A Pilot Clinical Trial of Exendin-4 in Alzheimer's Disease

Study Overview
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Brief Summary
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Background: Exendin-4 (or Exenatide) is a medication currently used to treat diabetes that has shown promising results in animal and cellular models of Alzheimer's disease. It is possible that Exendin-4 may be a treatment for Alzheimer's disease, which involves the gradual deterioration and death of neurons. Researchers are interested in studying the safety and comparing the effects of Exendin-4 with placebo on cognitive performance, clinical progression of dementia, various chemicals measured in blood and cerebrospinal fluid, and brain MRI, in individuals with early-stage Alzheimer's disease or mild cognitive impairment. Objectives: To determine the safety and tolerability of twice daily administration of Exendin-4, as well as to acquire preliminary evidence for effects on cognitive performance, clinical progression of dementia, various chemicals measured in blood and cerebrospinal fluid, and brain MRI, in individuals with early-stage Alzheimer's disease or mild cognitive impairment. Eligibility: Individuals at least 60 years of age who have objective evidence of early-stage Alzheimer's disease or mild cognitive impairment in screening testing. Design: Participants will be screened. Following the telephone screening, two in-person screening visits to determine eligibility. The screening visit will involve a medical history and neurological examination, tests of memory and cognition, a lumbar puncture, collection of blood and saliva samples, and brain Magnetic Resonance Imagine (MRI) studies. Participants will be required to appoint a Durable Power of Attorney for research and medical care during this protocol. Eligible participants will be divided into two groups (double-blind randomization). One group will receive Exendin-4 SC twice daily, and the other will receive a placebo. Participants will keep a medication diary and will be scheduled for additional study visits 1 and 2 weeks after the start of the treatment. Participants will have regular followup visits with blood tests, cognitive tests, imaging studies, and other examinations 6, 12, and 18 months after the start of the treatment. Another lumbar puncture may be performed optionally at the 18-month followup visit.

Detailed Description
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Objective: Exendin-4 (or exenatide) is a medication currently used in the treatment of diabetes mellitus (DM). Exendin-4 has generated promising results as an agent protecting neurons from a number of assaults both in the laboratory and in studies on animals. Specifically, there is pre-clinical evidence that Exendin-4 may be a treatment for Alzheimer's disease (AD). Based on these facts, we conducted a pilot Phase II double blind randomized placebo-controlled clinical study to assess the safety and provide proof of concept for exendin-4 treatment in early Alzheimer's disease (AD), by demonstrating a response of disease biomarkers to the intervention. Our main hypothesis is that long-term administration of Exendin-4 in participants with amnestic MCI/early AD in FDA-approved doses is safe and will induce a change over time in AD biomarkers. Subject population: We intend to screen up to 100 potential participants in order to ensure that at least 40 participants (enrolled based on a clinical diagnosis of amnestic MCI/early AD and Cerebrospinal Fluid (CSF) biomarker evidence of AD) will be enrolled into treatment and complete the study. Design: Enrolled participants will be randomly assigned into one of two groups (Exendin-4 vs. Placebo) and will be followed at regular intervals for 18 months. Outcome measures: Safety and tolerability will be the primary outcomes. In addition, we will measure and assess the change over time of a number of exploratory outcomes with the intervention, including CSF and plasma biomarkers (such as CSF A42, tau, p181-tau and plasma A42/A40), cognitive performance measures (such as the Alzheimer's Disease Assessment scale, cognitive sub-scale, and other tests), clinical progression of dementia measures (such as the Clinical Dementia Rating scale sum-of-boxes), volumetric changes on structural brain MRI and changes in resting fMRI. All research will be performed on the National Institute on Aging (NIA) Clinical Research Unit located on the 5th floor of Harbor Hospital.

Official Title
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A Pilot Study of Exendin-4 in Alzheimer s Disease

Conditions
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Alzheimer's Disease, Mild Cognitive Impairment

Intervention / Treatment
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* Drug: Exendin-4 SC
* Drug: Placebo SC


