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)
Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Terminated
CT.gov ID
NCT02158936
Collaborator
(none)
356
158
2
22.7
2.3
0.1
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
356 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
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
Actual Study Start Date
:
Jun 10, 2014
Actual Primary Completion Date
:
Apr 30, 2016
Actual Study Completion Date
:
Apr 30, 2016
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Eltrombopag Eligible subject will receive a starting dose of eltrombopag of 200 milligrams (mg) (100 mg for subjects of East Asian heritage). Dose modifications of eltrombopag will be 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 a safe and effective level (i.e. a level sufficient to avoid platelet transfusions and bleeding events). 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 eltrombopag daily for the full 28 days each cycle for as long as the subject is receiving azacitidine |
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
Drug: Azacitidine
Subcutaneous Injection (IV if local standard)
|
| Placebo Comparator: Placebo Eligible 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 eltrombopag daily for the full 28 days each cycle for as long as the subject is receiving azacitidine |
Drug: Azacitidine
Subcutaneous Injection (IV if local standard)
Drug: Placebo
Eltrombopag matching placebo tablets
Drug: Placebo
Eltrombopag matching placebo tablets will be supplied
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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
- 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
- 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
- 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
- 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
- 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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts 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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Novartis Investigative Site | Hartford | Connecticut | United States | 06105 |
| 2 | Novartis Investigative Site | Atlanta | Georgia | United States | 30322 |
| 3 | Novartis Investigative Site | Chicago | Illinois | United States | 60612 |
| 4 | Novartis Investigative Site | Anderson | Indiana | United States | 46016 |
| 5 | Novartis Investigative Site | Kansas City | Missouri | United States | 64128 |
| 6 | Novartis Investigative Site | San Luis | Missouri | United States | 63110 |
| 7 | Novartis Investigative Site | Bronx | New York | United States | 10461 |
| 8 | Novartis Investigative Site | Winston-Salem | North Carolina | United States | 27157 |
| 9 | Novartis Investigative Site | Seattle | Washington | United States | 98108 |
| 10 | Novartis Investigative Site | Milwaukee | Wisconsin | United States | 53226 |
| 11 | Novartis Investigative Site | Ciudad Autonoma de Buenos Aires | Argentina | 1114 | |
| 12 | Novartis Investigative Site | Ciudad Autonoma de Buenos Aires | Argentina | 1425 | |
| 13 | Novartis Investigative Site | Ciudad Autonoma de Buenos Aires | Argentina | C1181ACH | |
| 14 | Novartis Investigative Site | Santa Fe | Argentina | S3000ADL | |
| 15 | Novartis Investigative Site | Kogarah | New South Wales | Australia | 2217 |
| 16 | Novartis Investigative Site | Adelaide | South Australia | Australia | 5000 |
| 17 | Novartis Investigative Site | Clayton | Victoria | Australia | 3168 |
| 18 | Novartis Investigative Site | East Melbourne | Victoria | Australia | 3002 |
| 19 | Novartis Investigative Site | Melbourne | Victoria | Australia | 3000 |
| 20 | Novartis Investigative Site | Graz | Austria | 8036 | |
| 21 | Novartis Investigative Site | Innsbruck | Austria | A-6020 | |
| 22 | Novartis Investigative Site | Linz | Austria | 4020 | |
| 23 | Novartis Investigative Site | Rankweil | Austria | A-6830 | |
| 24 | Novartis Investigative Site | Salzburg | Austria | A-5020 | |
| 25 | Novartis Investigative Site | Steyr | Austria | 4400 | |
| 26 | Novartis Investigative Site | Vienna | Austria | 1140 | |
| 27 | Novartis Investigative Site | Brasschaat | Belgium | 2930 | |
| 28 | Novartis Investigative Site | Brugge | Belgium | 8000 | |
| 29 | Novartis Investigative Site | Leuven | Belgium | 3000 | |
| 30 | Novartis Investigative Site | Lodelinsart | Belgium | 6042 | |
| 31 | Novartis Investigative Site | Turnhout | Belgium | 2300 | |
| 32 | Novartis Investigative Site | Belo Horizonte | Minas Gerais | Brazil | 30130-100 |
| 33 | Novartis Investigative Site | Curitiba | Paraná | Brazil | 81520-060 |
| 34 | Novartis Investigative Site | Porto Alegre | Rio Grande Do Sul | Brazil | 90035-903 |
| 35 | Novartis Investigative Site | Florianopolis | Santa Catarina | Brazil | 88034-000 |
| 36 | Novartis Investigative Site | Sao Paulo | São Paulo | Brazil | 01236030 |
| 37 | Novartis Investigative Site | Sao Paulo | São Paulo | Brazil | 08270-070 |
| 38 | Novartis Investigative Site | Rio de Janeiro | Brazil | 20211-030 | |
| 39 | Novartis Investigative Site | Sao Paulo - SP | Brazil | 01323-900 | |
