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Alzheimer’s Disease Study II
A Placebo-Controlled, Double-Blind, Parallel-Group, 24 Month Study to Evaluate the Efficacy and Safety of E2609 in Subjects with Early Alzheimer’s Disease.
Eligibility and Recruitment Information
|Inclusion||1. MCI due to AD or Mild AD according to the National Institute of Aging – Alzheimer’s Association (NIA-AA) core clinical criteria and must have all of the following at Screening: a. MMSE score equal to or greater than 24 b. CDR global score of 0.5 c. CDR Memory Box score of 0.5 or greater 2. A history of subjective memory decline with gradual onset and slow progression over the last 1 year before Screening; this MUST be corroborated by a study partner. 3. Cognitive impairment of at least 1 SD from age-adjusted norms in total recall or delayed recall on the ISLT. 4. Positive biomarker for brain amyloid pathology as indicated by at least 1 of the following: a. PET assessment of amyloid imaging agent uptake into brain. Note: amyloid PET screens will be performed according to local regulatory guidelines and thus may be restricted for those subjects who are not suitable for LP to obtain CSF for testing of eligibility. b. CSF AD assessment (eg, Aβ(1-42), tau: Aβ(1-42) ratio) NOTE: Subjects may undergo both the amyloid PET and CSF assessments, but need a positive amyloid result in only 1 of the 2 procedures to confirm eligibility. Subjects who consent to amyloid PET or CSF for eligibility purposes are not required to participate in the amyloid PET or CSF longitudinal substudies. Use of a historical amyloid positive PET (conducted within 12 months before the planned date of randomization) is acceptable for determination of eligibility but will not suffice for the baseline assessment if the subject wishes to consent to the amyloid PET longitudinal substudy. The historical imaging data must be made available to the sponsor. 5. Male or female subjects between 50 and 85 years of age, inclusive at the time of consent. 6. If receiving an AChEI or memantine or both for AD, must be on a stable dose for at least 12 weeks prior to Randomization. Treatment-naïve subjects with AD can be entered into the study. 7. Subjects must have been on stable doses of all other (ie, non-AD related) permitted concomitant medications for at least 4 weeks prior to Randomization, except for medications which are administered as short courses (eg, up to 3 weeks unless discussed and agreed with Medical Monitor) of treatment (eg, anti-infectives, oral steroids) or which are to be used on a Pro re nata (PRN) basis. Subjects who require a short course of treatment, such as anti-infectives or oral steroids, may be randomized once the acute illness has completely resolved, even if the concomitant medication continues. 8. Must have an identified study partner (defined as a person able to support the subject for the duration of the study and who spends at least 8 hours per week with the subject). The study partner must be literate and able to provide written informed consent. In addition, this person must be willing and able to provide follow-up information on the subject throughout the course of the study. This person must, in the opinion of the investigator, spend sufficient time with the subject on a regular basis such that they can reliably fulfill the requirements of being a study partner. A study partner need not be living in the same residence with the subject. For such a study partner not residing with the subject, the investigator has to be satisfied that the subject can contact the study partner readily during the times when the study partner is not with the subject. Study partners need to provide input to the following assessments: CDR, FAQ, EQ-5D, QOL-AD, Zarit’s Burden Interview, NPI-10, and the clinical assessment of suicidality. Consideration can occur for the investigator to decide whether the study partner can provide information over the telephone or whether the study partner must attend the study visits in person with the subject. 9. Provide written informed consent. Subjects must, in the investigator's judgment, have the capacity to consent (capacity to consent should be determined in accordance with applicable professional standards and local laws/regulations).|
|Exclusion||1. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin test. 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. Females of child-bearing potential who: a. 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 an oral contraceptive (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 b. 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 the European Union, 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 condom plus diaphragm or cervical/vault cap with spermicide. NOTE: All females will be considered to be of child-bearing 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 (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing) 2. Any condition that may be contributing to cognitive impairment above and beyond that caused by the subject’s AD 3. Subjects with a history of seizures within 5 years of Screening or subjects with disturbance likely to be due to seizures within 5 years of Screening 4. History of transient ischemic attacks (TIA) or stroke within 12 months of Screening 5. Modified Hachinski Ischemia Score greater than 4 at Screening 6. Any of the following psychiatric symptoms: a. Psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or delusions) that, in the opinion of the investigator, could interfere with study procedures b. Has a “yes” answer to C-SSRS suicidal ideation items 4 or 5, or any suicidal behavior within 6 months before Screening, at Screening, or at the Randomization Visit, or has been hospitalized or treated for suicidal behavior in the past 5 years before Screening 7. Have any contraindications to 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 a. Have any evidence of other clinically significant lesions that could indicate a dementia diagnosis other than AD on brain MRI at Screening. b. Exhibit other significant pathological findings on central read of the brain MRI at Screening, including but not limited to: an area of superficial siderosis; evidence of cerebral vasogenic edema; evidence of cerebral contusion, encephalomalacia, aneurysms, vascular malformations, or infective lesions; evidence of multiple lacunar infarcts; evidence of stroke involving a major vascular territory; severe small vessel or diffuse white matter disease as defined by a score of 3 on the age-related white matter changes scare (Wahlund, et al., 2001); 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). 