This was a non-randomized, open-label, phase II study to assess the efficacy and safety of eltrombopag in Japanese moderate or more severe aplastic anemia (AA) subjects with a platelet count <30,000/microliter who were refractory to anti-thymocyte globulin (ATG)-based immunosuppressive therapy (IST), who have relapsed after ATG-based IST, or who are ineligible for ATG-based IST.

Eltrombopag was expected to improve trilineage blood cells and decrease transfusion frequency based on the result from the previous study in patients with severe AA. This study used the hematologic response rate, defined as the proportion of subjects showing improvement in at least one of the three blood cell lineages or a decrease in blood transfusion volume, as the primary endpoint.

A total of 36 subjects were screened and 21 were enrolled in the study. Treatment with eltrombopag started at 25 milligram (mg)/day and increased by 25 mg/day every 2 weeks according to the platelet count up to 100 mg/day. Response assessment was performed at 3 months after starting the study treatment (Week 13). Subjects in whom the treatment was assessed as effective continued with the study treatment. Subjects in whom the treatment was assessed as effective (when meeting any of the response criteria) at 6 months after starting the study treatment (Week 26) might enter the extension phase and continue the treatment with eltrombopag. The primary endpoint was the hematologic response rate at Week26.

Key Inclusion Criteria:

• Subject has given written informed consent. If a subject is under 20 years, both the subject and the subject's legally acceptable representative have to give informed consent.
• Japanese subjects aged >=18 and <80 years at the time of informed consent.
• Diagnosis of moderate (stage II) or more Aplastic Anemia (AA) with platelet count <30,000/microliter (based on the diagnosis criteria of AA established by the Study Group on Idiopathic Hematopoietic Disorder as a part of Research on Measures for Intractable Diseases supported by Health and Labor Science Research Grants).
• Subjects who became refractory to Anti-thymocyte globulin (ATG)-based Immunosuppressive therapy (IST), who have relapsed after ATG-based IST, or who are ineligible for ATG-based IST. Note: Refractory or relapsed subjects to whom re-treatment with ATG is indicated should not be enrolled in the study. Subjects who have a sibling donor with matched human leukocyte antigen (HLA) should not be enrolled in the study. However, such subjects may be enrolled if the disease relapsed after hematopoietic stem cell transplantation (HSCT), if HSCT is not indicated, or the subject does not want to undergo HSCT.
• Adequate organ function at screening and Day 1 as defined as follows: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <=3 × central laboratory upper limit of normal (ULN); Creatinine, total bilirubin, and alkaline phosphatase (ALP) <1.5 × central laboratory ULN (total bilirubin <2.5 × central laboratory ULN with Gilbert's Syndrome)
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS): 0 or 1
• Subjects with QT interval corrected for heart rate by Fridericia's formula (QTcF) <450 milliseconds (msec) or QTcF<480 msec with branch block. Corrected QT interval duration (QTc) is QT interval corrected by Fridericia formula (QTcF), machine or manual over read. QTcF is based on single or averaged QTc value of triplicate electrocardiogram (ECG).
• Subjects who meet one of the following conditions: Male subjects who have a female partner of childbearing potential must either have a prior vasectomy or agree to use an acceptable contraception from time of enrollment in the study until 16 weeks after the last dose of eltrombopag (based upon the lifecycle of sperm); Female subjects of non-childbearing potential (who are physiologically unable to become pregnant) defined as: Premenopausal women with documented bilateral oophorectomy, bilateral tubal ligation, or hysterectomy; or postmenopausal women after at least 12 months of natural amenorrhea [if uncertain, postmenopausal state should be confirmed by hematology result of follicle stimulating hormone (FSH) >40 milli international unit /milliliter (mIU/mL) or estradiol <40 picogram (pg)/mL (<140 picomole /Liter (pmole/L)].; Female subjects of childbearing potential: Defined as those not meeting the definition of non-childbearing potential. Female subjects of childbearing potential must have a negative serum human chorionic gonadotropin (hCG) or urine pregnancy test within 7 days prior to the first dose of study treatment. It is recommended that the pregnancy test should be performed as close as possible to the first dose of study treatment. Female subjects with a positive pregnancy test must be excluded from the study. Subjects with a negative pregnancy test must use acceptable contraception including abstinence after the pregnancy test. Subjects must agree to use the acceptable contraception including abstinence from 14 days prior to the first dose of study treatment until 28 days after the last dose of eltrombopag.

Key Exclusion Criteria:

• Treatment with ATG in the past 12 months. Note: Subjects who are receiving cyclosporine or anabolic steroids (excluding danazol) at a stable dose may be enrolled if laboratory values are stable at screening.
• Congenital aplastic anemia (e.g., Fanconi anemia, congenital dyskeratosis)
• Paroxysmal nocturnal hemoglobinuria (PNH) granulocyte clone size determined by flow cytometry >=50%
• Presence of chromosomal aberration (-7/7q- detected by fluorescence in situ hybridization (FISH), or other aberrations detected by Giemsa (G)-band staining) Note: Subjects with the result by G-band staining (bone marrow aspiration) not adopted into the abnormal clone definition of An International System for Human Cytogenetic Nomenclature (ISCN) can be enrolled as no chromosomal aberration.
• Past history of thromboembolism or current use of anticoagulants. Note: Subjects with antiphospholipid antibody syndrome (APS) should not be enrolled.
• Past or current history of malignant tumor. Note: Subjects who have a history of completely resected malignant tumor and have been disease-free for 5 years are eligible.
• Subjects who test positive for hepatitis B surface (HBs) antigen, hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV) antibody at screening. Note: Subjects with inactive hepatitis B may be enrolled. Judgment of inactive hepatitis B will be done by the medical advisor.
• Subjects with concurrent uncontrollable severe infection (e.g., sepsis)
• Hepatic cirrhosis
• Cardiac disorder (congestive heart disease of New York Heart Association (NYHA) functional classification Grade II/III/IV), or arrhythmia with a risk of thrombosis (e.g., atrial fibrillation). Note: Subjects with NYHA Grade II due to cardiac disorder should not be enrolled but those with NYHA Grade II due to Aplastic Anemia (AA) may be enrolled.
• Alcohol or drug abuse
• Pregnant women (a positive serum or urine pregnancy test within 7 days prior to the first dose of study treatment) or lactating women. Note: Female subjects who are lactating are eligible to participate if they discontinue nursing prior to the first dose of study treatment and refrain from nursing until 5 days after the treatment completion.
• Past history of immediate or delayed hypersensitivity to compounds chemically similar to eltrombopag or their activators
• Treatment with another investigational product within 30 days or the period 5-fold longer than the half-life of the investigational product, whichever longer, prior to the first dose of eltrombopag
• Prior treatment with eltrombopag, romiplostim, or any other Thrombopoietin (TPO) receptor agonist
• Use of prohibited concomitant medications.