Kimberly Schafer

A Controlled Trial of Selegiline, Alpha-Tocopherol, or Both as Treatment for Alzheimer's Disease

BACKGROUND There is evidence that medications or vitamins that increase the levels of brain catecholamines and protect against oxidative damage may reduce the neuronal damage and slow the progression of Alzheimers disease. METHODS We conducted a double-blind, placebo-controlled, randomized, multicenter trial in patients with Alzheimers disease of moderate severity. A total of 341 patients received the selective monoamine oxidase inhibitor selegiline (10 mg a day), alpha-tocopherol (vitamin E, 2000 IU a day), both selegiline and alpha-tocopherol, or placebo for two years. The primary outcome was the time to the occurrence of any of the following: death, institutionalization, loss of the ability to perform basic activities of daily living, or severe dementia (defined as a Clinical Dementia Rating of 3). RESULTS Despite random assignment, the baseline score on the Mini-Mental State Examination was higher in the placebo group than in the other three groups, and this variable was highly predictive of the primary outcome (P<0.001). In the unadjusted analyses, there was no statistically significant difference in the outcomes among the four groups. In analyses that included the base-line score on the Mini-Mental State Examination as a covariate, there were significant delays in the time to the primary outcome for the patients treated with selegiline (median time, 655 days; P=0.012), alpha-tocopherol (670 days, P=0.001) or combination therapy (585 days, P=0.049), as compared with the placebo group (440 days). CONCLUSIONS In patients with moderately severe impairment from Alzheimers disease, treatment with selegiline or alpha-tocopherol slows the progression of disease.

A randomized controlled trial of prednisone in Alzheimer's disease

To the Editor: We read with interest the article by Aisen et al.,1 who found that low doses of prednisone are not effective in AD. In the article, inflammatory processes are discussed in the pathophysiology of dementia, and corresponding therapeutic approaches are pursued. However, no clear clinical evidence for this exciting hypothesis has been established yet. To acquire information about the inflammatory activity of patients with expected dementia transferred to our ward, we investigated eosinophilic cationic protein (ECP) in serum. ECP is a sensitive marker of inflammatory processes and often used as a marker in clinical studies.2 We have 41 patients (mean age 73.8 years, SD 7.8; 7 men, 34 women) in our study. …

Clinical Dementia Rating training and reliability in multicenter studies The Alzheimer's Disease Cooperative Study experience

Global ratings of dementia severity are used increasingly in clinical trials of anti-dementia compounds. Such ratings are clinically relevant, but their reliability in multicenter settings has not been determined. To evaluate the reliability of one global scale, the Clinical Dementia Rating (CDR), 82 investigators of the multicenter Alzheimers Disease Cooperative Study participated in a training and relibility protocol using videotaped assessments of subjects in various stages of Alzheimers disease. Following training, overall agreement of the investigators with “gold standard CDR scores was 83%. These results indicate that the training protocol is useful for establishing good levels of agreement in staging dementia severity and that the CDR can be standardized as a clinical global scale for multicenter studies of Alzheimers disease.

The Severe Impairment Battery: Concurrent Validity and the Assessment of Longitudinal Change in Alzheimer's Disease

Measurement of cognitive dysfunction in the early stages of Alzheimers disease (AD) has been well studied and there are many objective tests in use for this purpose. However, with the exception of clinical rating scales, such as the Clinical Dementia Rating Scale, Global Deterioration Scale, and Functional Assessment Staging, there are few objective measures of cognition in the more advanced stages of AD. Given a renewed interest in potential AD therapies, objective measures of mental functioning are needed to adequately assess change in more advanced AD patients. As part of an effort by the NIA-Alzheimers Disease Cooperative Study to evaluate new measures of efficacy for their utility in treatment studies, the Severe Impairment Battery (SIB) was examined in a 1-year evaluation of change across a wide range of AD severity. The data suggest that the SIB is a reliable and valid measure of progression, particularly in persons with moderate to severe AD. The SIB may therefore be a useful outcome measure in clinical trials that include patients with more advanced stages of AD.

Rationale and design of a multicenter study of selegiline and alpha-tocopherol in the treatment of Alzheimer disease using novel clinical outcomes. Alzheimer's Disease Cooperative Study.

