Extended Release Amantadine Safety and Efficacy Study in Levodopa-Induced Dyskinesia (EASED Study)

Study Overview
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Brief Summary
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This is a multi-center, randomized, double-blind, placebo-controlled, 4-arm parallel group study to evaluate the tolerability and efficacy of each of three dose levels of ADS-5102 oral capsules, an extended release formulation of amantadine, dosed once daily 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) higher amantadine plasma concentrations during daytime hours when dyskinesia as well as motor and non-motor symptoms of PD are most problematic, ii) low amantadine plasma concentrations overnight, which may reduce the sleep disturbances and vivid dreams occasionally associated with amantadine, and iii) a reduced initial rate of rise in plasma concentration, which is expected to improve overall tolerability of amantadine.

Official Title
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Extended Release Amantadine Safety and Efficacy Study in Levodopa-Induced Dyskinesia (EASED Study)

Conditions
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Dyskinesia, Levodopa Induced Dyskinesia, Parkinson's Disease

Intervention / Treatment
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* Drug: ADS-5102 (extended release amantadine HCl)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed a current IRB/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 , including any levodopa preparation administered not less than three times daily, and willing to continue the same doses and regimens during study participation Experiencing troublesome dyskinesia following levodopa dosing (peak dose dyskinesia) Able to understand and complete a standardized PD home diary, following training Exclusion Criteria: History of neurosurgical intervention related to Parkinson's disease (e.g. deep brain stimulation) History of seizures or stroke/TIA within 2 years of screening History of cancer within 5 years of screening, except adequately treated non-melanomatous skin cancers, localized bladder cancer, non-metastatic prostate cancer or in situ cervical cancer Estimated GFR < 50 mL/min/1.73m2 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, or has a positive pregnancy test result pre-dose 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

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Treatment A<br> | Drug: ADS-5102 (extended release amantadine HCl)<br>* Oral capsules to be administered once daily at bedtime, for 8 weeks<br>|
| Active Comparator: Treatment B<br>Low dose ADS-5102 (amantadine extended release) | Drug: ADS-5102 (extended release amantadine HCl)<br>* Oral capsules to be administered once daily at bedtime, for 8 weeks<br>|
| Active Comparator: Treatment C<br>A mid-dose ADS-5102 (amantadine extended release) | Drug: ADS-5102 (extended release amantadine HCl)<br>* Oral capsules to be administered once daily at bedtime, for 8 weeks<br>|
| Active Comparator: Treatment D<br>High dose ADS-5102 (amantadine extended release) | Drug: ADS-5102 (extended release amantadine HCl)<br>* Oral capsules to be administered once daily at bedtime, for 8 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Unified Dyskinesia Rating Scale (UDysRS) Total Score From Baseline to Week 8 | The UDysRS is a dyskinesia rating scale from 0-104, and it evaluates involuntary movements associated with PD. A higher score indicates more severe PD. The last observation carried forward (LOCF) method was used for analysis. Participants were summarized according to the actual treatment received. | Baseline (Day 1) and Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Fatigue Severity Score (FSS) From Baseline to Week 8 | The FSS is a 9-item self-reported scale, rating subject experience of fatigue during the previous 7 days. The total score, on a scale from 1-7, is represented by the mean of all answered items. The higher the score, the greater the fatigue severity. | Baseline (Day 1) and Week 8 | 
| Change in Total Objective Score (III, IV) of the UDysRS From Baseline to Week 8 | UDysRS Part III measures objective impairment (dyskinesia severity, anatomic distribution, and type, based on 4 observed activities); and Part IV measures objective disability based on Part III activities. The scores for the 2 Parts combined range from 0-44; a higher score represents more severe dyskinesia. | Baseline (Day 1) and Week 8 | 
| Change in ON Time Without Troublesome Dyskinesia (ON Without Dyskinesia Plus ON With Non-troublesome Dyskinesia) From Baseline to Week 8; Based on a Standardized PD Home Diary | A PD home diary was used to score 5 different conditions in 30-minute time 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 8 visit. | Baseline (Day 1) and Week 8 | 
| Change in Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Combined Scores (Parts I, II, III) From Baseline to Week 8 | 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 had sub scales ranging from normal = 0 to severe = 4. | Baseline (Day 1) and Week 8 | 
| Clinician's Global Impression of Change (CGI-C) in Overall PD Symptoms From Baseline to Week 8 | 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). | Baseline (Day 1) and Week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Levodopa-induced dyskinesia, Parkinsonism