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Clinical Trial Results:
A phase II, open-label, non-controlled, intra-patient dose-escalation study to characterize the pharmacokinetics after oral administration of eltrombopag in pediatric patients with refractory, relapsed or treatment-naive severe aplastic anemia or recurrent aplastic anemia. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com for complete trial results.

Summary
EudraCT number	2015-003166-91
Trial protocol	GB PT NL
Global end of trial date	27 Jan 2025

Results information
Results version number	v2(current)
This version publication date	09 Aug 2025
First version publication date	11 Apr 2025
Other versions	v1
Version creation reason

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

CETB115E2201

ISRCTN number

US NCT number

NCT03025698

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma, AG

Sponsor organisation address

Lichtstrasse 35, Basel, Switzerland, 4056

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)

Yes

EMA paediatric investigation plan number(s)

EMEA-000170-PIP03-13

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

22 Apr 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

22 Apr 2022

Global end of trial reached?

Yes

Global end of trial date

27 Jan 2025

Was the trial ended prematurely?

Main objective of the trial

To characterize the PK of eltrombopag at the highest dose after oral administration in pediatric patients with SAA.

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

30 Sep 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 4

Country: Number of subjects enrolled

Hong Kong: 3

Country: Number of subjects enrolled

Portugal: 1

Country: Number of subjects enrolled

Russian Federation: 10

Country: Number of subjects enrolled

Thailand: 9

Country: Number of subjects enrolled

United States: 24

Worldwide total number of subjects

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Study was conducted in 19 sites in 6 countries

Screening details

Participants received 25 mg daily (ages 1–6) or 50 mg daily (ages 6–<18) for up to 6 years. Doses were adjusted biweekly based on platelet counts, up to 150 mg max. Study included a 26-week treatment, 52-week follow-up, and 3-year long-term follow-up.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort A: Regimen 1

Arm description

Participants received hATG (ATGAM®), CsA and eltrombopag beginning on Day 1.

Arm type

Experimental

Investigational medicinal product name

Eltrombopag

Investigational medicinal product code

ETB115

Other name

Pharmaceutical forms

Film-coated tablet, Powder for oral solution

Routes of administration

Other use , Oral use

Dosage and administration details

Dose strengths of 12.5 mg, 25 mg, 50 mg, and 75 mg for film-coated tablet and 25 mg powder for oral soution

Cohort A: Regimen 2

Arm description

Participants received CsA and eltrombopag beginning on Day 1.

Arm type

Experimental

Investigational medicinal product name

Eltrombopag

Investigational medicinal product code

ETB115

Other name

Pharmaceutical forms

Film-coated tablet, Powder for oral solution

Routes of administration

Other use , Oral use

Dosage and administration details

Dose strengths of 12.5 mg, 25 mg, 50 mg, and 75 mg for film-coated tablet and 25 mg powder for oral soution

Cohort B

Arm description

Participants who previously had untreated SAA received hATG, CsA and eltrombopag beginning on Day 1.

Arm type

Experimental

Investigational medicinal product name

Eltrombopag

Investigational medicinal product code

ETB115

Other name

Pharmaceutical forms

Film-coated tablet, Powder for oral solution

Routes of administration

Other use , Oral use

Dosage and administration details

Dose strengths of 12.5 mg, 25 mg, 50 mg, and 75 mg for film-coated tablet and 25 mg powder for oral soution

Number of subjects in period 1	Cohort A: Regimen 1	Cohort A: Regimen 2	Cohort B
Started	10	4	37
Subjs who entered 26-wk treatment phase	10	4	37
Completed 26-wk treatment	7	4	25
Entered 52-wk post-trtment f/u Ph 1	9	4	26
Did not enter 52-wk post-trtmnt f/u Ph	1 ^[1]	0 ^[2]	11
Entered 3-yr post-trtmnt f/u 2	6	3	19
Did not complete PTFU2	1 ^[3]	1 ^[4]	9 ^[5]
Completed	5	2	10
Not completed	5	2	27
Adverse event, serious fatal	-	1	-
Physician decision	3	-	8
Participant/Guardian Decision	2	1	11
Adverse event, non-fatal	-	-	2
Progressive Disease	-	-	3
Treatment done/study exit unclear	-	-	2
Lost to follow-up	-	-	1

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Data provided for clarification
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Data provided for clarification
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Data provided for clarification
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Data provided for clarification
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Data provided for clarification

Baseline characteristics

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Reporting group title

Cohort A: Regimen 1

Reporting group description

Participants received hATG (ATGAM®), CsA and eltrombopag beginning on Day 1.

Reporting group title

Cohort A: Regimen 2

Reporting group description

Participants received CsA and eltrombopag beginning on Day 1.

Reporting group title

Cohort B

Reporting group description

Participants who previously had untreated SAA received hATG, CsA and eltrombopag beginning on Day 1.

Reporting group values	Cohort A: Regimen 1	Cohort A: Regimen 2	Cohort B	Total
Number of subjects	10	4	37	51
Age categorical
Units: Subjects
Children (2-11 years)	5	3	22	30
Adolescents (12-17 years)	5	1	15	21
Age Continuous
Units: Years
median (full range (min-max))	12.0 (4.0 to 17.0)	10.0 (7.0 to 12.0)	10.0 (2.0 to 17.0)	-
Sex: Female, Male
Units: Participants
Female	5	1	17	23
Male	5	3	20	28
Race/Ethnicity, Customized
Units: Subjects
Caucasian	4	2	24	30
Black	2	1	4	7
Asian	3	1	9	13
Unknown	1	0	0	1

End points

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Reporting group title

Cohort A: Regimen 1

Reporting group description

Participants received hATG (ATGAM®), CsA and eltrombopag beginning on Day 1.

Reporting group title

Cohort A: Regimen 2

Reporting group description

Participants received CsA and eltrombopag beginning on Day 1.

Reporting group title

Cohort B

Reporting group description

Participants who previously had untreated SAA received hATG, CsA and eltrombopag beginning on Day 1.

Subject analysis set title

Cohort A: Regimen 1 (1 to <6 years)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received hATG (ATGAM®), CsA and eltrombopag beginning on Day 1.

Subject analysis set title

Cohort A: Regimen 1 (6 to <18 years)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received hATG (ATGAM®), CsA and eltrombopag beginning on Day 1.

Subject analysis set title

Cohort A: Regimen 2 (6 to <18 years)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received CsA and eltrombopag beginning on Day 1.

Subject analysis set title

Cohort B (1 to < 6 years)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Previously untreated SAA, hATG (ATGAM®), CsA and eltrombopag begin on Day 1 and all patients will be treated with the same regimen

Subject analysis set title

Cohort B (6 to <18 years)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants who previously had untreated SAA received hATG, CsA and eltrombopag beginning on Day 1.

Subject analysis set title

Cohort A: Regimen 1 ( 1 to <6 years)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received hATG (ATGAM®), CsA and eltrombopag beginning on Day 1.

Subject analysis set title

Cohort A: Regimen 1 (6 to <18 years)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received hATG (ATGAM®), CsA and eltrombopag beginning on Day 1.

Subject analysis set title

Cohort A: Regimen 2 (6 to <18 years)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received CsA and eltrombopag beginning on Day 1.

Subject analysis set title

Cohort B (6 to <18 years)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants who previously had untreated SAA received hATG, CsA and eltrombopag beginning on Day 1.

Subject analysis set title

Cohort A: Regimen 1

Subject analysis set type

Full analysis

Subject analysis set description

Participants received hATG (ATGAM®), CsA and eltrombopag beginning on Day 1.

Subject analysis set title

Cohort B (1 to <6 years)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Previously untreated SAA, hATG (ATGAM®), CsA and eltrombopag begin on Day 1 and all patients will be treated with the same regimen

Subject analysis set title

Cohort B (6 to <18 years)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Previously untreated SAA, hATG (ATGAM®), CsA and eltrombopag begin on Day 1 and all patients will be treated with the same regimen

Subject analysis set title

Cohort A: Regimen 1 (6 to <18 years)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received hATG (ATGAM®), CsA and eltrombopag beginning on Day 1.

Subject analysis set title

Cohort B (1 to <6 years)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Previously untreated SAA, hATG (ATGAM®), CsA and eltrombopag begin on Day 1 and all patients will be treated with the same regimen

Subject analysis set title

Cohort B (6 to <18 years)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Previously untreated SAA, hATG (ATGAM®), CsA and eltrombopag begin on Day 1 and all patients will be treated with the same regimen

Subject analysis set title

Cohort A: Regimen 2 (6 to <18 years)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received CsA and eltrombopag beginning on Day 1.

Subject analysis set title

Cohort B (6 to <18 years)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Previously untreated SAA, hATG (ATGAM®), CsA and eltrombopag begin on Day 1 and all patients will be treated with the same regimen

Subject analysis set title

Cohort A: Regimen 2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received CsA and eltrombopag beginning on Day 1

Subject analysis set title

Cohort A: Regimen 1

Subject analysis set type

Full analysis

Subject analysis set description

Participants received hATG (ATGAM®), CsA and eltrombopag beginning on Day 1.

Subject analysis set title

Total (Cohorts A (Regimen 1 & 2) and B

Subject analysis set type

Per protocol

Subject analysis set description

All participants in Cohort A Regimen 1, Cohort A Regimen 2 and B.

