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Clinical Trial Results:
A Phase I/II open-label, single-arm, multi-center study of ruxolitinib added to corticosteroids in pediatric subjects with Grade II-IV acute graft vs. host disease after allogeneic hematopoietic stem cell transplantation. 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/CtrdWeb/home.nov for complete trial results.

Summary
EudraCT number	2018-000422-55
Trial protocol	SI BE FR DE ES NL IT DK CZ
Global end of trial date	02 Feb 2023

Results information
Results version number	v1(current)
This version publication date	18 Aug 2023
First version publication date	18 Aug 2023
Other versions

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

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Trial information

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Sponsor protocol code

CINC424F12201

ISRCTN number

US NCT number

NCT03491215

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma, AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

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

Scientific contact

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

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000901-PIP03-16

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?

Yes

Analysis stage

Final

Date of interim/final analysis

02 Feb 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

02 Feb 2023

Was the trial ended prematurely?

Main objective of the trial

Phase l: To assess pharmacokinetic (PK) parameters of ruxolitinib for subjects with acute GvHD and SR-acute GvHD and define an age appropriate RP2D for each of the groups 2-4. .Group 2: age = 6 to < 12 years .Group 3: age = 2 to < 6 years .Group 4: age = 28 days to < 2 years Phase ll: To measure the activity of ruxolitinib in subjects with acute GvHD or SR-acute GvHD assessed by Overall Response Rate (ORR) at Day 28.

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

21 Feb 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 1

Country: Number of subjects enrolled

Denmark: 1

Country: Number of subjects enrolled

France: 14

Country: Number of subjects enrolled

Italy: 7

Country: Number of subjects enrolled

Belgium: 3

Country: Number of subjects enrolled

Japan: 6

Country: Number of subjects enrolled

Korea, Republic of: 5

Country: Number of subjects enrolled

Spain: 8

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

45 subjects enrolled in the study & treated with the confirmed RP2D; at least 20% had treatment naïve acute GvHD & at least 40% had SR-acute GvHD. Single arm study with subjects grouped as follows: Group 1: subjects ≥ 12y to < 18y, Group 2: subjects ≥ 6y to < 12y, Group 3: subjects ≥ 2y to < 6y, Group 4 was to include subjects ≥ 28 days to < 2y.

Screening details

Five subjects were to be enrolled to each age group with no minimum for Group 4. The study was conducted in 8 countries and 19 centers.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID

Arm description

All patients received ruxolitinib (RUX) 10 mg BID tablet in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Arm type

Experimental

Investigational medicinal product name

Ruxolitinib

Investigational medicinal product code

INC424

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ruxolitinib 10 mg BID

Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID

Arm description

All patients received RUX 5mg BID in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Arm type

Experimental

Investigational medicinal product name

Ruxolitinib

Investigational medicinal product code

INC424

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Ruxolitinib 5 mg hard non-gelatin capsule formulation

Investigational medicinal product name

Ruxolitinib

Investigational medicinal product code

INC424

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ruxolitinib 5 mg BID

Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID

Arm description

All patients received RUX 4mg/m^2 BID in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Arm type

Experimental

Investigational medicinal product name

Ruxolitinib

Investigational medicinal product code

INC424

Other name

Pharmaceutical forms

Oral liquid

Routes of administration

Oral use

Dosage and administration details

Ruxolitinib 4mg/m2 BID

Investigational medicinal product name

Ruxolitinib

Investigational medicinal product code

INC424

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Ruxolitinib 4mg/m2 BID

Number of subjects in period 1	Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID
Started	18	12	15
Completed	11	10	14
Not completed	7	2	1
Adverse event, serious fatal	6	2	1
Physician decision	1	-	-

Baseline characteristics

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Reporting group title

Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID

Reporting group description

All patients received ruxolitinib (RUX) 10 mg BID tablet in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Reporting group title

Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID

Reporting group description

All patients received RUX 5mg BID in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Reporting group title

Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID

Reporting group description

All patients received RUX 4mg/m^2 BID in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Reporting group values	Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID	Total
Number of subjects	18	12	15	45
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	12	15	27
Adolescents (12-17 years)	18	0	0	18
Adults (18-64 years)	0	0	0	0
From 65-84 years	0	0	0	0
85 years and over	0	0	0	0
Age Continuous
Units: Months
arithmetic mean (standard deviation)	172.7 ( 18.94 )	86.1 ( 11.08 )	45.5 ( 14.57 )	-
Sex: Female, Male
Units: Participants
Female	5	7	5	17
Male	13	5	10	28
Race/Ethnicity, Customized
Units: Subjects
White	11	5	4	20
Asian	3	3	5	11
Missing -Note: race is not collected in France	4	4	6	14

Subject analysis set title

Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID capsule

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received RUX 5mg BID capsule in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID liquid

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received RUX 4mg/m^2 BID liquid in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID tablet

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received RUX 5mg BID tablet in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received RUX 4mg/m^2 BID capsule in addition to corticosteroids +/- calcineurin inhibitor (CNI)

Subject analysis set title

Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID tablet

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received RUX 5mg BID tablet in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received RUX 4mg/m^2 BID capsule in addition to corticosteroids +/- calcineurin inhibitor (CNI)

Subject analysis set title

Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID liquid

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received RUX 4mg/m^2 BID liquid in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID tablet

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received RUX 5mg BID tablet in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received RUX 4mg/m^2 BID capsule in addition to corticosteroids +/- calcineurin inhibitor (CNI)

Subject analysis set title

Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received ruxolitinib (RUX) 10 mg BID in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

All subjects (Group 1, Group 2 & Group 3)

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received ruxolitinib (RUX) regardless of dose and age group, in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

All Subjects (Group 1, Group 2 & Group 3)

Subject analysis set type

Full analysis

Subject analysis set description

All patients received ruxolitinib (RUX) regardless of dose and age group, in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

All Subjects (Group 1, Group 2, & Group 3)

Subject analysis set type

Full analysis

Subject analysis set description

All patients received ruxolitinib (RUX) regardless of dose and age group, in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

All subjects (Group 1, Group 2 & Group 3)

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received ruxolitinib (RUX) regardless of dose and age group, in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

All subjects (Group 1, Group 2 & Group 3)

Subject analysis set type

Full analysis

Subject analysis set description

All patients received ruxolitinib (RUX) regardless of dose and age group, in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

Group 1: ≥ 12y to < 18y - RUX 10mg BID

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received ruxolitinib (RUX) 10 mg BID in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

Overall Response Rate (ORR) at Day 28 (>=2y-<6y)

Subject analysis set type

Sub-group analysis

Subject analysis set description

ORR is defined as the percentage of patients demonstrating a complete response (CR) or partial response (PR) without requirement for additional systemic therapies for an earlier progression, mixed response or non-response. This assessment is for participants in group 3.

Subject analysis set title

ORR at Day 28 (>=6y-<12y)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

ORR at Day 28 (>=12y-<18y)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Durable response rate (DRR) at Day 56 (>=2-<12)

Subject analysis set type

Sub-group analysis

Subject analysis set description

DRR at Day 56 was defined as the percentage of all subjects who achieved a complete response (CR) or partial response (PR) at Day 28 and maintained a CR or PR at Day 56. This assessment was for participants from age 12 years and above.

Subject analysis set title

AUClast Day 1: 1st quartile

Subject analysis set type

Sub-group analysis

Subject analysis set description

AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast).

Subject analysis set title

AUClast Day 1: 2nd quartile

Subject analysis set type

Sub-group analysis

Subject analysis set description

AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast).

Subject analysis set title

AUClast Day 1: 3rd quartile

Subject analysis set type

Sub-group analysis

Subject analysis set description

AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast).

Subject analysis set title

AUClast Day 1: 4th quartile

Subject analysis set type

Sub-group analysis

Subject analysis set description

AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast).

Subject analysis set title

Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received RUX 4mg/m^2 BID capsule in addition to corticosteroids +/- calcineurin inhibitor (CNI)

Subject analysis set title

Bleeding (>=2y-<6y)

Subject analysis set type

Sub-group analysis

Subject analysis set description

These are the participants who had at least one bleeding event in group 3.

Subject analysis set title

Bleeding (>=6y-<12y)

Subject analysis set type

Sub-group analysis

Subject analysis set description

These are the participants who had at least one bleeding event in group 2.

Subject analysis set title

Bleeding (>=12y-<18y

Subject analysis set type

Sub-group analysis

Subject analysis set description

These are the participants who had at least one bleeding event in group 1.

Subject analysis set title

Infection (>=2y-<6y

Subject analysis set type

Sub-group analysis

Subject analysis set description

These are the participants who had at least one infection in group 3.

Subject analysis set title

Infection (>=6y-<12y)

Subject analysis set type

Sub-group analysis

Subject analysis set description

These are the participants who had at least one infection in group 2.

Subject analysis set title

Infection (>=12y-<18y)

Subject analysis set type

Sub-group analysis

Subject analysis set description

These are the participants who had at least one infection in group 1.

