Efficacy and Safety of Amantadine Hydrogen Chloride (HCl) ER Tablets in Parkinson's Disease Subjects With LID

Study Overview
=================
Brief Summary
-----------------
The purpose of this multi-center, randomized, double-blind, parallel-group, 26 week study is to compare the efficacy and safety of two different dose levels of Amantadine Extended Release Tablets to placebo for the treatment of levodopa induced dyskinesia in patients with Parkinson's disease.

Detailed Description
-----------------
This study was terminated early due to slow enrollment with 135 of 162 planned subjects enrolled. Amantadine HCl ER has been used for many years as a treatment for Parkinson's disease. It has been reported in the literature to effectively treat the motor complications of levodopa, especially dyskinesia, but it must be given 2 to 4 times a day. The purpose of this multi-center, randomized, double-blind, parallel-group, 26 week study is to compare the efficacy and safety of two different dose levels of Amantadine Extended Release Tablets to placebo for the treatment of levodopa induced dyskinesia in patients with Parkinson's disease. The dose will be given once a day in the morning so that amantadine concentrations are maintained throughout the day for treating the levodopa induced dyskinesia, but will be lower during the night, potentially reducing the negative impact of amantadine on sleep.

Official Title
-----------------
A Multicenter, Randomized, Placebo-controlled, Double-blind, 26 Week Study to Evaluate the Efficacy and Safety of Amantadine HCl Extended Release Tablets in Parkinson's Disease Subjects With Levodopa-Induced Dyskinesias

Conditions
-----------------
Parkinson's Disease, Levodopa Induced Dyskinesia (LID)

Intervention / Treatment
-----------------
* Drug: amantadine HCl ER
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed Institutional Review Board (IRB)/ Independent Ethics Committee (IEC) informed consent form. Idiopathic Parkinson's disease per the United Kingdom (UK) Parkinson's Disease Society Brain Bank criteria. Male or female 30 to 85 years old. Levodopa induced, predictable peak-effect dyskinesia considered problematic and/or disabling. Screening serum creatinine level within normal range On stable doses of all oral anti-Parkinson's medication, including any levodopa preparation, for 30 days and be willing to remain on the same doses throughout the trial. The subject/caregiver must demonstrate the ability to complete an accurate home diary based on training and evaluation during the screening period. Exclusion Criteria: Secondary parkinsonian syndrome, such as vascular, postinflammatory,drug-induced, neoplastic and post-traumatic parkinsonism or any atypical parkinsonian syndrome (e.g., Progressive Supranuclear Palsy, Multi-System Atrophy, etc.); Use of amantadine within 14 days before study start, or previously had an adverse event to amantadine Currently taking neuroleptics and atypical antipsychotic agents, acetylcholinesterase inhibitors, apomorphine, rimantadine, memantine and dextromethorphan and quinidine if used in combination for treating dyskinesia. History of neurosurgical intervention for treating Parkinson's s disease (i.e. pallidotomy or implanted with a deep brain stimulator) Any medical condition or past medical history that would increase the risk of exposure to Amantadine HCl Extended Release Tablets or interfere with safety and efficacy evaluations. History of cancer within 5 years of screening with following exceptions: adequately treated non-melanomatous skin cancers, localized bladder cancer, non-metastatic prostate cancer or in situ cervical cancer. History or current diagnosis of schizophrenia or bipolar disorder; Inadequately treated Major Depressive Disorder. Subjects on stable doses of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) are eligible for the study; Is at imminent risk of suicide or had a suicide attempt within 6 months of screening History or current diagnosis of Impulse Control Disorder Calculated plasma creatinine clearance of <60 mL/min at screening History of or currently has any of the following clinically significant conditions, cardiovascular, respiratory, renal, hepatic, or gastrointestinal disease Any clinically significant vital sign, ECG, or laboratory abnormalities; A positive test for HIV antibody or history of HIV; hepatitis B surface antigen unless the positive test followed a recent (<28 days) vaccination for hepatitis B; hepatitis C antibody; A positive urine drug test. Pregnant or breastfeeding at screening or has a positive pregnancy test 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 the screening visit to at least 4 weeks after the completion of study treatment. History of alcohol or narcotic substance abuse ≤1 year before screening. Has dementia or another psychiatric illness that prevents provision of informed consent. Has a known hypersensitivity to the study treatment(s), based on known allergies to drugs of the same class including rimantadine HCl and memantine HCl. Has participated in other studies involving investigational drugs or surgeries within the last 30 days or investigational biologics within the last 6 months prior to screening. Plans to undergo major elective surgery during the course of the study. Received administration of Live Attenuated Influenza Vaccine (LAIV) within 2 weeks. Cognitive impairment, as evidenced by a score <26 on the Montreal Cognitive Assessment (MoCA) at the screening visit.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 240mg amantadine HCl ER tablets<br>amantadine HCl ER, 240 mg tablets, once daily, 22 weeks | Drug: amantadine HCl ER<br>* Subjects are given either 240 mg amantadine HCl ER tablet or 320 mg amantadine HCl ER tablet<br>* Other names: Osmolex ER Tablet;|
| Experimental: 320mg amantadine HCl ER tablets<br>amantadine HCl ER, 320 mg tablets, once daily, 22 weeks | Drug: amantadine HCl ER<br>* Subjects are given either 240 mg amantadine HCl ER tablet or 320 mg amantadine HCl ER tablet<br>* Other names: Osmolex ER Tablet;|
| Placebo Comparator: Placebo Tablets for Amantadine<br>Placebo, tablets, once daily, 26 weeks. | Drug: Placebo<br>* subjects are given an identical placebo tablet<br>* Other names: Placebo tablets;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Unified Dyskinesia Rating Scale | The Unified Dyskinesia Rating Scale is a validated tool for assessment of dyskinesia (involuntary movements) in Parkinson's Disease patients. Rating consists of the change from baseline to Day 98 of the sum of the 26 questions comprising the questionnaire. Each question in the questionnaire is rated on a 5 point scale from 0-4 where 0 is a better outcome. Questions assess: over the past week total hours with dyskinesia and total hours without dyskinesia; problems with speech, chewing and swallowing, eating, dressing, hygiene, handwriting, hobbies, balance, socializing, emotions, spasm or cramps, pain without dystonia and pain from dystonia. The minimum (better) value is 0 and the maximum (worse) value is 130. | Change from baseline to Day 98 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mobility State Self-Assessment - Subject Diary Cards | hange from baseline in the number of awake hours without troublesome dyskinesia (involuntary movements). Every half hour the subject will indicate in the diary if the medication has (ON) or has not (OFF) produced benefits in terms of mobility, slowness and rigidity. Valid diaries of the 3 consecutive days prior to each visit will be averaged with respect to the number of awake hours without troublesome dyskinesia. The change from baseline in the number of waking hours that subjects report being ON without troublesome dyskinesias will be analyzed at analysis visits Day 14 and Day 98 of treatment. Higher scores mean a better outcome and the maximum value is 24 hours. | Day 14 and Day 98 of treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Parkinson's Disease, Levodopa Induced Dyskinesia (LID), LID, Parkinsonism, Dyskinesia