Primary: Eltrombopag PK parameters: AUCtau, AUClast

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End point title

Eltrombopag PK parameters: AUCtau, AUClast ^[1]

End point description

AUC tau: Area under the curve calculated to the end of the dosing interval ( tau) (mass*time/volume) AUC last: Area under the curve calculated to the last quantifiable concentration point (Tlast) (mass*time/volume)

End point type

Primary

End point timeframe

at least 11 weeks after dose initiation or later when patients are taking the highest dose, up to Week 78

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 analysis was done for this endpoint

End point values	Cohort A: Regimen 1 (1 to <6 years)	Cohort A: Regimen 1 (6 to <18 years)	Cohort A: Regimen 2 (6 to <18 years)	Cohort B (1 to < 6 years)	Cohort B (6 to <18 years)
Number of subjects analysed	1	7	3	8	19
Units: hr*ng/mL
geometric mean (geometric coefficient of variation)
AUCtau (n = 1, 4, 1, 6, 10)	272000 ( 999 )	285000 ( 72.4 )	406000 ( 999 )	502000 ( 65.6 )	275000 ( 52.6 )
AUClast (n = 1,5, 3, 8, 15)	272000 ( 999 )	300000 ( 60.2 )	166000 ( 196 )	477000 ( 52.5 )	259000 ( 75.1 )

No statistical analyses for this end point

Primary: Eltrombopag PK parameter: Cmax

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End point title

Eltrombopag PK parameter: Cmax ^[2]

End point description

Cmax is the observed maximum plasma concentration following administration (mass/volume)

End point type

Primary

End point timeframe

at least 11 weeks after dose initiation or later when patients are taking the highest dose, up to Week 78

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 analysis was done for this endpoint

End point values	Cohort B (1 to < 6 years)	Cohort A: Regimen 1 ( 1 to <6 years)	Cohort A: Regimen 1 (6 to <18 years)	Cohort A: Regimen 2 (6 to <18 years)	Cohort B (6 to <18 years)
Number of subjects analysed	8	1	5	2	15
Units: ng/mL
geometric mean (geometric coefficient of variation)	27100 ( 40.6 )	16100 ( 999 )	14500 ( 66.7 )	14300 ( 56.7 )	15600 ( 47.2 )

No statistical analyses for this end point

Primary: Eltrombopag PK parameter: Ctrough at the highest dose level

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End point title

Eltrombopag PK parameter: Ctrough at the highest dose level ^[3]

End point description

Ctrough is the pre-dose plasma concentration (mass/volume).

End point type

Primary

End point timeframe

at least 11 weeks after dose initiation or later when patients are taking the highest dose, up to Week 78

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 analysis was done for this endpoint

End point values	Cohort A: Regimen 1 (1 to <6 years)	Cohort B (1 to < 6 years)	Cohort A: Regimen 1 (6 to <18 years)	Cohort A: Regimen 2 (6 to <18 years)	Cohort B (6 to <18 years)
Number of subjects analysed	1	8	5	2	15
Units: ng/mL
geometric mean (geometric coefficient of variation)	5470 ( 999 )	13400 ( 113 )	9930 ( 68.7 )	9900 ( 32.3 )	9670 ( 64.5 )

No statistical analyses for this end point

Secondary: Percentage of participants with an overall response and percentage of participants with a platelet response

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End point title

Percentage of participants with an overall response and percentage of participants with a platelet response

End point description

Overall response rate (ORR) is defined as the percentage of participants who have achieved a complete response (CR) or partial response (PR) by the Investigator. CR criteria: Platelet (PLT) and red blood cell (RBC) transfusion independence, Normal age-adjusted Hgb, PLT >100 × 10^9/L and absolute neutrophil count (ANC) >1.5 × 10^9/L. PR: PLT and RBC Transfusion independence and at least 2 of the following criteria: Reticulocytes >30 × 10^9/L, PLT >30 × 10^9/L, ANC >1.5 x 10^9L. PLT transfusion independence is defined as a period for at least 28 days without PLT transfusion. Platelet response rate (PRR): Platelet response is comprised of CR + PR based on the following criteria: CR: PLT >100 × 10^9/L; PR: PLT >30 × 10^9/L

End point type

Secondary

End point timeframe

Week 12, Week 26, Week 52, Week 78

End point values	Cohort A: Regimen 1	Cohort A: Regimen 2	Cohort B
Number of subjects analysed	10	4	37
Units: Percentage of participants
number (confidence interval 95%)
ORR: Week 12	30.0 (6.7 to 65.2)	50.0 (6.8 to 93.2)	13.5 (4.5 to 28.8)
ORR: Week 26	70.0 (34.8 to 93.3)	75.0 (19.4 to 99.4)	45.9 (29.5 to 63.1)
ORR: Week 52	50.0 (18.7 to 81.3)	50.0 (6.8 to 93.2)	43.2 (27.1 to 60.5)
ORR: Week 78	50.0 (18.7 to 81.3)	75.0 (19.4 to 99.4)	40.5 (24.8 to 57.9)
PRR: Week 12	70.0 (34.8 to 93.3)	75.0 (19.4 to 99.4)	67.6 (50.2 to 82.0)
PRR: Week 26	60.0 (26.2 to 87.8)	100 (39.8 to 100.0)	70.3 (53.0 to 84.1)
PRR: Week 52	50.0 (18.7 to 81.3)	75.0 (19.4 to 99.4)	48.6 (31.9 to 65.6)
PRR: Week 78	50.0 (18.7 to 81.3)	75.0 (19.4 to 99.4)	45.9 (29.5 to 63.1)

No statistical analyses for this end point

Secondary: Hematologic counts (platelets (blood), neutrophils (blood))

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End point title

Hematologic counts (platelets (blood), neutrophils (blood))

End point description

Individual Platelets (PLT) and neutrophil counts were summarized for all participants.

End point type

Secondary

End point timeframe

Week 12, Week 26, Week 52, Week 78, Week 130, Week 182, Week 234

End point values	Cohort A: Regimen 1	Cohort A: Regimen 2	Cohort B
Number of subjects analysed	10	4	37
Units: x 10^9 cells/L
median (full range (min-max))
Week 12: Platelets (blood) (n = 10, 4, 35)	40.500 (5.00 to 260.00)	73.500 (17.00 to 172.00)	50.000 (3.00 to 338.00)
Week 26: Platelets (blood) (n = 10, 4, 31)	60.500 (3.00 to 222.00)	122.500 (49.00 to 182.00)	106.000 (3.00 to 230.00)
Week 52: Platelets (blood) (n = 7, 4, 19)	147.000 (7.00 to 164.00)	160.500 (22.00 to 240.00)	163.000 (28.00 to 318.00)
Week 78: Platelets (blood) (n = 6, 3, 18)	133.500 (6.00 to 308.00)	140.000 (88.00 to 273.00)	152.500 (28.00 to 278.00)
Week 130: Platelets (blood) (n = 6, 2, 9)	155.000 (43.00 to 195.00)	138.500 (128.00 to 149.00)	139.000 (31.00 to 245.00)
Week 182: Platelets (blood) (n = 6, 2, 5)	173.000 (9.00 to 221.00)	149.000 (127.00 to 171.00)	182.000 (104.00 to 223.00)
Week 234: Platelets (blood) (n = 5, 1, 6)	176.000 (110.00 to 196.00)	129.000 (129.00 to 129.00)	189.000 (147.00 to 264.00)
Week 12: Neutrophils (blood)	1.795 (0.72 to 11.72)	1.555 (1.01 to 4.15)	1.100 (0.00 to 8.10)
Week 26: Neutrophils (blood) (n = 10, 4, 31)	2.495 (0.52 to 4.60)	1.258 (0.78 to 1.63)	1.640 (0.40 to 4.47)
Week 52: Neutrophils (blood) (n = 7, 4, 19)	3.110 (0.17 to 4.29)	1.721 (1.11 to 3.47)	2.600 (0.83 to 5.75)
Week 78: Neutrophils (blood) (n = 6, 3, 18)	3.617 (1.02 to 4.91)	1.234 (0.56 to 1.34)	2.292 (0.69 to 5.41)
Week 130: Neutrophils (blood) (n = 6, 2, 9)	2.732 (1.04 to 6.72)	0.892 (0.57 to 1.21)	1.690 (1.30 to 2.67)
Week 182: Neutrophils (blood) (n = 6, 2, 5)	3.014 (1.00 to 6.09)	1.471 (0.61 to 2.33)	3.100 (2.07 to 4.30)
Week 234: Neutrophils (blood) (n = 5, 1, 6)	2.630 (2.04 to 4.40)	1.200 (1.20 to 1.20)	2.078 (1.02 to 4.70)

No statistical analyses for this end point

Secondary: Hematologic counts (hemoglobin (blood))

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End point title

Hematologic counts (hemoglobin (blood))

End point description

Individual hemoglobin (Hgb) counts were summarized for all participants.

End point type

Secondary

End point timeframe

Week 12, Week 26, Week 52, Week 78, Week 130, Week 182, Week 234

End point values	Cohort A: Regimen 1	Cohort A: Regimen 2	Cohort B
Number of subjects analysed	10	4	37
Units: g/L
median (full range (min-max))
Week 12 (n = 10, 4, 35)	89.5 (64 to 131)	87.0 (81 to 94)	88.0 (57 to 130)
Week 26 (n = 10, 4, 31)	101.0 (59 to 128)	98.5 (93 to 102)	95.0 (44 to 125)
Week 52 (n = 7, 4, 19)	116.0 (52 to 138)	104.5 (95 to 117)	110.0 (92 to 133)
Week 78 (n = 6, 3, 18)	118.5 (67 to 138)	92.0 (89 to 119)	117.0 (97 to 148)
Week 130 (n = 6, 2, 9)	119.5 (88 to 141)	125.5 (122 to 129)	126.0 (109 to 142)
Week 182 (n = 6, 2, 5)	126.0 (96 to 138)	125.5 (115 to 136)	127.0 (66 to 129)
Week 234 (n = 5, 1, 6)	126.0 (116 to 147)	128.0 (128 to 128)	125.0 (110 to 144)

No statistical analyses for this end point

Secondary: Total duration of Red Blood Cell (RBC) transfusion independence during the treatment period

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End point title

Total duration of Red Blood Cell (RBC) transfusion independence during the treatment period

End point description

RBC transfusion independence is defined as a period of time of at least 56 days without RBC transfusion. Duration of RBC transfusion independence is defined as a period of time of at least 56 days without RBC transfusion. First transfusion duration was calculated as the date of the day before the first transfusion after baseline minus the date of first exposure eltrombopag + 1.

