Randomized Trial of Extended Release Amantadine in Parkinson`s

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
University of Kansas Medical Center, Kansas City, KS; 2The Parkinson’s Institute, Sunnyvale, CA; 3University of South Florida, Tampa, FL;
4
Georgia Regents University, Augusta, GA; 5Parkinson’s Disease Center, Boca Raton, FL; 6Parkinson’s & Movement Disorder Institute, Fountain Valley, CA;
7
Iowa Health Physicians, Des Moines, IA and 8Adamas Pharmaceuticals, Emeryville, CA
1
Background
Results
• 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.
• The demographics and baseline characteristics appeared to be balanced
across treatment groups.
Table 1. Demographics and Baseline Characteristics
260 mg
ADS-5102
(N=20)
Placebo
(N=22)
340 mg
ADS-5102
(N=21)
420 mg
ADS-5102
(N=20)
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. Placebo
Outcome Measure
260 mg
340 mg
420 mg
ADS-5102
ADS-5102
ADS-5102
(N=19)
(N=20)
(N=19)
LS Mean Treatment Difference vs. Placebo (95% CI)
Objectives
• Investigate the safety, efficacy and tolerability of once-nightly administration
of 3 dose levels of ADS-5102 for LID in PD
Analysis of UDysRS outcome measures
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.
• 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).
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
Change in UDysRS Score (LS Mean +/- SE)
• 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
260 mg
ADS-5102
Placebo
0
340 mg
ADS-5102
Preferred Term, n (%)
-20
p=0.005
5
Disconnuaons
- Other (N=2)
- Bradykinesia
- 2° to Schedule
Completed
N=20
Disconnuaons
- AEs (N=3)
Completed
N=17
420 mg
ADS-5102
N=20
Disconnuaons
- AEs (N=3)
Completed
N=18
0
420 mg
ADS-5102
(N=20)
Conclusions
-10
-15
-20
-25
0
1
2
3
4
Weeks
5
6
7
8
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.
Placebo
6.1
340 mg
ADS-5102
7.7
4.5
• 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.
340 mg
ADS-5102
(N=21)
-5
Week 8
7.8
8.0
3.2
8.2
4.4
3.4
Disconnuaons
- AEs (N=8)
Completed
N=12
260 mg
ADS-5102
(N=20)
Placebo
260 mg ADS-5102
340 mg ADS-5102
420 mg ADS-5102
Baseline
340 mg
ADS-5102
N=21
Placebo
(N=22)
Figure 3. Change in UDysRS Total Score Over Time by Treatment Group
(Reduction in UDysRS Indicates Improvement)
6.9
260 mg
ADS-5102
N=20
420 mg
ADS-5102
(N=20)
p=0.013
Randomized
N=83
Placebo
N=22
340 mg
ADS-5102
(N=21)
Table 4. Treatment Emergent Adverse Events in >10% (>2 Subjects) in Any
Active Treatment Group
-15
7.5
4.3
7.6
11.5
3.2
1.8
Placebo
Placeb
o
340 mg ADS-5102
Screened
N=131
260 mg
ADS-5102
(N=20)
-10
Figure 4. 24-Hour PD Diary Parameters (Mean Hours) at Baseline and Week 8
(340 mg ADS-5102 and Placebo)
Figure 1. Subject Disposition
Placebo
(N=22)
420 mg
ADS-5102
-5
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.
Table 3. Safety Overview
-25
Change in UDysRS Score (LS Mean +/- SE)
Key Exclusion criteria
• 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).
Figure 2. Change in UDysRS Total Score from Baseline to Week 8
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
Safety Results
ASLEEP
OFF
ON with
Troublesome
Dyskinesia
ON without
Troublesome
Dyskinesia
• 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, respectively).
• 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 Disclosures
We 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-5102
Presented at the 17th International Congress of Parkinson’s
Disease and Movement Disorders (MDS), June 16-20, 2013,
Sydney, Australia