Trial Outcomes & Findings for 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) (NCT NCT02158936)

Last Updated: 2017-12-12

Results Overview

A subject is defined as being platelet transfusion independent if they received no platelet transfusions within the first 4 cycles of treatment with azacitidine. Subjects who died or withdrew from investigational product within the first four cycles were treated as failures (i.e. not transfusion independent) in the analysis

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

356 participants

Primary outcome timeframe

4 cycles (Cycle = 28 days)

Results posted on

2017-12-12

Participant Flow

A total of 356 patients were enrolled in the study and 2 patients did not receive treatment.

Participant milestones

Participant milestones
Measure	Eltrombopag Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
Overall Study STARTED	179	177
Overall Study Treated	177	177
Overall Study Untreated	2	0
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	179	177

Reasons for withdrawal

Reasons for withdrawal
Measure	Eltrombopag Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
Overall Study Study closed/ terminated	57	77
Overall Study Azacitidine tx discontinued	53	46
Overall Study Adverse Event	39	24
Overall Study Withdrawal by Subject	15	16
Overall Study Physician Decision	15	13
Overall Study Lost to Follow-up	0	1

Baseline Characteristics

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)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Eltrombopag n=179 Participants Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo n=177 Participants Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine	Total n=356 Participants Total of all reporting groups
Age, Continuous	68.3 years STANDARD_DEVIATION 12.82 • n=5 Participants	69.4 years STANDARD_DEVIATION 10.58 • n=7 Participants	68.8 years STANDARD_DEVIATION 11.76 • n=5 Participants
Sex: Female, Male Female	69 Participants n=5 Participants	53 Participants n=7 Participants	122 Participants n=5 Participants
Sex: Female, Male Male	110 Participants n=5 Participants	124 Participants n=7 Participants	234 Participants n=5 Participants
Race/Ethnicity, Customized White	146 participants n=5 Participants	148 participants n=7 Participants	294 participants n=5 Participants
Race/Ethnicity, Customized East Asian/Japanese/S.E. Asian	26 participants n=5 Participants	23 participants n=7 Participants	49 participants n=5 Participants
Race/Ethnicity, Customized Central/South Asian	0 participants n=5 Participants	2 participants n=7 Participants	2 participants n=5 Participants
Race/Ethnicity, Customized Other	4 participants n=5 Participants	4 participants n=7 Participants	8 participants n=5 Participants
Race/Ethnicity, Customized Missing	3 participants n=5 Participants	0 participants n=7 Participants	3 participants n=5 Participants
IPSS risk score Int - 1 (0.5-1.0)	64 participants n=5 Participants	61 participants n=7 Participants	125 participants n=5 Participants
IPSS risk score Int - 2 (1.5 - 2.0)	77 participants n=5 Participants	83 participants n=7 Participants	160 participants n=5 Participants
IPSS risk score High Risk (≥ 2.5)	38 participants n=5 Participants	33 participants n=7 Participants	71 participants n=5 Participants
Platelet Count < 10	10 participants n=5 Participants	10 participants n=7 Participants	20 participants n=5 Participants
Platelet Count ≥ 10 - <20	35 participants n=5 Participants	30 participants n=7 Participants	65 participants n=5 Participants
Platelet Count ≥ 20 - <50	83 participants n=5 Participants	84 participants n=7 Participants	167 participants n=5 Participants
Platelet Count ≥ 50 - <100	49 participants n=5 Participants	53 participants n=7 Participants	102 participants n=5 Participants
Platelet Count ≥ 100	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Platelet Count missing	2 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants
Platelet transfusion dependence Yes	29 participants n=5 Participants	37 participants n=7 Participants	66 participants n=5 Participants
Platelet transfusion dependence No	150 participants n=5 Participants	140 participants n=7 Participants	290 participants n=5 Participants

PRIMARY outcome

Timeframe: 4 cycles (Cycle = 28 days)

