Thrombocytopaenia
Conditions
Keywords
thrombocytopenia, myelodysplastic syndromes, MDS, thrombopoietin, azacitidine, Eltrombopag, myelodysplastic syndromes (MDS)
Brief 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.
Interventions
DRUGEltrombopag
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
DRUGAzacitidine
Subcutaneous Injection (IV if local standard)
DRUGPlacebo
Eltrombopag matching placebo tablets
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Were Platelet Transfusion Independent During Cycles 1-4 of Azacitidine Therapy | 4 cycles (Cycle = 28 days) | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Summary of Progression Free Survival From Investigator Assessment (ITT) | First day of each cycle (Cycles 3+), at the end of therapy visit and every 3 months in follow-up for approximately 2 years | 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 |
| Summary of Progression Free Survival From Central Review (ITT) | First day of each cycle (Cycles 3+), at the end of therapy visit and every 3 months in follow-up for approximately 2 years | 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 |
| Summary of AML Progression From Investigator Assessment and Central Review (ITT) | First day of each cycle (Cycles 3+), at the end of therapy visit and every 3 months in follow-up for approximately 2 years | 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 |
| Best Disease Response From Investigator Assessment (ITT) | 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 |
| Best Disease Response From Central Review (ITT) | 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 |
| Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) | 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 |
| Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) | 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 |
| Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | 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 |
| Bleeding Adverse Events (AEs) >= Grade 3 | 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 |
| Overall Survival (OS) | 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 |
| Functional Assessment of Chronic Disease Therapy-fatigue Subscale (FACIT-Fatigue) (ITT) | 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.) |
| Medical Resource Utilization (MRU): Event -Hospitalizations Inpatient and Outpatient | 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 |
| Medical Resource Utilization (MRU): Event and Use of Site Specific Medical Resources - Non-study Laboratory Tests | 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 |
| Medical Resource Utilization (MRU): Use of Site Specific Medical Resources | 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 |
| Summary of Post-Hoc Estimates of Steady-state Eltrombopag Cmax and Cmin Pharmacokinetic Parameters for a 50 mg Dose | 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 | 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) |
| Summary of Post-Hoc Estimates of Steady-state Eltrombopag AUC0 Infinity Pharmacokinetic Parameters for a 50 mg Dose | 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 | 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) |
| AUC0-infinity -Pharmacokinetic(s) Parameter of Azacitidine | Cycle 2 Day 1: Pre-dose, 15 min, 0.5, 1, 2 and 4 hr post dose | 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. |
| Cmax -Pharmacokinetic Parameter of Azacitidine | Cycle 2 Day 1: Pre-dose, 15 min, 0.5, 1, 2 and 4 hr post dose | 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. |
| Number of of Subjects With Azacitidine Dose Delays, Dose Reductions, Interruptions | 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 |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Czechia, Denmark, France, Germany, Greece, Hong Kong, Hungary, Ireland, Israel, Italy, Mexico, Norway, Peru, Poland, Puerto Rico, Russia, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), United States
Participant flow
Pre-assignment details
A total of 356 patients were enrolled in the study and 2 patients did not receive treatment.
Participants by arm
| Arm | Count |
|---|---|
| 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 | 179 |
| 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 | 177 |
| Total | 356 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 39 | 24 |
| Overall Study | Azacitidine tx discontinued | 53 | 46 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 15 | 13 |
| Overall Study | Study closed/ terminated | 57 | 77 |
| Overall Study | Withdrawal by Subject | 15 | 16 |
Baseline characteristics
| Characteristic | Total | Eltrombopag | Placebo |
|---|---|---|---|
| Age, Continuous | 68.8 years STANDARD_DEVIATION 11.76 | 68.3 years STANDARD_DEVIATION 12.82 | 69.4 years STANDARD_DEVIATION 10.58 |
| IPSS risk score High Risk (≥ 2.5) | 71 participants | 38 participants | 33 participants |
| IPSS risk score Int - 1 (0.5-1.0) | 125 participants | 64 participants | 61 participants |
| IPSS risk score Int - 2 (1.5 - 2.0) | 160 participants | 77 participants | 83 participants |
| Platelet Count < 10 | 20 participants | 10 participants | 10 participants |
| Platelet Count ≥ 100 | 0 participants | 0 participants | 0 participants |
| Platelet Count ≥ 10 - <20 | 65 participants | 35 participants | 30 participants |
| Platelet Count ≥ 20 - <50 | 167 participants | 83 participants | 84 participants |
| Platelet Count ≥ 50 - <100 | 102 participants | 49 participants | 53 participants |
| Platelet Count missing | 2 participants | 2 participants | 0 participants |
| Platelet transfusion dependence No | 290 participants | 150 participants | 140 participants |
| Platelet transfusion dependence Yes | 66 participants | 29 participants | 37 participants |
| Race/Ethnicity, Customized Central/South Asian | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized East Asian/Japanese/S.E. Asian | 49 participants | 26 participants | 23 participants |
| Race/Ethnicity, Customized Missing | 3 participants | 3 participants | 0 participants |
| Race/Ethnicity, Customized Other | 8 participants | 4 participants | 4 participants |
| Race/Ethnicity, Customized White | 294 participants | 146 participants | 148 participants |
| Sex: Female, Male Female | 122 Participants | 69 Participants | 53 Participants |
| Sex: Female, Male Male | 234 Participants | 110 Participants | 124 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 159 / 177 | 153 / 177 |
| serious Total, serious adverse events | 128 / 177 | 100 / 177 |
Outcome results
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
Time frame: 4 cycles (Cycle = 28 days)
Population: Intent-to-Treat population, comprised of all randomized patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag | Number of Participants Who Were Platelet Transfusion Independent During Cycles 1-4 of Azacitidine Therapy | Yes - platelet transfusion independent | 28 Participants |
| Eltrombopag | Number of Participants Who Were Platelet Transfusion Independent During Cycles 1-4 of Azacitidine Therapy | No - platelet transfusion independent | 151 Participants |
| Placebo | Number of Participants Who Were Platelet Transfusion Independent During Cycles 1-4 of Azacitidine Therapy | Yes - platelet transfusion independent | 55 Participants |
| Placebo | Number of Participants Who Were Platelet Transfusion Independent During Cycles 1-4 of Azacitidine Therapy | No - platelet transfusion independent | 122 Participants |
p-value: 195% CI: [0.21, 0.65]Cochran-Mantel-Haenszel
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.
Time frame: 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
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Eltrombopag | AUC0-infinity -Pharmacokinetic(s) Parameter of Azacitidine | 840 hr.ng/mL | Geometric Coefficient of Variation 53 |
| Placebo | AUC0-infinity -Pharmacokinetic(s) Parameter of Azacitidine | 641 hr.ng/mL | Geometric Coefficient of Variation 67 |
90% CI: [0.99, 1.74]ANOVA
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
Time frame: At end of Cycle 6 (cycle=28 days) or end of therapy, whichever came first
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag | Best Disease Response From Central Review (ITT) | Partial response - PR | 2 participant |
| Eltrombopag | Best Disease Response From Central Review (ITT) | Progressive disease | 24 participant |
| Eltrombopag | Best Disease Response From Central Review (ITT) | Marrow complete response | 2 participant |
| Eltrombopag | Best Disease Response From Central Review (ITT) | Not evaluable | 26 participant |
| Eltrombopag | Best Disease Response From Central Review (ITT) | Stable disease | 23 participant |
| Eltrombopag | Best Disease Response From Central Review (ITT) | Overall Response (CR+Marrow+PR) | 15 participant |
| Eltrombopag | Best Disease Response From Central Review (ITT) | Complete response - CR | 11 participant |
| Placebo | Best Disease Response From Central Review (ITT) | Overall Response (CR+Marrow+PR) | 19 participant |
| Placebo | Best Disease Response From Central Review (ITT) | Complete response - CR | 7 participant |
| Placebo | Best Disease Response From Central Review (ITT) | Marrow complete response | 5 participant |
| Placebo | Best Disease Response From Central Review (ITT) | Partial response - PR | 7 participant |
| Placebo | Best Disease Response From Central Review (ITT) | Stable disease | 31 participant |
