RAISE: Randomized Placebo-Controlled Idiopathic Thrombocytopenic Purpura (ITP) Study With Eltrombopag
Condition: Purpura, Thrombocytopaenic, Idiopathic
MeSH terms: Purpura; Purpura, Thrombocytopenic; Purpura, Thrombocytopenic, Idiopathic
Intervention: eltrombopag; Placebo
Intervention description: Subjects will initiate treatment with either 50 mg eltrombopag or matching placebo once daily. Based upon the subjects platelet count at each visit, the dose of eltrombopag may be adjusted either up or down.; Subjects will initiate treatment with either 50 mg eltrombopag or matching placebo once daily. Based upon the subjects platelet count at each visit, the dose of eltrombopag may be adjusted either up or down
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 197.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: ITP; idiopathic; platelets; purpura; thrombocytopenia; Idiopathic Thrombocytopenic Purpura; thrombocytopenic

Summary:

      The rationale for this Phase III study is to evaluate the 6 month safety and efficacy of
      eltrombopag in the treatment of previously treated subjects with chronic ITP. The starting
      dose of eltrombopag, 50 mg, once daily was selected based upon the observed efficacy, safety
      and pharmacokinetics in a dose-finding Study (TRA100773). This Phase III study is a
      randomized, double-blind, placebo-controlled, Phase III study, to evaluate efficacy, safety
      and tolerability of eltrombopag, initially administered as 50 mg oral tablets once daily for
      six months in adult subjects with previously treated chronic ITP. Subjects will be randomized
      2:1, eltrombopag to placebo, and will be stratified based upon splenectomy status, use of ITP
      medication at baseline and baseline platelet count less than or equal to 15,000/µL. Subjects
      will receive study medication for 6 months, during which the dose of study medication may be
      adjusted based upon individual platelet counts. In addition, subjects may taper off
      concomitant ITP medications and may receive any rescue treatments as dictated by local
      standard of care. After discontinuation of study medication, subjects will complete follow-up
      visits at weeks 1, 2, 4 and months 3 and 6.
    

Eligibility criteria:

        Inclusion criteria:

          -  A subject will be eligible for inclusion in this study only if all of the following
             criteria apply:

          -  Subject has signed and dated a written informed consent.

          -  Adults (≥18 years) diagnosed with chronic ITP according to the American Society for
             Hematology/British Committee for Standards in Hematology (ASH/BCSH) guidelines
             [George, 1996; BCSH, 2003], and platelet count < 30,000/μL on Day 1 (or within 24
             hours prior to dosing on Day 1). In addition, a peripheral blood smear should support
             the diagnosis of ITP with no evidence of other causes of thrombocytopenia (e.g.
             pseudothrombocytopenia, myelofibrosis). The physical examination should not suggest
             any disease which may cause thrombocytopenia other than ITP.

          -  Subjects who have previously received one or more prior ITP therapies. Previous
             treatments for ITP include but are not limited to corticosteroids, immunoglobulins,
             azathioprine, danazol, cyclophosphamide and/or rituximab.

          -  Subjects must have either initially responded (platelet count > 100,000/μL) to a
             previous ITP therapy or have had a bone marrow examination consistent with ITP within
             3 years to rule out myelodysplastic syndromes or other causes of thrombocytopenia.

          -  Previous therapy for ITP with immunoglobulins (IVIg and anti-D) must have been
             completed at least 1 week prior to randomization and the platelet count must show a
             clear downward trend after the last treatment with immunoglobulins. Previous treatment
             for ITP with splenectomy, rituximab and cyclophosphamide must have been completed at
             least 4 weeks prior to randomization, or clearly be 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 randomization. Subjects treated with cyclosporine A, mycophenolate mofetil or
             danazol must be receiving a dose that has been stable for at least 3 months prior to
             randomization. The medication should be continued with a stable dose for the initial 6
             weeks of study "Concomitant ITP Therapy")

          -  Prothrombin time (PT/INR) and activated partial thromboplastin time (aPTT) must be
             within 80 to 120% of the normal range with no history of hypercoagulable state.

          -  A complete blood count (CBC), within the reference range (including WBC differential
             not indicative of a disorder other than ITP), with the following exceptions:

          -  < 30,000 platelets/μL on Day 1 (or within 24 hours of Day 1) is required for
             inclusion,

          -  Hemoglobin: Subjects with hemoglobin levels between 10 g/dL (100 g/L) and the lower
             limit of normal are eligible for inclusion, if anemia is clearly attributable to ITP
             (excessive blood loss).

          -  ANC ≥ 1500/μL (1.5 x 10^9/L) is required for inclusion (elevated WBC/ANC due to
             steroid treatment is acceptable).

          -  The following clinical chemistries MUST NOT exceed the upper limit of normal (ULN)
             reference range by more than 20%: creatinine, ALT, AST, total bilirubin, and alkaline
             phosphatase. In addition, total albumin must not be below the lower limit of normal
             (LLN) by more than 10%.

          -  Subject is practicing an acceptable method of contraception (documented in chart).
             Female subjects (or female partners of male subjects) must either be of
             non-childbearing potential (hysterectomy, bilateral oophorectomy, bilateral tubal
             ligation or post-menopausal > 1 year), or of childbearing potential and 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);

          -  Male partner is sterile prior to entry into the study and is the only partner of the
             female;

          -  Systemic contraceptives (combined or progesterone only). Subject is able to understand
             and comply with protocol requirements and instructions and intends to complete the
             study as planned.

        Exclusion criteria:

          -  A subject will NOT be eligible for inclusion in this study if any of the following
             criteria apply:

          -  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 malignant disease and/or history of cancer treatment with cytotoxic
             chemotherapy and/or radiotherapy.

          -  Any prior history of arterial or venous thrombosis (stroke, transient ischemic attack,
             myocardial infarction, deep vein thrombosis or pulmonary embolism), AND ≥ two of the
             following risk factors: hormone replacement therapy, systemic contraception
             (containing estrogen), smoking, diabetes, hypercholesterolemia, medication for
             hypertension, cancer, hereditary thrombophilic disorders (e.g., Factor V Leiden, ATIII
             deficiency, etc), or any other family history of arterial or venous thrombosis.

          -  Pre-existing cardiovascular disease (congestive heart failure, New York Heart
             Association [NYHA] Grade III/IV), or arrhythmia known to increase the risk of
             thromboembolic events (e.g. atrial fibrillation), or subjects with a QTc >450 msec.

          -  Female subjects who are nursing or pregnant (positive serum or urine b-human chorionic
             gonadotrophin pregnancy test) at screening or pre-dose on Day 1.

          -  History of alcohol/drug abuse.

          -  Treatment with an investigational drug within 30 days or five half-lives (whichever is
             longer) preceding the first dose of study medication.

          -  Subject 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 the study start and until the end of the study.

          -  History of platelet agglutination abnormality that prevents reliable measurement of
             platelet counts.

          -  All subjects with 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 for active
             hepatitis at the time of subject screening. If a potential subject has no clinical
             history that would support HIV infection or hepatitis infection, no further laboratory
             screening is necessary; however, standard medical practice would suggest further
             evaluation of patients who have risk factors for these infections.

          -  Previous participation in a clinical study with eltrombopag.

          -  Patients planning to have cataract surgery.

          -  In France, a subject is neither affiliated with nor a beneficiary of a social security
             category.