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| 44 | Novartis Investigative Site | Québec | Canada | G1J 1Z4 | |
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| 51 | Novartis Investigative Site | Koebenhavn Oe | Denmark | 2100 | |
| 52 | Novartis Investigative Site | Angers Cedex 9 | France | 49933 | |
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| 54 | Novartis Investigative Site | Le Mans | France | 72000 | |
| 55 | Novartis Investigative Site | Paris Cedex 12 | France | 75571 | |
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| 57 | Novartis Investigative Site | Pringy Cedex | France | 74374 | |
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| 72 | Novartis Investigative Site | Shatin, New Territories | Hong Kong | ||
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| 93 | Novartis Investigative Site | Seoul | Korea, Republic of | 05505 | |
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| 95 | Novartis Investigative Site | Seoul | Korea, Republic of | 06591 | |
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| 99 | Novartis Investigative Site | Monterrey | Nuevo León | Mexico | 64460 |
| 100 | Novartis Investigative Site | Oaxaca | Mexico | 68000 | |
| 101 | Novartis Investigative Site | Bergen | Norway | N-5021 | |
| 102 | Novartis Investigative Site | Oslo | Norway | 0027 | |
| 103 | Novartis Investigative Site | Lima | Peru | Lima 11 | |
| 104 | Novartis Investigative Site | Lima | Peru | Lima 31 | |
| 105 | Novartis Investigative Site | Krakow | Poland | 31-501 | |
| 106 | Novartis Investigative Site | Legnica | Poland | 59-200 | |
| 107 | Novartis Investigative Site | Lublin | Poland | 20-081 | |
| 108 | Novartis Investigative Site | Opole | Poland | 45-061 | |
| 109 | Novartis Investigative Site | Slupsk | Poland | 76-200 | |
| 110 | Novartis Investigative Site | Torun | Poland | 87-100 | |
| 111 | Novartis Investigative Site | San Juan | Puerto Rico | 00927 | |
| 112 | Novartis Investigative Site | Kaluga | Russian Federation | 248007 | |
| 113 | Novartis Investigative Site | Moscow | Russian Federation | 115478 | |
| 114 | Novartis Investigative Site | Moscow | Russian Federation | 125167 | |
| 115 | Novartis Investigative Site | Moscow | Russian Federation | 129301 | |
| 116 | Novartis Investigative Site | Penza | Russian Federation | 440071 | |
| 117 | Novartis Investigative Site | St Petersburg | Russian Federation | 193024 | |
| 118 | Novartis Investigative Site | St'Petersburg | Russian Federation | 197341 | |
| 119 | Novartis Investigative Site | Oviedo | Asturias | Spain | 33011 |
| 120 | Novartis Investigative Site | Barcelona | Spain | 08035 | |
| 121 | Novartis Investigative Site | Barcelona | Spain | 08036 | |
| 122 | Novartis Investigative Site | Gerona | Spain | 17007 | |
| 123 | Novartis Investigative Site | La Laguna (Santa Cruz De Tenerife) | Spain | 38320 | |
| 124 | Novartis Investigative Site | Leon | Spain | 24071 | |
| 125 | Novartis Investigative Site | León | Spain | 24071 | |
| 126 | Novartis Investigative Site | Madrid | Spain | 28007 | |
| 127 | Novartis Investigative Site | Madrid | Spain | 28034 | |
| 128 | Novartis Investigative Site | Madrid | Spain | 28046 | |
| 129 | Novartis Investigative Site | Majadahonda (Madrid) | Spain | 28222 | |
| 130 | Novartis Investigative Site | Malaga | Spain | 29010 | |
| 131 | Novartis Investigative Site | Málaga | Spain | 29010 | |
| 132 | Novartis Investigative Site | Oviedo | Spain | 33006 | |
| 133 | Novartis Investigative Site | Palma de Mallorca | Spain | 07014 | |
| 134 | Novartis Investigative Site | Palma de Mallorca | Spain | 07198 | |
| 135 | Novartis Investigative Site | Pozuelo De Alarcon/Madrid | Spain | 28223 | |
| 136 | Novartis Investigative Site | Pozuelo De Alarcón/Madrid | Spain | 28223 | |
| 137 | Novartis Investigative Site | Salamanca | Spain | 37007 | |
| 138 | Novartis Investigative Site | Valencia | Spain | 46010 | |
| 139 | Novartis Investigative Site | Valencia | Spain | 46026 | |
| 140 | Novartis Investigative Site | Goteborg | Sweden | SE-413 45 | |
| 141 | Novartis Investigative Site | Göteborg | Sweden | SE-413 45 | |
| 142 | Novartis Investigative Site | Stockholm | Sweden | SE-141 86 | |
| 143 | Novartis Investigative Site | Uppsala | Sweden | SE-751 85 | |
| 144 | Novartis Investigative Site | Aarau | Switzerland | 5001 | |
| 145 | Novartis Investigative Site | Bellinzona | Switzerland | 6500 | |
| 146 | Novartis Investigative Site | Bern | Switzerland | 3010 | |
| 147 | Novartis Investigative Site | Zuerich | Switzerland | 8091 | |
| 148 | Novartis Investigative Site | Changhua | Taiwan | 500 | |
| 149 | Novartis Investigative Site | Kaohsiung | Taiwan | 807 | |
| 150 | Novartis Investigative Site | Kaohsiung | Taiwan | 833 | |
| 151 | Novartis Investigative Site | Taipei | Taiwan | 112 | |
| 152 | Novartis Investigative Site | Bangkok | Thailand | 10400 | |
| 153 | Novartis Investigative Site | Bangkok | Thailand | 10700 | |
| 154 | Novartis Investigative Site | ChiangMai | Thailand | 50000 | |
| 155 | Novartis Investigative Site | Ankara | Turkey | 06590 | |
| 156 | Novartis Investigative Site | Izmir | Turkey | 35100 | |
| 157 | Novartis Investigative Site | Izmir | Turkey | 35340 | |
