Study of a new medication for childhood chronic immune thrombocytopenic purpura, ITP, a blood disorder of low platelet counts that can lead to bruising easily, bleeding gums, and/or bleeding inside the body

INTERVENTION:

Product Name: ELTROMBOPAG Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

ELTROMBOPAG CAS Number: 496775‐62‐3 Current Sponsor code: SB‐497115 Other descriptive name: REVOLADE, PROMACTA Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 12.5‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use Product Name: ELTROMBOPAG Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

ELTROMBOPAG CAS Number: 496775‐62‐3 Current Sponsor code: SB‐497115 Other descriptive name: REVOLADE, PROMACTA Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 25‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use Product Name: ELTROMBOPAG Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

ELTROMBOPAG CAS Number: 496775‐62‐3 Current Sponsor code: SB‐497115 Other descriptive name: REVOLADE, PROMACTA Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use Product Name: ELTROMBOPAG Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

ELTROMBOPAG CAS Number: 496775‐62‐3 Current Sponsor code: SB‐497115 Other descriptive name: REVOLADE, PROMACTA Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 75‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use Product Name: ELTROMBOPAG Product Code: SB‐497115 Pharmaceutical Form: Powder for oral suspension INN or Proposed

INN:

ELTROMBOPAG CAS Number: 496775‐62‐3 Current Sponsor code: SB‐497115 Other descriptive name: REVOLADE, PROMACTA Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 20‐ Pharmaceutical form

CONDITION:

Therapeutic area: Diseases [C] ‐ Immune System Diseases [C20] To assess the efficacy of eltrombopag, relative to placebo, in achieving platelet counts of = 50 Gi/L, when administered to pediatric subjects with previously treated chronic ITP during the first 12 weeks of Part 1, the randomized treatment period. ; MedDRA version: 14.1 Level: PT Classification code 10021245 Term: Idiopathic thrombocytopenic purpura System Organ Class: 10005329 ‐ Blood and lymphatic system disorders

SECONDARY OUTCOME:

Secondary end point(s): The proportion of subjects receiving eltrombopag, compared to placebo, who achieve platelet counts = 50 ; Gi/L for at least 6 out of 8 weeks, between weeks 5‐12 of Part 1. ; Weighted mean platelet change (area under the platelet‐time curve divided by duration), for subjects receiving eltrombopag relative to placebo, from baseline to Week 12 of Part 1. ; The proportion of subjects receiving eltrombopag, compared to placebo, who achieve platelet counts = 50 Gi/L at any time during the first 6 weeks of Part 1. ; The proportion of subjects receiving eltrombopag, compared to placebo, who achieve platelet counts = 50 Gi/L at any time during the first 12 weeks of Part 1. ; The proportion of subjects achieving platelet counts = 50 Gi/L at any time during Part 2. ; Maximum period of time with platelet counts continuously = 50 Gi/L for subjects receiving eltrombopag relative to placebo during the first 12 weeks of Part 1. ; The proportion of weeks in which subjects achieve platelet counts = 50 Gi/L, between weeks 4‐24 of Part 2. ; Maximum period of time with platelet counts continuously = 50 Gi/L during Part 2. ; The proportion of subjects who reduced or discontinued baseline concomitant ITP medications during Part 2.

PRIMARY OUTCOME:

Main Objective: To assess the efficacy of eltrombopag, relative to placebo, in achieving platelet counts of = 50 Gi/L, when administered to pediatric subjects with previously treated chronic ITP during the first 12 weeks of Part 1, the randomized treatment period. Primary end point(s): The odds of achieving platelet counts = 50 Gi/L during the first 12 weeks of Part 1, the randomized treatment period, for subjects receiving eltrombopag relative to placebo. Secondary Objective: • To describe the efficacy of eltrombopag in achieving platelet counts = 50 Gi/L when administered to pediatric subjects with previously treated chronic ITP. • To assess the efficacy of eltrombopag in achieving sustained platelet counts = 50 Gi/L when administered to pediatric subjects with previously treated chronic ITP. • To describe the effect of eltrombopag on reduction and/or interruption of concomitant ITP therapies, when administered for 24 weeks to pediatric subjects with previously treated chronic ITP.; • To describe the effect of eltrombopag on the need for rescue ITP medication when administered to pediatric subjects with previously treated chronic ITP. • To assess the efficacy of eltrombopag in decreasing the incidence and severity of bleeding symptoms when administered in pediatric subjects with previously treated chronic. Please refer to the protocol for The remaining objectives P12 Timepoint(s) of evaluation of this end point: Primary endpoint will be based on platelet counts obtained through the first 12 weeks of Part 1. ; The proportion of subjects receiving eltrombopag, relative to placebo, who required protocol‐defined rescue treatment during Part 1. ; The proportion of subjects who required protocol‐defined rescue treatment during Part 2. ; Incidence and severity of symptoms associated with ITP, including bleeding, bruising and petechiae, measured using the World Health Organization (WHO) Bleeding Scale for subjects receiving eltrombopag relative to placebo, during Part 1. ; Incidence and severity of symptoms associated with ITP, including bleeding, bruising and petechiae, measured using the WHO Bleeding Scale during Part 2. ; Safety and tolerability parameters including blood pressure and heart rate, ophthalmic examinations, clinical laboratory assessments and frequency of all adverse events, categorized using Common Terminology Criteria for Adverse Events (CTCAE) v4 toxicity grades. ; PK data collected in this study will be included in a population PK analysis in order to estimate primary model‐based PK parameters such as CL/F, Q/F, Vc/F, Vp/F, and ka and the influence of potential covariates on these parameters. ; Timepoint(s) of evaluation of this end point: Secondary endpoints span up to 13 weeks in Part 1 and up to 24 weeks in Part 2.

INCLUSION CRITERIA:

1. Written informed consent must be obtained from the subject’s guardian and accompanying informed assent from the subject (for children over 6 years old). 2. Subjects must be between 1 year and <18 years of age at Day 1. 3. Subjects will have a confirmed diagnosis of chronic ITP for at least 1 year, at screening, according to the guidelines published in the International Working Group Report [Rodeghiero, 2009]. 4. A peripheral blood smear or bone marrow examination will support the diagnosis of ITP with no evidence of other causes of thrombocytopenia. 5. Subjects must be refractory or have relapsed after at least one prior ITP therapy, or subjects must be unable, for a medical reason, to continue other ITP treatments. 6. Subjects must have a Day 1 (or within 48 hours prior) platelet count <30 Gi/L. 7. Previous therapy for ITP with immunoglobulins (IVIg and anti‐D) must have been completed at least 2 weeks prior to Day 1, or these therap