| Eligibility |
Inclusion Criteria:
1. Subject must sign an informed consent form (ICF) indicating that he or she understands
the purpose of, and procedures required for, the study and is willing to participate
in the study.
2. In the Investigator's opinion, the subject is able to understand and comply with
protocol requirements, instructions, and protocol stated restrictions and is likely to
complete the study as planned.
3. Male or female between 18 and 65 years of age, extremes included.
4. Female subjects must not be a woman of childbearing potential defined as:
1. Postmenopausal:
A postmenopausal state is defined as no menses for at least 12 months without an
alternative medical explanation, confirmed by a high follicle-stimulating hormone
(FSH) level in the postmenopausal range at screening.
OR
2. Permanently sterile:
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and
bilateral oophorectomy.
5. Male subjects must agree to wear a condom during sexual intercourse and their female
sexual partners should agree to use effective means of contraception (Section 7.2.3).
These contraceptive measures must be implemented, at a minimum, from the start of
dosing until at least 90 days after the last dose.
NOTE: Contraceptive use should be consistent with local regulations regarding the use
of contraceptive methods for subjects participating in clinical studies.
6. Subjects must have a body mass index (BMI) of 18.0 to 32.0 kg/m2, extremes included.
7. Subjects must be nonsmokers for at least 3 months prior to enrollment.
8. Subjects must have a 12-lead electrocardiogram (ECG) that meets the following criteria
at screening:
1. Heart rate between 40 and 100 beats per minute [bpm], extremes included;
2. QT interval corrected for heart rate (QTc) according to Fridericia's formula
(QTcF) <450 ms (males) or <470 ms (females);
3. QRS interval <120 ms;
4. PR interval =110 to =220 ms;
5. In addition to fulfilling the above ECG criteria, ECG morphology must have no
clinically significant abnormalities observed.
9. Subjects must be deemed to be in good overall health by the Investigator on the basis
of a medical evaluation that reveals the absence of any clinically significant
abnormality and includes a physical examination, medical history, vital signs, and the
results of blood chemistry, blood coagulation and hematology tests, and a urinalysis
performed at screening.
10. Subject must be willing and able to adhere to the Prohibited Medication requirements
(Appendix B) and Special Precautions (Section 6.12).
Exclusion Criteria:
1. Subject with a) a medical history of thyroid disorder or b) abnormal thyroid
stimulating hormone (TSH), free thyroxine (T4) or total triiodothyronine (T3) during
screening, and Day -1 or c) known sensitivity to thyroid medications.
2. The following laboratory values at screening are exclusionary:
1. ALT or AST > upper limit of normal (ULN),
2. Total bilirubin >1.2× ULN, unless Gilbert's Syndrome is suspected
3. Subjects with any current or previous illness that, in the opinion of the
Investigator, might confound the results of the study or pose an additional risk in
administering study drug to the subject or that could prevent, limit, or confound the
protocol specified assessments or study results' interpretation. This may include, but
is not limited to, renal, cardiac, vascular, pulmonary, gastrointestinal, hepatologic,
endocrine, neurologic, dermatologic, hematologic, rheumatologic, psychiatric,
neoplastic, or metabolic disturbances.
4. Subjects with a past history of cardiac arrhythmias, risk factors for Torsade de
Pointes syndrome (e.g., hypokalemia, family history of long QT Syndrome) or history or
clinical evidence at screening of significant or unstable cardiac disease such as:
angina, congestive heart failure, myocardial infarction, diastolic dysfunction,
significant arrhythmia, coronary heart disease, clinically significant ECG
abnormalities, moderate to severe valvular disease or uncontrolled hypertension.
Evidence on ECG of heart block or bundle branch block, inclusive of first-degree AV
block and incomplete bundle branch block, is also exclusionary.
5. History of unexplained syncope.
6. Subjects with a history of clinically significant (in the opinion of the Investigator)
drug allergy such as, but not limited to, sulfonamides or drug allergy witnessed in
previous studies with experimental drugs.
7. Subjects with a recent (within 1 year of enrollment) history or current evidence of
use of amphetamines, barbiturates, narcotic or other drugs of abuse/recreational drug
use (including cannabis).
