A Study to Assess Safety and Target Engagement of E2814 in Participants With Mild to Moderate Cognitive Impairment Due to Dominantly Inherited Alzheimer's Disease
Primary Purpose
Alzheimer Disease
Status
Recruiting
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
E2814
Sponsored by
About this trial
This is an interventional treatment trial for Alzheimer Disease focused on measuring E2814, Alzheimer disease, Dominantly inherited Alzheimer disease, Mild and moderate cognitive impairment, Central nervous system disease
Eligibility Criteria
Inclusion Criteria:
- Male or female, age 18 to 80 years at the time of informed consent
- Individuals who are confirmed to be mutation positive for presenilin 1 (PSEN1), amyloid precursor protein (APP), or presenilin 2 (PSEN2) gene that is associated with DIAD
- Clinical Dementia Rating - Sum of Boxes (CDR-SB) score 5 to 12 at Screening
- Evidence of positive amyloid status based on historical or screening amyloid PET
- Able to undergo magnetic resonance imaging (MRI), lumbar puncture (LP), PET, and complete all study-related testing and evaluations
- Has a study partner who in the investigator's judgment is able to provide accurate information as to the participant's cognitive and functional abilities, who agrees to provide information at the study visits which require informant input for scale completion
Exclusion Criteria:
- Clinically significant illness that required medical treatment within 8 weeks before the first dose or a clinically significant infection that required medical treatment within 4 weeks before first dose
- Females who are breastfeeding or pregnant at Screening or Baseline
Females of childbearing potential who:
Within 3 months before screening, did not use a highly effective method of contraception
- Any neurological condition that may be contributing to cognitive impairment above and beyond that caused by the participant's Alzheimer's disease (AD)
- History of transient ischemic attacks, stroke, or seizures within 12 months of Screening
- History of clinically important carotid or vertebrobasilar stenosis, plaque, or other prominent risk factor for stroke or cerebral haemorrhage (including atrial fibrillation and anticoagulation). Low dose aspirin (less than or equal to [<=] 325 milligram [mg] daily) is not exclusionary
- Any current psychiatric diagnosis or symptoms, (example, hallucinations, major depression, or delusions) that could interfere with study procedures in the participant
- Geriatric Depression Scale (GDS) score greater than or equal to 8 at Screening
- Contraindications to MRI scanning, including but not limited to pacemaker/cardiac defibrillator, neurostimulators, ferromagnetic metal implants (example, in skull and cardiac devices other than those approved as safe for use in MRI scanners)
- Evidence of other clinically significant lesions on brain MRI at Screening that could indicate a dementia diagnosis other than AD
- Other significant pathological findings on brain MRI at Screening
- Hypersensitivity to E2814 or any of the excipients, or to any monoclonal antibody (mAb) treatment
- Any immunological disease which is not adequately controlled, or which requires treatment with immunoglobulins, systemic monoclonal antibodies (or derivatives of monoclonal antibodies), systemic immunosuppressants, or plasmapheresis during the study
- With a bleeding disorder of current chronic use of anticoagulants (example, warfarin, dabigatran, rivaroxaban or apixaban) or of clopidogrel is exclusionary. Limited (occasional or isolated) use of anticoagulants/antiplatelet compounds in cases such as surgical procedures
- Have thyroid stimulating hormone outside of normal range. Other tests of thyroid function with results outside the normal range should only be exclusionary if they are considered clinically significant by the investigator
- Hemoglobin A1c (HgbA1c) greater than (>) 8 percent (%) (retesting is permitted if slightly elevated) or poorly controlled insulin-dependent diabetes (including hypoglycemic episodes). Participants may be rescreened after 3 months to allow optimization of diabetic control
- Abnormally low serum vitamin B12 levels for the testing laboratory
