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

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

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.

Study Overview

• Status: Completed
• Conditions: Parkinson Disease
• Intervention / Treatment: Drug: Amantadine; Drug: placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 210
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Aix en Provence, France, 13616
    • CHG Aix en Provence
  • Bordeaux, France, 33604
    • CHU de Bordeaux
  • Cahors, France, 46005
    • CH Jean Rougier
  • Clermont-Ferrand, France, 63003
    • CHU Clermont-Ferrand
  • Dijon, France, 21079
    • CHU Dijon
  • Lille, France, 59037
    • CHU Lille
  • Limoges, France, 87042
    • Chu Dupuytren
  • Lyon, France, 69003
    • Hopital Lyon
  • Marseille, France, 13385
    • Hopital De La Timone
  • Montauban, France, 82013
    • CH Montauban
  • Montpellier, France, 34295
    • Hopital Saint Eloi
  • Nantes, France, 44093
    • CHU de Nantes
  • Narbonne, France, 11108
    • CH de Narbonne
  • Paris, France, 75013
    • Hopital Pitie Salpetriere
  • Poitiers, France, 86021
    • Hopital Jean Bernard
  • Rouen, France, 76031
    • CH Charles Nicolle
  • Strasbourg, France
    • CHU de Strasbourg
  • Toulouse, France, 31000
    • CHU de Toulouse

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 33 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Amantadine; Patients with amantadine	Drug: Amantadine; 200mg / day once daily in the morning and at noon - oral administration -; Other Names: active drug
Placebo Comparator: Placebo; Patients with amantadine placebo	Drug: placebo; 200mg / day once daily in the morning and at noon - oral administration -; 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

Collaborators and Investigators

• Sponsor: University Hospital, Toulouse
• Investigators: Principal Investigator: Olivier Rascol, MD, University Hospital, Toulouse

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2012
• Primary Completion (Actual): February 20, 2018
• Study Completion (Actual): February 26, 2019

Study Registration Dates

• First Submitted: February 20, 2012
• First Submitted That Met QC Criteria: February 20, 2012
• First Posted (Estimate): February 24, 2012

Study Record Updates

• Last Update Posted (Actual): February 5, 2021
• Last Update Submitted That Met QC Criteria: February 2, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Amantadine; Dyskinesia; L-DOPA; Early introduced treatment
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Dyskinesias; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Dopamine Agents; Antiparkinson Agents; Anti-Dyskinesia Agents; Amantadine
• Other Study ID Numbers: 11 253 01