Long-term Safety of Rivastigmine Capsule and Patch in Patients With Mild to Moderately-severe Dementia Associated With Parkinson's Disease (PDD)

A 76-week Prospective, Open-label, Multicenter Study to Evaluate the Long-term Effect of Rivastigmine Capsule and Transdermal Patch on Worsening of the Underlying Motor Symptoms of PD in Patients With Mild to Moderately Severe Dementia Associated With Parkinson's Disease (PDD)

The purpose of this study is to provide long-term safety data for rivastigmine capsule and transdermal patch treatments, in particular the effect of rivastigmine on worsening of the underlying motor symptoms of Parkinson's Disease (PD), in patients with mild to moderately severe dementia associated with PD.

Study Overview

• Status: Completed
• Conditions: Parkinson's Disease Dementia
• Intervention / Treatment: Drug: Rivastigmine capsule; Drug: Rivastigmine transdermal patch

• Study Type: Interventional
• Enrollment (Actual): 583
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1425CDC
    • Novartis Investigative Site
  • Buenos Aires
    • Ciudad Autonoma de Bs As, Buenos Aires, Argentina, C1122AAL
      • Novartis Investigative Site
  • Capital Federal
    • Buenos Aires, Capital Federal, Argentina, C1429DUC
      • Novartis Investigative Site
  • Santa Fe
    • Rosario, Santa Fe, Argentina, S2000BZL
      • Novartis Investigative Site
• Australia
  • New South Wales
    • Kogarah, New South Wales, Australia, 2217
      • Novartis Investigative Site
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Novartis Investigative Site
    • Malvern, Victoria, Australia, 3144
      • Novartis Investigative Site
    • Melbourne, Victoria, Australia, 3050
      • Novartis Investigative Site
    • Prahran, Victoria, Australia, 3181
      • Novartis Investigative Site
• Austria
  • Graz, Austria, 8036
    • Novartis Investigative Site
  • Innsbruck, Austria, 6020
    • Novartis Investigative Site
  • Linz, Austria, A-4020
    • Novartis Investigative Site
  • Linz, Austria, 4020
    • Novartis Investigative Site
  • Vienna, Austria, 1220
    • Novartis Investigative Site
• Belgium
  • Antwerpen, Belgium, 2018
    • Novartis Investigative Site
  • Bruxelles, Belgium, 1200
    • Novartis Investigative Site
  • Edegem, Belgium, 2650
    • Novartis Investigative Site
  • Jette, Belgium, 1090
    • Novartis Investigative Site
  • Kortrijk, Belgium, 8500
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
  • Liege, Belgium, 4000
    • Novartis Investigative Site
  • Wilrijk, Belgium, 2610
    • Novartis Investigative Site
• Canada
  • Quebec, Canada, G1R 3X5
    • Novartis Investigative Site
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N1
      • Novartis Investigative Site
  • British Columbia
    • Vancouver, British Columbia, Canada, V6T 2B5
      • Novartis Investigative Site
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3J 3T1
      • Novartis Investigative Site
  • Ontario
    • Kitchener, Ontario, Canada, N2H 5Z8
      • Novartis Investigative Site
    • London, Ontario, Canada, N6A 5A5
      • Novartis Investigative Site
    • Ottawa, Ontario, Canada, K1G 4G3
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M4N 3M5
      • Novartis Investigative Site
    • Windsor, Ontario, Canada, N8X 5A6
      • Novartis Investigative Site
  • Quebec
    • Greenfield Park, Quebec, Canada, J4V 2J2
      • Novartis Investigative Site
    • Montreal, Quebec, Canada, H2L 4M1
      • Novartis Investigative Site
    • Montreal, Quebec, Canada, H3G 1A4
      • Novartis Investigative Site
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4T 1A5
      • Novartis Investigative Site
• France
  • Amiens Cedex, France, 80054
    • Novartis Investigative Site
  • Clermont, France, 63003
    • Novartis Investigative Site
  • Lille Cedex, France, 59037
    • Novartis Investigative Site
  • Marseille Cedex, France, 13385
    • Novartis Investigative Site
  • Montpellier Cedex 5, France, 34295
    • Novartis Investigative Site
  • Paris Cedex, France, 75651
    • Novartis Investigative Site
  • Pessac Cedex, France, 33604
    • Novartis Investigative Site
  • Rennes, France, F-35043
    • Novartis Investigative Site
  • Roanne, France, 42328
    • Novartis Investigative Site
• Germany
  • Bad Nauheim, Germany, 61231
    • Novartis Investigative Site
  • Beelitz-Heilstaetten, Germany, 14547
    • Novartis Investigative Site
  • Berlin, Germany, 10713
    • Novartis Investigative Site
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Bonn, Germany, 53105
    • Novartis Investigative Site
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Goettingen, Germany, 37075
    • Novartis Investigative Site
  • Hamburg, Germany, 21075
    • Novartis Investigative Site
  • Kassel, Germany, 34128
    • Novartis Investigative Site
  • Leipzig, Germany, 04103
    • Novartis Investigative Site
  • Leun-Biskirchen, Germany, 35638
    • Novartis Investigative Site
  • Luebben, Germany, 15907
    • Novartis Investigative Site
  • Mainz, Germany, D-55131
    • Novartis Investigative Site
  • Marburg, Germany, 35032
    • Novartis Investigative Site
  • Muenchen, Germany, 80804
    • Novartis Investigative Site
  • Munchen, Germany, 81675
    • Novartis Investigative Site
  • Nuernberg, Germany, 90402
    • Novartis Investigative Site
  • Ulm, Germany, 89081
    • Novartis Investigative Site
  • Ulm, Germany, 89073