Subject analysis sets values	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID capsule	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID liquid	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID tablet	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID tablet	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID liquid	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID tablet	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule	Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID	All subjects (Group 1, Group 2 & Group 3)	All Subjects (Group 1, Group 2 & Group 3)	All Subjects (Group 1, Group 2, & Group 3)	All subjects (Group 1, Group 2 & Group 3)	All subjects (Group 1, Group 2 & Group 3)	Group 1: ≥ 12y to < 18y - RUX 10mg BID	Overall Response Rate (ORR) at Day 28 (>=2y-<6y)	ORR at Day 28 (>=6y-<12y)	ORR at Day 28 (>=12y-<18y)	Durable response rate (DRR) at Day 56 (>=2-<12)	AUClast Day 1: 1st quartile	AUClast Day 1: 2nd quartile	AUClast Day 1: 3rd quartile	AUClast Day 1: 4th quartile	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule	Bleeding (>=2y-<6y)	Bleeding (>=6y-<12y)	Bleeding (>=12y-<18y	Infection (>=2y-<6y	Infection (>=6y-<12y)	Infection (>=12y-<18y)
Number of subjects	2	8	8	7	5	5	5	7	6	18	38	45	45	27	45	18	15	11	19	23	7	8	7	8	15	15	11	19	15	11	19
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age Continuous
Units: Months
arithmetic mean (standard deviation)	154 ( 58.1 )	259 ( 53.6 )	372 ( 58.6 )	239 ( 65.3 )	1.66 ( 17.5 )	1.86 ( 29.9 )	1.78 ( 66.3 )	9.07 ( 214.0 )	6.18 ( 195.8 )	83.3 ( )	( )	( )	( )	( )	( )	0.0 ( )	13 ( )	10 ( )	17 ( )	20 ( )	( )	( )	( )	( )	( )	( )	( )	( )	( )	( )	( )
Sex: Female, Male
Units: Participants
Female
Male
Race/Ethnicity, Customized
Units: Subjects
White
Asian
Missing -Note: race is not collected in France

End points

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Reporting group title

Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID

Reporting group description

All patients received ruxolitinib (RUX) 10 mg BID tablet in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Reporting group title

Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID

Reporting group description

All patients received RUX 5mg BID in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Reporting group title

Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID

Reporting group description

All patients received RUX 4mg/m^2 BID in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID capsule

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received RUX 5mg BID capsule in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID liquid

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received RUX 4mg/m^2 BID liquid in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID tablet

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received RUX 5mg BID tablet in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received RUX 4mg/m^2 BID capsule in addition to corticosteroids +/- calcineurin inhibitor (CNI)

Subject analysis set title

Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID tablet

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received RUX 5mg BID tablet in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received RUX 4mg/m^2 BID capsule in addition to corticosteroids +/- calcineurin inhibitor (CNI)

Subject analysis set title

Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID liquid

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received RUX 4mg/m^2 BID liquid in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID tablet

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received RUX 5mg BID tablet in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received RUX 4mg/m^2 BID capsule in addition to corticosteroids +/- calcineurin inhibitor (CNI)

Subject analysis set title

Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received ruxolitinib (RUX) 10 mg BID in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

All subjects (Group 1, Group 2 & Group 3)

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received ruxolitinib (RUX) regardless of dose and age group, in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

All Subjects (Group 1, Group 2 & Group 3)

Subject analysis set type

Full analysis

Subject analysis set description

All patients received ruxolitinib (RUX) regardless of dose and age group, in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

All Subjects (Group 1, Group 2, & Group 3)

Subject analysis set type

Full analysis

Subject analysis set description

All patients received ruxolitinib (RUX) regardless of dose and age group, in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

All subjects (Group 1, Group 2 & Group 3)

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received ruxolitinib (RUX) regardless of dose and age group, in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

All subjects (Group 1, Group 2 & Group 3)

Subject analysis set type

Full analysis

Subject analysis set description

All patients received ruxolitinib (RUX) regardless of dose and age group, in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

Group 1: ≥ 12y to < 18y - RUX 10mg BID

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received ruxolitinib (RUX) 10 mg BID in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Subject analysis set title

Overall Response Rate (ORR) at Day 28 (>=2y-<6y)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

ORR at Day 28 (>=6y-<12y)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

ORR at Day 28 (>=12y-<18y)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Durable response rate (DRR) at Day 56 (>=2-<12)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

AUClast Day 1: 1st quartile

Subject analysis set type

Sub-group analysis

Subject analysis set description

AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast).

Subject analysis set title

AUClast Day 1: 2nd quartile

Subject analysis set type

Sub-group analysis

Subject analysis set description

AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast).

Subject analysis set title

AUClast Day 1: 3rd quartile

Subject analysis set type

Sub-group analysis

Subject analysis set description

AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast).

Subject analysis set title

AUClast Day 1: 4th quartile

Subject analysis set type

Sub-group analysis

Subject analysis set description

AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast).

Subject analysis set title

Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients received RUX 4mg/m^2 BID capsule in addition to corticosteroids +/- calcineurin inhibitor (CNI)

Subject analysis set title

Bleeding (>=2y-<6y)

Subject analysis set type

Sub-group analysis

Subject analysis set description

These are the participants who had at least one bleeding event in group 3.

Subject analysis set title

Bleeding (>=6y-<12y)

Subject analysis set type

Sub-group analysis

Subject analysis set description

These are the participants who had at least one bleeding event in group 2.

Subject analysis set title

Bleeding (>=12y-<18y

Subject analysis set type

Sub-group analysis

Subject analysis set description

These are the participants who had at least one bleeding event in group 1.

Subject analysis set title

Infection (>=2y-<6y

Subject analysis set type

Sub-group analysis

Subject analysis set description

These are the participants who had at least one infection in group 3.

Subject analysis set title

Infection (>=6y-<12y)

Subject analysis set type

Sub-group analysis

Subject analysis set description

These are the participants who had at least one infection in group 2.

Subject analysis set title

Infection (>=12y-<18y)

Subject analysis set type

Sub-group analysis

Subject analysis set description

These are the participants who had at least one infection in group 1.

Primary: Phase I: Measurement of pharmacokinetic (PK) parameter, AUClast, in aGvHD and SR-aGvHD patients

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End point title

Phase I: Measurement of pharmacokinetic (PK) parameter, AUClast, in aGvHD and SR-aGvHD patients ^[1]

End point description

Measurement in acute GvHD and SR-acute GvHD subjects used extensive PK sampling in Groups 1-3 and sparse sampling in Group 4. AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast).

End point type

Primary

End point timeframe

Day 1

Notes
[1] - 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 statistical Analysis was planned.

End point values	Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID capsule	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID liquid	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID tablet	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule
Number of subjects analysed	5	2	8	8	7
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)	252 ( 186.6 )	154 ( 58.1 )	259 ( 53.6 )	372 ( 58.6 )	239 ( 65.3 )

Group 3 vs Group 2

Statistical analysis description

Group 3 vs Group 2

Comparison groups

Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID tablet v Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID capsule v Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule v Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID liquid

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[2]

Method

Parameter type

GMR

Point estimate

0.801

Confidence interval

level

90%

sides

2-sided

lower limit

0.49

upper limit

1.311

Notes
[2] - Comparison

Group 2 vs. Group 1

Statistical analysis description

Group 2 vs. Group 1

Comparison groups

Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID v Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID tablet v Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID capsule

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[3]

Method

Parameter type

GMR

Point estimate

1.237

Confidence interval

level

90%

sides

2-sided

lower limit

0.639

upper limit

2.394

Notes
[3] - Comparison

Group 3 vs. Group 1

Statistical analysis description

Group 3 vs. Group 1

Comparison groups

Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID v Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule v Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID liquid

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[4]

Method

Parameter type

GMR

Point estimate

0.991

Confidence interval

level

90%

sides

2-sided

lower limit

0.532

upper limit

1.846

Notes
[4] - Comparison

Primary: Phase I: Measurement of PK parameter, Cmax, in aGvHD and SR-aGvHD patients

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End point title

Phase I: Measurement of PK parameter, Cmax, in aGvHD and SR-aGvHD patients ^[5]

End point description

Measurement in acute GvHD and SR-acute GvHD subjects used extensive PK sampling in Groups 1-3 and sparse sampling in Group 4. Cmax: The maximum (peak) observed plasma drug concentration

End point type

Primary

End point timeframe

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 statistical Analysis was planned.

End point values	Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID capsule	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID liquid	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID tablet	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule
Number of subjects analysed	5	2	8	8	7
Units: ng/ML
geometric mean (geometric coefficient of variation)	66.1 ( 169.8 )	49.4 ( 45.7 )	66.5 ( 60.8 )	105 ( 71.4 )	61.2 ( 81.1 )

Group 3 vs. Group 2

Statistical analysis description

Group 3 vs. Group 2

Comparison groups

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[6]

Method

Parameter type

GMR

Point estimate

0.709

Confidence interval

level

90%

sides

2-sided

lower limit

0.425

upper limit

1.184

Notes
[6] - Comparison

Group 3 vs. Group 1

Statistical analysis description

Group 3 vs. Group 1

Comparison groups

Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID v Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule v Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID liquid

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[7]

Method

Parameter type

GMR

Point estimate

0.968

Confidence interval

level

90%

sides

2-sided

lower limit

0.506

upper limit

1.851

Notes
[7] - Comparison

Group 2 vs. Group 1

Statistical analysis description

Group 2 vs. Group 1

Comparison groups

Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID v Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID tablet v Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID capsule

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[8]

Method

Parameter type

GMR

Point estimate

1.365

Confidence interval

level

90%

sides

2-sided

lower limit

0.686

upper limit

2.714

Notes
[8] - Comparison

Primary: Phase I: Measurement of PK parameter, T1/2, in aGvHD and SR-aGvHD patients

Top of page

End point title

Phase I: Measurement of PK parameter, T1/2, in aGvHD and SR-aGvHD patients ^[9] ^[10]

End point description

Measurement in acute GvHD and SR-acute GvHD subjects used extensive PK sampling in Groups 1-3 and sparse sampling in Group 4. T1/2: The elimination half-life associated with the terminal slope (Lambda_z ) of a semi logarithmic concentration-time curve

End point type

Primary

End point timeframe

Day 1

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

End point values	Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID capsule	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID tablet	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID liquid
Number of subjects analysed	2	2	5	5	5
Units: ng/ml
geometric mean (geometric coefficient of variation)	1.33 ( 31.7 )	1.50 ( 6.5 )	1.66 ( 17.5 )	1.86 ( 29.9 )	1.78 ( 66.3 )

No statistical analyses for this end point

Primary: Phase I: Measurement of PK parameter, Ctrough, in aGvHD and SR-aGvHD patients

Top of page

End point title

Phase I: Measurement of PK parameter, Ctrough, in aGvHD and SR-aGvHD patients ^[11]

End point description

Measurement in acute GvHD and SR-acute GvHD subjects used extensive PK sampling in Groups 1-3 and sparse sampling in Group 4. Ctrough: The minimum observed plasma concentration at the end of an administration interval (corresponding to the pre-dose concentration prior to the following administration).

