Study of Rivastigmine to Treat Parkinsonian Apathy Without Dementia
Condition: Parkinson's Disease; Apathy; no Dementia
MeSH terms: Parkinson Disease; Dementia
Study type: Interventional
Phase: Phase 3

Summary: 
      Apathy usually refers to a set of behavioural, emotional and cognitive features as a reduced
      interest and participation in main activities of daily life, a lack of initiative, a trend
      toward an early withdrawal from started activities, an indifference and a flattening of
      affect. We have validated a new specific scale (Lille Apathy Rating Scale, LARS) in order to
      detect and quantify apathy in Parkinson's disease (PD). Apathy was shown to be frequent in PD
      with a prevalence of 32%. It has suggested that the medial frontal and limbic cholinergic
      deficits may underlie apathy in neurodegenerative disorders like Alzheimer's disease (AD).
      Such a hypothesis is supported by recent evidence indicating the beneficial effects of
      cholinesterase inhibitors on neuropsychiatric symptoms, mainly apathy, in AD patients. As the
      efficacy of rivastigmine on cognition has also been shown in PD, we aimed to assess with a
      randomized, double-blind, placebo-controlled, parallel-group, multicenter trial, the efficacy
      and acceptability of a 6 months treatment with rivastigmine on apathy in 60 patients with PD
      without dementia. The primary end point will be the LARS score and the secondary end points
      will be the cognitive, behavioural and motor symptoms of PD. Two add-on studies will be
      proposed: first the measure of choline and glutamate peaks on Magnetic Resonance Spectrometry
      focused on the structures implicated in apathy in order to give insights in the
      physiopathological mechanisms of the treatment. Secondly, the recording of the REM sleep
      behavior disorders in relation with the cholinergic part of the pedunculopontine nucleus.
      Regarding that apathy could be one of the first steps toward PD dementia, treating very early
      could have substantial implications on the patients and their caregiver.
    

Detailed description: 
      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:

        1. Tolerability :

           Number of subjects (%) who discontinue the study, Number of subjects (%) who discontinue
           the study due to AEs.

        2. 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:

        1. one patch of 4.6 mg/day during 1 month, then one patch of 9.5 mg/day during 5 months

        2. 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
    

Intervention name(s): rivastigmine; placebo
Intervention type(s): Drug; Drug
Intervention description(s): transdermal patch of rivastigmine of 9.5 mg/day; transdermal patch of placebo
Other intervention name(s): cholinesterase inhibitors (Exelon); transdermal patch without active substance
Intervention MeSH terms: Rivastigmine; Cholinesterase Inhibitors
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Parkinson's disease; Apathy; Rivastigmine; transdermal patch; anticholinesterasic; acetylcholine