Official Title: “An Open-Label Exploratory Study With Memantine: Correlation Between Proton Magnetic Resonance Spectroscopy, Cerebrospinal Fluid Biomarkers, and Cognition in Patients With Mild to Moderate Alzheimer's Disease”

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.

Study Type: Interventional

Study Design: Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment

Study Primary Completion Date: February 2010

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.

Intervention(s) in this Clinical Trial

• Drug: memantine
  • 24-week observational lead-in period, wherein patients already on a stable dose of donepezil, rivastigmine, or galantamine continue on that dose, followed by a 24-week open-label memantine period, wherein patients receive open-label memantine treatment titrated to a dose of 10 mg orally b.i.d., in addition to their ongoing stable cholinesterase inhibitor treatment

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: single-arm
  • 24-week observational lead-in period, wherein patients already on a stable dose of donepezil, rivastigmine, or galantamine continue on that dose, followed by a 24-week open-label memantine period, wherein patients receive open-label memantine treatment titrated to a dose of 20 mg per day, in addition to their ongoing stable cholinesterase inhibitor treatment

Primary Measures

• Relative levels of myo-inositol (mI), N-acetylaspartate (NAA), total creatine (Cr), and choline (Cho) by single voxel 1H MRS
  • Time Frame: 48 weeks
    Safety Issue?: No

Secondary Measures

• CSF beta-amyloid, tau, and phosphorylated tau levels
  • Time Frame: 48 weeks
    Safety Issue?: No
• MMSE, ADAS-cog, ADCS-ADL, NPI, Trails A and B, Animal Naming and FAS verbal fluency, logical memory, visual reproduction, digit span, clock-drawing, presidents, Rey-Osterreith figure copying and recall, judgment of line orientation, semantic distance
  • Time Frame: 48 weeks
    Safety Issue?: No

Inclusion Criteria:

• 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 NINCDS-ADRDA criteria.
• 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
• Screening.
• 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 Investigator.
• 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 testing procedures.
• 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 study assessments.

Exclusion Criteria:

• 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 shards.
• 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 is contraindicated.
• 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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 50 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: North Shore Long Island Jewish Health System

Overall Clinical Trial Officials and Contacts

Marc L Gordon, M.D. Principal Investigator North Shore Long Island Jewish Health System  

Overall Contact: Erica Christen, R.N. 516-487-3492 EChriste@nshs.edu

Information obtained from ClinicalTrials.gov on September 05, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00551161

Study ID Number: NAM-MD-50

ClinicalTrials.gov Identifier: NCT00551161

Health Authority: United States: Institutional Review Board