End point type

Secondary

End point timeframe

From date of first dose to approx. 4.5 years

End point values	Cohort A: Regimen 1	Cohort A: Regimen 2	Cohort B
Number of subjects analysed	6	3	25
Units: days
median (full range (min-max))
approx. 3 years	355.0 (185 to 860)	430.0 (262 to 558)	267.0 (58 to 1074)
approx. 4.5 years	355.0 (185 to 1637)	430.0 (262 to 558)	267.0 (58 to 1296)

No statistical analyses for this end point

Secondary: Total duration of Platelet (PLT) transfusion independence during the treatment period

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End point title

Total duration of Platelet (PLT) transfusion independence during the treatment period

End point description

Platelet transfusion independence during the treatment period is defined as the duration from the first day of the 28-day period without PLT transfusion until the occurrence of a PLT transfusion after the period free from any PLT transfusion. Duration of PLT transfusion independence is defined as a period of time of at least 28 days without platelet transfusion. First transfusion duration was calculated as the date of the day before the first transfusion after baseline minus the date of first exposure eltrombopag + 1.

End point type

Secondary

End point timeframe

From date of first dose to approx. 4.5 years

End point values	Cohort A: Regimen 1	Cohort A: Regimen 2	Cohort B
Number of subjects analysed	8	4	28
Units: days
median (full range (min-max))
approx. 3 years	252.0 (36 to 860)	360.5 (139 to 560)	268.0 (34 to 1100)
approx. 4.5 years	252.0 (36 to 1637)	360.5 (139 to 560)	268.0 (34 to 1322)

No statistical analyses for this end point

Secondary: Maximum duration of Red Blood Cell (RBC) transfusion independence

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End point title

Maximum duration of Red Blood Cell (RBC) transfusion independence

End point description

RBC transfusion independence is defined as a period of time of at least 56 days without RBC transfusion. Maximum duration of RBC transfusion independence is defined as the maximum duration among the durations of RBC transfusion independence. First transfusion duration was calculated as the date of first transfusion after baseline minus the date of first exposure eltrombopag + 1.

End point type

Secondary

End point timeframe

From date of first dose to approx. 4.5 years

End point values	Cohort A: Regimen 1	Cohort A: Regimen 2	Cohort B
Number of subjects analysed	6	3	25
Units: days
median (full range (min-max))
approx. 3 years	355.0 (185 to 860)	321.0 (262 to 430)	259.0 (58 to 1074)
approx. 4.5 years	355.0 (185 to 1637)	321.0 (262 to 430)	262.0 (58 to 1296)

No statistical analyses for this end point

Secondary: Maximum duration of platelet (PLT) transfusion independence

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End point title

Maximum duration of platelet (PLT) transfusion independence

End point description

Maximum duration of PLT transfusion independence is defined as the maximum duration among the durations of PLT transfusion independence. First transfusion duration was calculated as the date of first transfusion after baseline minus the date of first exposure eltrombopag + 1.

End point type

Secondary

End point timeframe

From date of first dose to approx. 4.5 years

End point values	Cohort A: Regimen 1	Cohort A: Regimen 2	Cohort B
Number of subjects analysed	8	4	28
Units: days
median (full range (min-max))
approx. 3 years	252.0 (36 to 860)	360.5 (64 to 560)	249.5 (34 to 1067)
approx. 4.5 years	252.0 (36 to 1637)	360.5 (64 to 560)	249.5 (34 to 1289)

No statistical analyses for this end point

Secondary: Overall Bone marrow cellularity

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End point title

Overall Bone marrow cellularity

End point description

Percentage of cells in bone marrow biopsy - a comprehensive diagnostic evaluation to distinguish between the various bone marrow disorders.

End point type

Secondary

End point timeframe

Screening, Week 26, Week 52, Week 78, Week 130, Week 184, Week 234

End point values	Cohort A: Regimen 1	Cohort A: Regimen 2	Cohort B
Number of subjects analysed	10	4	33
Units: Percentage of cells
median (full range (min-max))
Overall cellularity (OC): Screening (n=10, 4, 26)	11.5 (5.0 to 30.0)	32.5 (20.0 to 50.0)	4.0 (2.0 to 40.0)
OC: Week 26 (n = 8, 3, 30)	30.0 (10.0 to 50.0)	30.0 (20.0 to 50.0)	22.5 (2.0 to 55.0)
OC: Week 52 (n = 5, 3, 16)	35.0 (5.0 to 45.0)	50.0 (50.0 to 65.0)	35.0 (3.0 to 55.0)
OC: Week 78 (n = 6, 1, 15)	32.5 (5.0 to 50.0)	50.0 (50.0 to 50.0)	35.0 (3.0 to 70.0)
OC: Week 130 (n = 4, 1, 10)	40.0 (40.0 to 50.0)	45.0 (45.0 to 45.0)	42.5 (10.0 to 60.0)
OC: Week 182 (n = 3, 1, 8)	60.0 (30.0 to 60.0)	45.0 (45.0 to 45.0)	45.0 (40.0 to 60.0)
OC: Week 234 (n = 4, 0, 4)	52.5 (30.0 to 55.0)	999 (999 to 999)	47.5 (25.0 to 60.0)
Hematologic cellularity (HC): Screening(n=10,4,26)	5.0 (1.0 to 25.0)	22.5 (10.0 to 45.0)	1.5 (1.0 to 25.0)
HC: Week 26 (n = 8, 3, 30)	21.0 (5.0 to 45.0)	25.0 (15.0 to 40.0)	17.5 (1.0 to 50.0)
HC: Week 52 (n = 5, 3, 16)	30.0 (30.0 to 40.0)	45.0 (45.0 to 45.0)	27.5 (2.0 to 50.0)
HC: Week 78 (n = 6, 1, 15)	25.0 (3.0 to 40.0)	40.0 (40.0 to 40.0)	30.0 (2.0 to 50.0)
HC: Week 130 (n = 4, 1, 10)	30.0 (30.0 to 40.0)	35.0 (35.0 to 35.0)	37.5 (8.0 to 50.0)
HC: Week 182 (n = 3, 1, 8)	50.0 (25.0 to 50.0)	35.0 (35.0 to 35.0)	40.0 (25.0 to 80.0)
HC: Week 234 (n = 4, 0, 4)	45.0 (25.0 to 50.0)	999 (999 to 999)	37.5 (20.0 to 50.0)

No statistical analyses for this end point

Secondary: Bone marrow morphology

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End point title

Bone marrow morphology ^[4]

End point description

Percentage of morphology (erythropoiesis, granulopoiesis, megakaryopoiesis, CD34+ (blast cells) cells in bone marrow aspirate - a comprehensive diagnostic evaluation to distinguish between the various bone marrow disorders.

End point type

Secondary

End point timeframe

Screening, Week, 26, Week 52, Week 78, Week 130, Week 182, Week 234

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done for this endpoint

End point values	Cohort A: Regimen 2	Cohort B	Cohort A: Regimen 1
Number of subjects analysed	4	37	10
Units: Percentage of cells
median (full range (min-max))
Erythroid cells: Screening (n = 10, 4, 26)	27.0 (19.0 to 39.0)	5.0 (0.0 to 38.0)	11.5 (0.0 to 28.0)
Erythroid cells: Week 26 (n = 9, 3, 30)	12.0 (2.0 to 22.0)	18.0 (0.0 to 55.0)	10.0 (1.0 to 25.0)
Erythroid cells: Week 52 (n = 6, 3, 16)	12.0 (2.0 to 17.0)	14.5 (1.0 to 28.0)	13.0 (4.0 to 37.0)
Erythroid cells: Week 78 (n = 6, 1, 14)	15.0 (15.0 to 15.0)	20.5 (4.0 to 26.0)	14.0 (5.0 to 20.0)
Erythroid cells: Week 130 (n = 3, 1, 10)	15.0 (15.0 to 15.0)	17.0 (4.0 to 32.0)	19.0 (11.0 to 22.0)
Erythroid cells: Week 182 (n = 3, 1, 8)	24.0 (24.0 to 24.0)	16.5 (7.0 to 32.0)	26.0 (8.0 to 33.0)
Erythroid cells: Week 234 (n = 4, 0, 4)	999 (999 to 999)	18.0 (13.0 to 33.0)	13.0 (5.0 to 20.0)
Neutrophil: Screening (n = 10, 4, 26)	29.5 (19.0 to 48.0)	8.0 (0.0 to 45.0)	33.0 (1.0 to 48.0)
Neutrophil cells: Week 26 (n = 9, 3, 30)	47.0 (29.0 to 66.0)	50.0 (17.0 to 78.0)	52.0 (34.0 to 63.0)
Neutrophil: Week 52 (n = 6, 3, 16)	62.0 (57.0 to 67.0)	52.5 (20.0 to 76.0)	48.5 (32.0 to 59.0)
Neutrophil: Week 78 (n = 6, 1, 14)	53.0 (53.0 to 53.0)	52.0 (34.0 to 67.0)	43.0 (4.0 to 54.0)
Neutrophil cells: Week 130 (n = 3, 1, 10)	51.0 (51.0 to 51.0)	53.0 (39.0 to 65.0)	50.0 (44.0 to 50.0)
Neutrophil cells: Week 182 (n = 3, 1, 8)	51.0 (51.0 to 51.0)	32.5 (5.0 to 59.0)	40.0 (25.0 to 56.0)
Neutrophil cells: Week 234 (n = 4, 0, 4)	999 (999 to 999)	33.5 (25.0 to 36.0)	43.5 (30.0 to 56.0)
Blast cells: Screening (n = 10, 4, 26)	1.0 (0.0 to 5.0)	0.0 (0.0 to 3.0)	0.00 (0.0 to 1.0)
Blast cells: Week 26 (n = 9, 3, 30)	1.0 (0.0 to 2.0)	0.0 (0.0 to 1.0)	0.0 (0.0 to 2.0)
Blast cells: Week 52 (n = 6, 3, 16)	1.0 (0.0 to 2.0)	0.0 (0.0 to 1.0)	0.0 (0.0 to 1.0)
Blast cells: Week 78 (n = 6, 1, 14)	0.0 (0.0 to 0.0)	1.0 (0.0 to 2.0)	0.0 (0.0 to 1.0)
Blast cells: Week 130 (n = 3, 1, 10)	0.0 (0.0 to 0.0)	0.5 (0.0 to 2.0)	0.0 (0.0 to 1.0)
Blast cells: Week 182 (n = 3, 1, 8)	0.0 (0.0 to 0.0)	1.0 (0.0 to 26.0)	0.0 (0.0 to 1.0)
Blast cells: Week 234 (n = 4, 0, 4)	999 (999 to 999)	1.0 (0.0 to 2.0)	0.0 (0.0 to 2.0)

No statistical analyses for this end point

Secondary: Bone marrow cytogenetics

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End point title

Bone marrow cytogenetics

End point description

Number of bone marrow cytogenetics (chromosomal structure) by kryotyping and Fluorescence in situ hybridization (FISH). This is a comprehensive diagnostic evaluation to distinguish between the various bone marrow disorders.

