AHEAD 3-45 Study: A Clinical Study to Investigate the Effects of BAN2401 in Subjects With Preclinical Alzheimer’s Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Eisai Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

21 Jul 2021 → ongoing

Decision date (initial)

2024-06-06

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Eisai Limited

External identifiers

EU CT number

2024-510888-39-00

EudraCT number

2020-004244-28

WHO UTN

U1111-1306-2397

ClinicalTrials.gov

NCT04468659

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Efficacy, Pharmacokinetic, Safety

Core Study

A45 Trial (Preclinical AD with Elevated Amyloid):
To determine whether treatment with BAN2401 is superior to placebo on change from baseline of the Preclinical Alzheimer Cognitive Composite 5 (PACC5) at 216 weeks of treatment.
A3 Trial (Early Preclinical AD with Intermediate Amyloid Beta [Aβi]):
To determine whether treatment with BAN2401 is superior to placebo in reducing brain amyloid accumulation as measured by amyloid PET at 216 weeks of treatment.

Extension Phase
 To evaluate the long-term safety and tolerability of BAN2401 in subjects enrolled in the Extension Phase.

Secondary objectives 6

1. A45 Trial - To determine whether treatment with BAN2401 is superior to placebo in reducing brain amyloid levels as measured by amyloid positron emission tomography (PET) at 96 and 216 weeks of treatment.
2. A45 Trial - To determine whether treatment with BAN2401 is superior to placebo on brain tau pathology as measured by tau PET at 96 and 216 weeks of treatment.
3. A45 Trial - To determine whether treatment with BAN2401 is superior to placebo on the change from baseline in the Cognitive Function Index (CFI) at 216 weeks of treatment.
4. A45 Trial - To evaluate the safety and tolerability of BAN2401 relative to placebo.
5. A3 Trial - To determine whether treatment with BAN2401 is superior to placebo on brain tau pathology as measured by tau PET at 216 weeks of treatment.
6. A3 Trial - To evaluate the safety and tolerability of BAN2401 relative to placebo.

Conditions and MedDRA coding

Early Preclinical Alzheimer’s Disease and Intermediate Amyloid

Regulatory references

Plan to share IPD

Yes

IPD plan description

Eisai's data sharing commitment and further information on how to request data can be found on our website http://eisaiclinicaltrials.com/.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Male or female, age 55 to 80 years inclusive at the time of informed consent, with a plasma biomarker result that is predictive of intermediate or elevated brain amyloid at Screening or known before Screening to have elevated or intermediate amyloid according to previous PET, CSF, or plasma testing. a. Those 55 to 64 must have 1 of the following additional risk factors, given the relatively low rates of amyloid positivity <65 years, before Screening: i. First degree relative diagnosed with dementia onset before age 75, or ii. Known to possess at least 1 APOE4 allele, or iii. Known before Screening to have elevated brain amyloid according to previous plasma biomarker results, PET imaging, or CSF testing.
2. Global CDR score of 0 at Screening
3. Mini Mental State Examination (MMSE) score ≥27 (with educational adjustments) at Screening. Educational adjustment requirements are: a. If ≤12 years of education, MMSE required to be ≥25 b. If 13 to 15 years (inclusive) of education, MMSE required to be ≥26 c. If ≥16 years of education, MMSE required to be ≥27
4. Wechsler Memory Scale-Revised Logical Memory subscale II (WMS-R LM II) score at Screening of ≥6
5. A45 Trial: Elevated brain amyloid pathology by amyloid PET: defined as approximately >40 centiloids on Screening scan. A3 Trial: Intermediate levels of brain amyloid pathology by amyloid PET: defined as approximately 20 to 40 centiloids on screening scan.
6. Has a study partner that is willing to participate as a source of information and has approximately weekly contact with the subject (contact can be in-person, via telephone or electronic communication). The study partner must have sufficient contact such that the investigator feels the study partner can provide meaningful information about the subject’s daily function.
7. Provide written (or electronic, if allowed per country-specific regulations) informed consent
8. Willing and able to comply with all aspects of the protocol
9. Extension Phase 1.Completed the Core Study, or meet the following progression criteria during the Core Study: • Two (2) consecutive CDR visits with Global Scores > zero when measured at least 6 months apart within the Core Study • The Principal investigator's confirmation that the participant has clinically declined consistent progression to EAD 2. Must continue to have a study partner who is willing and able to provide follow-up information on the subject throughout the course of the Extension Phase. The study partner must provide separate written informed consent for the Extension Phase. Study partners must continue to have sufficient contact such that the investigator feels the study partner can provide meaningful information about the subject's daily functions. 3. Provide written informed consent for the Extension Phase. If a subject lacks capacity to consent in the investigator's opinion, the subject's assent should be obtained, if required and in accordance with local laws, regulations, and customs, plus the written informed consent of a legal representative (capacity to consent and the definition of a legal representative should be determined in accordance with applicable local laws and regulations). In countries where local laws, regulations, and customs do not permit subjects who lack capacity to consent to participate in this study (eg, Spain), they will not be enrolled. 4. Willing and able to comply with all aspects of the protocol.