8. Excessive use of alcohol defined as regular consumption of =14 standard drinks/week
for women and =21 standard drinks/week for men (Chalasani et al. 2018). For current
definition of a standard drink, please refer to the National Institute on Alcohol
Abuse and Alcoholism website (https://www.niaaa.nih.gov/what-standard-drink).
9. Unwilling to abstain from alcohol use for 1 week prior to start of study through end
of study follow up.
10. Positive results for urine drug screen, alcohol or cotinine test at screening and Day
-1.
11. Subjects with current:
1. Hepatitis A virus infection (confirmed by hepatitis A antibody immunoglobulin M
[IgM]).
2. Hepatitis B infection defined as presence of HBsAg or HBV core antibody.
3. Hepatitis C virus (HCV) infection (confirmed by HCV antibody and/or HCV RNA).
4. Hepatitis E virus: Anti-HEV IgM-positive and/or detectable HEV RNA level.
5. Human immunodeficiency virus type 1 (HIV-1) or HIV-2 infection (confirmed by
antibodies) at screening.
6. Acute infection at the time of enrollment. If an acute infection is considered
resolved prior to enrollment, the subject remains eligible.
12. Male subjects who plan to father a child while enrolled in this study or within 90
days after the last dose of study drug.
13. Subject receiving, or urgently requiring, any lipid lowering therapy (e.g., statins).
Prior use (at least 1 month prior to screening) of lipid lowering therapy is not
exclusionary.
14. Subject who has taken or requires treatment with any disallowed therapies as noted in
Prohibited Medications (Appendix B) and Special Precautions (Section 6.12) within 1
week or 5 half-lives (whichever is longer) before the planned first dose of study drug
or during dosing; use of sensitive CYP3A4 substrates, inhibitors/inducers of CYP3A4,
inhibitors of OATP1B1, OATP1B3, and/or BCRP transporters (see Appendix B), within 28
days or 5 half-lives (whichever is longer) prior to the first dose of study drug is
prohibited.
15. Consumption of grapefruit, grapefruit juice, and Seville oranges within 14 days prior
to study drug administration.
16. Consumption of apple or orange juice, citrus fruits, vegetables from the mustard green
family (e.g., kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts,
mustard), and charbroiled meats within 7 days prior to study drug administration.
17. Consumption of any food or drink/beverage containing quinine (e.g., tonic, bitter
lemon, bitter alcoholic beverages containing quinine) within 24 hours prior to study
drug administration.
18. Consumption of any food or drink/beverage containing poppy seeds or codeine containing
formulation within 72 hours of screening and admission to study site.
19. Known hypersensitivity or previous adverse events (AEs) with atorvastatin,
rosuvastatin or other statins.
20. Subjects who received an investigational agent within 4 weeks (or 5 half-lives,
whichever is longer) prior to enrollment.
21. Subjects currently participating in another clinical or medical interventional
research study.
22. Subjects with any laboratory result that is considered clinically significant by the
Investigator at screening. Abnormal values of ALT, AST, total bilirubin, TSH, free T4,
and total T3 are exclusionary regardless of any clinical significance assessment by
the Investigator (see Exclusion Criteria 1 and 2).
23. Clinically significant abnormal vital signs (evaluated in the supine position after 5
minutes of rest), confirmed with retesting after at least 5 minutes of additional rest
and at the discretion of the PI. Vital sign reference ranges to assess eligibility are
as follows:
1. Systolic blood pressure: >90 to =140 mmHg
2. Diastolic blood pressure: =45 to =90 mmHg
3. Pulse rate: =40 to =100 beats per minute
24. Physical examination findings that are considered clinically significant in the
opinion of the Investigator and likely to adversely impact study conduct and/or
interpretation are exclusionary.
25. Subjects who had major surgery (e.g., requiring general anesthesia) within 12 weeks
before enrollment, or will not have fully recovered from surgery, or have surgery
planned during the time the subject is expected to participate in the study, or within
4 weeks after the last dose of study drug.
26. Subjects with renal dysfunction [e.g., estimated creatinine clearance <80 mL/min/1.73
m2 at screening, calculated by the Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) formula]. CKD-EPI should not be corrected for subjects of African ancestry.
27. Subject is an employee of the Sponsor, the Investigator or study site, with direct
involvement in the proposed study or other studies under the direction of that
Investigator or study site, as well as family members of the employees or the
Investigator.
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