End point type

Primary

End point timeframe

Day 7

Notes
[11] - 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 statistical Analysis was planned.

End point values	Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID capsule	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID liquid	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID tablet	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule
Number of subjects analysed	6	2	8	7	6
Units: ng/ml
geometric mean (geometric coefficient of variation)	8.85 ( 538.6 )	1.71 ( 1.2 )	3.99 ( 277.1 )	9.07 ( 214.0 )	6.18 ( 195.8 )

Group 3 vs. Group 2

Statistical analysis description

Group 3 vs. Group 2

Comparison groups

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[12]

Method

Parameter type

GMR

Point estimate

0.765

Confidence interval

level

90%

sides

2-sided

lower limit

0.256

upper limit

2.28

Notes
[12] - Comparison

Group 2 vs. Group 1

Statistical analysis description

Group 2 vs. Group 1

Comparison groups

Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID v Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID tablet v Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID capsule

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[13]

Method

Parameter type

GMR

Point estimate

0.707

Confidence interval

level

90%

sides

2-sided

lower limit

0.178

upper limit

2.817

Notes
[13] - Comparison

Group 3 vs. Group 1

Statistical analysis description

Group 3 vs. Group 1

Comparison groups

Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID v Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule v Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID liquid

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[14]

Method

Parameter type

GMR

Point estimate

0.541

Confidence interval

level

90%

sides

2-sided

lower limit

0.145

upper limit

2.023

Notes
[14] - Comparison

Primary: Phase I: Age-based determination of recommended phase 2 dose (RP2D) for each of the groups 2 - 4 using AUClast

Top of page

End point title

Phase I: Age-based determination of recommended phase 2 dose (RP2D) for each of the groups 2 - 4 using AUClast ^[15] ^[16]

End point description

Phase I: Age-based determination of RP2D was be based on observed PK parameters: • Group 2: age ≥ 6 to < 12 years • Group 3: age ≥ 2 to < 6 years • Group 4: age = 28 days to < 2 years The RP2D for Groups 2 and 3 was assessed for both activity and safety in Phase II, over a 24-week period. AUClast: The AUC from time zero to the last measurable concentration sampling time (Tlast).

End point type

Primary

End point timeframe

28 Days

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical Analysis was planned.
[16] - 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 statistical Analysis was planned.

End point values	Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID capsule	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID liquid	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID tablet	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule
Number of subjects analysed	5	2	8	8	7
Units: h*ng/mL
geometric mean (geometric coefficient of variation)	252 ( 186.6 )	154 ( 58.1 )	259 ( 53.6 )	372 ( 58.6 )	239 ( 65.3 )

No statistical analyses for this end point

Primary: Phase I: Age-based determination of recommended phase 2 dose (RP2D) for each of the groups 2 - 4 using Cmax

Top of page

End point title

Phase I: Age-based determination of recommended phase 2 dose (RP2D) for each of the groups 2 - 4 using Cmax ^[17] ^[18]

End point description

Phase I: Age-based determination of RP2D was be based on observed PK parameters: • Group 2: age ≥ 6 to < 12 years • Group 3: age ≥ 2 to < 6 years • Group 4: age = 28 days to < 2 years The RP2D for Groups 2 and 3 was assessed for both activity and safety in Phase II, over a 24-week period. Cmax: The maximum (peak) observed plasma drug concentration.

End point type

Primary

End point timeframe

28 Days

Notes
[17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical Analysis was planned.
[18] - 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 statistical Analysis was planned.

End point values	Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID capsule	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID liquid	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID tablet	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule
Number of subjects analysed	5	2	8	8	7
Units: ng/mL
geometric mean (geometric coefficient of variation)	66.1 ( 169.8 )	49.4 ( 45.7 )	66.5 ( 60.8 )	105 ( 71.4 )	61.2 ( 81.1 )

No statistical analyses for this end point

Primary: Phase I: Age-based determination of recommended phase 2 dose (RP2D) for each of the groups 2 - 4 using Ctrough

Top of page

End point title

Phase I: Age-based determination of recommended phase 2 dose (RP2D) for each of the groups 2 - 4 using Ctrough ^[19] ^[20]

End point description

Phase I: Age-based determination of RP2D was be based on observed PK parameters: • Group 2: age ≥ 6 to < 12 years • Group 3: age ≥ 2 to < 6 years • Group 4: age = 28 days to < 2 years The RP2D for Groups 2 and 3 was assessed for both activity and safety in Phase II, over a 24-week period. Ctrough: The minimum observed plasma concentration at the end of an administration interval (corresponding to the pre-dose concentration prior to the following administration).

End point type

Primary

End point timeframe

28 Days

Notes
[19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical Analysis was planned.
[20] - 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 statistical Analysis was planned.

End point values	Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID capsule	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID liquid	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID tablet	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule
Number of subjects analysed	6	2	8	8	6
Units: ng/ml
geometric mean (geometric coefficient of variation)	8.85 ( 538.6 )	1.71 ( 1.2 )	3.99 ( 277.1 )	10.6 ( 208.1 )	6.18 ( 195.8 )

No statistical analyses for this end point

Primary: Phase II: Overall response rate (ORR)

Top of page

End point title

Phase II: Overall response rate (ORR) ^[21] ^[22]

End point description

Phase II: ORR is defined as the percentage of patients demonstrating a complete response (CR) or partial response (PR) without requirement for additional systemic therapies for an earlier progression, mixed response or non-response. Scoring of response was relative to the organ stage at the start of the study treatment.

End point type

Primary

End point timeframe

Day 28

Notes
[21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical Analysis was planned.
[22] - 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 statistical Analysis was planned.

End point values	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID	Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID
Number of subjects analysed	12	15	18
Units: Percentage of participants
number (confidence interval 90%)	83.3 (56.2 to 97.0)	86.7 (63.7 to 97.6)	83.3 (62.3 to 95.3)

No statistical analyses for this end point

Secondary: Percentage of all patients who achieved a complete response (CR) or partial response (PR) (Durable Overall Response Rate (ORR))

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End point title

Percentage of all patients who achieved a complete response (CR) or partial response (PR) (Durable Overall Response Rate (ORR)) ^[23]

End point description

Durable ORR at Day 56 was defined as the percentage of all subjects who achieved a complete response (CR) or partial response (PR) at Day 28 and maintained a CR or PR at Day 56. Complete-response was defined as a score of 0 for the acute GvHD grading in all evaluable organs that indicates complete resolution of all signs and symptoms of acute GvHD in all evaluable organs without administration of additional systemic therapies for any earlier progression, mixed response or non-response of acute GvHD. Partial response was defined as improvement of 1 stage in 1 or more organs involved with acute GvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapies for an earlier progression, mixed response or non-response of acute GvHD.

End point type

Secondary

End point timeframe

Day 56

Notes
[23] - 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 statistical Analysis was planned.

End point values	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID	Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID
Number of subjects analysed	12	15	18
Units: Percentage of participants
number (confidence interval 90%)	75.0 (47.3 to 92.8)	73.3 (48.9 to 90.3)	55.6 (34.1 to 75.6)

No statistical analyses for this end point

Secondary: Percentage of patients who achieved OR (CR+PR) at Day 14

Top of page

End point title

Percentage of patients who achieved OR (CR+PR) at Day 14 ^[24]

End point description

ORR at Day 14 was defined as the proportion of subjects with CR or PR at Day 14 according to standard criteria.

End point type

Secondary

End point timeframe

Day 14

Notes
[24] - 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 statistical Analysis was planned.

End point values	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID	Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID
Number of subjects analysed	12	15	18
Units: Percentage of participants
number (confidence interval 90%)	66.7 (39.1 to 87.7)	86.7 (63.7 to 97.6)	72.2 (50.2 to 88.4)

No statistical analyses for this end point

Secondary: PK parameter: Area under the curve (AUClast) versus safety

Top of page

End point title

PK parameter: Area under the curve (AUClast) versus safety

End point description

To assess pharmacokinetic/pharmacodynamic relationship (comparison of AUClast with safety). This analysis includes subjects from both F12201 study (pediatrics) and C2301 study (adolescents+adults).

