Effects of Rivastigmine Patch on Activities of Daily Living and Cognition in Patients With Severe Dementia of the Alzheimer's Type (ACTION) (Study Protocol CENA713DUS44, NCT00948766) and a 24 Week Open-label Extension to Study CENA713DUS44 (ACTION)

A 24 Week, Prospective, Randomized, Parallel-group, Double-blind, Multi-center Study (ENA713DUS44) Comparing the Effects of Rivastigmine Patch 15 cm^2 vs. Rivastigmine Patch 5 cm^2 on ACTivities of Daily Living and CognitION in Patients With Severe Dementia of the Alzheimer's Type (ACTION) and a 24-week Open-label Extension to Study ENA713DUS44

The core study assessed the efficacy of a higher dose of rivastigmine 13.3 mg/24 h transdermally (15 cm^2 patch) compared to a lower dose of the rivastigmine 4.6 mg/24 h transdermally (5 cm^2 patch) in patients with Severe Dementia of the Alzheimer's Type in a 24-week study. The extension study obtained additional safety and efficacy data, as well as provided the higher dose rivastigmine patch to all patients who completed the core study for an additional 24 weeks.

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Drug: Rivastigmine 4.6 mg/24 h (5 cm^2); Drug: Rivastigmine 9.5 mg/24 h (10 cm^2); Drug: Rivastigmine 13.3 mg/24 h (15 cm^2); Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 716
• Phase: Phase 4

Contacts and Locations

Study Locations

• Puerto Rico
  • Bayamon, Puerto Rico, 00959
    • Metro Medical Center
  • San Juan, Puerto Rico, 00918
    • INSPIRA Clinical Research
• United States
  • Arizona
    • Tempe, Arizona, United States, 85282
      • Clinical Research Advantage Inc./Neurological. Physicians of Arizona, Inc
    • Tucson, Arizona, United States, 86741
      • Northwest Neuro Specialist, PLLC
  • Arkansas
    • Conway, Arkansas, United States, 72034
      • IHS Research Center Inc.
  • California
    • Berkeley, California, United States, 94705
      • East Bay Physicians Medical Group
    • Costa Mesa, California, United States, 92626
      • ATP Clinical Research, Inc.
    • Fresno, California, United States, 93720
      • Margolin Brain Institute
    • Fresno, California, United States, 90502
      • Neuro Pain Medical Center
    • Garden Grove, California, United States, 92845
      • Collaborative Neuroscience Network Inc.
    • Poway, California, United States, 92064
      • PCND Neuroscience Research Institute Inc./The Center for Memory and Aging
    • Redlands, California, United States, 92374
      • Anderson Clinical Research
    • San Francisco, California, United States, 94109
      • San Francisco Clinical Research Center
    • Santa Ana, California, United States, 92701
      • Neuropsychiatric Research Center of Orange County
    • Sherman Oaks, California, United States, 91403
      • California Neuroscience Research Medical Group, inc.
    • Temecula, California, United States, 92591
      • Viking Clinical Research Center
    • Torrance, California, United States, 90502
      • Collaborative Neuroscience Network, Inc
  • Colorado
    • Aurora, Colorado, United States, 80014
      • Senior Care of Colorado
  • Florida
    • Boca Raton, Florida, United States, 33431
      • Clinical Research Studies Dept. of Clinical Science and Medical Education
    • Deerfield Beach, Florida, United States, 33064
      • Quantum Laboratories Memory Disorder Center
    • Delray Beach, Florida, United States, 33445
      • Brain Matters Research, Inc.
    • Fort Lauderdale, Florida, United States, 33308
      • Neurologic Consultants, PA
    • Fort Walton Beach, Florida, United States, 32547
      • White-Wilson Medical Center
    • Hallandale Beach, Florida, United States, 33009
      • MD Clinical
    • Hollywood, Florida, United States, 33021
      • Sunrise Clinical Research, Inc
    • Orlando, Florida, United States, 32806
      • Compass Research, LLC
    • Pensacola, Florida, United States, 32514
      • Integrity Research, LLC
    • Port Charlotte, Florida, United States, 33952
      • Neurostudies, Inc.
    • Tampa, Florida, United States, 33613
      • Stedman Clinical Trials, LLC
    • Venice, Florida, United States, 34285
      • Center for Clinical Trials
    • West Palm Beach, Florida, United States, 33407
      • Premiere Research Institute
  • Illinois
    • Elk Grove Village, Illinois, United States, 60007
      • Alexian Brothers Neuroscience Institute
  • Indiana
    • Elkhart, Indiana, United States, 46514
      • Elkhart Clinic, LLC
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Medical Center
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University Of Kansas Medical Center
    • Lenexa, Kansas, United States, 66214
      • MidAmerica Neuroscience Reseach Institute
    • Manhattan, Kansas, United States, 66502
      • Precise Clinical Research Solutions
  • Louisiana
    • Shreveport, Louisiana, United States, 71103
      • LSU Health Sciences Center/Department of Psychiatry Psychopharmacology Research Clinic
    • Shreveport, Louisiana, United States, 71104
      • J. Gary Booker, MD APMC
  • Maryland
    • Baltimore, Maryland, United States, 21208
      • PharmaSite Research
    • Easton, Maryland, United States, 21601
      • The Samuel and Alexia Bratton Memory Clinic, William Hill Inc
  • Massachusetts
    • Pittsfield, Massachusetts, United States, 01201
      • Neuroscience Research of the Berkshires
  • Michigan
    • Clinton Township, Michigan, United States, 48035
      • Michigan Neurology Associates, P.C.
    • Detroit, Michigan, United States, 48201
      • Wayne State University/Detroit Medical Center
    • Muskegon, Michigan, United States, 49442
      • West Michigan Clinical Research
  • Minnesota
    • St. Paul, Minnesota, United States, 55114
      • Orr & Associates Memory and Geriatric Behavioral Health Clinic
  • Mississippi
    • Hattiesburg, Mississippi, United States, 39401