    • Novartis Investigative Site
  • Wolfach, Germany, 77709
    • Novartis Investigative Site
• Italy
  • Cassino, Italy, 03043
    • Novartis Investigative Site
  • Napoli, Italy, 80131
    • Novartis Investigative Site
  • Napoli, Italy, 80138
    • Novartis Investigative Site
  • BA
    • Bari, BA, Italy, 70121
      • Novartis Investigative Site
  • BO
    • Bologna, BO, Italy, 40138
      • Novartis Investigative Site
  • BS
    • Brescia, BS, Italy, 25123
      • Novartis Investigative Site
  • FG
    • Foggia, FG, Italy, 71100
      • Novartis Investigative Site
  • IS
    • Pozzilli, IS, Italy, 86077
      • Novartis Investigative Site
  • LU
    • Lido di Camaiore, LU, Italy, 55041
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20100
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00133
      • Novartis Investigative Site
    • Roma, RM, Italy, 00185
      • Novartis Investigative Site
    • Roma, RM, Italy, 00163
      • Novartis Investigative Site
    • Roma, RM, Italy, 00179
      • Novartis Investigative Site
  • TS
    • Trieste, TS, Italy, 34149
      • Novartis Investigative Site
  • VI
    • Arcugnano, VI, Italy, 36057
      • Novartis Investigative Site
• Netherlands
  • Sittard, Netherlands, 6131 BK
    • Novartis Investigative Site
  • AB
    • Zwolle, AB, Netherlands, 8025
      • Novartis Investigative Site
  • AN
    • Blaricum, AN, Netherlands, 1261
      • Novartis Investigative Site
  • AZ
    • Maastricht, AZ, Netherlands, 6202
      • Novartis Investigative Site
  • CK
    • Breda, CK, Netherlands, 4818
      • Novartis Investigative Site
  • ER
    • Enschede, ER, Netherlands, 7513
      • Novartis Investigative Site
  • GC
    • Tilburg, GC, Netherlands, 5022
      • Novartis Investigative Site
  • GZ
    • Groningen, GZ, Netherlands, 9713
      • Novartis Investigative Site
  • JL
    • Hertogenbosch, JL, Netherlands, 5232
      • Novartis Investigative Site
  • PC
    • Heerlen, PC, Netherlands, 6419
      • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08035
    • Novartis Investigative Site
  • Barcelona, Spain, 08014
    • Novartis Investigative Site
  • Barcelona, Spain, 08028
    • Novartis Investigative Site
  • Barcelona, Spain, 08190
    • Novartis Investigative Site
  • Madrid, Spain, 28034
    • Novartis Investigative Site
• Turkey
  • Adana, Turkey, 01330
    • Novartis Investigative Site
  • Antalya, Turkey, 07059
    • Novartis Investigative Site
  • Istanbul, Turkey, 34093
    • Novartis Investigative Site
  • Izmir, Turkey, 35340
    • Novartis Investigative Site
  • Kocaeli, Turkey, 41380
    • Novartis Investigative Site
  • Sihhiye/Ankara, Turkey, 06100
    • Novartis Investigative Site
  • Yenisehir/Izmir, Turkey, 35120
    • Novartis Investigative Site
• United Kingdom
  • Blackburn, United Kingdom, BB2 3HH
    • Novartis Investigative Site
  • Blandford Forum, Dorset, United Kingdom
    • Novartis Investigative Site
  • Christchurch, Dorset, United Kingdom, BH 232JX
    • Novartis Investigative Site
  • Newcastle, United Kingdom, NE4 5PL
    • Novartis Investigative Site
  • Oxford, United Kingdom, OX3 9DU
    • Novartis Investigative Site
  • Peterborough, United Kingdom, PE3 6DA
    • Novartis Investigative Site
  • Southampton, United Kingdom, SO30 3JB
    • Novartis Investigative Site
  • Vale of Glamorgan, United Kingdom, CF64 2XX
    • Novartis Investigative Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85004
      • 21st Century Neurology
  • California
    • Reseda, California, United States, 91335
      • Neurosearch, Inc.
    • Ventura, California, United States, 93003
      • Neurosearch II, Inc.
  • Florida
    • Hollywood, Florida, United States, 33021
      • Sunrise Clinical Research, Inc.
    • Naples, Florida, United States, 34102
      • Collier Neurologic Specialists
  • Georgia
    • Suwanee, Georgia, United States, 30024
      • Comprehensive Neurology Specialists, PC
  • Idaho
    • Meridian, Idaho, United States, 83646
      • Neurological Associates
  • Illinois
    • Glenview, Illinois, United States, 60026
      • Evanstan Northwestern Healthcare Medical Group
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • New York
    • Syracuse, New York, United States, 13210-1853
      • Neurological Care of Central NY
  • Ohio
    • Akron, Ohio, United States, 44302
      • Neurology & Neuroscience Associates, Inc.
  • Pennsylvania
    • Erie, Pennsylvania, United States, 16506
      • Square 1 Clinical Research
    • Pittsburgh, Pennsylvania, United States, 15243
      • Research Protocol Management Solutions
  • Texas
    • Dallas, Texas, United States, 75231
      • Neurology Specialists of Dallas
  • Utah
    • Bountiful, Utah, United States, 84010
      • Progressive Clinical Research
  • Washington
    • Seattle, Washington, United States, 98108
      • Veterans Affairs Puget Sound Health Care System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 85 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of idiopathic Parkinson's disease, according to the UK Parkinson's disease Society Brain Bank criteria
• Diagnosis of Parkinson's disease dementia according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, with onset of symptoms of dementia at least 2 years following the first diagnosis of idiopathic Parkinson's disease
• Mini Mental State Examination score of ≥10 and ≤ 26 (at Screening Visit only)

