Study of Rivastigmine to Treat Parkinsonian Apathy Without Dementia

NCT ID: NCT00767091

Last Updated: 2012-04-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-03-31
• Study Completion Date: 2012-01-31

Brief 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

Conditions

Parkinson's Disease; Apathy; no Dementia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Active treatment

A: transdermal rivastigmine at 4.6 mg per day during one month then 9.5 mg per day during 5 months.

Group Type: ACTIVE_COMPARATOR

rivastigmine

Intervention Type: DRUG

transdermal patch of rivastigmine of 9.5 mg/day

placebo

transdermal patch of placebo

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

transdermal patch of placebo

Interventions

rivastigmine

transdermal patch of rivastigmine of 9.5 mg/day

Intervention Type: DRUG

placebo

transdermal patch of placebo

Intervention Type: DRUG

Other Intervention Names

cholinesterase inhibitors (Exelon); transdermal patch without active substance

Eligibility Criteria

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

• Minimum Eligible Age: 15 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital, Lille

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

David Devos, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Department of Neurology, University Hospital, Lille

Locations

Devos

Lille, Nord, France

Countries

France

References

Devos D, Moreau C, Maltete D, Lefaucheur R, Kreisler A, Eusebio A, Defer G, Ouk T, Azulay JP, Krystkowiak P, Witjas T, Delliaux M, Destee A, Duhamel A, Bordet R, Defebvre L, Dujardin K. Rivastigmine in apathetic but dementia and depression-free patients with Parkinson's disease: a double-blind, placebo-controlled, randomised clinical trial. J Neurol Neurosurg Psychiatry. 2014 Jun;85(6):668-74. doi: 10.1136/jnnp-2013-306439. Epub 2013 Nov 11.

Reference Type: DERIVED

PMID: 24218528 (View on PubMed)

Other Identifiers

2008/0817

Identifier Type: OTHER

Identifier Source: secondary_id

2008-002578-36

Identifier Type: -

Identifier Source: org_study_id