      • Neurological Research Clinic, Hattiesburg Clinic
    • Ocean Springs, Mississippi, United States, 39564
      • The Neuroscience Center
  • Missouri
    • St Louis, Missouri, United States, 63117
      • Sky, LLC.
    • St. Louis, Missouri, United States, 63104
      • St. Louis University
  • Nebraska
    • Lincoln, Nebraska, United States, 68510
      • Premier Psychiatric Research Institute, LLC
    • Omaha, Nebraska, United States, 68105
      • University of Nebraska Medical Center
  • New Jersey
    • Eatontown, New Jersey, United States, 07724
      • Memory Enhancement Center of America, Inc.
    • Manchester, New Jersey, United States, 08759
      • Alzheimer's Research Corporation
    • Mt. Arlington, New Jersey, United States, 07856
      • NeuroCognitive Institute
    • New Brunswick, New Jersey, United States, 08903
      • UMDNJ-Robert Wood Johnson Medical Center
    • Stratford, New Jersey, United States, 08084
      • UMDNJ-School of Osteopathic Medicine Center
    • Toms River, New Jersey, United States, 08755
      • Memory Enhancement Center of NJ
  • New York
    • Albany, New York, United States, 12205
      • Upstate Clinical Research, LLC
    • Amherst, New York, United States, 14226
      • Dent Neurological Institute
    • Liverpool, New York, United States, 13088
      • Neurological Care of Central NY
    • New York, New York, United States, 10021
      • Eastside Comprehensive Medical Center, LLC
    • Orangeburg, New York, United States, 10962
      • Nathan S. Kline Institute for Psychiatric Research
    • Staten Island, New York, United States, 10312
      • Richmond Behavioral Associates
    • Staten Island, New York, United States, 10305
      • Behavioral Medical Research Of Staten Island
    • White Plains, New York, United States, 10605
      • The Burke Rehabilitation Hospital
  • North Carolina
    • Charlotte, North Carolina, United States, 28211
      • Alzheimer's Memory Center
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Winston Salem, North Carolina, United States, 27103
      • Clinical Trials of America, Inc.
  • Ohio
    • Centerville, Ohio, United States, 45459
      • Valley Medical Research
    • Cincinnati, Ohio, United States, 45219
      • University Neurology, Inc.
  • Oregon
    • Portland, Oregon, United States, 97225
      • Cognitive Assessment Clinic
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18104
      • LeHigh Center for Clinical Research
    • Bridgeville, Pennsylvania, United States, 15017
      • Paramount Clinical Research
    • Coatesville, Pennsylvania, United States, 19320
      • Department of Veterans Affairs Medical Center
    • Greensburg, Pennsylvania, United States, 15601
      • Westmoreland Neurology Associates, Inc.
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
    • Pittsburg, Pennsylvania, United States, 15243
      • Research Protocol Management Specialists
  • Rhode Island
    • East Providence, Rhode Island, United States, 02914
      • Rhode Island Mood & Memory Research Institute
  • Tennessee
    • Franklin, Tennessee, United States, 37067
      • Psychiatric Consultants, PC
    • Knoxville, Tennessee, United States, 37920
      • Volunteer Research Group
  • Texas
    • Baytown, Texas, United States, 77521
      • Jacinto Medical Group, PA
    • Dallas, Texas, United States, 75231
      • Future Search Trials
    • Galveston, Texas, United States, 77555
      • University of Texas Medical Branch
    • San Antonio, Texas, United States, 78229
      • Innovative Clinical Trials
    • San Antonio, Texas, United States, 78229
      • Radiant Research Inc.
    • Wichita Falls, Texas, United States, 76309
      • Grayline Clinical Drug Trials
  • Vermont
    • Bennington, Vermont, United States, 05201
      • The Memory Clinic
  • Virginia
    • Arlington, Virginia, United States, 22205
      • TLC Neurology, P.L.L.C
    • Charlottesville, Virginia, United States, 22903
      • UVA Neurology
    • Richmond, Virginia, United States, 23230
      • Alliance Research Group, LLC
    • Richmond, Virginia, United States, 23226
      • Neurological Associates, Inc.
    • Williamsburg, Virginia, United States, 23185
      • The Center for Excellence in Aging and Geriatric Health
  • Washington
    • Tacoma, Washington, United States, 98405
      • Internal Medicine Northwest
  • Wisconsin
    • Waukesha, Wisconsin, United States, 53188
      • Independent Psychiatric Consultants, SC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Core study