End point type

Secondary

End point timeframe

Screening, Week 12, Week 26, Week 52, Week 78, Week 130, Week 182, Week 234

End point values	Cohort A: Regimen 1	Cohort A: Regimen 2	Cohort B
Number of subjects analysed	10	4	37
Units: Participants
FISH Chr 7 @ Screening: Normal	10	4	26
FISH Chr 7 @ Screening: Abnormal	0	0	0
FISH Chr 7@ Screening: Not Available	0	0	2
FISH Chr 7 @ Week 12: Normal	9	2	26
FISH Chr 7 @ Week 12: Abnormal	0	0	0
FISH Chr 7 @ Week 12: Not Available	0	0	1
FISH Chr 7 @ Week 26: Normal	8	3	28
FISH Chr 7 @ Week 26: Abnormal	0	0	0
FISH Chr 7 @ Week 26: Not Available	1	0	1
FISH Chr 7 @ Week 52: Normal	6	3	15
FISH Chr 7 @ Week 52: Abnormal	0	0	0
FISH Chr 7 @ Week 52: Not Available	0	0	1
FISH Chr 7 @ Week 78: Normal	6	1	13
FISH Chr 7 @ Week 78: Abnormal	0	0	0
FISH Chr 7 @ Week 78: Not Available	0	0	2
FISH Chr 7 @ Week 130: Normal	2	1	9
FISH Chr 7 @ Week 130: Abnormal	0	0	0
FISH Chr 7 @ Week 130: Not Available	1	0	1
FISH Chr 7 @ Week 182: Normal	3	1	8
FISH Chr 7 @ Week 182: Abnormal	0	0	0
FISH Chr 7 @ Week 182: Not Available	0	0	0
FISH Chr 7 @ Week 234: Normal	4	0	4
FISH Chr 7 @ Week 234: Abnormal	0	0	0
FISH Chr 7 @ Week 234: Not Available	0	0	0
Karyotype @ Screening: Normal	8	4	19
Karyotype @ Screening: Abnormal	0	0	0
Karyotype @ Screening: Not Available	2	0	8
Karyotype @ Week 12: Normal	8	2	25
Karyotype @ Week 12: Abnormal	1	0	0
Karyotype @ Week 12: Not Available	0	0	6
Karyotype @ Week 26: Normal	7	3	25
Karyotype @ Week 26: Abnormal	1	0	1
Karyotype @ Week 26: Not Available	1	0	5
Karyotype @ Week 52: Normal	5	3	15
Karyotype @ Week 52: Abnormal	1	0	0
Karyotype @ Week 52: Not Available	0	0	2
Karyotype @ Week 78: Normal	4	1	13
Karyotype @ Week 78: Abnormal	1	0	0
Karyotype @ Week 78: Not Available	1	0	2
Karyotype @ Week 130: Normal	2	1	8
Karyotype @ Week 130: Abnormal	0	0	0
Karyotype @ Week 130: Not Available	2	0	2
Karyotype @ Week 182: Normal	3	1	7
Karyotype @ Week 182: Abnormal	0	0	1
Karyotype @ Week 182: Not Available	0	0	0
Karyotype @ Week 234: Normal	4	0	4
Karyotype @ Week 234: Abnormal	0	0	0
Karyotype @ Week 234: Not Available	0	0	0

No statistical analyses for this end point

Secondary: Acceptability and palatability for both tablets and powder formulation for oral solution (PfOS)

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End point title

Acceptability and palatability for both tablets and powder formulation for oral solution (PfOS)

End point description

Standardized (total) summary score, ranged from 0-100, (where 0 means worst and 100 means the best), was derived from all items from the questionnaire based on a scoring matrix. The questionnaire was completed by parents and caregivers of patients under 12 years of age (ObsRO) and a questionnaire completed by patients 12 years and older (PRO).

End point type

Secondary

End point timeframe

any day from Day 1 of drug initiation up to Week 78

End point values	Cohort A: Regimen 1	Cohort A: Regimen 2	Cohort B
Number of subjects analysed	10	4	16
Units: scores on a scale (of acceptability)
median (full range (min-max))
Acceptability (including palatability) - Tablet	71.0 (58.0 to 96.0)	75.0 (58.0 to 88.0)	71.0 (46.0 to 96.0)
Acceptability (incl. palatability)- PfOS (n=0,0,8)	999 (999 to 999)	999 (999 to 999)	71.0 (32.0 to 82.0)

No statistical analyses for this end point

Secondary: Clonal evolution to Paroxysmal Nocturnal Hemoglobinuria (PNH)

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End point title

Clonal evolution to Paroxysmal Nocturnal Hemoglobinuria (PNH)

End point description

Percentage of participants with clonal evolution to Paroxysmal Nocturnal Hemoglobinuria (PNH).

End point type

Secondary

End point timeframe

Baseline, Week (W) 26 Day (D) 1, W52D1, W78D1, W130D1, W182D1, W234D1

End point values	Cohort A: Regimen 1	Cohort A: Regimen 2	Cohort B
Number of subjects analysed	10	4	37
Units: Percentage of participants
number (not applicable)
Baseline: Positive clonal evolution	20.0	25.0	29.7
Baseline: Negative clonal evolution	80.0	75.0	64.9
Baseline: Missing	0.0	0.0	5.4
W26D1: Positive clonal evolution	10.0	50.0	8.1
W26D1: Negative clonal evolution	80.0	25.0	64.9
W26D1: Missing	10.0	25.0	27.0
W52D1: Positive clonal evolution	0	25.0	2.7
W52D1: Negative clonal evolution	30.0	25.0	29.7
W52D1: Missing	70.0	50.0	67.6
W78D1: Positive clonal evolution	0	25.0	0
W78D1: Negative clonal evolution	40.0	25.0	21.6
W78D1: Missing	60.0	50.0	78.4
W130D1: Positive clonal evolution	0	0	0
W130D1: Negative clonal evolution	30.0	0	8.1
W130D1: Missing	70.0	100.0	91.9
W182D1: Positive clonal evolution	10.0	0	2.7
W182D1: Negative clonal evolution	20.0	0	8.1
W182D1: Missing	70.0	100.0	89.2
W234D1: Positive clonal evolution	0	0	2.7
W234D1: Negative clonal evolution	30.0	0	2.7
W234D1: Missing	70.0	100.0	94.6

No statistical analyses for this end point

Secondary: Alternate overall response rate (aORR)

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End point title

Alternate overall response rate (aORR)

End point description

Alternate overall responses were derived using hematological parameters (i.e., hemoglobin, platelet, reticulocyte, and ANC). aORR is defined as the percentage of participants who achieved an alternate complete response (aCR) or an alternate partial response (aPR)

End point type

Secondary

End point timeframe

Week 12, Week 26, Week 52, Week 78

End point values	Cohort A: Regimen 1	Cohort A: Regimen 2	Cohort B
Number of subjects analysed	10	4	37
Units: Percentage of participants
number (confidence interval 95%)
Week 12	90.0 (55.5 to 99.7)	100 (39.8 to 100.0)	64.9 (47.5 to 79.8)
Week 26	90.0 (55.5 to 99.7)	100 (39.8 to 100.0)	75.7 (58.8 to 88.2)
Week 52	60.0 (26.2 to 87.8)	100 (39.8 to 100.0)	40.5 (24.8 to 57.9)
Week 78	50.0 (18.7 to 81.3)	75.0 (19.4 to 99.4)	48.6 (31.9 to 65.6)

No statistical analyses for this end point

Secondary: Pharmacokinetics (PK) of eltrombopag at the starting dose (AUCtau)

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End point title

Pharmacokinetics (PK) of eltrombopag at the starting dose (AUCtau)

End point description

PK parameter, AUCtau. AUC tau: Area under the curve calculated to the end of the dosing interval (tau) (mass*time/volume)

End point type

Secondary

End point timeframe

Week 3 Day 1

End point values	Cohort A: Regimen 1	Cohort A: Regimen 2	Cohort B
Number of subjects analysed	5	3	12
Units: hr*ng/mL
geometric mean (geometric coefficient of variation)	367000 ( 35.6 )	350000 ( 47.7 )	441000 ( 55.2 )

No statistical analyses for this end point

Secondary: PK of eltrombopag at the starting dose (Ctrough)

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End point title

PK of eltrombopag at the starting dose (Ctrough) ^[5]

End point description

PK parameter, Ctrough Ctrough is the pre-dose plasma concentration (mass/volume).

End point type

Secondary

End point timeframe

Week 3 Day 1

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done for this endpoint

End point values	Cohort A: Regimen 1	Cohort B	Cohort A: Regimen 2
Number of subjects analysed	6	16	3
Units: ng/mL
geometric mean (geometric coefficient of variation)	8760 ( 72.9 )	13200 ( 52.2 )	10900 ( 66.6 )

No statistical analyses for this end point

Secondary: PK of eltrombopag at the starting dose (Cmax)

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End point title

PK of eltrombopag at the starting dose (Cmax)

End point description

PK parameter, Cmax Cmax is the observed maximum plasma concentration following administration (mass/volume)

End point type

Secondary

End point timeframe

Week 3 Day 1

End point values	Cohort A: Regimen 1	Cohort A: Regimen 2	Cohort B
Number of subjects analysed	6	3	16
Units: ng/mL
geometric mean (geometric coefficient of variation)	19700 ( 46.5 )	21000 ( 24.5 )	24000 ( 51.0 )

No statistical analyses for this end point

Secondary: Number of Red Blood Cells (RBC) transfusions

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End point title

Number of Red Blood Cells (RBC) transfusions

End point description

Number of transfusions during the treatment period refers to total number of RBC transfusions participants have received while on treatment.

