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

NCT01255163 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: 10042310-AG-0423
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 1

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.

Conditions

Alzheimer's Disease; Mild Cognitive Impairment

Keywords

Alzheimer's; Brain insulin resistance; Diabetes

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Incidence of Nausea

  Tolerability of exenatide (nausea is the most common expected adverse event of exenatide)

  18 months

Secondary Outcomes (8)

• Mini Mental State Examination (MMSE)

  18 months

• Alzheimer's Disease Assessment Scale-cognitive Subscale (ADAS-cog70)

  18 months

• Clinical Dementia Rating (CDR) Global Score

  18 months

• Clinical Dementia Rating (CDR) Sum of Boxes

  18 months

• Cerebrospinal Fluid (CSF) Total Tau

  18 months

Study Arms (2)

Exendin-4

EXPERIMENTAL

Exenatide 5 mcg or 10 mcg SC twice daily

Drug: Exendin-4 SC

Placebo

PLACEBO COMPARATOR

Placebo SC twice daily

Drug: Placebo SC

Interventions

Exendin-4 SC DRUG

Exenatide 5 mcg or 10 mcg SC twice daily

Also known as: Exenatide SC

Exendin-4

Placebo SC DRUG

Placebo SC twice daily

Also known as: Placebo SC twice daily

Placebo

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• National Institute on Aging (NIA): lead

Study Sites (1)

National Institute on Aging, Clinical Research Unit

Baltimore, Maryland, 21224, United States

Location

Related Publications (5)

• 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.

  PMID: 21147038 BACKGROUND

• 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.

  PMID: 22476196 BACKGROUND

• Liu QR, Zhu M, Chen Q, Mustapic M, Kapogiannis D, Egan JM. Novel Hominid-Specific IAPP Isoforms: Potential Biomarkers of Early Alzheimer's Disease and Inhibitors of Amyloid Formation. Biomolecules. 2023 Jan 13;13(1):167. doi: 10.3390/biom13010167.

  PMID: 36671553 DERIVED

• 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.

  PMID: 31518224 DERIVED

• 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.

  PMID: 27871675 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Alzheimer Disease; Cognitive Dysfunction; Diabetes Mellitus

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Limitations and Caveats

The study was terminated after AstraZeneca withdrew support. Early termination lead to small number of subjects analyzed.

Results Point of Contact

• Title: Dimitrios Kapogiannis, Clinical Investigator
• Organization: National Institute on Aging (NIA/NIH)

kapogiannisd@mail.nih.gov

410-350-3953

Study Officials

• Dimitrios I Kapogiannis, M.D.

  National Institute on Aging (NIA)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blind study with code kept by NIA Pharmacist who did not share with Investigators and had no interaction with participants and caregivers.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Model Details: Double-blind randomized placebo-controlled.

Study Record Dates

• First Submitted: December 4, 2010
• First Posted: December 7, 2010
• Study Start: November 21, 2010
• Primary Completion: November 18, 2016
• Study Completion: November 18, 2016
• Last Updated: February 22, 2018
• Results First Posted: February 22, 2018

Record last verified: 2018-01

Locations

US (1)