Study of the Relative Oral Bioavailability of AL-3778 Tablets and Drug Interaction With Entecavir or Tenofovir Disoproxil Fumarate in Healthy Volunteers
Study of the Relative Oral Bioavailability of AL-3778 Tablets and Drug Interaction With Entecavir or Tenofovir Disoproxil Fumarate in Healthy Volunteers
This is an open-label, randomized, multi-part study to evaluate the relative oral
 bioavailability of a tablet formulation of AL-3778 (formerly NVR 3-778) administered under
 fasted and fed conditions (Parts 1 and 2) and the drug-drug interaction between AL-3778 and
 entecavir or tenofovir disoproxil fumarate (Part 3).
Main Inclusion Criteria for All Subjects:

 1. Subject has provided written consent.

 2. In the investigator's opinion, the subject is able to understand and comply with
 protocol requirements, instructions, and study restrictions and is likely to complete
 the study as planned.

 3. Subject is in good health as deemed by the investigator, based on the totality of
 findings following a medical evaluation, including medical history, physical
 examination, laboratory tests and ECG.

 4. Male or female, 18-60 years of age.

 5. Body mass index 18-30 kg/m2, inclusive. The minimum weight is 50 kg.

 6. A female subject is eligible to participate in this study if she is of
 non-childbearing potential (defined as females with a documented tubal ligation,
 bilateral oophorectomy or hysterectomy) or postmenopausal (defined as 12 months of
 spontaneous amenorrhea and follicle stimulating hormone level within the laboratory's
 reference range for postmenopausal females). A post-menopausal female receiving
 hormone replacement therapy who is willing to discontinue hormone therapy 28 days
 before study drug dosing and agrees to remain off hormone replacement therapy for the
 duration of the study may be eligible for study participation.

 7. If male, subject is surgically sterile or practicing required forms of birth control
 until 6 months after the last dose of the study drug(s). Males must agree to refrain
 from sperm donation from check-in through 6 months after the last dose of the study
 drug(s).

 8. Subject has been a nonsmoker and has not used nicotine or nicotine-containing products
 for at least 6 months.

 9. Subjects who participated in Part 1 and/or Part 2 may participate in subsequent
 Part(s) upon satisfactory completion of a posttreatment visit, 7 days (+2 days)
 following the subject's last dose, and provided they continue to meet all of the
 inclusion criteria and none of the exclusion criteria.

 Main exclusion criteria:

 1. Subject is mentally or legally incapacitated, has significant emotional problems at
 the time of prestudy (screening) visit or expected during the conduct of the study or
 has a history of a clinically significant psychiatric disorder over the last 5 to 10
 years.

 2. Subject has a history of any illness that, in the opinion of the investigator, would
 confound the objectives or results of the study or poses an additional risk to the
 subject by their participation in the study.

 3. Subject has an estimated creatinine clearance of ≤80 mL/min based on the
 Cockcroft-Gault equation; An actual creatinine clearance, as determined by a 24-hour
 urine collection, may be used in place of, or in conjunction with, the Cockcroft-Gault
 equation; subjects who have an actual or estimated creatinine clearance within 10% of
 80 mL/min may be enrolled in the study at the discretion of the investigator.

 4. Pregnant or nursing (lactating) females, confirmed by a positive human chorionic
 gonadotropin laboratory test or females contemplating pregnancy. Men whose female
 partners are pregnant or contemplating pregnancy from the date of screening until 6
 months after their last dose of study drugs.

 5. Clinically significant cardiovascular, respiratory, skeletal, renal, gastrointestinal,
 hematologic, hepatic, immunological, neurologic, endocrine, genitourinary
 abnormalities or disease or any other medical illness as determined by the
 investigator or Sponsor's Medical Monitor.

 6. Subject has a history of malignancy except completely excised basal cell carcinoma or
 squamous cell carcinoma of the skin.

 7. Subject lacks or has poor peripheral venous access.

 8. Positive screening result for hepatitis B, hepatitis C and/or HIV serology.

 9. Any condition that, in the opinion of the investigator, would compromise the study's
 objectives or the well-being of the subject or prevent the subject from meeting the
 study requirements.

 10. Clinically significant abnormal ECG findings. Particularly, a history or family
 history of prolonged QT syndrome (eg, torsade de pointes) or sudden cardiac death.

 11. ECG with PR >200 ms, QRS >120 ms, QTcF >450 ms, as assessed by triplicate 12-lead ECG
 at the screening visit.

 12. Subject has had major surgery, or clinically significant blood loss or elective blood
 donation of significant volume (ie, >500 mL) within 60 days of first dose of study
 drug; >1 unit of plasma within 7 days of first dose of study drug.

 13. Abnormal heart rate, respiratory rate, temperature or blood pressure values outside of
 the normal range (evaluated in a semi-recumbent or recumbent position after 5 minutes
 of rest). One repeat measurement after an additional 5 minutes of rest is permitted.

 14. Evidence of active infection.

 15. Unwilling to abstain from alcohol for at least 48 hours prior to the start of dosing
 through the study completion visit.

 16. History of regular alcohol intake >7 units per week of alcohol for females and >14
 units per week for males (one unit is defined as 10 g alcohol) within 3 months of the
 screening visit.

 17. The subject has a positive screening or Day -1 drugs of abuse screen.

 18. The use of concomitant medications, including prescription, over the counter
 medications, and herbal medications (such as St. John's Wort [Hypericum perforatum])
 within 30 days prior to the first dose of study medication is excluded, unless
 approved by the Sponsor's Medical Monitor. Occasional use of ibuprofen/paracetamol/
 acetaminophen is permitted.

 19. Subject has received an investigational drug (including investigational vaccines) or
 used an invasive investigational medical device within 90 days before the planned
 study drug.

 20. Subject has a history of significant multiple and/or severe allergies, or has had an
 anaphylactic reaction or significant intolerability to prescription or
 non-prescription drugs or food.

 21. Hypersensitivity to the active substances or to any of the excipients of AL-3778,
 entecavir or tenofovir disoproxil fumarate.

 22. Subject has known allergy to heparin or history of heparin-induced thrombocytopenia.

 23. Abnormal biochemistry or hematology laboratory results obtained at screening
 determined to be clinically significant by the Investigator. Screening ALT, AST, GGT,
 albumin, and total bilirubin must be within normal ranges. Creatine kinase >1.5 x ULN
 is exlusionary

 24. Unwillingness or inability to comply with the study protocol for any other reason.