Randomized Trial of Extended Release Amantadine in Parkinson’s … · 2014-03-21 · Randomized Trial of Extended Release Amantadine in Parkinson’s Disease Patients with Levodopa-induced

Randomized Trial of Extended Release Amantadine in Parkinson’s Disease Patients with Levodopa-induced

Dyskinesia (EASED Study)Rajesh Pahwa1, Caroline M Tanner2, Robert A Hauser3, Kapil D Sethi4, Stuart H Isaacson5, Daniel D Truong6,

Lynn K Struck7, Mary Jean Stempien8 and Gregory T Went8

1University of Kansas Medical Center, Kansas City, KS; 2The Parkinson’s Institute, Sunnyvale, CA; 3University of South Florida, Tampa, FL; 4Georgia Regents University, Augusta, GA; 5Parkinson’s Disease Center, Boca Raton, FL; 6Parkinson’s & Movement Disorder Institute, Fountain Valley, CA;

7Iowa Health Physicians, Des Moines, IA and 8Adamas Pharmaceuticals, Emeryville, CA

Background• Levodopa-induced dyskinesia (LID) is a dose-limiting adverse effect of

Parkinson’s disease (PD) treatment that can be disabling, and negatively impact quality of life. There is currently no approved treatment for LID.

• Amantadine has multiple mechanisms of action, including acting as an NMDA receptor antagonist, and as a mild dopamine agonist. Amantadine has shown activity in several small LID clinical studies.

• ADS-5102 is a proprietary, investigational, extended-release formulation of amantadine HCl. Designed for once-nightly administration, ADS-5102's unique “chronotherapeutic” profile is characterized by a slow initial increase in amantadine plasma concentrations, expected to result in high plasma concentrations during the daytime hours when LID can be troublesome, and low plasma concentrations overnight.

• ADS-5102 is being investigated at daily dose strengths between 1.3 and 2.1-fold higher than those typically used for immediate-release amantadine.

Objectives• Investigate the safety, efficacy and tolerability of once-nightly administration

of 3 dose levels of ADS-5102 for LID in PD

Methods• Randomized, double-blind, placebo-controlled, parallel-group study

conducted at 31 U.S. clinical trial sites (NCT 01397422).• Consented and eligible PD patients with troublesome LID were randomized in

a 1:1:1:1 ratio, to placebo or one of 3 dose levels of ADS-5102 (260 mg, 340 mg, 420 mg), dosed once-nightly for 8 weeks.

• Active treatment started at 260 mg, followed by dose increases at one week intervals (340 mg, then 420 mg), depending on treatment assignment.

• Safety measures included adverse events and routine safety laboratory tests that were reviewed during the study by an independent data monitoring committee.

Key Inclusion criteria• 30-85 years old with PD by UK brain bank clinical diagnostic criteria• Score of at least 2 on part IV, item 4.2 (functional impact of dyskinesia) of the

MDS-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) at screening and Day 1

• At least two 30 minute intervals of ON Time with troublesome dyskinesia between the hours of 9 am-4 pm, documented on a 24-hour PD diary

• Current antiparkinsonian medications, including levodopa preparations, were to be unchanged for 30 days prior to screening, and during the study

Key Exclusion criteria• History of deep brain stimulation• History of exclusively diphasic, off state, myoclonic, dystonic or akathetic

dyskinesia without peak dose dyskinesia• Presence of cognitive impairment, as evidenced by a MMSE of less than 24• Estimated GFR <50 mL/min/1.73 m2

• Current treatment with apomorphine or dopamine receptor antagonists• Use of amantadine within 30 days prior to screening, or documented inability

to tolerate amantadine

Outcome measures• Primary: Change from baseline to Week 8 in the Unified Dyskinesia Rating

Scale (UDysRS) Total Score • Secondary: Change from baseline to Week 8 in the following:

• Fatigue Severity Scale (FSS)• UDysRS Total Objective Score (III, IV) • MDS-UPDRS combined score (parts I, II and III)• MDS-UPDRS, part IV, items 4.1 and 4.2 • PD home diary: ON Time without troublesome dyskinesia, ON Time with

troublesome dyskinesia, ON Time with dyskinesia, OFF Time• Clinician’s Global Impression of Change in overall PD symptoms including

dyskinesia • Parkinson’s Disease Questionnaire (PDQ-39), a quality of life measure

Statistical methods• All efficacy analyses shown were conducted using a modified intent-to-treat

(MITT) analysis population.• An ANCOVA model assessed significance with change from baseline as the

dependent variable, treatment group as a factor, and the baseline value as a covariate.

• Missing data were imputed using pre-specified algorithms.