Population: Intent-to-Treat population, comprised of all randomized patients

Outcome measures

Outcome measures
Measure	Eltrombopag n=179 Participants Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo n=177 Participants Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
Number of Participants Who Were Platelet Transfusion Independent During Cycles 1-4 of Azacitidine Therapy Yes - platelet transfusion independent	28 Participants	55 Participants
Number of Participants Who Were Platelet Transfusion Independent During Cycles 1-4 of Azacitidine Therapy No - platelet transfusion independent	151 Participants	122 Participants

SECONDARY outcome

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

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

Outcome measures

Outcome measures
Measure	Eltrombopag n=179 Participants Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo n=177 Participants Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
Overall Survival (OS)	57 deaths (events)	51 deaths (events)

SECONDARY outcome

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

Population: The intent-to-treat (ITT) population included all the patients randomized in the study

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

Outcome measures

Outcome measures
Measure	Eltrombopag n=72 Participants Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo n=66 Participants Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
Summary of Progression Free Survival From Investigator Assessment (ITT) Death	34 participants	36 participants
Summary of Progression Free Survival From Investigator Assessment (ITT) Disease progression	38 participants	30 participants

SECONDARY outcome

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

Population: The intent-to-treat (ITT) population included all the patients randomized in the study

Outcome measures

Outcome measures
Measure	Eltrombopag n=179 Participants Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo n=177 Participants Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
Summary of Progression Free Survival From Central Review (ITT) Death	44 participants	41 participants
Summary of Progression Free Survival From Central Review (ITT) Disease progression	32 participants	26 participants

SECONDARY outcome

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

Population: The intent-to-treat (ITT) population included all the patients randomized in the study

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

Outcome measures

Outcome measures
Measure	Eltrombopag n=179 Participants Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo n=177 Participants Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
Summary of AML Progression From Investigator Assessment and Central Review (ITT) Participants progressed-AML - investigator assess	27 participants	16 participants
Summary of AML Progression From Investigator Assessment and Central Review (ITT) Participants progressed to AML - Central Review	21 participants	10 participants

SECONDARY outcome

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

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

Outcome measures

Outcome measures
Measure	Eltrombopag n=140 Participants Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo n=150 Participants Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
Best Disease Response From Investigator Assessment (ITT) Complete response - CR	15 participant	26 participant
Best Disease Response From Investigator Assessment (ITT) Marrow complete response	8 participant	14 participant
Best Disease Response From Investigator Assessment (ITT) Partial response - PR	13 participant	22 participant
Best Disease Response From Investigator Assessment (ITT) Stable disease	50 participant	47 participant
Best Disease Response From Investigator Assessment (ITT) Progressive disease	22 participant	8 participant
Best Disease Response From Investigator Assessment (ITT) Not evaluable	32 participant	33 participant
Best Disease Response From Investigator Assessment (ITT) Overall Response (CR+Marrow+PR	36 participant	62 participant

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Eltrombopag n=88 Participants Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo n=105 Participants Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
Best Disease Response From Central Review (ITT) Complete response - CR	11 participant	7 participant
Best Disease Response From Central Review (ITT) Marrow complete response	2 participant	5 participant
Best Disease Response From Central Review (ITT) Partial response - PR	2 participant	7 participant
Best Disease Response From Central Review (ITT) Stable disease	23 participant	31 participant
Best Disease Response From Central Review (ITT) Progressive disease	24 participant	17 participant
Best Disease Response From Central Review (ITT) Not evaluable	26 participant	38 participant
Best Disease Response From Central Review (ITT) Overall Response (CR+Marrow+PR)	15 participant	19 participant

SECONDARY outcome

Timeframe: 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)

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

Outcome measures

Outcome measures
Measure	Eltrombopag n=179 Participants Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo n=177 Participants Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) Platelets	56 participants	57 participants
Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) Neutrophils	12 participants	13 participants
Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) Hemoglobin	1 participants	1 participants
Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) Platelets and neutrophils	10 participants	11 participants
Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) Platelets and hemoglobin	1 participants	1 participants
Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) Neutrophils and hemoglobin	1 participants	1 participants
Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) Platelets, neutrophils and hemoglobin	1 participants	1 participants

SECONDARY outcome

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

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

Outcome measures

Outcome measures
Measure	Eltrombopag n=179 Participants Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo n=177 Participants Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
Number of Participants Who Were Platelet Transfusion Independent (ITT Set) Screening (179,177)	127 participants	121 participants
Number of Participants Who Were Platelet Transfusion Independent (ITT Set) Cycle 1 (175,173)	68 participants	87 participants
Number of Participants Who Were Platelet Transfusion Independent (ITT Set) Cycle 2 (135,158)	62 participants	87 participants
Number of Participants Who Were Platelet Transfusion Independent (ITT Set) Cycle 3 (105,131)	68 participants	94 participants
Number of Participants Who Were Platelet Transfusion Independent (ITT Set) Cycle 4 (93,116)	58 participants	91 participants
Number of Participants Who Were Platelet Transfusion Independent (ITT Set) Cycle 5 (76,108)	49 participants	76 participants
Number of Participants Who Were Platelet Transfusion Independent (ITT Set) Cycle 6 (65,90)	41 participants	62 participants
Number of Participants Who Were Platelet Transfusion Independent (ITT Set) Cycle 7 (47,74)	29 participants	50 participants
Number of Participants Who Were Platelet Transfusion Independent (ITT Set) Cycle 8 (37,61)	20 participants	42 participants
Number of Participants Who Were Platelet Transfusion Independent (ITT Set) Cycle 9 (28,46)	19 participants	36 participants
Number of Participants Who Were Platelet Transfusion Independent (ITT Set) Cycle 10 (23,38)	18 participants	28 participants
Number of Participants Who Were Platelet Transfusion Independent (ITT Set) Cycle 11 (19,29)	13 participants	20 participants
Number of Participants Who Were Platelet Transfusion Independent (ITT Set) Cycle 12 (15,21)	10 participants	15 participants
Number of Participants Who Were Platelet Transfusion Independent (ITT Set) Cycle 13 (12,16)	7 participants	10 participants
Number of Participants Who Were Platelet Transfusion Independent (ITT Set) Cycle 14 (6,11)	3 participants	6 participants
Number of Participants Who Were Platelet Transfusion Independent (ITT Set) Cycle 15 (3,5)	2 participants	3 participants
Number of Participants Who Were Platelet Transfusion Independent (ITT Set) Cycle 16 (0,3)	0 participants	3 participants
Number of Participants Who Were Platelet Transfusion Independent (ITT Set) Cycle 17 (0,3)	0 participants	0 participants

SECONDARY outcome

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

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

Outcome measures

Outcome measures
Measure	Eltrombopag n=177 Participants Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo n=177 Participants Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
Bleeding Adverse Events (AEs) >= Grade 3 Any event - Grade 3	9 participant	12 participant
Bleeding Adverse Events (AEs) >= Grade 3 Any event - Grade 4	2 participant	2 participant
Bleeding Adverse Events (AEs) >= Grade 3 Any event - Grade 5	1 participant	4 participant

SECONDARY outcome

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

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

Outcome measures

Outcome measures
Measure	Eltrombopag n=179 Participants Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo n=177 Participants Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
Number of of Subjects With Azacitidine Dose Delays, Dose Reductions, Interruptions Overall dose delay	82 participant	88 participant
Number of of Subjects With Azacitidine Dose Delays, Dose Reductions, Interruptions Overall dose reduction	7 participant	16 participant
Number of of Subjects With Azacitidine Dose Delays, Dose Reductions, Interruptions Overall dose interruption	3 participant	13 participant

SECONDARY outcome

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

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

Outcome measures

Outcome measures
Measure	Eltrombopag n=179 Participants Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo n=177 Participants Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Mobility C1, D1 (176, 173) L1- no problem walking	94 participant	105 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Mobility C1,D1 (176, 173) L2- some problem walking	81 participant	66 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Mobility C1, D1 (176,173) L3- confined to bed	1 participant	2 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Mobility Wk 4 FU (71,72) L1- no problem walking	40 participant	48 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Mobility Wk 4 FU (71,72) L2- some problem walking	29 participant	22 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Mobility Wk 4 FU (71,72) L3- confined to bed	2 participant	2 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Self-Care C1, D1 (176,173) L1-no problems	140 participant	125 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Self-Care C1, D1 (176,173) L2-some problems	32 participant	20 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Self-Care C1, D1 (176,173) L3-unable to	4 participant	51 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Self-Care Wk4 FU (71,72) L1-no problems	56 participant	62 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Self-Care Wk4 FU(71,72) L2-some problems	13 participant	9 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Self-Care Wk4 FU (71,72) L2-unable to wash/dress	2 participant	1 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Usual activities C1,D1(175,173) L1-no problem	97 participant	94 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Usual activities C1,D1(175,173) L2-some problem	71 participant	68 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Usual activities C1,D1(175,173) L3-unable to	7 participant	11 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Usual activities Wk4 FU (71,72) L1-no problem	36 participant	41 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Usual activities Wk4 FU (71,72) L1-some problem	29 participant	25 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Usual activities Wk4 FU (71,72) L3-unable to	6 participant	6 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Pain/discomfort C1,D1(176,173) L1-none	97 participant	89 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Pain/discomfort C1,D1(176,173) L2-moderate	74 participant	78 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Pain/discomfort C1,D1(176,173) L3-extreme	5 participant	6 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Pain/discomfort Wk4 FU (71,72) L1-none	38 participant	40 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Pain/discomfort Wk4 FU (71,72) L2-moderate	28 participant	27 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Pain/discomfort Wk4 FU (71,72) L3-extreme	5 participant	5 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Anxiety/depression C1 D1(176,173) L1-none	96 participant	112 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Anxiety/depression C1 D1(176,173) L2-moderately	74 participant	56 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Anxiety/depression C1 D1(176,173) L3-extremely	6 participant	5 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Anxiety/depression Wk4 FU(71,72) L1-none	44 participant	45 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Anxiety/depression Wk4 FU(71,72) L2-moderately	24 participant	25 participant
Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) Anxiety/depression Wk4 FU(71,72) L3-extremely	3 participant	2 participant

SECONDARY outcome

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

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.)

Outcome measures

Outcome measures
Measure	Eltrombopag n=179 Participants Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo n=177 Participants Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
Functional Assessment of Chronic Disease Therapy-fatigue Subscale (FACIT-Fatigue) (ITT) Cycle 1 Day 1 (175,172)	17.401 scores Standard Deviation 11.0279	15.951 scores Standard Deviation 10.9911
Functional Assessment of Chronic Disease Therapy-fatigue Subscale (FACIT-Fatigue) (ITT) Week 4 Follow-up (68,70)	16.669 scores Standard Deviation 10.7266	14.898 scores Standard Deviation 12.2362

SECONDARY outcome

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

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

Outcome measures

Outcome measures
Measure	Eltrombopag n=179 Participants Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo n=177 Participants Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
Medical Resource Utilization (MRU): Event -Hospitalizations Inpatient and Outpatient In-patient hospitalizations - entire study (91,66)	23.9 days Standard Deviation 24.33	27.1 days Standard Deviation 33.81
Medical Resource Utilization (MRU): Event -Hospitalizations Inpatient and Outpatient Out-patient hospitalizations - entire study (4,2)	9.5 days Standard Deviation 16.34	2.5 days Standard Deviation 0.71

SECONDARY outcome

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

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

Outcome measures

Outcome measures
Measure	Eltrombopag n=179 Participants Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo n=177 Participants Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
Medical Resource Utilization (MRU): Event and Use of Site Specific Medical Resources - Non-study Laboratory Tests	88 tests	105 tests