- History of human immunodeficiency virus (HIV) infection, history of hepatitis B infection within the past year, history of hepatitis C infection which has not been adequately treated, or history of spirochete infection of the central nervous system (example, syphilis, Lyme, or borreliosis)
- Any other clinically significant abnormalities in physical examination, vital signs, laboratory tests, or ECG at Screening or Baseline which in the opinion of the investigator require further investigation or treatment or which may interfere with study procedures or safety
- Malignant neoplasms within 3 years of Screening (except for basal or squamous cell carcinoma in situ of the skin, or localized prostate cancer in male participant, or localized breast cancer in female participants)
- Answers "yes" to Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation Type 4 or 5, or any suicidal behavior assessment within 6 months before Screening, at Screening, or at the Baseline Visit, or has been hospitalized or treated for any suicidal behavior in lifetime
- Known or suspected history of drug or alcohol abuse or dependence within 2 years before Screening or a positive urine drug test at Screening
- Any other medical conditions (example, cardiac, respiratory, gastrointestinal, renal disease) which are not stably and adequately controlled, or which in the opinion of the investigator could affect the participant's safety or interfere with the study assessments
- Concurrent participation in a clinical study involving any anti-amyloid therapies (including any mAb therapies) within 6 months before Screening
- Concurrent participation in a clinical study involving any anti-tau therapies
- Participated in any other investigational medication or device study in the 3 months or 5 half-lives (whichever is longer) of the medication before Screening
- Planned surgery which requires general anesthesia that would take place during the study
- Visual or hearing impairment that would prevent the participant from performing psychometric tests accurately
Sites / Locations
- UC San Diego Altman Clinical and Translational Research Insititute ClinicRecruiting
- Indiana University School of Medicine, Health Partners, Adult Neurology ClinicRecruiting
- National Hospital for Neurology and Neurosurgery (NHNN) University College London(UCL) Hospitals NHS Foundation TrustRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Cohort A, Phase 1b and 2: E2814
Cohort B: E2814
Arm Description
Participants will receive E2814 as an intravenous infusion at set intervals over 12 weeks in Phase 1b and over 96 weeks in Phase 2.
Participants will receive E2814 as an intravenous infusion at set intervals over 52 weeks.
Outcomes
Primary Outcome Measures
Cohort A, Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Cohort A, Phase 2 and Cohort B: Number of Participants With TEAEs
Cohort A, Phase 1b: Number of Participants With Serious Adverse Events (SAEs)
Cohort A, Phase 2 and Cohort B: Number of Participants With SAEs
Cohort A, Phase 1b: Number of Participants With Markedly Abnormal Laboratory Values
Cohort A, Phase 2 and Cohort B: Number of Participants With Markedly Abnormal Laboratory Values
Cohort A, Phase 1b: Number of Participants With Clinically Significant Vital Signs Values
Cohort A, Phase 2 and Cohort B: Number of Participants With Clinically Significant Vital Signs Values
Cohort A, Phase 1b: Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings
Cohort A, Phase 2 and Cohort B: Number of Participants With Clinically Significant ECG Findings
Cohort A: Change From Baseline in CSF Free and Bound MTBR-tau at 12 Weeks
Cohort A: Change From Baseline in Total MTBR-tau at 12 Weeks
Secondary Outcome Measures
Cohort A and Cohort B, Cmax: Maximum Observed Plasma Concentration for E2814
Cohort A and Cohort B, Tmax: Time to Reach the Maximum Plasma Concentration for E2814
Cohort A and Cohort B, AUC(0-672h): Area Under the Plasma Concentration-time Curve From Zero Time to 672 Hours for E2814
Cohort A and Cohort B, Cmax Serum: Maximum Observed Serum Concentration for E2814
Cohort A and Cohort B, Tmax Serum: Time to Reach the Maximum Serum Concentration for E2814
Cohort A and Cohort B, AUC(0-672h) Serum: Area Under the Serum Concentration-time Curve From Zero Time to 672 Hours for E2814
CSF Concentrations of E2814
Serum anti-E2814 Antibody Concentration
Plasma anti-E2814 Antibody Concentration
