A Study of the Safety and Efficacy of Memantine in Moderate to Severe Alzheimer's Disease

A Randomized, Double-Blind, Placebo-Controlled Evaluation of the Safety and Efficacy of Memantine in Patients With Moderate-to-Severe Dementia of the Alzheimer's Type

The objective of this study is to evaluate the safety, tolerability, and efficacy of memantine compared to placebo in outpatients diagnosed with moderate-to-severe dementia of the Alzheimer's type on a concurrent acetylcholinesterase inhibitor (AChEI).

Study Overview

• Status: Completed
• Conditions: Dementia of the Alzheimer's Type
• Intervention / Treatment: Drug: Placebo; Drug: memantine ER

Detailed Description

Memantine is a therapeutic agent that represents a unique class of Alzheimer's disease (AD) treatment options. A once daily (QD) dosing regimen in an AD population would simplify administration for the caregiver. The purpose of this study is to evaluate the safety and efficacy of modified release memantine taken once daily in outpatients with moderate-to-severe AD on a concurrent AChEI.

• Study Type: Interventional
• Enrollment (Actual): 677
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, 1419HDN
    • Forest Investigative Site 102
  • Buenos Aires, Argentina, C1062ABF
    • Forest Investigative Site 118
  • Buenos Aires, Argentina, C1117ABE
    • Forest Investigative Site 109
  • Buenos Aires, Argentina, C1122AAJ
    • Forest Investigative Site 104
  • Buenos Aires, Argentina, C1126AAB
    • Forest Investigative Site 108
  • Buenos Aires, Argentina, C1181ACH
    • Forest Investigative Site 114
  • Buenos Aires, Argentina, C1209AAB
    • Forest Investigative Site 106
  • Buenos Aires, Argentina, C1405CNF
    • Forest Investigative Site 119
  • Buenos Aires, Argentina, C1413FWO
    • Forest Investigative Site 122
  • Buenos Aires, Argentina, C1419AHN
    • Forest Investigative Site 107
  • Buenos Aires, Argentina, C1425AGP
    • Forest Investigative Site 111
  • Buenos Aires, Argentina, C1425BPK
    • Forest Investigative Site 121
  • Buenos Aires, Argentina, C1428AQK
    • Forest Investigative Site 115
  • Buenos Aires, Argentina, C1428AQK
    • Forest Investigative Site 116
  • Cordoba, Argentina, X5000ALB
    • Forest Investigative Site 112
  • Cordoba, Argentina, X5004AOA
    • Forest Investigative Site 124
  • Mendoza, Argentina, M5500HYF
    • Forest Investigative Site 110
  • Mendoza, Argentina, M5504FMI
    • Forest Investigative Site 125
  • Santa Fe, Argentina, S3000FWO
    • Forest Investigative Site 120
  • Buenos Aires
    • Banfield, Buenos Aires, Argentina, B1828CKR
      • Forest Investigative Site 103
    • La Plata, Buenos Aires, Argentina, B1900AVG
      • Forest Investigative Site 105
    • Lanus, Buenos Aires, Argentina, C1824IBR
      • Forest Investigative Site 123
  • Santa Fe
    • Rosario, Santa Fe, Argentina, S2000DSV
      • Forest Investigative Site 113
• Chile
  • Antofagasta, Chile
    • Forest Investigative Site 302
  • Santiago, Chile
    • Forest Investigative Site 304
  • Santiago, Chile
    • Forest Investigative Site 312
  • Valdivia, Chile
    • Forest Investigative Site 306
  • Elqui
    • Coquimbo, Elqui, Chile
      • Forest Investigative Site 308
  • Santiago
    • Las Condes, Santiago, Chile
      • Forest Investigative Site 301
    • Las Condes, Santiago, Chile
      • Forest Investigative Site 309
    • Providencia, Santiago, Chile
      • Forest Investigative Site 303
    • Providencia, Santiago, Chile
      • Forest Investigative Site 310
    • Recoleta, Santiago, Chile
      • Forest Investigative Site 313
    • San Ramon, Santiago, Chile
      • Forest Investigative Site 305
• Mexico
  • Aguascalientes, Mexico, 20230
    • Forest Investigative Site 206
  • San Luis Potosi, Mexico, 78090
    • Forest Investigative Site 210
  • Coahuila
    • Saltillo, Coahuila, Mexico, 25000
      • Forest Investigative Site 212
  • Federal District
    • Mexico City, Federal District, Mexico, 14000
      • Forest Investigative Site 202
    • Mexico City, Federal District, Mexico, 14050
      • Forest Investigative Site 207
  • Guanajuato
    • Leon, Guanajuato, Mexico, 37000
      • Forest Investigative Site 211
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44610
      • Forest Investigative Site 205
    • Zapopan, Jalisco, Mexico, 45200
      • Forest Investigative Site 203
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 44610