End point type

Secondary

End point timeframe

From date of first dose to approx. 4.5 years

End point values	Cohort A: Regimen 1	Cohort A: Regimen 2	Cohort B
Number of subjects analysed	10	4	37
Units: RBC transfusions
median (full range (min-max))
approx. 3 years (n = 8, 3, 33)	7.0 (1 to 17)	3.0 (1 to 34)	7.0 (1 to 26)
approx. 4.5 years (n =8, 3, 33)	7.0 (1 to 17)	3.0 (1 to 34)	7.0 (1 to 26)

No statistical analyses for this end point

Secondary: Number of Platelet (PLT) transfusions

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End point title

Number of Platelet (PLT) transfusions

End point description

Number of transfusions during the treatment period refers to total number of PLT transfusions participants have received while on treatment.

End point type

Secondary

End point timeframe

From date of first dose to approx. 4.5 years

End point values	Cohort A: Regimen 1	Cohort A: Regimen 2	Cohort B
Number of subjects analysed	10	4	37
Units: Platelet transfusions
median (full range (min-max))
approx. 3 years (n = 8, 1, 34)	13.0 (3 to 48)	53.0 (53 to 53)	13.0 (2 to 65)
approx. 4.5 years (n = )	13.0 (3 to 48)	53.0 (53 to 53)	13.0 (2 to 65)

No statistical analyses for this end point

Secondary: Frequency of Red Blood Cell (RBC) transfusions

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End point title

Frequency of Red Blood Cell (RBC) transfusions

End point description

Frequency of transfusions during the treatment period refers to number of RBC transfusions during the treatment period divided by number of months of treatment duration.

End point type

Secondary

End point timeframe

From date of first dose to approx. 4.5 years

End point values	Cohort A: Regimen 1	Cohort A: Regimen 2	Cohort B
Number of subjects analysed	10	4	37
Units: RBC transfusions per month
median (full range (min-max))
approx. 3 years (n = 8, 3, 33)	1.5 (0 to 4)	0.2 (0 to 3)	0.9 (0 to 5)
approx. 4.5 years (n = 8, 3, 33)	1.5 (0 to 4)	0.2 (0 to 3)	0.9 (0 to 5)

No statistical analyses for this end point

Secondary: Exposure (AUCtau) - response relationship of eltrombopag and overall response rate by age groups

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End point title

Exposure (AUCtau) - response relationship of eltrombopag and overall response rate by age groups

End point description

Pharmacokinetic parameter (AUCtau) of eltrombopag at the highest dose in relationship to overall response rate in regard to complete response (CR), partial response (PR) and no response (NR). AUC tau: Area under the curve calculated to the end of the dosing interval (tau) (mass*time/volume)

End point type

Secondary

End point timeframe

at least 11 weeks after dose initiation or later when patients are taking the highest dose, up to Week 78

End point values	Cohort A: Regimen 1 (1 to <6 years)	Cohort A: Regimen 1 (6 to <18 years)	Cohort A: Regimen 2 (6 to <18 years)	Cohort B (6 to <18 years)	Cohort B (1 to <6 years)
Number of subjects analysed	1	7	3	19	8
Units: hr*ng/mL
geometric mean (geometric coefficient of variation)
No response (NR):	816000 ( 0 )	390000 ( 0 )	999 ( 999 )	999 ( 999 )	1260000 ( 27.0 )
Complete response (CR):	999 ( 999 )	769000 ( 87.3 )	999 ( 999 )	503000 ( 57.4 )	2260000 ( 0 )
Partial response (PR):	999 ( 999 )	999 ( 999 )	1220000 ( 0 )	963000 ( 80.6 )	671000 ( 0 )

No statistical analyses for this end point

Secondary: Frequency of Platelet (PLT) transfusions

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End point title

Frequency of Platelet (PLT) transfusions

End point description

Frequency of transfusions during the treatment period refers to number of PLT transfusions during the treatment period divided by number of months of treatment duration.

End point type

Secondary

End point timeframe

From date of first dose to approx. 4.5 years

End point values	Cohort A: Regimen 1	Cohort A: Regimen 2	Cohort B
Number of subjects analysed	10	4	37
Units: Platelet transfusions per month
median (full range (min-max))
approx. 3 years (n = 8, 1, 34)	2.0 (0 to 14)	4.2 (4.2 to 4.2)	2.0 (0 to 13)
approx. 4.5 years (n = 8, 1, 34)	2.0 (0 to 14)	4.2 (4.2 to 4.2)	1.9 (0 to 13)

No statistical analyses for this end point

Secondary: Exposure (Cmax, Ctrough) - response relationship of eltrombopag and overall response rate by age groups

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End point title

Exposure (Cmax, Ctrough) - response relationship of eltrombopag and overall response rate by age groups

End point description

Pharmacokinetic parameters (Cmax and Ctrough) of eltrombopag at the highest dose in relationship to overall response rate in regard to complete response (CR), partial response (PR) and no response (NR). Cmax is the observed maximum plasma concentration following administration (mass/volume). Ctrough is the pre-dose plasma concentration (mass/volume).

End point type

Secondary

End point timeframe

at least 11 weeks after dose initiation or later when patients are taking the highest dose, up to Week 78

End point values	Cohort A: Regimen 1 (1 to <6 years)	Cohort A: Regimen 2 (6 to <18 years)	Cohort A: Regimen 1 (6 to <18 years)	Cohort B (1 to <6 years)	Cohort B (6 to <18 years)
Number of subjects analysed	1	2	3	4	9
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cmax: No Response (n = 1, 2, 0, 4, 2)	48400 ( 0 )	999 ( 999 )	33900 ( 115 )	84900 ( 32.6 )	39200 ( 33.1 )
Cmax: Complete Response (n = 0, 3, 0, 1, 9)	999 ( 999 )	999 ( 999 )	35700 ( 88.3 )	112000 ( 0 )	31200 ( 63.7 )
Cmax: Partial Response (n = 0, 0, 2, 3, 4)	999 ( 999 )	24800 ( 212 )	999 ( 999 )	60500 ( 26.6 )	54000 ( 54.4 )
Ctrough: No Response (n = 1, 2, 0, 4, 2)	16400 ( 0 )	999 ( 999 )	19900 ( 106 )	37800 ( 32.6 )	18500 ( 43.6 )
Ctrough: Complete Response (n = 0, 3, 0, 1, 9)	999 ( 999 )	999 ( 999 )	27000 ( 104 )	84700 ( 0 )	20100 ( 72.8 )
Ctrough: Partial Response (n = 0, 0, 2, 3, 4)	999 ( 999 )	17100 ( 151 )	999 ( 999 )	23800 ( 194 )	35300 ( 65.9 )

No statistical analyses for this end point

Secondary: Exposure (AUCtau) - response relationship of eltrombopag and platelet response rate by age groups

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End point title

Exposure (AUCtau) - response relationship of eltrombopag and platelet response rate by age groups

End point description

Pharmacokinetic parameter (AUCtau) of eltrombopag at the highest dose in relationship to platelet response rate. AUC tau: Area under the curve calculated to the end of the dosing interval ( tau) (mass*time/volume)

End point type

Secondary

End point timeframe

at least 11 weeks after dose initiation or later when patients are taking the highest dose, up to Week 78

End point values	Cohort A: Regimen 1 (1 to <6 years)	Cohort A: Regimen 1 (6 to <18 years)	Cohort B (1 to <6 years)	Cohort B (6 to <18 years)	Cohort A: Regimen 2 (6 to <18 years)
Number of subjects analysed	1	3	4	9	1
Units: hr*ng/mL
geometric mean (geometric coefficient of variation)
No Response	816000 ( 0 )	999 ( 999 )	999 ( 999 )	1280000 ( 0 )	999 ( 999 )
Complete Response	999 ( 999 )	769000 ( 87.3 )	1670000 ( 45.2 )	563000 ( 67.3 )	1220000 ( 0 )
Partial Response	999 ( 999 )	390000 ( 0 )	1090000 ( 43.5 )	999 ( 999 )	999 ( 999 )

No statistical analyses for this end point

Secondary: Exposure (Cmax, Ctrough) - response relationship of eltrombopag and platelet response rate by age groups

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End point title

Exposure (Cmax, Ctrough) - response relationship of eltrombopag and platelet response rate by age groups

End point description

Pharmacokinetic parameters (Cmax and Ctrough) of eltrombopag at the highest dose in relationship to platelet response rate. Cmax is the observed maximum plasma concentration following administration (mass/volume). Ctrough is the pre-dose plasma concentration (mass/volume).

End point type

Secondary

End point timeframe

at least 11 weeks after dose initiation or later when patients are taking the highest dose, up to Week 78

End point values	Cohort A: Regimen 1 (1 to <6 years)	Cohort A: Regimen 1 (6 to <18 years)	Cohort B (1 to <6 years)	Cohort A: Regimen 2 (6 to <18 years)	Cohort B (6 to <18 years)
Number of subjects analysed	1	3	4	1	12
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cmax: No Response (n = 1, 1, 0, 0, 2)	48400 ( 0 )	64900 ( 0 )	999 ( 999 )	999 ( 999 )	39200 ( 33.1 )
Cmax: Complete Response (n = 0, 3, 1, 4, 12)	999 ( 999 )	35700 ( 88.3 )	80900 ( 31.7 )	62400 ( 0 )	35200 ( 65.8 )
Cmax: Partial Response n = 0, 1, 0, 4, 1)	999 ( 999 )	17700 ( 0 )	74000 ( 42.1 )	999 ( 999 )	66600 ( 0 )
Ctrough: No Response (n = 1, 3, 0, 0, 1)	16400 ( 0 )	1 ( 36800 )	999 ( 999 )	999 ( 999 )	45000 ( 0 )
Ctrough: Complete Response (n = 0, 3, 1, 4, 12)	999 ( 999 )	27000 ( 104 )	50100 ( 48.6 )	37100 ( 0 )	22700 ( 75.3 )
Ctrough: Partial Response (n = 0, 1, 0, 4, 12)	999 ( 999 )	10800 ( 0 )	24600 ( 132 )	999 ( 999 )	18500 ( 43.6 )

No statistical analyses for this end point

Post-hoc: All Collected Deaths

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End point title

All Collected Deaths ^[6]

End point description

On-treatment deaths were collected from the first dose of study treatment up to 30 days after last dose of study medication, for a maximum duration of 234 weeks. Post-treatment survival follow-up deaths were collected 31 days after last dose of study medication until date of the last follow-up for the primary analysis, up to 234 weeks.

