Efficacy and Safety of Rivastigmine Transdermal Patch in Patients With Mild to Moderate Alzheimer's Disease

A 24-week, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Dose-finding Evaluation of the Efficacy, Safety, and Tolerability of the Once-daily Rivastigmine Transdermal Patch in Patients With Probable Alzheimer's Disease (MMSE 10-20)

The purpose of this study was to investigate the 5cm^2 and 10cm^2 doses of rivastigmine transdermal patch in terms of efficacy and safety in patients with probable Alzheimer's Disease (MMSE [Mini Mental State Examination] 10-20). A 52-week extension phase evaluated the safety and tolerability of long-term treatment by rivastigmine transdermal patch in patients with probable Alzheimer's Disease (AD).

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Drug: Placebo; Drug: Rivastigmine transdermal patch

Detailed Description

Patients were randomly assigned in a double-blind manner to one of the 3 treatment arms (placebo, rivastigmine 5 cm^2 and rivastigmine 10 cm^2) in a ratio of 1:1:1. During the Double-blind treatment phase, patients entered a 16-week Titration Period followed by an 8-week Maintenance Period. During the open-label extension phase, all patients started treatment with a 2.5 cm^2 patch and the dose was increased to 10 cm^2 over a 16-week titration period, followed by a maintenance period of 36 weeks.

• Study Type: Interventional
• Enrollment (Actual): 859
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Hokkaido
    • Hokkaido region, Hokkaido, Japan
      • Novartis Investigative Site

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:

• A diagnosis of dementia of the Alzheimer's type according to the DSM-IV criteria
• A clinical diagnosis of probable AD according to NINCDS/ADRDA criteria
• An MMSE score of > or = 10 and < or = 20

Exclusion Criteria:

• A current DSM-IV diagnosis of major depression
• Taken rivastigmine in the past
• A score of > 5 on the Modified Hachinski Ischemic Scale (MHIS) Other protocol-defined inclusion/exclusion criteria may apply

Other protocol-defined inclusion/exclusion criteria may apply

Extension Phase Eligibility Criteria

Inclusion Criteria:

• Patients who have completed the Double-blind Treatment Phase on study medication

Exclusion Criteria

• Patients who have any important protocol deviations until the completion of the Double-blind Treatment Phase