      • Forest Investigative Site 208
    • Monterrey, Nuevo Leon, Mexico, 64710
      • Forest Investigative Site 204
  • Sinaloa
    • Culiacan, Sinaloa, Mexico, 80400
      • Forest Investigative Site 213
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85004
      • Forest Investigative Site 010
  • California
    • Costa Mesa, California, United States, 92626
      • Forest Investigative Site 062
    • Fresno, California, United States, 93720
      • Forest Investigative Site 050
    • San Francisco, California, United States, 94118
      • Forest Investigative Site 024
    • Santa Ana, California, United States, 92705
      • Forest Investigative Site 071
  • Colorado
    • Denver, Colorado, United States, 80262
      • Forest Investigative Site 002
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Forest Investigative Site 021
    • Boynton Beach, Florida, United States, 33426
      • Forest Investigative Site 052
    • Delray Beach, Florida, United States, 33445
      • Forest Investigative Site 070
    • Fort Myers, Florida, United States, 33912
      • Forest Investigative Site 065
    • Hallandale Beach, Florida, United States, 33009
      • Forest Investigative Site 043
    • Hallandale Beach, Florida, United States, 33009
      • Forest Investigative Site 044
    • Miami, Florida, United States, 33137
      • Forest Investigative Site 001
    • North Miami, Florida, United States, 33161
      • Forest Investigative Site 034
    • Orlando, Florida, United States, 32806
      • Forest Investigative Site 068
    • Palm Beach Gardens, Florida, United States, 33410
      • Forest Investigative Site 038
    • Saint Petersburg, Florida, United States, 33709
      • Forest Investigative Site 008
    • Tampa, Florida, United States, 33617
      • Forest Investigative Site 028
  • Georgia
    • Snellville, Georgia, United States, 30078
      • Forest Investigative Site 009
  • Illinois
    • Joliet, Illinois, United States, 60435
      • Forest Investigative Site 069
  • Michigan
    • Kalamazoo, Michigan, United States, 49048
      • Forest Investigative Site 045
  • Missouri
    • Saint Loius, Missouri, United States, 63104
      • Forest Investigative Site 014
  • New Jersey
    • Long Branch, New Jersey, United States, 07742
      • Forest Investigative Site 064
    • Morristown, New Jersey, United States, 07960
      • Forest Investigative Site 011
    • New Brunswick, New Jersey, United States, 08903
      • Forest Investigative Site 003
  • New York
    • Albany, New York, United States, 12205
      • Forest Investigative Site 048
    • Buffalo, New York, United States, 14215
      • Forest Investigative Site 006
    • White Plains, New York, United States, 10605
      • Forest Investigative Site 004
  • Ohio
    • Centerville, Ohio, United States, 45459
      • Forest Investigative Site 027
    • Toledo, Ohio, United States, 43623
      • Forest Investigative Site 012
  • Oregon
    • Portland, Oregon, United States, 97210
      • Forest Investigative Site 020
  • Pennsylvania
    • Greensburg, Pennsylvania, United States, 15601
      • Forest Investigative Site 032
    • Jenkintown, Pennsylvania, United States, 19046
      • Forest Investigative Site 018
  • Rhode Island
    • East Providence, Rhode Island, United States, 02914
      • Forest Investigative Site 067
  • Texas
    • Austin, Texas, United States, 78757
      • Forest Investigative Site 041
    • San Antonio, Texas, United States, 78229
      • Forest Investigative Site 017
  • Virginia
    • Richmond, Virginia, United States, 23229
      • Forest Investigative Site 013
  • Washington
    • Tacoma, Washington, United States, 98405
      • Forest Investigative Site 026

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

Inclusion Criteria:

• Ambulatory patients aged >/= 50 years
• Diagnostic evidence of probable Alzheimer's disease consistent with criteria from the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)
• Confirmatory magnetic resonance imaging (MRI) or computed tomographic (CT) scan within the prior 12 months.
• Mini-Mental State Examination (MMSE) scores >/= 3 and </= 14 at Screening (Visit 1) and Baseline (Visit 2)
• Ongoing daily acetylcholinesterase inhibitor (AChEI) therapy at a stable dose for at least 3 months prior to Screening (Visit 1). It is preferred that patients continue to receive the same AChEI therapy for the duration of the study.

