Eltrombopag in Combination With Rabbit Anti-thymocyte Globulin/Cyclosporine A in Naive Aplastic Anemia (AA) Subjects
Condition: Aplastic Anemia
MeSH terms: Anemia; Anemia, Aplastic
Intervention: Eltrombopag; Rabbit ATG; CsA
Intervention description: Eltrombopag was provided as white round film-coated tablets containing 12.5 mg or 25 mg of eltrombopag free acid (SB-497115-GR, eltrombopag).; Rabbit ATG, as an intravenous drip infusion, diluted by 500 mL of saline or 5% glucose injection was administered at a dose of 2.5 to 3.75 mg per kg per day as a slow intravenous infusion over 6 hours.; CsA as capsules, oral solution, or fine granule, was administered at a dose of 3 mg per kg twice a day.
Intervention MeSH terms: Thymoglobulin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Masking: None (Open Label)
Enrollment: 10.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Eltrombopag; rabbit anti-thymocyte globulin; additive effect; cyclosporine A; bone marrow; hematopoietic stem cells; pancytopenia; leukopenia; platelets; throbocytopenia; mature blood cells; bone marrow biopsy

Summary:

      This was an open label, non-randomized, phase II study of eltrombopag in combination with
      rabbit ATG/CsA in subjects with moderate or more severe AA who did not received prior
      ATG/ALG-based immunosuppressive therapy. The objective was to assess additive effects of
      eltorombopag on overall response rate (ORR) at 6 months (Week 26) of treatment with ATG/CsA.
      Subjects were assessed at least weekly for safety during the period from the start of ATG/CsA
      to 4 weeks after the start of administration of eltrombopag. After that, subjects had visits
      every 2 weeks until Week 26. Subjects in whom the treatment was assessed as effective at Week
      26 could continued treatment with eltrombopag after 6 months when clinically indicated at the
      discretion of the investigator. There were five follow-up visits: at discontinuation of the
      treatment of eltrombopag, and Weeks 1, 2, 3, 4 and 26 after treatment discontinuation. As
      this study was the first Japanese phase II study in which this product was administered in
      combination with ATG/CsA to subjects with naive moderate or more severe AA, the subject
      number of this study was determined to be 10 based on the feasibility survey.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Japanese subjects aged >=18 and <71 years at the time of informed consent. Note:
             subjects aged >=71 and <75 may be eligible when clinically indicated at the discretion
             of the investigator by mutual agreement with Novartis medical advisor.

          -  Diagnosed with moderate or more severe AA according to the diagnostic criteria of AA.
             The severity classification is: Stage I - Mild - Other than the stages below; Stage II
             - Moderate - At least two of the following conditions are met: Reticulocyte
             <60,000/microliter, Neutrophil <1,000/microliter, Platelet <50,000/microliter; Stage
             III - Moderately severe - At least two of the following conditions are met and regular
             red blood cell transfusion (a need for transfusion of >=2 units per month) is
             required: Reticulocyte <60,000/microliter, Neutrophil <1,000/microliter, Platelet
             <50,000/microliter; Stage IV - Severe - At least two of the following conditions are
             met: Reticulocyte <20,000/microliter, Neutrophil <500/microliter, Platelet
             <20,000/microliter; Stage V - Very severe - At least one of the following conditions
             is met in addition to neutrophil <200/microliter: Reticulocyte <20,000/microliter,
             Platelet <20,000/microliter.

          -  Subjects who are considered an indication for the treatment with rabbit ATG and CsA.

          -  Adequate baseline organ function defined by the following criteria: Alanine
             aminotransferase (ALT), aspartate aminotransferase (AST)<=3 × local upper limit of
             normal (ULN) Creatinine, total bilirubin, and alkaline phosphatase (ALP) <1.5 × local
             ULN (total bilirubin <2.5 × local ULN with Gilbert's Syndrome)

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status (PS): 0 or 1

          -  Subjects with QTcF<450 millisecond (msec) or QTcF<480 msec with branch block: QTc is
             QT interval corrected by Fridericia formula (QTcF), machine ,or manual overread. QTcF
             is based on single or averaged QTc value of triplicate ECG.

          -  Subjects are able to understand and comply with protocol requirements and
             instructions.

          -  Subjects have signed and dated informed consent.

          -  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 method of 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
             units (mIU)/milliliter (mL) or estradiol <40 picogram (pg)/mL (<140 picomoles
             (pmol)/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 ATG/CsA. It is recommended
             that the pregnancy test should be performed as close as possible to the first dose of
             ATG/CsA. 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
             ATG/CsA until 28 days after the last dose of eltrombopag.

        Exclusion Criteria:

          -  Diagnosis of congenital AA (e.g. Fanconi anemia or Dyskeratosis congenital).

          -  Subjects who have a sibling donor with matched human leukocyte antigen (HLA) or who
             underwent hematopoietic stem cell transplantation (HSCT) previously. However, such
             subjects may be enrolled if HSCT is not indicated, or the subject does not want to
             undergo HSCT.

          -  Subjects with abnormal chromosome (monosomy 7 detected by fluorescence in situ
             hybridization (FISH), or other aberrations detected by G-band staining). Note:
             Subjects with abnormal chromosome which is not adopted into the clone definition of An
             International System for Human Cytogenetic Nomenclature (ISCN) may be enrolled after
             consulting with medical monitor.

          -  Previous ATG/ALG-based immunosuppressive therapy or steroid pulse therapy for AA.

          -  Treatment with CsA within 6 months before administration of ATG.

          -  Subjects with a paroxysmal nocturnal hemoglobinuria (PNH) clone size in granulocytes
             of >50% by flow cytometric analysis.

          -  Pre-existing cardiac disease (congestive heart failure New York Heart Association
             (NYHA) Grade II/III/IV), or arrhythmias known to involve the risk of thromboembolic
             events (e.g. atrial fibrillation)

          -  Past history of thromboembolic event (including anti-phospholipid antibody syndrome)
             and current use of anticoagulants.

          -  Subjects with past or current malignancy. 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.

          -  Infection not adequately responding to appropriate therapy.

          -  Subject with liver cirrhosis

          -  Subjects with any clinically significant severe cardiac, renal, or hepatic medical
             condition.

          -  Pregnant women (a positive serum or urine pregnancy test within 7 days prior to the
             first dose of ATG/CsA or lactating women) Note: Female subjects who are lactating are
             eligible to participate if they discontinue nursing prior to the first dose of ATG/CsA
             and refrain from nursing until 5 days after the completion of treatment with
             eltrombopag.

          -  Known hypersensitivity, intolerance or allergy to rabbit ATG, cyclosporine A,
             eltrombopag or any of their excipients.

          -  Current alcohol or drug abuse.

          -  Treatment with an investigational drug within 30 days or 5 half-lives (whichever is
             longer) proceeding the first dose of ATG/CsA.

          -  Subjects who is not candidates for ATG.

          -  Subjects who is not candidates for CsA.

          -  History of treatment with eltrombopag, romiplostim or other thrombopoietin-receptor
             (TPO-R) agonists.