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Participants received daily matching placebo patch for the duration of the 24-week double-blind treatment phase of the study.	Drug: Placebo; Placebo transdermal patch was provided in the following sizes: 2.5 cm^2, 5 cm^2, 7.5 cm^2 and 10 cm^2. The caregiver applied one patch on the back of a patient, placed alternately from the right to the left side at approximately the same time each day.
Experimental: rivastigmine 5 cm^2; During the 16-week titration period patients received daily rivastigmine 2.5 cm^2 patch for the first 4 weeks and thereafter daily rivastigmine 5 cm^2 patch. For patients who experienced intolerability, the dose was adjusted to rivastigmine 2.5 cm^2 daily. Patients then entered the 8-week maintenance period during which time they continued to receive the dose of rivastigmine they were taking at the end of the titration period.	Drug: Rivastigmine transdermal patch; Rivastigmine transdermal patch was provided in the following sizes and doses: 2.5 cm^2 (4.5 mg), 5 cm^2 (9 mg), 7.5 cm^2 (13.5 mg), and 10 cm^2 (18 mg). The caregiver applied one patch on the back of a patient, placed alternately from the right to the left side at approximately the same time each day.
Experimental: Rivastigmine 10 cm^2; During the 16-week titration period patients received daily rivastigmine 2.5 cm^2 patch for the first 4 weeks, rivastigmine 5 cm^2 patch for the next 4 weeks, rivastigmine 7.5 cm^2 patch for the next 4 weeks and then rivastigmine 10 cm^2 patch for the final 4 weeks. For patients who experienced intolerability, the dose was adjusted downward. Patients then entered the 8-week maintenance period during which time they continued to receive the dose of rivastigmine they were taking at the end of the titration period.	Drug: Rivastigmine transdermal patch; Rivastigmine transdermal patch was provided in the following sizes and doses: 2.5 cm^2 (4.5 mg), 5 cm^2 (9 mg), 7.5 cm^2 (13.5 mg), and 10 cm^2 (18 mg). The caregiver applied one patch on the back of a patient, placed alternately from the right to the left side at approximately the same time each day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in the Alzheimer's Disease Assessment Scale - Japan Cognitive Subscale (ADAS-J Cog)	The Alzheimer's Disease Assessment Scale - Japan cognitive subscale (ADAS-J cog) was used to measure change in cognitive function. The ADAS-J cog score ranges from 0-70, with higher total scores indicating more impairment. A negative change score indicates improvement from baseline.	Baseline and Week 24
Overall Clinical Rating of Change From Baseline to Week 24 Measured by the Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J)	The overall clinical rating of change from baseline to week 24 measured by the 7-point CIBIC plus-J scale. The Clinician's Interview-Based Impression of Change plus Caregiver Input consists of 3 subscales: Disability Assessment of Dementia Scale, Behavioral Pathology in Alzheimer's Disease Rating Scale and Mental Function Impairment Scale, as well as the Clinician's Global Impression of Change (CGIC). Participants are scored according to the following: Markedly improved; Moderately improved; Minimally improved; Unchanged; Minimally worse; Moderately worse; Markedly worse	Baseline and Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Mini-Mental State Examination (MMSE)	The MMSE is a screening test for cognitive dysfunction. The test consists of five sections (orientation, registration, attention-calculation, recall, and language); the total score can range from 0 to 30, with a higher score indicating better function. A positive change score indicates improvement from baseline.	Baseline and Week 24
Change From Baseline in CIBIC Plus-J Score Disability Assessment for Dementia (DAD)	The Disability Assessment for Dementia (DAD) was used to assess levels of difficulty in activities of daily living (ADL). The DAD is administered through an interview with the caregiver. A total score is obtained by adding the rating for each question and converting this to a total score out of 100 (%). Higher scores represent less disability in ADL while lower scores indicate more dysfunction. A positive change score indicates an improvement from baseline.	Baseline and Week 24
Change From Baseline in CIBIC Plus-J Score Behavioral Pathology in Alzheimer's Disease Rating Scale (Behave-AD)	BEHAVE-AD was used to assess patient behavior and psychiatric symptoms. It covers symptoms in seven categories: paranoid and delusional ideation, hallucinations, activity disturbances, diurnal rhythm disturbances, aggressiveness, affective disorders and anxieties, and phobias. Caregivers rate behavioral symptoms on a 0-3 scale. The total score can range from 0 to 66, with a lower score indicating better function. A negative change score indicates an improvement from baseline.	Baseline and Week 24
Change From Baseline in CIBIC Plus-J Score Mental Function Impairment Scale (MENFIS)	MENFIS was used to assess patient cognitive and psychiatric function, and evaluates core symptoms of dementia including cognitive, motivational and emotional aspects. The total score ranges from 0 to 78. The higher the score, the greater the functional deficit. A negative change score indicates an improvement from baseline.	Baseline and Week 24
Extension Phase: Change From Extension Phase Baseline to End of Extension in Mini-Mental State Examination (MMSE)	The MMSE is a screening test for cognitive dysfunction. The test consists of five sections (orientation, registration, attention-calculation, recall, and language); the total score can range from 0 to 30, with a higher score indicating better function. A positive change score indicates improvement. This outcome measured the change in MMSE from the beginning of the open-label extension phase through to Week 52 of the extension phase.	Extension Phase Baseline and Week 52 of extension phase
Extension Phase: Change From Extension Phase Baseline to End of Extension in CIBIC Plus-J Score Disability Assessment for Dementia (DAD)	The Disability Assessment for Dementia (DAD) was used to assess levels of difficulty in activities of daily living. The DAD is administered through an interview with the caregiver. A total score is obtained by adding the rating for each question and converting this to a total score out of 100 (%). Higher scores represent less disability in activities of daily living while lower scores indicate more dysfunction. A positive change score indicates an improvement from baseline.	Extension Phase Baseline and Week 52 of extension phase
Extension Phase: Change From Extension Phase Baseline to End of Extension in Modified Crichton Scale	The Modified Crichton Scale includes a total of seven items evaluated in eight grades that assess basic activities of daily living, communication functions, psychiatric symptoms and quality of life; the total score can range from 0 to 56, with a lower score indicating better function. A negative change score indicates an improvement from baseline.	Extension Phase Baseline and Week 52 of extension phase

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Collaborators: Ono Pharmaceutical Co. Ltd

Study record dates

Study Major Dates

• Study Start: January 1, 2007
• Primary Completion (Actual): March 1, 2009
• Study Completion (Actual): April 1, 2010

Study Registration Dates

• First Submitted: January 11, 2007
• First Submitted That Met QC Criteria: January 12, 2007
• First Posted (Estimate): January 17, 2007

Study Record Updates

• Last Update Posted (Estimate): February 10, 2014
• Last Update Submitted That Met QC Criteria: January 14, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: rivastigmine，Alzheimer's Disease, transdermal patch
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease; 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: CENA713D1301; CENA713D1301E1