Efficacy and Safety Study of Eltrombopag in Pediatric Patients With Thrombocytopenia From Chronic Idiopathic Thrombocytopenic Purpura (ITP)
Condition: Purpura, Thrombocytopaenic, Idiopathic
MeSH terms: Thrombocytopenia; Purpura; Purpura, Thrombocytopenic; Purpura, Thrombocytopenic, Idiopathic
Intervention: eltrombopag; Placebo
Intervention description: thrombopoietin receptor agonist; placebo for comparison
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 82.0
Sex: All
Minimum age: 1 Year
Maximum age: 17 Years
Healthy volunteers: No
Keywords: idiopathic thrombocytopenic purpura; thrombocytopenia; pharmacodynamics; ITP; eltrombopag; pharmacokinetics; chronic ITP; pediatrics

Summary:

      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.
    

Eligibility criteria:

        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.