| 158 | Novartis Investigative Site | Samsun | Turkey | 55139 |
Sponsors and Collaborators
- Novartis Pharmaceuticals
Investigators
- Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT02158936
Other Study ID Numbers:
- 112121
First Posted:
Jun 9, 2014
Last Update Posted:
Dec 12, 2017
Last Verified:
Sep 1, 2017
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Novartis Pharmaceuticals
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | A total of 356 patients were enrolled in the study and 2 patients did not receive treatment. |
| Arm/Group Title | Eltrombopag | Placebo |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Period Title: Overall Study | ||
| STARTED | 179 | 177 |
| Treated | 177 | 177 |
| Untreated | 2 | 0 |
| COMPLETED | 0 | 0 |
| NOT COMPLETED | 179 | 177 |
Baseline Characteristics
| Arm/Group Title | Eltrombopag | Placebo | Total |
|---|---|---|---|
| Arm/Group Description | 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 | 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 of all reporting groups |
| Overall Participants | 179 | 177 | 356 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
68.3
(12.82)
|
69.4
(10.58)
|
68.8
(11.76)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
69
38.5%
|
53
29.9%
|
122
34.3%
|
| Male |
110
61.5%
|
124
70.1%
|
234
65.7%
|
| Race/Ethnicity, Customized (participants) [Number] | |||
| White |
146
81.6%
|
148
83.6%
|
294
82.6%
|
| East Asian/Japanese/S.E. Asian |
26
14.5%
|
23
13%
|
49
13.8%
|
| Central/South Asian |
0
0%
|
2
1.1%
|
2
0.6%
|
| Other |
4
2.2%
|
4
2.3%
|
8
2.2%
|
| Missing |
3
1.7%
|
0
0%
|
3
0.8%
|
| IPSS risk score (participants) [Number] | |||
| Int - 1 (0.5-1.0) |
64
35.8%
|
61
34.5%
|
125
35.1%
|
| Int - 2 (1.5 - 2.0) |
77
43%
|
83
46.9%
|
160
44.9%
|
| High Risk (≥ 2.5) |
38
21.2%
|
33
18.6%
|
71
19.9%
|
| Platelet Count (participants) [Number] | |||
| < 10 |
10
5.6%
|
10
5.6%
|
20
5.6%
|
| ≥ 10 - <20 |
35
19.6%
|
30
16.9%
|
65
18.3%
|
| ≥ 20 - <50 |
83
46.4%
|
84
47.5%
|
167
46.9%
|
| ≥ 50 - <100 |
49
27.4%
|
53
29.9%
|
102
28.7%
|
| ≥ 100 |
0
0%
|
0
0%
|
0
0%
|
| missing |
2
1.1%
|
0
0%
|
2
0.6%
|
| Platelet transfusion dependence (participants) [Number] | |||
| Yes |
29
16.2%
|
37
20.9%
|
66
18.5%
|
| No |
150
83.8%
|
140
79.1%
|
290
81.5%
|
Outcome Measures
| Title | Number of Participants Who Were Platelet Transfusion Independent During Cycles 1-4 of Azacitidine Therapy |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Intent-to-Treat population, comprised of all randomized patients |
| Arm/Group Title | Eltrombopag | Placebo |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 179 | 177 |
| Yes - platelet transfusion independent |
28
15.6%
|
55
31.1%
|
| No - platelet transfusion independent |
151
84.4%
|
122
68.9%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Eltrombopag, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 1.000 |
| Comments | One sided p value | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Stratified by Interactive Voice Response System (IVRS) stratification factors | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.37 | |
| Confidence Interval |
(2-Sided) 95% 0.21 to 0.65 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Overall Survival (OS) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Eltrombopag | Placebo |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 179 | 177 |
| Number [deaths (events)] |
57
|
51
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Eltrombopag, Placebo |
|---|---|---|
| Comments | 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 factors | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.164 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.42 | |
| Confidence Interval |
(2-Sided) 95% 0.97 to 2.08 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Summary of Progression Free Survival From Investigator Assessment (ITT) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The intent-to-treat (ITT) population included all the patients randomized in the study |
| Arm/Group Title | Eltrombopag | Placebo |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 72 | 66 |
| Death |
34
19%
|
36
20.3%
|
| Disease progression |
38
21.2%
|
30
16.9%
|
| Title | Summary of Progression Free Survival From Central Review (ITT) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The intent-to-treat (ITT) population included all the patients randomized in the study |
| Arm/Group Title | Eltrombopag | Placebo |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 179 | 177 |
| Death |
44
24.6%
|
41
23.2%
|
| Disease progression |
32
17.9%
|
26
14.7%
|
| Title | Summary of AML Progression From Investigator Assessment and Central Review (ITT) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The intent-to-treat (ITT) population included all the patients randomized in the study |
| Arm/Group Title | Eltrombopag | Placebo |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 179 | 177 |
| Participants progressed-AML - investigator assess |
27
15.1%
|
16
9%
|
| Participants progressed to AML - Central Review |
21
11.7%
|
10
5.6%
|
