A Three-part Study of Eltrombopag in Thrombocytopenic Subjects with Myelodysplastic Syndromes or Acute Myeloid Leukemia (Part 1: open-label, Part 2: randomized, double-blind, Part 3: extension)

INTERVENTION:

Trade Name: Revolade Product Name: Eltrombopag Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

ELTROMBOPAG CAS Number: 496775‐61‐2 Current Sponsor code: SB‐497115 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 Trade Name: Revolade Product Name: Eltrombopag Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

ELTROMBOPAG CAS Number: 496775‐61‐2 Current Sponsor code: SB‐497115 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 Trade Name: Revolade Product Name: Eltrombopag Product Code: SB‐497115 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

ELTROMBOPAG CAS Number: 496775‐61‐2 Current Sponsor code: SB‐497115 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use

CONDITION:

Therapeutic area: Diseases [C] ‐ Immune System Diseases [C20] Thrombocytopenic Subjects with Myelodysplastic Syndromes or Acute Myeloid Leukemia ; MedDRA version: 14.0 Level: LLT Classification code 10028534 Term: Myelodysplastic syndrome NOS System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) ; MedDRA version: 14.0 Level: LLT Classification code 10060356 Term: Acute myeloid leukaemia without mention of remission System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps)

SECONDARY OUTCOME:

Secondary end point(s): Part 2 of Study:; Secondary endpoints compare the following in subjects treated with eltrombopag and placebo:; ? Hematologic improvement (platelets, neutrophils and hemoglobin); ? Assessment of platelet counts throughout the study; ? Number of platelet transfusions; ? Duration of platelet transfusion‐independence.; ? The occurrence and severity of bleeding, measured using the WHO Bleeding Scale.; ? Disease response and disease progression; ? Physical exam findings, clinical monitoring, vital signs, clinical laboratory tests, and adverse event reporting (including; hemorrhagic and transfusion‐related adverse events).; ? Medical resource utilization, including specifically due to thrombocytopenia and hemorrhage.; ? FACT‐TH‐18 and the EQ‐5D Timepoint(s) of evaluation of this end point: Screening, Baseline, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 11, End of Therapy ? Week 12, Early Withdrawal Visit, Follow Up Visits ? Week 1, 2, 3 & 4

PRIMARY OUTCOME:

Main Objective: Part 1 open‐label, 8 week first part of the study are:; ? To evaluate the safety and tolerability of eltrombopag.; ? To determine optimal dose escalation scheme for use in Part 2 of the study by assessing the dose of eltrombopag required to achieve platelet count response.; ? To characterize plasma eltrombopag pharmacokinetics (steady‐state plasma eltrombopag Cmax, tmax, AUC(0‐?), CL/F, and half‐life).; Part 2: ? The primary objective of this study is to determine reduction in the number of clinically relevant thrombocytopenic events; (CRTE) in subjects with MDS or AML who have Grade 4 thrombocytopenia (<25 Gi/L) and are treated with eltrombopag compared to those treated with placebo.; Part 3: The objectives of the study are to evaluate the long‐term durability of clinical benefit and the long‐term safety and tolerability of eltrombopag in subjects with MDS and AML Primary end point(s): Part 2 of Study:; The primary endpoint is clinically relevant thrombocytopenic events (CRTE) during weeks 5‐12 of treatment. CRTE are defined as:; ? platelet counts <10 Gi/L, or; ? platelet transfusions, or; ? ?Grade 3 hemorrhagic adverse events. Secondary Objective: Part 2 of Study:; Secondary objectives compare the following in subjects treated with eltrombopag and placebo:; ? To evaluate hematologic improvement; ? To evaluate the effect of eltrombopag on platelet counts; ? To evaluate the effect of eltrombopag on the need for platelet transfusions.; ? To evaluate the effect of eltrombopag on the duration of platelet transfusion independence.; ? To evaluate the effect of eltrombopag on bleeding symptoms.; ? To evaluate MDS and AML disease outcomes; ? To evaluate the safety and tolerability of eltrombopag.; ? To evaluate effect of eltrombopag on medical resource utilization.; ? To evaluate effect of eltrombopag on healthrelated quality of life. Timepoint(s) of evaluation of this end point: Screening, Baseline, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 11, ; End of Therapy ? Week 12, ; Early Withdrawal Visit, Follow up Visit ? Week 1, 2, 3 & 4

INCLUSION CRITERIA:

Subjects eligible for enrolment in the study must meet all of the following criteria: 1. Adult subjects (18 years of age or older) with MDS or AML (bone marrow blasts ?50%) with thrombocytopenia due to bone marrow insufficiency from the disease or prior treatment. Subjects with transient thrombocytopenia due to active treatment with disease modifying agents or chemotherapy (except for hydroxyurea) are excluded. 2. Subjects must have Grade 4 thrombocytopenia (platelet counts <25 Gi/L) due to bone marrow insufficiency (or platelet count ?25 Gi/L due to platelet transfusion). In addition, subjects must have had at least one of the following during the 4 week screening period: platelet transfusion, or symptomatic bleeding or platelet count <10 Gi/L. Subjects whose thrombocytopenia below 10 Gi/L is due to causes other than bone marrow insufficiency (e.g., fever, infection, autoimmune disease) are not eligible. 3. Subjects must have platelet count, bleedin