A Randomized, Double-blind, Placebo-controlled Study to Assess Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Pharmacodynamic Response of Repeated Intravenous Infusions of BAN2401 in Subjects With Mild Cognitive Impairment Due to Alzheimer's Disease and Mild Alzheimer's Disease

The purpose of this study is to assess the safety, tolerability, pharmacokinetics, immunogenicity, and pharmacodynamic response of repeated intravenous infusions of BAN2401 in subjects with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and mild Alzheimer's disease.

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Drug: BAN2401 2.5 mg/kg; Drug: BAN2401 5 mg/kg; Drug: BAN2401 10 mg/kg; Drug: Placebo

Detailed Description

This is a multicenter, randomized, placebo-controlled, double-blind, multiple ascending dose study in a total of 24 subjects (8 subjects per cohort) with MCI due to AD and mild AD. The study consists of three cohorts to evaluate the safety, tolerability and PK of BAN2401 at three dose levels (2.5, 5, and 10 mg/kg). Each cohort consists of Screening Period before randomization, Treatment Period from randomization to last dose, and Follow-up Period after last dose. Cohorts 1, 2, and 3 will receive 2.5 mg/kg, 5 mg/kg, and 10 mg/kg of BAN2401, respectively.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Hyogo
    • Kobe, Hyogo, Japan
  • Miyagi
    • Sendai, Miyagi, Japan
  • Okayama
    • Kurashiki, Okayama, Japan
  • Tokyo
    • Koto-ku, Tokyo, Japan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

MCI due to AD

1. Subjects who have clinical and cognitive symptoms consistent with the National Institute on Aging-Alzheimer's Association (NIA-AA) core criteria for MCI
2. Subjects who have a Clinical Dementia Rating (CDR) of 0.5 and a memory box score of 0.5 or greater at Screening
3. Subjects who report a history of subjective memory decline with slow progression at least 1 year before Screening, or subjects whose information provider or attending physician reports a history of memory decline with slow progression at least 1 year before Screening

4. Subjects with objective impairment in episodic memory as indicated by 1-1.5 standard deviations below age-adjusted mean in the Wechsler Memory Scale-Revised (WMS-R) logical memory II (delayed recall) at Screening:

   • less than or equal to 15 for age 50 to 64 years
   • less than or equal to 12 for age 65 to 69 years
   • less than or equal to 11 for age 70 to 74 years
   • less than or equal to 9 for age 75 to 79 years
   • less than or equal to 7 for age 80 to 90 years

   Mild AD

5. Subjects who meet the NIA-AA core clinical criteria for probable AD

6. Subjects who have a CDR of 0.5 or 1.0 and a memory box score of 0.5 or greater at Screening

   All subjects

7. Male or female subjects aged between 50 and 90 years, inclusive, at obtaining informed consent
8. Subjects who have an Mini Mental State Examination (MMSE) score greater than or equal to 22 and less than or equal to 30 at Screening
9. Body Mass Index (BMI) less than 35 kg/m2 at Screening
10. Females must not be pregnant or lactating, and specified contraceptive precautions must be followed
11. Subjects must have identified caregivers/informants
12. Must have an informant or a caregiver who will provide written informed consent voluntarily and is able to spend 3 days a week with the subject (4 hours per day), and is able to support the subject during the study period by providing necessary patient information, assisting treatment compliance, and accompanying the subject to all scheduled visits (if needed) throughout the study.
13. Provide voluntary written informed consent (obtaining as much as possible from subjects, but mandatory from their legal guardians).
14. Willing and able to comply with all aspects of the protocol.

