A Pilot Clinical Trial of Exendin-4 in Alzheimer's Disease
Condition: Alzheimer's Disease; Mild Cognitive Impairment
MeSH terms: Alzheimer Disease; Cognitive Dysfunction
Intervention: Exendin-4 SC; Placebo SC
Intervention description: Exenatide 5 mcg or 10 mcg SC twice daily; Placebo SC twice daily
Intervention MeSH terms: Exenatide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Double-blind randomized placebo-controlled.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Double-blind study with code kept by NIA Pharmacist who did not share with Investigators and had no interaction with participants and caregivers.
Enrollment: 57.0
Sex: All
Minimum age: 60 Years
Healthy volunteers: No
Keywords: Alzheimer's; Brain insulin resistance; Diabetes

Summary:

      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.
    

Eligibility criteria:

        -  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.