Inclusion Criteria:

• Diagnosis of probable Alzheimer's disease (AD) according to National Institute of Neurological Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria.
• A Mini-Mental State Examination (MMSE) score of ≥ 3 and ≤ 12.
• Be able to complete at least 1 item on the Severe Impairment Battery (SIB).
• Residing with someone in the community or in regular contact with the primary caregiver.
• Be ambulatory or ambulatory with aid.

Exclusion Criteria:

• An advanced, severe, progressive, or unstable disease of any type that may interfere with efficacy and safety assessments or put the patient at special risk.
• Patients currently residing in a nursing home.
• Any current medical or neurological condition other than AD that could explain the patient's dementia.
• A current diagnosis of probable or possible vascular dementia.
• A current diagnosis of severe or unstable cardiovascular disease.
• A current diagnosis of bradycardia (< 50 beats per minute [bpm]), sick-sinus syndrome, or conduction defects.
• Clinically significant urinary obstruction.
• History of malignancy of any organ system within the past 5 years unless patient is verified to be in stable condition with no active metastasis.
• Current diagnosis of an active skin lesion/disorder that would prevent the patient from using a transdermal patch every day.
• A known exaggerated pharmacological sensitivity or hypersensitivity to drugs similar to rivastigmine, or to other cholinergic compounds.
• Taken any of the following substances (at the time of the Baseline Visit [Visit 2]).
• Succinylcholine-type muscle relaxants during the previous 2 weeks.
• Lithium during the previous 2 weeks.
• An investigational drug during the previous 4 weeks.
• A drug or treatment known to cause major organ system toxicity during the previous 4 weeks.
• Rivastigmine (oral or transdermal patch), donepezil, galantamine, other cholinesterase inhibitors (eg, tacrine, physostigmine, or pyridostigmine), or other approved treatments for Alzheimer's disease during the previous 2 weeks, with exception of stable treatment with memantine for at least 3 months before study entry (Visit 1).
• Centrally acting anticholinergic drugs including tricyclic and tetracyclic antidepressants during the previous 4 weeks.
• Selegiline unless taken at a stable dose during the previous 4 weeks.
• Peripheral anticholinergics not taken at a stable dose during the previous 4 weeks.

Extension study

Inclusion Criteria:

• Complete the double-blind phase (Week 24) of the core study.
• Provide, if mentally competent, a separate written informed consent prior to participation in the extension study. In addition, the patient's caregiver, will provide written informed consent prior to the patient's participation in the open-label extension study. If the patient is not able to provide written informed consent, written informed consent must be obtained from the legally authorized representative on the patient's behalf.
• Continue to reside with someone in the community or in regular contact with the primary caregiver; patients who reside in an assisted living facility are eligible to participate.
• Continue to have a primary caregiver willing to accept responsibility for supervising treatment (eg, application and removal of the patch daily at approximately the same time of day), assessing the condition of the patient throughout the extension study.
• Must be medically stable and tolerating the current dose of rivastigmine patch as determined by the investigator.