End point type

Post-hoc

End point timeframe

On-treatment deaths: from first dose of study treatment up to 30 days post treatment, approx. 234 weeks; Post-treatment survival follow-up deaths: from Day 31 to approx. 234 weeks

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done for this endpoint

End point values	Cohort A: Regimen 2	Cohort B	Cohort A: Regimen 1	Total (Cohorts A (Regimen 1 & 2) and B
Number of subjects analysed	4	37	10	51
Units: Participants
Total deaths	1	0	0	1
On-treatment deaths	0	0	0	0
Post-treatment deaths	1	0	0	1

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse Events (AEs) were collected from first dosing (Day 1) until date of the last follow-up, up to 234 weeks.

Adverse event reporting additional description

An Adverse Event (AE) is any untoward medical occurrence in a clinical investigation participant after providing written informed consent for participation in the study. Therefore, an AE may or may not be temporarily or causally associated with the use of a medicinal (investigational) product.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.1

Reporting group title

Cohort A - Regimen 1

Reporting group description

Cohort A - Regimen 1

Reporting group title

Total Patients

Reporting group description

Total Patients

Reporting group title

Cohort B

Reporting group description

Cohort B

Reporting group title

Cohort A - Regimen 2

Reporting group description

Cohort A - Regimen 2

Reporting group title

Total Cohort A

Reporting group description

Total Cohort A

Serious adverse events	Cohort A - Regimen 1	Total Patients	Cohort B	Cohort A - Regimen 2	Total Cohort A
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 10 (40.00%)	29 / 51 (56.86%)	23 / 37 (62.16%)	2 / 4 (50.00%)	6 / 14 (42.86%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	2 / 10 (20.00%)	11 / 51 (21.57%)	8 / 37 (21.62%)	1 / 4 (25.00%)	3 / 14 (21.43%)
occurrences causally related to treatment / all	0 / 2	0 / 16	0 / 9	0 / 5	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Serum sickness
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Abnormal uterine bleeding
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Hypoxia
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oropharyngeal pain
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory disorder
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillar exudate
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Product issues
Device malfunction
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Platelet count decreased
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Liver function test increased
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Toxicity to various agents
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sunburn
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Headache
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	1 / 10 (10.00%)	7 / 51 (13.73%)	5 / 37 (13.51%)	1 / 4 (25.00%)	2 / 14 (14.29%)
occurrences causally related to treatment / all	0 / 2	0 / 14	0 / 8	0 / 4	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gingival pain
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Drug-induced liver injury
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Petechiae
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Azotaemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	0 / 10 (0.00%)	3 / 51 (5.88%)	2 / 37 (5.41%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacillus bacteraemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchiolitis
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metapneumovirus infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Klebsiella sepsis
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes simplex
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	1 / 37 (2.70%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	1 / 37 (2.70%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Varicella
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Magnesium metabolism disorder
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypomagnesaemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	1 / 37 (2.70%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Cohort A - Regimen 1	Total Patients	Cohort B	Cohort A - Regimen 2	Total Cohort A
Total subjects affected by non serious adverse events
subjects affected / exposed	10 / 10 (100.00%)	51 / 51 (100.00%)	37 / 37 (100.00%)	4 / 4 (100.00%)	14 / 14 (100.00%)
Vascular disorders
Hyperaemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1	1
Thrombophlebitis
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	1	0	0	1
Hypotension
subjects affected / exposed	0 / 10 (0.00%)	3 / 51 (5.88%)	2 / 37 (5.41%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	3	2	1	1
Poor peripheral circulation
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1	1
Hypertension
subjects affected / exposed	4 / 10 (40.00%)	20 / 51 (39.22%)	15 / 37 (40.54%)	1 / 4 (25.00%)	5 / 14 (35.71%)
occurrences all number	8	29	19	2	10
General disorders and administration site conditions
Catheter site pain
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	2	0	0
Pyrexia
subjects affected / exposed	3 / 10 (30.00%)	14 / 51 (27.45%)	10 / 37 (27.03%)	1 / 4 (25.00%)	4 / 14 (28.57%)
occurrences all number	4	22	15	3	7
Pain
subjects affected / exposed	1 / 10 (10.00%)	3 / 51 (5.88%)	2 / 37 (5.41%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	3	2	0	1
Oedema peripheral
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	1 / 37 (2.70%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	2	1	1	1
Non-cardiac chest pain
subjects affected / exposed	0 / 10 (0.00%)	3 / 51 (5.88%)	2 / 37 (5.41%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	3	2	1	1
Feeling hot
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	1 / 37 (2.70%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	2	1	1	1
Fatigue
subjects affected / exposed	0 / 10 (0.00%)	5 / 51 (9.80%)	5 / 37 (13.51%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	7	7	0	0
Face oedema
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	1 / 37 (2.70%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	2	1	1	1
Chills
subjects affected / exposed	1 / 10 (10.00%)	4 / 51 (7.84%)	3 / 37 (8.11%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	4	3	0	1
Immune system disorders
Serum sickness
subjects affected / exposed	2 / 10 (20.00%)	8 / 51 (15.69%)	6 / 37 (16.22%)	0 / 4 (0.00%)	2 / 14 (14.29%)
occurrences all number	2	8	6	0	2
Haemophagocytic lymphohistiocytosis
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1	1
Anaphylactic shock
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1	1
Reproductive system and breast disorders
Heavy menstrual bleeding
subjects affected / exposed	2 / 10 (20.00%)	3 / 51 (5.88%)	1 / 37 (2.70%)	0 / 4 (0.00%)	2 / 14 (14.29%)
occurrences all number	3	6	3	0	3
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	2 / 10 (20.00%)	8 / 51 (15.69%)	5 / 37 (13.51%)	1 / 4 (25.00%)	3 / 14 (21.43%)
occurrences all number	3	14	10	1	4
Acute respiratory distress syndrome
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	1	0	0	1
Cough
subjects affected / exposed	2 / 10 (20.00%)	5 / 51 (9.80%)	3 / 37 (8.11%)	0 / 4 (0.00%)	2 / 14 (14.29%)
occurrences all number	3	7	4	0	3
Laryngospasm
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	2	2	0	0	2
Nasal obstruction
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	2	0	2	2
Oropharyngeal pain
subjects affected / exposed	1 / 10 (10.00%)	5 / 51 (9.80%)	3 / 37 (8.11%)	1 / 4 (25.00%)	2 / 14 (14.29%)
occurrences all number	1	7	5	1	2
Rhinorrhoea
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	1 / 37 (2.70%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	5	1	4	4
Tonsillar exudate
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	1	0	0	1
Nasal congestion
subjects affected / exposed	0 / 10 (0.00%)	4 / 51 (7.84%)	3 / 37 (8.11%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	5	4	1	1
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 10 (0.00%)	5 / 51 (9.80%)	5 / 37 (13.51%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	5	5	0	0
Insomnia
subjects affected / exposed	0 / 10 (0.00%)	3 / 51 (5.88%)	3 / 37 (8.11%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	3	3	0	0
Psychotic disorder
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	1	0	0	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	7 / 10 (70.00%)	24 / 51 (47.06%)	16 / 37 (43.24%)	1 / 4 (25.00%)	8 / 14 (57.14%)
occurrences all number	14	47	32	1	15
Aspartate aminotransferase increased
subjects affected / exposed	6 / 10 (60.00%)	20 / 51 (39.22%)	13 / 37 (35.14%)	1 / 4 (25.00%)	7 / 14 (50.00%)
occurrences all number	11	36	24	1	12
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 10 (10.00%)	3 / 51 (5.88%)	1 / 37 (2.70%)	1 / 4 (25.00%)	2 / 14 (14.29%)
occurrences all number	1	3	1	1	2
Blood bilirubin increased
subjects affected / exposed	6 / 10 (60.00%)	24 / 51 (47.06%)	18 / 37 (48.65%)	0 / 4 (0.00%)	6 / 14 (42.86%)
occurrences all number	16	55	39	0	16
Blood creatinine increased
subjects affected / exposed	5 / 10 (50.00%)	19 / 51 (37.25%)	12 / 37 (32.43%)	2 / 4 (50.00%)	7 / 14 (50.00%)
occurrences all number	13	31	15	3	16
Blood folate decreased
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1	1
Blood glucose increased
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	1 / 37 (2.70%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	2	1	1	1
Blood magnesium decreased
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	2	0	0
Blood phosphorus increased
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1	1
Blood pressure increased
subjects affected / exposed	0 / 10 (0.00%)	6 / 51 (11.76%)	5 / 37 (13.51%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	6	5	1	1
Blood urea increased
subjects affected / exposed	4 / 10 (40.00%)	12 / 51 (23.53%)	5 / 37 (13.51%)	3 / 4 (75.00%)	7 / 14 (50.00%)
occurrences all number	7	21	6	8	15
Klebsiella test positive
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1	1
Liver function test increased
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	2	0	0
SARS-CoV-2 test negative
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	5	0	5	5
Serum ferritin increased
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	2	0	0
Staphylococcus test positive
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1	1
Immunosuppressant drug level increased
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1	1
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	1	0	0	1
Contusion
subjects affected / exposed	1 / 10 (10.00%)	5 / 51 (9.80%)	3 / 37 (8.11%)	1 / 4 (25.00%)	2 / 14 (14.29%)
occurrences all number	1	6	4	1	2
Infusion related reaction
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	2	0	0
Procedural pain
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	2	0	0
Refractoriness to platelet transfusion
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	2	0	0
Transfusion reaction
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	2	0	0
Cardiac disorders
Tachycardia
subjects affected / exposed	0 / 10 (0.00%)	3 / 51 (5.88%)	2 / 37 (5.41%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	4	3	1	1
Nervous system disorders
Headache
subjects affected / exposed	2 / 10 (20.00%)	10 / 51 (19.61%)	8 / 37 (21.62%)	0 / 4 (0.00%)	2 / 14 (14.29%)
occurrences all number	6	16	10	0	6
Dizziness
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	2	0	0
Syncope
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	1	0	0	1