Figure 1. Subject DispositionFigure 1. Subject DispositionFigure 1. Subject Disposition

ScreenedScreenedScreenedN=131 N=131 N=131

Randomized Randomized Randomized N=83 N=83 N=83

340 mg 340 mg 340 mg ADS-5102 ADS-5102 ADS-5102

N=21 N=21 N=21


N=20 N=20 N=20

Discon�nua�ons Discon�nua�ons Discon�nua�ons - Other (N=2) - Other (N=2) - Other (N=2) - - - BradykinesiaBradykinesiaBradykinesia - 2° to Schedule - 2° to Schedule - 2° to Schedule

CompletedCompletedCompletedN=20 N=20 N=20

CompletedCompletedCompletedN=12N=12N=12




N=20 N=20 N=20

Discon�nua�ons Discon�nua�ons Discon�nua�ons - - - AEs (N=3) AEs (N=3) AEs (N=3)



Placebo Placebo Placebo N=22 N=22 N=22

• 83 subjects were randomized in the study. The MITT population included 80 subjects; one subject was excluded from each of the active treatment groups according to pre-defined exclusion criteria.

Results• The demographics and baseline characteristics appeared to be balanced

across treatment groups.

Table 1. Demographics and Baseline Characteristics Table 1. Demographics and Baseline Characteristics Table 1. Demographics and Baseline Characteristics

Placebo Placebo Placebo (N=22)(N=22)(N=22)

260 mg260 mg260 mgADS-5102ADS-5102ADS-5102

(N=20)(N=20)(N=20)


(N=21)(N=21)(N=21)


(N=20)(N=20)(N=20)

Analysis of UDysRS outcome measures• The primary efficacy analysis was the comparison of 340 mg ADS-5102 to

placebo in mean change in UDysRS Total Score from baseline to Week 8. A significant decrease in UDysRS (improvement in LID) was observed (LS mean treatment difference = -11.3, p=0.005) (Figures 2 and 3).

• The comparison of 420 mg ADS-5102 to placebo was prespecified in a hierarchical testing approach and also met statistical significance (LS mean treatment difference = -10.0, p=0.013), whereas 260 mg ADS-5102 did not (LS mean treatment difference = -5.6, p=0.159) (Figures 2 and 3).

• A dose response was confirmed for the treatment groups in mean change from baseline to Week 8 in UDysRS Total Score (p<0.01).

• ADS-5102 significantly reduced the UDysRS Total Objective Score (III, IV) as compared to placebo at both the 340 mg and 420 mg dose levels (p=0.004 and p=0.0004, respectively).

Figure 2. Change in UDysRS Total Score from Baseline to Week 8Figure 2. Change in UDysRS Total Score from Baseline to Week 8Figure 2. Change in UDysRS Total Score from Baseline to Week 8

-25 -25 -25

-20 -20 -20

-15 -15 -15

-10 -10 -10

-5 -5 -5

0 0 0 Placebo Placebo Placebo

260 mg260 mg260 mgADS-5102 ADS-5102 ADS-5102



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p=0.005p=0.005p=0.005p=0.013p=0.013p=0.013

Figure 3. Change in UDysRS Total Score Over Time by Treatment Group Figure 3. Change in UDysRS Total Score Over Time by Treatment Group Figure 3. Change in UDysRS Total Score Over Time by Treatment Group (Reduction in UDysRS Indicates Improvement)(Reduction in UDysRS Indicates Improvement)(Reduction in UDysRS Indicates Improvement)

-25 -25 -25

-20 -20 -20

-15 -15 -15

-10 -10 -10

-5 -5 -5

0 0 0

5 5 5

0 10 10 1 2 3 4 5 6 7 82 3 4 5 6 7 82 3 4 5 6 7 8

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Weeks Weeks Weeks

Placebo Placebo Placebo 260 mg ADS-5102 260 mg ADS-5102 260 mg ADS-5102 340 mg ADS-5102 340 mg ADS-5102 340 mg ADS-5102 420 mg ADS-5102 420 mg ADS-5102 420 mg ADS-5102

Analysis of PD diary parameters• A visual representation of PD diary parameters at baseline and week 8 for

340 mg ADS-5102 and placebo groups are shown below.

Figure 4. 24-Hour PD Diary Parameters (Mean Hours) at Baseline and Week 8 Figure 4. 24-Hour PD Diary Parameters (Mean Hours) at Baseline and Week 8 Figure 4. 24-Hour PD Diary Parameters (Mean Hours) at Baseline and Week 8 (340 mg ADS-5102 and Placebo)(340 mg ADS-5102 and Placebo)(340 mg ADS-5102 and Placebo)

7.57.57.5

4.34.34.34.54.54.5

7.77.77.7 7.67.67.6

3.23.23.2

1.81.81.8

11.511.511.5

7.87.87.8

3.23.23.26.16.16.1

6.96.96.9 8.28.28.2

3.43.43.44.44.44.4

8.08.08.0

ON with ON with ON with Troublesome Troublesome Troublesome DyskinesiaDyskinesiaDyskinesiaON without ON without ON without Troublesome Troublesome Troublesome DyskinesiaDyskinesiaDyskinesia

ASLEEPASLEEPASLEEPOFFOFFOFF

BaselineBaselineBaseline WWWeek eek eek 888

PlaceboPlaceboPlacebo

340 mg 340 mg 340 mg ADS-5102ADS-5102ADS-5102

Plac

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340

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ADS-

5102

340

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ADS-

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340

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Additional Efficacy Analyses• The results of analyses of additional efficacy outcome measures, including PD

Diary and MDS-UPDRS, are summarized in Table 2.

Table 2: Additional Analyses: Change from Baseline to Week 8 vs. PlaceboTable 2: Additional Analyses: Change from Baseline to Week 8 vs. PlaceboTable 2: Additional Analyses: Change from Baseline to Week 8 vs. PlaceboTable 2: Additional Analyses: Change from Baseline to Week 8 vs. PlaceboTable 2: Additional Analyses: Change from Baseline to Week 8 vs. PlaceboTable 2: Additional Analyses: Change from Baseline to Week 8 vs. Placebo

Outcome MeasureOutcome MeasureOutcome Measure


(N=19)(N=19)(N=19)


(N=20)(N=20)(N=20)


(N=19)(N=19)(N=19)LS Mean Treatment Difference vs. Placebo (95% CI)LS Mean Treatment Difference vs. Placebo (95% CI)LS Mean Treatment Difference vs. Placebo (95% CI)

Safety Results• The safety population included all 83 randomized and treated subjects.• Treatment emergent AEs were common in all treatment groups, and most

were mild to moderate in severity. Severe drug-related AEs were: 260 mg (1 subject: suicidal ideation); 340 mg (3 subjects: confusional state,

hallucinations, dizziness, muscle spasms, peripheral edema); 420 mg (5 subjects: balance disorder, anxiety, hallucinations, psychotic disorder, hypersensitivity, increased hepatic enzymes, dry mouth, constipation).

Table 3. Safety OverviewTable 3. Safety OverviewTable 3. Safety Overview

Placebo Placebo Placebo (N=22)(N=22)(N=22)


(N=20)(N=20)(N=20)


(N=21)(N=21)(N=21)


(N=20)(N=20)(N=20)

Table 4. Treatment Emergent Adverse Events in >10% (>2 Subjects) in Any Table 4. Treatment Emergent Adverse Events in >10% (>2 Subjects) in Any Table 4. Treatment Emergent Adverse Events in >10% (>2 Subjects) in Any Active Treatment Group Active Treatment Group Active Treatment Group

Preferred Term, n (%)Preferred Term, n (%)Preferred Term, n (%) Placebo Placebo Placebo (N=22)(N=22)(N=22)


(N=20)(N=20)(N=20)


(N=21)(N=21)(N=21)


(N=20)(N=20)(N=20)

Conclusions• The study met its primary endpoint. Both the 340 mg and 420 mg ADS-5102

dose levels significantly reduced LID as measured by the change in UDysRS Total Score over 8 weeks versus placebo (p=0.005 and p=0.013, respectively).

• ADS-5102 significantly increased ON Time without Troublesome Dyskinesia at the 260 mg, 340 mg and 420 mg dose levels as measured by patient diaries (p=0.004, p=0.008 and p=0.018, respectively), consistent with the changes observed in the UDysRS.

• Both the 340 mg and the 420 mg ADS-5102 dose levels significantly reduced the UDysRS Total Objective Score (III, IV) (p=0.004 and p=0.0004, respec-tively).

• ADS-5102 resulted in statistically significant improvements in the functional impact of dyskinesia at the 260 mg, 340 mg, and 420 mg dose levels by MDS-UPDRS (part IV, item 4.2) (p=0.014, p=0.002, p<0.001, respectively).

• Treatment with ADS-5102 did not result in clinical worsening of PD as measured by the MDS-UPDRS combined score (parts I, II, and III).

• ADS-5102 was generally well tolerated and reported adverse event terms were consistent with Parkinson’s disease and the known amantadine safety profile.

Acknowledgements and DisclosuresWe acknowledge and thank the study participants, the EASED Study Investigators and their staff and the members of the IDMC. Charles Davis, CSD Biostatistics, Inc., April Ruby, and Natalie McClure of Adamas provided support in the design, conduct and analysis of the study. Christopher Goetz, Rush University was instrumental in training raters in the proper use of the UDysRS. MJS, a consultant to Adamas and GTW, an employee of Adamas both received compensation and stock options. RP, CT, RH and KS are on the EASED steering committee and received compensation for this service. SI, DT and LS are EASED Study investigators and have not received any personal compensation from Adamas. This study was sponsored by Adamas Pharmaceuticals, Inc.In memory of Adamas’ friend and colleague, Efraim Shek, PhD, one of the inventors of ADS-5102Presented at the 17th International Congress of Parkinson’s Disease and Movement Disorders (MDS), June 16-20, 2013, Sydney, Australia

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Randomized Trial of Extended Release Amantadine in Parkinson’s … · 2014-03-21 · Randomized Trial of Extended Release Amantadine in Parkinson’s Disease Patients with Levodopa-induced