• Bleeding Score [ Time Frame: 1 year ]
  Poor bleeding score (binary) at 1, 2, 3, 4 weeks, 12 weeks, and 1 year after study enrollment defined as World Health Organization (WHO) Bleeding Scale ≥ 2 or Modified Buchanan Scale ≥ 3
• Number of rescue therapies [ Time Frame: 12 weeks ]
  Cumulative number of rescue therapies required during the first 12 weeks of treatment
• Platelet response [ Time Frame: 12 weeks ]
  Platelet response (binary), defined as ≥ 6 of 8 weeks with platelets >50 x10^9/L during weeks 5-12 of therapy, but patient required a rescue treatment during weeks 1-2 of study
• Need for treatment [ Time Frame: 6 months ]
  No further need for treatment (binary) after 12 weeks or 6 months of study
• Treatment response [ Time Frame: 1 year ]
  Treatment response (binary endpoints) at 1 year defined as:

  • CR is defined as platelet count >/= 150 x 10^9/L
  • Primary Remission at 1 year is defined as CR at 1 year with no second-line agents required and >/= 3 months after discontinuing most recent platelet active medication
  • Disease resolution at 1 year is defined as complete response (CR) at 1 year >/= 3 months after discontinuing most recent platelet active medication. May have received a second-line therapy, excluding rituximab or splenectomy.
  • Disease stability at 1 year is defined as platelets >/= 50 x 10^9/L but <150 x 10^9/L >/= 3 months after discontinuing most recent platelet active medication.
• Number of 2nd line therapies [ Time Frame: 52 weeks ]
  Number of 2nd-line therapies in weeks 13-52
• Regulatory T-Cells [ Time Frame: 1 year ]
  Absolute change in percentage of CD4+25+Foxp3+ regulatory T cells from baseline at 12 weeks and 1 year
• KIT Scores [ Time Frame: 1 year ]
  Change in parent proxy-reported Kids ITP tool (KIT) overall scores from baseline at 1 week, 4 weeks, 12 weeks, and 1 year after study enrollment
• Hockenberry Fatigue Scale-Parent [ Time Frame: 1 year ]
  Total scale intensity ratings (continuous) from the Hockenberry Fatigue Scale-Parent (FS-P) at 1 week, 4 weeks, 12 weeks, and 1 year
• Blood Iron values [ Time Frame: 1 year ]
  Serum iron, total iron binding capacity (TIBC), transferrin saturation, ferritin, mean corpuscular volume (MCV), and hemoglobin at 12 weeks, 6 months, and 1 year after study enrollment
• Safety evaluations [ Time Frame: 1 year ]
  Safety evaluations as defined by:

  • Abnormal liver function tests (LFTs):

  ALT ≥ 3 x upper limit of normal (ULN) in patients with normal baseline ALT ≥ 3 x baseline or ≥ 5 x ULN (whichever is lower) in patients with abnormal baseline ALT ≥ 3 x ULN AND bilirubin ≥ 1.5 x ULN (>35% direct)

