A subject meeting any of the exclusion criteria listed below must be excluded from the trial:
1. Rosen-modified Hachinski Ischemia Score > 4 at Screening (i.e., evidence of vascular dementia).
2. Known history of stroke or evidence from screening MRI scan that is clinically important in the investigator's opinion.
3. Evidence of a clinically relevant neurological disorder other than probable AD at Screening, including but not limited to: vascular dementia, parkinsonism, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, progressive supranuclear palsy, neurosyphilis, dementia with Lewy bodies, other types of dementia, mental retardation, hypoxic cerebral damage, cognitive impairment due to other disorders, or head trauma with loss of consciousness that led to persistent cognitive deficits.
Protocol A4 Changes: The subject has evidence of a clinically relevant neurological disorder other than the disease being studied (ie, probable AD) at Screening, including but not limited to: vascular dementia, parkinsonism, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, progressive supranuclear palsy, neurosyphilis, dementia with Lewy bodies, posterior cortical atrophy, logopenic primary progressive aphasia, other types of dementia, mental retardation, hypoxic cerebral damage, cognitive impairment due to other disorders, or head trauma with loss of consciousness that led to persistent cognitive deficits.
4. History of seizures or epilepsy within the last 5 years before Screening.
5. Evidence of a clinically relevant or unstable psychiatric disorder, based on DSM-IV-TR criteria, including schizophrenia or other psychotic disorder, bipolar disorder, major depression, or delirium. Major depression in remission is not exclusionary.
6. Evidence of a current episode of major depression based on investigator's judgment. A score on the 15-item Geriatric Depression Scale of 5 or more requires an assessment by an appropriate health care professional to evaluate for the presence of major depression. Subjects with a score of 5 or more who are not diagnosed with major depression following such an assessment may be included in the trial.
7. At imminent risk of self-harm, based on clinical interview or on the Columbia Suicidality Severity Rating Scale (C-SSRS), or of harm to others in the opinion of the investigator. Subjects must be excluded if they report suicidal ideation with intent, with or without a plan (i.e., suicidal ideation Type 4 or 5 on the C-SSRS) in the past 1 month or suicidal behavior in the past 6 months.
8. History of alcoholism or drug dependency/abuse within the last 5 years before Screening.
9. Unwilling or not eligible to undergo an MRI scan (eg, metal implants, obesity).
10. MRI scan obtained at Screening shows evidence of:
a. a neurological disorder other than probable AD or
b. > 4 cerebral microhemorrhages (regardless of their anatomical location or diagnostic characterization as "possible" or "definite"),
c. a single area of superficial siderosis,
d. evidence of a prior macrohemorrhage,
e. > 3 lacunar infarcts,
f. any cortical infarct over 10 mm,
g. or any other clinically significant finding (eg, any lesion that may account for their cognitive impairment, including but not limited to brain tumor, severe white matter disease, arteriovenous malformation, cavernous hemangioma, or any infarct in a strategic subcortical location).
11. At Screening has
a. alanine aminotransferase (ALT) ≥ 3 x upper limit of normal (ULN), OR
b. aspartate aminotransferase (AST) ≥ 3 x ULN, OR
c. total bilirubin (T-BIL) ≥ 1.5 x ULN.
i. Should a liver function test (LFT) be abnormal (ALT/AST >ULN but < 3x ULN, T-BIL > ULN but < 1.5 x ULN) at Screening but not meet the specified criteria, the investigator should attempt to characterize at entry the reason(s) for the elevation (eg, alcohol abuse, metabolic syndrome with fatty liver, etc.).
ii. Subjects with suspected Gilbert's Syndrome who have isolated T-BILI ≥ 1.5 x ULN may enter the trial upon genetic confirmation (eg, uridine diphosphate glucuronosyltransferase 1A1 [UGT1A1] assessment).
12. History of hepatitis or liver disease that, in the opinion of the investigator, has been active within the six months prior to Screening.
13. Recent or ongoing, uncontrolled, clinically significant medical condition within 3 months of the Screening Visit other than the condition being studied such that, in the judgment of the investigator, participation in the trial would pose a significant medical risk to the subject. (Such as, but not limited to, diabetes, hypertension, thyroid or endocrine disease, congestive heart failure, angina, cardiac or gastrointestinal disease, dialysis, or abnormal renal function with estimated creatinine clearance < 30 mL/min.)
Controlled co-morbid conditions (including diabetes, hypertension, heart disease, etc.) are not exclusionary if stable within three months of the Screening Visit. All concomitant medications, supplements, or other substances must be kept as stable as medically possible during the trial. Note: urinary tract infections at screening are not exclusionary if adequately treated (as documented by repeat urinalysis) prior to baseline.