| Title | Best Disease Response From Investigator Assessment (ITT) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Eltrombopag | Placebo |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 140 | 150 |
| Complete response - CR |
15
|
26
|
| Marrow complete response |
8
|
14
|
| Partial response - PR |
13
|
22
|
| Stable disease |
50
|
47
|
| Progressive disease |
22
|
8
|
| Not evaluable |
32
|
33
|
| Overall Response (CR+Marrow+PR |
36
|
62
|
| Title | Best Disease Response From Central Review (ITT) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Eltrombopag | Placebo |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 88 | 105 |
| Complete response - CR |
11
|
7
|
| Marrow complete response |
2
|
5
|
| Partial response - PR |
2
|
7
|
| Stable disease |
23
|
31
|
| Progressive disease |
24
|
17
|
| Not evaluable |
26
|
38
|
| Overall Response (CR+Marrow+PR) |
15
|
19
|
| Title | Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT) |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Eltrombopag | Placebo |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 179 | 177 |
| Platelets |
56
31.3%
|
57
32.2%
|
| Neutrophils |
12
6.7%
|
13
7.3%
|
| Hemoglobin |
1
0.6%
|
1
0.6%
|
| Platelets and neutrophils |
10
5.6%
|
11
6.2%
|
| Platelets and hemoglobin |
1
0.6%
|
1
0.6%
|
| Neutrophils and hemoglobin |
1
0.6%
|
1
0.6%
|
| Platelets, neutrophils and hemoglobin |
1
0.6%
|
1
0.6%
|
| Title | Number of Participants Who Were Platelet Transfusion Independent (ITT Set) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Eltrombopag | Placebo |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 179 | 177 |
| Screening (179,177) |
127
70.9%
|
121
68.4%
|
| Cycle 1 (175,173) |
68
38%
|
87
49.2%
|
| Cycle 2 (135,158) |
62
34.6%
|
87
49.2%
|
| Cycle 3 (105,131) |
68
38%
|
94
53.1%
|
| Cycle 4 (93,116) |
58
32.4%
|
91
51.4%
|
| Cycle 5 (76,108) |
49
27.4%
|
76
42.9%
|
| Cycle 6 (65,90) |
41
22.9%
|
62
35%
|
| Cycle 7 (47,74) |
29
16.2%
|
50
28.2%
|
| Cycle 8 (37,61) |
20
11.2%
|
42
23.7%
|
| Cycle 9 (28,46) |
19
10.6%
|
36
20.3%
|
| Cycle 10 (23,38) |
18
10.1%
|
28
15.8%
|
| Cycle 11 (19,29) |
13
7.3%
|
20
11.3%
|
| Cycle 12 (15,21) |
10
5.6%
|
15
8.5%
|
| Cycle 13 (12,16) |
7
3.9%
|
10
5.6%
|
| Cycle 14 (6,11) |
3
1.7%
|
6
3.4%
|
| Cycle 15 (3,5) |
2
1.1%
|
3
1.7%
|
| Cycle 16 (0,3) |
0
0%
|
3
1.7%
|
| Cycle 17 (0,3) |
0
0%
|
0
0%
|
| Title | Bleeding Adverse Events (AEs) >= Grade 3 |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Eltrombopag | Placebo |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 177 | 177 |
| Any event - Grade 3 |
9
|
12
|
| Any event - Grade 4 |
2
|
2
|
| Any event - Grade 5 |
1
|
4
|
| Title | Number of of Subjects With Azacitidine Dose Delays, Dose Reductions, Interruptions |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Eltrombopag | Placebo |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 179 | 177 |
| Overall dose delay |
82
|
88
|
| Overall dose reduction |
7
|
16
|
| Overall dose interruption |
3
|
13
|
| Title | Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Eltrombopag | Placebo |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 179 | 177 |
| Mobility C1, D1 (176, 173) L1- no problem walking |
94
|
105
|
| Mobility C1,D1 (176, 173) L2- some problem walking |
81
|
66
|
| Mobility C1, D1 (176,173) L3- confined to bed |
1
|
2
|
| Mobility Wk 4 FU (71,72) L1- no problem walking |
40
|
48
|
| Mobility Wk 4 FU (71,72) L2- some problem walking |
29
|
22
|
| Mobility Wk 4 FU (71,72) L3- confined to bed |
2
|
2
|
| Self-Care C1, D1 (176,173) L1-no problems |
140
|
125
|
| Self-Care C1, D1 (176,173) L2-some problems |
32
|
20
|
| Self-Care C1, D1 (176,173) L3-unable to |
4
|
51
|
| Self-Care Wk4 FU (71,72) L1-no problems |
56
|
62
|
| Self-Care Wk4 FU(71,72) L2-some problems |
13
|
9
|
| Self-Care Wk4 FU (71,72) L2-unable to wash/dress |
2
|
1
|
| Usual activities C1,D1(175,173) L1-no problem |
97
|
94
|
| Usual activities C1,D1(175,173) L2-some problem |
71
|
68
|
| Usual activities C1,D1(175,173) L3-unable to |
7
|
11
|
| Usual activities Wk4 FU (71,72) L1-no problem |
36
|
41
|
| Usual activities Wk4 FU (71,72) L1-some problem |
29
|
25
|
| Usual activities Wk4 FU (71,72) L3-unable to |
6
|
6
|
| Pain/discomfort C1,D1(176,173) L1-none |
97
|
89
|
| Pain/discomfort C1,D1(176,173) L2-moderate |
74
|
78
|
| Pain/discomfort C1,D1(176,173) L3-extreme |
5
|
6
|
| Pain/discomfort Wk4 FU (71,72) L1-none |
38
|
40
|
| Pain/discomfort Wk4 FU (71,72) L2-moderate |
28
|
27
|
| Pain/discomfort Wk4 FU (71,72) L3-extreme |
5
|
5
|
| Anxiety/depression C1 D1(176,173) L1-none |
96
|
112
|
| Anxiety/depression C1 D1(176,173) L2-moderately |
74
|
56
|
| Anxiety/depression C1 D1(176,173) L3-extremely |
6
|
5
|
| Anxiety/depression Wk4 FU(71,72) L1-none |
44
|
45
|
| Anxiety/depression Wk4 FU(71,72) L2-moderately |
24
|
25
|
| Anxiety/depression Wk4 FU(71,72) L3-extremely |
3
|
2
|
| Title | Functional Assessment of Chronic Disease Therapy-fatigue Subscale (FACIT-Fatigue) (ITT) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Eltrombopag | Placebo |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 179 | 177 |
| Cycle 1 Day 1 (175,172) |
17.401
(11.0279)
|
15.951
(10.9911)
|
| Week 4 Follow-up (68,70) |
16.669
(10.7266)
|
14.898
(12.2362)
|