End point type

Secondary

End point timeframe

24 weeks

End point values	Bleeding (>=2y-<6y)	Bleeding (>=6y-<12y)	Bleeding (>=12y-<18y	Infection (>=2y-<6y	Infection (>=6y-<12y)	Infection (>=12y-<18y)
Number of subjects analysed	15	11	19	15	11	19
Units: Rvent rate
number (not applicable)	6.7	18.2	26.3	60	63.6	52.6

No statistical analyses for this end point

Secondary: Duration of response (DOR)

Top of page

End point title

Duration of response (DOR)

End point description

Duration of response was defined as the time from first response (PR or CR) until acute GvHD progression, or the date of additional systemic therapy for acute GvHD. Death without prior observation of acute GvHD progression, and onset of chronic GvHD are considered to be competing risks. Duration of response will be censored at the last response assessment prior to or at the analysis cut-off date, if no events/competing risks occurred on or before 4 weeks (28 days) after the last GvHD assessment. The estimated probability of loss of response at 1, 2 and 6 months after participant's first achievement of CR or PR has been reported.

End point type

Secondary

End point timeframe

Months 1, 2 & 6

End point values	All subjects (Group 1, Group 2 & Group 3)
Number of subjects analysed	38
Units: Probability of loss of response
number (confidence interval 95%)
1 Month	2.63 (0.20 to 11.98)
2 Months	5.41 (0.95 to 16.13)
6 Months	20.37 (8.74 to 35.40)

No statistical analyses for this end point

Secondary: Weekly cumulative steroid dose for each patient up to Day 56

Top of page

End point title

Weekly cumulative steroid dose for each patient up to Day 56 ^[25]

End point description

The weekly cumulative steroid dose was calculated for each subject up to Day 56 and the overall cumulative steroid dose was calculated for each subject at Day 56.

End point type

Secondary

End point timeframe

up to 56 days (Week 1 - Week 8)

Notes
[25] - 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 statistical Analysis was planned.

End point values	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID	Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID
Number of subjects analysed	12	15	18
Units: mg/kg
arithmetic mean (standard deviation)
Week 1	14.1 ( 4.60 )	11.9 ( 5.32 )	12.6 ( 6.04 )
Week 2	26.1 ( 9.91 )	21.0 ( 8.03 )	21.9 ( 10.79 )
Week 3 (n = 17, 12, 15)	36.5 ( 17.18 )	29.0 ( 10.20 )	30.1 ( 16.14 )
Week 4 ( n= 16, 10, 14)	46.9 ( 24.91 )	36.8 ( 12.95 )	37.5 ( 21.19 )
Week 5 (n = 16, 10, 14)	55.2 ( 31.52 )	42.0 ( 14.76 )	42.6 ( 24.05 )
Week 6 (n =13, 10, 10)	61.8 ( 35.80 )	48.8 ( 17.68 )	48.9 ( 24.57 )
Week 7 ( n = 11, 9, 10	60.6 ( 35.75 )	53.7 ( 19.32 )	51.5 ( 28.34 )
Weel 8 (n = 9, 7, 10)	73.6 ( 43.11 )	58.1 ( 20.50 )	61.3 ( 30.29 )

No statistical analyses for this end point

Secondary: Overall Survival (OS) per Kaplan Meier

Top of page

End point title

Overall Survival (OS) per Kaplan Meier

End point description

OS is defined as the time from the start of treatment to the date of death due to any cause. If a subject was not known to have died, then OS was censored at the latest date the subject was known to be alive. The estimated survival probability at 1,2,6,12,18 months after start of treatment has been reported. (on or before the cut-off date).

End point type

Secondary

End point timeframe

1 Month (M), 2 M, 6M, 12M, 18M

End point values	All Subjects (Group 1, Group 2 & Group 3)
Number of subjects analysed	45
Units: survival probability
number (confidence interval 95%)
1 Month	100 (100 to 100)
2 Months	100 (100 to 100)
6 Months	93.33 (80.74 to 97.80)
12 Months	88.83 (75.22 to 95.19)
18 Months	79.72 (64.64 to 88.90)

No statistical analyses for this end point

Secondary: Event-Free Survival (EFS) per Kaplan-Meier estimates

Top of page

End point title

Event-Free Survival (EFS) per Kaplan-Meier estimates

End point description

EFS is defined as the time from start of treatment to the date of hematologic disease relapse/progression, graft failure, or death due to any cause. If a subject was not known to have any event, then EFS was censored at the latest date the subject was known to be alive (on or before the cut-off date).The estimated probability of event free at 1,2,6,12,18 months after start of treatment has been reported.

End point type

Secondary

End point timeframe

1 Month (M), 2 M, 6M, 12M, 18M

End point values	All Subjects (Group 1, Group 2 & Group 3)
Number of subjects analysed	45
Units: probability of event free
number (confidence interval 95%)
1 Month	100 (100 to 100)
2 Months	97.78 (88.25 to 99.68)
6 Months	91.11 (78.03 to 96.57)
12 Months	86.61 (72.59 to 93.75)
18 Months	79.77 (64.72 to 88.93)

No statistical analyses for this end point

Secondary: Failure-Free Survival (FFS)

Top of page

End point title

Failure-Free Survival (FFS)

End point description

Failure-free survival was defined as the time from start date of treatment to any of the following: hematologic relapse/progression, non-relapse mortality (NRM) or addition of new systemic acute GvHD treatment. The estimated probability of the onset of failure event at 1,2,6,12,18,24 months after start of treatment has been reported.

End point type

Secondary

End point timeframe

1 Month (M), 2M, 6M, 12M, 18M, 24M

End point values	All Subjects (Group 1, Group 2, & Group 3)
Number of subjects analysed	45
Units: Prob. of the onset of failure event
number (confidence interval 95%)
1 Month	11.11 (4.02 to 22.27)
2 Months	13.33 (5.34 to 25.01)
6 Months	26.67 (14.72 to 40.18)
12 Months	26.67 (14.72 to 40.18)
18 Months	28.97 (16.48 to 42.68)
24 Months	28.97 (16.48 to 42.68)

No statistical analyses for this end point

Secondary: Non Relapse Mortality (NRM)

Top of page

End point title

Non Relapse Mortality (NRM)

End point description

NRM is defined as the time from start of treatment to date of death not preceded by hematologic disease relapse/progression. The estimated probability of non-relapse mortality at 1,2,6,12,16,24 months after start of treatment has been reported.

End point type

Secondary

End point timeframe

Month (M) 1, M2, M6, M12, M18, M24

End point values	All Subjects (Group 1, Group 2 & Group 3)
Number of subjects analysed	45
Units: Probability of non-relapse mortality
number (confidence interval 95%)
1 Month	999 (999 to 999)
2 Months	999 (999 to 999)
6 Months	4.44 (0.79 to 13.47)
12 Months	8.95 (2.81 to 19.58)
18 Months	13.50 (5.40 to 25.31)
24 Months	13.50 (5.40 to 25.31)

No statistical analyses for this end point

Secondary: Incidence of Malignancy Relapse/Progression (MR)

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End point title

Incidence of Malignancy Relapse/Progression (MR)

End point description

MR was defined as the time from start of treatment to hematologic malignancy relapse/progression. Calculated for patients with underlying hematologic malignant disease. The estimated probability of non-relapse mortality at 1,2,6,12,16,24 months after start of treatment has been reported.

End point type

Secondary

End point timeframe

Month (M) 1, M2, M6, M12, M18, M24,

End point values	All subjects (Group 1, Group 2 & Group 3)
Number of subjects analysed	27
Units: Prob. of malignancy relapse/progression
number (confidence interval 95%)
Month 1	999 (999 to 999)
Month 2	3.70 (0.25 to 16.23)
Month 6	7.41 (1.24 to 21.37)
12 Months	7.41 (1.24 to 21.37)
18 Months	11.28 (2.74 to 26.60)
Month 24	11.28 (2.74 to 26.60)

No statistical analyses for this end point

Secondary: Cumulative Incidence of cGvHD

Top of page

End point title

Cumulative Incidence of cGvHD

End point description

cGvHD is defined as the diagnosis of any cGvHD including mild, moderate, severe. Incidence of chronic GvHD was the time from the start of treatment to onset of chronic GvHD. Cumulative incidence of chronic GvHD was estimated, accounting for deaths without prior onset of chronic GvHD and hematologic disease relapse/progression as the competing risks. The estimated probability of cGvHD at 1, 2, 6, 12, 18 and 24 months after start of treatment has been reported.

End point type

Secondary

End point timeframe

Month (M) 1, M2, M6, M12, M18, M24

End point values	All subjects (Group 1, Group 2 & Group 3)
Number of subjects analysed	45
Units: Probability of the onset of cGvHD
number (confidence interval 95%)
1 Month	999 (999 to 999)
2 Months	2.22 (0.17 to 10.29)
6 Months	11.11 (4.01 to 22.29)
12 Months	20.07 (9.80 to 32.94)
18 Months	24.65 (13.11 to 38.09)
24 Months	24.65 (13.11 to 38.09)

No statistical analyses for this end point

Secondary: Graft Failure

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End point title

Graft Failure ^[26]

End point description

This was assessed by donor cell chimerism, defined as initial whole blood or marrow donor chimerism for those who had ≥5% donor cell chimerism at baseline. If donor cell chimerism declined to <5% on subsequent measurements, graft failure was declared.

End point type

Secondary

End point timeframe

2 years

Notes
[26] - 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 statistical Analysis was planned.

End point values	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID	Group 1: ≥ 12y to < 18y - RUX 10mg BID
Number of subjects analysed	12	15	18
Units: Percentage of participants
number (not applicable)	0.0	0.0	0.0

No statistical analyses for this end point

Secondary: Questionnaire on acceptability and palatability

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End point title

Questionnaire on acceptability and palatability

End point description

Responses from the acceptability and palatability of the study drug (only for subjects administered with oral pediatric formulation starting treatment Day 1) were evaluated from a questionnaire completed by subjects, with the help from parents or caregivers as needed at the following visits: Day 1 (after first dose), Week 4 (1 month) ((after either morning or evening dose of that visit date), Week 24 (6 months) (after either morning or evening dose of that visit date). The choices for taste of the medication were, 'Not good or bad', 'Very good or Good', or 'Bad'. The choices for aftertaste of the medication were, 'Not good or bad' or 'Bad'. The choices for the smell of the medication were, 'Not good or bad' or 'Bad'.

End point type

Secondary

End point timeframe

Day 1, Week 4 (1 month), Week 24 (6 months)

End point values	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID capsule	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID liquid	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule
Number of subjects analysed	2	8	7
Units: Responses from participants
Day 1: Evaluator: Patient	0	1	0
Day 1: Evaluator: Legal guardian	0	3	0
Day 1: Evaluator: Parent	1	2	4
Day 1: Evaluator: Caregiver	0	1	0
Day 1: Evaluator: Health care professional	1	1	3
Day 1: Taste of Medicine: Very good	0	3	0
Day 1: Taste of Medicine: Good	1	2	0
Day 1: Taste of Medicine: Not good or bad	1	0	3
Day 1: Taste of Medicine: Bad	0	0	2
Day 1: Taste of Med: Unable to answer question	0	3	2
Day 1: Aftertaste of Medicine: Very good	0	1	0
Day 1: Aftertaste of Medicine: Good	0	1	1
Day 1: Aftertaste of Medicine: Not good or bad	2	1	3
Day 1: Aftertaste of Medicine: Bad	0	0	2
Day 1: Aftertaste of Medicine: Very bad	0	1	0
Day1:Aftertaste of Med:Unable to answer question	0	4	1
Day 1: Smell of Medicine: Very good	0	1	0
Day 1: Smell of Medicine: Good	0	1	0
Day 1: Smell of Medicine: Not good or bad	2	3	4
Day 1: Smell of Medicine: Bad	0	0	1
Day 1: Smell of Med: Unable to answer question	0	3	2
Week 4: Evaluator: Legal guardian	0	2	1
Week 4: Evaluator: Parent	1	4	5
Week 4: Evaluator: Health care professional	1	2	0
W4: Evaluator: NA as pt. disc. before assessment	0	0	1
Week 4: Taste of Medicine: Good	2	4	1
Week 4: Taste of Medicine: Not good or bad	0	1	4
Week 4: Taste of Medicine: Very bad	0	0	1
W4:Taste of Med: Unable to answer the question	0	3	0
W4: Taste of Med: NA as pt. disc. before assess.	0	0	1
Week 4: Aftertaste of Medicine: Good	0	2	1
Week 4: Aftertaste of Medicine: Not good or bad	2	1	3
Week 4: Aftertaste of Medicine: Bad	0	0	1
W4: Aftertaste of Med:Unable to answer the quest	0	5	1
Wk4:Aftertaste of Med:NA pt. disc b4 asses	0	0	1
Week 4: Smell of Medicine: Very good	0	1	0
Week 4: Smell of Medicine: Not good or bad	2	3	5
Week 4: Smell of Medicine: Bad	0	1	0
W4: Smell of Med: Unable to answer the quest.	0	3	1
W4: Smell of Med: NA pt. disc. b4 asses.	0	0	1
Week 24: Evaluator: Patient	0	1	1
Week 24: Evaluator: Parent	0	0	1
W24: Evaluator: Health care professional	0	1	0
W24: Evaluator: NA as pt. disc. b4 assess	2	6	5
Week 24: Taste of Medicine: Very good	0	2	0
Week 24: Taste of Medicine: Good	0	0	1
W24: Taste of Medicine: Not good or bad	0	0	1
W24:Taste of Med: NA as pt. disc. before assess.	2	6	5
Week 24: Aftertaste of Medicine: Very good	0	1	0
W24: Aftertaste of Medicine: Not good or bad	0	0	2
W24:Aftertaste of Med: Unable to answer question	0	1	0
W24: Aftertaste of Med: NA as pt. disc. b4 asses.	2	6	5
Week 24: Smell of Medicine: Very good	0	1	0
Week 24: Smell of Medicine: Good	0	1	0
Week 24: Smell of Medicine: Not good or bad	0	0	2
W24: Smell of Med: NA as pt. disc. b4 asses.	2	6	5

No statistical analyses for this end point

Secondary: PK parameter - maximum serum concentration (Cmax) versus efficacy

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End point title

PK parameter - maximum serum concentration (Cmax) versus efficacy ^[27]

End point description

To assess pharmacokinetic/pharmacodynamic relationship (comparison of Cmax with efficacy). Cmax: The maximum (peak) observed plasma drug concentration.

End point type

Secondary

End point timeframe

24 weeks

Notes
[27] - 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 statistical Analysis was planned.

End point values	Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID
Number of subjects analysed	0 ^[28]
Units: ng/ML
geometric mean (geometric coefficient of variation)	( )

Notes
[28] - The relationship between Cmax & efficacy was not investigated.

No statistical analyses for this end point

Secondary: PK parameter: Minimum serum concentration (Ctrough) versus safety

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End point title

PK parameter: Minimum serum concentration (Ctrough) versus safety ^[29]

End point description

To assess pharmacokinetic/pharmacodynamic relationships (comparison of Ctrough with safety). Ctrough: The minimum observed plasma concentration at the end of an administration interval (corresponding to the pre-dose concentration prior to the following administration).

End point type

Secondary

End point timeframe

24 weeks

Notes
[29] - 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 statistical Analysis was planned.

End point values	Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID
Number of subjects analysed	0 ^[30]
Units: ng/ml
geometric mean (geometric coefficient of variation)	( )

Notes
[30] - The relationship between Ctrough & safety was not investigated.

No statistical analyses for this end point

Secondary: PK parameter: Cmax versus safety

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End point title

PK parameter: Cmax versus safety ^[31]

End point description

To assess pharmacokinetic/pharmacodynamics relationship (comparison of Cmax with safety). Cmax: The maximum (peak) observed plasma drug concentration.

End point type

Secondary

End point timeframe

24 weeks

Notes
[31] - 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 statistical Analysis was planned.

End point values	Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID
Number of subjects analysed	0 ^[32]
Units: ng/ML
geometric mean (geometric coefficient of variation)	( )

Notes
[32] - The relationship between Cmax & safety was not investigated.

No statistical analyses for this end point

Secondary: PK parameter: AUClast versus efficacy

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End point title

PK parameter: AUClast versus efficacy

End point description

To assess the pharmacokinetic/pharmacodynamics relationship (comparison of AUClast with efficacy) by means of responders. This analysis includes subjects from both F12201 study (pediatrics) and C2301 study (adolescents + adults). Median taAUC was derived based on PopPK predicted time-averaged AUC0-12 until response.

End point type

Secondary

End point timeframe

Day 28 (OR), Day 56 (DRR)

End point values	Overall Response Rate (ORR) at Day 28 (>=2y-<6y)	ORR at Day 28 (>=6y-<12y)	ORR at Day 28 (>=12y-<18y)	Durable response rate (DRR) at Day 56 (>=2-<12)
Number of subjects analysed	15	11	19	23
Units: response rate
number (not applicable)	86.7	90.9	89.5	87

No statistical analyses for this end point

Secondary: PK parameter: Ctrough versus efficacy

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End point title

PK parameter: Ctrough versus efficacy ^[33]

End point description

To assess pharmacokinetic/pharmacodynamics relationship (comparison of Ctrough with efficacy). Ctrough: The minimum observed plasma concentration at the end of an administration interval (corresponding to the pre-dose concentration prior to the following administration).

End point type

Secondary

End point timeframe

24 weeks

Notes
[33] - 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 statistical Analysis was planned.

End point values	Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID
Number of subjects analysed	0 ^[34]
Units: ng/ml
geometric mean (geometric coefficient of variation)	( )

Notes
[34] - The relationship between Ctrough & efficacy was not investigated.

No statistical analyses for this end point

Secondary: PK parameter: AUClast versus PD biomarkers

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End point title

PK parameter: AUClast versus PD biomarkers

End point description

Describe the relationship between AUC and PD biomarkers. This analysis includes subjects from both F12201 study (pediatrics) and C2301 study adolescents+adults). Population was divided by four level of exposure using AUClast Day 1 quartiles.

End point type

Secondary

End point timeframe

Week 4

End point values	AUClast Day 1: 1st quartile	AUClast Day 1: 2nd quartile	AUClast Day 1: 3rd quartile	AUClast Day 1: 4th quartile
Number of subjects analysed	7	8	7	8
Units: Week 4 percentage change from baseline
median (inter-quartile range (Q1-Q3))
Biomarker: IL10	0.00 (-85.64 to 225.33)	-22.43 (-76.22 to 0.00)	-79.71 (-89.63 to -47.49)	-50.72 (-58.01 to 73.55)
Biomarker: IL6	-59.48 (-69.78 to 0.00)	-10.40 (-80.48 to 0.00)	0.00 (-67.78 to 0.00)	181.48 (0.00 to 376.54)
Biomarker: IL8	-63.63 (-70.48 to -21.03)	42.57 (-22.15 to 201.65)	31.79 (-48.56 to 329.67)	60.02 (-41.74 to 280.49)
Biomarker: TNFA	-61.45 (-74.05 to -56.96)	0.00 (-31.03 to 33.67)	-35.34 (-65.90 to -1.41)	21.49 (-48.52 to 311.76)
Biomarker: CD4 Assay (CD4 T cells) (%),	-40.49 (-42.67 to -35.51)	98.07 (16.40 to 206.34)	-3.07 (-17.66 to 115.79)	-42.67 (-62.47 to 92.71)
Biomarker: CD8 Assay (CD8 T cells) (%),	-51.80 (-69.95 to -20.07)	64.71 (6.18 to 118.32)	104.17 (-34.38 to 270.84)	33.77 (-76.27 to 114.61)
Biomarker: FOXP3 Assay (Treg cells) (%)	115.79 (-26.03 to 124.24)	43.15 (2.08 to 52.17)	57.14 (-16.49 to 79.73)	-11.11 (-60.56 to 119.05)
Biomarker: IL14A Assay (Th17 cells) (%)	5.33 (-33.75 to 10.78)	140.91 (-25.53 to 570.83)	-7.69 (-18.92 to 131.25)	38.73 (-57.47 to 203.45)
Biomarker: LRP5 Assay (B cells) (%),	-15.00 (-30.00 to 122.78)	25.78 (-42.86 to 300.00)	140.00 (37.80 to 142.86)	105.26 (-30.77 to 650.00)
MVD Assay (NK cells) (%)	-23.82 (-24.21 to 65.52)	61.81 (34.74 to 98.53)	22.54 (-18.99 to 69.08)	-0.71 (-34.19 to 72.62)

No statistical analyses for this end point

Secondary: PK parameter: Cmax versus PD biomarkers

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End point title

PK parameter: Cmax versus PD biomarkers ^[35]

End point description

To assess pharmacokinetic/pharmacodynamic relationship (comparison of Cmax with PD biomarkers). Cmax: The maximum (peak) observed plasma drug concentration.

End point type

Secondary

End point timeframe

24 weeks

Notes
[35] - 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 statistical Analysis was planned.

End point values	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID
Number of subjects analysed	0 ^[36]
Units: ng/ML
geometric mean (geometric coefficient of variation)	( )

Notes
[36] - The relationship between Cmax & PD biomarker was not investigated.

No statistical analyses for this end point

Secondary: Percentage of patients who achieved Best Overall Response (BOR) up to Day 28

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End point title

Percentage of patients who achieved Best Overall Response (BOR) up to Day 28 ^[37]

End point description

The best overall response (BOR) was defined as percentage of participants with (complete response (CR) or partial response (PR) at any time point and up to and including Day 28 and before the start of additional systemic therapy for acute GvHD (aGvHD).

End point type

Secondary

End point timeframe

Up to 28 days and before start of additional aGvHD therapy

Notes
[37] - 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 statistical Analysis was planned.

End point values	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID	Group 1: ≥ 12y to < 18y - RUX 10mg BID
Number of subjects analysed	12	15	18
Units: Percentage of participants
number (confidence interval 95%)	91.7 (66.1 to 99.6)	93.3 (83.7 to 98.2)	94.4 (76.2 to 99.7)

No statistical analyses for this end point

Secondary: PK parameter: Ctrough versus PD biomarkers

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End point title

PK parameter: Ctrough versus PD biomarkers ^[38]

End point description

To assess pharmacokinetic/pharmacodynamics relationship (Ctrough with PD biomarkers). Ctrough: The minimum observed plasma concentration at the end of an administration interval (corresponding to the pre-dose concentration prior to the following administration).

End point type

Secondary

End point timeframe

24 weeks

Notes
[38] - 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 statistical Analysis was planned.

End point values	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID
Number of subjects analysed	0 ^[39]
Units: ng/ml
geometric mean (geometric coefficient of variation)	( )

Notes
[39] - The relationship between Ctrough & PD biomarker was not investigated.

No statistical analyses for this end point

Post-hoc: All Collected Deaths

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End point title

All Collected Deaths ^[40]

End point description

Adverse events and 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 380 days. Post-treatment survival follow-up deaths were collected 31 days after last dose of study medication until the end of the study, up to approx. 23 months.

End point type

Post-hoc

End point timeframe

AEs & On-treatment deaths: Up to approx. 380 days (13 months), Post-treatment survival follow-up deaths: Up to approx. 23 months after the end of treatment

Notes
[40] - 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 statistical Analysis was planned.

End point values	Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID	Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID	Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID capsule
Number of subjects analysed	12	18	15
Units: Participants
Total deaths	2	6	1
On-treatment deaths	0	0	0
Post-treatment deaths	2	6	1

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events and 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 380 days.

Adverse event reporting additional description

Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Deaths in the post treatment survival follow-up are not considered Adverse Events. The total number at risk in the post treatment survival includes patients that entered the post treatment survival follow-up period.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.1

Reporting group title

Arm: Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID

Reporting group description

All patients received ruxolitinib (RUX) 10 mg BID in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Reporting group title

Arm: Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID

Reporting group description

All patients received RUX 5mg BID in addition to corticosteroids +/-calcineurin inhibitor (CNI)

Reporting group title

Arm: Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID

Reporting group description

All patients received RUX 4mg/m^2 BID in addition to corticosteroids +/-calcineurin inhibitor (CNI

Reporting group title

All Subjects

Reporting group description

All Subjects from Group 1, Group 2 and Group 3 who were enrolled and participated in the study