14. History or current evidence of long QT syndrome, QTC interval ≥ 470 milliseconds (for male subjects) or ≥ 480 milliseconds (for female subjects), or torsades de pointes.
Protocol A4 Changes: The subject has a history or current evidence of long QT syndrome, QTC interval ≥ 470 milliseconds (for male subjects) or ≥ 480 milliseconds (for female subjects), or torsades de pointes. (Note: Determination of QTc interval at Screening will be based on the average of three measurements, using the Fridericia formula for correction.)
15. History of malignancy occurring within the five years immediately before Screening, except for a subject who has been adequately treated for:
a. basal cell or squamous cell skin cancer,
b. in situ cervical cancer, or
c. localized prostate carcinoma; or
d. has undergone potentially curative therapy with no evidence of recurrence for ≥ 3 year post-therapy, and who is deemed at low risk for recurrence by her/his treating physician.
16. Has clinically significant vitamin B12 or folate deficiency in the six months immediately before screening or vitamin B12 or folate deficiency in addition to increased serum homocysteine or methylmelonic acid levels at screening as determined by central laboratory normal values.
17. Is pregnant, attempting to become pregnant, or nursing children.
18. Received any protocol-prohibited medications, supplements or other substances more recently than the indicated period before screening.
19. Anticipates receiving any of the protocol-prohibited medications, supplements or other substances during the current trial.
Please see the document "Prohibited Medications, Supplements and Other Substances" in the "Other Documents" page of this study application for a complete list of prohibited medications.
20. Known allergy or sensitivity to the excipients in the investigational product(s).
21. Any clinically significant condition or situation, other than the condition being studied, that, in the opinion of the investigator, would interfere with the trial evaluations, required procedures (eg, ophthalmological monitoring) or optimal participation in the trial.
22. Has used any investigational drugs or has been participating in any other clinical trial within the 30 days immediately before Screening.
23. History of a hypersensitivity reaction to more than three drugs.
24. History of erythroderma (exfoliative dermatitis), DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms), Stevens-Johnson Syndrome or toxic epidermal necrolysis.
25. Has tested positive for HIV.
26. Has a close family member (including the caregiver) who is among the personnel of the investigational or sponsor staff directly involved with this trial.
27. Has exudative (wet) age-related macular degeneration, active proliferative diabetic retinopathy, myopia or hyperopia > 8 diopters, pigment dispersion syndrome, pseudo-exfoliation syndrome, pigmentary glaucoma, glaucoma that requires > 2 classes of medications, IOP > 21 mmHg (at the Screening Visit), clinically significant macula edema with diabetic retinopathy or advanced cataract to the degree that does not allow SD-OCT measurement, nystagmus, or other significant retinal diseases causing such significant distortion that baseline measurements would be too greatly abnormal to allow reasonable detection of possible change.
Additional Exclusion Criteria for Safety Cohort
28. History of an ongoing medical condition that has been poorly controlled within 6 months of the Screening Visit (such as, but not limited to, syncope, hypotension, diabetes, hypertension, cerebrovascular disease, thyroid disease, endocrine disturbance, congestive heart failure, cardiac or gastrointestinal disease, dialysis, or abnormal renal function with estimated creatinine clearance < 30 mL/min) other than the condition being studied such that, in the judgment of the investigator, a subject's participation in the trial would pose a significant medical risk.
29. History of congestive heart failure (moderate or greater severity), myocardial infarction, heart surgery, syncope, bradycardia, or clinically significant hypotension within one year immediately before Screening.
30. Has used warfarin within one month before Screening (NOTE: antiplatelet drugs are acceptable).
31. Has used digoxin within one month before Screening.
32. Has used a strong P-glycoprotein (P-gp) inhibitor (eg, carvedilol, dronedarone, erythromycin, probenecid , quercetin, quinidine, ranolazine, and verapamil) within one month before Screening.
33. Has trans-illumination defects of the iris, irregularly shaped pupil, or cataract surgery within 6 months before Screening. Results of drug-drug interaction trials with warfarin, digoxin, and itraconazole (a strong P-gp inhibitor) are expected to be available before the initiation of the Main Cohort and the protocol will be amended as needed.
Additional Exclusion Criteria for the CSF Substudy
34. Increased intracranial pressure (ICP), bleeding diathesis (eg, from use of anticoagulants), skin infection at lumbar puncture (LP) site, or prior history of LP-associated headache(s).
Our site will not be participating in the PET substudy at this time.