Efficacy and Safety Study of Eltrombopag in Pediatric Patients With Thrombocytopenia From Chronic Idiopathic Thrombocytopenic Purpura (ITP)

A Three Part, Staggered Cohort, Open-label and Double Blind, Randomized, Placebo Controlled Study to Investigate the Efficacy, Safety, Tolerability and Pharmacokinetics of Eltrombopag, a Thrombopoietin Receptor Agonist, in Previously Treated Pediatric Patients With Chronic ITP.

Phase II, multi-center, 3 part, staggered cohort, open-label and double blind, randomized, placebo controlled study involving 3 age-determined cohorts (Cohort 1: between 12 and 17 years old; Cohort 2: between 6 and 11 years old; Cohort 3: between 1 and 5 years old). Daily dosing with eltrombopag will begin with 5 patients in the oldest age cohort in an open label fashion, and a review of safety, pharmacokinetic and platelet count data will be performed regularly. If no safety concerns are identified after 12 weeks, 18 additional patients will be randomised to placebo or eltrombopag (2:1 randomisation). After 7 weeks of randomized treatment, all patients will receive eltrombopag in an open label fashion. The total duration of treatment with eltrombopag will be 24 weeks. If at the time of the aforementioned 12 week review of the first 5 patients no safety issues are identified, dosing will begin in the next lower age cohort with an initial group of 5 patients. The same procedure will be followed in terms of safety review and subsequent enrolment and randomisation of the additional patients. Initiation of the younger age cohort will take place once data from the previous has been evaluated. Doses will be adjusted according to platelet counts and tolerability. The study will include a review of the safety data by a Data Safety Monitoring Board.

Inclusion Criteria:

• Subjects between 1 year and <18 years of age at Day 1.
• Written informed consent from subject's guardian and accompanying informed assent from subject (for children over 6 years old).
• Confirmed diagnosis of chronic ITP, according to the American Society of Hematology / British Committee for Standards in Haematology (ASH/BCSH) guidelines [George, 1996; BCSH, 2003]. In addition, a peripheral blood smear or bone marrow examination should support the diagnosis of ITP with no evidence of other causes of thrombocytopenia.
• Subjects who are refractory or have relapsed after at least one prior ITP therapy or are not eligible, for a medical reason, for other treatments.
• Day 1 (or within 48 hours prior) platelet count <30 Gi/L.
• Previous therapy for ITP with immunoglobulins (IVIg and anti-D) must have been completed at least 2 weeks prior to Day 1 or have been clearly ineffective.
• Subjects treated with concomitant ITP medication (e.g. corticosteroids or azathioprine) must be receiving a dose that has been stable for at least 4 weeks prior to Day 1.
• Previous treatment for ITP with splenectomy, rituximab and cyclophosphamide must have been completed at least 4 weeks prior to Day 1 or have clearly been ineffective.
• Subjects must have prothrombin time (PT/INR) and activated partial thromboplastin time (aPTT) within 80 to 120% of the normal range.
• Subjects must have a complete blood count (CBC) not suggestive of another hematological disorder.
• The following clinical chemistries for the subjects MUST NOT exceed the upper limit of normal (ULN) reference range by more than 20%: creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, and alkaline phosphatase. In addition, total albumin must not be below the lower limit of normal (LLN) by more than 10%.
• For subjects of child-bearing potential (after menarche): subject must not be sexually active or is practicing an acceptable method of contraception (documented in chart). Female subjects (or female partners of male subjects) must use one of the following highly effective methods of contraception (i.e., Pearl Index <1.0%) from two weeks prior to administration of study medication, throughout the study, and 28 days after completion or premature discontinuation from the study:
• Complete abstinence from intercourse;
• Intrauterine device (IUD);
• Two forms of barrier contraception (diaphragm plus spermicide, and for males condom plus spermicide);
• Systemic contraceptives (combined or progesterone only).

Exclusion Criteria:

• Any clinically relevant abnormality, other than ITP, identified on the screening examination or any other medical condition or circumstance, which in the opinion of the investigator makes the subject unsuitable for participation in the study or suggests another primary diagnosis (e.g. thrombocytopenia is secondary to another disease).
• Concurrent or past malignant disease, including myeloproliferative disorder.
• Subjects who are not suitable for continuation of their current therapy for at least 7 additional additional weeks.
• Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding Day 1.
• History of platelet agglutination abnormality that prevents reliable measurement of platelet counts.
• Diagnosis of secondary immune thrombocytopenia, including those with laboratory or clinical evidence of HIV infection, anti-phospholipid antibody syndrome, chronic hepatitis B infection, hepatitis C virus infection, or any evidence of active hepatitis at the time of subject screening.
• Subject with Evans syndrome (autoimmune thrombocytopenia and autoimmune hemolysis).
• Subjects with known inherited thrombocytopenia (e.g. MYH-9 disorders)
• Subjects treated with drugs that affect platelet function (including but not limited to aspirin, clopidogrel and/or NSAIDs) or anti-coagulants for >3 consecutive days within 2 weeks of Day 1.
• Subjects who have previously received eltrombopag or any other thrombopoietin receptor agonist.
• For female subjects who have reached menarche status, an inability or unwillingness to provide a blood or urine specimen for pregnancy testing.
• Female subjects who are pregnant or lactating.