Serious adverse events	Arm: Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID	Arm: Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID	Arm: Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID	All Subjects
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 18 (61.11%)	7 / 12 (58.33%)	6 / 15 (40.00%)	24 / 45 (53.33%)
number of deaths (all causes)	6	2	1	9
number of deaths resulting from adverse events	0	0	0	0
Vascular disorders
Shock haemorrhagic
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 18 (5.56%)	1 / 12 (8.33%)	2 / 15 (13.33%)	4 / 45 (8.89%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Graft versus host disease in gastrointestinal tract
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Respiratory failure
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary haemorrhage
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
Pulmonary embolism
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract inflammation
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Adenovirus test positive
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
White blood cell count decreased
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cytomegalovirus test positive
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Transplant dysfunction
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Pericardial effusion
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Posterior reversible encephalopathy syndrome
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	1 / 18 (5.56%)	1 / 12 (8.33%)	0 / 15 (0.00%)	2 / 45 (4.44%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune thrombocytopenia
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic disorder
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Gastric haemorrhage
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal haemorrhage
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal failure
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	2 / 18 (11.11%)	0 / 12 (0.00%)	0 / 15 (0.00%)	2 / 45 (4.44%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
COVID-19
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Adenovirus infection
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cytomegalovirus viraemia
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	1 / 15 (6.67%)	2 / 45 (4.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	2 / 18 (11.11%)	0 / 12 (0.00%)	0 / 15 (0.00%)	2 / 45 (4.44%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
Skin infection
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral haemorrhagic cystitis
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	1 / 15 (6.67%)	2 / 45 (4.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye infection viral
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acidosis
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Arm: Group 1: subjects ≥ 12y to < 18y - RUX 10mg BID	Arm: Group 2: subjects ≥ 6y to < 12y - RUX 5mg BID	Arm: Group 3: subjects ≥ 2y to < 6y - RUX 4mg/m^2 BID	All Subjects
Total subjects affected by non serious adverse events
subjects affected / exposed	18 / 18 (100.00%)	12 / 12 (100.00%)	15 / 15 (100.00%)	45 / 45 (100.00%)
Vascular disorders
Microangiopathy
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Capillary leak syndrome
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Hypertension
subjects affected / exposed	2 / 18 (11.11%)	2 / 12 (16.67%)	5 / 15 (33.33%)	9 / 45 (20.00%)
occurrences all number	2	2	5	9
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Catheter site erythema
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Chills
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Face oedema
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Oedema
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Oedema peripheral
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Pyrexia
subjects affected / exposed	2 / 18 (11.11%)	2 / 12 (16.67%)	2 / 15 (13.33%)	6 / 45 (13.33%)
occurrences all number	4	5	2	11
Immune system disorders
Hypogammaglobulinaemia
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	1 / 15 (6.67%)	2 / 45 (4.44%)
occurrences all number	1	0	1	2
Acute graft versus host disease in intestine
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	2	0	0	2
Allergy to immunoglobulin therapy
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Drug hypersensitivity
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Graft versus host disease in skin
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Reproductive system and breast disorders
Penile erosion
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Bronchial disorder
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Cough
subjects affected / exposed	1 / 18 (5.56%)	2 / 12 (16.67%)	1 / 15 (6.67%)	4 / 45 (8.89%)
occurrences all number	1	1	1	3
Epistaxis
subjects affected / exposed	2 / 18 (11.11%)	0 / 12 (0.00%)	0 / 15 (0.00%)	2 / 45 (4.44%)
occurrences all number	3	0	0	3
Productive cough
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Pulmonary oedema
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Rhinitis allergic
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Rhinorrhoea
subjects affected / exposed	1 / 18 (5.56%)	1 / 12 (8.33%)	0 / 15 (0.00%)	2 / 45 (4.44%)
occurrences all number	1	1	0	2
Oropharyngeal pain
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Psychiatric disorders
Insomnia
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Depression
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Investigations
Adenovirus test positive
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	2 / 15 (13.33%)	2 / 45 (4.44%)
occurrences all number	0	0	2	2
Alanine aminotransferase increased
subjects affected / exposed	6 / 18 (33.33%)	2 / 12 (16.67%)	3 / 15 (20.00%)	11 / 45 (24.44%)
occurrences all number	6	2	3	11
Amylase increased
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Aspartate aminotransferase increased
subjects affected / exposed	2 / 18 (11.11%)	0 / 12 (0.00%)	3 / 15 (20.00%)	5 / 45 (11.11%)
occurrences all number	2	0	2	4
Blood bilirubin increased
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Blood cholesterol increased
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	1 / 15 (6.67%)	2 / 45 (4.44%)
occurrences all number	1	0	2	3
Weight decreased
subjects affected / exposed	0 / 18 (0.00%)	2 / 12 (16.67%)	0 / 15 (0.00%)	2 / 45 (4.44%)
occurrences all number	0	2	0	2
C-reactive protein increased
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Cytomegalovirus test positive
subjects affected / exposed	1 / 18 (5.56%)	1 / 12 (8.33%)	4 / 15 (26.67%)	6 / 45 (13.33%)
occurrences all number	1	2	8	11
Epstein-Barr virus test positive
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 18 (5.56%)	2 / 12 (16.67%)	2 / 15 (13.33%)	5 / 45 (11.11%)
occurrences all number	2	3	5	10
Lipase increased
subjects affected / exposed	2 / 18 (11.11%)	1 / 12 (8.33%)	1 / 15 (6.67%)	4 / 45 (8.89%)
occurrences all number	2	0	1	3
Lymphocyte count decreased
subjects affected / exposed	1 / 18 (5.56%)	2 / 12 (16.67%)	1 / 15 (6.67%)	4 / 45 (8.89%)
occurrences all number	1	1	2	4
Neutrophil count decreased
subjects affected / exposed	5 / 18 (27.78%)	2 / 12 (16.67%)	5 / 15 (33.33%)	12 / 45 (26.67%)
occurrences all number	12	3	18	33
Platelet count decreased
subjects affected / exposed	0 / 18 (0.00%)	3 / 12 (25.00%)	6 / 15 (40.00%)	9 / 45 (20.00%)
occurrences all number	0	6	15	21
Prothrombin time abnormal
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Roseolovirus test positive
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
SARS-CoV-2 test negative
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Transaminases increased
subjects affected / exposed	2 / 18 (11.11%)	0 / 12 (0.00%)	0 / 15 (0.00%)	2 / 45 (4.44%)
occurrences all number	3	0	0	3
Blood creatinine increased
subjects affected / exposed	1 / 18 (5.56%)	1 / 12 (8.33%)	2 / 15 (13.33%)	4 / 45 (8.89%)
occurrences all number	1	1	2	4
Weight increased
subjects affected / exposed	1 / 18 (5.56%)	2 / 12 (16.67%)	0 / 15 (0.00%)	3 / 45 (6.67%)
occurrences all number	1	2	0	3
White blood cell count decreased
subjects affected / exposed	0 / 18 (0.00%)	2 / 12 (16.67%)	5 / 15 (33.33%)	7 / 45 (15.56%)
occurrences all number	0	2	8	10
Injury, poisoning and procedural complications
Anaphylactic transfusion reaction
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Post procedural contusion
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Post procedural haemorrhage
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	0	0	0
Subcutaneous haematoma
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Cardiac disorders
Ventricular fibrillation
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Bradycardia
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Cardiac failure
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Sinus tachycardia
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Tachycardia
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Nervous system disorders
Posterior reversible encephalopathy syndrome
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Generalised tonic-clonic seizure
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Headache
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	1 / 15 (6.67%)	2 / 45 (4.44%)
occurrences all number	1	0	0	1
Neuralgia
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Paraesthesia
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Post herpetic neuralgia
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Restless legs syndrome
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Blood and lymphatic system disorders
Coagulopathy
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Anaemia
subjects affected / exposed	6 / 18 (33.33%)	5 / 12 (41.67%)	10 / 15 (66.67%)	21 / 45 (46.67%)
occurrences all number	7	8	21	36
Febrile neutropenia
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	1 / 15 (6.67%)	2 / 45 (4.44%)
occurrences all number	0	1	1	2
Hyperleukocytosis
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Iron deficiency anaemia
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Leukocytosis
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Leukopenia
subjects affected / exposed	3 / 18 (16.67%)	0 / 12 (0.00%)	0 / 15 (0.00%)	3 / 45 (6.67%)
occurrences all number	3	0	0	3
Lymphopenia
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Thrombocytopenia
subjects affected / exposed	6 / 18 (33.33%)	0 / 12 (0.00%)	3 / 15 (20.00%)	9 / 45 (20.00%)
occurrences all number	6	0	3	9
Thrombotic microangiopathy
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Neutropenia
subjects affected / exposed	6 / 18 (33.33%)	2 / 12 (16.67%)	1 / 15 (6.67%)	9 / 45 (20.00%)
occurrences all number	10	4	3	17
Eye disorders
Dry eye
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	1 / 15 (6.67%)	2 / 45 (4.44%)
occurrences all number	1	0	1	2
Eye disorder
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 18 (0.00%)	2 / 12 (16.67%)	3 / 15 (20.00%)	5 / 45 (11.11%)
occurrences all number	0	2	3	5
Angular cheilitis
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Constipation
subjects affected / exposed	1 / 18 (5.56%)	2 / 12 (16.67%)	2 / 15 (13.33%)	5 / 45 (11.11%)
occurrences all number	1	2	2	5
Diarrhoea
subjects affected / exposed	3 / 18 (16.67%)	1 / 12 (8.33%)	1 / 15 (6.67%)	5 / 45 (11.11%)
occurrences all number	4	1	1	6
Intestinal haemorrhage
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Nausea
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Vomiting
subjects affected / exposed	1 / 18 (5.56%)	1 / 12 (8.33%)	2 / 15 (13.33%)	4 / 45 (8.89%)
occurrences all number	1	1	4	6
Anal fissure
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	0	0	0
Hepatobiliary disorders
Hepatotoxicity
subjects affected / exposed	2 / 18 (11.11%)	0 / 12 (0.00%)	0 / 15 (0.00%)	2 / 45 (4.44%)
occurrences all number	2	0	0	2
Hypertransaminasaemia
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	3	0	0	3
Hepatic steatosis
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Skin and subcutaneous tissue disorders
Hirsutism
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	1 / 15 (6.67%)	2 / 45 (4.44%)
occurrences all number	0	1	1	2
Acne
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Bullous haemorrhagic dermatosis
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Dermatitis contact
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Dry skin
subjects affected / exposed	0 / 18 (0.00%)	2 / 12 (16.67%)	1 / 15 (6.67%)	3 / 45 (6.67%)
occurrences all number	0	2	1	3
Ecchymosis
subjects affected / exposed	2 / 18 (11.11%)	0 / 12 (0.00%)	0 / 15 (0.00%)	2 / 45 (4.44%)
occurrences all number	2	0	0	2
Eczema
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Eczema asteatotic
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Erythema
subjects affected / exposed	1 / 18 (5.56%)	1 / 12 (8.33%)	0 / 15 (0.00%)	2 / 45 (4.44%)
occurrences all number	1	1	0	2
Night sweats
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Pain of skin
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Petechiae
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Pruritus
subjects affected / exposed	0 / 18 (0.00%)	2 / 12 (16.67%)	0 / 15 (0.00%)	2 / 45 (4.44%)
occurrences all number	0	2	0	2
Purpura
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Skin fissures
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Skin striae
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Rash
subjects affected / exposed	2 / 18 (11.11%)	1 / 12 (8.33%)	0 / 15 (0.00%)	3 / 45 (6.67%)
occurrences all number	2	1	0	3
Renal and urinary disorders
Cystitis haemorrhagic
subjects affected / exposed	2 / 18 (11.11%)	1 / 12 (8.33%)	0 / 15 (0.00%)	3 / 45 (6.67%)
occurrences all number	2	1	0	3
Glycosuria
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Ketonuria
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	2	0	0	2
Micturition urgency
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Polyuria
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	0	0	0
Proteinuria
subjects affected / exposed	2 / 18 (11.11%)	1 / 12 (8.33%)	1 / 15 (6.67%)	4 / 45 (8.89%)
occurrences all number	2	1	1	4
Renal impairment
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Urinary tract pain
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	1 / 18 (5.56%)	2 / 12 (16.67%)	1 / 15 (6.67%)	4 / 45 (8.89%)
occurrences all number	1	2	1	4
Cushingoid
subjects affected / exposed	1 / 18 (5.56%)	1 / 12 (8.33%)	0 / 15 (0.00%)	2 / 45 (4.44%)
occurrences all number	1	1	0	2
Secondary adrenocortical insufficiency
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Musculoskeletal and connective tissue disorders
Amyotrophy
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Arthralgia
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Back pain
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Limb discomfort
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Muscle contracture
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Osteopenia
subjects affected / exposed	1 / 18 (5.56%)	1 / 12 (8.33%)	0 / 15 (0.00%)	2 / 45 (4.44%)
occurrences all number	1	1	0	2
Pain in extremity
subjects affected / exposed	1 / 18 (5.56%)	1 / 12 (8.33%)	0 / 15 (0.00%)	2 / 45 (4.44%)
occurrences all number	2	2	0	4
Infections and infestations
Atypical pneumonia
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Bacteraemia
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Bronchitis
subjects affected / exposed	2 / 18 (11.11%)	0 / 12 (0.00%)	1 / 15 (6.67%)	3 / 45 (6.67%)
occurrences all number	2	0	1	3
COVID-19
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	2 / 15 (13.33%)	2 / 45 (4.44%)
occurrences all number	0	0	2	2
Cystitis
subjects affected / exposed	2 / 18 (11.11%)	0 / 12 (0.00%)	0 / 15 (0.00%)	2 / 45 (4.44%)
occurrences all number	3	0	0	3
Cytomegalovirus infection
subjects affected / exposed	3 / 18 (16.67%)	0 / 12 (0.00%)	0 / 15 (0.00%)	3 / 45 (6.67%)
occurrences all number	4	0	0	4
Fungal infection
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	4	4
Cytomegalovirus viraemia
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Device related infection
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	1 / 15 (6.67%)	2 / 45 (4.44%)
occurrences all number	2	0	1	3
Ear infection
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Epstein-Barr virus infection
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	1 / 15 (6.67%)	2 / 45 (4.44%)
occurrences all number	1	0	1	2
Epstein-Barr virus infection reactivation
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	3 / 15 (20.00%)	4 / 45 (8.89%)
occurrences all number	0	1	3	4
Fungal foot infection
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Cytomegalovirus infection reactivation
subjects affected / exposed	2 / 18 (11.11%)	1 / 12 (8.33%)	1 / 15 (6.67%)	4 / 45 (8.89%)
occurrences all number	3	1	1	5
Herpes simplex
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Klebsiella infection
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Mucosal infection
subjects affected / exposed	2 / 18 (11.11%)	0 / 12 (0.00%)	0 / 15 (0.00%)	2 / 45 (4.44%)
occurrences all number	2	0	0	2
Nail infection
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Nasopharyngitis
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Oral candidiasis
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Urinary tract infection
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	1 / 15 (6.67%)	2 / 45 (4.44%)
occurrences all number	0	1	1	2
Otitis externa
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Otitis media
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Rhinitis
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	1 / 15 (6.67%)	2 / 45 (4.44%)
occurrences all number	1	0	1	2
Sinusitis
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Staphylococcal sepsis
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Upper respiratory tract infection
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Oral herpes
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Varicella zoster virus infection
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Viraemia
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Viral haemorrhagic cystitis
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Vulvovaginal mycotic infection
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Vulvovaginitis
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	0	0	0
Metabolism and nutrition disorders
Central obesity
subjects affected / exposed	1 / 18 (5.56%)	1 / 12 (8.33%)	1 / 15 (6.67%)	3 / 45 (6.67%)
occurrences all number	1	1	1	3
Decreased appetite
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Folate deficiency
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Hyperferritinaemia
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Hyponatraemia
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1
Hyperkalaemia
subjects affected / exposed	0 / 18 (0.00%)	1 / 12 (8.33%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	0	1	0	1
Hypertriglyceridaemia
subjects affected / exposed	2 / 18 (11.11%)	0 / 12 (0.00%)	0 / 15 (0.00%)	2 / 45 (4.44%)
occurrences all number	2	0	0	2
Hypoalbuminaemia
subjects affected / exposed	2 / 18 (11.11%)	3 / 12 (25.00%)	0 / 15 (0.00%)	5 / 45 (11.11%)
occurrences all number	4	5	0	9
Hypoglycaemia
subjects affected / exposed	0 / 18 (0.00%)	0 / 12 (0.00%)	1 / 15 (6.67%)	1 / 45 (2.22%)
occurrences all number	0	0	1	1
Hypokalaemia
subjects affected / exposed	4 / 18 (22.22%)	3 / 12 (25.00%)	1 / 15 (6.67%)	8 / 45 (17.78%)
occurrences all number	4	3	0	7
Hypomagnesaemia
subjects affected / exposed	2 / 18 (11.11%)	1 / 12 (8.33%)	1 / 15 (6.67%)	4 / 45 (8.89%)
occurrences all number	3	1	0	4
Hyperglycaemia
subjects affected / exposed	3 / 18 (16.67%)	0 / 12 (0.00%)	0 / 15 (0.00%)	3 / 45 (6.67%)
occurrences all number	3	0	0	3
Hypophosphataemia
subjects affected / exposed	0 / 18 (0.00%)	2 / 12 (16.67%)	1 / 15 (6.67%)	3 / 45 (6.67%)
occurrences all number	0	2	2	4
Metabolic acidosis
subjects affected / exposed	1 / 18 (5.56%)	0 / 12 (0.00%)	0 / 15 (0.00%)	1 / 45 (2.22%)
occurrences all number	1	0	0	1

