A Proof-of-Mechanism, Open-Label, Parallel Group Study With an Open-Label Extension Phase to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of E2511 in Participants With Early Alzheimer's Disease
A Proof-of-Mechanism, Open-Label, Parallel Group Study With an Open-Label Extension Phase to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of E2511 in Participants With Early Alzheimer's Disease
The primary purpose of this study is to evaluate proof of mechanism (POM) and long-term safety and tolerability of E2511 in participants with Early AD. The study consists of 2 parts. In Part A, participants will be randomly assigned to receive either E2511 or donepezil. In Part B, participants will receive E2511 only. Once Part A and Part B participants complete the Core Trial (which includes Pretreatment and Treatment phases) they will have the option to enter the Extension Phase where they will receive E2511 for 18 months.
Inclusion Criteria:
For participants diagnosed with mild cognitive impairment (MCI) due to AD-intermediate likelihood:
For participants diagnosed with mild AD dementia:
Mini Mental State Examination (MMSE) score >=22 and less than or equal to (<=) 30 at Screening.
Evidence of brain amyloid pathology as indicated by one of the following:
Nonsmoking and nonvaping, male or female, aged >=50 years and <=85 years old, at the time of informed consent.
Body Mass Index (BMI) greater than 17 and less than 35 at Screening.
Have an identified trial partner (defined as a person able to support the participant for the duration of the trial and who spends at least 8 hours per week with the participant). The trial partner must provide separate written informed consent. In addition, this person must be willing and able to provide follow-up information on the participant throughout the course of the trial. This person must, in the opinion of the investigator, spend sufficient time with the participant on a regular basis such that the trial partner can reliably fulfill the trial requirements. A permanent trial partner need not be living in the same residence with the participant. For such a trial partner not residing with the participant, the investigator has to be satisfied that the participant can contact the trial partner readily during the times when the trial partner is not with the participant. If in doubt about whether a participant's care arrangements are suitable for inclusion, the investigator should discuss this with the medical monitor. Trial partners need to participate in person for visits where clinical assessments, such as CDR (global and CDR-SB), take place.
Able to undergo CSF lumbar puncture and not receiving any anticoagulant therapy or currently suffering from a medical condition that may require initiation of any anticoagulant therapy at Screening.
Provide written informed consent. If a participant lacks the capacity to consent in the investigator's opinion, the participant'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).
Willing and able to comply with all aspects of the protocol including multiple CSF collections.
Exclusion Criteria:
Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a minimum sensitivity of 25 International Units per Liter [IU/L] or equivalent units of β-hCG [or hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of trial drug.
Females of childbearing potential who:
Within 28 days before trial entry, did not use a highly effective method of contraception, which includes any of the following:
Do not agree to use a highly effective method of contraception (as described above) throughout the entire trial period and for 28 days after trial drug discontinuation.
NOTE: It is permissible that if a highly effective method of contraception is not appropriate or acceptable to the participant, then the participant must agree to use a medically acceptable method of contraception, i.e., double-barrier methods of contraception such as latex or synthetic condom plus diaphragm or cervical/vault cap with spermicide. 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 group, and without other known or suspected cause) or have been sterilized surgically (i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing).
Males who have not had a successful vasectomy (confirmed azoospermia) if their female partners meet the exclusion criteria above (i.e., the female partners are of childbearing potential and are not willing to use a highly effective contraceptive method throughout the trial period and for 5 times the half-life of the trial drug plus 90 days after trial drug discontinuation). No sperm donation is allowed during the trial period and for 5 times the half-life of the trial drug plus 90 days after trial drug discontinuation.
Any neurological condition that may be contributing to cognitive impairment above and beyond that caused by the participant's MCI or AD.
History of transient ischemic attacks, stroke, or seizures within 12 months of Screening.
Any lifetime history of psychiatric disease (including but not limited to depression or other mood disorders, bipolar disorder, psychotic disorders, including schizophrenia, panic attacks, anxiety disorders).
Any suicidal ideation with intent with or without a plan at Screening or within 6 months of Screening (i.e., answering "Yes" to questions 4 or 5 on the Suicidal Ideation section of the C-SSRS).
Any lifetime suicidal behavior (per the Suicidal Behavior Section of the C-SSRS).
Contraindications to magnetic resonance imaging (MRI) scanning, including cardiac pacemaker/defibrillator, and ferromagnetic metal implants (eg, 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, including but not limited to: evidence of cerebral contusion, encephalomalacia, aneurysms, vascular malformations, or infective lesions; evidence of multiple lacunar infarcts or stroke involving a major vascular territory, severe small vessel, or white matter disease; space occupying lesions; or brain tumors (however, lesions diagnosed as meningiomas or arachnoid cysts and less than 1 centimeter [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.