Change From Baseline in CSF Concentrations of Total tau (t-tau) and Phosphorylated tau (p-tau)
Change From Baseline in tau Positron Emission Tomography (PET) Signal
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04971733
Brief Title
A Study to Assess Safety and Target Engagement of E2814 in Participants With Mild to Moderate Cognitive Impairment Due to Dominantly Inherited Alzheimer's Disease
Official Title
An Open-Label Phase 1b/2 Study to Assess Safety and Target Engagement of E2814 in Subjects With Mild to Moderate Cognitive Impairment Due to Dominantly Inherited Alzheimer's Disease
Study Type
Interventional
2. Study Status
Record Verification Date
November 2022
Overall Recruitment Status
Recruiting
Study Start Date
June 28, 2021 (Actual)
Primary Completion Date
April 22, 2025 (Anticipated)
Study Completion Date
April 22, 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Eisai Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
The primary objective of the study is to assess the safety and tolerability of intravenous (IV) infusions of E2814 in participants with dominantly inherited Alzheimer's disease (DIAD), and to evaluate target engagement (TE) of E2814 on microtubule binding region (MTBR)-tau species in cerebrospinal fluid (CSF) in participants with DIAD.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alzheimer Disease
Keywords
E2814, Alzheimer disease, Dominantly inherited Alzheimer disease, Mild and moderate cognitive impairment, Central nervous system disease
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
13 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Cohort A, Phase 1b and 2: E2814
Arm Type
Experimental
Arm Description
Participants will receive E2814 as an intravenous infusion at set intervals over 12 weeks in Phase 1b and over 96 weeks in Phase 2.
Arm Title
Cohort B: E2814
Arm Type
Experimental
Arm Description
Participants will receive E2814 as an intravenous infusion at set intervals over 52 weeks.
Intervention Type
Drug
Intervention Name(s)
E2814
Intervention Description
E2814 intravenous infusion.
Primary Outcome Measure Information:
Title
Cohort A, Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Time Frame
Up to 20 weeks
Title
Cohort A, Phase 2 and Cohort B: Number of Participants With TEAEs
Time Frame
Up to 108 weeks
Title
Cohort A, Phase 1b: Number of Participants With Serious Adverse Events (SAEs)
Time Frame
Up to 20 weeks
Title
Cohort A, Phase 2 and Cohort B: Number of Participants With SAEs
Time Frame
Up to 108 weeks
Title
Cohort A, Phase 1b: Number of Participants With Markedly Abnormal Laboratory Values
Time Frame
Up to 20 weeks
Title
Cohort A, Phase 2 and Cohort B: Number of Participants With Markedly Abnormal Laboratory Values
Time Frame
Up to 108 weeks
Title
Cohort A, Phase 1b: Number of Participants With Clinically Significant Vital Signs Values
Time Frame
Up to 20 weeks
Title
Cohort A, Phase 2 and Cohort B: Number of Participants With Clinically Significant Vital Signs Values
Time Frame
Up to 108 weeks
Title
Cohort A, Phase 1b: Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings
Time Frame
Up to 20 weeks
Title
Cohort A, Phase 2 and Cohort B: Number of Participants With Clinically Significant ECG Findings
Time Frame
Up to 108 weeks
Title
Cohort A: Change From Baseline in CSF Free and Bound MTBR-tau at 12 Weeks
Time Frame
Baseline up to Week 12
Title
Cohort A: Change From Baseline in Total MTBR-tau at 12 Weeks
Time Frame
Baseline up to Week 12
Secondary Outcome Measure Information:
Title
Cohort A and Cohort B, Cmax: Maximum Observed Plasma Concentration for E2814
Time Frame
Cohort A, Days 1 and 85: 0-24 hours post-infusion; Cohort B: Pre-dose and immediately at the end of the infusion on Day 1 up to Day 449
Title
Cohort A and Cohort B, Tmax: Time to Reach the Maximum Plasma Concentration for E2814
Time Frame
Cohort A, Days 1 and 85: 0-24 hours post-infusion; Cohort B: Pre-dose and immediately at the end of the infusion on Day 1 up to Day 449
Title
Cohort A and Cohort B, AUC(0-672h): Area Under the Plasma Concentration-time Curve From Zero Time to 672 Hours for E2814
Time Frame
Cohort A, Days 1 and 85: 0-672 hours post-infusion; Cohort B, Day 1 up to Day 449: 0-672 hours post-infusion
Title
Cohort A and Cohort B, Cmax Serum: Maximum Observed Serum Concentration for E2814