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Eltrombopag n=179 Participants Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo n=177 Participants Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
Medical Resource Utilization (MRU): Use of Site Specific Medical Resources Medical or surgical specialist visits	49 visits	58 visits
Medical Resource Utilization (MRU): Use of Site Specific Medical Resources Home healthcare visits by medical professional	89 visits	97 visits
Medical Resource Utilization (MRU): Use of Site Specific Medical Resources Primary physician care visits	89 visits	97 visits
Medical Resource Utilization (MRU): Use of Site Specific Medical Resources Nurse practitioner, physic assistant, nurse visits	89 visits	97 visits
Medical Resource Utilization (MRU): Use of Site Specific Medical Resources Telephone consultations	89 visits	97 visits
Medical Resource Utilization (MRU): Use of Site Specific Medical Resources Emergency visits not resulting in hospital stay	89 visits	97 visits

SECONDARY outcome

Timeframe: 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

Population: All patients with evaluable eltrombopag dosing, actual sampling time, and eltrombopag concentration data were included in the population PK dataset and analysis.

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)

Outcome measures

Outcome measures
Measure	Eltrombopag n=163 Participants Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
Summary of Post-Hoc Estimates of Steady-state Eltrombopag Cmax and Cmin Pharmacokinetic Parameters for a 50 mg Dose Cmax	7.70 μg/mL Geometric Coefficient of Variation 36.8	—
Summary of Post-Hoc Estimates of Steady-state Eltrombopag Cmax and Cmin Pharmacokinetic Parameters for a 50 mg Dose Cmin	4.41 μg/mL Geometric Coefficient of Variation 49.9	—

SECONDARY outcome

Timeframe: 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

Population: All patients with evaluable eltrombopag dosing, actual sampling time, and eltrombopag concentration data were included in the population PK dataset and analysis.

Outcome measures

Outcome measures
Measure	Eltrombopag n=163 Participants Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
Summary of Post-Hoc Estimates of Steady-state Eltrombopag AUC0 Infinity Pharmacokinetic Parameters for a 50 mg Dose	135 hr.μg/mL Geometric Coefficient of Variation 43.1	—

SECONDARY outcome

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

Population: all patients with evaluable azacitidine dosing, actual sampling time, and azacitidine concentration data were included in the NCA dataset and analysis

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.

Outcome measures

Outcome measures
Measure	Eltrombopag n=22 Participants Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo n=23 Participants Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
AUC0-infinity -Pharmacokinetic(s) Parameter of Azacitidine	840 hr.ng/mL Geometric Coefficient of Variation 53	641 hr.ng/mL Geometric Coefficient of Variation 67

SECONDARY outcome

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

Population: All patients with evaluable azacitidine dosing, actual sampling time, and azacitidine concentration data were included in the NCA dataset and analysis

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.

Outcome measures

Outcome measures
Measure	Eltrombopag n=26 Participants Starting dose is 200 mg (100 mg for East Asian heritage). Dose modifications permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at safe, effective level (level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive Azacitidine 75 mg/meter\^2 is administered subcutaneously once daily for 7 days every 28 days, for at least 6 cycles, if tolerated, until they are no longer receiving benefit (at least stable disease), disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle if subject is receiving azacitidine	Placebo n=26 Participants Subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive matching placebo daily for the full 28 days each cycle for as long as the subject is receiving azacitidine
Cmax -Pharmacokinetic Parameter of Azacitidine	744 ng/mL Geometric Coefficient of Variation 91	535 ng/mL Geometric Coefficient of Variation 89

Adverse Events

Eltrombopag

Serious events: 128 serious events

Other events: 159 other events

Deaths: 0 deaths

Placebo

Serious events: 100 serious events

Other events: 153 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharma AG

Phone: 862-778-8300

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novaratis does not prohibit any investigation from publishing. Any publications from a single-site are postposed until the publication of the pooled data (ie. data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Measure	Eltrombopag n=177 participants at risk Eltrombopag	Placebo n=177 participants at risk Placebo
Blood and lymphatic system disorders Anaemia	18.1% 32/177 • Timeframe for AE AE additional description	10.7% 19/177 • Timeframe for AE AE additional description
Blood and lymphatic system disorders Febrile neutropenia	7.3% 13/177 • Timeframe for AE AE additional description	5.6% 10/177 • Timeframe for AE AE additional description
Blood and lymphatic system disorders Leukopenia	5.1% 9/177 • Timeframe for AE AE additional description	2.8% 5/177 • Timeframe for AE AE additional description
Blood and lymphatic system disorders Neutropenia	29.4% 52/177 • Timeframe for AE AE additional description	24.9% 44/177 • Timeframe for AE AE additional description
Blood and lymphatic system disorders Thrombocytopenia	7.9% 14/177 • Timeframe for AE AE additional description	7.9% 14/177 • Timeframe for AE AE additional description
Gastrointestinal disorders Abdominal pain	4.0% 7/177 • Timeframe for AE AE additional description	6.8% 12/177 • Timeframe for AE AE additional description
Gastrointestinal disorders Abdominal pain upper	5.1% 9/177 • Timeframe for AE AE additional description	4.0% 7/177 • Timeframe for AE AE additional description
Gastrointestinal disorders Constipation	27.1% 48/177 • Timeframe for AE AE additional description	32.2% 57/177 • Timeframe for AE AE additional description
Gastrointestinal disorders Diarrhoea	23.7% 42/177 • Timeframe for AE AE additional description	14.1% 25/177 • Timeframe for AE AE additional description
Gastrointestinal disorders Gingival bleeding	7.3% 13/177 • Timeframe for AE AE additional description	5.1% 9/177 • Timeframe for AE AE additional description
Gastrointestinal disorders Nausea	30.5% 54/177 • Timeframe for AE AE additional description	26.0% 46/177 • Timeframe for AE AE additional description
Gastrointestinal disorders Stomatitis	5.1% 9/177 • Timeframe for AE AE additional description	1.7% 3/177 • Timeframe for AE AE additional description
Gastrointestinal disorders Vomiting	18.6% 33/177 • Timeframe for AE AE additional description	16.4% 29/177 • Timeframe for AE AE additional description
General disorders Asthenia	15.8% 28/177 • Timeframe for AE AE additional description	19.2% 34/177 • Timeframe for AE AE additional description
General disorders Chills	4.5% 8/177 • Timeframe for AE AE additional description	6.2% 11/177 • Timeframe for AE AE additional description
General disorders Fatigue	17.5% 31/177 • Timeframe for AE AE additional description	15.3% 27/177 • Timeframe for AE AE additional description
General disorders Injection site pain	4.0% 7/177 • Timeframe for AE AE additional description	5.1% 9/177 • Timeframe for AE AE additional description
General disorders Oedema peripheral	12.4% 22/177 • Timeframe for AE AE additional description	6.2% 11/177 • Timeframe for AE AE additional description
General disorders Pyrexia	24.9% 44/177 • Timeframe for AE AE additional description	22.6% 40/177 • Timeframe for AE AE additional description
Infections and infestations Nasopharyngitis	4.0% 7/177 • Timeframe for AE AE additional description	5.1% 9/177 • Timeframe for AE AE additional description
Infections and infestations Pneumonia	6.8% 12/177 • Timeframe for AE AE additional description	5.1% 9/177 • Timeframe for AE AE additional description