Exclusion Criteria:

• An advanced, severe, or unstable disease of any type that may interfere with the primary and secondary variable evaluations
• A score of 5 (wheelchair bound or bedridden) in the "on"-state on the Modified Hoehn and Yahr Staging (UPDRS Part V)
• A current diagnosis of any primary neurodegenerative disorder other than idiopathic PD
• A current diagnosis of any treatable dementia (hypothyroidism, syphilis, vitamin B12 or folate deficiency) that is verified by the investigator to be the cause of dementia.
• A current diagnosis of probably vascular dementia according to the National Institute of Neurological Disorders and Stroke and the Association International pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria
• A current diagnosis of a major depressive episode according to DSM-IV criteria
• A history of stereotaxic brain surgery for Parkinson's disease
• A known exaggerated pharmacological sensitivity or hypersensitivity to drugs similar to rivastigmine or to other cholinergic compounds

Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Rivastigmine capsule; Rivastigmine capsules starting at a total dose of 3 mg/day (1.5 mg twice daily orally) titrated up in 3 mg/day increments every 4 weeks to a final dose of 12 mg/day (6 mg twice daily orally). The 12 mg/day dose or the highest dose tolerated was maintained until week 76.	Drug: Rivastigmine capsule; Rivastigmine capsules orally twice a day. Target dose 12 mg/day.; Other Names: Exelon®
EXPERIMENTAL: Rivastigmine patch; Rivastigmine patch once a day in the morning, worn for 24 hours, starting at 5 cm^2 (delivering 4.6 mg rivastigmine over a 24 hour period) for 4 weeks then titrated up to 10 cm^2 daily (delivering 9.5 mg rivastigmine over a 24 hour period). The 10 cm^2 patch or the highest well tolerated dose was maintained until week 76.	Drug: Rivastigmine transdermal patch; Rivastigmine patch once a day in the morning, worn for 24 hours. Target dose 10 cm^2/day delivering 9.5 mg over a 24 hour period.; Other Names: Exelon®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Adverse Events (AEs) Due, or Potentially Due, to Worsening of Parkinson Disease (PD) Motor Symptoms (Tremor, Muscle Rigidity, Bradykinesia, Fall)	The AEs were summarized by presenting the number and percentage of patients having any of the 4 AEs or discontinued due to any of the 4 predefined AEs (tremor, muscle rigidity, bradykinesia, and fall)in each treatment group. The 95% CIs associated with the rates were also presented.	76 Weeks
Percentage of Participants With Study Drug Discontinuations Due to Predefined AEs That Are Due, or Potentially Due, to Worsening of PD Motor Symptoms (Tremor, Muscle Rigidity, Bradykinesia, Fall)	The discontinuations due to these AEs were summarized by presenting the number and percentage of patients having any of the 4 AEs or discontinued due to any of the 4 predefined AEs (tremor, muscle rigidity, bradykinesia, and fall) in each treatment group. The 95% CIs associated with these rates were also presented.	76 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Unified Parkinson Disease Rating Scale (UPDRS) Part III Motor Examination Scores at Weeks 8, 16, 24, 52 and 76 (or Early Discontinuation) Compared to Baseline	Unified Parkinson Disease Rating Scale (UPDRS) is a 6 part Parkinson's disease specific rating scale that estimates clinical function taking into consideration both disability (functional deficits) and impairment (objective clinical signs). Part III records the motor examination in Items 18-31 rated on a scale of 0 to 4 with (0 being absent/ normal and 4 being the worse) for a total possible score of 0 to 56.	From Baseline to Weeks 8, 16, 24, 52 and 76