| Title | Medical Resource Utilization (MRU): Event -Hospitalizations Inpatient and Outpatient |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Eltrombopag | Placebo |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 179 | 177 |
| In-patient hospitalizations - entire study (91,66) |
23.9
(24.33)
|
27.1
(33.81)
|
| Out-patient hospitalizations - entire study (4,2) |
9.5
(16.34)
|
2.5
(0.71)
|
| Title | Medical Resource Utilization (MRU): Event and Use of Site Specific Medical Resources - Non-study Laboratory Tests |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Eltrombopag | Placebo |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 179 | 177 |
| Number [tests] |
88
|
105
|
| Title | Medical Resource Utilization (MRU): Use of Site Specific Medical Resources |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Eltrombopag | Placebo |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 179 | 177 |
| Medical or surgical specialist visits |
49
|
58
|
| Home healthcare visits by medical professional |
89
|
97
|
| Primary physician care visits |
89
|
97
|
| Nurse practitioner, physic assistant, nurse visits |
89
|
97
|
| Telephone consultations |
89
|
97
|
| Emergency visits not resulting in hospital stay |
89
|
97
|
| Title | Summary of Post-Hoc Estimates of Steady-state Eltrombopag Cmax and Cmin Pharmacokinetic Parameters for a 50 mg Dose |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients with evaluable eltrombopag dosing, actual sampling time, and eltrombopag concentration data were included in the population PK dataset and analysis. |
| Arm/Group Title | Eltrombopag |
|---|---|
| Arm/Group Description | 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 |
| Measure Participants | 163 |
| Cmax |
7.70
(36.8)
|
| Cmin |
4.41
(49.9)
|
| Title | Summary of Post-Hoc Estimates of Steady-state Eltrombopag AUC0 Infinity Pharmacokinetic Parameters for a 50 mg Dose |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients with evaluable eltrombopag dosing, actual sampling time, and eltrombopag concentration data were included in the population PK dataset and analysis. |
| Arm/Group Title | Eltrombopag |
|---|---|
| Arm/Group Description | 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 |
| Measure Participants | 163 |
| Geometric Mean (Geometric Coefficient of Variation) [hr.μg/mL] |
135
(43.1)
|
| Title | AUC0-infinity -Pharmacokinetic(s) Parameter of Azacitidine |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| all patients with evaluable azacitidine dosing, actual sampling time, and azacitidine concentration data were included in the NCA dataset and analysis |
| Arm/Group Title | Eltrombopag | Placebo |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 22 | 23 |
| Geometric Mean (Geometric Coefficient of Variation) [hr.ng/mL] |
840
(53)
|
641
(67)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Eltrombopag, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Geometric mean ratio |
| Estimated Value | 1.31 | |
| Confidence Interval |
(2-Sided) 90% 0.990 to 1.74 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Cmax -Pharmacokinetic Parameter of Azacitidine |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients with evaluable azacitidine dosing, actual sampling time, and azacitidine concentration data were included in the NCA dataset and analysis |
| Arm/Group Title | Eltrombopag | Placebo |
|---|---|---|
| Arm/Group Description | 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 | 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 |
| Measure Participants | 26 | 26 |
| Geometric Mean (Geometric Coefficient of Variation) [ng/mL] |
744
(91)
|
535
(89)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Eltrombopag, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Geometric mean ratio |
| Estimated Value | 1.39 | |
| Confidence Interval |
(2-Sided) 90% 0.970 to 1.99 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Adverse Events
| Time Frame | Timeframe for AE | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | AE additional description | |||
| Arm/Group Title | Eltrombopag | Placebo | ||
| Arm/Group Description | Eltrombopag | Placebo | ||
All Cause Mortality |
||||
| Eltrombopag | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Eltrombopag | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 128/177 (72.3%) | 100/177 (56.5%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 5/177 (2.8%) | 7/177 (4%) | ||
| Cytopenia | 0/177 (0%) | 1/177 (0.6%) | ||
| Disseminated intravascular coagulation | 1/177 (0.6%) | 0/177 (0%) | ||
| Febrile neutropenia | 47/177 (26.6%) | 33/177 (18.6%) | ||
| Leukocytosis | 0/177 (0%) | 1/177 (0.6%) | ||
| Neutropenia | 3/177 (1.7%) | 3/177 (1.7%) | ||
| Thrombocytopenia | 2/177 (1.1%) | 2/177 (1.1%) | ||
| Cardiac disorders | ||||
| Acute coronary syndrome | 1/177 (0.6%) | 0/177 (0%) | ||
| Acute myocardial infarction | 2/177 (1.1%) | 1/177 (0.6%) | ||
| Angina pectoris | 0/177 (0%) | 1/177 (0.6%) | ||
| Aortic valve stenosis | 1/177 (0.6%) | 0/177 (0%) | ||
| Atrial fibrillation | 4/177 (2.3%) | 2/177 (1.1%) | ||
| Cardiac arrest | 0/177 (0%) | 1/177 (0.6%) | ||
| Cardiac failure | 3/177 (1.7%) | 1/177 (0.6%) | ||
| Cardiac failure congestive | 3/177 (1.7%) | 1/177 (0.6%) | ||
| Cardiovascular deconditioning | 0/177 (0%) | 1/177 (0.6%) | ||
| Coronary artery disease | 1/177 (0.6%) | 0/177 (0%) | ||
| Myocardial infarction | 0/177 (0%) | 1/177 (0.6%) | ||
| Papillary muscle infarction | 0/177 (0%) | 1/177 (0.6%) | ||
| Pericardial effusion | 0/177 (0%) | 1/177 (0.6%) | ||
| Pericarditis | 0/177 (0%) | 1/177 (0.6%) | ||
| Pericarditis constrictive | 0/177 (0%) | 1/177 (0.6%) | ||
| Ear and labyrinth disorders | ||||
| Vertigo positional | 1/177 (0.6%) | 0/177 (0%) | ||
| Endocrine disorders | ||||
| Adrenal insufficiency | 1/177 (0.6%) | 0/177 (0%) | ||
| Eye disorders | ||||
| Cataract | 0/177 (0%) | 1/177 (0.6%) | ||
| Gastrointestinal disorders | ||||
| Abdominal pain | 1/177 (0.6%) | 1/177 (0.6%) | ||
| Anal fistula | 1/177 (0.6%) | 0/177 (0%) | ||
| Colitis | 2/177 (1.1%) | 0/177 (0%) | ||
| Colitis ischaemic | 0/177 (0%) | 1/177 (0.6%) | ||
| Constipation | 2/177 (1.1%) | 0/177 (0%) | ||
| Diarrhoea | 3/177 (1.7%) | 0/177 (0%) | ||
| Duodenal ulcer | 0/177 (0%) | 1/177 (0.6%) | ||
| Dyspepsia | 1/177 (0.6%) | 0/177 (0%) | ||
| Enterocolitis | 0/177 (0%) | 2/177 (1.1%) | ||
| Faeces discoloured | 1/177 (0.6%) | 0/177 (0%) | ||
| Functional gastrointestinal disorder | 1/177 (0.6%) | 0/177 (0%) | ||
| Gastric haemorrhage | 1/177 (0.6%) | 0/177 (0%) | ||
| Gastrointestinal haemorrhage | 1/177 (0.6%) | 5/177 (2.8%) | ||
| Gingival bleeding | 1/177 (0.6%) | 1/177 (0.6%) | ||
| Haematemesis | 0/177 (0%) | 1/177 (0.6%) | ||
| Haemorrhoids | 1/177 (0.6%) | 0/177 (0%) | ||
| Intestinal haemorrhage | 0/177 (0%) | 1/177 (0.6%) | ||
| Large intestinal haemorrhage | 0/177 (0%) | 1/177 (0.6%) | ||
| Melaena | 1/177 (0.6%) | 0/177 (0%) | ||
| Mouth haemorrhage | 1/177 (0.6%) | 0/177 (0%) | ||
| Neutropenic colitis | 1/177 (0.6%) | 0/177 (0%) | ||
| Pancreatitis acute | 1/177 (0.6%) | 0/177 (0%) | ||
| Rectal haemorrhage | 1/177 (0.6%) | 0/177 (0%) | ||
| Small intestinal ulcer haemorrhage | 1/177 (0.6%) | 0/177 (0%) | ||
| Subileus | 0/177 (0%) | 1/177 (0.6%) | ||
| Upper gastrointestinal haemorrhage | 1/177 (0.6%) | 0/177 (0%) | ||
| Vomiting | 0/177 (0%) | 1/177 (0.6%) | ||
| General disorders | ||||
| Asthenia | 3/177 (1.7%) | 2/177 (1.1%) | ||
| Chest pain | 0/177 (0%) | 1/177 (0.6%) | ||
| Chills | 2/177 (1.1%) | 0/177 (0%) | ||
| General physical health deterioration | 3/177 (1.7%) | 3/177 (1.7%) | ||
| Inflammation | 1/177 (0.6%) | 0/177 (0%) | ||
| Injection site haemorrhage | 0/177 (0%) | 1/177 (0.6%) | ||
| Malaise | 1/177 (0.6%) | 2/177 (1.1%) | ||
| Mucosal haemorrhage | 0/177 (0%) | 1/177 (0.6%) | ||
| Oedema | 0/177 (0%) | 1/177 (0.6%) | ||
| Pyrexia | 20/177 (11.3%) | 8/177 (4.5%) | ||
| Hepatobiliary disorders | ||||
| Cholecystitis | 1/177 (0.6%) | 0/177 (0%) | ||
| Cholecystitis acute | 1/177 (0.6%) | 0/177 (0%) | ||
| Cholelithiasis | 0/177 (0%) | 1/177 (0.6%) | ||
| Drug-induced liver injury | 2/177 (1.1%) | 0/177 (0%) | ||
| Hepatic failure | 1/177 (0.6%) | 0/177 (0%) | ||
| Liver disorder | 1/177 (0.6%) | 0/177 (0%) | ||
| Liver injury | 1/177 (0.6%) | 0/177 (0%) | ||
| Immune system disorders | ||||
| Drug hypersensitivity | 0/177 (0%) | 1/177 (0.6%) | ||
| Infections and infestations | ||||
| Abdominal infection | 1/177 (0.6%) | 0/177 (0%) | ||
| Abscess | 1/177 (0.6%) | 0/177 (0%) | ||
| Abscess limb | 1/177 (0.6%) | 2/177 (1.1%) | ||
| Anal abscess | 1/177 (0.6%) | 0/177 (0%) | ||
| Anal fistula infection | 1/177 (0.6%) | 0/177 (0%) | ||
| Anorectal infection | 1/177 (0.6%) | 0/177 (0%) | ||
| Appendicitis | 0/177 (0%) | 2/177 (1.1%) | ||
| Arthritis infective | 0/177 (0%) | 1/177 (0.6%) | ||
| Aspergillus infection | 1/177 (0.6%) | 0/177 (0%) | ||
| Bacteraemia | 0/177 (0%) | 1/177 (0.6%) | ||
| Bronchitis | 1/177 (0.6%) | 0/177 (0%) | ||
| Bronchopulmonary aspergillosis | 2/177 (1.1%) | 1/177 (0.6%) | ||
| Carbuncle | 1/177 (0.6%) | 1/177 (0.6%) | ||
| Cellulitis | 6/177 (3.4%) | 2/177 (1.1%) | ||
| Clostridium difficile colitis | 1/177 (0.6%) | 0/177 (0%) | ||
| Diverticulitis | 0/177 (0%) | 1/177 (0.6%) | ||
| Endocarditis bacterial | 1/177 (0.6%) | 0/177 (0%) | ||
| Enteritis infectious | 0/177 (0%) | 1/177 (0.6%) | ||
| Enterobacter sepsis | 1/177 (0.6%) | 0/177 (0%) | ||
| Enterococcal infection | 1/177 (0.6%) | 0/177 (0%) | ||
| Enterococcal sepsis | 0/177 (0%) | 1/177 (0.6%) | ||
| Epiglottitis | 1/177 (0.6%) | 0/177 (0%) | ||
| Escherichia infection | 2/177 (1.1%) | 0/177 (0%) | ||
| Escherichia sepsis | 1/177 (0.6%) | 2/177 (1.1%) | ||
| Extradural abscess | 0/177 (0%) | 1/177 (0.6%) | ||
| Fungaemia | 0/177 (0%) | 1/177 (0.6%) | ||
| Fungal pharyngitis | 0/177 (0%) | 1/177 (0.6%) | ||
| Furuncle | 1/177 (0.6%) | 0/177 (0%) | ||
| Gastroenteritis | 0/177 (0%) | 2/177 (1.1%) | ||
| Herpes zoster | 0/177 (0%) | 1/177 (0.6%) | ||
| Infection | 0/177 (0%) | 4/177 (2.3%) | ||
| Infectious colitis | 2/177 (1.1%) | 0/177 (0%) | ||
| Influenza | 1/177 (0.6%) | 0/177 (0%) | ||
| Klebsiella infection | 2/177 (1.1%) | 0/177 (0%) | ||
| Liver abscess | 0/177 (0%) | 1/177 (0.6%) | ||
| Lower respiratory tract infection | 2/177 (1.1%) | 0/177 (0%) | ||
| Lung infection | 1/177 (0.6%) | 1/177 (0.6%) | ||