Exclusion criteria 18

1. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]). For women of childbearing potential, 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.
2. Females of childbearing potential who:  Within 28 days before study entry, did not use a highly effective method of contraception, which includes any of the following: o total abstinence (if it is their preferred and usual lifestyle) o an intrauterine device or intrauterine hormone-releasing system o a contraceptive implant o an oral contraceptive (with additional barrier method) (Subject must be on a stable dose of the same oral contraceptive product for at least 28 days before dosing and throughout the study and for 28 days after study drug discontinuation.) o have a vasectomized partner with confirmed azoospermia  Do not agree to use a highly effective method of contraception (as described above) throughout the entire study period and for 28 days after study drug discontinuation For sites outside of Europe, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the subject, then the subject must agree to use a medically acceptable method of contraception, ie, double-barrier methods of contraception such as latex or synthetic condom plus diaphragm or cervical/vault cap with spermicide. (revised per Amendment 03) NOTE: All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age range, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing).
3. History of transient ischemic attacks (TIA), stroke, or seizures within 12 months of Screening
4. Current or history within the past 2 years of psychiatric diagnosis or symptoms (eg, hallucinations, major depression, or delusions) that, in the opinion of the investigator, could interfere with study procedures
5. Contraindications to 3 Tesla MRI scanning, including cardiac pacemaker/defibrillator, ferromagnetic metal implants (eg, in-skull and cardiac devices other than those approved as safe for use in MRI scanners), or exhibit other significant pathological findings on brain MRI at Screening, including but not limited to: more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter); a single macrohemorrhage greater than 10 mm at greatest diameter; an area of superficial siderosis; evidence of vasogenic edema; cerebral contusion, encephalomalacia, aneurysms greater than 6 mm, or any aneurysms that have not been stable in size for the past 2 years, vascular malformations that are at high risk for hemorrhage, or infective lesions; evidence of multiple lacunar infarcts (that in the opinion of the investigator, may impact cognition), stroke involving a major vascular territory, severe small vessel, or severe diffuse white matter disease; space occupying lesions; or brain tumors (however, lesions diagnosed as meningiomas or arachnoid cysts and less than 1 cm at their greatest diameter need not be exclusionary). Other minor or clinically insignificant MRI abnormalities, as agreed by the medical monitor and after discussion with the investigator, may not be exclusionary.
6. Hypersensitivity to any monoclonal antibody treatment
7. 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
8. Bleeding disorder that is not under adequate control (including a platelet count <50,000 or INR >1.5) at Screening
9. Results of laboratory tests conducted during Screening that are outside the limits defined in the protocol
10. Known to be human immunodeficiency virus (HIV) positive
11. Any other clinically significant abnormalities that in the opinion of the investigator require further investigation or treatment or may interfere with study procedures or safety.
12. 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 subjects with treatment cycles completed at least 6 months before Screening). Subjects who had malignant neoplasms but who have had at least 3 years of documented uninterrupted remission before Screening need not be excluded.
13. Answer "yes" to C-SSRS suicidal ideation Type 4 or 5, or any suicidal behavior assessment within 6 months before Screening, at Screening, or at Baseline, or has been hospitalized or treated for suicidal behavior in the past 5 years before Screening
14. Known or suspected history of drug or alcohol abuse or dependence within 2 years before Screening or a positive urine drug test at Screening. Subjects who test positive for benzodiazepines, opioids, or THC in urine drug testing need not be excluded unless in the clinical opinion of the investigator this is due to potential drug abuse
15. Taking prohibited medications.
16. Participation in a clinical study involving those compounds defined in the protocol.
17. Planned surgery during the Prerandomization Phase or within 3 months of Randomization, which requires general anesthesia
18. Extension Phase 1. Discontinued from the Core Study or from study treatment. 2. Under study drug interruption due to ARIA or other AE at the time of transition to the Extension Phase.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. A45 Trial: Change from baseline in PACC5 at 216 weeks.
2. A3 Trial: Change from baseline in amyloid PET SUVr at 216 weeks.

Secondary endpoints 4

1. A45 Trial: Change from baseline in amyloid PET SUVr at 96 and 216 weeks
2. A45 Trial: Change from baseline in tau PET SUVr at 96 and 216 weeks
3. A45 Trial: Change from baseline in CFI at 216 weeks
4. A3 Trial: Change from baseline in tau PET SUVr at 216 weeks

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Eisai Limited

Sponsor organisation

Eisai Limited

Address

European Knowledge Center, Mosquito Way Mosquito Way

City

Hatfield

Postcode

AL10 9SN

Country

United Kingdom

Scientific contact point

Organisation

Eisai Limited

Contact name

Medical Information

Public contact point

Organisation

Eisai Limited

Contact name

Medical Information

Third parties 15

Locations

1 EU/EEA country · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 18 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications