A Study of Eltrombopag or Placebo in Combination With Azacitidine in Subjects With International Prognostic Scoring System (IPSS) Intermediate-1, Intermediate-2 or High-risk Myelodysplastic Syndromes (MDS)

Overall Survival (OS)

Overall survival is defined as the time from randomization until death due to any cause and deaths have been presented. Subjects still alive at the time of the analysis and subjects who have withdrawn from the study will be censored at the time of last contact

Time frame: Randomization until death or end of study, approximately 2 years

Summary of Progression Free Survival From Investigator Assessment (ITT)

Progression-free survival, defined as the time from randomization until either disease progression or death. The modified 2006 IWG criteria for MDS used for progression assessment For patients with: Less than 5% BM blasts: ≥ 50% increase in blasts to \> 5% blasts; 5% - \<10% BM blasts: ≥ 50% increase to \> 10% blasts; 10% - \<20% BM blasts: ≥ 50% increase to \> 20% blasts; 20% - 30% BM blasts: ≥ 50% increase to \> 30% blasts

Time frame: First day of each cycle (Cycles 3+), at the end of therapy visit and every 3 months in follow-up for approximately 2 years

Summary of Progression Free Survival From Central Review (ITT)

Progression-free survival, defined as the time from randomization until either disease progression or death. The modified 2006 IWG criteria for MDS used for progression assessment For patients with: Less than 5% BM blasts: ≥ 50% increase in blasts to \> 5% blasts; 5% - \<10% BM blasts: ≥ 50% increase to \> 10% blasts; 10% - \<20% BM blasts: ≥ 50% increase to \> 20% blasts; 20% - 30% BM blasts: ≥ 50% increase to \> 30% blasts

Time frame: First day of each cycle (Cycles 3+), at the end of therapy visit and every 3 months in follow-up for approximately 2 years

Summary of AML Progression From Investigator Assessment and Central Review (ITT)

Progression to AML in MDS patients with baseline bone marrow blast \< 20% was defined as meeting definition of disease progression according to the modified 2006 IWG response criteria for MDS with the additional requirement that bone marrow blast or peripheral blast increases from \< 20% at baseline to ≥ 20% postbaseline. Progression assessment For patients with: Less than 5% BM blasts: ≥ 50% increase in blasts to \> 5% blasts; 5% - \<10% BM blasts: ≥ 50% increase to \> 10% blasts; 10% - \<20% BM blasts: ≥ 50% increase to \> 20% blasts; 20% - 30% BM blasts: ≥ 50% increase to \> 30% blasts

Time frame: First day of each cycle (Cycles 3+), at the end of therapy visit and every 3 months in follow-up for approximately 2 years

Best Disease Response From Investigator Assessment (ITT)

Best disease response is categorized as complete remission (CR), partial remission (PR), or marrow CR, stable disease, disease progression, or as non-evaluable; according to modified 2006 International Working Group (IWG) criteria for MDS

Time frame: At end of Cycle 6 (cycle=28 days) or end of therapy, whichever came first

Best Disease Response From Central Review (ITT)

Best disease response is categorized as complete remission (CR), partial remission (PR), or marrow CR, stable disease, disease progression, or as non-evaluable; according to modified 2006 International Working Group (IWG) criteria for MDS

Time frame: At end of Cycle 6 (cycle=28 days) or end of therapy, whichever came first

Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT)

HI based on the modified IWG criteria for MDS. HI - Platelets (BL \<100Gi/L), response criteria= BL \<20: increase to\>20 and 100% at least for 56 days or BL \>=20: absolute increase of \>=30. HI - Neutrophils (BL \<1.0 Gi/L), response criteria=100% increase and an absolute increase \>0.5 Gi/L over BL for at least 56 days. HI-Hemoglobin (BL \<g/dL), response criteria=Hgb increase by \>=1.5 g/dL over BL, RBC transfusions(given for Hgb\<=9.0) reduced by \>=4 per 8w from BL

Time frame: From Day 1 to 4-week follow-up (samples collected weekly in Cycle 1, Days 1 and 15 in Cycles 2-6 and Day 1 of Cycles >=7)

Number of Participants Who Were Platelet Transfusion Independent (ITT Set)

Platelet transfusion independence is defined for each cycle as the number of participants who continue to the end of a cycle without requiring a platelet transfusion

Time frame: From Day 1 to end of study treatment up to approximately 2 years

Bleeding Adverse Events (AEs) >= Grade 3

Bleeding will be assessed by recording AEs or serious adverse events (SAEs) as graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0