8. Subjects who have a history of moderate to severe hepatic impairment (eg, Child-Pugh Class B or C). Any 2 of the following criteria at Screening would exclude the subject: INR ≥ 1.7; bilirubin ≥ 1.5 × ULN; albumin < LLN; ascites or hepatic encephalopathy. Please note that a single significant abnormality could meet criteria for moderate impairment. 9. Results of laboratory tests conducted during screening that are outside the following limits: a. Absolute lymphocyte count (ALC) below Lower Limit of Normal (LLN) or below 800 per mm3 (whichever is higher); ALC will be derived from the complete blood count (CBC) with differential representing the normal lymphocytes (with atypical lymphocytes removed and presented as a separate count if they are present) and calculated by the white blood cell count × percentage of lymphocytes. b. Thyroid stimulating hormone (TSH) above 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 subjects whether or not they are taking thyroid supplements) c. Abnormally low (below LLN) serum Vitamin B12 levels (if subject is taking Vitamin B12 injections, level should be at or above the LLN) 10. Subjects at risk of increased risk of infection, specifically: a. Subjects with chronic viral hepatitis. Subjects with a history of chronic viral hepatitis C may be included if they meet the following requirements: 1) evidence of treatment with direct antiviral combination therapy 2) evidence of sustained virological response at least 12 weeks post-treatment. The inclusion of subjects with a history of chronic viral hepatitis C must be discussed and agreed with the Medical Monitor. b. A history of active tuberculosis disease (TB), a history of ophthalmic shingles or a history of ocular herpes simplex virus (HSV) infection c. Any active infection within the last 4 weeks before randomization. For such cases, the timing of randomization can be extended (up to 4 weeks) to allow the infection to resolve d. Any immunological disease which is not adequately controlled, or which requires treatment with biologic drugs during the study. History of immunoglobulin deficiency or other immunodeficiency disorders (including subjects known to be HIV positive) 11. Have received any live vaccine/live attenuated vaccine in the 3 months before randomization 12. Any chronic inflammatory disease that is not adequately controlled or that requires systemic immunosuppressive or immunomodulatory therapy. NOTE: The following subjects do not need to be excluded: a. Subjects with seasonal or perennial allergic rhinitis, asthma, or chronic obstructive pulmonary disease where the condition is considered to be stable and adequately controlled by inhaled steroids. b. Hashimoto’s thyroiditis but who are stable on thyroid replacement therapy and not on systemic immunosuppressive therapy. c. Cutaneous manifestations of immunological disease that do not require systemic immunosuppressive therapy or systemic immunomodulatory therapy (ie, topical steroid treatment is permitted) 13. Any other clinically significant abnormalities, such as: a. Physical examination or vital signs 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. b. Laboratory tests or ECG at Screening that in the opinion of the investigator require further investigation or treatment or may interfere with study procedures or safety. c. Other medical conditions (eg, cardiac, respiratory, gastrointestinal, psychiatric, renal disease) which are not adequately and stably controlled, or which in the opinion of the investigator(s) could affect the subject’s safety or interfere with the study assessments d. Illiteracy, or severe visual or hearing impairment that would prevent the subject from performing psychometric tests accurately 14. A prolonged QTc interval calculated using Fridericia’s formula (QTcF) interval (QTcF greater than 450 ms according to central reading at Screening). If the QTcF is greater than 450 ms on the first single 12-lead ECG, 2 additional 12 lead ECGs will be performed 1 minute apart and the mean of the 3 QTcF values will be calculated. 15. Malignant neoplasms within 5 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 prior to screening). Subjects who had malignant neoplasms but who have had at least 5 years of documented uninterrupted remission before Screening need not be excluded. 16. Hypopigmentation conditions (eg, albinism and vitiligo). Hypopigmentation associated with scarring need not be exclusionary 17. Known or suspected history of drug or alcohol abuse or dependence within 2 years before Screening 18. Taking prohibited medications 19. Have participated in a clinical study involving: a. any therapeutic monoclonal antibody, protein derived from a monoclonal antibody, immunoglobulin therapy, or vaccine within 6 months before Screening for whom it cannot be documented that they were randomized only to placebo or never received study drug b. elenbecestat (E2609) c. any new chemical entity for AD with last study drug dose occurring within 6 months prior to Screening unless it can be documented that the subject received only placebo d. any other investigational medication (unless it can be documented that the subject received only placebo) or device within 8 weeks or 5 half-lives (whichever is longer) before randomization 20. Planned surgery which requires general, spinal or epidural anesthesia that would take place during the study. Planned surgery which requires only local anesthesia and which can be undertaken as day case without inpatient stay postoperatively need not result in exclusion if in the opinion of the investigator this operation does not interfere with study procedures and subject safety.|
|Location||Orlando, FL, Melbourne, FL, The Villages, FL|