This study is currently under development. We designed a randomized double-blind placebo-controlled clinical trial to assess the safety and therapeutic efficacy of Exendin-4 treatment in early Alzheimer's disease. The study was approved by the NIA Scientific Committee and the Clinical Investigator's meeting. An application for a waiver for a investigational new drug (IND) was submitted to the Food and Drug Administration (FDA). Submission to the local institutional review board (IRB)for approval is currently pending. The trial will unfold in two Phases. First, we will conduct a 6-month duration pilot study (Phase I) to assess feasibility of the study of Exendin-4 treatment in early AD, defined by clinical criteria, neuropsychological testing and cerebrospinal fluid biomarkers. Once the feasibility goal has been met, a subsequent Phase II double-blind placebo-controlled trial study will be conducted to assess the safety and therapeutic efficacy of Exendin-4 treatment in early Alzheimer's disease. Participants enrolled in Phase I will continue their participation in Phase II and treatment will be provided to them without interruption. 230 participants can be screened under this protocol, with the goal of enrolling 115 participants into treatment. It is expected that the study will complete enrollment in two years. Enrolled participants will then be followed for three years. A telephone-screening interview will be performed by a study investigator with the participant and caregiver prior to Visit 1. Previous physician should have already diagnosed participants with either MCI or early AD. Moreover, it will be assessed whether the participant has had appropriate clinical investigation for the evaluation of dementia according to the current standards of care. The caregiver/participant will be asked to obtain relevant medical records from their treating primary physician or neurologist and bring with them on the initial visit. Then, will proceed with enrollment, which will include a detailed clinical evaluation, a lumbar puncture,MRI of the brain, blood draws (including APOE-4 genotyping), neuropsychological testing and oral glucose tolerance test. Final eligibility will depend on the result of CSF Abeta-42 (<192 pg/ml will be considered diagnostic for early AD);Delayed Paragraph Recall from the Wechsler Memory Scale-Revised 1.5-2 SD below age and education adjusted norms;Clinical Dementia Rating (CDR of 0.5 or 1) memory box score must be at least 0.5;Mini Mental Status Exam (MMSE) >20;and Hamilton Depression rating scale score of less than or equal to 12 on the 17-item scale. Then, if the inclusion criteria are met (and there are no reasons for exclusion, such as other neurological or psychiatric disease, psychotropic medication use, etc), participants will be randomized to one of the two treatment groups: Exendin-4 vs. Placebo. The NIA pharmacist and one Associate Investigator (AI) will remain unblinded and will perform stratification and randomization. The Principal Investigator (PI) and all but one of the AIs as well as the participant and caregiver will be blinded in regards to treatment assignment. Following, group assignment, patients will be started on treatment. They will return for safety visits in 1, 2, 4 weeks and 3 months. During each safety visits, we will perform clinical evaluations and measure amylase/lipase (given the reported cases of pancreatitis with Exendin-4 treatment) and fasting glucose. Then, participants will have experimental visits in 6, 12, 18, 24 and 36 months. In each one of those, efficacy measures will be collected via clinical evaluation, a lumbar puncture,MRI of the brain, blood draws (including APOE-4 genotyping), neuropsychological testing and oral glucose tolerance test. The primary efficacy analysis will take place after completion of the study and unblinding of the investigators. The primary efficacy outcome measure will be the rate of cognitive and behavioral decline, assessed by one measure of cognition (ADAS-cog) and one measure of overall functional status (CDR-sum of boxes). Several secondary outcome measures will be obtained for correlational analyses.Cognitive data and MR images will be de-identified by the non-blinded AI so that interim analysis of the data (in terms of secondary outcomes) can take place by the PI and the other AIs at 6, 12, and 18 months and at 2 and 3 years. Other than Alzheimer's disease, Exendin-4 has shown promise (from pre-clinical studies) for the treatment of other neurodegenerative diseases (such as Parkinson's and Huntington's diseases) and Stroke. With the accumulation of clinical experience and scientific information from the initial study on Alzheimer's disease, it is expected that new ideas will be generated and new projects may unfold for treatment of these or other neurodegenerative diseases.
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