Study of the effect of the thrombopoietin receptor agonist eltrombopag on thrombocytopenia and megakaryopoiesis of patients with lower and intermediate-1 risk myelodysplastic syndromes.

INTERVENTION:

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

INN:

ELTROMBOPAG CAS Number: 496775‐61‐2 Current Sponsor code: SB‐497115 Concentration unit: mg milligram(s) Concentration type: range Concentration number: 25‐100

CONDITION:

Patients with lower and intermediate‐1 risk myelodysplastic syndromes. Therapeutic area: Diseases [C] ‐ Blood and lymphatic diseases [C15]

PRIMARY OUTCOME:

Main Objective: Evaluation of the proportion of patients with an increase of the platelet count (eltrombopag effect on platelet count), according to the international criteria.; Measurement of survival, differentiation and maturation characteristics of BMMCs & megakaryotic progenitor cells throughout the study’s duration. Primary end point(s): Evaluation of the platelet count throughout the duration of the study and evaluation of the type of response according to international criteria.; Measurement of platelet response parameters before treatment and at end of month 3, month 12 and month 24. Secondary Objective: 1. Safety and tolerability of eltrombopag.; 2. Change in bone marrow blast counts from baseline and as well as differences in % of bone marrow blasts between the two groups.; 3. Progression of disease. ; 4. Overall survival.; 5. Number of platelet transfusions.; 6. Duration of platelet transfusion‐independence.; 7. Incidence and severity of bleeding.; 8. Changes in hemoglobin levels and neutrophil counts. Timepoint(s) of evaluation of this end point: Throughout the duration of the study.

SECONDARY OUTCOME:

Secondary end point(s): • Clinical examination findings, clinical follow‐up, vital signs, laboratory tests and reported adverse events (including bleeding and transfusion‐related AEs). ; • Percentage of blasts in blood or/and bone marrow. ; • Percentage of neutrophils, platelets, haemoglobin, appearance of chloroma, appearance of B symptoms. ; • Disease response, disease progression, final outcome. ; • Number of platelet transfusions. ; • Duration of platelet transfusion‐independence. ; • Incidence and severity of bleeding (according WHO Bleeding Scale). ; • Improvement in haemoglobin levels, platelets and neutrophil counts. Timepoint(s) of evaluation of this end point: Throughout the duration of the study.

INCLUSION CRITERIA:

1. Adult subjects (= 18 years old) with low and intermediate‐1 MDS type according to the WHO classification and IPSS. 2. Mean baseline platelet count <30x Gi/L or <50 Gi/L with bleeding manifestations. 3. Patients with data on platelet count, bleeding and platelet transfusions covering a period of at least 4 weeks before enrolment. 4. Bone marrow examination 4 weeks before randomization. 5. Supportive/palliative therapies such as cytokines (except for IL‐11; oprelvekin), valproic acid and all‐trans retinoic acid are allowed, provided those therapies have been at a stable dose for 4 weeks or were completed 4 weeks prior to enrolment into this study. 6. ECOG Status 0‐2. 7. Adequate baseline liver and renal function defined by the criteria below: • total bilirubin (except for Gilbert’s Syndrome) = 1.5xULN • ALT and AST = 3xULN • serum creatinine = 1.5mg/dl or calculated creatinine clearance = 40ml/min (calculated buy the Cock