We are studying subjects with mild to moderate Alzheimer's disease who have been on a stable
dose of any cholinesterase inhibitor [donepezil (Aricept), rivastigmine (Exelon), or
galantamine (Razadyne)] for at least 3 months, and have not previously taken memantine
(Namenda). This is an open-label study, with magnetic resonance spectroscopy (MRS) as the
primary outcome measure, along with neuropsychological testing, and optional lumbar
puncture, evaluating patients on their stable dose of a cholinesterase inhibitor over 24
weeks, followed by another 24 weeks on memantine in combination with stable dose of
cholinesterase inhibitor. The purpose of this study is to characterize the progression of
disease using MRS, cerebrospinal fluid (CSF) biomarkers, and cognitive outcome measures, and
to determine whether changes in cognitive function on neuropsychological testing are
correlated to changes in MR spectroscopic and/or CSF biomarkers.
Alzheimer's disease (AD) is the most common cause of dementia. The current US prevalence is
estimated at over 4 million people, and it ranks as the 8th leading cause of mortality in
the United States, accounting for over 60,000 deaths per year.
Memantine is the newest medication approved by the FDA for the treatment of AD. Since it
works on a different transmitter system, it can be used in combination with the other
FDA-approved treatments for AD, tacrine, donepezil, rivastigmine, or galantamine
(collectively referred to as cholinesterase inhibitors).
It remains to be determined what effect currently available AD treatments have on the
underlying structural and functional correlates of the dementia process. While preclinical
evidence suggests that memantine decreases neuronal toxicity in vitro, it is not clear
whether this translates into a beneficial effect in patients with AD.
One of the most pressing challenges underlying clinical trials in AD is the need to validate
reliable surrogate biomarkers of disease progression. Proton magnetic resonance
spectroscopy (MRS) allows for in vivo detection and measurement of brain metabolites. The
spectroscopic features that have been most consistently observed in AD patients, as compared
with patients with other causes of dementia, or with normal subjects, have been elevated
myo-inositol (mI) and reduced N-acetylaspartate (NAA) .
Evaluation of cerebrospinal fluid (CSF) via lumbar puncture affords a minimally invasive
window into the biochemical substrate enveloping the brain. Multiple previous studies of AD
patients compared with control subjects have demonstrated decreased CSF beta-amyloid, and
elevated CSF tau protein. Previous longitudinal studies have documented the stability of
CSF beta-amyloid over one year and CSF tau over two years in AD, suggesting that these may
be possible stable target measures for therapeutic intervention.
The purpose of this study is to characterize the progression of disease using MRS, CSF
biomarkers, and cognitive outcome measures in patients with mild to moderate Alzheimer's
disease after 24 weeks of observational treatment with stable dose of a cholinesterase
inhibitor, and after another 24 weeks of open-label memantine treatment in addition to
stable dose of a cholinesterase inhibitor.
- Written informed consent must be obtained from either the subject (if they have
decisional capacity) or a Legally Authorized Representative (LAR) (as required by
state or local law and the IRB), prior to the initiation of any study-specific
procedures. (If a subject is unable to fully consent for himself/herself, but has
capacity to appoint a research proxy, the legally authorized research proxy will be
asked to sign consent, with the subject signing assent.)
- Male or female outpatients at least 50 years of age at Screening.
- If female, the patient must be at least two years postmenopausal or surgically
sterile at Screening.
- The patient has a current diagnosis of probable Alzheimer's disease consistent with
- The patient has a knowledgeable and reliable caregiver who will accompany the patient
to all clinic visits during the course of the study.
- Mini-Mental State Examination (MMSE) score of at least 15 and not greater than 26 at
- Ongoing therapy with a stable dose of donepezil, rivastigmine, or galantamine for at
least three months at the time of Screening.
- Physical examination, laboratory evaluations, and EKG results at Screening must be
normal, or abnormal findings must be judged not clinically significant by the
- The patient's MRI scan conducted as part of Screening (Visit 1) must be consistent
with a diagnosis of Alzheimer's disease, and must not include any findings that could
confound the spectroscopic analysis of subsequent MRIs (e.g., large cortical stroke,
tumor, or other space-occupying brain lesions).
- Vision and hearing (hearing aid permissible) must be sufficient for compliance with
- The patient and/or their Legally Authorized Representative, and their caregiver must
be able to speak, read, and understand English sufficiently to understand the nature
of the study, to provide written informed consent, and to allow completion of all
- Clinically significant vitamin B12 deficiency at Screening.
- Patients with a modified Hachinski ischemia score greater than 4 at Screening.
- Patients with evidence of clinically significant and active pulmonary,
gastrointestinal, renal, hepatic, endocrine, or cardiovascular system disease.
Patients with controlled hypertension and right bundle branch block (complete or
partial) may be included in the study. Patients with thyroid disease may also be
included in the study provided they are euthyroid on treatment. Patients with
controlled diabetes may also be included.
- Patients with severe renal impairment (estimated creatinine clearance < 35 mL/min).
- Patients with systolic blood pressure (while sitting) greater then than 180 mm Hg or
less then 90 mm Hg, or diastolic blood pressure (while sitting) greater than 100 mm
Hg or less than 50 mm Hg at Screening.
- Patients with evidence of other neurological disorders including, but not limited to,
stroke, Parkinson's disease, seizure disorder, hydrocephalus, or head injury with
loss of consciousness within the past five years at Screening.
- Patients with a current DSM-IV Axis I disorder other than Alzheimer's disease,
including schizophrenia or schizoaffective disorder, bipolar disorder, current major
depressive episode, psychosis, panic disorder, or post-traumatic stress disorder.
- Patients with dementia complicated by other organic disease.
- Patients who have had a previous brain scan (MRI or CT) with results inconsistent
with a diagnosis of probable Alzheimer's disease.
- Patients with an oncological diagnosis (hematological or solid tumor) which is
currently being treated, or for which there has been treatment within the year
preceding Screening, or for which there is still evidence of active disease. (Note:
Patients with local dermatological tumors at such as basal or squamous cell carcinoma
may be included.)
- Patients with an object in the head or neck which would invalidate or obstruct the
successful completion of an MRI scan, or patients who have other contraindications to
MRI, including those with implanted ferromagnetic material or devices such as cardiac
pacemakers, deep brain stimulators, cochlear implants, or intraocular metallic
- Patients who are claustrophobic and/or unable to tolerate MRI at Screening, or whom
the Investigator believes will not be able to tolerate further scans scheduled during
the course of the study.
- Patients with a known or suspected history (within the past 5 years at Screening) of
alcoholism or drug abuse.
- Patients who are on an unstable dose of a cholinesterase inhibitor (donepezil,
rivastigmine, or galantamine), are currently taking more than one cholinesterase
inhibitor at Screening, who are likely to require a change in cholinesterase drug
dose during the course of the study, or for whom a cholinesterase inhibitor therapy
- Patients with a history of severe drug allergy or hypersensitivity, or patients with
known hypersensitivity to memantine, amantadine, rimantadine, or lactose.
- Patients who have been previously treated with or have participated in an
investigational study of neramexane, memantine, or amantadine.
- Patients previously treated with commercial memantine.
- Patients who have been in an investigational drug study or who have received
treatment with an investigational drug within 30 days or 5 half-lives (whichever is
longer) of Screening.
- Patients or caregivers who are unwilling or unable to abide by the visit schedule and
other requirements of the study.
- Any condition which would make the patient or caregiver unsuitable for the study in
the opinion of the Investigator.