Tremor
subjects affected / exposed	1 / 10 (10.00%)	2 / 51 (3.92%)	1 / 37 (2.70%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	2	1	0	1
Blood and lymphatic system disorders
Aplastic anaemia
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	2	0	0
Febrile neutropenia
subjects affected / exposed	2 / 10 (20.00%)	11 / 51 (21.57%)	8 / 37 (21.62%)	1 / 4 (25.00%)	3 / 14 (21.43%)
occurrences all number	2	17	14	1	3
Haemolysis
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1	1
Lymphadenopathy
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	2	0	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1	1
Eye disorders
Eye pain
subjects affected / exposed	1 / 10 (10.00%)	2 / 51 (3.92%)	1 / 37 (2.70%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	2	3	1	0	2
Dry eye
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	3	3	0	0
Conjunctival haemorrhage
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	2	0	2	2
Choroidal effusion
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1	1
Accommodation disorder
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	1	0	0	1
Gastrointestinal disorders
Enterocolitis
subjects affected / exposed	2 / 10 (20.00%)	5 / 51 (9.80%)	3 / 37 (8.11%)	0 / 4 (0.00%)	2 / 14 (14.29%)
occurrences all number	3	8	5	0	3
Gastritis
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	1	0	0	1
Constipation
subjects affected / exposed	0 / 10 (0.00%)	6 / 51 (11.76%)	6 / 37 (16.22%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	6	6	0	0
Chronic gastritis
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	1	0	0	1
Aphthous ulcer
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	1 / 37 (2.70%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	4	1	3	3
Anal haemorrhage
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	1	0	0	1
Abdominal pain upper
subjects affected / exposed	0 / 10 (0.00%)	6 / 51 (11.76%)	5 / 37 (13.51%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	7	5	2	2
Abdominal pain
subjects affected / exposed	1 / 10 (10.00%)	16 / 51 (31.37%)	13 / 37 (35.14%)	2 / 4 (50.00%)	3 / 14 (21.43%)
occurrences all number	1	21	17	3	4
Abdominal distension
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	2	0	0
Diarrhoea
subjects affected / exposed	0 / 10 (0.00%)	10 / 51 (19.61%)	9 / 37 (24.32%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	15	11	4	4
Stomatitis
subjects affected / exposed	1 / 10 (10.00%)	8 / 51 (15.69%)	6 / 37 (16.22%)	1 / 4 (25.00%)	2 / 14 (14.29%)
occurrences all number	1	10	6	3	4
Small intestinal obstruction
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	1	0	0	1
Periodontal disease
subjects affected / exposed	1 / 10 (10.00%)	2 / 51 (3.92%)	1 / 37 (2.70%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	2	1	0	1
Oral pain
subjects affected / exposed	1 / 10 (10.00%)	2 / 51 (3.92%)	1 / 37 (2.70%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	2	1	0	1
Oral blood blister
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	2	0	0
Odynophagia
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	3	0	3	3
Nausea
subjects affected / exposed	2 / 10 (20.00%)	20 / 51 (39.22%)	17 / 37 (45.95%)	1 / 4 (25.00%)	3 / 14 (21.43%)
occurrences all number	2	31	27	2	4
Mucous stools
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1	1
Mouth ulceration
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	1 / 37 (2.70%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	2	1	1	1
Haematochezia
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	3	0	3	3
Gingival swelling
subjects affected / exposed	0 / 10 (0.00%)	3 / 51 (5.88%)	3 / 37 (8.11%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	3	3	0	0
Gingival pain
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	2	0	0
Gingival hypertrophy
subjects affected / exposed	0 / 10 (0.00%)	7 / 51 (13.73%)	4 / 37 (10.81%)	3 / 4 (75.00%)	3 / 14 (21.43%)
occurrences all number	0	8	5	3	3
Gingival bleeding
subjects affected / exposed	0 / 10 (0.00%)	6 / 51 (11.76%)	5 / 37 (13.51%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	10	7	3	3
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	2	0	0
Tongue ulceration
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	2	0	2	2
Vomiting
subjects affected / exposed	1 / 10 (10.00%)	21 / 51 (41.18%)	18 / 37 (48.65%)	2 / 4 (50.00%)	3 / 14 (21.43%)
occurrences all number	1	38	31	6	7
Hepatobiliary disorders
Ocular icterus
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	3	3	0	0	3
Jaundice
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	2	0	0
Hyperbilirubinaemia
subjects affected / exposed	1 / 10 (10.00%)	3 / 51 (5.88%)	2 / 37 (5.41%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	2	4	2	0	2
Skin and subcutaneous tissue disorders
Skin hyperpigmentation
subjects affected / exposed	2 / 10 (20.00%)	4 / 51 (7.84%)	2 / 37 (5.41%)	0 / 4 (0.00%)	2 / 14 (14.29%)
occurrences all number	2	5	3	0	2
Acne
subjects affected / exposed	1 / 10 (10.00%)	2 / 51 (3.92%)	1 / 37 (2.70%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	2	1	0	1
Alopecia
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1	1
Ecchymosis
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	3	3	0	0	3
Erythema
subjects affected / exposed	0 / 10 (0.00%)	3 / 51 (5.88%)	1 / 37 (2.70%)	2 / 4 (50.00%)	2 / 14 (14.29%)
occurrences all number	0	3	1	2	2
Hirsutism
subjects affected / exposed	0 / 10 (0.00%)	5 / 51 (9.80%)	3 / 37 (8.11%)	2 / 4 (50.00%)	2 / 14 (14.29%)
occurrences all number	0	5	3	2	2
Petechiae
subjects affected / exposed	0 / 10 (0.00%)	5 / 51 (9.80%)	3 / 37 (8.11%)	2 / 4 (50.00%)	2 / 14 (14.29%)
occurrences all number	0	10	8	2	2
Pruritus
subjects affected / exposed	0 / 10 (0.00%)	5 / 51 (9.80%)	4 / 37 (10.81%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	5	4	1	1
Rash
subjects affected / exposed	1 / 10 (10.00%)	11 / 51 (21.57%)	10 / 37 (27.03%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	12	11	0	1
Rash maculo-papular
subjects affected / exposed	1 / 10 (10.00%)	4 / 51 (7.84%)	2 / 37 (5.41%)	1 / 4 (25.00%)	2 / 14 (14.29%)
occurrences all number	1	5	3	1	2
Rash papular
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1	1
Urticaria
subjects affected / exposed	1 / 10 (10.00%)	7 / 51 (13.73%)	6 / 37 (16.22%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	3	9	6	0	3
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 10 (10.00%)	5 / 51 (9.80%)	3 / 37 (8.11%)	1 / 4 (25.00%)	2 / 14 (14.29%)
occurrences all number	1	8	6	1	2
Azotaemia
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	1	0	0	1
Nephropathy toxic
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	1	0	0	1
Paroxysmal nocturnal haemoglobinuria
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	1	0	0	1
Renal failure
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1	1
Renal impairment
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1	1
Renal tubular acidosis
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1	1
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	2 / 10 (20.00%)	3 / 51 (5.88%)	1 / 37 (2.70%)	0 / 4 (0.00%)	2 / 14 (14.29%)
occurrences all number	2	3	1	0	2
Cushingoid
subjects affected / exposed	1 / 10 (10.00%)	2 / 51 (3.92%)	1 / 37 (2.70%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	2	1	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 10 (10.00%)	6 / 51 (11.76%)	4 / 37 (10.81%)	1 / 4 (25.00%)	2 / 14 (14.29%)
occurrences all number	3	9	5	1	4
Kyphosis
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	1	0	0	1
Musculoskeletal chest pain
subjects affected / exposed	1 / 10 (10.00%)	2 / 51 (3.92%)	1 / 37 (2.70%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	3	2	0	1
Pain in extremity
subjects affected / exposed	2 / 10 (20.00%)	9 / 51 (17.65%)	5 / 37 (13.51%)	2 / 4 (50.00%)	4 / 14 (28.57%)
occurrences all number	3	11	6	2	5
Tendon pain
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1	1
Back pain
subjects affected / exposed	1 / 10 (10.00%)	4 / 51 (7.84%)	2 / 37 (5.41%)	1 / 4 (25.00%)	2 / 14 (14.29%)
occurrences all number	2	5	2	1	3
Infections and infestations
Bacterial disease carrier
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1	1
Vascular device infection
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	1	0	0	1
Tonsillitis
subjects affected / exposed	1 / 10 (10.00%)	5 / 51 (9.80%)	4 / 37 (10.81%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	8	7	0	1
Soft tissue infection
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	1	0	0	1
Rhinitis
subjects affected / exposed	2 / 10 (20.00%)	4 / 51 (7.84%)	2 / 37 (5.41%)	0 / 4 (0.00%)	2 / 14 (14.29%)
occurrences all number	2	5	3	0	2
Respiratory tract infection viral
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	1	0	0	1
Pharyngitis
subjects affected / exposed	1 / 10 (10.00%)	3 / 51 (5.88%)	2 / 37 (5.41%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	3	2	0	1
Paronychia
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	2	0	0
Nasopharyngitis
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	1 / 37 (2.70%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	2	1	1	1
Molluscum contagiosum
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1	1
Gingivitis
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	1	0	0	1
Fungal infection
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	1 / 37 (2.70%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	2	1	1	1
Escherichia bacteraemia
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	1	0	0	1
Epididymitis
subjects affected / exposed	0 / 10 (0.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1	1
COVID-19
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	2	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 10 (0.00%)	8 / 51 (15.69%)	7 / 37 (18.92%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	11	9	2	2
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	1 / 10 (10.00%)	5 / 51 (9.80%)	4 / 37 (10.81%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	6	5	0	1
Decreased appetite
subjects affected / exposed	0 / 10 (0.00%)	6 / 51 (11.76%)	5 / 37 (13.51%)	1 / 4 (25.00%)	1 / 14 (7.14%)
occurrences all number	0	6	5	1	1
Dehydration
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	2	0	0
Fluid retention
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	2	0	0
Hyperglycaemia
subjects affected / exposed	1 / 10 (10.00%)	4 / 51 (7.84%)	3 / 37 (8.11%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	9	8	0	1
Hyperkalaemia
subjects affected / exposed	2 / 10 (20.00%)	3 / 51 (5.88%)	1 / 37 (2.70%)	0 / 4 (0.00%)	2 / 14 (14.29%)
occurrences all number	6	7	1	0	6
Hypermagnesaemia
subjects affected / exposed	1 / 10 (10.00%)	1 / 51 (1.96%)	0 / 37 (0.00%)	0 / 4 (0.00%)	1 / 14 (7.14%)
occurrences all number	2	2	0	0	2
Hypervolaemia
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	2	0	0
Hypomagnesaemia
subjects affected / exposed	3 / 10 (30.00%)	19 / 51 (37.25%)	15 / 37 (40.54%)	1 / 4 (25.00%)	4 / 14 (28.57%)
occurrences all number	7	30	21	2	9
Hyponatraemia
subjects affected / exposed	1 / 10 (10.00%)	3 / 51 (5.88%)	1 / 37 (2.70%)	1 / 4 (25.00%)	2 / 14 (14.29%)
occurrences all number	1	5	1	3	4
Iron overload
subjects affected / exposed	2 / 10 (20.00%)	6 / 51 (11.76%)	4 / 37 (10.81%)	0 / 4 (0.00%)	2 / 14 (14.29%)
occurrences all number	2	6	4	0	2
Metabolic acidosis
subjects affected / exposed	1 / 10 (10.00%)	2 / 51 (3.92%)	0 / 37 (0.00%)	1 / 4 (25.00%)	2 / 14 (14.29%)
occurrences all number	1	3	0	2	3
Vitamin D deficiency
subjects affected / exposed	0 / 10 (0.00%)	2 / 51 (3.92%)	2 / 37 (5.41%)	0 / 4 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	2	0	0

