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A Study to Evaluate Safety, Tolerability, and Efficacy of BAN2401 in Subjects With Early Alzheimer's Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01767311
Recruitment Status : Active, not recruiting
First Posted : January 14, 2013
Last Update Posted : December 3, 2019
Sponsor:
Information provided by (Responsible Party):
Eisai Inc.

Tracking Information
First Submitted Date  ICMJE January 8, 2013
First Posted Date  ICMJE January 14, 2013
Last Update Posted Date December 3, 2019
Actual Study Start Date  ICMJE December 20, 2012
Estimated Primary Completion Date January 27, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 13, 2018)
  • Core Study: Change from Baseline in the Alzheimer's Disease Composite Score (ADCOMS) at 12 months [ Time Frame: Baseline and 12 months ]
  • Core Study and Extension Phase: Safety will be assessed by monitoring and recording all adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: From the time the participant signs the informed consent form until 3 months after the last dose of study drug or through the last visit, whichever is longer; up to 78 months ]
    Safety assessments will consist of monitoring and recording all AEs and SAEs; regular monitoring of hematology, blood chemistry, and urine values; periodic measurement of vital signs and electrocardiograms (ECGs); safety magnetic resonance imaging (MRI); and performance of physical examinations.
Original Primary Outcome Measures  ICMJE
 (submitted: January 10, 2013)
Change from baseline in the derived Composite Clinical Score at 12 months [ Time Frame: 12 months ]
Change History Complete list of historical versions of study NCT01767311 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 27, 2019)
  • Core Study: Change from Baseline at 18 Months in Brain Amyloid Pathophysiology as Measured by Amyloid Positron Emission Tomography (PET) [ Time Frame: Baseline and 18 Months ]
  • Core Study: Change from Baseline in the ADCOMS at 18 Months [ Time Frame: Baseline and 18 Months ]
  • Core Study: Change from Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) at 18 Months [ Time Frame: Baseline and 18 Months ]
  • Core Study: Change from Baseline in Alzheimer Disease Assessment Scale - Cognitive Subscale (ADAS-cog) at 18 Months [ Time Frame: Baseline and 18 Months ]
  • Core Study: Change from Baseline in Cerebrospinal fluid (CSF) Biomarkers (Aβ[1-42], t-tau, and p-tau) at 18 Months [ Time Frame: Baseline and 18 Months ]
  • Core Study: Change from Baseline in Total Hippocampal Volume at 18 Months as Measured by Volumetric Magnetic Resonance Imaging (vMRI) [ Time Frame: Baseline and 18 months ]
  • Core Study: Change from Baseline at 12 Months in Brain Amyloid Pathophysiology as Measured by Amyloid PET [ Time Frame: Baseline and 12 Months ]
  • Core Study: Change from baseline at 12 months on clinical status for the following assessments: ADCOMS, CDR-SB, and ADAS-cog [ Time Frame: Baseline and 12 Months ]
  • Core Study: Change from Baseline in CSF Biomarkers (Aβ[1-42], t-tau, and p-tau) at 12 Months [ Time Frame: Baseline and 12 Months ]
  • Core Study: Change from Baseline in Total Hippocampal Volume at 6 and 12 Months as Measured by vMRI [ Time Frame: Baseline, 6 and 12 Months ]
  • Core Study: Change from Baseline in Left and Right Hippocampal Volume at 6, 12, and 18 Months as Measured by vMRI [ Time Frame: Baseline and 6, 12 and 18 Months ]
  • Core Study: Change from Baseline in Whole Brain Volume at 6, 12, and 18 Months as Measured by vMRI [ Time Frame: Baseline and 6, 12 and 18 Months ]
  • Core Study: Change from Baseline in Total Ventricular Volume at 6, 12, and 18 Months as Measured by vMRI [ Time Frame: Baseline and 6, 12 and 18 Months ]
  • Extension Phase: Change from Baseline in Brain Amyloid Levels as Measured by Amyloid PET at at 3 months (Cohort 1) or 6 months (Cohort 2), and 12 and 24 months [ Time Frame: Extension Phase: Baseline, 3 months (Visit 50 [Extension Week 13], Cohort 1) or 6 months (Visit 57 [Extension Week 27], Cohort 2), and 12 and 24 months (Visit 70 [Extension Week 53], Visit 96 [Extension Week 105]) ]
  • Extension Phase: Change from end of Core Study in Brain Amyloid Levels as Measured by Amyloid PET at the Baseline of Extension Phase [ Time Frame: End of Core Study (Month 18) up to Baseline of Extension Phase ]
  • Extension Phase: Percentage of Amyloid Positive Participants Over Time [ Time Frame: Extension Phase: Baseline up to 24 months ]
Original Secondary Outcome Measures  ICMJE
 (submitted: January 10, 2013)
  • Change from baseline in the derived Composite Clinical Score at 18 months [ Time Frame: 18 months ]
  • Change from baseline in total hippocampal volume at 6 months using vMRI [ Time Frame: 6 months ]
  • Change from baseline in total hippocampal volume at 12 months using vMRI [ Time Frame: 12 months ]