Exclusion Criteria

1. Any neurological condition that may affect cognitive impairment
2. History of transient ischemic attacks (TIA), stroke, or seizures within 12 months of Screening
3. Any psychiatric diagnosis or symptoms (e.g., hallucinations, major depression, or delusions) that could interfere with study procedures in the subject
4. Any medical devices contraindicated for MRI scanning (e.g., cardiac pacemaker/defibrillator, ferromagnetic metal implants, any devices other than those approved as safe for use in MRI scanners)
5. Evidence of infection, tumor, stroke or other clinically significant lesions that could indicate a dementia diagnosis other than AD on brain MRI at Screening
6. Evidence of other clinically significant lesions that could indicate a dementia diagnosis other than AD on brain MRI at Screening, or other significant pathological findings on brain MRI at Screening
7. A prolonged QT interval (QTcF greater than or equal to 450 ms) as demonstrated by a repeated ECG at Screening
8. Any other clinically significant conditions (e.g., cardiac, respiratory, gastrointestinal, renal disease) that in the opinion of the investigator(s) could affect the subject's safety or interfere with the study assessments
9. Severe visual or hearing impairment that would prevent the subject from performing psychometric tests accurately.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BAN2401 2.5 mg/kg; Cohorts 1: Intravenous infusions of 2.5 mg/kg BAN2401	Drug: BAN2401 2.5 mg/kg; Cohorts 1: Intravenous infusions of 2.5 mg/kg BAN2401 for 60 +/- 10 minutes.
Experimental: BAN2401 5 mg/kg; Cohorts 2: Intravenous infusions of 5 mg/kg BAN2401	Drug: BAN2401 5 mg/kg; Cohorts 2: Intravenous infusions of 5 mg/kg BAN2401 for 60 +/- 10 minutes.
Experimental: BAN2401 10 mg/kg; Cohorts 3: Intravenous infusions of 10 mg/kg BAN2401	Drug: BAN2401 10 mg/kg; Cohorts 3: Intravenous infusions of 10 mg/kg BAN2401 for 60 +/- 10 minutes
Placebo Comparator: Placebo; Intravenous infusions of placebo for 60 +/- 10 minutes.	Drug: Placebo; Intravenous infusions of placebo for 60 +/- 10 minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Adverse Events as a Measure of Safety and Tolerability	Safety assessment variables will include all adverse events (AEs) including serious and non-serious AEs; laboratory parameters (hematology, blood chemistry, and urinalysis); vital signs; electrocardiograms; and physical examination; as well as a risk of suicide using C-SSRS and brain MRI.	Up to 14 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of BAN2401: Maximum Concentration (Cmax)	Cmax after single and repeated administrations based on non-compartmental analysis.	Up to 14 weeks
Pharmacokinetics of BAN2401: time attain to Cmax (tmax)	tmax after single and repeated administrations based on non-compartmental analysis.	Up to 14 weeks
Pharmacokinetics of BAN2401: Area under the curve (AUC)	AUC after single and repeated administrations based on non-compartmental analysis.	Up to 14 weeks
Pharmacokinetics of BAN2401: Drug Clearance (CL)	CL after single and repeated administrations based on non-compartmental analysis.	Up to 14 weeks
Pharmacokinetics of BAN2401: apparent volume of distribution at steady state (Vss)	Vss after single and repeated administrations based on non-compartmental analysis.	Up to 14 weeks
Investigation of the effect of repeated intravenous infusions of BAN2401 on the immunogenicity and CSF biomarkers	Summary statistics (mean, standard deviation, median, minimum and maximum) will be calculated for each measurement of CSF concentrations of AB1-40, AB1-42, AB1-x, total tau and p-tau and their percent changes from baseline.	Up to 14 weeks
Investigation of the effect of apolipoprotein allele4 (ApoE4) on the safety, tolerability and pharmacodynamic (PD) response of repeated intravenous infusions of BAN2401		Up to 14 weeks

Collaborators and Investigators

• Sponsor: Eisai Co., Ltd.

Study record dates

Study Major Dates

• Study Start: September 1, 2013
• Primary Completion (Actual): March 1, 2015
• Study Completion (Actual): May 1, 2015

Study Registration Dates

• First Submitted: January 9, 2014
• First Submitted That Met QC Criteria: March 19, 2014
• First Posted (Estimate): March 24, 2014

Study Record Updates

• Last Update Posted (Estimate): June 8, 2015
• Last Update Submitted That Met QC Criteria: June 4, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: Alzheimer's disease; mild cognitive impairment
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Cognition Disorders; Alzheimer Disease; Cognitive Dysfunction
• Other Study ID Numbers: BAN2401-J081-104