| Eligibility |
Inclusion Criteria:
- Male or female aged 45-75 years at the time of informed consent.
- Unless confirmed to be azoospermic (vasectomized or secondary to medical cause), males
must agree to use a male condom plus partner use of an additional contraceptive method
from the start of confinement or Day -1 up to 90 days after the last study drug
administration when having penile-vaginal intercourse with a woman of childbearing
potential who is not currently pregnant. Sperm donation is not allowed during this
period. Note: Men with a pregnant or breastfeeding partner must agree to remain
abstinent from penile-vaginal intercourse or use a condom during each episode of
penile-vaginal penetration.
- Females of childbearing potential must have a negative serum pregnancy test during
Screening and a negative urine pregnancy test before first dose of study drug. In
addition, they must be willing to abstain from egg collection or donation from start
of Screening through 90 days after the last study drug administration.
- Females of childbearing potential (i.e., not postmenopausal or surgically sterile) who
have a male partner must agree to one of the following options from signing of
informed consent through 90 days after the last study drug administration: use of a
highly effective method of birth control, or confirmed sterilization of a monogamous
partner, or practice abstinence.
- Females of non-childbearing potential may be enrolled if they are postmenopausal or
have documented evidence of surgical sterilization.
- Stable medical conditions for at least 3 months prior to Screening visit (e.g.,
hypertension, dyslipidemia)
- Stable use of vitamin E (up to 400 IU daily), estrogens, aspirin (75-300 mg daily),
blood pressure medications (except for adrenergic agents), and cholesterol-lowering
agents for at least 3 months prior to screening is allowed.
- In generally good health based on medical and surgical history, BMI, physical
examination, vital signs, 12-lead ECG and laboratory values, including hematology and
chemistry values.
- Clinical laboratory values within normal limits or, if abnormal, must be judged to be
clinically insignificant.
- Able to understand and sign the written Informed Consent Form (ICF).
- Willing to follow the protocol requirements and comply with protocol restrictions.
In addition, for subjects with MCI:
- Must meet the criteria for amnestic Mild Cognitive Impairment (MCI), as per the
National Institute on Aging-Alzheimer's Association core clinical criteria.
- No dementia according to International Classifications of Diseases (ICD)-10 and
Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV.
- A score of greater than or equal to one standard deviation below age and educational
norms in the Digit Symbol Substitution Test (DSST) during screening.
- A memory complaint reported by the subject or his/her partner.
- Cognitive decline not primarily caused by vascular, traumatic, or medical problems.
- Preserved basic activities of daily living and no more than minimal impairment.
In addition, for subjects with PD:
- Parkinson's disease (PD) defined by the cardinal sign, bradykinesia, plus the presence
of at least 1 of the following: resting tremor, rigidity, or impairment of postural
reflexes, and without any other known or suspected cause of Parkinsonism
- Modified Hoehn & Yahr stage = 3 during "On" period as documented in the 3 months prior
to Screening.
- Mini Mental Status Examination (MMSE) score =26.
- If taking medications for PD, subjects on stable (=3 months prior to Day 1)
levodopa/carbidopa or levodopa/benserazide, monoamine oxidase type B inhibitors,
dopamine agonists or catechol-O-methyltransferase inhibitors are allowed. Subjects on
ß-antagonists are not allowed.
Exclusion Criteria:
- Female subjects who are pregnant or lactating.
- History of any significant cardiovascular, hepatic, renal, pulmonary, hematologic,
gastrointestinal, endocrine, immunologic, dermatologic, neurologic, metabolic,
psychological, or musculoskeletal disease.
- Subjects with a history of malignant disease, including solid tumours and hematologic
malignancies (except basal cell and squamous cell carcinomas of the skin that have
been completely excised and are considered cured).
- Calculated creatinine clearance of =60 mL/min.
- Positive screening test for human immunodeficiency virus (HIV).
- Positive screening test for hepatitis C antibody (HCV Ab) or current hepatitis B
infection (defined as positive for hepatitis B surface antigen [HBsAg] at Screening).
Subjects with immunity to hepatitis B (defined as negative HBsAg and positive
hepatitis B core antibody [anti-HBc]) are eligible to participate in the study.
- Positive test for and current infection with severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) at Screening, or evidence of possible ongoing infection
based on body temperature (> 37.3 oC), blood oxygen (<90 %) at the start of first
confinement or Day -1.
- History of epilepsy, seizure disorder or any unexplained black-outs.
- Suicidal ideation with actual intent or plan ("Yes" answer on the Columbia-Suicide
Severity Rating Scale [C-SSRS] ideation items 4 or 5) within 3 months prior to study
Screening.
- History of drug or alcohol abuse =12 months prior to Screening.
- History of tobacco use including cigarettes, cigars, vapes or e-cigarettes =6 months
prior to Screening.
- A positive test for drugs of abuse, cotinine or alcohol during Screening or prior to
dosing.
- Unwilling or unable to abstain from alcohol or caffeine for 48 hours prior to dosing
until end of each confinement or dosing period.
- Current use of any prohibited medication, over-the-counter medication, or herbal
supplements/products.
- History of relevant cardiovascular disease including angina, hypertension (unless
currently under control with stable medications), heart failure, coronary
insufficiency, cardiac arrhythmias, diabetes mellitus, hyperthyroidism, convulsion
disorders, bronchial asthma, clinically significant sinus bradycardia and greater than
first degree conduction block.
- Clinically significant abnormal clinical laboratory test values.
- Clinically significant abnormalities in 12-lead ECG, including marked baseline
prolongation of QT/QTcF interval (e.g., repeated demonstration of a QTcF interval >450
msec) at Screening.
- Prior treatment with any investigational drug =30 days prior to dosing (Day 1), or =5
half-lives of the drug (whichever is longer), or current enrolment in any other study
treatment or disease study.
- Vaccinations =14 days prior to dosing.
- Donation or loss of =500 mL of blood or plasma within 30 days prior to dosing.
- Inability to undergo a clinical MRI of the brain without contrast.
- Clinically significant brain abnormalities based on T1 weighted MRI during screening.
- Any other reason which prompts the Principal Investigator to consider that it is not
in the best interest of the subject to participate in the study.
|