| Placebo | Best Disease Response From Central Review (ITT) | Progressive disease | 17 participant |
| Placebo | Best Disease Response From Central Review (ITT) | Not evaluable | 38 participant |
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
Time frame: At end of Cycle 6 (cycle=28 days) or end of therapy, whichever came first
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag | Best Disease Response From Investigator Assessment (ITT) | Partial response - PR | 13 participant |
| Eltrombopag | Best Disease Response From Investigator Assessment (ITT) | Progressive disease | 22 participant |
| Eltrombopag | Best Disease Response From Investigator Assessment (ITT) | Marrow complete response | 8 participant |
| Eltrombopag | Best Disease Response From Investigator Assessment (ITT) | Not evaluable | 32 participant |
| Eltrombopag | Best Disease Response From Investigator Assessment (ITT) | Stable disease | 50 participant |
| Eltrombopag | Best Disease Response From Investigator Assessment (ITT) | Overall Response (CR+Marrow+PR | 36 participant |
| Eltrombopag | Best Disease Response From Investigator Assessment (ITT) | Complete response - CR | 15 participant |
| Placebo | Best Disease Response From Investigator Assessment (ITT) | Overall Response (CR+Marrow+PR | 62 participant |
| Placebo | Best Disease Response From Investigator Assessment (ITT) | Complete response - CR | 26 participant |
| Placebo | Best Disease Response From Investigator Assessment (ITT) | Marrow complete response | 14 participant |
| Placebo | Best Disease Response From Investigator Assessment (ITT) | Partial response - PR | 22 participant |
| Placebo | Best Disease Response From Investigator Assessment (ITT) | Stable disease | 47 participant |
| Placebo | Best Disease Response From Investigator Assessment (ITT) | Progressive disease | 8 participant |
| Placebo | Best Disease Response From Investigator Assessment (ITT) | Not evaluable | 33 participant |
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
Time frame: From Day 1 to 4-week follow-up up to approximately 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag | Bleeding Adverse Events (AEs) >= Grade 3 | Any event - Grade 3 | 9 participant |
| Eltrombopag | Bleeding Adverse Events (AEs) >= Grade 3 | Any event - Grade 4 | 2 participant |
| Eltrombopag | Bleeding Adverse Events (AEs) >= Grade 3 | Any event - Grade 5 | 1 participant |
| Placebo | Bleeding Adverse Events (AEs) >= Grade 3 | Any event - Grade 3 | 12 participant |
| Placebo | Bleeding Adverse Events (AEs) >= Grade 3 | Any event - Grade 4 | 2 participant |
| Placebo | Bleeding Adverse Events (AEs) >= Grade 3 | Any event - Grade 5 | 4 participant |
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.
Time frame: 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
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Eltrombopag | Cmax -Pharmacokinetic Parameter of Azacitidine | 744 ng/mL | Geometric Coefficient of Variation 91 |
| Placebo | Cmax -Pharmacokinetic Parameter of Azacitidine | 535 ng/mL | Geometric Coefficient of Variation 89 |
90% CI: [0.97, 1.99]ANOVA
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.)
Time frame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up) up to approximately 2 years
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag | Functional Assessment of Chronic Disease Therapy-fatigue Subscale (FACIT-Fatigue) (ITT) | Cycle 1 Day 1 (175,172) | 17.401 scores | Standard Deviation 11.0279 |
| Eltrombopag | Functional Assessment of Chronic Disease Therapy-fatigue Subscale (FACIT-Fatigue) (ITT) | Week 4 Follow-up (68,70) | 16.669 scores | Standard Deviation 10.7266 |
| Placebo | Functional Assessment of Chronic Disease Therapy-fatigue Subscale (FACIT-Fatigue) (ITT) | Cycle 1 Day 1 (175,172) | 15.951 scores | Standard Deviation 10.9911 |
| Placebo | Functional Assessment of Chronic Disease Therapy-fatigue Subscale (FACIT-Fatigue) (ITT) | Week 4 Follow-up (68,70) | 14.898 scores | Standard Deviation 12.2362 |
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 \<g/dL), response criteria=Hgb increase by \>=1.5 g/dL over BL, RBC transfusions(given for Hgb\<=9.0) reduced by \>=4 per 8w from BL
Time frame: From Day 1 to 4-week follow-up (samples collected weekly in Cycle 1, Days 1 and 15 in Cycles 2-6 and Day 1 of Cycles >=7)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag | Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) | Hemoglobin | 1 participants |
| Eltrombopag | Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) | Platelets and hemoglobin | 1 participants |
| Eltrombopag | Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) | Neutrophils | 12 participants |
| Eltrombopag | Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) | Neutrophils and hemoglobin | 1 participants |
| Eltrombopag | Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) | Platelets and neutrophils | 10 participants |
| Eltrombopag | Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) | Platelets, neutrophils and hemoglobin | 1 participants |
| Eltrombopag | Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) | Platelets | 56 participants |
| Placebo | Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) | Platelets, neutrophils and hemoglobin | 1 participants |
| Placebo | Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) | Platelets | 57 participants |
| Placebo | Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) | Neutrophils | 13 participants |
| Placebo | Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) | Hemoglobin | 1 participants |
| Placebo | Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) | Platelets and neutrophils | 11 participants |
| Placebo | Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) | Platelets and hemoglobin | 1 participants |
| Placebo | Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) | Neutrophils and hemoglobin | 1 participants |
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
Time frame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up) up to approximately 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eltrombopag | Medical Resource Utilization (MRU): Event and Use of Site Specific Medical Resources - Non-study Laboratory Tests | 88 tests |
| Placebo | Medical Resource Utilization (MRU): Event and Use of Site Specific Medical Resources - Non-study Laboratory Tests | 105 tests |
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
Time frame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up) up to approximately 2 years
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag | Medical Resource Utilization (MRU): Event -Hospitalizations Inpatient and Outpatient | In-patient hospitalizations - entire study (91,66) | 23.9 days | Standard Deviation 24.33 |
| Eltrombopag | Medical Resource Utilization (MRU): Event -Hospitalizations Inpatient and Outpatient | Out-patient hospitalizations - entire study (4,2) | 9.5 days | Standard Deviation 16.34 |
| Placebo | Medical Resource Utilization (MRU): Event -Hospitalizations Inpatient and Outpatient | In-patient hospitalizations - entire study (91,66) | 27.1 days | Standard Deviation 33.81 |
| Placebo | Medical Resource Utilization (MRU): Event -Hospitalizations Inpatient and Outpatient | Out-patient hospitalizations - entire study (4,2) | 2.5 days | Standard Deviation 0.71 |
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
Time frame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up) up to approximately 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag | Medical Resource Utilization (MRU): Use of Site Specific Medical Resources | Medical or surgical specialist visits | 49 visits |
| Eltrombopag | Medical Resource Utilization (MRU): Use of Site Specific Medical Resources | Home healthcare visits by medical professional | 89 visits |
| Eltrombopag | Medical Resource Utilization (MRU): Use of Site Specific Medical Resources | Primary physician care visits | 89 visits |
| Eltrombopag | Medical Resource Utilization (MRU): Use of Site Specific Medical Resources | Nurse practitioner, physic assistant, nurse visits | 89 visits |
| Eltrombopag | Medical Resource Utilization (MRU): Use of Site Specific Medical Resources | Telephone consultations | 89 visits |
| Eltrombopag | Medical Resource Utilization (MRU): Use of Site Specific Medical Resources | Emergency visits not resulting in hospital stay | 89 visits |
| Placebo | Medical Resource Utilization (MRU): Use of Site Specific Medical Resources | Telephone consultations | 97 visits |
| Placebo | Medical Resource Utilization (MRU): Use of Site Specific Medical Resources | Medical or surgical specialist visits | 58 visits |
| Placebo | Medical Resource Utilization (MRU): Use of Site Specific Medical Resources | Nurse practitioner, physic assistant, nurse visits | 97 visits |
| Placebo | Medical Resource Utilization (MRU): Use of Site Specific Medical Resources | Home healthcare visits by medical professional | 97 visits |
| Placebo | Medical Resource Utilization (MRU): Use of Site Specific Medical Resources | Emergency visits not resulting in hospital stay | 97 visits |
| Placebo | Medical Resource Utilization (MRU): Use of Site Specific Medical Resources | Primary physician care visits | 97 visits |
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
Time frame: From Day 1 to 4-week follow-up up to approximately 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag | Number of of Subjects With Azacitidine Dose Delays, Dose Reductions, Interruptions | Overall dose delay | 82 participant |
| Eltrombopag | Number of of Subjects With Azacitidine Dose Delays, Dose Reductions, Interruptions | Overall dose reduction | 7 participant |
| Eltrombopag | Number of of Subjects With Azacitidine Dose Delays, Dose Reductions, Interruptions | Overall dose interruption | 3 participant |
| Placebo | Number of of Subjects With Azacitidine Dose Delays, Dose Reductions, Interruptions | Overall dose interruption | 13 participant |
| Placebo | Number of of Subjects With Azacitidine Dose Delays, Dose Reductions, Interruptions | Overall dose delay | 88 participant |
| Placebo | Number of of Subjects With Azacitidine Dose Delays, Dose Reductions, Interruptions | Overall dose reduction | 16 participant |
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
Time frame: From Day 1 to end of study treatment up to approximately 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Screening (179,177) | 127 participants |
| Eltrombopag | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 1 (175,173) | 68 participants |
| Eltrombopag | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 2 (135,158) | 62 participants |
| Eltrombopag | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 3 (105,131) | 68 participants |
| Eltrombopag | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 4 (93,116) | 58 participants |
| Eltrombopag | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 5 (76,108) | 49 participants |
| Eltrombopag | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 6 (65,90) | 41 participants |
| Eltrombopag | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 7 (47,74) | 29 participants |
| Eltrombopag | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 8 (37,61) | 20 participants |
| Eltrombopag | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 9 (28,46) | 19 participants |
| Eltrombopag | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 10 (23,38) | 18 participants |
| Eltrombopag | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 11 (19,29) | 13 participants |
| Eltrombopag | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 12 (15,21) | 10 participants |
| Eltrombopag | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 13 (12,16) | 7 participants |
| Eltrombopag | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 14 (6,11) | 3 participants |
| Eltrombopag | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 15 (3,5) | 2 participants |
| Eltrombopag | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 16 (0,3) | 0 participants |
| Eltrombopag | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 17 (0,3) | 0 participants |
| Placebo | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 13 (12,16) | 10 participants |
| Placebo | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Screening (179,177) | 121 participants |
| Placebo | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 9 (28,46) | 36 participants |
| Placebo | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 1 (175,173) | 87 participants |
| Placebo | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 17 (0,3) | 0 participants |
| Placebo | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 2 (135,158) | 87 participants |
| Placebo | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 10 (23,38) | 28 participants |
| Placebo | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 3 (105,131) | 94 participants |
| Placebo | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 14 (6,11) | 6 participants |
| Placebo | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 4 (93,116) | 91 participants |
| Placebo | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 11 (19,29) | 20 participants |
| Placebo | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 5 (76,108) | 76 participants |
| Placebo | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 16 (0,3) | 3 participants |
| Placebo | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 6 (65,90) | 62 participants |
| Placebo | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 12 (15,21) | 15 participants |
| Placebo | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 7 (47,74) | 50 participants |
| Placebo | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 15 (3,5) | 3 participants |
| Placebo | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) | Cycle 8 (37,61) | 42 participants |
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
Time frame: Randomization until death or end of study, approximately 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eltrombopag | Overall Survival (OS) | 57 deaths (events) |
| Placebo | Overall Survival (OS) | 51 deaths (events) |
Comparison: Confidence Intervals estimated using the Brookmeyer-Crowley method. Hazard ratios are estimated using the Pike estimator. A hazard ratio \<1 indicates a lower risk with eltrombopag compared with Placebo. Log-rank test stratified by IVRS stratification factorsp-value: 0.16495% CI: [0.97, 2.08]Log Rank
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
Time frame: From Day 1 to 4-week follow-up up to approximately 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Eltrombopag | 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 |
| Placebo | 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 | 2 participant |
| Placebo | 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 | 105 participant |
| Placebo | 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 | 66 participant |
| Placebo | 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 | 2 participant |
| Placebo | 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 | 48 participant |
| Placebo | 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 | 22 participant |
| Placebo | 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 |
| Placebo | 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 | 125 participant |
| Placebo | 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 | 20 participant |
| Placebo | 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 | 51 participant |
| Placebo | 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 | 62 participant |
| Placebo | 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 | 9 participant |
| Placebo | 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 | 1 participant |
| Placebo | 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 | 94 participant |
| Placebo | 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 | 68 participant |
| Placebo | 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 | 11 participant |
| Placebo | 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 | 41 participant |