Malignant neoplasms within 3 years of Screening (except for basal or squamous cell carcinoma in situ of the skin, localized prostate cancer in male participants, or localized breast cancer in female participants). Participants who had malignant neoplasms but who have had at least 3 years of documented uninterrupted remission before Screening need not be excluded.
A clinically significant ECG abnormality, including a marked prolonged corrected QT interval (Fridericia's Correction Formula) (eg, a repeated demonstration of a QTcF interval greater than [>] 450 milliseconds [ms]).
Participants with a bleeding disorder that is not under adequate control (including a platelet count <50,000 or international normalized ratio [INR] >1.5). Participants who are on anticoagulant therapy are not permitted to be enrolled.
Have thyroid-stimulating hormone above the 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. This applies to all participants whether or not they are taking thyroid supplements. If the thyroid-stimulating hormone returns to normal range with thyroid replacement therapy, then participants may be allowed to enroll without rescreening if they meet all other inclusion criteria and did not meet any exclusion criteria.
Abnormally low serum vitamin B12 levels for the testing laboratory (if a participant is taking vitamin B12 injections, level should be at or above the lower limit of normal for the testing laboratory). Levels of vitamin B12 may be confirmed with reflex testing to include methylmalonic acid analysis, if available in the region. If vitamin B12 levels return to normal range with supplement treatment, then participants may be allowed to enroll without rescreening if they meet all other inclusion criteria and did not meet any exclusion criteria.
Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, and renal disease) that in the opinion of the investigator(s) could affect the participant's safety or interfere with the trial assessments. Any other medical conditions (eg, cardiac, respiratory, gastrointestinal, and renal disease) that are not stably and adequately controlled or that in the opinion of the investigator(s) could affect the participant's safety or interfere with the trial assessments.
Any history of or concomitant medical condition that in the opinion of the investigator(s) would compromise the participant's ability to safely complete the trial.
Planned surgery that requires general, spinal, or epidural anesthesia that would take place during the trial. Planned surgery that requires only local anesthesia and that can be undertaken as a day case without inpatient stay postoperatively need not result in exclusion if in the opinion of the investigator this operation does not interfere with trial procedures and participant's safety.
Known to be human immunodeficiency virus positive.
Known or suspected history of drug or alcohol abuse or dependence within 2 years before Screening or a positive urine drug test at Screening. Participants who test positive for benzodiazepines or opioids in urine drug testing need not be excluded if, in the clinical opinion of the investigator, this is due to the participant taking prior/concomitant medications containing benzodiazepines or opioids for a medical condition and not due to drug abuse.
Severe visual or hearing impairment that would prevent the participant from performing psychometric tests accurately.
Active viral hepatitis (A, B, or C) as demonstrated by positive serology at Screening.
Currently enrolled in another clinical trial or used any investigational drug or device within 28 days or 5 half-lives of the other investigational drug, whichever is longer, preceding informed consent.
Receipt of blood products within 4 weeks, or donation of blood within 8 weeks, or donation of plasma within 1 week of dosing.
Participants who contravene the restrictions on medications, food, beverages, physical activities, and others as defined in the protocol at Screening or Baseline.
Participants with contraindications to lumbar puncture.
Known hypersensitivity to donepezil hydrochloride or to piperidine derivatives.
Taking a cholinesterase inhibitor unless willing to discontinue cholinesterase inhibitor treatment for 21 days before Screening and until the last visit during the Core Trial.
Participation in a clinical trial for AD involving any antisense oligonucleotide or silencing ribonucleic acid (RNA) therapies targeting amyloid or tau unless it can be documented that the participant only received placebo.
Participation in a clinical trial for AD involving pharmaceutical intervention other than antisense oligonucleotide or silencing RNA therapies (eg, small molecules, monoclonal antibodies) within 6 months of Screening unless it can be documented that the participant only received placebo.
Participants who have taken approved anti-amyloid monoclonal antibodies (eg, LEQEMBI, KISUNLA) within 6 months of Screening.
Any history of surgery that may affect pharmacokinetic (PK) profiles of trial drug (eg, hepatectomy, nephrectomy, digestive organ resection) or participants who have a congenital abnormality in metabolism at Screening.
Any other findings that the investigator feels would increase the risk of having an adverse outcome from participation in the trial.
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