Time frame: From Day 1 to 4-week follow-up up to approximately 2 years

Number of of Subjects With Azacitidine Dose Delays, Dose Reductions, Interruptions

The proportion of subjects with any delay, reduction or interruption in dosage of Azacitidine excluding those for non-medical reasons will be analyzed

Time frame: From Day 1 to 4-week follow-up up to approximately 2 years

Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™)

The EQ-5D is a general health status and health utility measure which captures 5 dimensions of health state: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. (EQ-5D is a trademark of the Stichting EuroQol Group) . C=cycle, D=Day

Time frame: From Day 1 to 4-week follow-up up to approximately 2 years

Functional Assessment of Chronic Disease Therapy-fatigue Subscale (FACIT-Fatigue) (ITT)

The FACIT-Fatigue subscale measures severity and impact of fatigue on functioning and Health Related QoL experienced in the past 7 days. Scale is a 13 item measure of fatigure. Items are scored on a 0-4 response scale ranging from "not at all" to "very much so". All items are summed to create a single fatigure score with a range from 0 to 52. Items are reverse scored when appropriate to provide a scale in which higher scores represent better functioning or less fatiigue (The FACIT Fatigue Scale is owned by David Cella, Ph.D.)

Time frame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up) up to approximately 2 years

Medical Resource Utilization (MRU): Event -Hospitalizations Inpatient and Outpatient

MRU data will be collected for each subject. Events corresponding to unscheduled (not scheduled per protocol) hospitalizations

Time frame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up) up to approximately 2 years

Medical Resource Utilization (MRU): Event and Use of Site Specific Medical Resources - Non-study Laboratory Tests

MRU data will be collected for each subject. Events corresponding to unscheduled (not scheduled per protocol) hospitalizations, office visits including consultations, laboratory and diagnostic tests (lab results, imaging etc.), and procedures prior to therapy initiation and during therapy will be collected

Time frame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up) up to approximately 2 years

Medical Resource Utilization (MRU): Use of Site Specific Medical Resources

MRU data will be collected for each subject. Events corresponding to unscheduled (not scheduled per protocol) hospitalizations, office visits including consultations, laboratory and diagnostic tests (lab results, imaging etc.), and procedures prior to therapy initiation and during therapy will be collected

Time frame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up) up to approximately 2 years

Summary of Post-Hoc Estimates of Steady-state Eltrombopag Cmax and Cmin Pharmacokinetic Parameters for a 50 mg Dose

Eltrombopag concentrations were analyzed using a population PK model along with data from other studies in healthy volunteers and in patients with MDS and/or AML. Post-hoc PK parameters were derived. Only patients from this study were included (163)

Time frame: Cycle 1, Week 2: Pre-dose, 1.5 and 3 hour post dose; Cycle 1, Week 3: 4, 5.5, and 7 hours post dose

Summary of Post-Hoc Estimates of Steady-state Eltrombopag AUC0 Infinity Pharmacokinetic Parameters for a 50 mg Dose

Eltrombopag concentrations were analyzed using a population PK model along with data from other studies in healthy volunteers and in patients with MDS and/or AML. Post-hoc PK parameters were derived. Only patients from this study were included (163)

Time frame: Cycle 1, Week 2: Pre-dose, 1.5 and 3 hour post dose; Cycle 1, Week 3: 4, 5.5, and 7 hours post dose

AUC0-infinity -Pharmacokinetic(s) Parameter of Azacitidine

An analysis of variance (ANOVA) on AUC0-infinity. The PK parameters were log transformed prior to analysis. The model included treatment as a fixed effect. Point estimates and their associated 90% CI were constructed for the differences in PK parameter values. The point estimates and their associated 90% CI were then back transformed to provide point estimates and 90% CI for the azacitidine + eltrombopag:azacitidine + placebo PK parameter ratios.

Time frame: Cycle 2 Day 1: Pre-dose, 15 min, 0.5, 1, 2 and 4 hr post dose

Cmax -Pharmacokinetic Parameter of Azacitidine

An analysis of variance (ANOVA) on Cmax . The PK parameters were log transformed prior to analysis. The model included treatment as a fixed effect. Point estimates and their associated 90% CI were constructed for the differences in PK parameter values. The point estimates and their associated 90% CI were then back transformed to provide point estimates and 90% CI for the azacitidine + ltrombopag:azacitidine + placebo PK parameter ratios.

Time frame: Cycle 2 Day 1: Pre-dose, 15 min, 0.5, 1, 2 and 4 hr post dose