| Neutropenic infection | 0/177 (0%) | 1/177 (0.6%) | ||
| Neutropenic sepsis | 3/177 (1.7%) | 0/177 (0%) | ||
| Orchitis | 1/177 (0.6%) | 0/177 (0%) | ||
| Osteomyelitis | 1/177 (0.6%) | 0/177 (0%) | ||
| Pneumonia | 20/177 (11.3%) | 17/177 (9.6%) | ||
| Pneumonia bacterial | 0/177 (0%) | 1/177 (0.6%) | ||
| Pneumonia necrotising | 1/177 (0.6%) | 0/177 (0%) | ||
| Pseudomonal sepsis | 0/177 (0%) | 1/177 (0.6%) | ||
| Pulmonary mycosis | 1/177 (0.6%) | 0/177 (0%) | ||
| Pulmonary sepsis | 0/177 (0%) | 1/177 (0.6%) | ||
| Pyomyositis | 1/177 (0.6%) | 0/177 (0%) | ||
| Respiratory tract infection | 2/177 (1.1%) | 1/177 (0.6%) | ||
| Sepsis | 10/177 (5.6%) | 7/177 (4%) | ||
| Septic shock | 10/177 (5.6%) | 5/177 (2.8%) | ||
| Skin infection | 0/177 (0%) | 1/177 (0.6%) | ||
| Splenic abscess | 0/177 (0%) | 1/177 (0.6%) | ||
| Staphylococcal infection | 1/177 (0.6%) | 0/177 (0%) | ||
| Streptococcal sepsis | 1/177 (0.6%) | 0/177 (0%) | ||
| Systemic mycosis | 0/177 (0%) | 1/177 (0.6%) | ||
| Tongue fungal infection | 0/177 (0%) | 1/177 (0.6%) | ||
| Upper respiratory tract infection | 2/177 (1.1%) | 0/177 (0%) | ||
| Urinary tract infection | 4/177 (2.3%) | 5/177 (2.8%) | ||
| Urinary tract infection enterococcal | 0/177 (0%) | 1/177 (0.6%) | ||
| Urinary tract infection pseudomonal | 0/177 (0%) | 1/177 (0.6%) | ||
| Viral infection | 1/177 (0.6%) | 0/177 (0%) | ||
| Injury, poisoning and procedural complications | ||||
| Concussion | 0/177 (0%) | 1/177 (0.6%) | ||
| Facial bones fracture | 0/177 (0%) | 1/177 (0.6%) | ||
| Fall | 1/177 (0.6%) | 4/177 (2.3%) | ||
| Femoral neck fracture | 0/177 (0%) | 1/177 (0.6%) | ||
| Femur fracture | 1/177 (0.6%) | 1/177 (0.6%) | ||
| Humerus fracture | 0/177 (0%) | 1/177 (0.6%) | ||
| Post procedural complication | 0/177 (0%) | 1/177 (0.6%) | ||
| Spinal compression fracture | 0/177 (0%) | 1/177 (0.6%) | ||
| Subdural haematoma | 2/177 (1.1%) | 0/177 (0%) | ||
| Transfusion reaction | 0/177 (0%) | 1/177 (0.6%) | ||
| Upper limb fracture | 1/177 (0.6%) | 0/177 (0%) | ||
| Investigations | ||||
| Alanine aminotransferase increased | 1/177 (0.6%) | 0/177 (0%) | ||
| Blood lactate dehydrogenase increased | 2/177 (1.1%) | 0/177 (0%) | ||
| Blood osmolarity decreased | 1/177 (0.6%) | 0/177 (0%) | ||
| Electrocardiogram QT prolonged | 1/177 (0.6%) | 0/177 (0%) | ||
| Liver function test increased | 1/177 (0.6%) | 0/177 (0%) | ||
| Oxygen saturation decreased | 1/177 (0.6%) | 0/177 (0%) | ||
| Platelet count decreased | 0/177 (0%) | 1/177 (0.6%) | ||
| White blood cell count decreased | 0/177 (0%) | 1/177 (0.6%) | ||
| Metabolism and nutrition disorders | ||||
| Dehydration | 3/177 (1.7%) | 0/177 (0%) | ||
| Gout | 0/177 (0%) | 1/177 (0.6%) | ||
| Hypercalcaemia | 1/177 (0.6%) | 1/177 (0.6%) | ||
| Hyperglycaemia | 1/177 (0.6%) | 0/177 (0%) | ||
| Hyperkalaemia | 0/177 (0%) | 1/177 (0.6%) | ||
| Hypokalaemia | 2/177 (1.1%) | 0/177 (0%) | ||
| Hyponatraemia | 1/177 (0.6%) | 0/177 (0%) | ||
| Iron overload | 1/177 (0.6%) | 0/177 (0%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Back pain | 0/177 (0%) | 2/177 (1.1%) | ||
| Bone pain | 1/177 (0.6%) | 0/177 (0%) | ||
| Haemarthrosis | 0/177 (0%) | 1/177 (0.6%) | ||
| Intervertebral disc protrusion | 0/177 (0%) | 1/177 (0.6%) | ||
| Muscular weakness | 0/177 (0%) | 1/177 (0.6%) | ||
| Myositis | 0/177 (0%) | 1/177 (0.6%) | ||
| Osteoarthritis | 0/177 (0%) | 1/177 (0.6%) | ||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Acute leukaemia | 1/177 (0.6%) | 1/177 (0.6%) | ||
| Acute myeloid leukaemia | 4/177 (2.3%) | 1/177 (0.6%) | ||
| B-cell lymphoma | 1/177 (0.6%) | 1/177 (0.6%) | ||
| Myelodysplastic syndrome | 1/177 (0.6%) | 1/177 (0.6%) | ||
| Myelofibrosis | 1/177 (0.6%) | 0/177 (0%) | ||
| Neoplasm | 0/177 (0%) | 1/177 (0.6%) | ||
| Renal neoplasm | 1/177 (0.6%) | 0/177 (0%) | ||
| Thyroid cancer | 0/177 (0%) | 1/177 (0.6%) | ||
| Transitional cell carcinoma | 0/177 (0%) | 1/177 (0.6%) | ||
| Tumour associated fever | 1/177 (0.6%) | 0/177 (0%) | ||
| Nervous system disorders | ||||
| Amnesia | 0/177 (0%) | 1/177 (0.6%) | ||
| Cerebral haemorrhage | 0/177 (0%) | 1/177 (0.6%) | ||
| Dizziness | 0/177 (0%) | 1/177 (0.6%) | ||
| Haemorrhage intracranial | 0/177 (0%) | 1/177 (0.6%) | ||
| Ischaemic stroke | 1/177 (0.6%) | 0/177 (0%) | ||
| Memory impairment | 0/177 (0%) | 1/177 (0.6%) | ||
| Presyncope | 0/177 (0%) | 1/177 (0.6%) | ||
| Syncope | 1/177 (0.6%) | 1/177 (0.6%) | ||
| Psychiatric disorders | ||||
| Agitation | 0/177 (0%) | 1/177 (0.6%) | ||
| Delirium | 1/177 (0.6%) | 0/177 (0%) | ||
| Hypomania | 1/177 (0.6%) | 0/177 (0%) | ||
| Renal and urinary disorders | ||||
| Acute kidney injury | 7/177 (4%) | 2/177 (1.1%) | ||
| Haematuria | 0/177 (0%) | 3/177 (1.7%) | ||
| Nephritis | 1/177 (0.6%) | 0/177 (0%) | ||
| Renal failure | 1/177 (0.6%) | 0/177 (0%) | ||
| Renal tubular disorder | 0/177 (0%) | 1/177 (0.6%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Acute pulmonary oedema | 0/177 (0%) | 1/177 (0.6%) | ||
| Acute respiratory distress syndrome | 1/177 (0.6%) | 0/177 (0%) | ||
| Acute respiratory failure | 2/177 (1.1%) | 2/177 (1.1%) | ||
| Chronic obstructive pulmonary disease | 1/177 (0.6%) | 0/177 (0%) | ||
| Dyspnoea | 1/177 (0.6%) | 0/177 (0%) | ||
| Epistaxis | 0/177 (0%) | 2/177 (1.1%) | ||
| Hypoxia | 0/177 (0%) | 1/177 (0.6%) | ||
| Interstitial lung disease | 0/177 (0%) | 1/177 (0.6%) | ||
| Lung disorder | 0/177 (0%) | 1/177 (0.6%) | ||
| Oropharyngeal pain | 0/177 (0%) | 1/177 (0.6%) | ||
| Pleural effusion | 2/177 (1.1%) | 0/177 (0%) | ||
| Pneumonitis | 1/177 (0.6%) | 0/177 (0%) | ||
| Pulmonary embolism | 2/177 (1.1%) | 1/177 (0.6%) | ||
| Pulmonary haemorrhage | 0/177 (0%) | 1/177 (0.6%) | ||
| Pulmonary hypertension | 1/177 (0.6%) | 0/177 (0%) | ||
| Respiratory failure | 4/177 (2.3%) | 1/177 (0.6%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Acute febrile neutrophilic dermatosis | 0/177 (0%) | 1/177 (0.6%) | ||
| Erythema | 1/177 (0.6%) | 0/177 (0%) | ||
| Hypersensitivity vasculitis | 0/177 (0%) | 1/177 (0.6%) | ||
| Petechiae | 1/177 (0.6%) | 0/177 (0%) | ||
| Pyoderma gangrenosum | 0/177 (0%) | 1/177 (0.6%) | ||
| Rash maculo-papular | 1/177 (0.6%) | 0/177 (0%) | ||
| Skin lesion | 1/177 (0.6%) | 1/177 (0.6%) | ||
| Vascular disorders | ||||
| Aortic aneurysm | 0/177 (0%) | 1/177 (0.6%) | ||
| Aortic dilatation | 1/177 (0.6%) | 0/177 (0%) | ||
| Deep vein thrombosis | 2/177 (1.1%) | 0/177 (0%) | ||
| Haematoma | 1/177 (0.6%) | 0/177 (0%) | ||
| Hypotension | 3/177 (1.7%) | 3/177 (1.7%) | ||
| Orthostatic hypotension | 1/177 (0.6%) | 0/177 (0%) | ||
| Phlebitis | 1/177 (0.6%) | 0/177 (0%) | ||
| Venous thrombosis limb | 0/177 (0%) | 1/177 (0.6%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Eltrombopag | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 159/177 (89.8%) | 153/177 (86.4%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 32/177 (18.1%) | 19/177 (10.7%) | ||
| Febrile neutropenia | 13/177 (7.3%) | 10/177 (5.6%) | ||
| Leukopenia | 9/177 (5.1%) | 5/177 (2.8%) | ||
| Neutropenia | 52/177 (29.4%) | 44/177 (24.9%) | ||
| Thrombocytopenia | 14/177 (7.9%) | 14/177 (7.9%) | ||
| Gastrointestinal disorders | ||||
| Abdominal pain | 7/177 (4%) | 12/177 (6.8%) | ||
| Abdominal pain upper | 9/177 (5.1%) | 7/177 (4%) | ||
| Constipation | 48/177 (27.1%) | 57/177 (32.2%) | ||
| Diarrhoea | 42/177 (23.7%) | 25/177 (14.1%) | ||
| Gingival bleeding | 13/177 (7.3%) | 9/177 (5.1%) | ||
| Nausea | 54/177 (30.5%) | 46/177 (26%) | ||
| Stomatitis | 9/177 (5.1%) | 3/177 (1.7%) | ||
| Vomiting | 33/177 (18.6%) | 29/177 (16.4%) | ||
| General disorders | ||||
| Asthenia | 28/177 (15.8%) | 34/177 (19.2%) | ||
| Chills | 8/177 (4.5%) | 11/177 (6.2%) | ||
| Fatigue | 31/177 (17.5%) | 27/177 (15.3%) | ||
| Injection site pain | 7/177 (4%) | 9/177 (5.1%) | ||
| Oedema peripheral | 22/177 (12.4%) | 11/177 (6.2%) | ||
| Pyrexia | 44/177 (24.9%) | 40/177 (22.6%) | ||
| Infections and infestations | ||||
| Nasopharyngitis | 7/177 (4%) | 9/177 (5.1%) | ||
| Pneumonia | 12/177 (6.8%) | 9/177 (5.1%) | ||
| Upper respiratory tract infection | 9/177 (5.1%) | 11/177 (6.2%) | ||
| Urinary tract infection | 9/177 (5.1%) | 8/177 (4.5%) | ||
| Investigations | ||||
| Alanine aminotransferase increased | 10/177 (5.6%) | 3/177 (1.7%) | ||
| Blood bilirubin increased | 13/177 (7.3%) | 2/177 (1.1%) | ||
| Neutrophil count decreased | 12/177 (6.8%) | 11/177 (6.2%) | ||
| Platelet count decreased | 9/177 (5.1%) | 5/177 (2.8%) | ||
| White blood cell count decreased | 10/177 (5.6%) | 4/177 (2.3%) | ||
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 27/177 (15.3%) | 21/177 (11.9%) | ||
| Hypokalaemia | 19/177 (10.7%) | 17/177 (9.6%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 6/177 (3.4%) | 11/177 (6.2%) | ||
| Back pain | 13/177 (7.3%) | 10/177 (5.6%) | ||
| Pain in extremity | 9/177 (5.1%) | 14/177 (7.9%) | ||
| Nervous system disorders | ||||
| Dizziness | 17/177 (9.6%) | 14/177 (7.9%) | ||
| Headache | 20/177 (11.3%) | 13/177 (7.3%) | ||
| Psychiatric disorders | ||||
| Insomnia | 16/177 (9%) | 9/177 (5.1%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 23/177 (13%) | 29/177 (16.4%) | ||
| Dyspnoea | 24/177 (13.6%) | 12/177 (6.8%) | ||
| Epistaxis | 14/177 (7.9%) | 18/177 (10.2%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Erythema | 11/177 (6.2%) | 6/177 (3.4%) | ||
| Petechiae | 11/177 (6.2%) | 11/177 (6.2%) | ||
| Pruritus | 12/177 (6.8%) | 12/177 (6.8%) | ||
| Rash | 19/177 (10.7%) | 11/177 (6.2%) | ||
| Vascular disorders | ||||
| Haematoma | 10/177 (5.6%) | 12/177 (6.8%) | ||
| Hypertension | 2/177 (1.1%) | 11/177 (6.2%) | ||
| Hypotension | 12/177 (6.8%) | 5/177 (2.8%) | ||
Limitations/Caveats
The IDMC recommended terminating the study for futility (primary) and safety (secondary). Due to early termination of the trial, the final analysis of OS took place at the same time as the final analysis of the primary end point.
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
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.
Results Point of Contact
| Name/Title | Study Director |
|---|---|
| Organization | Novartis Pharma AG |
| Phone | 862-778-8300 |
Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT02158936
Other Study ID Numbers:
- 112121
First Posted:
Jun 9, 2014
Last Update Posted:
Dec 12, 2017
Last Verified:
Sep 1, 2017