  • Incidence of adverse events
  • Incidence of serious adverse events

• Time to response [ Time Frame: 1 year ]
  Time to response (platelets >30x10^9/L, and at least 2-fold increase in the baseline count and absence of bleeding) (IWG definition)
• Platelet-specific endpoints [ Time Frame: 1 year ]
  Treatment response (platelets >30x10^9/L, and at least 2-fold increase in the baseline count and absence of bleeding) (IWG definition) at 12 weeks
• Time to platelet count [ Time Frame: 1 year ]
  Time to platelet count >100x10^9/L and absence of bleeding (IWG definition)
• Treatment response [ Time Frame: 1 year ]
  Treatment response (platelet count >100x10^9/L and absence of bleeding) (IWG definition) at 12 weeks
• Loss of treatment response [ Time Frame: 1 year ]
  Loss of treatment response (platelet count below 30x10^9/L, or less than 2-fold increase in the baseline count or bleeding) (IWG definition) at any time during the study period after achieving response during the first 12 weeks
• Extreme thrombocytosis [ Time Frame: 1 year ]
  Extreme thrombocytosis (platelets >1 x10^12/L)
• Patient-reported outcomes endpoints [ Time Frame: 1 year ]
  Change in child self-reported and parent impact KIT scores from baseline at 1 week, 4 weeks, 12 weeks, and 1 year after study enrollment
• Change in Hockenberry fatigue [ Time Frame: 1 year ]
  Change in Hockenberry fatigue (FS-C, FS-A, FS-P) scores from baseline at 1 week, 4 weeks, 12 weeks, and 1 year after study enrollment
• Global Change Scale scores [ Time Frame: 1 year ]
  Global Change Scale scores at 1 week, 4 weeks, 12 weeks, and 1 year after study enrollment
• Number of Hospitalizations [ Time Frame: 1 year ]
  Number of hospitalizations

This is a prospective, open label, randomized, two-arm, multi-center Phase 3 trial.

Patients with newly diagnosed ITP are randomized 2:1 to receive the experimental treatment, eltrombopag, or investigator's choice of 3 standard therapies. The primary objective is to determine if the proportion of patients with platelet response is significantly greater in patients treated with eltrombopag compared to those treated with standard therapies.

• Drug: Eltrombopag

  Starting dose for eltrombopag will be based on manufacturer recommendations, and drug will be titrated to effect per guidelines.

  • Children 1 to 5 years: Initial: 25 mg once daily
  • Children ≥6 years and Adolescents: Initial: 50 mg once daily (25 mg once daily for patients of East-Asian ethnicity [e.g., Chinese, Japanese, Korean, Taiwanese])

  Dose should be titrated based on platelet response. Maximum dose: 75 mg once daily.

• Drug: Steroids
  Prednisone/Prednisolone 4mg/kg/day (Max 120 mg/day) x 4 day
• Drug: IVIG
  IVIG 1 g/kg x1 (no steroids for pre-medication or adjunctive therapy)
• Drug: Rho(D) Immune Globulin
  Anti-D globulin 75 mcg/kg x1 (no steroids for pre-medication or adjunctive therapy)

• Experimental: Eltrombopag
  Patients randomized to eltrombopag will be treated for 12 weeks, with the possibility to continue therapy for up to 1 year depending on response.
  Intervention: Drug: Eltrombopag
• Active Comparator: Standard first-line therapy

  Subjects randomized to the standard therapy arm will receive one of three treatments at the discretion of the treating physician. Patients who previously failed standard management prior to study entry must be treated with a different agent than their original failed agent. e.g. Patient who failed steroids could receive either IVIg or anti-D if randomized to the standard treatment arm.

  Standard therapy will be administered as commercially available drug.

  Investigator may choose amongst the following:

  • IVIg: IVIG 1 g/kg x1 (no steroids for pre-medication or adjunctive therapy)
  • Steroids: Prednisone/Prednisolone 4 mg/kg/day (Max 120 mg/day) x 4 days
  • Rho(D) Immune Globulin: Anti-D globulin 75 mcg/kg x1 (no steroids for pre-medication or adjunctive therapy)
  Interventions:

  • Drug: Steroids
  • Drug: IVIG
  • Drug: Rho(D) Immune Globulin

Inclusion Criteria:

• Age: 1- <18 years
• Newly diagnosed ITP (<3 months from diagnosis (first abnormal platelet count), per international working group definition17)
• Platelets <30 x 10^9/L at screening
• Requires pharmacologic treatment from the perspective of the treating clinician.

Need to treat is at the discretion of the investigator, but there should be clinical equipoise about the use of eltrombopag vs standard treatment options (patients should not, in the opinion of the investigator, require concomitant therapy at time of enrollment).

• Treatment options include one of three standard therapies, (IVIg, steroids, or Anti-D). For example, if patient has previously shown no response to IVIg or steroids and is Rh-negative, patient would not be eligible for study.

