Martin R. Farlow, MD, Indiana University 1979 - US grants

This clinical trial will evaluate single dose safety, tolerance and pharmacokinetics in elderly, non-demented, healthy volunteers. The study will be conducted at two clinical sites having access to a General Clinical Research Center. Eight subjects will be recruited (four from each clinical site). Each subject will receive a single oral dose of AIT-082 or placebo on a weekly basis for five weeks. Subjects will be permitted to advance to a higher dose only if the preceding dose is deemed safe and well tolerated. Subjects will be observed for adverse reactions throughout the study. Blood and urine will be collected to determine the pharmacokinetic parameters of AIT-082. Preliminary efficacy data utilizing neuropsychological performance tests will be obtained which may suggest beneficial effects of AIT-082 on memory in humans. The study will be a randomized, double-blind, parallel group, dose escalation trial. The eight patients will be randomized across two clinical sites. Six subjects will receive escalating doses of the active agent (AIT-082). Two subjects will receive placebo throughout the study. Standard statistical methods will be used to explore differences in vital signs and laboratory safety results at each dose. The frequency of physical exam abnormalities and adverse events in patients receiving AIT-082 will be tabulated and compared at each incremental dose as well as to subjects receiving placebo medication only. The pharmacokinetic parameters (e.g. AUC, Cl/F, Kel, Cmax, tmax, t 1/2, U0-24 hr) for AIT-082 will be derived using standard software (e.g. SAS, PCNONLIN or MKMODEL) at the different dose levels. Neuropsychological performance will be summarized and examined statistically to determine if there is preliminary evidence of a dose related treatment effect (Friedman's test).

NDD094 is potentially new therapeutic agent for Alzheimer's disease (AD). Preclinical experiments indicate the NDD094 has been found to influence the course of lesion-induced structural and functional brain abnormalities in the animal model that resembles some of the cognitive and behavioral disturbance found in patients with AD. If it has similar effects in patients with AD, it may improve both the behavioral and cognitive disturbances associated with the disease and may retard or arrest disease progression. This protocol describes a Phase IIA study for the NDd094 in patients with AD. This clinical trial is designed to determine the maximum tolerated dose of NDD094 in patients with AD, to assess safety and tolerability of the doses tested and to study its pharmacokinetics in this population. Efficacy data will be tracked in individual patients in order to justify continued long-term treatment. The study will be conducted at two clinical sites, both the Outpatient clinic, room 3124 and the General Clinical Research Center. There will be three, sequential, escalating-dose cohorts of 36 patients (27 NND094; 9 placebo). Subjects will be observed for adverse reactions throughout the study. Blood and urine will be collected to determine drug concentration and pharmacokinetic evaluations. Primary efficacy data utilizing neuropsychological performance tests will be obtained which may suggest possible effects of NDD094 on memory in humans.

The Clinical Core is critical to the function of the Indiana Alzheimer Disease Center. Its role is to recruit, clinically characterize and longitudinally follow patients with MCI, AD, non-AD and mixed dementia and healthy controls. A major emphasis is to identify and clinically characterize families with AD and new genetically distinct non-AD dementias with emphasis on identifying patients in the earliest stages of illness. These patients will be further characterized by the Neuropathology Core. In conjunction with the Neuropathology Core, the Clinical Core will obtain and bank biology materials (DNA, plasma and CSF) from participating subjects to support studies pertaining to dementias. Patients from the Clinical Core will be offered as appropriate participation in ADNI, LOAD, investigational drug trials and other local and multicenter research studies. We will continue to support the Indianapolis-lbadan Study and NCRAD. We will continue our educational efforts in the general elderly as well as African American communities to communicate and facilitate autopsy. After autopsy, clinical-genetic-neuropathological correlation will increase the understanding of AD and non-AD dementias and support further investigations of biochemical abnormalities and/or underlying disease mechanisms.

The Clinical Core is critical to the function of the Indiana Alzheimer Disease Center. Its role is to recruit, clinically characterize and longitudinally follow patients with MCI, AD, non-AD and mixed dementia and healthy controls. A major emphasis is to identify and clinically characterize families with AD and new genetically distinct non-AD dementias with emphasis on identifying patients in the earliest stages of illness. These patients will be further characterized by the Neuropathology Core. In conjunction with the Neuropathology Core, the Clinical Core will obtain and bank biology materials (DNA, plasma and CSF) from participating subjects to support studies pertaining to dementias. Patients from the Clinical Core will be offered as appropriate participation in ADNI, LOAD, investigational drug trials and other local and multicenter research studies. We will continue to support the NCRAD. We will continue our educational efforts in the general elderly as well as African American communities to communicate and facilitate autopsy. After autopsy, clinical-genetic-neuropathological correlation will increase the understanding of AD and non-AD dementias and support further investigations of biochemical abnormalities and/or underlying disease mechanisms.

Summary As the number of Alzheimer's disease (AD) patients increases rapidly, a simple and specific blood test to diagnose AD is needed. Our recent research discovered that a single peripheral injection of pramlintide can move amyloid-? peptide (A?) from the brain into the blood in AD mouse models, and the level of A? increase in the blood correlates well with the existing amount of A? in the brain. Based on this finding, the proposed study is to further the development of a blood test for AD patients that we initiated by a single injection of pramlintide as the challenge for biomarker changes in blood. This challenge test will be a diagnostic test for AD similar in principle to the glucose tolerance test that shows abnormalities specifically in diabetic patients. The central hypothesis is that a single pramlintide injection will significantly induce a change in a group of AD-related factors in the blood of AD patients but not in those with normal cognition, and the signature of these changes will correlate with the AD biomarkers in the central nervous system (CNS). We will recruit 240 subjects from 3 clinical research centers to conduct the pramlintide challenge test. There will be three specific aims. Aim 1 is to investigate whether a single injection of pramlintide induces a dose-dependent increase in A? in the blood of AD patients. Aim 2 is to investigate whether the pattern of AD biomarker changes in the pramlintide challenge test correlates with AD biomarkers in CSF. Aim 3 is to determine whether the pattern of AD biomarker changes in the pramlintide challenge test correlate with amyloid burden in the brain. Pramlintide is non-amyloidogenic amylin analog, and is an FDA-approved drug for diabetes with a favorable safety profile. Should our proposed study support the concept of the amylin challenge test as a diagnostic test for AD, this test will be able to be conducted in a doctor's office. 1