A Study to Assess the Safety and Efficacy of Eltrombopag in Japanese Subjects With Refractory, Moderate or More Severe Aplastic Anemia
Condition: Cytopaenia
MeSH terms: Anemia; Anemia, Aplastic
Intervention: Eltrombopag 12.5 mg; Eltrombopag 25 mg
Intervention description: White, round, film-coated tablets containing 12.5 mg of eltrombopag free acid (SB-497115-GR, eltrombopag) in each tablet; White, round, film-coated tablets containing 25 mg of eltrombopag free acid (SB-497115-GR, eltrombopag) in each tablet
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 21.0
Sex: All
Minimum age: 18 Years
Maximum age: 79 Years
Healthy volunteers: No
Keywords: Eltrombopag; Aplastic Anemia (AA); Thrombocytopenia; Thrombopoietin; Bone Marrow; Bone Marrow Biopsy; Hematopoietic Stem Cells; Mature Blood Cells; Pancytopenia; Leukopenia; Platelets

Summary:

      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.
    

Eligibility criteria:

        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.