Eltrombopag vs Standard Front Line Management for Newly Diagnosed Immune Thrombocytopenia (ITP) in Children

Inclusion Criteria:

• Age: 1- <18 years

• Newly diagnosed ITP (<3 months from diagnosis (first abnormal platelet count), perinternational 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, orAnti-D). For example, if patient has previously shown no response to IVIg orsteroids 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 receivedprevious treatment OR

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

• Failure of observation: no platelet recovery (>30 x 10^9/L) withobservation >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 plateletsfall below 30 x10^9/L

• Family willing and able to return for required lab studies

Exclusion Criteria:

• Severe bleeding: Buchanan Overall Grade 4 or 5 bleeding, or severe bleedingrequiring emergent treatment at the discretion of the provider. (e.g., intracranialhemorrhage, 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 ifno clinical suspicion)

• Evans Syndrome: positive direct Coombs with evidence of active hemolysis (elevatedlactate dehydrogenase (LDH) or reticulocyte count not attributable to recenttreatment 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 potentialbenefits of participating in the study outweigh the potential risks ofthromboembolic 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., uncontrolledhypertension, history of labile hypertension),

• History of known structural abnormalities (e.g. cardiomyopathy).

• History or current diagnosis of cardiac disease indicating significant risk ofsafety for patients participating in the study such as uncontrolled or significantcardiac 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., sustainedventricular tachycardia, and clinically significant second or third degree AVblock without a pacemaker.)

• Long QT syndrome, family history of idiopathic sudden death, congenital long QTsyndrome or additional risk factors for cardiac repolarization abnormality, asdetermined by the investigator.

• Known immediate or delayed hypersensitivity reaction to eltrombopag or itsexcipient.

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

• Total abstinence (when this is in line with the preferred and usual lifestyleof the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,post-ovulation methods) and withdrawal are not acceptable methods ofcontraception

• Female sterilization (have had surgical bilateral oophorectomy with or withouthysterectomy), total hysterectomy, or tubal ligation at least six weeks beforetaking study treatment. In case of oophorectomy alone, only when thereproductive status of the woman has been confirmed by follow up hormone levelassessment

• Male sterilization (at least 6 months prior to screening). The vasectomizedmale partner should be the sole partner for that subject

• Barrier methods of contraception: Condom or Occlusive cap. For the UK: withspermicidal foam/gel/film/cream/ vaginal suppository

• Use of oral, injected or implanted hormonal methods of contraception orplacement of an intrauterine device (IUD) or intrauterine system (IUS), orother forms of hormonal contraception that have comparable efficacy (failurerate <1%), for example hormone vaginal ring or transdermal hormonecontraception. In case of use of oral contraception women should have beenstable on the same pill for a minimum of 3 months before taking studytreatment.

• Male patients who are sexually active and do not agree to abstinence or to use acondom during intercourse while taking eltrombopag, and for 7 days after stoppingtreatment.

• History of alcohol/drug abuse

• Presence of a medical condition that in the opinion of the Investigator wouldcompromise the safety of the patient or the quality of the data.

• Concurrent participation in an investigational study within 30 days prior toenrollment or within 5-half-lives of the investigational product, whichever islonger. Note: parallel enrollment in a non-therapeutic trial such as diseaseregistry 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 at a grade 2 level will be excludedfrom the patient-reported outcome component of the study, as will non-Englishspeaking patients and/or parents when there is no availability of translatedversions in their spoken language . They will not be excluded from all other aspectsof the study