| Eligibility |
Inclusion Criteria:
To qualify for enrollment, subjects must meet all of the following inclusion criteria:
All Subjects:
- Capable of understanding the written informed consent document; willingly provides
valid, signed written informed consent; willing and able to comply with the study
schedule, requirements, and restrictions.
- Continuous non smoker who has not used nicotine containing products for at least 3
months prior to the first dosing.
- Body mass index (BMI) = 18.0 and = 32.0 kg/m2 at the screening visit.
- In good general health, free from clinically significant medical or psychiatric
illness, based on medical/surgical history, physical examination, and clinical
laboratory tests.
- All laboratory parameters (serum chemistry, hematology, coagulation, and urinalysis)
are within the reference range or considered not clinically significant by the PI, at
the screening visit.
- Negative results for human immunodeficiency virus (HIV), Hepatitis B virus (HBV), and
Hepatitis C virus (HCV) tests (as outlined in protocol) at the screening visit.
- Female subjects must have negative results for pregnancy test at the screening visit
and the first check-in and must not be lactating.
- Able to swallow multiple capsules.
- Adequate venous access in the left or right arm to allow collection of the required
blood samples.
Parts 1 (SAD) and 2 (MAD):
- Healthy, adult, male or female, 19-60 years of age, inclusive, at the screening visit.
- Females of childbearing potential .
- Females of non-childbearing potential are defined as follows:
- Individuals who have undergone one of the following sterilization procedures
at least 6 months prior to the first dosing:
- hysteroscopic sterilization;
- bilateral tubal ligation or bilateral salpingectomy;
- hysterectomy;
- bilateral oophorectomy. or
- Individuals who are postmenopausal (PMP) with amenorrhea for at least 1 year
prior to the first dosing and follicle stimulating hormone (FSH) serum
levels consistent with PMP status.
- Females of childbearing potential and male subjects must follow protocol-specified
contraception guidance.
- Vital signs must be within the protocol-specified ranges.
- No presence of a clinically significant ECG abnormality as judged by the PI or
qualified designee and as per protocol-specified ranges.
Part 3 (Elderly):
- Healthy, adult, male or female, 65-85 years of age, inclusive, at the screening visit.
- Females of childbearing potential.
- Females of non-childbearing potential are defined as follows:
- Individuals who have undergone one of the following sterilization procedures
at least 6 months prior to the first dosing:
- hysteroscopic sterilization;
- bilateral tubal ligation or bilateral salpingectomy;
- hysterectomy;
- bilateral oophorectomy. or
- Individuals who are postmenopausal (PMP) with amenorrhea for at least 1 year
prior to the first dosing and follicle stimulating hormone (FSH) serum
levels consistent with PMP status.
or
- Individuals who are PMP with amenorrhea for at least 1 year prior to the first dosing
and FSH serum levels consistent with PMP status.
- Females of childbearing potential and male subjects must follow protocol
specified contraception guidance.
- Vital signs must be within the protocol-specified ranges.
- QTcF interval is =450 msec (males) or =470 msec (females) and has ECG findings
considered normal or not clinically significant by the PI or designee at the
screening visit and prior to the first dosing.
Part 4 (Food Effect):
- Healthy, adult, male or female, 19-60 years of age, inclusive, at the screening visit.
- Females of childbearing potential.
- Females of non-childbearing potential are defined as follows:
- Individuals who have undergone one of the following sterilization procedures
at least 6 months prior to the first dosing:
- hysteroscopic sterilization;
- bilateral tubal ligation or bilateral salpingectomy;
- hysterectomy;
- bilateral oophorectomy. or
- Individuals who are PMP with amenorrhea for at least 1 year prior to the
first dosing and FSH serum levels consistent with PMP status.
- Females of childbearing potential and male subjects must follow protocol specified
contraception guidance.
- Vital signs must be within the protocol-specified ranges.
- QTcF interval is =450 msec (males) or =470 msec (females) and has ECG findings
considered normal or not clinically significant by the PI or designee at the screening
visit and prior to the first dosing.
- Able to completely consume a standardized high-fat/high-calorie breakfast as required
by the study protocol.
Exclusion Criteria:
- Subjects who meet any of the following criteria must be excluded from the study:
All Subjects:
- Is mentally or legally incapacitated or has significant emotional problems at the time
of the screening visit or expected during the conduct of the study.
- History or presence of malignancy within the past 2 years, with the exception of
adequately treated localized skin cancer (basal cell or squamous cell carcinoma) or
carcinoma in-situ of the cervix.
- History of any illness that, in the opinion of the PI or designee, might confound the
results of the study or poses an additional risk to the subject by their participation
in the study in the opinion of the PI or designee.
- Evidence of clinically relevant medical illness including cardiovascular,
hematological, psychiatric, gastrointestinal, hepatic, renal, rheumatologic,
autoimmune, endocrine, pulmonary, neurologic or dermatologic disorder in the opinion
of the PI or designee.
- History of skin rash(es) associated with the use of any medication(s).
- Any condition (e.g., chronic diarrhea) or prior surgery (e.g., gastric bypass) that
could interfere with drug absorption, distribution, metabolism, or excretion.
- Clinically significant surgical procedure within 90 days prior to the screening visit.
- Clinically significant acute illness or infection within 14 days prior to the first
dosing.
- History of significant drug allergies including a history of anaphylactic reaction.
- Family history of sudden death in an otherwise healthy individual.
- Positive urine cotinine at the screening visit or at first check-in.
- Excessive use of alcohol, defined as weekly intake in excess of 14 units of alcohol (1
unit = 12 fluid ounces of beer, 5 fluid ounces of wine, or 1.5 fluid ounces [1 shot]
of distilled spirits or liquor), within 6 months prior to the screening visit.
- Positive test result for alcohol or drugs of abuse at the screening visit or first
check-in, or history of alcohol and/or drug abuse within the past 2 years prior to the
screening visit.
- Heavy caffeine drinker (defined as consumption of >5 servings of caffeinated beverages
[e.g., coffee, tea, cola, energy drinks] per day).
- Refusal to refrain from strenuous physical activity from screening until first
check-in.
- Unwillingness to avoid sun and/or phototherapy exposure for 72 hours after the last
dose of study drug.
- Has been on a diet incompatible with the on study diet, in the opinion of the PI or
designee, within the 30 days prior to the first dosing.
- Use of any investigational drug or device within 30 days or biologics for 90 days (or
5 half-lives of the drug, whichever is the longer) prior to the first dosing, or
currently participating in another study of an investigational drug or biologics, or a
medical device.
- Loss or donation of >500 mL blood within 56 days prior to study drug administration,
or donation of plasma within 30 days prior to the first dosing.
- Employee or family member of the PI, study site personnel, or Sponsor.
- Any other reason that, in the opinion of the PI, would render the subject unsuitable
for study enrollment.
Parts 1 (SAD):
- History or presence of:
- risk factors for Torsade de Pointes (e.g., heart failure, cardiomyopathy, or
family history of Long QT Syndrome or sudden unexpected cardiac death at a young
age);
- sick sinus syndrome, second or third degree atrioventricular block, myocardial
infarction, pulmonary congestion, symptomatic or significant cardiac arrhythmia,
prolonged QTcF interval, or conduction abnormalities;
- ischemic heart disease, symptomatic arrhythmias, or poorly controlled
hypertension.
- conditions predisposing to QT prolongation including pathological Q-wave.
- Unable to refrain from or anticipates the use of:
- any drugs, including prescription and non prescription medications, herbal
remedies, or vitamin supplements beginning 14 days prior to the first dosing;
- any drugs known to be significant inducers of CYP enzymes and/or P gp, including
St. John's Wort, for 28 days prior to the first dosing. Appropriate sources
(e.g., Flockhart Table™) will be consulted to confirm lack of PK/pharmacodynamic
(PD) interaction with study drug;
- any drugs that prolong the QT/QTc interval within 14 days (or 5 half-lives,
whichever is longer) prior to the first dosing.
- Allergy to band aids, adhesive dressing, or medical tape.
- Glomerular filtration rate (GFR) = 80 mL/min/1.73 m2, as estimated by the Chronic
Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
Part 2 (MAD):
- History or presence of:
- risk factors for Torsade de Pointes (e.g., heart failure, cardiomyopathy, or
family history of Long QT Syndrome or sudden unexpected cardiac death at a young
age);
- sick sinus syndrome, second or third degree atrioventricular block, myocardial
infarction, pulmonary congestion, symptomatic or significant cardiac arrhythmia,
prolonged QTcF interval, or conduction abnormalities;
- ischemic heart disease, symptomatic arrhythmias, or poorly controlled
hypertension.
- conditions predisposing to QT prolongation including pathological Q-wave.
- Unable to refrain from or anticipates the use of:
- any drugs, including prescription and non prescription medications, herbal
remedies, or vitamin supplements beginning 14 days prior to the first dosing;
- any drugs known to be significant inducers of CYP enzymes and/or P gp, including
St. John's Wort, for 28 days prior to the first dosing. Appropriate sources
(e.g., Flockhart Table™) will be consulted to confirm lack of PK/PD interaction
with study drug;
- any drugs that prolong the QT/QTc interval within 14 days (or 5 half-lives,
whichever is longer) prior to the first dosing.
- Is at risk of suicide. Has attempted suicide in the past 12 months or Is at risk of
suicide, as determined by the PI, psychiatric interview and/or the baseline C-SSRS.
- Allergy to band aids, adhesive dressing, or medical tape.
- GFR = 80 mL/min/1.73 m2, as estimated by the CKD-EPI equation.
Part 3 (Elderly):
- Is at risk of suicide. Has attempted suicide in the past 12 months or Is at risk of
suicide, as determined by the PI, psychiatric interview and/or the baseline C-SSRS.
- Unable to refrain from or anticipates the use of:
- any drugs, including prescription and non prescription medications, herbal
remedies, or vitamin supplements beginning 14 days prior to the first dosing.
Thyroid hormone replacement medication (refer to protocol) will be allowed;
- any drugs known to be significant inducers of CYP enzymes and/or P gp, including
St. John's Wort, for 28 days prior to the first dosing. Appropriate sources
(e.g., Flockhart Table™) will be consulted to confirm lack of PK/PD interaction
with study drug.
- GFR = 70 mL/min/1.73 m2, as estimated by the CKD-EPI equation.
Part 4 (Food Effect):
- Is lactose intolerant.
- Unable to refrain from or anticipates the use of:
- any drugs, including prescription and non prescription medications, herbal
remedies, or vitamin supplements beginning 14 days prior to the first dosing;
- any drugs known to be significant inducers of CYP enzymes and/or P gp, including
St. John's Wort, for 28 days prior to the first dosing. Appropriate sources
(e.g., Flockhart Table™) will be consulted to confirm lack of PK/PD interaction
with study drug.
- GFR = 80 mL/min/1.73 m2, as estimated by the CKD-EPI equation.
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