Study of Rivastigmine to Treat Parkinsonian Apathy Without Dementia

Overall study duration: 2 years. Planned inclusion period: 12 months. Study duration for individual patients: 7 months (2 weeks between screening and randomization, 6 months of double-blind treatment and then a 2-week wash-out period).

Primary objective (V1 and V6):

To assess efficacy of anticholinesterasic treatment (trans-dermal patch of rivastigmine , Exelon®) on parkinsonian apathy assessed by the Lille Apathy Rating Scale in patients with advanced Parkinson's disease without dementia or depression

Additional Efficacy Endpoints (V1 and V6):

• the NeuroPsychiatric Inventory, the apathy/retardation subscore of the MADRS (tri-dimensional analysis, the Activity of Daily Living scale, the simple and complex reaction times (selective attention), the quality of life (PDQ-39), the "Zarit" scale and the Clinical Global Impression of Change, Independence Scale, Mattis score, MMSE
• Gait: time and number of steps and freezing at the Stand Walk Sit test, the Tinetti scale, the UPDRS I, II, III et IV, the self questionnaire of Giladi
• Sleep quality: during two successive polysomnography recordings (sleep pattern, measures of the rapid eye movement (REM) sleep time, daytime sleepiness (PDSS and Epworth), and Sleep Latency Test
• Magnetic Resonance Spectroscopy on the measures of the choline/creatine and glutamate/creatine peaks (medial frontal cortex, limbic cortex, caudate nucleus, putamen, pedunculopontine nucleus) on 3 Tesla MRI

Safety and Tolerability Endpoints (V1, V3 and V6):

Safety and tolerability will be evaluated with reference to the following:

• Tolerability :

Number of subjects (%) who discontinue the study, Number of subjects (%) who discontinue the study due to AEs.

• Safety Measures :

AE incidence, Safety laboratory values, Vital signs, Blood pressure monitoring, ECG, Physical and neurological examination.

Study Design

Multicentric pilot study: 36-week double blind, placebo-controlled phase. After being found eligible to participate in the study, subjects will be allocated in a 1:1 ratio into one of the following two treatment groups based on a randomization scheme with blocks stratified:

• one patch of 4.6 mg/day during 1 month, then one patch of 9.5 mg/day during 5 months
• one patch of placebo during 6 months

Schedule: 7 visits

• Four consultations: screening (V0), randomisation (V1, 15 days after V0), (V3) visit after 3 months and termination (V7, 6 months after randomisation)
• Two phone calls (V2, V4)

Patients :

60 subjects with Parkinson's disease duration of more than 5 years, without dementia (Mattis Dementia Rating Scale ≥ 130, MMSE ≥ 27 and DSM IV), without major depression (MADRS < 18) who have developed apathy (defined by a score of - 16 or more at the LARS) despite an optimal dopaminergic treatment No additional therapy will be permitted during the study.

Investigational Medicinal Product (IMP) & Dosage:

Rivastigmine, or matching placebo, administered by transdermal patch a day in the morning:

4.6 mg a day during one month, 9.5 mg a day during five months

Centres :

Lille :

• Department of Neurology, University Hospital, Lille : Pr L. Defebvre, Pr K. Dujardin, Dr D. Devos, Pr Destee, Mme Delliaux. Dr A Kreisler, Dr C Simonin, Dr C. Moreau
• Department of Pharmacology, Faculté de Médecine, Lille II : R. Bordet
• Department of Clinical Neurophysiology, sleep laboratory : Pr P. Derambure, Dr C. Monaca
• Department of Neuroradiology : Pr J. Pruvo Dr C. Delmaire Dr P. Jissendi, Dr G. Soto Ares, Pr X. Leclerc
• Department of Statistics, CERIM, Faculté de Médecine Lille II : Dr P. Devos, Dr A. Duamel
• Lille III University : Dr P. Sockeel Méthodologiste

Amiens :

• Department of Neurology, University Hospital, Amiens : Pr P. Krystkowiak, Pr O. Godefroy, Dr Gérard, Dr Dupuy, Pr Deramon, Pr JM Macron, Dr Rose

Rouen :

• Department of Neurology, University Hospital, Rouen, . Dr D. Maltête, Pr. D. Hannequin, Dr. O. Martinaud, Dr E. Gérardin, Pr. B. Mihout, Mmes C. Aubier-Girard, S Bioux, E. Bliaux, D. Pouliquen

Caen :

• Department of Neurology, University Hospital,Caen, : Pr G. Defer, Pr F. Viader, Dr Guillamo Dr Marié, Dr Carluer, Mme Lebrun

Inclusion criteria

• Clinical diagnosis of Parkinson's disease: Gibb and Gelb criteria
• Apathy defined by a score of - 16 or more on the LARS scale (Sockeel et al., 2006)and criteria of Marin (1991)
• No dementia according to DSM IV with MMSE Score≥ 27 and Mattis score≥ 130
• Under stable dopaminergic treatment for 3 months

Exclusion criteria

• Depression according to DSM-IV criteria and a score < 18 on the MADRS
• Subthalamic stimulation of less than one year
• Subthalamic stimulation without stable parameters for 3 months
• Subject older than 80 years
• Severe rest tremor with a subscore > or= 3 on the UPDRS part
• Parkinson related Psychosis in progress
• Hypersensibility to cholinesterase inhibitors or carbamates
• Myocardial infarction, other cardiac affections
• Severe hepatic insufficiency
• Sever medical illness
• Skin diseases interfering with transdermal patch
• Pregnancy
• Incapacity to give the consent