A Multiple Ascending Dose Study in Healthy Volunteers and Patients With Alzheimer's Disease

Prior treatment

• Use of psychoactive medications (typical neuroleptics, narcotic analgesics, antiparkinsonian medications, systemic corticosteroids, or medications with significant central anticholinergic activity) within 2 weeks or 5 half-lives (whichever is greater) prior to study drug administration and for the duration of the trial.
• Use of medications with potential drug-drug interactions (see Appendix A for a list of these medications) within 2 weeks or 5 half-lives (whichever is greater) prior to study drug administration and for the duration of the trial.
• Use of anticoagulants within 30 days or 5 half-lives (whichever is greater) prior to study drug administration and for the duration of the trial.
• Use of another investigational agent within 30 days or 5 half-lives (whichever is greater) prior to screening and for the duration of the trial.
• Hospitalization or change of chronic concomitant medication within 4 weeks prior to baseline
• Screening MRI of the brain indicative of significant abnormality, including, but not limited to, prior hemorrhage or infarct \>1 cm3, \>3 lacunar infarcts, cerebral contusion, encephalomalacia, aneurysm, vascular malformation, subdural hematoma, hydrocephalus, or space-occupying lesion (e.g., abscess or brain tumor such as meningioma)
• Nootropic drugs except stable AD meds (acetylcholinesterase inhibitors and memantine) for 12 weeks prior to baseline
• Use of psychoactive medications (typical neuroleptics, narcotic analgesics, antiparkinsonian medications, systemic corticosteroids, or medications with significant central anticholinergic activity) within 2 weeks or 5 half-lives (whichever is greater) prior to study drug administration and for the duration of the trial
• Use of medications with potential drug-drug interactions (see Appendix A for a list of these medications) within 2 weeks or 5 half-lives (whichever is greater) prior to study drug administration and for the duration of the trial.
• Use of anticoagulants within 30 days or 5 half-lives (whichever is greater) prior to study drug administration and for the duration of the trial
• Use of investigational amyloid lowering therapies within 2 months prior to study drug administration and for the duration of the trial.
• Use of another investigational agent within 30 days or 5 half-lives (whichever is greater) prior to screening and for the duration of the trial

Other illness

• Any significant neurologic disease, such as AD, Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities.
• A current Diagnostic and Statistical Manual of Mental Disorders, Fifth revision (DSM V) diagnosis of active major depression, schizophrenia or bipolar disorder. Participants with depressive symptoms successfully managed by a stable dose of an antidepressant are allowed entry.
• Positive urine drug screen for amphetamines, barbiturates, benzodiazepines, cocaine, opiates, tetrahydrocannabinol (THC), ethanol or cotinine (stable prescribed amphetamines or benzodiazepines for a non-exclusionary medical condition are permitted) or positive alcohol breathalyzer test
• History of alcohol or substance abuse or dependence within the past 2 years (DSM IV criteria).
• Clinically significant or unstable medical condition, including uncontrolled hypertension, uncontrolled diabetes, or significant cardiac, pulmonary, renal, hepatic, endocrine, or other systemic disease in the opinion of the PI, may either put the participant at risk because of participation in the study, or influence the results, or the participant's ability to participate in the study.
• Any disorder that could interfere with the absorption, distribution, metabolism or excretion of drugs (e.g., small bowel disease, Crohn's disease, celiac disease, or liver disease.)
• Seropositive for human immunodeficiency virus (HIV).
• History of acute/chronic hepatitis B or C and/or carriers of hepatitis B (seropositive for hepatitis B surface antigen \[HbsAg\] or anti-hepatitis C \[HCV\] antibody).
• Any contraindications for MRI studies, such as claustrophobia, the presence of metal (ferromagnetic) implants, metal fragments or foreign objects in the eyes, skin, or body or a cardiac pacemaker.
• A current DSM V diagnosis of active major depression, schizophrenia or bipolar disorder. Participants with depressive symptoms successfully managed by a stable dose of an antidepressant are allowed entry.
• Clinically significant or unstable medical condition, including uncontrolled hypertension, uncontrolled diabetes, or significant cardiac, pulmonary, renal, hepatic, endocrine, or other systemic disease that in the opinion of the PI, may either put the participant at risk because of participation in the study, or influence the results, or impair the participant's ability to participate in the study.
• Any disorder that could interfere with the absorption, distribution, metabolism or excretion of drugs (e.g., small bowel disease, Crohn's disease, celiac disease, or liver disease.)
• History of alcohol or substance abuse or dependence within the past 2 years (DSM IV criteria).
• Suspected or known allergy to any components of the study treatments
• Any condition, which in the opinion of the investigator or Project Director (PD) makes the participant unsuitable for inclusion

