A Clinical Trial of Exendin-4 for the Treatment of Alzheimer's Disease

This study is currently recruiting participants.
Verified August 2013 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute on Aging (NIA) )
ClinicalTrials.gov Identifier:
NCT01255163
First received: December 4, 2010
Last updated: April 4, 2014
Last verified: August 2013
  Purpose

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.

Condition Intervention Phase
Alzheimer's Disease
Drug: Exendin-4 (Exenatide)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double-Blind
Primary Purpose: Treatment
Official Title: A Pilot Study of Exendin-4 in Alzheimer s Disease

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Clinical Dementia Rating (CDR) scale sum-of-boxes [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Alzheimer's Disease Assessment scale - cognitive sub-scale (ADAS-cog) [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Common Toxicity criteria [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Behavioral and cognitive performance measures [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Changes on structural and functional MRI and MRS [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Hormonal and metabolic changes and changes in cerebrospinal fluid and plasma Alzheimer s disease biomarkers. [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 230
Study Start Date: November 2010
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Exendin-4 (Exenatide)
    N/A
Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   60 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • 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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01255163

Contacts
Contact: Dimitrios I Kapogiannis, M.D. (301) 451-9286 kapogiannisd@mail.nih.gov

Locations
United States, Maryland
National Institute on Aging, Clinical Research Unit Recruiting
Baltimore, Maryland, United States, 21224
Sponsors and Collaborators
Investigators
Principal Investigator: Dimitrios I Kapogiannis, M.D. National Institute on Aging (NIA)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute on Aging (NIA) )
ClinicalTrials.gov Identifier: NCT01255163     History of Changes
Other Study ID Numbers: 100423, 10-AG-0423
Study First Received: December 4, 2010
Last Updated: April 4, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Alzheimer's
Neurotrophic
Memory
Diabetes
Placebo
Alzheimer Disease
AD

Additional relevant MeSH terms:
Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
Exenatide
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 14, 2014