Amantadine and L-DOPA-induced Dyskinesia in Early Parkinson's Disease

Study Overview
=================
Brief Summary
-----------------
Traditionally amantadine is used at the beginning of Parkinson Disease (PD) treatment in the early stages of the disease, as a modest antiparkinsonian symptomatic treatment. This treatment is usually maintained for no more than the first few months of management, before resorting to drugs deemed more effective as dopamine agonists and lévo-DOPA (L-DOPA). A more modern use of the drug is at a more advanced stage of PD when dyskinesia are already established and become disabling for the patients. There is no data between these two extremes of life stages of Parkinsonism. However, the mechanisms of action of amantadine and the pathophysiology of the motor complications induced by L-DOPA, in particular dyskinesia suggest that the early and prolonged use of amantadine in the early years of management, before L-DOPA-induced dyskinesia have already emerged, should have a positive impact on long-term occurrence and fate of these symptoms, possibly through a glutamatergic mechanism of brain plasticity-of the disease modification type.

Detailed Description
-----------------
Traditionally amantadine is used at the beginning of Parkinson Disease (PD) treatment in the early stages of the disease, as a modest antiparkinsonian symptomatic treatment. This treatment is usually maintained for no more than the first few months of management, before resorting to drugs deemed more effective as dopamine agonists and lévo-DOPA (L-DOPA). A more modern use of the drug is at a more advanced stage of PD when dyskinesia are already established and become disabling for the patients. There is no data between these two extremes of life stages of Parkinsonism. However, the mechanisms of action of amantadine and the pathophysiology of the motor complications induced by L-DOPA, in particular dyskinesia suggest that the early and prolonged use of amantadine in the early years of management, before L-DOPA-induced dyskinesia have already emerged, should have a positive impact on long-term occurrence and fate of these symptoms, possibly through a glutamatergic mechanism of brain plasticity-of the disease modification type. The primary purpose of this study is to demonstrate that early introduction of treatment with amantadine (200 mg / d) in the early years of therapeutic care, that is to say during the honeymoon of levodopa (early phase of disease <3 years of diagnosis <1 year of L-dopa and lack of complications of levodopa therapy) decreases the rate of subjects with abnormal involuntary dyskinetic movements after 18 months of follow-up.

Official Title
-----------------
Impact of Amantadine on L-DOPA-induced Dyskinesia in Early Parkinson's Disease: a Placebo-controlled Randomized Study (the PREMANDYSK Study)

Conditions
-----------------
Parkinson Disease

Intervention / Treatment
-----------------
* Drug: Amantadine
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age over 35 years, Patients having signed an informed consent before any specific study procedures, Patients having a health Insurance Coverage (according to local regulatory requirements), Patients suffering from idiopathic Parkinson's disease meeting the definition criteria of the UKPD Brain Bank (Gibb and Lees, 1988), Parkinson's disease diagnosed for <3 years, Patients receiving treatment with L-DOPA from <1year, Lack of complications of levodopa therapy Patients receiving a stable antiparkinsonian treatment that may involve, in addition to L-DOPA, a dopamine agonist, a monoamine oxidase-B (MAO-B) or a catecholamine O-methyl transferase (COMT) inhibitor, an anti-cholinergic for at least 2 months before enrollment and in whom we presume it will be possible to maintain this treatment unchanged during the study period (except the dose of L-dopa which can be adjusted during the study after the third month of Phase 1). Exclusion Criteria: Atypical parkinsonian syndromes, Drug-induced Parkinsonism, Juvenile Parkinson, Patients with complications of levodopa therapy Inability to keep the current stable antiparkinsonian treatment during the study period, apart from L-DOPA, Pretreatment with amantadine, amantadine counter-indication Neuroleptic treatment, Patients with dementia, Mini Mental Status (MMS) <26, Patient with behavioral disorder, ECMP item ≥ 3 Female subjects of childbearing potential without effective contraception

Ages Eligible for Study
-----------------
Minimum Age: 35 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: Amantadine<br>Patients with amantadine | Drug: Amantadine<br>* 200mg / day once daily in the morning and at noon - oral administration -<br>* Other names: active drug;|
| Placebo Comparator: Placebo<br>Patients with amantadine placebo | Drug: placebo<br>* 200mg / day once daily in the morning and at noon - oral administration -<br>* Other names: placebo of amantadine;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| after 18 months of Phase 1 of the study | Rate of patient with abnormal involuntary dyskinetic movements (as specifically defined in the protocol) after 18 months of Phase 1 of the study (amantadine versus placebo). | after 18 months of follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| abnormal involuntary dyskinetic movements at the end of phase 3 of the study (wash out) | Rate of patients with abnormal involuntary dyskinetic movements at the end of phase 3 of the study (wash out) | 22 months after inclusion | 
| motor fluctuations after 18 months of Phase 1 of the study | Rate of patients with non-motor fluctuations after 18 months of Phase 1 (defined by the specific scale developed by the Marseille team involved in the project) | 18 months after inclusion | 
| Time to onset of dyskinesias | Time to onset of dyskinesias defined as the study visit at which the investigator answers yes for the first time the question do you think this patient has dyskinesia as defined in Protocol  | each visits | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Dyskinesia, L-DOPA, Early introduced treatment, Amantadine