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)

Thrombocytopaenia Clinical Trial

Official title:

A Randomized, Double-blind, Placebo-controlled, Phase III, Multi-centre Study of Eltrombopag or Placebo in Combination With Azacitidine in Subjects With IPSS Intermediate-1, Intermediate 2 and High-risk Myelodysplastic Syndromes (MDS) SUPPORT: A StUdy of eltromboPag in myelodysPlastic SyndrOmes Receiving azaciTidine

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02158936
• Other study ID #: 112121
• Status: Terminated
• Phase: Phase 3
• First received: June 5, 2014
• Last updated: November 12, 2017
• Start date: June 10, 2014
• Est. completion date: April 30, 2016

Study information

• Verified date: September 2017
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Eltrombopag olamine (SB-497115-GR) is an orally bioavailable, small molecule thrombopoietin receptor agonist that may be beneficial in medical disorders associated with thrombocytopenia. Eltrombopag has been shown to increase platelet counts in patients with thrombocytopenia from various etiologies (Idiopathic thrombocytopenic purpura [ITP], liver disease, aplastic anemia and chemotherapy induced thrombocytopenia). Approximately 350 subjects will be randomized in a 1:1 ratio (175 into the eltrombopag arm and 175 into the placebo arm). Approximately 55 subjects will be enrolled into the azacitidine. Subjects with intermediate-1, intermediate-2 or high risk MDS by IPSS, and baseline platelet count of <75 Giga (10^9) per liter (Gi/L) will only be enrolled. This is a randomized, double-blind, parallel group, placebo-controlled study designed to explore the platelet supportive care effects of eltrombopag versus placebo in combination with the standard of care hypomethylating agent, azacitidine. The primary objective of this study is to determine the effect of eltrombopag versus placebo on the proportion of subjects who are platelet transfusion free during the first 4 cycles of azacitidine therapy. Key secondary endpoints include overall survival, disease response, and disease progression.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 356
• Est. completion date: April 30, 2016
• Est. primary completion date: April 30, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age >=18 years (For subjects in Taiwan, Age >= 20 years)

• MDS by World Health Organization (WHO) or French-American-British (FAB) classification

• Intermediate 1, intermediate 2 or high risk MDS by IPSS

• At least one platelet count < 75 Gi/L

• Eastern Cooperative Oncology Group (ECOG) Status 0-2

• Adequate baseline organ function defined by the criteria below: total bilirubin =< 1.5x the upper limit of normal (ULN) except for Gilbert's syndrome or cases clearly not indicative of inadequate liver function (i.e. elevation of indirect [haemolytic] bilirubin in the absence of alanine aminotransferase [ALT] abnormality); ALT =< 2.5xULN; creatinine =< 2.5xULN

• Subjects with a corrected QT interval (QTc) <450 milliseconds (msec) or <480msec for subjects with bundle branch block. The QTc is the QT interval corrected for heart rate according to Fridericia's formula (QTcF), machine or manual overread. For subject eligibility and withdrawal, QTcF will be used. For purposes of data analysis, QTcF will be used. The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period

• Subject is able to understand and comply with protocol requirements and instructions

• Subject has signed and dated informed consent

• Women must be either of non-child bearing potential, or women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study

• Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days of first dose of study treatment and agree to use effective contraception during the study and for 3 months following the last dose of study treatment

• Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception from time of randomization until 16 weeks after the last dose of study treatment

• French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category

Exclusion Criteria:

• Previous treatment with hypomethylating agent or induction chemotherapy for MDS

• Proliferative type chronic myelomonocytic leukemia with white blood cell count >12 Gi/L at any time during the 28 days before Day 1

• History of treatment with eltrombopag, romiplostim or other thrombopoietin receptor (TPO-R) agonists

• Previous allogeneic stem-cell transplantation

• Known thrombophilic risk factors. Exception: Subjects for whom the potential benefits of participating in the study outweigh the potential risks of thromboembolic events, as determined by the investigator

• Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of investigational product (eltrombopag/placebo)

• Active and uncontrolled infections, including hepatitis B or C

• Human Immunodeficiency Virus (HIV) infection

• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to eltrombopag or its excipient, or azacitidine, that contraindicates the subjects' participation

• Pregnant or lactating female

• Any serious and/or unstable pre-existing medical condition (including any advanced malignancy other than the disease under study), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance with the study procedures

• French subjects: the French subject has participated in any study using an investigational drug during the previous 30 days

Related Conditions & MeSH terms

• Myelodysplastic Syndromes
• Preleukemia
• Syndrome
• Thrombocytopaenia
• Thrombocytopenia

Intervention

Drug:
• Eltrombopag
Eltrombopag will be round film-coated tablets containing eltrombopag equivalent to 50 mg (white to off-white), 200 mg and 300 mg (green) of eltrombopag free acid
• Azacitidine
Subcutaneous Injection (IV if local standard)
• Placebo
Eltrombopag matching placebo tablets
• Placebo
Eltrombopag matching placebo tablets will be supplied

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires
Argentina	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires
Argentina	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires
Argentina	Novartis Investigative Site	Santa Fe
Australia	Novartis Investigative Site	Adelaide	South Australia
Australia	Novartis Investigative Site	Clayton	Victoria
Australia	Novartis Investigative Site	East Melbourne	Victoria
Australia	Novartis Investigative Site	Kogarah	New South Wales
Australia	Novartis Investigative Site	Melbourne	Victoria
Austria	Novartis Investigative Site	Graz
Austria	Novartis Investigative Site	Innsbruck
Austria	Novartis Investigative Site	Linz
Austria	Novartis Investigative Site	Rankweil
Austria	Novartis Investigative Site	Salzburg
Austria	Novartis Investigative Site	Steyr
Austria	Novartis Investigative Site	Vienna
Belgium	Novartis Investigative Site	Brasschaat
Belgium	Novartis Investigative Site	Brugge
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Lodelinsart
Belgium	Novartis Investigative Site	Turnhout
Brazil	Novartis Investigative Site	Belo Horizonte	Minas Gerais
Brazil	Novartis Investigative Site	Curitiba	Paraná
Brazil	Novartis Investigative Site	Florianopolis	Santa Catarina
Brazil	Novartis Investigative Site	Porto Alegre	Rio Grande Do Sul
Brazil	Novartis Investigative Site	Rio de Janeiro
Brazil	Novartis Investigative Site	Sao Paulo	São Paulo
Brazil	Novartis Investigative Site	Sao Paulo	São Paulo
Brazil	Novartis Investigative Site	Sao Paulo - SP
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Quebec
Canada	Novartis Investigative Site	Québec
Canada	Novartis Investigative Site	Sherbrooke	Quebec
Canada	Novartis Investigative Site	Toronto	Ontario
Czechia	Novartis Investigative Site	Brno
Czechia	Novartis Investigative Site	Ostrava
Czechia	Novartis Investigative Site	Praha
Czechia	Novartis Investigative Site	Praha 10
Czechia	Novartis Investigative Site	Praha 2
Denmark	Novartis Investigative Site	Aarhus
Denmark	Novartis Investigative Site	Koebenhavn Oe
France	Novartis Investigative Site	Angers Cedex 9
France	Novartis Investigative Site	Caen Cedex 9
France	Novartis Investigative Site	Le Mans
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Paris Cedex 12
France	Novartis Investigative Site	Pringy Cedex
Germany	Novartis Investigative Site	Dresden	Sachsen
Germany	Novartis Investigative Site	Duesseldorf	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Duesseldorf	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Duisburg	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Goettingen	Niedersachsen
Germany	Novartis Investigative Site	Muenchen	Bayern
Germany	Novartis Investigative Site	Stuttgart	Baden-Wuerttemberg
Greece	Novartis Investigative Site	Athens,
Greece	Novartis Investigative Site	Larisa
Greece	Novartis Investigative Site	Patra
Greece	Novartis Investigative Site	Thessaloniki
Greece	Novartis Investigative Site	Thessaloniki
Hong Kong	Novartis Investigative Site	Chai Wan
Hong Kong	Novartis Investigative Site	Hong Kong
Hong Kong	Novartis Investigative Site	Shatin, New Territories
Hong Kong	Novartis Investigative Site	Tuen Mun
Hungary	Novartis Investigative Site	Debrecen
Hungary	Novartis Investigative Site	Szeged
Ireland	Novartis Investigative Site	Dublin
Ireland	Novartis Investigative Site	Galway
Ireland	Novartis Investigative Site	James Street
Ireland	Novartis Investigative Site	Limerick
Ireland	Novartis Investigative Site	Tallaght, Dublin
Israel	Novartis Investigative Site	Haifa
Israel	Novartis Investigative Site	Holon
Israel	Novartis Investigative Site	Jerusalem
Israel	Novartis Investigative Site	Jerusalem
Israel	Novartis Investigative Site	Kfar Saba
Israel	Novartis Investigative Site	Petach-Tikva
Israel	Novartis Investigative Site	Tel Aviv
Italy	Novartis Investigative Site	Firenze	Toscana
Italy	Novartis Investigative Site	Genova	Liguria
Italy	Novartis Investigative Site	Modena	Emilia-Romagna
Italy	Novartis Investigative Site	Novara	Piemonte
Italy	Novartis Investigative Site	Reggio Calabria	Calabria
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Mexico	Novartis Investigative Site	Monterrey	Nuevo León
Mexico	Novartis Investigative Site	Oaxaca
Norway	Novartis Investigative Site	Bergen
Norway	Novartis Investigative Site	Oslo
Peru	Novartis Investigative Site	Lima
Peru	Novartis Investigative Site	Lima
Poland	Novartis Investigative Site	Krakow
Poland	Novartis Investigative Site	Legnica
Poland	Novartis Investigative Site	Lublin
Poland	Novartis Investigative Site	Opole
Poland	Novartis Investigative Site	Slupsk
Poland	Novartis Investigative Site	Torun
Puerto Rico	Novartis Investigative Site	San Juan
Russian Federation	Novartis Investigative Site	Kaluga
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Penza
Russian Federation	Novartis Investigative Site	St Petersburg
Russian Federation	Novartis Investigative Site	St'Petersburg
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Gerona
Spain	Novartis Investigative Site	La Laguna (Santa Cruz De Tenerife)
Spain	Novartis Investigative Site	Leon
Spain	Novartis Investigative Site	León
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Majadahonda (Madrid)
Spain	Novartis Investigative Site	Malaga
Spain	Novartis Investigative Site	Málaga
Spain	Novartis Investigative Site	Oviedo
Spain	Novartis Investigative Site	Oviedo	Asturias
Spain	Novartis Investigative Site	Palma de Mallorca
Spain	Novartis Investigative Site	Palma de Mallorca
Spain	Novartis Investigative Site	Pozuelo De Alarcon/Madrid
Spain	Novartis Investigative Site	Pozuelo De Alarcón/Madrid
Spain	Novartis Investigative Site	Salamanca
Spain	Novartis Investigative Site	Valencia
Spain	Novartis Investigative Site	Valencia
Sweden	Novartis Investigative Site	Goteborg
Sweden	Novartis Investigative Site	Göteborg
Sweden	Novartis Investigative Site	Stockholm
Sweden	Novartis Investigative Site	Uppsala
Switzerland	Novartis Investigative Site	Aarau
Switzerland	Novartis Investigative Site	Bellinzona
Switzerland	Novartis Investigative Site	Bern
Switzerland	Novartis Investigative Site	Zuerich
Taiwan	Novartis Investigative Site	Changhua
Taiwan	Novartis Investigative Site	Kaohsiung
Taiwan	Novartis Investigative Site	Kaohsiung
Taiwan	Novartis Investigative Site	Taipei
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	ChiangMai
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Izmir
Turkey	Novartis Investigative Site	Izmir
Turkey	Novartis Investigative Site	Samsun
United States	Novartis Investigative Site	Anderson	Indiana
United States	Novartis Investigative Site	Atlanta	Georgia
United States	Novartis Investigative Site	Bronx	New York
United States	Novartis Investigative Site	Chicago	Illinois
United States	Novartis Investigative Site	Hartford	Connecticut
United States	Novartis Investigative Site	Kansas City	Missouri
United States	Novartis Investigative Site	Milwaukee	Wisconsin
United States	Novartis Investigative Site	San Luis	Missouri
United States	Novartis Investigative Site	Seattle	Washington
United States	Novartis Investigative Site	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  Czechia,  Denmark,  France,  Germany,  Greece,  Hong Kong,  Hungary,  Ireland,  Israel,  Italy,  Korea, Republic of,  Mexico,  Norway,  Peru,  Poland,  Puerto Rico,  Russian Federation,  Spain,  Sweden,  Switzerland,  Taiwan,  Thailand,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants Who Were Platelet Transfusion Independent During Cycles 1-4 of Azacitidine Therapy	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	4 cycles (Cycle = 28 days)
Secondary	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	Randomization until death or end of study, approximately 2 years
Secondary	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	First day of each cycle (Cycles 3+), at the end of therapy visit and every 3 months in follow-up for approximately 2 years
Secondary	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	First day of each cycle (Cycles 3+), at the end of therapy visit and every 3 months in follow-up for approximately 2 years
Secondary	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	First day of each cycle (Cycles 3+), at the end of therapy visit and every 3 months in follow-up for approximately 2 years
Secondary	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	At end of Cycle 6 (cycle=28 days) or end of therapy, whichever came first
Secondary	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	At end of Cycle 6 (cycle=28 days) or end of therapy, whichever came first
Secondary	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	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)
Secondary	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	From Day 1 to end of study treatment up to approximately 2 years
Secondary	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	From Day 1 to 4-week follow-up up to approximately 2 years
Secondary	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	From Day 1 to 4-week follow-up up to approximately 2 years
Secondary	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	From Day 1 to 4-week follow-up up to approximately 2 years
Secondary	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.)	From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up) up to approximately 2 years
Secondary	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	From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up) up to approximately 2 years
Secondary	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	From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up) up to approximately 2 years
Secondary	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	From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up) up to approximately 2 years
Secondary	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)	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
Secondary	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)	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
Secondary	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.	Cycle 2 Day 1: Pre-dose, 15 min, 0.5, 1, 2 and 4 hr post dose
Secondary	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.	Cycle 2 Day 1: Pre-dose, 15 min, 0.5, 1, 2 and 4 hr post dose