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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 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: September 13, 2014
Last verified: August 2014
  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 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 to on congestive performance, overall clinical progression, 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, as well as to acquire preliminary evidence for the 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 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. 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 and 2 weeks after the start of the treatment.
  • Participants will have regular followup visits with blood tests, imaging studies, and other examinations 6, 12, and18 months after the start of the treatment. Another lumbar puncture may be performed optionally at the 18-month followup visit.

Condition Intervention Phase
Alzheimer's Disease
Mild Cognitive Impairment
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:
  • Safety and tolerability of Exendin-4 administered twice daily via SC injections [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Behavioral and cognitive performance measures [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  • Changes on structural and functional MRI and MRS [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  • Hormonal and metabolic changes and changes in cerebrospinal fluid and plasma Alzheimer s disease biomarkers. [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  • Clinical Dementia Rating (CDR) scale sum-of-boxes [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  • Alzheimer's Disease Assessment scale - cognitive sub-scale (ADAS-cog) [ Time Frame: 18 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 100
Study Start Date: November 2010
Estimated Study Completion Date: July 2016
Estimated Primary Completion Date: July 2016 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Exendin-4 (Exenatide)
    N/A
Detailed Description:

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 propose a pilot Phase II double blind randomized placebo-controlled clinical study to assess the safety and provide proof of concept for efficacy of 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 biochemical biomarkers (such as CSF BDNF, 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), overall clinical progression measures (such as the Clinical Dementia Rating scale sum-of-boxes), volumetric changes on structural brain MRI and changes in default mode network activation on 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.

  Eligibility

Ages Eligible for Study:   60 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  • Hamilton Depression Scale score of less than or equal to 12 on the 17-item scale
  • CSF Abeta42 < 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 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 18-month protocol

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).
  • 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, at the discretion of the Principal Investigator. Participants who develop psychiatric conditions necessitating treatment after their enrollment will not be dropped from the study. The high incidence of late-onset depression among individuals with MCI and AD requires that certain participants with depression, at the discretion of the Principal Investigator, 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.
  • Personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2.
  • 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
  • History of repeated hypoglycemia
  • 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 (metacresol, mannitol, glacial acetic acid, sodium acetate trihydrate, water for injection)
  • 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01255163

Contacts
Contact: Dimitrios I Kapogiannis, M.D. (410) 350-3953 kapogiannisd@mail.nih.gov

Locations
United States, Maryland
National Institute on Aging, Clinical Research Unit Recruiting
Baltimore, Maryland, United States, 21224
Contact: NIA Studies Recruitment    410-350-3941    niastudiesrecruitment@mail.nih.gov   
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: September 13, 2014
Health Authority: United States: Federal Government

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

Additional relevant MeSH terms:
Alzheimer Disease
Cognition Disorders
Mild Cognitive Impairment
Brain Diseases
Central Nervous System Diseases
Delirium, Dementia, Amnestic, Cognitive Disorders
Dementia
Mental Disorders
Nervous System Diseases
Neurodegenerative Diseases
Tauopathies
Exenatide
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Hypoglycemic Agents
Incretins
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on November 25, 2014