Time Frame
Cohort A, Days 1 and 85: 0-24 hours post-infusion; Cohort B: Pre-dose and immediately at the end of the infusion on Day 1 up to Day 449
Title
Cohort A and Cohort B, Tmax Serum: Time to Reach the Maximum Serum Concentration for E2814
Time Frame
Cohort A, Days 1 and 85: 0-24 hours post-infusion; Cohort B: Pre-dose and immediately at the end of the infusion on Day 1 up to Day 449
Title
Cohort A and Cohort B, AUC(0-672h) Serum: Area Under the Serum Concentration-time Curve From Zero Time to 672 Hours for E2814
Time Frame
Cohort A, Days 1 and 85: 0-672 hours post-infusion; Cohort B, Day 1 up to Day 449: 0-672 hours post-infusion
Title
CSF Concentrations of E2814
Time Frame
Cohort A: From first dose the study drug up to 12 weeks after last dose (up to 120 weeks); Cohort B: From first dose the study drug up to 52 weeks
Title
Serum anti-E2814 Antibody Concentration
Time Frame
Cohort A: From first dose the study drug up to 12 weeks after last dose (up to 120 weeks); Cohort B: From first dose the study drug up to 12 weeks after last dose (up to 64 weeks)
Title
Plasma anti-E2814 Antibody Concentration
Time Frame
Cohort A: From first dose the study drug up to 12 weeks after last dose (up to 120 weeks); Cohort B: From first dose the study drug up to 12 weeks after last dose (up to 64 weeks)
Title
Change From Baseline in CSF Concentrations of Total tau (t-tau) and Phosphorylated tau (p-tau)
Time Frame
Cohort A: From first dose the study drug up to 12 weeks after last dose (up to 120 weeks); Cohort B: From first dose the study drug up to 52 weeks
Title
Change From Baseline in tau Positron Emission Tomography (PET) Signal
Time Frame
Cohort A: Baseline up to 108 weeks; Cohort B: Baseline up to 52 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Male or female, age 18 to 80 years at the time of informed consent
Individuals who are confirmed to be mutation positive for presenilin 1 (PSEN1), amyloid precursor protein (APP), or presenilin 2 (PSEN2) gene that is associated with DIAD
Clinical Dementia Rating - Sum of Boxes (CDR-SB) score 5 to 12 at Screening
Evidence of positive amyloid status based on historical or screening amyloid PET
Able to undergo magnetic resonance imaging (MRI), lumbar puncture (LP), PET, and complete all study-related testing and evaluations
Has a study partner who in the investigator's judgment is able to provide accurate information as to the participant's cognitive and functional abilities, who agrees to provide information at the study visits which require informant input for scale completion
Exclusion Criteria:
Clinically significant illness that required medical treatment within 8 weeks before the 1st dose or a clinically significant infection that required medical treatment within 4 weeks before 1st dose
Females who are breastfeeding or pregnant at Screening or Baseline
Females of childbearing potential who:
Within 3 months before screening, did not use a highly effective method of contraception
Any neurological condition that may be contributing to cognitive impairment above and beyond that caused by the participant's Alzheimer's disease (AD)
History of transient ischemic attacks, stroke, or seizures within 12 months of Screening
History of clinically important carotid or vertebrobasilar stenosis, plaque, or other prominent risk factor for stroke or cerebral haemorrhage (including atrial fibrillation and anticoagulation). Low dose aspirin (less than or equal to [<=] 325 milligram [mg] daily) is not exclusionary
Any current psychiatric diagnosis or symptoms, (example, hallucinations, major depression, or delusions) that could interfere with study procedures in the participant
Geriatric Depression Scale (GDS) score greater than or equal to 8 at Screening
Contraindications to MRI scanning, including but not limited to pacemaker/cardiac defibrillator, neurostimulators, ferromagnetic metal implants (example, in skull and cardiac devices other than those approved as safe for use in MRI scanners)
Evidence of other clinically significant lesions on brain MRI at Screening that could indicate a dementia diagnosis other than AD
Other significant pathological findings on brain MRI at Screening
Hypersensitivity to E2814 or any of the excipients, or to any monoclonal antibody (mAb) treatment