• Patient population includes both:

  1. Upfront treatment: Patient within 10 days of ITP diagnosis who has not received previous treatment OR

  2. Treatment failure: Patients who have failed standard management (observation or treatment with one or more first-line agents)

     • Failure of observation: no platelet recovery (>30 x 10^9/L) with observation >10 days from diagnosis, with need to treat
     • Poor response to first-line agent (platelets remain <30 x10^9/L)
     • Initial response to first-line agent, but response wanes and platelets fall below 30 x10^9/L

Exclusion Criteria:

• Severe bleeding: Buchanan Overall Grade 4 or 5 bleeding, or severe bleeding requiring emergent treatment at the discretion of the provider. (e.g., intracranial hemorrhage, pulmonary hemorrhage, bleeding with ongoing need for pRBC transfusion)
• Prior treatment with TPO-RA (eltrombopag or romiplostim)
• Known secondary ITP (due to lupus, CVID, ALPS)
• Known HIV (or history of HIV positivity) or Hepatitis C (screening not required if no clinical suspicion)
• Evans Syndrome: positive direct Coombs with evidence of active hemolysis (elevated lactate dehydrogenase (LDH) or reticulocyte count not attributable to recent treatment or bleeding)
• Any Malignancy
• History of stem cell transplant or solid organ transplant
• aspartate aminotransferase (AST) or ALT >2 x upper limit of normal (ULN)
• Total bilirubin >1.5 × ULN
• Subjects with liver cirrhosis (as determined by the investigator)
• Creatinine >2.5 × ULN
• Known active or uncontrolled infections not responding to appropriate therapy
• On anticoagulation or anti-platelet agents
• Known thrombophilic risk factors. Exception: Subjects for whom the potential benefits of participating in the study outweigh the potential risks of thromboembolic events, as determined by the investigator.
• Baseline ophthalmic problems that may potentiate cataract development

• Impaired cardiac function, such as:

  • Known prolonged QTc, with corrected QTc >450 msec
  • Other clinically significant cardio-vascular disease (e.g., uncontrolled hypertension, history of labile hypertension),
  • History of known structural abnormalities (e.g. cardiomyopathy).

• History or current diagnosis of cardiac disease indicating significant risk of safety for patients participating in the study such as uncontrolled or significant cardiac disease, including any of the following:

  • Recent myocardial infarction (within last 6 months),
  • Uncontrolled congestive heart failure,
  • Unstable angina (within last 6 months),
  • Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker.)
  • Long QT syndrome, family history of idiopathic sudden death, congenital long QT syndrome or additional risk factors for cardiac repolarization abnormality, as determined by the investigator.
• Known immediate or delayed hypersensitivity reaction to eltrombopag or its excipient.

• Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study. Women of childbearing potential (have achieved menarche) must have a negative serum or urine pregnancy test and agree to use basic methods of contraception (if sexually active) or maintain abstinence for the duration of the study. Basic contraception methods include:

  • Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
  • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
  • Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that subject
  • Barrier methods of contraception: Condom or Occlusive cap. For the UK: with spermicidal foam/gel/film/cream/ vaginal suppository
  • Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
• Male patients who are sexually active and do not agree to abstinence or to use a condom during intercourse while taking eltrombopag, and for 7 days after stopping treatment.
• History of alcohol/drug abuse
• Presence of a medical condition that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.
• Concurrent participation in an investigational study within 30 days prior to enrollment or within 5-half-lives of the investigational product, whichever is longer. Note: parallel enrollment in a non-therapeutic trial such as disease registry or biology study is permitted.

Other Eligibility Criteria Considerations All patients and/or their parents or legal guardians must sign a written informed consent (and assent when applicable)

• Patients and/or parents who are unable to read English at a grade 2 level will be excluded from the patient-reported outcome component of the study. They will not be excluded from all other aspects of the study

• Boston Children's Hospital
• University of California, San Francisco