Exclusion Criteria:

• Patients with a modified Hachinski Ischemia Score greater than 4 at Screening.
• Patients who have taken memantine within one month of Screening (Visit 1)
• Patients who have a known hypersensitivity to memantine, neramexane, rimantadine, or amantadine.
• Patients whose AChEI therapy is likely to be interrupted or discontinued during the course of the study.
• Patients who are receiving therapy with more than one AChEI.
• Patients with computed tomography (CT) or magnetic resonance imaging (MRI) evidence of hydrocephalus, stroke, a space-occupying lesion, cerebral infection, or any clinically significant central nervous system disease other than Alzheimer's disease.
• Patients with a DSM-IV Axis I disorder other than Alzheimer's disease, including amnestic disorders, schizophrenia or schizoaffective disorder, bipolar disorder, current major depressive episode, psychosis, panic, or post-traumatic stress disorder.
• Patients who, in the clinician's judgement, are likely to be placed in a nursing home within the next 6 months.
• Patients who had evidence of other neurological disorders that included, but were not limited to, stroke, Parkinson's disease, seizure disorder, or head injury with loss of consciousness within the prior 5 years
• Patients who had dementia that was complicated by other organic disease
• Patients who had dementia complicated by the presence of predominant delusions

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
Placebo Comparator: Placebo; Oral administration, once daily.	Drug: Placebo; Matching placebo oral administration once daily.
Active Comparator: Memantine ER; 28mg, once daily. Oral administration for 24 weeks.	Drug: memantine ER; 28mg(7mg capsules) once daily and oral administration for 24 weeks.; Other Names: Namenda XR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Severe Impairment Battery (SIB) at Week 24 (LOCF)	The SIB was developed for the evaluation of cognitive function in patients with more advanced dementia, and evaluates the areas of memory, language, praxis, orientation, and attention. The SIB test items consist of simple, one-step commands presented with gestural cues that are repeated if necessary. The test contains 51 items, and the range of possible scores is 0 to 100 (with 0 being the worst result). The SIB has been shown to be a valid and reliable instrument sensitive to longitudinal change.	Baseline to week 24
Clinician's Interview-Based Impression of Change With Caregiver Input (CIBIC-plus) at Week 24 (LOCF)	The CIBIC-Plus is a measure of an overall clinical effect and is based on a comprehensive evaluation at Baseline and later visits of four domains: general (overall clinical status), functional (including activities of daily living), cognitive, and behavioral. A skilled clinician interviews the patient, and includes information supplied by a knowledgeable caregiver. The CIBIC-Plus is a rating of the patient's global status relative to Baseline, ranging from a score of 1, indicating "marked improvement" to a score of 4, indicating "no change" to a score of 7, indicating "marked worsening."	Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in the 19-Item Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL19) Scale at Week 24 (LOCF)	The ADCS-ADL19 modified inventory consists of 19 items used to measure the functional capabilities of patients with moderate to severe dementia. Each activity-of-daily-living (ADL) item comprises a series of hierarchical subquestions ranging from the highest level of independent performance to complete loss of ability to perform the ADL Inventory. The inventory is performed by interviewing a person in close contact with the patient and covers the most usual and consistent performance of the patient over the preceding 4 weeks. Response range is 0 (total disability) to 54 (total independence).	Baseline to week 24

Collaborators and Investigators

• Sponsor: Forest Laboratories
• Investigators: Study Director: Stephen M Graham, PhD, Forest Laboratories

Publications and helpful links

General Publications

• Grossberg GT, Alva G, Hendrix S, Ellison N, Kane MC, Edwards J. Memantine ER Maintains Patient Response in Moderate to Severe Alzheimer's Disease: Post Hoc Analyses From a Randomized, Controlled, Clinical Trial of Patients Treated With Cholinesterase Inhibitors. Alzheimer Dis Assoc Disord. 2018 Jul-Sep;32(3):173-178. doi: 10.1097/WAD.0000000000000261.

Study record dates

Study Major Dates

• Study Start: June 1, 2005
• Primary Completion (Actual): October 1, 2007
• Study Completion (Actual): January 1, 2008

Study Registration Dates

• First Submitted: May 3, 2006
• First Submitted That Met QC Criteria: May 4, 2006
• First Posted (Estimate): May 5, 2006

Study Record Updates

• Last Update Posted (Estimate): September 16, 2010
• Last Update Submitted That Met QC Criteria: August 25, 2010
• Last Verified: August 1, 2010

More Information

Terms related to this study

• Keywords: Alzheimer's disease; memantine; moderate to severe Alzheimer's disease
• 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; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Dopamine Agents; Antiparkinson Agents; Anti-Dyskinesia Agents; Memantine
• Other Study ID Numbers: MEM-MD-50