Levodopa Induced Dyskinesia (LID), Parkinson's Disease
Conditions
Keywords
Parkinson's Disease, Levodopa Induced Dyskinesia (LID), LID, Parkinsonism, Dyskinesia
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.
Interventions
DRUGamantadine HCl ER
Subjects are given either 240 mg amantadine HCl ER tablet or 320 mg amantadine HCl ER tablet
DRUGPlacebo
subjects are given an identical placebo tablet
Sponsors
Adamas Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to 85 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Unified Dyskinesia Rating Scale | Change from baseline to Day 98 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mobility State Self-Assessment - Subject Diary Cards | Day 14 and Day 98 of treatment | 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. |
Countries
Canada, France, Germany, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 240mg Amantadine HCl ER Tablets Amantadine HCl ER Tablets 240mg daily for 22 weeks post two week titration phase.
Amantadine HCl ER (ALLAY-LID II) | 45 |
| 320mg Amantadine HCl ER Tablets Amantadine HCl ER Tablets 320mg daily for 22 weeks post two week titration phase.
Amantadine HCl ER (ALLAY-LID II) | 46 |
| Placebo Tablets for Amantadine Placebo Tablets matching Amantadine HCl ER Tablets taken daily for 26 weeks.
Placebo | 44 |
| Total | 135 |
Baseline characteristics
| Characteristic | 240mg Amantadine HCl ER Tablets | 320mg Amantadine HCl ER Tablets | Placebo Tablets for Amantadine | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 45 Participants | 46 Participants | 44 Participants | 135 Participants |
| Age, Continuous | 63.9 years STANDARD_DEVIATION 8.88 | 63.0 years STANDARD_DEVIATION 8.98 | 63.5 years STANDARD_DEVIATION 10.36 | 63.5 years STANDARD_DEVIATION 9.36 |
| Region of Enrollment Canada | 3 participants | 1 participants | 2 participants | 6 participants |
| Region of Enrollment France | 10 participants | 7 participants | 8 participants | 25 participants |
| Region of Enrollment Germany | 7 participants | 6 participants | 6 participants | 19 participants |
| Region of Enrollment Spain | 10 participants | 9 participants | 5 participants | 24 participants |
| Region of Enrollment United States | 15 participants | 23 participants | 23 participants | 61 participants |
| Sex: Female, Male Female | 16 Participants | 21 Participants | 18 Participants | 55 Participants |
| Sex: Female, Male Male | 29 Participants | 25 Participants | 26 Participants | 80 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 45 | 0 / 46 | 0 / 44 |
| other Total, other adverse events | 36 / 45 | 38 / 46 | 29 / 44 |
| serious Total, serious adverse events | 1 / 45 | 4 / 46 | 6 / 44 |
Outcome results
Primary
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.
Time frame: Change from baseline to Day 98
Population: Intent to treat population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 240mg Amantadine HCl ER Tablets | Unified Dyskinesia Rating Scale | Mean Change from Baseline (SD) | -15.2 score on a scale | Standard Deviation 15.58 |
| 240mg Amantadine HCl ER Tablets | Unified Dyskinesia Rating Scale | Visit 2 (Baseline) | 41.3 score on a scale | Standard Deviation 13.91 |
| 240mg Amantadine HCl ER Tablets | Unified Dyskinesia Rating Scale | Visit 7 (Day 98)/Stable Dose LOCF [1] | 41.3 score on a scale | Standard Deviation 13.98 |
| 320mg Amantadine HCl ER Tablets | Unified Dyskinesia Rating Scale | Mean Change from Baseline (SD) | -13.7 score on a scale | Standard Deviation 10.95 |
| 320mg Amantadine HCl ER Tablets | Unified Dyskinesia Rating Scale | Visit 2 (Baseline) | 36.3 score on a scale | Standard Deviation 12.4 |
| 320mg Amantadine HCl ER Tablets | Unified Dyskinesia Rating Scale | Visit 7 (Day 98)/Stable Dose LOCF [1] | 36.3 score on a scale | Standard Deviation 12.4 |
| Placebo Tablets for Amantadine | Unified Dyskinesia Rating Scale | Mean Change from Baseline (SD) | -9.0 score on a scale | Standard Deviation 10.62 |
| Placebo Tablets for Amantadine | Unified Dyskinesia Rating Scale | Visit 7 (Day 98)/Stable Dose LOCF [1] | 40.7 score on a scale | Standard Deviation 13.98 |
| Placebo Tablets for Amantadine | Unified Dyskinesia Rating Scale | Visit 2 (Baseline) | 40.7 score on a scale | Standard Deviation 13.98 |
p-value: 0.03195% CI: [-10.5, -0.5]ANCOVA
p-value: 0.01195% CI: [-11.5, -1.5]ANCOVA
Secondary
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.
Time frame: Day 14 and Day 98 of treatment
Population: The number analyzed is the number of subjects with values at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 240mg Amantadine HCl ER Tablets | Mobility State Self-Assessment - Subject Diary Cards | Visit 7 (Day 98)/Stable Dose LOCF [1] | 12.7 Hours | Standard Deviation 3.91 |
| 240mg Amantadine HCl ER Tablets | Mobility State Self-Assessment - Subject Diary Cards | Visit 2 (Baseline) | 10.4 Hours | Standard Deviation 3.76 |
| 240mg Amantadine HCl ER Tablets | Mobility State Self-Assessment - Subject Diary Cards | Mean Change in Hours from Baseline (SD) | 2.3 Hours | Standard Deviation 3.25 |
| 320mg Amantadine HCl ER Tablets | Mobility State Self-Assessment - Subject Diary Cards | Visit 7 (Day 98)/Stable Dose LOCF [1] | 13.3 Hours | Standard Deviation 3.83 |
| 320mg Amantadine HCl ER Tablets | Mobility State Self-Assessment - Subject Diary Cards | Visit 2 (Baseline) | 9.8 Hours | Standard Deviation 3.48 |
| 320mg Amantadine HCl ER Tablets | Mobility State Self-Assessment - Subject Diary Cards | Mean Change in Hours from Baseline (SD) | 3.6 Hours | Standard Deviation 3.93 |
| Placebo Tablets for Amantadine | Mobility State Self-Assessment - Subject Diary Cards | Visit 2 (Baseline) | 9.1 Hours | Standard Deviation 3.48 |
| Placebo Tablets for Amantadine | Mobility State Self-Assessment - Subject Diary Cards | Mean Change in Hours from Baseline (SD) | 1.6 Hours | Standard Deviation 3.56 |
| Placebo Tablets for Amantadine | Mobility State Self-Assessment - Subject Diary Cards | Visit 7 (Day 98)/Stable Dose LOCF [1] | 11.1 Hours | Standard Deviation 4.03 |