Clinical trial NCT02322021: Dose-Finding Study To Evaluate Safety, Tolerability, and Efficacy of E2609 in Participants With Mild Cognitive Impairment Due to Alzheimer's Disease (Prodromal Alzheimer's Disease) and Mild to Moderate Dementia Due to Alzheimer's Disease
Official title: A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, Proof-of-Concept, Dose-Finding Study To Evaluate Safety, Tolerability, and Efficacy of E2609 in Subjects With Mild Cognitive Impairment Due to Alzheimer's Disease (Prodromal Alzheimer's Disease) and Mild to Moderate Dementia Due to Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Alzheimer Disease
Dementia, Alzheimer Type
Keywords: E2609
Mild Cognitive Impairment
Mild to Moderate Dementia
Alzheimer's Disease
Prodromal Alzheimer's Disease
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
Collaborators: name: Biogen
First posted: 2014-12-22
Enrollment: 70
Sex: ALL
Minimum age (years): 50
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase 2 study to evaluate safety and efficacy in participants with Mild Cognitive Impairment due to Alzheimer's Disease/Prodromal Alzheimer's Disease (referred to as MCI/Prodromal) and mild to moderate dementia due to Alzheimer's Disease (referred to as mild to moderate AD). This study will have a Core Phase and an Extension Phase.


Eligibility criteria: Inclusion criteria:

Participants must meet all of the following criteria to be included in this study:

1. Meets the core clinical research criteria of the National Institute on Aging-Alzheimer's Association (NIA-AA) for MCI due to AD (which is consistent with Prodromal AD) or AD dementia and is 'staged' or classified as either MCI or mild to moderate dementia.
2. Amyloid positive Positron Emission Tomography (PET) image based on centralized PET scan reading.
3. Male or female, age 50 to 85 years, inclusive at time of consent.
4. Must have an identified caregiver or informant who is willing and able to provide follow-up information on the participant throughout the course of the study.
5. If receiving an Acetylcholinesterase Inhibitor (AChEI) or memantine, must have been on a stable dose for at least 12 weeks before the Baseline cognitive assessments, with no plans for dose adjustment in the foreseeable future. Treatment-naive participants can be entered into the study but there should be no plans to initiate treatment with AChEIs or memantine at the time of entry into the study.
6. Must have been on stable doses of all other permitted chronically used concomitant medications (that is, not related to their cognitive decline) for at least 4 weeks before randomization.

Exclusion criteria:

Participants who meet any of the following criteria will be excluded from this study:

1. Any neurological condition that may be contributing to cognitive impairment above and beyond that caused by the participant's AD pathology, including any co-morbidities such as cerebrovascular disease, detected by medical history, neurological examination, or magnetic resonance imaging (MRI).
2. History of transient ischemic attacks or stroke within 12 months of Screening.
3. History of epilepsy.
4. Evidence of depression on a rating scale at Screening or any psychiatric diagnosis or symptoms, (example, hallucinations, major depression, etc.) that could confound the diagnosis or could interfere with study assessments or procedures. This includes suicidal ideation or suicidal behavior within 6 months prior to Screening, or hospitalization or treatment for suicidal behavior in the past 5 years.
5. Abnormally low serum vitamin B12.
6. Thyroid stimulating hormone above the normal range. This applies to all participants regardless of whether or not they are taking thyroid supplements.
7. Participants with liver disease (hepatic impairment), at Screening or Baseline. Participant with Gilbert's syndrome need not be excluded.
8. Not able to have a MRI, PET scanning, or cerebrospinal fluid (CSF) collection by Lumbar Puncture (LP).
9. Severe visual or hearing impairment that would prevent the participant from performing psychometric tests accurately.
10. History of immunodeficiency disorders.
11. Participants with chronic viral hepatitis.
12. History of Tuberculosis (TB). Participants with no history of TB will be tested for previous TB exposure and a positive test will be exclusionary.
13. History of ophthalmic shingles or ocular Herpes Simplex Virus (HSV) infection.
14. Any live vaccine in the 3 months or any active infection within the last 4 weeks before study drug administration (that is, randomization).
15. Any chronic inflammatory disease that is not adequately controlled or requires immunosuppressive or immunomodulatory therapy.
16. T helper cell, cytotoxic T cell, or B cell absolute counts below normal.
17. Immunoglobulin (Ig) IgG, IgA, or IgM levels below normal at Screening or Baseline, unless both the Investigator and the Medical Monitor agree that the finding is not clinically significant.
18. Clinically significant deviation from normal in physical examination, vital signs, or clinical laboratory tests at Screening or Baseline.
19. Exclusionary cardiac factors include: prolonged QT interval greater than 450 millisecond from Electrocardiograms (ECGs); history of risk factors for torsade de pointes or the use of concomitant medications that prolong the QT/corrected QT interval (QTc); left bundle branch block; persistent low or high heart rate; persistent low or high blood pressure; history of cardiac arrhythmias; other clinically significant ECG abnormalities.
20. Type 1 or Type 2 diabetes mellitus that is not well controlled.
21. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell carcinoma in situ of the skin, or localized prostate cancer that did not require systemic therapy; these do not exclude the participant).
22. Medical conditions (example, cardiac, respiratory, gastrointestinal, renal disease) that are not stably controlled, or which, in the opinion of the investigator(s), could affect the participant's safety or interfere with the study assessments.
23. Hypopigmentation conditions (example, albinism and vitiligo).
24. Known or suspected history of drug or alcohol dependency or abuse within 2 years, current use of recreational drugs or a positive urine drug test.
25. Planned surgery that requires general, spinal, or epidural anesthesia that would take place during the study.
26. Participation in any other interventional clinical study related to cognitive impairment within 6 months before Screening unless it can be documented that the participant was in a placebo treatment arm.
27. Currently enrolled in another clinical study or used any investigational drug or device within 60 days or 5 half-lives of the investigational medication (whichever is longer) proceeding informed consent.
28. Hypersensitivity to the study drug or any of the excipients or to other Beta Secretase Cleaving Enzyme (BACE) inhibitors, or to the PET tracer, or components of its formulation.
29. Females who are lactating or pregnant. Females of childbearing potential who do not agree to adhere to the protocol specified methods for avoiding pregnancy.
30. Males who do not meet the protocol requirements for avoiding their partners becoming pregnant. Sperm donation is not permitted.