Infections and infestations Upper respiratory tract infection	5.1% 9/177 • Timeframe for AE AE additional description	6.2% 11/177 • Timeframe for AE AE additional description
Infections and infestations Urinary tract infection	5.1% 9/177 • Timeframe for AE AE additional description	4.5% 8/177 • Timeframe for AE AE additional description
Investigations Alanine aminotransferase increased	5.6% 10/177 • Timeframe for AE AE additional description	1.7% 3/177 • Timeframe for AE AE additional description
Investigations Blood bilirubin increased	7.3% 13/177 • Timeframe for AE AE additional description	1.1% 2/177 • Timeframe for AE AE additional description
Investigations Neutrophil count decreased	6.8% 12/177 • Timeframe for AE AE additional description	6.2% 11/177 • Timeframe for AE AE additional description
Investigations Platelet count decreased	5.1% 9/177 • Timeframe for AE AE additional description	2.8% 5/177 • Timeframe for AE AE additional description
Investigations White blood cell count decreased	5.6% 10/177 • Timeframe for AE AE additional description	2.3% 4/177 • Timeframe for AE AE additional description
Metabolism and nutrition disorders Decreased appetite	15.3% 27/177 • Timeframe for AE AE additional description	11.9% 21/177 • Timeframe for AE AE additional description
Metabolism and nutrition disorders Hypokalaemia	10.7% 19/177 • Timeframe for AE AE additional description	9.6% 17/177 • Timeframe for AE AE additional description
Musculoskeletal and connective tissue disorders Arthralgia	3.4% 6/177 • Timeframe for AE AE additional description	6.2% 11/177 • Timeframe for AE AE additional description
Musculoskeletal and connective tissue disorders Back pain	7.3% 13/177 • Timeframe for AE AE additional description	5.6% 10/177 • Timeframe for AE AE additional description
Musculoskeletal and connective tissue disorders Pain in extremity	5.1% 9/177 • Timeframe for AE AE additional description	7.9% 14/177 • Timeframe for AE AE additional description
Nervous system disorders Dizziness	9.6% 17/177 • Timeframe for AE AE additional description	7.9% 14/177 • Timeframe for AE AE additional description
Nervous system disorders Headache	11.3% 20/177 • Timeframe for AE AE additional description	7.3% 13/177 • Timeframe for AE AE additional description
Psychiatric disorders Insomnia	9.0% 16/177 • Timeframe for AE AE additional description	5.1% 9/177 • Timeframe for AE AE additional description
Respiratory, thoracic and mediastinal disorders Cough	13.0% 23/177 • Timeframe for AE AE additional description	16.4% 29/177 • Timeframe for AE AE additional description
Respiratory, thoracic and mediastinal disorders Dyspnoea	13.6% 24/177 • Timeframe for AE AE additional description	6.8% 12/177 • Timeframe for AE AE additional description
Respiratory, thoracic and mediastinal disorders Epistaxis	7.9% 14/177 • Timeframe for AE AE additional description	10.2% 18/177 • Timeframe for AE AE additional description
Skin and subcutaneous tissue disorders Erythema	6.2% 11/177 • Timeframe for AE AE additional description	3.4% 6/177 • Timeframe for AE AE additional description
Skin and subcutaneous tissue disorders Petechiae	6.2% 11/177 • Timeframe for AE AE additional description	6.2% 11/177 • Timeframe for AE AE additional description
Skin and subcutaneous tissue disorders Pruritus	6.8% 12/177 • Timeframe for AE AE additional description	6.8% 12/177 • Timeframe for AE AE additional description
Skin and subcutaneous tissue disorders Rash	10.7% 19/177 • Timeframe for AE AE additional description	6.2% 11/177 • Timeframe for AE AE additional description
Vascular disorders Haematoma	5.6% 10/177 • Timeframe for AE AE additional description	6.8% 12/177 • Timeframe for AE AE additional description
Vascular disorders Hypertension	1.1% 2/177 • Timeframe for AE AE additional description	6.2% 11/177 • Timeframe for AE AE additional description
Vascular disorders Hypotension	6.8% 12/177 • Timeframe for AE AE additional description	2.8% 5/177 • Timeframe for AE AE additional description