| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Parkinson’s Disease Subjects with Levodopa-Induced Dyskinesias |
|
| E.1.1.1 | Medical condition in easily understood language |
| Parkinson’s Disease Subjects with Levodopa-Induced Dyskinesias |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061536 |
| E.1.2 | Term | Parkinson's disease |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Demonstrate the efficacy of Amantadine Extended Release (ER) Tablets versus placebo on the Unified Dyskinesia Rating Scale (UDysRS) in patients with Levodopa-Induced Dyskinesia (LID) after 12 weeks of treatment at a fixed dose. |
|
| E.2.2 | Secondary objectives of the trial |
• Compare the efficacy of Amantadine ER Tablets (AERT) versus placebo on the UDysRS in patients with LID after 22 weeks of treatment at a fixed dose
• To compare the change in the percent of waking hours that subjects report being “OFF” during 12 and 22 weeks of treatment with AERT versus placebo using the Mobility State Self-Assessment (Subject Diary Cards; SDC)
• To compare the change in the percent of waking hours that subjects report having no dyskinesias during “ON” time during 12 and 22 weeks of treatment with AERT versus placebo using the Mobility State Self-Assessment (SDC)
• To compare the change in the MDS-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) score in Parts II and III, in Parkinson’s Disease subjects with LID during 12 and 22 weeks of treatment with AERT versus placebo
• To evaluate the relationship between amantadine plasma concentrations and clinical efficacy, safety and renal function during 22 weeks of treatment with AERT |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For a subject to be eligible for participation in this study, all of the following criteria must be met at screening. Subject must:
1. Sign an informed consent form (ICF) indicating that they have been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts.
2. Have been diagnosed with idiopathic Parkinson's disease as defined by the UK Parkinson's Disease Society Brain Bank criteria.
3. Be male or female 30 to 85 years old.
4. Have levodopa induced, predictable peak-effect dyskinesia that are considered by the subject to be problematic and/or disabling.
5. Have screening serum creatinine level within the normal range for the testing laboratory.
6. Have been 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 course of the subject’s participation in the trial.
7. The subject/caregiver must demonstrate the ability to complete an accurate home diary based on training and evaluation during the screening period. |
|
| E.4 | Principal exclusion criteria |
A subject will not be eligible for participation in this study if any of the following criteria apply. The subject:
1. Is diagnosed with secondary parkinsonian syndrome, such as vascular, post-inflammatory, drug-induced, neoplastic and post-traumatic parkinsonism or any atypical parkinsonian syndrome (e.g., Progressive Supranuclear Palsy, Multi-System Atrophy, etc.)
2. Has used amantadine in any dosage or pharmaceutical form within the past 14 days, or has previously interrupted the use of amantadine due to an adverse event
3. Is currently using medications that would potentially interfere with the actions of the study medication or outcome variables, including neuroleptics and atypical antipsychotic agents, acetylcholinesterase inhibitors, apomorphine, rimantadine, memantine and dextromethorphan and quinidine if used in combination for treating dyskinesia.
4. Has a history of pallidotomy or other ablative surgery for the treatment of PD, or is implanted with a uni- or bilateral deep brain stimulator
5. Has any medical condition or past medical history that, in the Investigator's judgment, would increase the risk of exposure to Amantadine HCl Extended Release Tablets or interfere with safety and efficacy evaluations. These include:
o seizure disorders or history of seizures other than childhood febrile convulsions
o history of glaucoma
o current hallucinations
o urinary retention
o abuse of legal or illegal drugs within the past 12 months
6. Has a history of cancer within 5 years of screening that may compromise the life-expectancy of the subject; exceptions are adequately treated non-melanomatous skin cancers, localized bladder cancer, non-metastatic prostate cancer or in situ cervical cancer.
7. Has a history or current diagnosis of schizophrenia or bipolar disorder
8. Has current diagnosis of inadequately treated Major Depressive Disorder. Subjects who are on stable doses of selective serotonin reuptake inhibitors (SSRIs) or serotonin -norepinephrine reuptake inhibitors (SNRIs) for depression are eligible for the study
9. Is at imminent risk of suicide (score of 4 or 5 on the C-SSRS) or had a suicide attempt within 6 months of the screening visit.