Primary outcomes:
measure: Core Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: Up to 21 months
measure: Core Phase: Number of Participants With Serious Adverse Events (SAEs)
timeFrame: Up to 21 months
measure: Core Phase: Number of Participants With Treatment Emergent Markedly Abnormal Laboratory Safety Test Values
timeFrame: Up to 21 months
measure: Core Phase: Number of Participants With Markedly Abnormal Vital Sign Values
timeFrame: Month 0(Baseline,Week 2,Week 3,Week 4);Month 1(Week 5,Week 7);Month 2(Week 9,Week 11);Month 3(Week 13);Month 4(Week 17);Month 5(Week 21);Month 6(Week 27);Month 9(Week 40);Month 12(Week 53);Month 15(Week 66);Month 18(Week 79) and Follow-up at Month 1 and 3
measure: Core Phase: Number of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings
timeFrame: Up to 21 months
measure: Extension Phase: Number of Participants With TEAEs and SAEs
timeFrame: Up to 34 months
measure: Extension Phase: Number of Participants With Markedly Abnormal Vital Sign Values
timeFrame: Up to 34 months
measure: Extension Phase: Number of Participants With Markedly Abnormal ECG Findings
timeFrame: Up to 34 months
measure: Extension Phase: Number of Participants With Treatment Emergent Markedly Abnormal Laboratory Safety Test Values
timeFrame: Up to 34 months
measure: Extension Phase: Number of Participants With Abnormal Magnetic Resonance Imaging (MRI) Findings
timeFrame: Up to 34 months
Secondary outcomes:
measure: Core Phase: Percent Change From Baseline in Cerebrospinal Fluid (CSF) Amyloid (A) Beta(1-x) and Abeta(1-42) After 1 Month and 18 Months of Treatment
timeFrame: Month 1 (Week 5) and Month 18 (Week 79)
measure: Core Phase: Mean Concentration of Elenbecestat in CSF
timeFrame: Month 1 (Week 5) and Month 18 (Week 79)
measure: Core Phase: Mean Concentration of Elenbecestat in Plasma
timeFrame: Month 0 (Week 3), Month 3 (Week 13), Month 6 (Week 27), Month 12 (Week 53): Pre-dose, 1 to 6 hours Post-dose; Month 1 (Week 5), Month 18 (Week 79): Pre-dose, 4 to 8 hours Post-dose
measure: Extension Phase: Change From Extension Phase Baseline in the Mini-Mental State Examination (MMSE) Scores
timeFrame: Baseline, at Month 3, at Month 6, at Month 9, at Month 12, at Month 15, at Month 18, at Month 21, at Month 24, at Month 28 and at Month 32
measure: Extension Phase: Change From Extension Phase Baseline in the Functional Assessment Questionnaire (FAQ) Score
timeFrame: Baseline, at Month 3, at Month 6, at Month 9, at Month 12, at Month 15, at Month 18, at Month 21, at Month 24, at Month 28 and at Month 32
measure: Extension Phase: Percent Change From Extension Phase Baseline in Plasma Amyloid (A) Beta(1-x) Measurements at Months 12 and 24
timeFrame: Month 12 and Month 24
measure: Extension Phase: Percent Change From Extension Phase Baseline in Total Hippocampal Volume at Month 24
timeFrame: Month 24
measure: Extension Phase: Percent Change From Extension Phase Baseline in Left and Right Hippocampal Volume at Month 24
timeFrame: Month 24
measure: Extension Phase: Percent Change From Extension Phase Baseline in Whole Brain Volume at Month 24
timeFrame: Month 24
measure: Extension Phase: Percent Change From Extension Phase Baseline in Total Ventricular Volume at Month 24
timeFrame: Month 24
Other outcomes:
Locations:
city: Bellflower
country: United States
state: California
city: Costa Mesa
country: United States
state: California
city: Glendale
country: United States
state: California
city: Irvine
country: United States
state: California
city: Aventura
country: United States
state: Florida
city: Boca Raton
country: United States
state: Florida
city: Brooksville
country: United States
state: Florida
city: Lake Worth
country: United States
state: Florida
city: Orlando
country: United States
state: Florida
city: Port Charlotte
country: United States
state: Florida
city: Atlanta
country: United States
state: Georgia
city: Savannah
country: United States
state: Georgia
city: Wichita
country: United States
state: Kansas
city: Kalamazoo
country: United States
state: Michigan
city: Mount Arlington
country: United States
state: New Jersey
city: Scotch Plains
country: United States
state: New Jersey
city: Charlotte
country: United States
state: North Carolina
city: Dayton
country: United States
state: Ohio
city: Port Royal
country: United States
state: South Carolina
city: Dallas
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
Study officials:
References: