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Clinical Trial Results:
A randomized, blinded, placebo-controlled, dose finding study to assess the safety and efficacy of the oral thrombopoietin receptor agonist, eltrombopag, administered to subjects with acute myelogenous leukemia (AML) receiving induction chemotherapy.

Summary
EudraCT number	2013-000642-20
Trial protocol	BE HU PL GR
Global end of trial date	25 Jan 2017

Results information
Results version number	v1(current)
This version publication date	10 Feb 2018
First version publication date	10 Feb 2018
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

117146

ISRCTN number

US NCT number

NCT01890746

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma, AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.com

Scientific contact

Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

25 Jan 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

25 Jan 2017

Was the trial ended prematurely?

Main objective of the trial

To assess the safety and tolerability of eltrombopag versus placebo in subjects receiving standard induction therapy for acute myeloid leukemia (AML).

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

07 Sep 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 19

Country: Number of subjects enrolled

Belgium: 5

Country: Number of subjects enrolled

Canada: 5

Country: Number of subjects enrolled

Greece: 6

Country: Number of subjects enrolled

Hungary: 9

Country: Number of subjects enrolled

Israel: 17

Country: Number of subjects enrolled

Korea, Democratic People's Republic of: 43

Country: Number of subjects enrolled

Poland: 2

Country: Number of subjects enrolled

Russian Federation: 12

Country: Number of subjects enrolled

United States: 30

Worldwide total number of subjects

148

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

106

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants (Par.) diagnosed with Acute Myelogenous Leukemia (AML) of any subtype (except acute promyelocytic [M3] or acute megakaryocytic leukaemia [M7]) were eligible for the study.

Screening details

Sufficient number of participants were screened and 148 participants were randomized and entered in to the study. Participants were stratified by antecedent malignant hematologic disorder (yes versus no) and age (18-60 years versus >60 years), before they were randomized to receive study treatments.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Eltrombopag (ELQ) QD

Arm description

Par. received (rec) first line induction (IDN) chemotherapy (CTY) consisting of daunorubicin (DAU) bolus intravenous (IV) infusion (INF) on Days (D) 1-3 at a dose of 90 milligrams (mg)/square meter (m^2) for Par. 18-60 year (yr) or 60 mg/m^2 for >60 yr plus cytarabine (CB) 100 mg/m^2 continuous IV INF on D1-7. Par. rec ELT as 200 mg (100 mg for East-Asian Heritage [EAH]) once daily (QD) oral dose starting on D4 of initial IDN CTY at least 20 hours after end of D3 DAU INF. If platelet (PT) count was not >100 Giga (Gi)/Liter (L) after 7D the dose was increased to 300 mg (150 mg for EAH) QD until a PT count of at least 200 Gi/L was achieved, until remission was assessed by bone marrow biopsy, or for a maximum of 42D from the start of the CTY IDN cycle. Par. not aplastic after first cycle of IDN CTY rec re-IDN with a modified DAU dose of 45mg/m^2/day on D1-3 plus CB 100 mg/m^2/day on D1-7. For re-IDN Par., ELT was held from D1-3 of re-IDN, and resumed on D4 at the same dose and duration.

Arm type

Experimental

Investigational medicinal product name

Eltrombopag

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Eltrombopag 200 mg orally, once daily, beginning on Day 4 of the first cycle of induction. After 7 days, the dose of IP was increased to 300 mg if platelet counts were <100 Gi/L. IP continued until achievement of platelet count of at least 200 Gi/L or assessment of remission of bone marrow status or a maximum of 42 days after initiation of most recent induction. In subjects of East Asian heritage (e.g., Japanese, Chinese, Taiwanese, Korean, Thai): 100 mg orally once daily (a 50% dose reduction) was used; After 7 days, the dose of IP was increased to 150 mg if platelet counts were <100 Gi/L.

Placebo QD

Arm description

Participants received first line IDN CTY consisting of DAU bolus IV INF on Days 1-3 at a dose of 90 mg/m^2 for participants 18-60 years old or 60 mg/m^2 for participants >60 years of age plus cytarabine continuous IV INF on Days 1-7 at a dose of 100 mg/m^2. Participants received placebo QD oral dose starting on Day 4 of initial IDN CTY at least 20 hours after end of Day 3 DAU INF up to a maximum duration of 42 days.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo 200 mg orally, once daily, beginning on Day 4 of the first cycle of induction. After 7 days, the dose of IP was increased to 300 mg if platelet counts were <100 Gi/L. IP continued until achievement of platelet count of at least 200 Gi/L or assessment of remission of bone marrow status or a maximum of 42 days after initiation of most recent induction. In subjects of East Asian heritage (e.g., Japanese, Chinese, Taiwanese, Korean, Thai): 100 mg orally once daily (a 50% dose reduction) was used; After 7 days, the dose of IP was increased to 150 mg if platelet counts were <100 Gi/L.

Number of subjects in period 1	Eltrombopag (ELQ) QD	Placebo QD
Started	74	74
Completed	22	33
Not completed	52	41
Adverse event, serious fatal	39	30
Physician decision	3	2
Consent withdrawn by subject	5	8
Adverse event, non-fatal	1	-
Lost to follow-up	4	1

Baseline characteristics

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Reporting group title

Eltrombopag (ELQ) QD

Reporting group description

Reporting group title

Placebo QD

Reporting group description

Reporting group values	Eltrombopag (ELQ) QD	Placebo QD	Total
Number of subjects	74	74	148
Age categorical
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	56.7 ± 12.25	56.6 ± 11.58	-
Sex: Female, Male
Units: Subjects
Female	38	31	69
Male	36	43	79
Race/Ethnicity, Customized
Units: Subjects
African American/African Heritage\|	1	2	3
Asian - Central/South Asian Heritage\|	0	1	1
Asian - East Asian Heritage\|	26	17	43
Asian - South East Asian Heritage\|	0	1	1
White - Arabic/North African Heritage\|	5	3	8
White - White/Caucasian/European Heritage\|	42	50	92

End points

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Reporting group title

Eltrombopag (ELQ) QD

Reporting group description

Reporting group title

Placebo QD

Reporting group description

Primary: Number of participants with any adverse events (AE) and any serious adverse events (SAE) as a measure of safety and tolerability.

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End point title

Number of participants with any adverse events (AE) and any serious adverse events (SAE) as a measure of safety and tolerability. ^[1]

End point description

An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, is an important medical event that jeopardizes the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition, or is associated with liver injury and impaired liver function.

End point type

Primary

End point timeframe

From the time the first dose of study treatment was administered until 30 days following discontinuation of investigational product regardless of initiation of a new cancer therapy or transfer to hospice

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No Statistical analysis was performed for this endpoint.

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	71
Units: Participants
Any AE\|	72	66
Any SAE\|	24	14

No statistical analyses for this end point

Primary: Change from baseline in the left ventricular ejection fraction (LVEF).

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End point title

Change from baseline in the left ventricular ejection fraction (LVEF). ^[2]

End point description

LVEF is a measurement of the percentage of blood leaving heart each time it contracts. LVEF was assessed by an echocardiogram (ECHO) or Multiple Gated Acquisition scan (MUGA). Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Change from Baseline was calculated as the Day 42 value minus the Baseline value.

End point type

Primary

End point timeframe

Baseline and Day 42 of the latest chemotherapy cycle (Up to 8 weeks)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No Statistical analysis was performed for this endpoint.

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	71
Units: LVEF percent
arithmetic mean (standard deviation)
change from baseline to end of study (n = 57, 62)\|	-2.5 ± 7.81	-4.3 ± 8.54
baseline to worse post-baseline case (n =58,63)\|	-4.1 ± 8.61	-5.7 ± 9.05

No statistical analyses for this end point

Primary: Number of participants with worst-case grade changes from Baseline in the hematology parameters

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End point title

Number of participants with worst-case grade changes from Baseline in the hematology parameters ^[3]

End point description

The number of participants with a maximum post-baseline grade increase of Grade 3 (G3) or Grade 4 (G4) from their baseline grade are presented. Hematology parameters included only lab tests that are gradable by Common Terminology Criteria for Adverse Events (CTCAE) v4.0.

End point type

Primary

End point timeframe

Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No Statistical analysis was performed for this endpoint.

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	71
Units: Participants
Hemoglobin Low, G3\|	53	46
Leukocytes, G3\|	10	10
Leukocytes, G4\|	9	5
Lymphocytes Low, G3\|	31	26
Lymphocytes Low, G4\|	35	38
Neutrophils, G4\|	44	39
Platelets, G3\|	1	0
Platelets, G4\|	63	56

No statistical analyses for this end point

Primary: Number of participants with worst-case grade changes from Baseline in the clinical chemistry parameters

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End point title

Number of participants with worst-case grade changes from Baseline in the clinical chemistry parameters ^[4]

End point description

The number of participants with a maximum post-baseline grade increase of Grade 3 or Grade 4 from their baseline grade are presented. Clinical Clinical Chemistry parameters included only lab tests that are gradable by CTCAE v4.0.

End point type

Primary

End point timeframe

Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No Statistical analysis was performed for this endpoint.

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	71
Units: Participants
Alanine Aminotransferase, G3\|	1	5
Albumin, G3\|	6	4
Aspartate Aminotransferase, G3\|	0	1
Bilirubin, G3\|	1	4
Bilirubin, G4\|	0	1
Calcium Low, G3\|	0	1
Creatinine, G3\|	0	1
Creatinine, G4\|	1	0
Glucose High, G3\|	6	3
Glucose High, G4\|	0	1
Magnesium Low, G3\|	0	1
Magnesium High, G3\|	3	0
Phosphate, G3\|	10	19
Phosphate, G4\|	1	0
Potassium Low, G3\|	8	10
Potassium Low, G4\|	0	2
Potassium High, G3\|	4	0
Potassium High, G4\|	1	1
Sodium Low, G3\|	3	4
Urate, G4\|	3	0

No statistical analyses for this end point

Primary: Number of participants with liver events.

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End point title

Number of participants with liver events. ^[5]

End point description

The number of participants with liver enzyme (ALT, AST, ALP, Total bilirubin) abnormalities while receiving study treatment in each arm are presented.

End point type

Primary

End point timeframe

8 weeks

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No Statistical analysis was performed for this endpoint.

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	71
Units: Participants	2	6

No statistical analyses for this end point

Primary: Number of participants with worst-case changes from Baseline in electrocardiogram (ECG) values

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End point title

Number of participants with worst-case changes from Baseline in electrocardiogram (ECG) values ^[6]

End point description

The number of participants with worst case post-baseline changes (normal, abnormal - not clinically significant [NCS], abnormal - clinically significant [NS]) in ECG QT prolonged values are presented. The protocol does not define the criteria for normal, abnormal-NCS and abnormal CS ECG. The outcome was based solely on the investigator interpretation of ECG tracings.

End point type

Primary

End point timeframe

Baseline and Day 42 of the latest chemotherapy cycle (Up to 8 weeks)

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No Statistical analysis was performed for this endpoint.

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74 ^[7]	71 ^[8]
Units: Participants
Normal	34	33
Abnormal - NCS	23	29
Abnormal - CS	2	1

Notes
[7] - (n = 59, 63)
[8] - (n = 59, 63)

No statistical analyses for this end point

Primary: Number of participants with worst-case changes from Baseline in the Eastern Cooperative Oncology Group (ECOG) performance status

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End point title

Number of participants with worst-case changes from Baseline in the Eastern Cooperative Oncology Group (ECOG) performance status ^[9]

End point description

The number of participants with worst case post-baseline changes (improved, no change, deteriorated) are presented.

End point type

Primary

End point timeframe

Baseline and Day 42 of the latest chemotherapy cycle (Up to 8 weeks)

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No Statistical analysis was performed for this endpoint.

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	73	71
Units: Participants
Deteriorated\|	36	36
Improved\|	0	1
No Change\|	37	34

No statistical analyses for this end point

Primary: Worst-case change from Baseline in pulse rate values

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End point title

Worst-case change from Baseline in pulse rate values ^[10]

End point description

The worst-case post Baseline high and low changes in pulse rate values from Baseline are presented. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Post Baseline is defined as the highest and lowest non-missing post Baseline value respectively. Change from Baseline was calculated as the post Baseline value minus the Baseline value.

End point type

Primary

End point timeframe

Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)

Notes
[10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No Statistical analysis was performed for this endpoint.

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	71
Units: Beats/minute
arithmetic mean (standard deviation)
High, n=66, 67\|	18.48 ± 20.616	17.73 ± 15.112
Low, n=61, 55\|	-10.36 ± 14.039	-11.24 ± 12.123

No statistical analyses for this end point

Primary: Worst-case post Baseline change in blood pressure values from Baseline

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End point title

Worst-case post Baseline change in blood pressure values from Baseline ^[11]

End point description

The worst-case post Baseline high changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) values from Baseline are presented. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Change from Baseline was calculated as the visit value minus the Baseline value.

End point type

Primary

End point timeframe

Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No Statistical analysis was performed for this endpoint.

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	71
Units: millimeter of mercury (mmHg)
arithmetic mean (standard deviation)
SBP\|	14.59 ± 17.936	14.34 ± 14.626
DBP\|	9.38 ± 12.000	12.61 ± 10.947

No statistical analyses for this end point

Primary: Worst-case post Baseline change in temperature values from Baseline

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End point title

Worst-case post Baseline change in temperature values from Baseline ^[12]

End point description

The worst-case post Baseline high and low changes in temperature values from Baseline are presented. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Post Baseline was defined as the highest and lowest non-missing post Baseline value respectively. Change from Baseline was calculated as the post Baseline value minus the Baseline value.

End point type

Primary

End point timeframe

Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)

Notes
[12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No Statistical analysis was performed for this endpoint.

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	71
Units: Degrees Celsius
arithmetic mean (standard deviation)
High, n=70, 69\|	0.62 ± 0.941	0.77 ± 0.879
Low, n=47, 43\|	-0.44 ± 0.628	-0.63 ± 0.592

No statistical analyses for this end point

Secondary: Plasma pharmacokinetics (PK) parameter of daunorubicin: half-life (t1/2)

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End point title

Plasma pharmacokinetics (PK) parameter of daunorubicin: half-life (t1/2)

End point description

Daunorubicin half-life. PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.

End point type

Secondary

End point timeframe

Cycle 1 Day 3

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	72
Units: hour (h)
geometric mean (confidence interval 95%)	15.754 (13.969 to 17.766)	13.709 (12.103 to 15.527)

Daunorubicin: t1/2 comparison

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

^[13]

Method

Parameter type

Ratio of geometric means

Point estimate

114.9

Confidence interval

level

90%

sides

2-sided

lower limit

99.5

upper limit

132.7

Notes
[13] - Bioequivalence

Secondary: Plasma pharmacokinetics (PK) parameter of daunorubicinol: half-life (t1/2)

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End point title

Plasma pharmacokinetics (PK) parameter of daunorubicinol: half-life (t1/2)

End point description

Daunorubicinol half-life. PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.

End point type

Secondary

End point timeframe

Cycle 1 Day 3

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	72
Units: hour (h)
geometric mean (confidence interval 95%)	22.735 (21.187 to 24.396)	21.603 (20.232 to 23.067)

Daunorubicinol: t1/2 comparison

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

^[14]

Method

Parameter type

Ratio of geometric means

Point estimate

105.2

Confidence interval

level

90%

sides

2-sided

lower limit

97.1

upper limit

114

Notes
[14] - Bioequivalence

Secondary: Daunorubicin dose-normalized plasma: AUC(0-∞)

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End point title

Daunorubicin dose-normalized plasma: AUC(0-∞)

End point description

Daunorubicin AUC(0-∞). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.

End point type

Secondary

End point timeframe

Cycle 1 Day 3

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	72
Units: (h*ug/ml)/(mg/m2)
geometric mean (confidence interval 95%)	8.0807 (7.0672 to 9.2396)	8.7880 (7.3893 to 10.451)

Daunorubicin: AUC(0-∞) comparison

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

^[15]

Method

Parameter type

Ratio of geometric means

Point estimate

Confidence interval

level

90%

sides

2-sided

lower limit

76.8

upper limit

110.2

Notes
[15] - Bioequivalence

Secondary: Daunorubicinol dose-normalized plasma: AUC(0-∞)

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End point title

Daunorubicinol dose-normalized plasma: AUC(0-∞)

End point description

Daunorubicinol AUC(0-∞). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.

End point type

Secondary

End point timeframe

Cycle 1 Day 3

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	72
Units: (h*ug/ml)/(mg/m2)
geometric mean (confidence interval 95%)	63.997 (58.686 to 69.746)	62.835 (58.673 to 67.292)

Daunorubicinol: AUC(0-∞) comparison

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

^[16]

Method

Parameter type

Ratio of geometric means

Point estimate

101.8

Confidence interval

level

90%

sides

2-sided

lower limit

92.9

upper limit

111.7

Notes
[16] - Bioequivalence

Secondary: Daunorubicin dose-normalized plasma: AUC(24-∞)

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End point title

Daunorubicin dose-normalized plasma: AUC(24-∞)

End point description

Daunorubicin AUC(24-∞). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.

End point type

Secondary

End point timeframe

Cycle 1 Day 3

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	72
Units: (h*ug/ml)/(mg/m2)
geometric mean (confidence interval 95%)	0.87496 (0.76202 to 1.0046)	0.72315 (0.62633 to 0.83493)

Daunorubicin AUC(24-∞) comparison

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

^[17]

Method

Parameter type

Ratio of geometric means

Point estimate

121

Confidence interval

level

90%

sides

2-sided

lower limit

102.5

upper limit

142.8

Notes
[17] - Bioequivalence

Secondary: Daunorubicinol dose-normalized plasma: AUC(24-∞)

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End point title

Daunorubicinol dose-normalized plasma: AUC(24-∞)

End point description

Daunorubicinol AUC(24-∞). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.

End point type

Secondary

End point timeframe

Cycle 1 Day 3

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	72
Units: (h*ug/ml)/(mg/m2)
geometric mean (confidence interval 95%)	24.537 (22.052 to 27.301)	23.039 (21.169 to 25.074)

Daunorubicinol AUC(24-∞) comparison

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

^[18]

Method

Parameter type

Ratio of geometric means

Point estimate

106.5

Confidence interval

level

90%

sides

2-sided

lower limit

upper limit

119.4

Notes
[18] - Bioequivalence

Secondary: Daunorubicin dose-normalized plasma: AUC(0-t)

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End point title

Daunorubicin dose-normalized plasma: AUC(0-t)

End point description

Daunorubicin AUC(0-t). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.

End point type

Secondary

End point timeframe

Cycle 1 Day 3

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	72
Units: (h*ug/ml)/(mg/m2)
geometric mean (confidence interval 95%)	7.9523 (6.9485 to 9.1012)	8.6723 (7.2855 to 10.323)

Daunorubicin AUC(0-t) comparison

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

^[19]

Method

Parameter type

Ratio of geometric means

Point estimate

91.7

Confidence interval

level

90%

sides

2-sided

lower limit

76.5

upper limit

110

Notes
[19] - Bioequivalence

Secondary: Daunorubicinol dose-normalized plasma: AUC(0-t)

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End point title

Daunorubicinol dose-normalized plasma: AUC(0-t)

End point description

daunorubicinol AUC(0-t). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.

End point type

Secondary

End point timeframe

Cycle 1 Day 3

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	72
Units: (h*ug/ml)/(mg/m2)
geometric mean (confidence interval 95%)	62.463 (57.268 to 68.129)	61.608 (57.500 to 66.009)

Daunorubicinol AUC(0-t) comparison

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

^[20]

Method

Parameter type

Ratio of geometric means

Point estimate

101.4

Confidence interval

level

90%

sides

2-sided

lower limit

92.4

upper limit

111.2

Notes
[20] - Bioequivalence

Secondary: Daunorubicin dose-normalized plasma: AUC(24-t)

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End point title

Daunorubicin dose-normalized plasma: AUC(24-t)

End point description

Daunorubicin AUC(24-t). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.

End point type

Secondary

End point timeframe

Cycle 1 Day 3

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	72
Units: (h*ug/ml)/(mg/m2)
geometric mean (confidence interval 95%)	0.76524 (0.65947 to 0.88797)	0.59660 (0.48882 to 0.72813)

Daunorubicin AUC(24-t) comparison

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

^[21]

Method

Parameter type

Ratio of geometric means

Point estimate

120

Confidence interval

level

90%

sides

2-sided

lower limit

100.7

upper limit

142.6

Notes
[21] - Bioequivalence

Secondary: Daunorubicinol dose-normalized plasma: AUC(24-t)

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End point title

Daunorubicinol dose-normalized plasma: AUC(24-t)

End point description

Daunorubicinol AUC(24-t). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.

End point type

Secondary

End point timeframe

Cycle 1 Day 3

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	72
Units: (h*ug/ml)/(mg/m2)
geometric mean (confidence interval 90%)	22.963 (20.557 to 25.651)	21.821 (20.020 to 23.783)

Daunorubicinol AUC(24-t) comparison

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

^[22]

Method

Parameter type

Ratio of geometric means

Point estimate

105.2

Confidence interval

level

90%

sides

2-sided

lower limit

93.6

upper limit

118.3

Notes
[22] - Bioequivalence

Secondary: Daunorubicin dose-normalized plasma: Cmax

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End point title

Daunorubicin dose-normalized plasma: Cmax

End point description

Daunorubicin Cmax. PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.

End point type

Secondary

End point timeframe

Cycle 1 Day 3

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	72
Units: (ug/ml)/(mg/m2)
geometric mean (confidence interval 95%)	5.1527 (3.9561 to 6.7114)	6.4113 (4.6773 to 8.7882)

Daunorubicin: Cmax Cycle 1 comparison

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

^[23]

Method

Parameter type

Ratio of geometric means

Point estimate

80.4

Confidence interval

level

90%

sides

2-sided

lower limit

57.2

upper limit

113

Notes
[23] - Bioequivalence

Secondary: Daunorubicinol dose-normalized plasma: Cmax

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End point title

Daunorubicinol dose-normalized plasma: Cmax

End point description

Daunorubicinol Cmax. PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.

End point type

Secondary

End point timeframe

Cycle 1 Day 3

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	72
Units: (ug/ml)/(mg/m2)
geometric mean (confidence interval 95%)	3.5770 (3.0433 to 4.2044)	3.3640 (2.8433 to 3.9799)

Daunorubicinol: Cmax Cycle 1 comparison

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

^[24]

Method

Parameter type

Ratio of geometric means

Point estimate

106.3

Confidence interval

level

90%

sides

2-sided

lower limit

87.6

upper limit

129

Notes
[24] - Bioequivalence

Secondary: Cycle 2: Daunorubicin dose-normalized plasma: AUC(0-24)

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End point title

Cycle 2: Daunorubicin dose-normalized plasma: AUC(0-24)

End point description

Cycle 2 Daunorubicin AUC(0-24). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.

End point type

Secondary

End point timeframe

Cycle 2 Day 1

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	10	12
Units: (h*ug/ml)/(mg/m2)
geometric mean (confidence interval 95%)	10.315 (6.7932 to 15.662)	8.1146 (6.0221 to 10.934)

Daunorubicin: AUC(0-24) Cycle 2 comparison

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[25]

Method

Parameter type

Ratio of geometric means

Point estimate

127.1

Confidence interval

level

90%

sides

2-sided

lower limit

84.2

upper limit

191.9

Notes
[25] - Bioequivalence

Secondary: Cycle 2: Daunorubicinol dose-normalized plasma: AUC(0-24)

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End point title

Cycle 2: Daunorubicinol dose-normalized plasma: AUC(0-24)

End point description

Cycle 2 Daunorubicinol AUC(0-24). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.

End point type

Secondary

End point timeframe

Cycle 2 Day 1

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	10	12
Units: (h*ug/ml)/(mg/m2)
geometric mean (confidence interval 95%)	34.067 (26.479 to 43.829)	30.820 (24.148 to 39.335)

Daunorubicinol: AUC(0-24) Cycle 2 comparison

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[26]

Method

Parameter type

Ratio of geometric means

Point estimate

110.5

Confidence interval

level

90%

sides

2-sided

lower limit

83.9

upper limit

145.7

Notes
[26] - Bioequivalence

Secondary: Cycle 2: Daunorubicin dose-normalized plasma: Cmax

Top of page

End point title

Cycle 2: Daunorubicin dose-normalized plasma: Cmax

End point description

Cycle 2 Daunorubicin Cmax. PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.

End point type

Secondary

End point timeframe

Cycle 2 Day 1

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	10	12
Units: (ug/ml)/(mg/m2)
geometric mean (confidence interval 95%)	11.141 (4.3653 to 28.432)	3.8905 (1.2805 to 11.820)

Daunorubicin: Cmax Cycle 2 comparison

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[27]

Method

Parameter type

Ratio of geometric means

Point estimate

286.4

Confidence interval

level

90%

sides

2-sided

lower limit

90.1

upper limit

910.7

Notes
[27] - Bioequivalence

Secondary: Cycle 2: Daunorubicinol dose-normalized plasma: Cmax

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End point title

Cycle 2: Daunorubicinol dose-normalized plasma: Cmax

End point description

Cycle 2 Daunorubicinol Cmax. PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.

End point type

Secondary

End point timeframe

Cycle 2 Day 1

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	10	12
Units: (ug/ml)/(mg/m2)
geometric mean (confidence interval 95%)	4.0200 (2.5302 to 6.3870)	1.9868 (1.4247 to 2.7708)

Daunorubicinol: Cmax Cycle 2 comparison

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[28]

Method

Parameter type

Ratio of geometric means

Point estimate

202.3

Confidence interval

level

90%

sides

2-sided

lower limit

131.3

upper limit

311.8

Notes
[28] - Bioequivalence

Secondary: Number of platelet transfusions per week within cycles

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End point title

Number of platelet transfusions per week within cycles

End point description

This was the average number of platelet transfusions per week within cycles.

End point type

Secondary

End point timeframe

Post-Base line up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	74
Units: Participants
median (standard deviation)	1.5 ± 1.18	1.4 ± 1.22

No statistical analyses for this end point

Secondary: Time to platelet counts recovery >=20 Gi/L

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End point title

Time to platelet counts recovery >=20 Gi/L

End point description

Time to platelet counts 20 Gi/L for 3 consecutive days, unaided by transfusions, in patients with < 20 Gi/L after chemotherapy.

End point type

Secondary

End point timeframe

From last dose of chemotherapy to up to end of study year 2 assessment

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	70	68
Units: Participants	6	7

Time to platelet counts 20 Gi/L analysis

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

138

Analysis specification

Pre-specified

Analysis type

P-value

= 0.7461

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.84

Confidence interval

level

95%

sides

2-sided

lower limit

0.28

upper limit

2.48

Secondary: Time to platelet counts recovery >=100 Gi/L

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End point title

Time to platelet counts recovery >=100 Gi/L

End point description

Time to platelet counts 100 Gi/L, unaided by transfusions, in patients with < 100 Gi/L after chemotherapy.

End point type

Secondary

End point timeframe

From last dose of chemotherapy to up to end of study year 2 assessment

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	73
Units: Participants	48	51

Time to platelet counts 100 Gi/L analysis

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

P-value

= 0.6175

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.74

upper limit

1.63

Secondary: Number of participants who achieved platelet count recovery by Day 21

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End point title

Number of participants who achieved platelet count recovery by Day 21

End point description

Number of participants with platelet counts 20 Gi/L for 3 consecutive days, unaided by transfusions, in patients with < 20 Gi/L after chemotherapy.

End point type

Secondary

End point timeframe

By Day 21

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	70	68
Units: Count of participants	4	7

Platelet count recovery by 21 days analysis

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

138

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3224

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.5281

Confidence interval

level

95%

sides

2-sided

lower limit

0.1084

upper limit

2.2086

Secondary: Summary of platelet counts over time

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End point title

Summary of platelet counts over time

End point description

Platelet counts over time

End point type

Secondary

End point timeframe

Baseline, daily then weekly within cycle up to 42 days after last chemotherapy dose, end of therapy /remission assessment visit

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	74
Units: Gi/L
median (full range (min-max))
Baseline (n = 74, 74)\|	51.5 (5 to 241)	50.0 (9 to 232)
C1D1 (n = 59, 66)\|	52.0 (5 to 241)	48.5 (9 to 232)
C1D2 (n = 74, 74)\|	43.5 (4 to 237)	42.0 (5 to 368)
C1D3 (n = 72, 72)\|	35.5 (4 to 226)	37.0 (7 to 220)
C1D4 (n = 74, 69)\|	36.5 (3 to 227)	29.0 (5 to 146)
C1D5 (n = 73, 71)\|	33.0 (3 to 201)	29.0 (5 to 146)
C1D6 (n = 73, 69)\|	32.0 (4 to 164)	30.0 (6 to 125)
C1D7 (n = 73, 70)\|	27.0 (3 to 123)	27.0 (4 to 102)
C1D8 (n = 73, 69)\|	24.0 (2 to 99)	22.0 (4 to 80)
C1D9 (n= 72, 69)\|	20.5 (1 to 109)	19.0 (5 to 59)
C1D14 (n = 68, 68)\|	16.5 (0 to 70)	18.0 (1 to 81)
C1D21 (n = 51, 55)\|	39.0 (5 to 325)	25.0 (2 to 232)
C1D28 (n = 36, 29)\|	484.5 (14 to 1590)	121.0 (7 to 539)
C1D35 (n= 14, 14)\|	547.0 (15 to 1493)	181.0 (10 to 424)
C1D42 (n = 0, 1)\|	0 (0.0 to 0.0)	304.0 (304 to 304)
C2D1 (n =10, 12)\|	31.0 (12 to 1059)	30.5 (10 to 432)
C2D2 (n = 9, 12)\|	26.0 (3 to 831)	28.5 (8 to 400)
C2D3 (n = 10, 12)\|	25.5 (0 to 730)	29.0 (8 to 437)
C2D4 (n = 9, 12)\|	32.0 (2 to 678)	35.5 (11 to 454)
C2D5 (n= 10, 11)\|	37.0 (9 to 516)	22.0 (12 to 476)
C2D6 (n = 10, 12)\|	27.0 (4 to 430)	33.0 (7 to 533)
C2D7 (n = 7, 12)\|	24.0 (6 to 295)	28.5 (12 to 390)
C2D14 (n= 8, 11)\|	10.5 (3 to 31)	16.0 (6 to 66)
C2D21 (n = 8, 11)\|	27.0 (9 to 86)	38.0 (8 to 141)
C2D28 (n = 5, 6)\|	68.0 (48 to 333)	173.0 (32 to 479)
C2D35 (n = 2, 3)\|	515.0 (412 to 618)	272.0 (26 to 329)
C1D42 (n = 0, 2)\|	0 (0.0 to 0.0)	147.5 (45 to 250)

No statistical analyses for this end point

Secondary: Maximum duration (days) of platelet transfusion independence

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End point title

Maximum duration (days) of platelet transfusion independence

End point description

Maximum time period (in days) during which the patient did not receive any platelet transfusion

End point type

Secondary

End point timeframe

At differnt time points from start of treatment and up to end of study year 2 assessment

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	74
Units: Days
median (full range (min-max))	29.0 (2 to 57)	29.5 (2 to 77)

Platelet transfusion independence analyis

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

148

Analysis specification

Pre-specified

Analysis type

P-value

= 0.6942

Method

Wilcoxon rank-sum test

Confidence interval

Secondary: Percentage of patients who achieved platelet transfusion independence ≥ 28 days

Top of page

End point title

Percentage of patients who achieved platelet transfusion independence ≥ 28 days

End point description

Percentage of patients who achieved platelet transfusion independence ≥ 28 days.

End point type

Secondary

End point timeframe

From start of treatment and up to end of study year 2 assessment

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	74
Units: Percentage of participants	55	53

Platelet transfusion independence ≥ 28 days

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

148

Analysis specification

Pre-specified

Analysis type

P-value

= 0.7397

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.1151

Confidence interval

level

95%

sides

2-sided

lower limit

0.5585

upper limit

2.229

Secondary: Time to neutrophil engraftment based on number of events

Top of page

End point title

Time to neutrophil engraftment based on number of events

End point description

Time to ANC Gi/L for 3 consecutive days in patients with ANC < 0.5 Gi/L after chemotherapy

End point type

Secondary

End point timeframe

At different time points from last dose of chemotherapy up to end of study year 2 assessment

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	73
Units: Participants	12	5

Neutrofil engraftment analysis

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0781

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

2.46

Confidence interval

level

95%

sides

2-sided

lower limit

0.95

upper limit

6.38

Secondary: Summary of absolute neutrophil counts (ANC)

Top of page

End point title

Summary of absolute neutrophil counts (ANC)

End point description

Absolute neutrophil counts over time

End point type

Secondary

End point timeframe

Baseline, daily then weekly within cycle up to 42 days after last chemotherapy dose, end of therapy /remission assessment visit

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	7	8
Units: Gi/L
median (full range (min-max))
Baseline (n = 71, 72)\|	0.8 (0 to 37)	0.5 (0 to 50)
C1D1 (n = 55, 63)\|	0.8 (0 to 37)	0.6 (0 to 50)
C1D2 (n= 70, 72)\|	0.6 (0 to 41)	0.5 (0 to 41)
C1D3 (n = 66, 70)\|	0.6 (0 to 59)	0.4 (0 to 26)
C1D4 (n = 70, 64)\|	0.4 (0 to 35)	0.2 (0 to 17)
C1D5 (n = 70, 63)\|	0.3 (0 to 21)	0.2 (0 to 2)
C1D6 (n = 68, 63)\|	0.2 (0 to 35)	0.1 (0 to 1)
C1D7 (n = 69, 62)\|	0.1 (0 to 29)	0.1 (0 to 1)
C1D8 (n = 66, 58)\|	0.1 (0 to 21)	0.0 (0 to 1)
C1D9 (n = 66, 59)\|	0.0 (0 to 7)	0.0 (0 to 1)
C1D14 (n = 61, 56)\|	0.0 (0 to 1)	0.0 (0 to 0)
C1D21 (n = 52, 51)\|	0.6 (0 to 18)	0.3 (0 to 7)
C1D28 (n= 37, 29)\|	4.3 (0 to 47)	2.7 (0 to 25)
C1D35 (n = 14, 14)\|	2.2 (0 to 56)	1.7 (0 to 12)
C1D42 (n= 0, 1)\|	0.0 (0 to 0.0)	3.1 (3.1 to 3.1)
C2D1 (n = 10, 9)\|	0.1 (0 to 7)	0.0 (0 to 5)
C2D2 (n = 10, 9)\|	0.1 (0 to 3)	0.2 (0 to 4)
C2D3 (n = 9, 8)\|	0.2 (0 to 5)	0.5 (0 to 4)
C2D4 (n = 9, 9)\|	0.3 (0 to 3)	0.5 (0 to 2)
C2D5 (n = 10, 10)\|	0.2 (0 to 2)	0.1 (0 to 3)
C2D6 (n = 10, 10)\|	0.1 (0 to 1)	0.1 (0 to 3)
C2D7 (n= 9, 8)\|	0.0 (0 to 1)	0.1 (0 to 2)
C2D14 (n = 7, 8)\|	0.0 (0 to 0)	0.0 (0 to 0)

No statistical analyses for this end point

Secondary: Summary of hemoglobin

Top of page

End point title

Summary of hemoglobin

End point description

Hemoglobin level over time

End point type

Secondary

End point timeframe

Baseline, daily then weekly within cycle up to 42 days after last chemotherapy dose, end of therapy /remission assessment visit

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	74
Units: g/L
median (full range (min-max))
Baseline (n= 74, 74)\|	87.6 (63 to 123)	87.0 (67 to 121)
C1D1 (n= 60, 66)\|	88.0 (67 to 123)	86.0 (67 to 121)
C1D2 (n = 74, 74)\|	88.0 (58 to 124)	83.0 (62 to 130)
C1D3 (n = 74, 72)\|	86.0 (52 to 108)	82.0 (59 to 130)
C1D4 (n = 74, 70)\|	83.0 (60 to 105)	81.5 (46 to 120)
C1D5 (n = 74, 71)\|	84.0 (60 to 114)	83.0 (50 to 126)
C1D6 (n = 74, 70)\|	86.0 (67 to 118)	82.0 (52 to 119)
C1D7 (n = 74, 71)\|	85.0 (58 to 116)	83.0 (57 to 110)
C1D8 (n = 74, 70)\|	85.3 (65 to 118)	84.0 (57 to 108)
C1D9 (n = 74, 70)\|	84.5 (64 to 114)	81.5 (62 to 109)
C1D14 (n = 68, 68)\|	85.0 (60 to 123)	84.0 (59 to 109)
C1D21 (n = 52, 55)\|	88.0 (77 to 117)	88.0 (72 to 116)
C1D28 (n = 37, 29)\|	99.0 (78 to 138)	98.0 (79 to 125)
C1D35 (n = 14, 14)\|	99.0 (81 to 131)	94.0 (74 to 130)
C1D42 (n = 0, 1)\|	0 (0.0 to 0.0)	98.0 (98 to 98)
C2D1 (n = 10, 12)\|	94.5 (76 to 124)	82.5 (72 to 111)
C2D2 (n = 10, 12)\|	88.5 (72 to 112)	86.5 (69 to 104)
C2D3 (n = 10, 12)\|	86.5 (65 to 110)	80.0 (68 to 97)
C2D4 (n = 10, 12)\|	89.0 (72 to 106)	86.5 (74 to 109)
C2D5 (n = 10, 12)\|	88.0 (67 to 101)	84.0 (72 to 93)
C2D6 (n = 10, 12)\|	84.0 (68 to 102)	85.0 (70 to 96)
C2D7 (n = 10, 12)\|	84.5 (66 to 99)	83.0 (57 to 97)
C2D14 (n = 11, 8)\|	77.5 (66 to 101)	87.0 (79 to 96)
C2D21 (n = 11, 8)\|	86.0 (43 to 99)	91.0 (74 to 110)
C2D28 (n = 7, 5)\|	89.0 (80 to 92)	80.0 (72 to 114)
C2D35 (n = 3, 2)\|	104.0 (101 to 107)	87.0 (85 to 119)
C2D42 (n = 0, 2)\|	0 (0.0 to 0.0)	90.5 (86 to 95)

No statistical analyses for this end point

Secondary: Incidence and severity of hemorrhagic events

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End point title

Incidence and severity of hemorrhagic events

End point description

Incidence of bleeding events using WHO bleeding grade (G0=No bleeding, G1=Petechiae, G2=Mild blood loss, G3=Gross blood loss, G4=Debilitating blood loss) by week and cycle

End point type

Secondary

End point timeframe

Baseline, weekly within induction and re-induction cycles, end of therapy

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	74
Units: Count of participants
C1D7 - GRADE 0 (n = 73, 69)\|	58	47
C1D7 - GRADE 1 (n = 73, 69)\|	9	16
C1D7 - GRADE 2 (n = 73, 69)\|	5	6
C1D7 - GRADE 3 (n = 73, 69)\|	1	0
C1D14 - GRADE 0 (n = 68, 65)\|	42	43
C1D14 - GRADE 1 (n = 68, 65)\|	16	13
C1D14 - GRADE 2 (n = 68, 65)\|	5	6
C1D14 - GRADE 3 (n = 68, 65)\|	1	0
C1D21 - GRADE 0 (n = 52, 52)\|	36	43
C1D21 - GRADE 1 (n = 52, 53)\|	13	7
C1D21 - GRADE 2 (n = 52, 52)\|	3	1
C1D21 - GRADE 3 (n = 52, 52)\|	0	1
C1D28 - GRADE 0 (n = 37, 28)\|	31	25
C1D28 - GRADE 1 (n = 37, 28)\|	4	3
C1D28 - GRADE 2 (n = 37, 28)\|	2	0
C1D28 - GRADE 3 (n = 37, 28)\|	0	0
C1D35 - GRADE 0 (n =14, 13)\|	12	11
C1D35 - GRADE 1 (n =14, 13)\|	2	2
C1D35 - GRADE 2 (n =14, 13)\|	0	0
C1D35 - GRADE 3 (n =14, 13)\|	0	0
C1D42 - GRADE 0 (n =0, 1)\|	0	0
C1D42 - GRADE 1 (n =0, 1)\|	0	1
C1D42 - GRADE 2 (n =0, 1)\|	0	0
C1D42 - GRADE 3 (n =0, 1)\|	0	0
C2D1 - GRADE 0 (n = 10, 12)\|	8	8
C2D1 - GRADE 1 (n = 10, 12)\|	1	4
C2D1 - GRADE 2 (n = 10, 12)\|	1	0
C2D1 - GRADE 3 (n = 10, 12)\|	0	0
C2D7 - GRADE 0 (n = 10, 11)\|	9	8
C2D7 - GRADE 1 (n = 10, 11)\|	0	3
C2D7 - GRADE 2 (n = 10, 11)\|	1	0
C2D7 - GRADE 3 (n = 10, 11)\|	0	0
C2D14 - GRADE 0 (n = 8, 10)\|	8	7
C2D14 - GRADE 1 (n = 8, 10)\|	0	3
C2D14 - GRADE 2 (n = 8, 10)\|	0	0
C2D14 - GRADE 3 (n = 8, 10)\|	0	0
C2D21 - GRADE 0 (n = 8, 9)\|	7	7
C2D21 - GRADE 1 (n = 8, 9)\|	1	2
C2D21 - GRADE 2 (n = 8, 9)\|	0	0
C2D21 - GRADE 3 (n = 8, 9)\|	0	0
C2D28 - GRADE 0 (n = 5, 8)\|	5	7
C2D28 - GRADE 1 (n = 5, 8)\|	0	1
C2D28 - GRADE 2 (n = 5, 8)\|	0	0
C2D28 - GRADE 3 (n = 5, 8)\|	0	0
C2D35 - GRADE 0 (n = 3 , 3)\|	3	2
C2D35 - GRADE 1 (n = 3 , 3)\|	0	1
C2D35 - GRADE 2 (n = 3 , 3)\|	0	0
C2D35 - GRADE 3 (n = 3 , 3)\|	0	0
C2D42 - GRADE 0 (n = 0 , 1)\|	0	0
C2D42 - GRADE 1 (n = 0 , 1)\|	0	1
C2D42 - GRADE 2 (n = 0 , 1)\|	0	0
C2D42 - GRADE 3 (n = 0 , 1)\|	0	0
Remission visit GRADE 0 (n = 62, 62)\|	56	58
Remission visit GRADE 1 (n = 62, 62)\|	2	4
Remission visit GRADE 2 (n = 62, 62)\|	3	0
Remission visit GRADE 3 (n = 62, 62)\|	1	0

No statistical analyses for this end point

Secondary: Percentage of participants with disease response rate and type of response

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End point title

Percentage of participants with disease response rate and type of response

End point description

Disease response as assessed by the investigator using the AML International Working Group Response Assessment at the end of therapy/remission assessment visit; Complete remission (CR): Partial remission (PR):

End point type

Secondary

End point timeframe

Day 42 of the latest chemotherapy cycle (Up to 8 weeks)

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	74
Units: Percentage of participants
Overall response\|	70	73
Complete Remission (CR)\|	65	70
Partial Remission (PR)\|	5	3

Disease response rate/type analysis

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

148

Analysis specification

Pre-specified

Analysis type

P-value

= 0.7122

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.8749

Confidence interval

level

95%

sides

2-sided

lower limit

0.4023

upper limit

1.8943

Secondary: Overall survival (OS)

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End point title

Overall survival (OS)

End point description

Overall survival defined as the time form randomization until the date of death due to any cause.

End point type

Secondary

End point timeframe

From randomization to end of 2-year follow-up

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	74
Units: Count of participants	39	30

Overall survival analysis

Comparison groups

Eltrombopag (ELQ) QD v Placebo QD

Number of subjects included in analysis

148

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0688

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.54

Confidence interval

level

95%

sides

2-sided

lower limit

0.96

upper limit

2.47

Secondary: Number of participants who required Medical resource utilization

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End point title

Number of participants who required Medical resource utilization

End point description

Medical Resource Utilization pertained to unscheduled hospitalizations, unscheduled office visits, unscheduled laboratory tests, and unscheduled procedures.

End point type

Secondary

End point timeframe

At screening and from start of treatment to end of therapy/remission assessment visit (Day 42 of the latest chemotherapy cycle)

End point values	Eltrombopag (ELQ) QD	Placebo QD
Number of subjects analysed	74	74
Units: Count of participants
In-patient hospitalizations/ admissions?\|	3	4
Diagnostic imaging procedures performed?\|	3	4
Health care resources use or emergency visits?\|	8	6
Out-patient lab tests performed?\|	6	6

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse Events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit 2 up to the end of study ye

Adverse event reporting additional description

Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Eltrombopag

Reporting group description

Eltrombopag

Reporting group title

Placebo

Reporting group description

Placebo

Serious adverse events	Eltrombopag	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	24 / 74 (32.43%)	14 / 71 (19.72%)
number of deaths (all causes)	11	4
number of deaths resulting from adverse events	1	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 74 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	1 / 74 (1.35%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ejection fraction decreased
subjects affected / exposed	0 / 74 (0.00%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Congenital, familial and genetic disorders
Hydrocele
subjects affected / exposed	1 / 74 (1.35%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	2 / 74 (2.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 74 (1.35%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 74 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiomyopathy
subjects affected / exposed	0 / 74 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Left ventricular dysfunction
subjects affected / exposed	1 / 74 (1.35%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 74 (1.35%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Nervous system disorders
Cerebral haemorrhage
subjects affected / exposed	1 / 74 (1.35%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cerebrovascular accident
subjects affected / exposed	1 / 74 (1.35%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cognitive disorder
subjects affected / exposed	1 / 74 (1.35%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	2 / 74 (2.70%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	1 / 74 (1.35%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Generalised oedema
subjects affected / exposed	0 / 74 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 74 (1.35%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 74 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 74 (1.35%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 74 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic colitis
subjects affected / exposed	0 / 74 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary alveolar haemorrhage
subjects affected / exposed	1 / 74 (1.35%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 74 (1.35%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary haemorrhage
subjects affected / exposed	1 / 74 (1.35%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Respiratory failure
subjects affected / exposed	1 / 74 (1.35%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	3 / 74 (4.05%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Renal failure
subjects affected / exposed	1 / 74 (1.35%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Acinetobacter bacteraemia
subjects affected / exposed	0 / 74 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 74 (1.35%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 74 (1.35%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Catheter site infection
subjects affected / exposed	0 / 74 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Klebsiella sepsis
subjects affected / exposed	1 / 74 (1.35%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	0 / 74 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Perirectal abscess
subjects affected / exposed	0 / 74 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 74 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Sepsis
subjects affected / exposed	1 / 74 (1.35%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 2
Septic shock
subjects affected / exposed	2 / 74 (2.70%)	2 / 71 (2.82%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 2	0 / 0
Systemic candida
subjects affected / exposed	1 / 74 (1.35%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypernatraemia
subjects affected / exposed	0 / 74 (0.00%)	1 / 71 (1.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pseudohyperkalaemia
subjects affected / exposed	1 / 74 (1.35%)	0 / 71 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Eltrombopag	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	71 / 74 (95.95%)	66 / 71 (92.96%)
Vascular disorders
Hypertension
subjects affected / exposed	6 / 74 (8.11%)	8 / 71 (11.27%)
occurrences all number	6	13
Hypotension
subjects affected / exposed	5 / 74 (6.76%)	6 / 71 (8.45%)
occurrences all number	6	6
General disorders and administration site conditions
Asthenia
subjects affected / exposed	13 / 74 (17.57%)	13 / 71 (18.31%)
occurrences all number	15	17
Catheter site haemorrhage
subjects affected / exposed	4 / 74 (5.41%)	1 / 71 (1.41%)
occurrences all number	5	1
Chest pain
subjects affected / exposed	0 / 74 (0.00%)	4 / 71 (5.63%)
occurrences all number	0	4
Chills
subjects affected / exposed	21 / 74 (28.38%)	14 / 71 (19.72%)
occurrences all number	24	23
Fatigue
subjects affected / exposed	10 / 74 (13.51%)	11 / 71 (15.49%)
occurrences all number	10	11
Mucosal inflammation
subjects affected / exposed	9 / 74 (12.16%)	9 / 71 (12.68%)
occurrences all number	10	11
Oedema
subjects affected / exposed	6 / 74 (8.11%)	6 / 71 (8.45%)
occurrences all number	6	6
Oedema peripheral
subjects affected / exposed	12 / 74 (16.22%)	13 / 71 (18.31%)
occurrences all number	14	15
Pain
subjects affected / exposed	3 / 74 (4.05%)	6 / 71 (8.45%)
occurrences all number	3	8
Pyrexia
subjects affected / exposed	25 / 74 (33.78%)	17 / 71 (23.94%)
occurrences all number	31	22
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	1 / 74 (1.35%)	5 / 71 (7.04%)
occurrences all number	1	6
Cough
subjects affected / exposed	18 / 74 (24.32%)	18 / 71 (25.35%)
occurrences all number	22	23
Dyspnoea
subjects affected / exposed	5 / 74 (6.76%)	11 / 71 (15.49%)
occurrences all number	5	12
Epistaxis
subjects affected / exposed	18 / 74 (24.32%)	14 / 71 (19.72%)
occurrences all number	23	20
Haemoptysis
subjects affected / exposed	7 / 74 (9.46%)	2 / 71 (2.82%)
occurrences all number	7	2
Hiccups
subjects affected / exposed	4 / 74 (5.41%)	4 / 71 (5.63%)
occurrences all number	5	6
Hypoxia
subjects affected / exposed	4 / 74 (5.41%)	2 / 71 (2.82%)
occurrences all number	4	3
Nasal dryness
subjects affected / exposed	3 / 74 (4.05%)	5 / 71 (7.04%)
occurrences all number	3	5
Oropharyngeal pain
subjects affected / exposed	13 / 74 (17.57%)	13 / 71 (18.31%)
occurrences all number	15	14
Pleural effusion
subjects affected / exposed	2 / 74 (2.70%)	5 / 71 (7.04%)
occurrences all number	2	6
Productive cough
subjects affected / exposed	8 / 74 (10.81%)	4 / 71 (5.63%)
occurrences all number	9	6
Rhinorrhoea
subjects affected / exposed	8 / 74 (10.81%)	8 / 71 (11.27%)
occurrences all number	10	8
Psychiatric disorders
Anxiety
subjects affected / exposed	10 / 74 (13.51%)	7 / 71 (9.86%)
occurrences all number	10	9
Insomnia
subjects affected / exposed	16 / 74 (21.62%)	23 / 71 (32.39%)
occurrences all number	19	26
Investigations
Alanine aminotransferase increased
subjects affected / exposed	8 / 74 (10.81%)	14 / 71 (19.72%)
occurrences all number	10	14
Aspartate aminotransferase increased
subjects affected / exposed	5 / 74 (6.76%)	8 / 71 (11.27%)
occurrences all number	5	10
Blood bilirubin increased
subjects affected / exposed	6 / 74 (8.11%)	8 / 71 (11.27%)
occurrences all number	6	8
Neutrophil count decreased
subjects affected / exposed	4 / 74 (5.41%)	1 / 71 (1.41%)
occurrences all number	4	1
Platelet count decreased
subjects affected / exposed	7 / 74 (9.46%)	4 / 71 (5.63%)
occurrences all number	8	4
Serum ferritin increased
subjects affected / exposed	6 / 74 (8.11%)	2 / 71 (2.82%)
occurrences all number	6	2
Weight increased
subjects affected / exposed	1 / 74 (1.35%)	5 / 71 (7.04%)
occurrences all number	1	5
White blood cell count decreased
subjects affected / exposed	9 / 74 (12.16%)	5 / 71 (7.04%)
occurrences all number	10	5
Injury, poisoning and procedural complications
Procedural pain
subjects affected / exposed	5 / 74 (6.76%)	5 / 71 (7.04%)
occurrences all number	5	6
Transfusion reaction
subjects affected / exposed	10 / 74 (13.51%)	8 / 71 (11.27%)
occurrences all number	13	16
Cardiac disorders
Sinus tachycardia
subjects affected / exposed	1 / 74 (1.35%)	4 / 71 (5.63%)
occurrences all number	1	5
Nervous system disorders
Dizziness
subjects affected / exposed	11 / 74 (14.86%)	8 / 71 (11.27%)
occurrences all number	12	8
Headache
subjects affected / exposed	19 / 74 (25.68%)	20 / 71 (28.17%)
occurrences all number	23	30
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	7 / 74 (9.46%)	7 / 71 (9.86%)
occurrences all number	11	7
Febrile neutropenia
subjects affected / exposed	38 / 74 (51.35%)	42 / 71 (59.15%)
occurrences all number	45	53
Neutropenia
subjects affected / exposed	5 / 74 (6.76%)	5 / 71 (7.04%)
occurrences all number	6	6
Thrombocytopenia
subjects affected / exposed	4 / 74 (5.41%)	4 / 71 (5.63%)
occurrences all number	5	7
Thrombocytosis
subjects affected / exposed	5 / 74 (6.76%)	0 / 71 (0.00%)
occurrences all number	5	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	2 / 74 (2.70%)	4 / 71 (5.63%)
occurrences all number	3	4
Abdominal distension
subjects affected / exposed	2 / 74 (2.70%)	6 / 71 (8.45%)
occurrences all number	4	6
Abdominal pain
subjects affected / exposed	18 / 74 (24.32%)	17 / 71 (23.94%)
occurrences all number	22	18
Abdominal pain lower
subjects affected / exposed	0 / 74 (0.00%)	4 / 71 (5.63%)
occurrences all number	0	4
Abdominal pain upper
subjects affected / exposed	3 / 74 (4.05%)	12 / 71 (16.90%)
occurrences all number	3	14
Constipation
subjects affected / exposed	28 / 74 (37.84%)	21 / 71 (29.58%)
occurrences all number	36	27
Diarrhoea
subjects affected / exposed	42 / 74 (56.76%)	43 / 71 (60.56%)
occurrences all number	54	55
Dry mouth
subjects affected / exposed	7 / 74 (9.46%)	2 / 71 (2.82%)
occurrences all number	8	3
Dyspepsia
subjects affected / exposed	10 / 74 (13.51%)	9 / 71 (12.68%)
occurrences all number	11	13
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 74 (2.70%)	4 / 71 (5.63%)
occurrences all number	2	4
Gingival bleeding
subjects affected / exposed	6 / 74 (8.11%)	4 / 71 (5.63%)
occurrences all number	6	4
Gingival pain
subjects affected / exposed	4 / 74 (5.41%)	3 / 71 (4.23%)
occurrences all number	4	3
Gingival swelling
subjects affected / exposed	3 / 74 (4.05%)	5 / 71 (7.04%)
occurrences all number	5	5
Haemorrhoids
subjects affected / exposed	10 / 74 (13.51%)	9 / 71 (12.68%)
occurrences all number	10	10
Lip dry
subjects affected / exposed	4 / 74 (5.41%)	1 / 71 (1.41%)
occurrences all number	4	1
Mouth haemorrhage
subjects affected / exposed	5 / 74 (6.76%)	0 / 71 (0.00%)
occurrences all number	6	0
Mouth ulceration
subjects affected / exposed	2 / 74 (2.70%)	4 / 71 (5.63%)
occurrences all number	2	4
Nausea
subjects affected / exposed	37 / 74 (50.00%)	46 / 71 (64.79%)
occurrences all number	59	68
Proctalgia
subjects affected / exposed	4 / 74 (5.41%)	10 / 71 (14.08%)
occurrences all number	4	10
Stomatitis
subjects affected / exposed	19 / 74 (25.68%)	18 / 71 (25.35%)
occurrences all number	24	25
Vomiting
subjects affected / exposed	27 / 74 (36.49%)	27 / 71 (38.03%)
occurrences all number	39	45
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	1 / 74 (1.35%)	4 / 71 (5.63%)
occurrences all number	1	4
Erythema
subjects affected / exposed	5 / 74 (6.76%)	5 / 71 (7.04%)
occurrences all number	5	5
Hyperhidrosis
subjects affected / exposed	5 / 74 (6.76%)	2 / 71 (2.82%)
occurrences all number	9	2
Petechiae
subjects affected / exposed	12 / 74 (16.22%)	10 / 71 (14.08%)
occurrences all number	14	12
Pruritus
subjects affected / exposed	8 / 74 (10.81%)	8 / 71 (11.27%)
occurrences all number	9	10
Rash
subjects affected / exposed	22 / 74 (29.73%)	13 / 71 (18.31%)
occurrences all number	28	16
Rash maculo-papular
subjects affected / exposed	8 / 74 (10.81%)	6 / 71 (8.45%)
occurrences all number	8	6
Urticaria
subjects affected / exposed	4 / 74 (5.41%)	4 / 71 (5.63%)
occurrences all number	6	5
Renal and urinary disorders
Haematuria
subjects affected / exposed	1 / 74 (1.35%)	4 / 71 (5.63%)
occurrences all number	1	4
Urinary hesitation
subjects affected / exposed	5 / 74 (6.76%)	1 / 71 (1.41%)
occurrences all number	5	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	6 / 74 (8.11%)	3 / 71 (4.23%)
occurrences all number	6	4
Back pain
subjects affected / exposed	4 / 74 (5.41%)	15 / 71 (21.13%)
occurrences all number	4	15
Musculoskeletal pain
subjects affected / exposed	4 / 74 (5.41%)	5 / 71 (7.04%)
occurrences all number	4	5
Pain in extremity
subjects affected / exposed	8 / 74 (10.81%)	8 / 71 (11.27%)
occurrences all number	8	8
Infections and infestations
Bacteraemia
subjects affected / exposed	4 / 74 (5.41%)	1 / 71 (1.41%)
occurrences all number	4	1
Cellulitis
subjects affected / exposed	0 / 74 (0.00%)	6 / 71 (8.45%)
occurrences all number	0	6
Device related infection
subjects affected / exposed	6 / 74 (8.11%)	9 / 71 (12.68%)
occurrences all number	6	10
Oral candidiasis
subjects affected / exposed	1 / 74 (1.35%)	6 / 71 (8.45%)
occurrences all number	1	7
Pneumonia
subjects affected / exposed	8 / 74 (10.81%)	3 / 71 (4.23%)
occurrences all number	9	3
Sepsis
subjects affected / exposed	5 / 74 (6.76%)	3 / 71 (4.23%)
occurrences all number	5	3
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	22 / 74 (29.73%)	27 / 71 (38.03%)
occurrences all number	28	39
Fluid imbalance
subjects affected / exposed	12 / 74 (16.22%)	10 / 71 (14.08%)
occurrences all number	18	13
Fluid overload
subjects affected / exposed	6 / 74 (8.11%)	5 / 71 (7.04%)
occurrences all number	7	6
Hyperkalaemia
subjects affected / exposed	4 / 74 (5.41%)	2 / 71 (2.82%)
occurrences all number	5	2
Hypoalbuminaemia
subjects affected / exposed	6 / 74 (8.11%)	2 / 71 (2.82%)
occurrences all number	7	4
Hypocalcaemia
subjects affected / exposed	7 / 74 (9.46%)	10 / 71 (14.08%)
occurrences all number	9	10
Hypokalaemia
subjects affected / exposed	20 / 74 (27.03%)	27 / 71 (38.03%)
occurrences all number	22	36
Hypomagnesaemia
subjects affected / exposed	8 / 74 (10.81%)	13 / 71 (18.31%)
occurrences all number	12	20
Hyponatraemia
subjects affected / exposed	4 / 74 (5.41%)	4 / 71 (5.63%)
occurrences all number	5	6
Hypophosphataemia
subjects affected / exposed	10 / 74 (13.51%)	14 / 71 (19.72%)
occurrences all number	13	24
Iron overload
subjects affected / exposed	6 / 74 (8.11%)	3 / 71 (4.23%)
occurrences all number	6	3

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Were there any global substantial amendments to the protocol? Yes

26 Aug 2013

Amendment No. 1 changes from the original protocol were: The addition of an investigational product stopping criterion;  Clarifications and corrections to existing language throughout.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A randomized, blinded, placebo-controlled, dose finding study to assess the safety and efficacy of the oral thrombopoietin receptor agonist, eltrombopag, administered to subjects with acute myelogenous leukemia (AML) receiving induction chemotherapy.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of participants with any adverse events (AE) and any serious adverse events (SAE) as a measure of safety and tolerability.

Primary: Number of participants with any adverse events (AE) and any serious adverse events (SAE) as a measure of safety and tolerability.

Primary: Change from baseline in the left ventricular ejection fraction (LVEF).

Primary: Change from baseline in the left ventricular ejection fraction (LVEF).

Primary: Number of participants with worst-case grade changes from Baseline in the hematology parameters

Primary: Number of participants with worst-case grade changes from Baseline in the hematology parameters

Primary: Number of participants with worst-case grade changes from Baseline in the clinical chemistry parameters

Primary: Number of participants with worst-case grade changes from Baseline in the clinical chemistry parameters

Primary: Number of participants with liver events.

Primary: Number of participants with liver events.

Primary: Number of participants with worst-case changes from Baseline in electrocardiogram (ECG) values

Primary: Number of participants with worst-case changes from Baseline in electrocardiogram (ECG) values

Primary: Number of participants with worst-case changes from Baseline in the Eastern Cooperative Oncology Group (ECOG) performance status

Primary: Number of participants with worst-case changes from Baseline in the Eastern Cooperative Oncology Group (ECOG) performance status

Primary: Worst-case change from Baseline in pulse rate values

Primary: Worst-case change from Baseline in pulse rate values

Primary: Worst-case post Baseline change in blood pressure values from Baseline

Primary: Worst-case post Baseline change in blood pressure values from Baseline

Primary: Worst-case post Baseline change in temperature values from Baseline

Primary: Worst-case post Baseline change in temperature values from Baseline

Secondary: Plasma pharmacokinetics (PK) parameter of daunorubicin: half-life (t1/2)

Secondary: Plasma pharmacokinetics (PK) parameter of daunorubicin: half-life (t1/2)

Secondary: Plasma pharmacokinetics (PK) parameter of daunorubicinol: half-life (t1/2)

Secondary: Plasma pharmacokinetics (PK) parameter of daunorubicinol: half-life (t1/2)

Secondary: Daunorubicin dose-normalized plasma: AUC(0-∞)

Secondary: Daunorubicin dose-normalized plasma: AUC(0-∞)

Secondary: Daunorubicinol dose-normalized plasma: AUC(0-∞)

Secondary: Daunorubicinol dose-normalized plasma: AUC(0-∞)

Secondary: Daunorubicin dose-normalized plasma: AUC(24-∞)

Secondary: Daunorubicin dose-normalized plasma: AUC(24-∞)

Secondary: Daunorubicinol dose-normalized plasma: AUC(24-∞)

Secondary: Daunorubicinol dose-normalized plasma: AUC(24-∞)

Secondary: Daunorubicin dose-normalized plasma: AUC(0-t)

Secondary: Daunorubicin dose-normalized plasma: AUC(0-t)

Secondary: Daunorubicinol dose-normalized plasma: AUC(0-t)

Secondary: Daunorubicinol dose-normalized plasma: AUC(0-t)

Secondary: Daunorubicin dose-normalized plasma: AUC(24-t)

Secondary: Daunorubicin dose-normalized plasma: AUC(24-t)

Secondary: Daunorubicinol dose-normalized plasma: AUC(24-t)

Secondary: Daunorubicinol dose-normalized plasma: AUC(24-t)

Secondary: Daunorubicin dose-normalized plasma: Cmax

Secondary: Daunorubicin dose-normalized plasma: Cmax

Secondary: Daunorubicinol dose-normalized plasma: Cmax

Secondary: Daunorubicinol dose-normalized plasma: Cmax

Secondary: Cycle 2: Daunorubicin dose-normalized plasma: AUC(0-24)

Secondary: Cycle 2: Daunorubicin dose-normalized plasma: AUC(0-24)

Secondary: Cycle 2: Daunorubicinol dose-normalized plasma: AUC(0-24)

Secondary: Cycle 2: Daunorubicinol dose-normalized plasma: AUC(0-24)

Secondary: Cycle 2: Daunorubicin dose-normalized plasma: Cmax

Secondary: Cycle 2: Daunorubicin dose-normalized plasma: Cmax

Secondary: Cycle 2: Daunorubicinol dose-normalized plasma: Cmax

Secondary: Cycle 2: Daunorubicinol dose-normalized plasma: Cmax

Secondary: Number of platelet transfusions per week within cycles

Secondary: Number of platelet transfusions per week within cycles

Secondary: Time to platelet counts recovery >=20 Gi/L

Secondary: Time to platelet counts recovery >=20 Gi/L

Secondary: Time to platelet counts recovery >=100 Gi/L

Secondary: Time to platelet counts recovery >=100 Gi/L

Secondary: Number of participants who achieved platelet count recovery by Day 21

Secondary: Number of participants who achieved platelet count recovery by Day 21

Secondary: Summary of platelet counts over time

Secondary: Summary of platelet counts over time

Secondary: Maximum duration (days) of platelet transfusion independence

Secondary: Maximum duration (days) of platelet transfusion independence

Secondary: Percentage of patients who achieved platelet transfusion independence ≥ 28 days

Secondary: Percentage of patients who achieved platelet transfusion independence ≥ 28 days

Secondary: Time to neutrophil engraftment based on number of events

Secondary: Time to neutrophil engraftment based on number of events

Secondary: Summary of absolute neutrophil counts (ANC)

Secondary: Summary of absolute neutrophil counts (ANC)

Clinical Trial Results:
A randomized, blinded, placebo-controlled, dose finding study to assess the safety and efficacy of the oral thrombopoietin receptor agonist, eltrombopag, administered to subjects with acute myelogenous leukemia (AML) receiving induction chemotherapy.