Lab values

• Neutropenia defined as absolute neutrophils count of \<1,500/microliter.
• Thrombocytopenia defined as platelet count \<100,000/microliter.
• Clinically significant abnormalities in screening laboratories, including aspartate aminotransferase (AST) \>1.5 times the upper limit of normal (ULN); alanine aminotransferase (ALT) \>1.5 times ULN; total bilirubin \>1.5 times ULN; serum creatinine \>2.0 times ULN.
• Clinical or laboratory findings consistent with:
  • Other primary neurodegenerative disease or cognitive disorder (Lewy body disease, frontotemporal lobar disease, Huntington's disease, Jacob-Creutzfeld Disease, Down's syndrome, Parkinson's disease, amyotrophic lateral sclerosis, etc.)
  • Seizure disorder
  • Other infectious, metabolic or systemic diseases affecting the central nervous system (syphilis, present hypothyroidism, present vitamin B12 deficiency, other laboratory abnormalities, etc.)
• Neutropenia defined as absolute neutrophils count of \<1,500/microliter
• Thrombocytopenia defined as platelet count \<100,000/microliter.
• Clinically significant abnormalities in screening laboratories, including AST \>1.5 times ULN; ALT \>1.5 times ULN; total bilirubin \>1.5 times ULN; serum creatinine \>2.0 times ULN

Other

• Body mass index (BMI) \>38 kg/m2 or body weight \<50 kg.
• Current nicotine use or positive urine cotinine test.
• Geriatric Depression Scale (GDS) score of ≥5 and symptoms consistent with a current episode of major depression.
• BMI \>38 kg/m2 or body weight \<50 kg
• Living in a continuous care nursing facility
• Disability that may prevent the participant from completing all study requirements (e.g., blindness, deafness, severe language difficulty, etc.)
• Clinically significant abnormalities in B12 or thyroid function tests (TFTs) that might interfere with the study
• GDS score of ≥5 and symptoms consistent with a current episode of major depression.

• Men or women between the ages of 50 and 80 years, inclusive
• No history of cognitive impairment
• Capable of providing written informed consent and willing to comply with all study requirements and procedures
• Participant is not pregnant, lactating, or of childbearing potential
  • Non-childbearing potential for women is defined as postmenopausal (last natural menses greater than 24 months prior; menopausal status will be documented with serum follicle-stimulating hormone (FSH) or documentation of bilateral tubal ligation or hysterectomy
  • Male participants who are sexually active with a woman of childbearing potential must agree to use condoms during the trial and for 3 months after the last dose unless the woman is using an acceptable means of birth control. Acceptable forms of birth control include abstinence, birth control pills, or any double combination of intrauterine device (IUD), male or female condom, diaphragm, sponge, and cervical cap.
  • Male participants must also agree not to donate sperm for 90 days after the last dose.
• Montreal Cognitive Assessment (MOCA) \>25
• Men or women between the ages of 50 and 85 years, inclusive, at the time of first dose of investigational product (IP).
• Diagnosis of either amnestic mild cognitive impairment (aMCI) or mild dementia due to AD as defined by
  • Mild dementia due to AD
  • National Institute on Aging (NIA)-Alzheimer's Association core clinical criteria for dementia due to probable AD (McKhann 2011) and,
  • Mini Mental Status Exam (MMSE) score between 18 and 26 (inclusive)
  • Clinical Dementia Rating (CDR) global score of 0.5 or 1
  • aMCI due to AD
  • Subjective memory complaint preferably corroborated by an informant and,
  • Normal activities of daily living
  • CDR global score of 0.5
  • aMCI (Petersen 2004) as evidenced by abnormal memory function documented by scoring 1.5 SD below the education adjusted cutoff on the Logical Memory II subscale (Delayed Paragraph Recall) from the Wechsler Memory Scale - Revised (the maximum score is 25), and
  • 8 for 16 or more years of education
  • 4 for 8 15 years of education
  • 2 for 0 7 years of education
• Stable pharmacological treatment of any other chronic conditions for at least 4 weeks prior to baseline.
• Neuroimaging (MRI) obtained during screening consistent with the clinical diagnosis of AD as defined in Criteria 2 and without findings of significant exclusionary abnormalities (see Section 6.2.2, exclusion criteria, Number 4).
• Study partner is available who has frequent contact with the participant (e.g., average of 10 hours per week or more), and can participate in all study partner assessments for the duration of the protocol.
• Generally healthy with mobility (ambulatory or ambulatory-aided, i.e., walker or cane), vision and hearing (hearing aid permissible) sufficient for compliance with testing procedures as determined by the PI.
• Must be able to complete all screening evaluations
• Living at home or in the community (assisted living acceptable)
• Ability to swallow study medication.
• Modified Hachinski score ≤4
• Capable of providing written informed consent and willing to comply with all study requirements and procedures
• Participant is not pregnant, lactating, or of childbearing potential
  • Non-childbearing potential for women is defined as postmenopausal (last natural menses greater than 24 months prior; menopausal status will be documented with serum FSH or documentation of bilateral tubal ligation or hysterectomy
  • Male participants who are sexually active with a woman of childbearing potential must agree to use condoms during the trial and for 3 months after the last dose unless the woman is using an acceptable means of birth control. Acceptable forms of birth control include abstinence, birth control pills, or any double combination of IUD, male or female condom, diaphragm, sponge, and cervical cap.
  • Male participants must also agree not to donate sperm for 90 days after the last dose.