Change in Mattis Dementia Rating Scale (Mattis DRS-2) Scores at Weeks 16, 24, 52 and 76 Compared to Baseline	Mattis DRS-2 is a measure of cognitive status. The total score is the sum of 5 subscale scores: Attention [0-37], Initiation/Perservation [0-37] (performing alternating movements), Construction [0-6] (copying designs), Conceptualization [0-39] (similarities) and Memory [0-25] (sentence recall, design recognition)for a total possible score of 0-144. Higher score is reflective of better cognitive function, lower scores associated with more pronounced cognitive deficit. The change from baseline was calculated such that a positive number indicates an improvement.	From Baseline to Weeks 16, 24, 52 and 76
Change in Ten Point Clock Test (TPCT) Scores at Weeks 16, 24, 52 and 76 (or Early Discontinuation) Compared to Baseline	The Ten Point Clock Test measures executive functioning and visuospatial skills. Participants are asked to put numbers on the face of a clock and then make the clock read 10 minutes after 11. Points are awarded on a scale of 0 to 10 for spacing of specific numbers and the positions of the hands. The change from baseline was calculated such that a positive number indicates improvement.	From Baseline to Weeks 16, 24, 52 and 76
Change in Neuropsychiatric Inventory-10 (NPI-10) Scores at Weeks 16, 24, 52 and 76 (or Early Discontinuation) Compared to Baseline	The parameter for analysis was the change from baseline of total score of 10 items on the NPI scale (NPI-10). The total score is a sum of the 10 domains, where the score for a domain is defined as the product of frequency (range: 1-4) and severity (range: 1-3). Each domain has a maximum score of 12 and all domains were equally weighted for total score(thus the range for the total score is 0 to 120 with 0 being completely healthy to 120 which is the worse score patient can get). The change from baseline was calculated such that a negative number indicates an improvement (symptom reduction).	At Week 16, 24, 52 and 76 (or early discontinuation)
Change in Alzheimer's Disease Cooperative Study-Activities Of Daily Living (ADCS-ADL) Scores at Weeks 16, 24, 52 and 76 (or Early Discontinuation) Compared to Baseline	The 23 item caregiver-based ADL scale of the dementia Alzheimer's disease Cooperative Study-Activities of Daily Living (ADCS-ADL) was used for analysis. This is a caregiver rated questionnaire of 23 items, with possible scores over a range of 0-78, where 78 denote full functioning with no impairment. The total score was derived by adding up the item scores of the 23 items. The change from baseline was calculated such that a positive change indicates an improvement.	From Baseline to Week 16, 24, 52 and 76 (or early discontinuation)
UPDRS Part V Stage (Modified Hoehn and Yahr Staging)at Baseline, Week 8,16,24,52 and 76 (or Early Discontinuation)	Unified Parkinson Disease Rating Scale (UPDRS) is a 6 part Parkinson's disease specific rating scale that estimates clinical function taking into consideration both disability (functional deficits) and impairment (objective clinical signs). UPDRS Part V is assessed by the modified Hoehn and Yahr Staging Scale. The scale ranges from 0 (no signs of disease) to 5 (wheelchair bound or bedridden unless aided).	From Baseline to Week 8, 16, 24, 52 and 76 (or early discontinuation)

Collaborators and Investigators

• Sponsor: Novartis

Study record dates

Study Major Dates

• Study Start: January 1, 2008
• Primary Completion (ACTUAL): November 1, 2010

Study Registration Dates

• First Submitted: February 14, 2008
• First Submitted That Met QC Criteria: February 22, 2008
• First Posted (ESTIMATE): February 25, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): November 28, 2011
• Last Update Submitted That Met QC Criteria: October 19, 2011
• Last Verified: October 1, 2011

More Information

Terms related to this study

• Keywords: cholinesterase inhibitor; Parkinson's disease dementia; rivastigmine
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Dementia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Cholinergic Agents; Enzyme Inhibitors; Neuroprotective Agents; Protective Agents; Cholinesterase Inhibitors; Rivastigmine
• Other Study ID Numbers: CENA713B2315