To evaluate the efficacy of E5501 by measuring platelet response in subjects with chronic hepatitis C virus (HCV)-related thrombocytopenia who require antiviral treatment.

This study had three phases: Prerandomization (Screening), Randomization (Core Study), and Open-Label Extension (OLE). The Randomization Phase included Treatment Periods A1 and A2 and a Follow-up Period (for those participants not continuing into the OLE phase). The OLE Phase included Treatment Periods B1, B2, and B3 (depending on when a participant entered the OLE), and a Follow-up Period. Participants may have been followed for sustained viral response, if appropriate. In the Core Study (randomization phase) participants were randomized (in a 1:1:1:1 ratio) to receive one of four treatments (placebo or avatrombopag [10mg, 20mg, and 30mg] for up to 21 days. Participants who successfully completed Treatment Period A1, (platelet count >=100x10^9/L) initiated antiviral treatment with pegylated interferon (PEG-IFN) alpha-2a and progressed to Treatment Period A2. Participants with a platelet count >=150x10^9/L initiated antiviral treatment and progressed into Treatment Period B2, study drug was interrupted then eventually restarted at 10 mg daily once their platelet counts returned to acceptable levels. Those who were not considered successful after 21 days in Treatment Phase A1 were withdrawn from the Core Study (Part A) and were eligible to enter the OLE at Treatment Period B1. Participants who chose to not enter the OLE entered into the Follow-up Phase. At the end of Treatment Period A2, eligible participants could enter the OLE at Treatment Period B3. In the OLE Phase, participants entering into Open-label Treatment Period B1 began once-daily treatment with avatrombopag at a dose of 20 mg without titration for up to 21 days. Once the participant's platelet counts were sufficient, they entered Treatment Period B2. Participant's eligible to enter into Treatment Period B2 received avatrombopag and antiviral treatment for 13 weeks. Participants who successfully completed Treatment Period A2 or B2 could continue on antiviral treatment for up to a maximum of 48 weeks (including the 13 weeks in Treatment Periods A2 or B2) and open-label avatrombopag, at the investigator's discretion. In Treatment Period B3, the dose of avatrombopag was allowed to be titrated up or down in accordance with the participant's platelet count response, within the range of a minimum of 5 mg and a maximum of 50 mg. In the Follow-up Period, participants were seen at either a single 30-day follow-up visit or followed for the full 30 days after the last dose of avatrombopag.

Inclusion Criteria:

1. Males or females greater than or equal to 18 years of age
2. Women of childbearing potential must agree to use a highly effective method of contraception for at least one menstrual cycle prior to starting study drug, throughout the entire study period, and for 30 days after the last dose of study drug
3. Subjects with chronic HCV-related thrombocytopenia (defined as a platelet count greater than or equal to 20x10^9/L to 70x10^9/L) who require antiviral treatment
4. Chronic HCV infection (defined as the presence of anti-HCV antibodies and detectable serum HCV RNA levels)
5. Model for End-stage Liver disease score greater than or equal to 24
6. Adequate renal function as evidenced by a calculated creatinine clearance greater than or equal to 50 mL/minute per the Cockcroft and Gault formula
7. Life expectancy greater than or equal to 3 months

Exclusion Criteria: Subjects who meet any of the following criteria will be excluded from participation in the study:

1. Any history of arterial or venous thrombosis, including partial or complete thrombosis (e.g., stroke, transient ischemic attack, myocardial infarction, deep vein thrombosis or pulmonary embolism), thrombosis (partial or complete) in the main portal vein and portal vein branches, and thrombosis of any part of the splenic-mesenteric system
2. Any evidence of current portal vein thrombosis (PVT) as detected by Doppler sonography and portal vein flow rate less than 15 cm/second at Screening or within 30 days prior to Screening (revised per Amendment 02)
3. Any known family history of hereditary thrombophilic disorders (e.g., Factor V Leiden, antithrombin III deficiency)
4. Evidence of myocardial infarction in the last 6 months or uncompensated congestive heart failure (New York Heart Association Class III or IV)
5. Co-infection with human immunodeficiency virus (HIV) or hepatitis B or acute hepatitis C
6. Any prohibited concomitant medications or therapy that cannot be discontinued by Visit 1, e.g., subjects currently receiving interferon who cannot undergo a 4-week washout period prior to Screening, or subjects who receive blood products that affect platelet count within 1 week prior to Screening (revised per Amendment 02)
7. Weekly alcohol intake greater than 21 units (168 g) [male] and greater than 14 units (112 g) [female]
8. Any known medical condition, other than chronic liver disease, that can lead to thrombocytopenia
9. History of hepatocellular carcinoma, metastatic liver cancer, or liver transplantation (revised per Amendment 01) (revised per Amendment 02)
10. History of idiopathic thrombocytopenic Purpura (ITP)
11. History of myelodysplastic syndrome
12. History of pernicious anemia or subjects with vitamin B12 deficiency (defined as less than the lower limit of normal [LLN]) who have not had pernicious anemia excluded as a cause (Added per Amendment 02)
13. Evidence of clinically significant disease (e.g., cardiac, respiratory, gastrointestinal, renal disease) that, in the opinion of the investigator, could affect the subject's safety or study conduct
14. Subjects with a history of suicide attempts
15. Subjects with a history of hospitalization for depression within the past 5 years
16. Subjects with any current severe or poorly controlled psychiatric or seizure disorder
17. Current use of recreational drugs
18. Subjects who have participated in another investigational study within 30 days prior to Visit 1
19. Subjects with hypersensitivity, intolerance, or allergy to E5501 or any anti-HCV therapies or their ingredients
20. Any past or current (revised per Amendment 01) medical condition that, in the opinion of the investigator, would compromise the subject's ability to safely complete the study
21. Scheduled for surgery during the projected course of the study
22. Subjects who have any medical conditions or diseases that would contraindicate treatment with anti-HCV therapy (added per Amendment 01)
23. Subjects who are currently treated with proton pump inhibitors (PPIs) or H2-antagonist therapy but have not been receiving a stable dose for at least 6 weeks prior to randomization or have not completed these therapies more than 2 weeks prior to randomization (added per Amendment 01)
24. Fasting gastrin-17 blood levels exceeding 1.5 times the upper limit of normal (ULN) at Screening (including subjects on PPIs or H2 antagonists) (revised per Amendment 02)
25. Subjects with a history of gastric atrophy (added per Amendment 02)

For each participant, treatment emergent adverse events were collected from the first day of administration of study drug up to 30 days after the last dose of study drug or up to approximately 2.5 years.

Core Study Safety Analysis Set (SAS): All participants who received at least 1 dose of study drug and had at least 1 postdose safety assessment. OLE Safety Analysis Set: All participants who received at least 1 dose of avatrombopag study drug (either in the Core Study or the Extension Phase) and had a postdose safety assessment.