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Were there any global substantial amendments to the protocol? Yes

25 Apr 2017

Provided further clarification of the study population in Cohort A. Provided dose modification guidelines for G3/4 AEs that are not liver related and are not AEs of special interest. Designated that selected hematology, biochemistry tests and Cyclosporine (CsA) levels could be performed by local lab to facilitate the management of the patients by the site.

16 Aug 2017

Modified the ECG monitoring plan to include ECG evaluations at Tmax (time of Cmax) after single dose and at steady-state with eltrombopag treatment. Updated to include additional ECG assessments.

21 Dec 2017

Introduced an optional consent form to allow for screening bone marrow aspirate and biopsy specimens to be sent to and analyzed by the central laboratory prior to enrollment.

05 Oct 2018

Provided guidance regarding the use of medications belonging to the azole class of antifungal agents. Provided guidance regarding patients already receiving CsA at the time of study entry. Provided guidance regarding appropriate follow up for patients who discontinue eltrombopag prior to completion of the 26-week Treatment Period. Clarified changes of tablets of eltrombopag used in this study, visit frequency during long-term follow up, and ECG monitoring plan.

20 Aug 2020

Aligned bone marrow aspirate collection with bone marrow biopsy at Week 12 and Week 78 in order to monitor clonal evolution in the early and late phases of study treatment. Clarified the secondary objectives. Clarified requirements prior to PK sampling. Modified the process of bone marrow karyotyping at screening and added additional probes to improve screening for chromosomal abnormalities. Clarified exclusion and inclusion criteria. Modified guidelines for eltrombopag dose adjustment. Clarified study treatment modifications in case of bone marrow fibrosis and cytogenetic abnormalities. Clarified which abnormalities will not be reported as AEs or SAEs. Modified clonal evolution reporting so that it is consistent across all ETB115 clinical trials. Modified treatment for eltrombopag and CsA to be permitted beyond Week 104.

16 Apr 2021

Aligned protocol sections 5.1 ‘Patient population’ and 10.8 ‘Sample size calculation’ to the Pediatric Investigation Plan (PIP) for SAA (EMEA-000170-PIP03-13-M04). Modified objective for exploratory biomarker analysis. Added, as per Novartis guidance, risk mitigation procedures during the public health emergency declared by local or regional authorities.

20 Apr 2022

Removed objective #14 exploratory biomarker analysis of assessing proteomics in urine samples as the sample size collected was inadequate to perform a rigorous data analysis and correlate with treatment effect. Clarified that eltrombopag re-initiation was allowed only during the Study Treatment phase until Week 26. Clarified that patients whose SAA progressed during the Follow-up and Long-term Follow-up Period were to be discontinued from the study and that they may receive any SAA therapy at the discretion of the treating physician outside this study. Clarified that any case of MDS or AML must be reported as an adverse event throughout the study, including the Follow-up Period or the Long-term Follow-up Period. Clarified that any cytogenetic abnormality detected was to be recorded in the Cytogenetics CRF, and if clinically significant, was to be reported as an adverse event. Clarified that SAA progression, as determined by the investigator, was to be reported as an adverse event throughout the study, including the Follow-up Period or the Long-term Follow-up Period. Clarified that patients who progressed to MDS/AML or receive HSCT will be discontinued from the study, and they will not to be monitored during the Follow-up and Long-term Follow-up periods.

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Eltrombopag PK parameters: AUCtau, AUClast

Primary: Eltrombopag PK parameters: AUCtau, AUClast

Primary: Eltrombopag PK parameter: Cmax

Primary: Eltrombopag PK parameter: Cmax

Primary: Eltrombopag PK parameter: Ctrough at the highest dose level

Primary: Eltrombopag PK parameter: Ctrough at the highest dose level

Secondary: Percentage of participants with an overall response and percentage of participants with a platelet response

Secondary: Percentage of participants with an overall response and percentage of participants with a platelet response

Secondary: Hematologic counts (platelets (blood), neutrophils (blood))

Secondary: Hematologic counts (platelets (blood), neutrophils (blood))

Secondary: Hematologic counts (hemoglobin (blood))

Secondary: Hematologic counts (hemoglobin (blood))

Secondary: Total duration of Red Blood Cell (RBC) transfusion independence during the treatment period

Secondary: Total duration of Red Blood Cell (RBC) transfusion independence during the treatment period

Secondary: Total duration of Platelet (PLT) transfusion independence during the treatment period

Secondary: Total duration of Platelet (PLT) transfusion independence during the treatment period

Secondary: Maximum duration of Red Blood Cell (RBC) transfusion independence

Secondary: Maximum duration of Red Blood Cell (RBC) transfusion independence

Secondary: Maximum duration of platelet (PLT) transfusion independence

Secondary: Maximum duration of platelet (PLT) transfusion independence

Secondary: Overall Bone marrow cellularity

Secondary: Overall Bone marrow cellularity

Secondary: Bone marrow morphology

Secondary: Bone marrow morphology

Secondary: Bone marrow cytogenetics

Secondary: Bone marrow cytogenetics

Secondary: Acceptability and palatability for both tablets and powder formulation for oral solution (PfOS)

Secondary: Acceptability and palatability for both tablets and powder formulation for oral solution (PfOS)

Secondary: Clonal evolution to Paroxysmal Nocturnal Hemoglobinuria (PNH)

Secondary: Clonal evolution to Paroxysmal Nocturnal Hemoglobinuria (PNH)

Secondary: Alternate overall response rate (aORR)

Secondary: Alternate overall response rate (aORR)

Secondary: Pharmacokinetics (PK) of eltrombopag at the starting dose (AUCtau)

Secondary: Pharmacokinetics (PK) of eltrombopag at the starting dose (AUCtau)

Secondary: PK of eltrombopag at the starting dose (Ctrough)

Secondary: PK of eltrombopag at the starting dose (Ctrough)

Secondary: PK of eltrombopag at the starting dose (Cmax)

Secondary: PK of eltrombopag at the starting dose (Cmax)

Secondary: Number of Red Blood Cells (RBC) transfusions

Secondary: Number of Red Blood Cells (RBC) transfusions

Secondary: Number of Platelet (PLT) transfusions

Secondary: Number of Platelet (PLT) transfusions

Secondary: Frequency of Red Blood Cell (RBC) transfusions

Secondary: Frequency of Red Blood Cell (RBC) transfusions

Secondary: Exposure (AUCtau) - response relationship of eltrombopag and overall response rate by age groups

Secondary: Exposure (AUCtau) - response relationship of eltrombopag and overall response rate by age groups

Secondary: Frequency of Platelet (PLT) transfusions

Secondary: Frequency of Platelet (PLT) transfusions

Secondary: Exposure (Cmax, Ctrough) - response relationship of eltrombopag and overall response rate by age groups

Secondary: Exposure (Cmax, Ctrough) - response relationship of eltrombopag and overall response rate by age groups

Secondary: Exposure (AUCtau) - response relationship of eltrombopag and platelet response rate by age groups

Secondary: Exposure (AUCtau) - response relationship of eltrombopag and platelet response rate by age groups

Secondary: Exposure (Cmax, Ctrough) - response relationship of eltrombopag and platelet response rate by age groups

Secondary: Exposure (Cmax, Ctrough) - response relationship of eltrombopag and platelet response rate by age groups

Post-hoc: All Collected Deaths

Post-hoc: All Collected Deaths

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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