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Age > 60 Clinical Dementia Rating (global CDR) of 0.5 or 1. Memory box score must be at least 0.5. Mini Mental Status Exam (MMSE) > 20 Clinical diagnosis of (amnestic or mixed) MCI or early AD and Memory deficit on neuropsychological or clinical testing. Hamilton Depression Scale score of less than or equal to 12 on the 17-item scale CSF A beta 42 < 192 (+- 10%) pg/ml (given an intra-subject laboratory variability   10%) Medications stable for at least 4 weeks prior to screening. In particular: Participants may take stable doses of antidepressants, chronic anxiolytics or sedative hypnotics, if started at least 4 weeks or longer prior to screening Cholinesterase inhibitors and/or memantine are allowable, if started at least 4 weeks prior to screening Participants will not be asked to discontinue medications without permission from their primary care provider (PCP) or specialist. Fluency in English At the time of enrollment, participants must have the ability to provide informed consent and make health care decisions. An informant or caregiver who has frequent contact with the participant (e.g. an average of 10 hours per week or more) must be appointed to serve as Durable Power of Attorney (DPA) for research and medical care at NIA, accompany the participant to clinic visits and provide historical information regarding the participant s cognitive status, and assist participants with/administer injections of the investigational medication. Good general health with no additional disease states that could interfere with the study. EXCLUSION CRITERIA: Other significant neurological disease of the Central Nervous System (such as Parkinson s disease, atypical Parkinsons disease, Multi-infarct Dementia, Frontotemporal Dementia, Huntington s disease, Normal Pressure Hydrocephalus, brain tumor, Progressive Supranuclear Palsy, Epilepsy, Subdural Hematoma or Multiple Sclerosis) A history of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities Positive RPR or HIV Abnormal PT/PTT and INR (1.5 standard deviation over the upper normal limit) increasing the risk for LP related bleeding/hematoma; platelet count <100,000/microliters. Anti-coagulant therapy (such as coumadin). Aspirin up to 325 is allowed. Investigators unable to obtain CSF, failure of Lumbar Puncture after a limited number of unsuccessful attempts). History of psychiatric disease with significant impairment in thought processes (e.g. schizophrenia, bipolar disease, psychosis). Participants who develop psychiatric conditions necessitating treatment after their enrollment will not be dropped from the study. The high incidence of late-onset depression and anxiety among individuals with MCI and AD requires that participants with depression, and/or anxiety should not be excluded from the cohort to maintain the ecological validity of the results. Current abuse of alcoholic beverages (> 7 in women and >14 in men) or substance abuse. Known diagnosis of diabetes at the time of enrollment or new diagnosis of diabetes based on the findings of elevated fasting blood glucose (= or >126 mg/dl) and/or the oral glucose tolerance test at screening (>200 mg/dl at two hours). Severe renal impairment (creatinine clearance <30 ml/min) or end-stage renal disease. Individuals with moderate renal impairment (creatinine clearance 30 to 50 ml/min) may be enrolled in the study, but their BUN and Creatinine will be monitored during each visit after drug initiation and extra safety visits will be conducted at 3, 9, and 15 months. Current or previous treatment with Exendin-4 (Exenatide, trade name Byetta.) History of pancreatitis, active upper GI, hepatic or gallbladder disease Personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 History of repeated hypoglycemia Body mass index (BMI) < 18 on enrollment (given the expected weight loss caused by Exendin-4 and dementia). In the BLSA, participants with age > 65 had a mean BMI of 25.8 with SD of 3.9 Exendin-4 has been shown to cause an average 5.3 kg weight loss, with 95% CI: 6 to 4.5 kg (126). Allergy to Exendin-4 or to substances in the injection pen (metacresol, mannitol, glacial acetic acid, sodium acetate trihydrate, water for injection). Participation in other studies of investigational treatments for Alzheimer s disease in the last year.

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blind randomized placebo-controlled.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exendin-4<br>Exenatide 5 mcg or 10 mcg SC twice daily | Drug: Exendin-4 SC<br>* Exenatide 5 mcg or 10 mcg SC twice daily<br>* Other names: Exenatide SC;|
| Placebo Comparator: Placebo<br>Placebo SC twice daily | Drug: Placebo SC<br>* Placebo SC twice daily<br>* Other names: Placebo SC twice daily;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Incidence of Nausea | Tolerability of exenatide (nausea is the most common expected adverse event of exenatide) | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mini Mental State Examination (MMSE) | Scale range: 0 - 30 points (higher is better) | 18 months | 
| Alzheimer's Disease Assessment Scale-cognitive Subscale (ADAS-cog70) | Alzheimer's dementia scale cognitive sub-scale range: 0 - 70 points (higher is worse) | 18 months | 
| Clinical Dementia Rating (CDR) Global Score | Clinical Dementia Rating global score range: 0 (no dementia); 0.5 (Mild Cognitive Impairment); 1 (mild dementia); 2 (moderate dementia); 3 (severe dementia). Higher is worse. | 18 months | 
| Clinical Dementia Rating (CDR) Sum of Boxes | Sum of the Clinical Dementia Rating boxes (memory, orientation, judgment and problem solving, community affairs, home and hobbies, personal care). Each box is rated as 0, 0.5, 1, 2 or 3. Range for the sum of boxes is 0 - 18. Higher scores reflect a greater severity of dementia. | 18 months | 
| Cerebrospinal Fluid (CSF) Total Tau | Total Tau measured in CSF using Luminex xMAP technology and INNO-BIA Alz Bio3 kits (Research Use Only) provided by Fujirebio | 18 months | 
| Cerebrospinal Fluid phospho181-tau (CSF p181-tau) | p-181-Tau measured in CSF using Luminex xMAP technology and INNO-BIA Alz Bio3 kits (Research Use Only) provided by Fujirebio | 18 months | 
| Cerebrospinal Fluid Amyloid-beta 42 (CSF Abeta42) | Abeta42 peptide measured in CSF using Luminex xMAP technology and INNO-BIA Alz Bio3 kits (Research Use Only) provided by Fujirebio | 18 months | 
| Body Mass Index (BMI) | Body Mass Index defined as a person's weight in kilograms (kg) divided by his or her height in meters squared. | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's, Brain insulin resistance, Diabetes