Exclusion Criteria:

Refer to the core study protocol for full details of the exclusion criteria.

• Patients who discontinued the core study due to any reason are excluded.
• No additional exclusions may be applied by the investigator, in order to ensure that the study population will be representative of all eligible patients.

Other protocol-defined inclusion/exclusion criteria applied to the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rivastigmine 13.3 mg/24 h transdermal patch; In the core study, patients were titrated to the rivastigmine 13.3 mg/24 h dose in 2 steps. For Weeks 1-4, patients received rivastigmine 4.6 mg/24 h. For Weeks 5-8, patients received rivastigmine 9.5 mg/24 h and placebo. For Weeks 9-24, patients received rivastigmine 13.3 mg/24 h and placebo. In the extension study, all patients were switched to rivastigmine 9.5 mg/24 h for a 4-week titration period and were then titrated up to 13.3 mg/24 h for a further 20 weeks of treatment.	Drug: Rivastigmine 4.6 mg/24 h (5 cm^2); Rivastigmine was supplied in a 5 cm^2 patch which released 4.6 mg/24 h. Patches were changed daily.; Other Names: Exelon; Exelon patch; ENA713D; Drug: Rivastigmine 9.5 mg/24 h (10 cm^2); Rivastigmine was supplied in a 10 cm^2 patch which released 9.5 mg/24 h. Patches were changed daily.; Other Names: Exelon; ENA713D; Exelon path; Drug: Rivastigmine 13.3 mg/24 h (15 cm^2); Rivastigmine was supplied in a 15 cm^2 patch which released 13.3 mg/24 h. Patches were changed daily.; Other Names: Exelon; Exelon patch; ENA713D; Drug: Placebo; Placebo patches were identical in size and composition to the corresponding rivastigmine patches, except that they did not contain rivastigmine. Patches were changed daily.
Active Comparator: Rivastigmine 4.6 mg/24 h transdermal patch; In the core study, patients received rivastigmine 4.6 mg/24 h daily. For Weeks 1-4, patients received rivastigmine 4.6 mg/24 h. For Weeks 5-24, patients received rivastigmine 4.6 mg/24 h and placebo. No patients received this treatment in the extension study.	Drug: Rivastigmine 4.6 mg/24 h (5 cm^2); Rivastigmine was supplied in a 5 cm^2 patch which released 4.6 mg/24 h. Patches were changed daily.; Other Names: Exelon; Exelon patch; ENA713D; Drug: Placebo; Placebo patches were identical in size and composition to the corresponding rivastigmine patches, except that they did not contain rivastigmine. Patches were changed daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Core Study: Change From Baseline in the Alzheimer's Disease Cooperative Study-Activities of Daily Living-Severe Impairment Version (ADCS-ADL-SIV) Score at Week 24	The ADCS-ADL-SIV is designed to assess the patient's performance of both basic and instrumental activities of daily living such as those necessary for personal care, communicating and interacting with other people, maintaining a household, conducting hobbies and interests, and making judgments and decisions. For each of the 19 questions in the ADCS-ADL-SIV, there was either a forced choice of best response or a "yes" or "no" question with additional sub-questions. Responses for each item were obtained from the caregiver through an interview. Higher numbered scores and answers of "yes" reflected a more self-sufficient individual. The total score was calculated as the sum of all items and sub-questions and ranged from 0 to 54. A higher total score represented a higher functioning patient. A positive change score indicates improvement.	Baseline of the core study to Week 24 of the core study
Core Study: Change From Baseline in the Severity Impairment Battery (SIB) Score at Week 24	The SIB is a 40-item scale developed for the evaluation of the severity of cognitive dysfunction in more advanced Alzheimer Disease patients. The domains assessed included social interaction, memory, language, attention, orientation, praxis, visuo-spatial ability, construction, and orienting to name. The items of the SIB were developed as simple 1-step commands which are presented by a trained rater with gestural cues and repeated if necessary. The SIB was scored from 0 to 100, with higher scores reflecting higher levels of cognitive ability. A positive change score indicates improvement.	Baseline of the core study to Week 24 of the core study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Core Study: Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) Score at Week 24	The ADCS-CGIC assesses the clinical meaningfulness of a treatment based on the clinician's rating of change. The rating is provided by a trained clinician or psychometrician blinded to the patient's treatment. The rater interviewed the patient and caregiver separately at Baseline using a worksheet that provided space for notes and comments. At baseline, raters had access to all of the patient's available records and evaluations. The rater used a similar worksheet at follow-up visits, and referred to the baseline worksheet prior to making a rating of change. The worksheets were divided into 3 domains: mental/cognitive state, behavior, and functioning. Change ratings were based on a 7-point scale: Marked (1), moderate (2), and minimal improvement (3), no change (4), and marked (5), moderate (6), and minimal worsening (7). The percentage of patients in each of the 7 categories is reported.	Baseline of the core study to Week 24 of the core study
Core Study: Change From Baseline in the Neuropsychiatric Inventory (NPI-12) Score at Week 24	The NPI-12 assesses a wide range of behaviors encountered in patients with dementia to provide a means of distinguishing the frequency and severity of behavioral changes over time. Ten behavioral and 2 neurovegetative domains were evaluated in an interview with the caregiver given by a mental health professional. The scale included both frequency and severity ratings of each domain as well as a composite domain score (frequency x severity). The sum of the composite scores for the 12 domains yielded the NPI-12 total score. The NPI-12 was scored from 0 to 144, with lower scores reflecting improvement in psychiatric behavior. A negative change score indicates improvement.	Baseline of the core study to Week 24 of the core study
Extension Study: Change From Baseline in the Alzheimer's Disease Cooperative Study-Activities of Daily Living-Severe Impairment Version (ADCS-ADL-SIV) Score at Week 24	The ADCS-ADL-SIV is designed to assess the patient's performance of both basic and instrumental activities of daily living such as those necessary for personal care, communicating and interacting with other people, maintaining a household, conducting hobbies and interests, and making judgments and decisions. For each of the 19 questions in the ADCS-ADL-SIV, there was either a forced choice of best response or a "yes" or "no" question with additional sub-questions. Responses for each item were obtained from the caregiver through an interview. Higher numbered scores and answers of "yes" reflected a more self-sufficient individual. The total score was calculated as the sum of all items and sub-questions and ranged from 0 to 54. A higher total score represented a higher functioning patient. A positive change score indicates improvement.	Baseline of the core study to Week 24 of the extension study
Extension Study: Change From Baseline in the Severity Impairment Battery (SIB) Score at Week 24	The SIB is a 40-item scale developed for the evaluation of the severity of cognitive dysfunction in more advanced Alzheimer Disease patients. The domains assessed included social interaction, memory, language, attention, orientation, praxis, visuo-spatial ability, construction, and orienting to name. The items of the SIB were developed as simple 1-step commands which are presented by a trained rater with gestural cues and repeated if necessary. The SIB was scored from 0 to 100, with higher scores reflecting higher levels of cognitive ability. A positive change score indicates improvement.	Baseline of the core study to Week 24 of the extension study
Extension Study: Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) Score at Week 24	The ADCS-CGIC assesses the clinical meaningfulness of a treatment based on the clinician's rating of change. The rating is provided by a trained clinician or psychometrician blinded to the patient's treatment. The rater interviewed the patient and caregiver separately at Baseline using a worksheet that provided space for notes and comments. At baseline, raters had access to all of the patient's available records and evaluations. The rater used a similar worksheet at follow-up visits, and referred to the baseline worksheet prior to making a rating of change. The worksheets were divided into 3 domains: mental/cognitive state, behavior, and functioning. Change ratings were based on a 7-point scale: Marked (1), moderate (2), and minimal improvement (3), no change (4), and marked (5), moderate (6), and minimal worsening (7). The percentage of patients in each of the 7 categories is reported.	Baseline of the core study to Week 24 of the extension study

Collaborators and Investigators

• Sponsor: Novartis

Publications and helpful links

General Publications

• Grossberg GT, Farlow MR, Meng X, Velting DM. Evaluating high-dose rivastigmine patch in severe Alzheimer's disease: analyses with concomitant memantine usage as a factor. Curr Alzheimer Res. 2015;12(1):53-60. doi: 10.2174/1567205011666141218122835.

Helpful Links

• Online Screening Questionnaire is available

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Actual): January 1, 2012
• Study Completion (Actual): June 1, 2012

Study Registration Dates

• First Submitted: July 28, 2009
• First Submitted That Met QC Criteria: July 28, 2009
• First Posted (Estimate): July 29, 2009

Study Record Updates

• Last Update Posted (Estimate): August 28, 2013
• Last Update Submitted That Met QC Criteria: August 19, 2013
• Last Verified: August 1, 2013

More Information

Terms related to this study

• Keywords: dementia; Alzheimer's disease; Alzheimer's type
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Tauopathies; Dementia; 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: CENA713DUS44