This report describes the rationale and design of a clinical trial using selegiline (10 mg/day) and alpha-tocopherol (2,000 IU/day) to slow the progression of dementia in Alzheimer disease (AD). This study was developed by the Alzheimers Disease Cooperative Study (ADCS), a consortium of clinical research centers actively involved in AD research. The major goal of the consortium is to design and conduct clinical investigations leading to the development of treatments for AD. This study uses a randomized double-blind, placebo-controlled, 2 x 2 factorial, parallel group design to test two drugs for the treatment of AD. The primary outcome of the study is the time to reach any one of the following four endpoints: death, institutionalization, loss of two of three basic activities of daily living, and progression of Clinical Dementia Rating (CDR) stage from 2 to 3. Patients with moderately severe disease (CDR = 2) were enrolled and evaluated 10 times over a period of 2 years to determine if these agents reduce the time to reach any endpoint. A database from the Consortium to Establish a Registry for Alzheimers Disease indicated adequate power analyses to observe a treatment effect on this clinically meaningful outcome measure. Recruitment and baseline characteristics of the population are provided. The rationale for the choice of a factorial design, the use of a novel, clinically meaningful endpoint, and the selection of a cohort of patients with AD of moderate severity are discussed.

A multicenter evaluation of new treatment efficacy instruments for Alzheimer's disease clinical trials : Overview and general results

Evaluating treatment efficacy in Alzheimers disease (AD) clinical trials requires optimal assessment methods to determine the extent and clinical meaningful-ness of potential therapeutic effects of pharmacologic agents. Development of improved outcome measures for AD clinical trials is a major objective of the Alzheimers Disease Cooperative Study (ADCS), an NIA-sponsored, multisite clinical trials consortium. The ADCS Instrument Development Project evaluated the sensitivity, reliability and validity of new or improved measures in each of five assessment domains: (a) cognition (immediate and delayed memory, praxis, attention, and executive function); (b) clinical global change; (c) activities of daily living; (d) behavioral symptoms (agitation and other noncognitive symptoms); and (e) cognition in severely impaired patients. A total of 306 English-speaking subjects were enrolled in the study, including AD patients stratified by disease severity and cognitively normal, age-matched elderly subjects. Half were retested at 1 month and 2 months after baseline, and all received 6-and 12-month follow-up assessments. Spanish versions of these new measures are currently being evaluated. The development of this multisite study, the common methods and procedures, and a detailed description of the cohort are provided in this overview article. This multisite project demonstrates the feasibility of a consortium approach to instrument development. We were able to develop new instruments and efficiently evaluate their reliability and sensitivity to longitudinal change by capitalizing on the experience and patient resources of the participating ADCS research sites.

A multicenter, randomized, placebo controlled, multiple-dose, safety and pharmacokinetic study of AIT-082 (Neotrofin™) in mild Alzheimer's disease patients

A phase 1, randomized, double-blind, placebo-controlled, dose escalation study of the purine derivative, AIT-082 (Neotrofin, NeoTherapeutics) was conducted in mild Alzheimers disease (AD) patients to evaluate multiple-dose safety, tolerability, and pharmacokinetics. Possible short-term effects of AIT-082 on cognition and memory were preliminarily investigated. AIT-082 is currently being developed as a potential treatment for Alzheimers disease and other neurological disorders. Pre-clinical studies indicate that AIT-082 has memory enhancing properties, stimulates neuritogenesis and the production of neurotrophic factors. Patients received an oral dose of AIT-082 or placebo daily for one week. Thirty-six AD patients were divided into three dose cohorts; each dose cohort consisted of twelve patients with 8 patients randomized to AIT-082 and 4 to placebo. The 3 doses of AIT-082 evaluated in this study were 100 mg/day, 500 mg/day, and 2,000 mg/day. There were no serious adverse events at any dose and the drug was well tolerated without significant side effects. AIT-082 was orally and rapidly absorbed, resulting in peak serum concentrations within 2 hours with an elimination half-life of approximately 20 hours. Higher doses resulted in corresponding increases in peak concentrations and areas under the curve (AUC). There was an approximate 2-fold accumulation in AIT-082 with daily dosing (as reflected by the AUC) at steady state. There were no significant differences by treatment arm on the clinical or neuropsychological evaluations. AIT-082 was rapidly absorbed by the oral route with a half-life suitable for dosing once or twice daily. No problems with tolerability or safety were found. AIT-082 appears suitable for testing in larger clinical trials for the treatment of AD and other neurologic disorders.

