 (9.5%)
Musculoskeletal and connective tissue disorders
Back pain	4/60 (6.7%)		3/63 (4.8%)
Musculoskeletal pain	3/60 (5%)		1/63 (1.6%)
Arthralgia	3/60 (5%)		0/63 (0%)
Nervous system disorders
Dizziness	0/60 (0%)		14/63 (22.2%)
Headache	2/60 (3.3%)		4/63 (6.3%)
Balance disorder	3/60 (5%)		2/63 (3.2%)
Psychiatric disorders
Hallucination, any type	1/60 (1.7%)		18/63 (28.6%)
Hallucination, visual	1/60 (1.7%)		15/63 (23.8%)
Hallucination, auditory	0/60 (0%)		5/63 (7.9%)
Anxiety	1/60 (1.7%)		6/63 (9.5%)
Abnormal dreams	2/60 (3.3%)		4/63 (6.3%)
Depression	1/60 (1.7%)		4/63 (6.3%)
Skin and subcutaneous tissue disorders
Livedo reticularis	0/60 (0%)		6/63 (9.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.