  • Change from baseline in total hippocampal volume at 18 months using vMRI [ Time Frame: 18 months ]
  • Change from baseline at 12 months in brain amyloid levels as measured by amyloid PET [ Time Frame: 12 months ]
  • Change from baseline at 18 months in brain amyloid levels as measured by amyloid PET [ Time Frame: 18 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Evaluate Safety, Tolerability, and Efficacy of BAN2401 in Subjects With Early Alzheimer's Disease
Official Title  ICMJE A Placebo-Controlled, Double-Blind, Parallel-Group, Bayesian Adaptive Randomization Design and Dose Regimen-finding Study With an Open-Label Extension Phase to Evaluate Safety, Tolerability and Efficacy of BAN2401 in Subjects With Early Alzheimer's Disease
Brief Summary This is a multinational, multicenter, double-blind, placebo-controlled, parallel-group study using a Bayesian design with response adaptive randomization across placebo or 5 active arms of BAN2401 to determine clinical efficacy and to explore the dose response of BAN2401 using a composite clinical score (ADCOMS). BAN2401-G000-201 Core study is an 18-month study in which 3 dose levels (2.5, 5, and 10 mg/kg) are given biweekly (once every 2 weeks) to separate groups of participants and 2 dose levels (5 and 10 mg/kg) are given monthly (once every 4 weeks) to separate groups of participants. Participants will be from 2 clinical subgroups: mild cognitive impairment (MCI) due to Alzheimer's disease (AD) or mild Alzheimer's disease dementia. Frequent interim analyses will be conducted to continually update randomization allocation on the basis of the primary clinical endpoint. Any participant who completes the study treatment (Visit 42 [Week 79] of the Core study) or discontinues the Core Study will be eligible to participate in the Extension Phase, provided they meet the Extension Phase inclusion and exclusion criteria. Participants will receive 10 mg/kg biweekly for up to 24 months or until the drug is commercially available in the country, where the subject resides, or until the benefit-to-risk ratio from treatment with BAN2401 is no longer considered favorable, whichever comes first. The Follow-up Visit in the Extension Phase will take place 3 months after the last dose of study drug.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Alzheimer's Disease
Intervention  ICMJE
  • Drug: BAN2401 2.5 mg/kg
    2.5 mg/kg biweekly (once every 2 weeks) administered as a 60 minute i.v. infusion
  • Drug: BAN2401 5.0 mg/kg
    5.0 mg/kg biweekly (once every 2 weeks) administered as a 60 minute i.v. infusion
  • Drug: BAN2401 10 mg/kg
    10 mg/kg biweekly (once every 2 weeks) administered as a 60 minute i.v. infusion.
  • Drug: BAN2401 5.0 mg/kg
    5.0 mg/kg monthly (once every 4 weeks) administered as a 60 minute i.v. infusion. All participants will receive biweekly infusions, participants will have placebo infusion alternating with BAN2401
  • Drug: BAN2401 10 mg/kg
    10 mg/kg monthly (once every 4 weeks) administered as a 60 minute i.v. infusion. All participants will receive biweekly infusions, participants will have placebo infusion alternating with BAN2401
  • Drug: Placebo
    biweekly (once every 2 weeks) administered as a 60 minute i.v. infusion
Study Arms  ICMJE
  • Experimental: Core Study: BAN2401 2.5 mg/kg biweekly
    2.5 mg/kg biweekly
    Intervention: Drug: BAN2401 2.5 mg/kg
  • Experimental: Core Study: BAN2401 5.0 mg/kg biweekly
    5.0 mg/kg biweekly
    Intervention: Drug: BAN2401 5.0 mg/kg
  • Experimental: Core Study: BAN2401 10 mg/kg biweekly
    10 mg/kg biweekly
    Intervention: Drug: BAN2401 10 mg/kg
  • Experimental: Core Study: BAN2401 5.0 mg/kg monthly
    5.0 mg/kg monthly
    Intervention: Drug: BAN2401 5.0 mg/kg
  • Experimental: Core Study: BAN2401 10 mg/kg monthly
    10 mg/kg monthly
    Intervention: Drug: BAN2401 10 mg/kg
  • Placebo Comparator: Core Study: BAN2401-matched Placebo
    Matching placebo biweekly
    Intervention: Drug: Placebo
  • Experimental: Extension Phase: BAN2401 10 mg/kg
    All participants who fulfill Extension phase inclusion and exclusion criteria will have the option to participate in the Extension phase to receive BAN2401 10 mg/kg biweekly for up to 24 months or until the drug is commercially available in the country where the subject resides, or until the benefit-to-risk ratio from treatment with BAN2401 is no longer considered favorable, whichever comes first.
    Intervention: Drug: BAN2401 10 mg/kg
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: January 10, 2013)
800
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 27, 2022
Estimated Primary Completion Date January 27, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key Inclusion Criteria (Core Study) for Mild Cognitive Impairment due to Alzheimer's Disease

- Intermediate likelihood:

  1. Subjects who meet the National Institute of Aging - Alzheimer's Association (NIA-AA) core clinical criteria for mild cognitive impairment due to Alzheimer's disease - intermediate likelihood
  2. Subjects who have a CDR score of 0.5 and a Memory Box score of 0.5 or greater at Screening and Baseline
  3. Subjects who report a history of subjective memory decline with gradual onset and slow progression over the last one year before Screening; MUST be corroborated by an informant

Key Inclusion Criteria (Core Study) for Mild Alzheimer's Disease Dementia:

  1. Subjects who meet the NIA-AA core clinical criteria for probable Alzheimer's disease dementia
  2. Subjects who have a CDR score of 0.5-1.0 and a Memory Box score of 0.5 or greater at Screening and Baseline

Inclusion Criteria (Core Study) that must be met by all subjects:

  1. Subjects with objective impairment in episodic memory as indicated by at least 1 standard deviation below age-adjusted mean in the Wechsler Memory Scale - IV Logical Memory II (WMS-IV LMII):

    1. Less than or equal to 15 for age 50 to 64 years
    2. Less than or equal to 12 for age 65 to 69 years
    3. Less than or equal to 11 for age 70 to 74 years
    4. Less than or equal to 9 for age 75 to 79 years
    5. Less than or equal to 7 for age 80 to 90 years
  2. Positive amyloid load as indicated by PET or CSF assessment

    1. PET assessment of imaging agent uptake into brain
    2. CSF assessment of Aβ(1-42)
  3. Age between 50 and 90 years, inclusive
  4. Mini Mental State Examination (MMSE) score equal to or greater than 22, and equal to or less than 30, at Screening and Baseline
  5. Body Mass Index (BMI) greater than 17 and less than 35 at Screening or Baseline
  6. Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin assay [ß-hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
  7. Subjects on acetylcholinesterase inhibitor or memantine therapy or both for AD must be on a stable dose for at least 12 weeks prior to Baseline. Treatment naive subjects can be entered into the study. Unless otherwise stated, subjects must have been on stable doses of all other permitted concomitant medications (ie, non-AD related) for at least 4 weeks prior to Baseline.
  8. Subjects must have identified caregivers/informants
  9. Subjects must provide written informed consent

Key Exclusion Criteria (Core study):

  1. Any neurological condition that may be contributing to cognitive impairment above and beyond that caused by the subject's AD
  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. Geriatric Depression Scale (GDS) score ≥8 at Screening
  5. Contraindications to MRI scanning, including cardiac pacemaker/ defibrillator, ferromagnetic metal implants, e,g., in skull and cardiac devices other than those approved as safe for use in MR scanners
  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/QTc interval (QTc greater than 450 ms) as demonstrated by a repeated electrocardiogram (ECG)
  8. Certain other specified medical conditions
  9. Severe visual or hearing impairment that would prevent the subject from performing psychometric tests accurately

Inclusion Criteria (Extension Phase):

  1. Subjects who have completed Visit 42 (Week 79) of the Core Study or who discontinued study drug during the Core Study due to any of the following reasons:

    1. Alzheimer's Related Imaging Abnormality-Edema (ARIA-E)
    2. Amyloid related imaging abnormality hemorrhage (ARIA-H) (superficial siderosis, macrohemorrhage, or symptomatic microhemorrhage)
    3. Prohibited or restricted medications that were prohibited during Core Study conduct but are no longer prohibited in the Extension Phase
    4. Subjects who were APOE4 positive and receiving treatment with BAN2401 10 mg/kg biweekly
    5. Any reason for discontinuation not related to prohibited medications, including any AE that was considered not related to study drug, and that was not severe or life-threatening
  2. Must continue to have an identified caregiver or informant who is willing and able to provide follow-up information on the subject throughout the course of the Extension Phase
  3. Provide written informed consent. If a subject lacks capacity to consent in the investigator's opinion, the subject's assent should be obtained, if required in accordance with local laws, regulations and customs, plus the written informed consent of a legal representative should be obtained (capacity to consent and definition of legal representative should be determined in accordance with applicable local laws and regulations).
  4. Must be able to physically attend clinic visits and be willing and able to comply with all aspects of the protocol

Exclusion Criteria (Extension Phase):

  1. Subjects who discontinued from the study drug or from the the Core Study for reasons other than the following:

    1. ARIA-E
    2. ARIA-H (superficial siderosis, macrohemorrhage, or symptomatic microhemorrhage)
    3. Prohibited or restricted medications that were prohibited during Core Study conduct but are no longer prohibited in the Extension Phase
    4. Subjects who were APOE4 positive and receiving treatment with BAN2401 10 mg/kg biweekly
    5. AE that was considered not related to study drug, and that was not severe or life-threatening
  2. Are currently abstinent, and do not agree to use a double-barrier method (as described above) or refrain from becoming sexually active during the study period or for 28 days after study drug discontinuation.
  3. Severe visual or hearing impairment that would prevent the subject from performing psychometric tests accurately.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 50 Years to 90 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   France,   Germany,   Italy,   Japan,   Korea, Republic of,   Netherlands,   Spain,   Sweden,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01767311
Other Study ID Numbers  ICMJE BAN2401-G000-201
2012-002843-11 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Eisai Inc.
Study Sponsor  ICMJE Eisai Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Eisai Inc.
Verification Date July 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP