| Conditions: |
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Alzheimer's Disease |
| Purpose: |
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Background:
- Exendin-4 (or Exenatide) is a medication currently used to treat diabetes, but it has
shown promising results in tests of its effectiveness in protecting neurons from damaging
processes associated with Alzheimer's disease. It is possible that Exendin-4 may be a
suitable treatment for Alzheimer's disease, which involves the gradual deterioration and
death of neurons. Researchers are interested in comparing the effects of Exendin-4 with
placebo to determine long-term treatment outcomes for individuals with early-stage
Alzheimer's disease or mild cognitive impairment.
Objectives:
- To determine the safety and effectiveness of twice daily administration of Exendin-4 as a
treatment for early-stage Alzheimer's disease or mild cognitive impairment.
Eligibility:
- Individuals at least 65 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 with an initial telephone call to evaluate their level of
cognitive impairment.
- Following the telephone screening, two in-person screening visits will be required to
determine eligibility.
- The first screening visit will involve a medical history and neurological examination,
tests of memory and cognition, blood tests, and brain imaging studies. Participants
will be required to appoint a Durable Power of Attorney for research and medical care
during this protocol.
- The second screening visit will involve blood sugar testing, a lumbar puncture, and
collection of blood and saliva samples.
- Eligible participants will be divided into two groups. One group will receive
Exendin-4, and the other will receive a placebo. Participants will keep a medication
diary and will be scheduled for additional study visits 1, 2, 4 weeks and 3 months
after the start of the treatment.
- Participants will have regular followup visits with blood tests, imaging studies, and
other examinations 6, 9, 18, 24, and 36 months after the start of the treatment.
Another lumbar puncture will be performed at the 18-month followup visit.
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| Study Summary: |
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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 propose a double blind randomized placebo-controlled clinical trial
to assess the safety and efficacy of Exendin-4 treatment in participants with early
Alzheimer's disease (AD). Our main hypothesis is that long-term administration of Exendin-4
in participants with early AD or mild cognitive impairment (MCI) is safe and will slow the
progression of AD. 115 participants will be enrolled into treatment on the basis of symptoms
and signs characteristic of early AD and Cerebrospinal Fluid (CSF) biomarker results, out of
approximately 230 potential participants who will go through screening. Then, enrolled
participants will be randomly assigned into one of two groups (Exendin-4 vs. Placebo) and
will be followed at regular intervals for three years. The efficacy of Exendin-4 will be
primarily assessed in terms of cognitive measures of disease progression and secondarily in
terms of behavioral measures, changes on brain MRI and biomarkers. All research will be
performed on the National Institute on Aging (NIA) Clinical Research Unit located on the 5th
floor of Harbor Hospital.
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| Criteria: |
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- INCLUSION CRITERIA: (n = 115 participants enrolled into treatment out of
approximately 230 participants screened)
- 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
- Isolated or predominant episodic memory deficit, manifested as memory performance in
the Logical Memory subscale (Delayed Paragraph Recall) from the Wechsler Memory
Scale-III 1.5-2 SD below age adjusted norms
- Relatively intact performance (within 1.5 SD of age and education adjusted norms) for
other cognitive domains
- Hamilton Depression Scale score of less than or equal to 12 on the 17-item scale
- CSF Abeta < 190 (+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 lacking significant
anticholinergic side effects [if they are not currently depressed and do not
have lifelong history of depression or history of major depression within the
past 2 years or history of any episode of treatment-resistant depression
(requiring > 1 antidepressants, Electrocunvulsive therapy etc)]
- Estrogen replacement therapy is permissible
- Gingko biloba is permissible, but discouraged
- Washout from psychoactive medication (e.g., excluded anti-depressants, chronic
anxiolytics or sedative hypnotics, etc.) for at least 4 weeks prior to screening
- Cholinesterase inhibitors are allowable if started three months prior to
enrollment
- Adequate visual and auditory acuity to allow for neuropsychological testing
- An informant or caregiver who has frequent contact with the participant (e.g. an
average of 10 hours per week or more), must be available to provide history and
accompany the participant to all clinic visits and ability to sign informed consent
- Good general health with no additional disease states that could interfere with the
study
- Willing and able to complete all baseline assessments (including ApoE genotyping).
- Willing to have an initial Lumbar Puncture and provide CSF at protocol specified time
points
- Willing and able to participate in a 3-year protocol
- Completed 8 grades of education (or possess a work history sufficient to exclude
mental retardation at the discretion of the study investigators)
- Minimum literacy level to allow for neuropsychological testing, according to the
American National Adult Reading Test (ANART)
EXCLUSION CRITERIA:
- Other significant neurological disease of the Central Nervous System (such as
Parkinson's 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
- Significant neuroimaging abnormalities, previously known or discovered on the initial
MRI scan, including evidence of infection, infarction (> 3 mm in size) brain tumors
(other than small meningiomas), or other focal lesions, multiple lacunes or lacunes
in a critical memory structure or severe confluent microvascular disease (but not
mild white matter changes, which are frequent with aging).
- Abnormal blood levels of vitamin B12, TSH, or a positive RPR or HIV
- Coagulopathy or anti-coagulant therapy (such as coumadin) increasing the risk for LP
resulting in PT/PTT and INR within 1.5 standard deviation over the upper normal
limit.
- Investigators unable to obtain CSF at the clinical judgment of the investigator
performing the procedure (failure of Lumbar Puncture after a limited number of
unsuccessful attempts)
- History of significant psychiatric disease or chronic anxiolytic or neuroleptic
therapy (for dementia-related or other psychiatric disorder) at the time of
enrollment. Participants who develop psychiatric conditions necessitating treatment
after their enrollment will not be dropped from the study.
- Lifelong history of depression or bipolar disorder or history of major depression
within the past 2 years or history of any episode of treatment-resistant depression
(requiring > 1 antidepressants, ECT etc). The high incidence of late-onset
depression among individuals with MCI and AD requires that certain participants with
depression should be included in the cohort to maintain the ecological validity of
the results.
- Significant history of alcoholism or substance abuse (at the judgment of the
investigator).
- Known diagnosis of diabetes at the time of enrollment or new diagnosis diabetes based
on the findings of elevated fasting blood glucose (greater than or equal to 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 followed
closely. All participants, in whom BUN or creatinine increased after switching from 5
microg SC bid to 10 microg SC bid (but not with 5 microg SC bid), will be switched
back to 5 microg SC bid. If the BUN/Creatinine elevation persists one week later with
the lower dose, the participant will be withdrawn from the study.
- Current or previous treatment with Exendin-4
- AD or MCI participants who started cholinesterase inhibitor treatment less than three
months ago. These participants may be enrolled after three months of initiation of
treatment. Participants with AD may not be treated with memantine at the time of
enrollment (since this treatment is approved for moderate AD), but may subsequently
be placed on it, at the discretion of their treating physicians.
- History of pancreatitis, active upper GI, hepatic or gallbladder disease
- Amylase/lipase elevation at baseline
- History of repeated hypoglycemia
- Absence of a caregiver able to provide informed consent or able to provide history,
accompany participants during their study visits and (eventually) assist patients in
the administration of SC injections
- Body mass index (BMI) < 20 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.
- Allergy to Exendin-4 or to substances in the injection pen
- Participation in other studies of investigational treatments for Alzheimer's disease
- Refusal to consent to the initial Lumbar Puncture and ApoE genotyping
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| NCT ID: |
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NCT01255163 |
| Primary Contact: |
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Principal Investigator
Dimitrios I Kapogiannis, M.D.
National Institute on Aging (NIA)
Dimitrios I Kapogiannis, M.D.
Phone: (301) 451-9286
Email: kapogiannisd@mail.nih.gov
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| Backup Contact: |
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N/A |
| Location Contact: |
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Baltimore, Maryland 21224
United States
There is no listed contact information for this specific location.
Site Status: Recruiting |