The Spanish instrument protocol: Design and implementation of a study to evaluate treatment efficacy instruments for Spanish-speaking patients with Alzheimer's disease

Development of improved outcome measures for Alzheimers disease (AD) clinical trials is a major objective of the Alzheimers Disease Cooperative Study (ADCS), an NIA-sponsored, multisite clinical trials consortium. The ADCS is committed to recruiting and following minority patients in clinical trials. At present, a serious impediment to recruiting non-English-speaking minorities is the lack of instruments with adequate translation. Because Spanish is the second most commonly spoken language in the United States and because persons of Hispanic origin represent approximately 10% of the population, we conducted an instrument development protocol for Spanish-speaking patients. Evaluating treatment efficacy in Spanish-speaking AD patients requires the development of assessments that are comparable to those used for English-speaking participants in clinical trials. The ADCS Instrument Development Project evaluated the sensitivity, reliability, and validity of new or improved measures in each of five assessment domains: (a) cognition (immediate and delayed memory, praxis, attention, and executive function); (b) clinical global change; (c) activities of daily living; (d) behavioral symptoms (agitation and other noncognitive symptoms); and (e) cognition in severely impaired patients. These new treatment efficacy instruments were translated for Spanish speakers and a Spanish Instrument Study was conducted in parallel with the English version of the study. This report describes instrument translation, entry criteria, and recruitment procedures. In addition, the demographic and clinical characteristics of the cohort at baseline are presented and compared to the English-speaking cohort. Implications for the development of comparably sensitive Spanish language instruments are discussed.

A phase I study of AIT-082 in healthy elderly volunteers

A Phase I, double-blind, placebo-controlled, single-dose, escalation study of the purine derivative, AIT-082 (Neotrofin™, NeoTherapeutics, Inc.) was conducted in healthy elderly volunteers. This trial was designed to evaluate single-dose safety, tolerability, and pharmacokinetics. Potential cognitive domains that might benefit from AIT-082 were preliminarily investigated. AIT-082 is currently being developed as a potential treatment for Alzheimer’s disease (AD). Preclinical studies indicate that AIT-082 has memory-enhancing properties, stimulates neuritogenesis, and upregulates neurotrophic factors. Subjects received a single oral dose of AIT-082 or placebo on a weekly basis for 5 wk. All patients received a placebo dose at baseline. Six subjects received increasing doses of AIT-082 over the next 4 wk at doses of 0.6, 2.0, 6.0, and 20.0 mg of AIT-082 per kilogram of body weight. Two subjects received placebo throughout the trial. Nine subjects were recruited. One subject was withdrawn after the third treatment visit owing to poor venous access. There were no serious adverse events. The drug was well-tolerated. The time to peak drug concentration was approx 85 min with an elimination half-life of approx 17.6 h. Performance on the Number Comparison, Symbol Digit, and Trails A tests improved with AIT-082 dosing compared to baseline (placebo). In conclusion, AIT-082 was rapidly absorbed by the oral route with a half-life suitable for once daily dosing. No problems with tolerability or safety were demonstrated.

Interobserver disagreements on clinical dementia rating assessment: interpretation and implications for training.

The Clinical Dementia Rating (CDR) is a widely used semiobjective instrument for staging dementia severity. A global CDR score is reported that is derived from individual scores in six domains. In this study, we examined both agreement and disagreement, among raters and with a gold standard, to identify domain-specific and global dementia severity level ratings that would most benefit from further training or greater emphasis in future training. We found that raters-in-training experienced the most difficulty with rating normal and questionable dementia. They also had the most trouble scoring the memory domain. When they disagreed with the gold standard, they nearly always gave higher ratings. A third, extremely experienced group of raters were uniform in their high levels of agreement on each domain and the global CDR and tended to give lower ratings if they disagreed with the gold standard. Analysis of the agreement and disagreement patterns suggested that greater emphasis on the memory, home and hobbies, and orientation domains during CDR training, and increasing the information provided for the judgment and problem solving domain on the standardized CDR worksheets, could improve the consistency of raters and increase the efficiency with which they are trained to use the CDR.