Caregiver/Study Partner Exclusion Criteria:
Although Caregivers/Study Partners are not counted in the enrollment numbers as "subjects", there are reasons why a caregiver may not be able to participate in the trial:
Caregiver does not have a close relationship with the subject with AD.
Caregiver does not see him/her at least 3 days each week for a minimum of 6 waking hours each week.
Caregiver is unwilling or unable to go to all of the trial visits with him/her.
Caregiver is unwilling or unable to ensure that he/she takes the trial drug as instructed, and follow all of the trial requirements.
Caregiver is unable or unwilling to answer questions about the AD subject’s daily living activities, and his/her ability to understand, reason and make judgments.
Caregiver is unable or unwilling to follow all of the requirements of the trial as they pertain to your participation, or unwilling to consent to audio recording of selected interviews.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has a Rosen-modified Hachinski Ischemia Scale (MHIS) score > 4 at Screening (i.e., evidence of vascular dementia).
2. Has a known history of stroke or structural changes on screening MRI scan that are clinically important in the PI’s opinion, including signs indicative of vascular dementia, large infarct, lacunes in critical areas, space-occupying lesions, or extensive white matter disease.
3. Has evidence of a clinically relevant neurological disorder other than the disease being studied (i.e., 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.
4. Has a history of seizures or epilepsy within the last five years before Screening.
5. Has evidence of a clinically relevant or unstable psychiatric disorder, based on the DSM-IV-TR criteria, including schizophrenia or other psychotic disorder, bipolar disorder, major depression, substance abuse disorders, or delirium. Major depression in remission for >2 years is not exclusionary.
6. Has evidence of a current episode of major depression based on PI’s judgment. A score on the 15-item Geriatric Depression Scale (GDS) 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. Is at imminent risk of self-harm, based on clinical interview and responses on the CSSRS, or of harm to others in the opinion of the PI. Subjects must be excluded if they report suicidal ideation with intent, with or without a plan or method (e.g. positive response to Items 4 or 5 in assessment of suicidal ideation on the C-SSRS) in the past two months, or suicidal behavior in the past six months.
8. Has a history of alcoholism or drug dependency/abuse within the last 5 years of Screening.
9. Is unwilling or not eligible (e.g., metal implants, obesity) to undergo an MRI scan at the Screening Visit (see the MRI procedure manual and imaging charter for details).
10. Has one or more of the following laboratory findings:
a. Alanine aminotransferase (ALT) ≥ 3x upper limit of normal (ULN), OR
b. Aspartate aminotransferase (AST) ≥ 3x ULN, OR
c. Total bilirubin (T-BIL) ≥ 1.5x ULN.
Should a liver function test (LFT) be abnormal (ALT/AST > ULN but < 3x ULN, T-BIL > ULN but < 1.5x ULN) at Screening but not meet the specified criteria, the PI should attempt to characterize at entry the reason(s) for the elevation (e.g., alcohol abuse, metabolic syndrome with fatty liver, etc.). Subjects with suspected Gilbert’s Syndrome who have isolated T-BILI ≥ 1.5x ULN may enter the trial upon genetic confirmation (e.g., uridine disphosphate glucuronosyltransferase 1A1 [UGT1A1] assessment).
11. Has an estimated creatinine clearance of less than 50 mL/min, OR estimated creatinine clearance between 40 and 50 mL/min inclusive along with actual creatinine clearance (by 24-hour urine collection before randomization) of < 50 mL/min:
a. For Males: Creatinine Clearance = (140 – Age[yr]) x Weight (kg) serum creatinine (mg/dL) x 72
b. For Females: Creatinine Clearance = 0.85 x (140 – Age[yr]) x Weight (kg) serum creatinine (mg/dL) x 72
NOTE: A 24-hour creatinine clearance sample may be obtained and analyzed prior to randomization for subjects who have estimated creatinine clearance values of 40-50 mL/min, both inclusive. In this case, only subjects with creatinine clearance values ≥50 mL/min confirmed via 24-hour sampling will be considered for randomization at V3.
12. Has at least one of the following:
a. Clinically significant vitamin B12 deficiency, or increased thyroid stimulating hormone [TSH], in the six months immediately before Screening, or Vitamin B12 deficiency at Screening as determined by central laboratory normal values. (Treated B12 deficiency is allowed if stable normal levels on treatment), or
b. Abnormally elevated TSH as determined by central laboratory normal values.
13. Has a history of hepatitis or liver disease that, in the opinion of the PI, has been active within the six months prior to Screening.
14. Has a recent or ongoing, uncontrolled, clinically significant medical condition within 3 months of Screening (such as, but not limited to, diabetes, hypertension, thyroid or endocrine disease, congestive heart failure, angina, cardiac or gastrointestinal disease, dialysis) where participation in the trial would pose a significant medical risk to the subject. 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 Visit 3.
15. 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, as determined by an ECG read by a central ECG vendor.
16. Has a history of malignancy occurring within the five years immediately before Screening, except for a subject who had been adequately treated for:
a. Basal cell or squamous cell skin cancer,
b. In situ cervical cancer, or
c. Localized prostate carcinoma, or
d. Who had undergone potentially curative therapy with no evidence of recurrence for ≥ 3 years post-therapy, and who is deemed at low risk for recurrence by her/his treating physician.
17. Has donated blood products or has had phlebotomy of > 300 mL within 8 weeks of signing the informed consent, or intends to donate or receive blood products during participation in the trial.
18. Has had major surgery, (for example: abdominal, thoracic, cardiac or orthopedic surgery, or any procedure requiring general anesthesia) within 3 months prior to Screening.
19. Is currently participating in another investigational trial, or previously participated in another investigational trial (including any Merck & Co. Inc. studies) within 3 months prior to Screening.
20. Is or has an immediate family member (spouse or children) who is investigational site or sponsor staff directly involved with this trial.
21. Is pregnant, is attempting to become pregnant, or is nursing children.
22. Is unable to meet medication washout requirements prior to Visit 2, as listed in Table 3. See Section 5.5 and 220.127.116.11 for additional details.
23. Anticipates receiving any of the medications listed in Table 3 during the current trial.
Criteria to be assessed at Visit 3, prior to randomization:
24. Meets any Exclusion criteria previously assessed at Visit 1.
25. Is unable to tolerate trial medication from Visit 2 to Visit 3.
26. Has less than a 75% drug compliance rate for trial medication taken from Visit 2 to Visit 3, as assessed by a standard pill count.