Any immunological disease which is not adequately controlled, or which requires treatment with immunoglobulins, systemic monoclonal antibodies (or derivatives of monoclonal antibodies), systemic immunosuppressants, or plasmapheresis during the study
With a bleeding disorder of current chronic use of anticoagulants (example, warfarin, dabigatran, rivaroxaban or apixaban) or of clopidogrel is exclusionary. Limited (occasional or isolated) use of anticoagulants/antiplatelet compounds in cases such as surgical procedures
Have thyroid stimulating hormone outside of normal range. Other tests of thyroid function with results outside the normal range should only be exclusionary if they are considered clinically significant by the investigator
Hemoglobin A1c (HgbA1c) greater than (>) 8 percent (%) (retesting is permitted if slightly elevated) or poorly controlled insulin-dependent diabetes (including hypoglycemic episodes). Participants may be rescreened after 3 months to allow optimization of diabetic control
Abnormally low serum vitamin B12 levels for the testing laboratory
History of human immunodeficiency virus (HIV) infection, history of hepatitis B infection within the past year, history of hepatitis C infection which has not been adequately treated, or history of spirochete infection of the central nervous system (example, syphilis, Lyme, or borreliosis)
Any other clinically significant abnormalities in physical examination, vital signs, laboratory tests, or ECG at Screening or Baseline which in the opinion of the investigator require further investigation or treatment or which may interfere with study procedures or safety
Malignant neoplasms within 3 years of Screening (except for basal or squamous cell carcinoma in situ of the skin, or localized prostate cancer in male participant, or localized breast cancer in female participants)
Answers "yes" to Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation Type 4 or 5, or any suicidal behavior assessment within 6 months before Screening, at Screening, or at the Baseline Visit, or has been hospitalized or treated for any suicidal behavior in lifetime
Known or suspected history of drug or alcohol abuse or dependence within 2 years before Screening or a positive urine drug test at Screening
Any other medical conditions (example, cardiac, respiratory, gastrointestinal, renal disease) which are not stably and adequately controlled, or which in the opinion of the investigator could affect the participant's safety or interfere with the study assessments
Concurrent participation in a clinical study involving any anti-amyloid therapies (including any mAb therapies) within 6 months before Screening
Concurrent participation in a clinical study involving any anti-tau therapies
Participated in any other investigational medication or device study in the 3 months or 5 half-lives (whichever is longer) of the medication before Screening
Planned surgery which requires general anesthesia that would take place during the study
Visual or hearing impairment that would prevent the participant from performing psychometric tests accurately
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Eisai Medical Information
Phone
+1-888-274-2378
Email
esi_medinfo@eisai.com
Facility Information:
Facility Name
UC San Diego Altman Clinical and Translational Research Insititute Clinic
City
La Jolla
State/Province
California
ZIP/Postal Code
92037
Country
United States
Individual Site Status
Recruiting
Facility Name
Indiana University School of Medicine, Health Partners, Adult Neurology Clinic
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Individual Site Status
Recruiting
Facility Name
National Hospital for Neurology and Neurosurgery (NHNN) University College London(UCL) Hospitals NHS Foundation Trust
City
London
ZIP/Postal Code
WC1N 3BG
Country
United Kingdom
Individual Site Status
Recruiting
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Eisai's data sharing commitment and further information on how to request data can be found on our website http://eisaiclinicaltrials.com/.
Learn more about this trial
A Study to Assess Safety and Target Engagement of E2814 in Participants With Mild to Moderate Cognitive Impairment Due to Dominantly Inherited Alzheimer's Disease
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