Clinical trial NCT01255163: A Pilot Clinical Trial of Exendin-4 in Alzheimer's Disease
Official title: A Pilot Study of Exendin-4 in Alzheimer s Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Alzheimer's Disease
Mild Cognitive Impairment
Keywords: Alzheimer's
Brain insulin resistance
Diabetes
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2010-12-07
Enrollment: 57
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double-blind randomized placebo-controlled.
Primary purpose: TREATMENT

Brief 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.

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 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.

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.

Primary outcomes:
measure: Number of Participants With Incidence of Nausea
timeFrame: 18 months
Secondary outcomes:
measure: Mini Mental State Examination (MMSE)
timeFrame: 18 months
measure: Alzheimer's Disease Assessment Scale-cognitive Subscale (ADAS-cog70)
timeFrame: 18 months
measure: Clinical Dementia Rating (CDR) Global Score
timeFrame: 18 months
measure: Clinical Dementia Rating (CDR) Sum of Boxes
timeFrame: 18 months
measure: Cerebrospinal Fluid (CSF) Total Tau
timeFrame: 18 months
measure: Cerebrospinal Fluid phospho181-tau (CSF p181-tau)
timeFrame: 18 months
measure: Cerebrospinal Fluid Amyloid-beta 42 (CSF Abeta42)
timeFrame: 18 months
measure: Body Mass Index (BMI)
timeFrame: 18 months
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: National Institute on Aging, Clinical Research Unit
state: Maryland
Study officials:
affiliation: National Institute on Aging (NIA)
name: Dimitrios I Kapogiannis, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kapogiannis D, Mattson MP. Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease. Lancet Neurol. 2011 Feb;10(2):187-98. doi: 10.1016/S1474-4422(10)70277-5. Epub 2010 Dec 10.
citation: Bomfim TR, Forny-Germano L, Sathler LB, Brito-Moreira J, Houzel JC, Decker H, Silverman MA, Kazi H, Melo HM, McClean PL, Holscher C, Arnold SE, Talbot K, Klein WL, Munoz DP, Ferreira ST, De Felice FG. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Abeta oligomers. J Clin Invest. 2012 Apr;122(4):1339-53. doi: 10.1172/JCI57256.
citation: Mullins RJ, Mustapic M, Chia CW, Carlson O, Gulyani S, Tran J, Li Y, Mattson MP, Resnick S, Egan JM, Greig NH, Kapogiannis D. A Pilot Study of Exenatide Actions in Alzheimer's Disease. Curr Alzheimer Res. 2019;16(8):741-752. doi: 10.2174/1567205016666190913155950.
citation: Muscogiuri G, DeFronzo RA, Gastaldelli A, Holst JJ. Glucagon-like Peptide-1 and the Central/Peripheral Nervous System: Crosstalk in Diabetes. Trends Endocrinol Metab. 2017 Feb;28(2):88-103. doi: 10.1016/j.tem.2016.10.001. Epub 2016 Oct 27.