A Study to Assess Safety, Tolerability, Pharmacodynamics, Immunogenicity, Exploratory Clinical Efficacy, and Pharmacokinetics of Intravenous Infusions of E2814 in Healthy Participants and Participants With Prodromal Alzheimer's Disease (AD) to Moderate AD With and Without Detectable Tau Pathology

Healthy Volunteers Clinical Trial

Official title:

A Randomized, Double-Blind, Placebo-Controlled, Combined Single Ascending Dose, Multiple Ascending Dose and Proof-of-Principle Study to Assess Safety, Tolerability, Pharmacodynamics, Immunogenicity, Exploratory Clinical Efficacy, and Pharmacokinetics of Intravenous Infusions of E2814 in Healthy Subjects and Subjects With Prodromal Alzheimer's Disease to Moderate Alzheimer's Dementia With and Without Detectable Tau Pathology

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03852277
• Other study ID #: E2814-G000-101
• Secondary ID: 2018-004240-32
• Status: Not yet recruiting
• Phase: Phase 1/Phase 2
• Start date: February 26, 2019
• Est. completion date: February 23, 2023

Study information

• Verified date: February 2019
• Source: Eisai Inc.
• Contact: Eisai Medical Information
• Phone: +1-888-274-2378
• Email: esi_medinfo[@]eisai.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary purpose of the study is to evaluate the safety and tolerability of single and multiple ascending doses in healthy participants and participants with prodromal to moderate AD, respectively, and to demonstrate slowing in progression of tau pathology in the brain as determined by tau-positron emission tomography (PET) in participants with prodromal to moderate AD.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 275
• Est. completion date: February 23, 2023
• Est. primary completion date: February 23, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Healthy Volunteers

1. Nonsmoking, healthy male or female (Caucasian and Japanese), age greater than or equal to (>=) 18 years (>=20 years for Japanese participants) and less than or equal to (<=) 50 years at the time of informed consent.

Participants with Prodromal to Moderate AD

1. Meets the National Institute of Aging-Alzheimer's Association (NIA-AA) core clinical criteria for mild cognitive impairment due to AD (that is, prodromal AD), or have a clinical diagnosis of probable mild to moderate AD dementia by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria

2. For MAD: Must show evidence of amyloid by CSF determination of amyloid pathology and preferably tau tangle pathology which may be assessed by both CSF and tau-PET imaging, respectively

For Phase 2a: Must show evidence of both amyloid and tau tangle pathology by CSF determination of amyloid pathology and tau-PET imaging (tau pathology detectable above cut-point on composite standard uptake value ratios evaluation (SUVr) uptake in select brain normalized to the cerebellar crus gray), respectively

3. Participants recruited to the first 2 MAD cohorts must have a Mini Mental State Examination (MMSE) score >20; other subsequent cohorts must have MMSE score >16

4. Where symptomatic treatment of AD is clinically indicated, participants must be on stable treatment (example, with an acetylcholinesterase inhibitor (AChEI), memantine, or both) for at least 12 weeks before the Baseline Visit

Exclusion Criteria:

Healthy Volunteers

1. Clinically significant illness that requires medical treatment within 8 weeks or a clinically significant infection that requires medical treatment within 4 weeks of dosing

2. Evidence of disease that may influence the outcome of the study within 4 weeks before dosing; example, psychiatric disorders and disorders of the gastrointestinal tract, liver, kidney, respiratory system, endocrine system, hematological system, neurological system, or cardiovascular system, or participants who have a congenital abnormality in metabolism

Participants with Prodromal to Moderate AD

1. Any neurological condition that could be contributing to cognitive impairment above and beyond that caused by the participant's AD

2. Any psychiatric diagnosis or symptoms, example, hallucinations, major depression, or delusions that could interfere with assessment of cognition in the participant

3. A clinical contraindication to a lumbar puncture (LP), such as space-occupying brain lesion if examination suggests any suspicion of such a lesion

4. Treatment with low molecular weight heparin, warfarin, or thrombolytics (treatment with aspirin or nonsteroidal antiinflammatory agents is permitted)

5. History of transient ischemic attack (TIA), stroke, or seizures within 12 months of Screening

6. Evidence of infection, tumor, stroke, or other clinically significant lesions that could indicate a dementia diagnosis other than AD on brain magnetic resonance imaging (MRI) at Screening.

7. Participation in a clinical study involving any new chemical entities for AD in the 6 months before Screening

8. Participation in any other investigational medication or device study in the 8 weeks or 5 half-lives (whichever is longer) of the medication before randomization

9. Contraindications to MRI scanning, including cardiac pacemaker/defibrillator, ferromagnetic metal implants, example, in-skull and cardiac devices other than those approved as safe for use in MR scanners

10. Have a "yes" answer to Columbia Suicide Severity Rating Scale (C-SSRS) suicidal ideation questions nos. 4 or 5, or on the suicide behavior assessment within 6 months before Screening, at Screening, or at the Baseline Visit; has been hospitalized or treated for suicidal behavior in the past 5 years before Screening

11. Use of any medications that, in the opinion of the investigator, may contribute to cognitive impairment, put participants at higher risk for adverse events (AEs), or impair the participant's ability to perform cognitive testing or complete study procedures

Related Conditions & MeSH terms

• Alzheimer Disease
• Dementia
• Healthy Volunteers

Intervention

Drug:
• E2814
E2814 intravenous infusion.
• E2814-matched placebo
E2814-matched placebo intravenous infusion.

Locations

Country	Name	City	State
United States	Parexel International	Glendale	California

Sponsors (1)

Lead Sponsor	Collaborator
Eisai Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	SAD and MAD: Number of Participants With One or More Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE)		Baseline up to Day 140
Primary	Change From Baseline in tau-PET Standard Uptake Value Ratios Evaluation (SUVr) at Month 12		Baseline, Month 12
Secondary	Cmax: Maximum Observed Serum Concentration for E2814		Day 1: 0.5-24 hours; Day 56: 0.5-24 hours
Secondary	Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for E2814		Day 1: 0.5-24 hours; Day 56: 0.5-24 hours
Secondary	AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for E2814		Day 1: 0.5-24 hours; Day 56: 0.5-24 hours
Secondary	t½: Terminal Elimination Phase Half-life for E2814		Day 1: 0.5-24 hours; Day 56: 0.5-24 hours
Secondary	Serum anti-E2814 Antibody Concentration		Baseline, Day 336
Secondary	MAD: Change From Baseline in Free and Bound Microtubule Binding Region (MTBR)-tau and Total MTBR-tau at Month 2		Baseline, Month 2
Secondary	Phase 2a: Target Engagement (TE): Change From Baseline in Free and Bound MTBR-tau and Total MTBR-tau at Month 12		Baseline, Month 12
Secondary	Phase 2a: Presence or Absence of Relationship Between the Pharmacokinetics-Pharmacodynamic (PK-PD) of E2814 and Cerebrospinal Fluid (CSF) Biomarker	The PK-PD relationship between E2814 and CSF biomarkers will be assessed by plotting the E2814 exposure against the percent change from baseline. Further analysis will be performed if data permits.	Baseline, Day 336
Secondary	Phase2a: Number of Participants With One or More TEAE and SAE		Baseline up to Day 392