| Placebo | 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 | 25 participant |
| Placebo | 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 |
| Placebo | 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 | 89 participant |
| Placebo | 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 | 78 participant |
| Placebo | 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 | 6 participant |
| Placebo | 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 | 40 participant |
| Placebo | 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 | 27 participant |
| Placebo | 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 |
| Placebo | 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 | 112 participant |
| Placebo | 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 | 56 participant |
| Placebo | 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 | 5 participant |
| Placebo | 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 | 45 participant |
| Placebo | 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 | 25 participant |
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
Time frame: First day of each cycle (Cycles 3+), at the end of therapy visit and every 3 months in follow-up for approximately 2 years
Population: The intent-to-treat (ITT) population included all the patients randomized in the study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag | Summary of AML Progression From Investigator Assessment and Central Review (ITT) | Participants progressed-AML - investigator assess | 27 participants |
| Eltrombopag | Summary of AML Progression From Investigator Assessment and Central Review (ITT) | Participants progressed to AML - Central Review | 21 participants |
| Placebo | Summary of AML Progression From Investigator Assessment and Central Review (ITT) | Participants progressed-AML - investigator assess | 16 participants |
| Placebo | Summary of AML Progression From Investigator Assessment and Central Review (ITT) | Participants progressed to AML - Central Review | 10 participants |
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)
Time frame: Cycle 1, Week 2: Pre-dose, 1.5 and 3 hour post dose; Cycle 1, Week 3: 4, 5.5, and 7 hours post dose
Population: All patients with evaluable eltrombopag dosing, actual sampling time, and eltrombopag concentration data were included in the population PK dataset and analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Eltrombopag | 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
Summary of Post-Hoc Estimates of Steady-state Eltrombopag Cmax and Cmin Pharmacokinetic Parameters for a 50 mg Dose
Eltrombopag concentrations were analyzed using a population PK model along with data from other studies in healthy volunteers and in patients with MDS and/or AML. Post-hoc PK parameters were derived. Only patients from this study were included (163)
Time frame: Cycle 1, Week 2: Pre-dose, 1.5 and 3 hour post dose; Cycle 1, Week 3: 4, 5.5, and 7 hours post dose
Population: All patients with evaluable eltrombopag dosing, actual sampling time, and eltrombopag concentration data were included in the population PK dataset and analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag | 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 |
| Eltrombopag | 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
Summary of Progression Free Survival From Central Review (ITT)
Progression-free survival, defined as the time from randomization until either disease progression or death. The modified 2006 IWG criteria for MDS used for progression assessment For patients with: Less than 5% BM blasts: ≥ 50% increase in blasts to \> 5% blasts; 5% - \<10% BM blasts: ≥ 50% increase to \> 10% blasts; 10% - \<20% BM blasts: ≥ 50% increase to \> 20% blasts; 20% - 30% BM blasts: ≥ 50% increase to \> 30% blasts
Time frame: First day of each cycle (Cycles 3+), at the end of therapy visit and every 3 months in follow-up for approximately 2 years
Population: The intent-to-treat (ITT) population included all the patients randomized in the study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag | Summary of Progression Free Survival From Central Review (ITT) | Death | 44 participants |
| Eltrombopag | Summary of Progression Free Survival From Central Review (ITT) | Disease progression | 32 participants |
| Placebo | Summary of Progression Free Survival From Central Review (ITT) | Death | 41 participants |
| Placebo | Summary of Progression Free Survival From Central Review (ITT) | Disease progression | 26 participants |
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
Time frame: First day of each cycle (Cycles 3+), at the end of therapy visit and every 3 months in follow-up for approximately 2 years
Population: The intent-to-treat (ITT) population included all the patients randomized in the study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag | Summary of Progression Free Survival From Investigator Assessment (ITT) | Death | 34 participants |
| Eltrombopag | Summary of Progression Free Survival From Investigator Assessment (ITT) | Disease progression | 38 participants |
| Placebo | Summary of Progression Free Survival From Investigator Assessment (ITT) | Death | 36 participants |
| Placebo | Summary of Progression Free Survival From Investigator Assessment (ITT) | Disease progression | 30 participants |