10. Has a history of, or current diagnosis of Impulse Control Disorder or is judged to be at risk according to the QUIP-RS
11. Has an estimated plasma creatinine clearance of <60 mL/min at screening using the Cockroft-Gault equation
12. Has a history of or currently has any of the following clinically significant conditions, that in the investigator’s opinion may interfere with the study procedures or compromise the subject’s safety:
o Cardiovascular disease
o Respiratory disease
o Renal disease
o Hepatic disease
o Gastrointestinal disease
13. Upon evaluation at the screening visit, the subject has:
o Any clinically significant vital sign, ECG, or laboratory abnormalities
o A positive test for human immunodeficiency virus (HIV) antibody of a history of HIV
o A positive test for hepatitis B surface antigen unless the positive test followed a recent (<28 days) vaccination for hepatitis B and the vaccination record is available
o A positive test for hepatitis C antibody
o A positive urine drug test
14. The subject is female, and is pregnant or lactating (breastfeeding) at the time of screening or has a positive pregnancy test result pre-dose
15. 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.
16. Has a history of alcohol or narcotic substance abuse, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), ≤1 year before the screening visit. Has dementia or another psychiatric illness that prevents provision of informed consent.
17. 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.
18. 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 the screening visit.
19. Plans to undergo major elective surgery during the course of the study.
20. Has received administration of Live Attenuated Influenza Vaccine (LAIV) within 2 weeks.
21. Presence of cognitive impairment, as evidenced by a score <26 on the Montreal Cognitive Assessment (MoCA) at the screening visit. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The change from baseline to Day 98 (Visit 7) of treatment in the sum of the items comprising the Unified Dyskinesia Rating Scale (UDysRS). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints - Efficacy
• The change from baseline to Day 14 (Visit 4), Day 42 (Visit 5), Day 70 (Visit 6), Day 98 (Visit7), Day 126 (Visit 8), and Day 168 (Visit 9) of treatment in the sum of the items comprising the Unified Dyskinesia Rating Scale (UDysRS).
• The change from baseline to Day 14 (Visit 4), Day 42 (Visit 5), Day 70 (Visit 6), Day 98 (Visit 7), Day 126 (Visit 8), and Day 168 (Visit 9) of treatment in the percent of waking hours that subjects report being “OFF” in the Mobility State Self-Assessment (Subject Diaries).
• The change from baseline to Day 14 (Visit 4), Day 42 (Visit 5), Day 70 (Visit 6), Day 98 (Visit7), Day 126 (Visit 8), and Day 168 (Visit 9) of treatment in the percent of waking hours that subjects report being “ON” having no dyskinesias, non-troublesome dyskinesias, and troublesome dyskinesias in the Mobility State Self-Assessment (Subject Diaries).
• The change from baseline to Day 14 (Visit 4), Day 42 (Visit 5), Day 70 (Visit 6), Day 98 (Visit7), Day 126 (Visit 8), and Day 168 (Visit 9) of treatment in the sum of Parts II, and III of the MDS-UPDRS.
• The change from baseline to Day 14 (Visit 4), Day 42 (Visit 5), Day 70 (Visit 6), Day 98 (Visit7), Day 126 (Visit 8), and Day 168 (Visit 9) in the Fatigue Severity Scale (FSS).
Secondary Endpoints - Safety
• Safety and tolerability of Amantadine HCl Extended Release Tablets as assessed by frequency and nature of adverse events (AEs), laboratory results, vital sign measurements, physical examinations, and 12-lead electrocardiograms (ECGs)
• Assessment of the potential occurrence of psychiatric side effects (SCOPA-PC), sleep disorders, Livedo Reticularis and orthostatic hypotension
• Assessment of suicidality using the Columbia-Suicide Severity Rating Scale (C-SSRS) (Baseline/Screening), (Since Last Visit)
• Assessment of potential occurrence of Impulse Control Disorder using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease - Rating Scale (QUIP-RS)
• Relationship of plasma amantadine concentrations to clinical efficacy, safety, and renal function |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Endpoints - Efficacy:
- Day 14 (Visit 4), Day 42 (Visit 5), Day 70 (Visit 6), Day 98 (Visit 7), Day 126 (Visit 8), and Day 168 (Visit 9) of treatment
Secondary Endpoints - Safety:
- Until Day 182 (Final Visit) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| France |
| Germany |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 6 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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