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Were there any global substantial amendments to the protocol? Yes

01 Apr 2019

The main purpose of this amendment was to broaden the eligible subject populations, modify study assessment and revise safety dose modifications based on feedback from investigators on current practices in the management of acute GvHD. The number of subjects was expanded to a total of 45 subjects treated at the RP2D, thus increasing the number of subjects for safety and efficacy evaluation.

14 Oct 2020

The main purpose of amendment 2 was to update the guidelines regarding the management of ruxolitinib based on liver monitoring laboratory results, to update the inclusion criteria to allow for nasogastric tube administration of the pediatric formulation, to provide clarifications regarding the management of ruxolitinib tapering, to update contraception guidelines and pregnancy reporting requirements for female subjects of child-bearing potential and to clarify requirements for ruxolitinib post-trial access. The assessment of benefit and risk related to SARS-CoV-2 virus and the COVID-19 pandemic determined no substantial additional risk for subject safety at this time.

22 Jun 2022

The main purpose of this amendment to include public health emergency disruption proofing language, to provide guidance on subject management, including withdrawal of consent, and to decrease the minimum enrollment requirements of treatment-naïve subjects from 40% to at least 20% due to recruitment challenges. The sample remains representative of the study population and therefore the sample size was not re-estimated due to this modification.

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.

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/CtrdWeb/home.nov for complete trial results.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase I: Measurement of pharmacokinetic (PK) parameter, AUClast, in aGvHD and SR-aGvHD patients

Primary: Phase I: Measurement of pharmacokinetic (PK) parameter, AUClast, in aGvHD and SR-aGvHD patients

Primary: Phase I: Measurement of PK parameter, Cmax, in aGvHD and SR-aGvHD patients

Primary: Phase I: Measurement of PK parameter, Cmax, in aGvHD and SR-aGvHD patients

Primary: Phase I: Measurement of PK parameter, T1/2, in aGvHD and SR-aGvHD patients

Primary: Phase I: Measurement of PK parameter, T1/2, in aGvHD and SR-aGvHD patients

Primary: Phase I: Measurement of PK parameter, Ctrough, in aGvHD and SR-aGvHD patients

Primary: Phase I: Measurement of PK parameter, Ctrough, in aGvHD and SR-aGvHD patients

Primary: Phase I: Age-based determination of recommended phase 2 dose (RP2D) for each of the groups 2 - 4 using AUClast

Primary: Phase I: Age-based determination of recommended phase 2 dose (RP2D) for each of the groups 2 - 4 using AUClast

Primary: Phase I: Age-based determination of recommended phase 2 dose (RP2D) for each of the groups 2 - 4 using Cmax

Primary: Phase I: Age-based determination of recommended phase 2 dose (RP2D) for each of the groups 2 - 4 using Cmax

Primary: Phase I: Age-based determination of recommended phase 2 dose (RP2D) for each of the groups 2 - 4 using Ctrough

Primary: Phase I: Age-based determination of recommended phase 2 dose (RP2D) for each of the groups 2 - 4 using Ctrough

Primary: Phase II: Overall response rate (ORR)

Primary: Phase II: Overall response rate (ORR)

Secondary: Percentage of all patients who achieved a complete response (CR) or partial response (PR) (Durable Overall Response Rate (ORR))

Secondary: Percentage of all patients who achieved a complete response (CR) or partial response (PR) (Durable Overall Response Rate (ORR))

Secondary: Percentage of patients who achieved OR (CR+PR) at Day 14

Secondary: Percentage of patients who achieved OR (CR+PR) at Day 14

Secondary: PK parameter: Area under the curve (AUClast) versus safety

Secondary: PK parameter: Area under the curve (AUClast) versus safety

Secondary: Duration of response (DOR)

Secondary: Duration of response (DOR)

Secondary: Weekly cumulative steroid dose for each patient up to Day 56

Secondary: Weekly cumulative steroid dose for each patient up to Day 56

Secondary: Overall Survival (OS) per Kaplan Meier

Secondary: Overall Survival (OS) per Kaplan Meier

Secondary: Event-Free Survival (EFS) per Kaplan-Meier estimates

Secondary: Event-Free Survival (EFS) per Kaplan-Meier estimates

Secondary: Failure-Free Survival (FFS)

Secondary: Failure-Free Survival (FFS)

Secondary: Non Relapse Mortality (NRM)

Secondary: Non Relapse Mortality (NRM)

Secondary: Incidence of Malignancy Relapse/Progression (MR)

Secondary: Incidence of Malignancy Relapse/Progression (MR)

Secondary: Cumulative Incidence of cGvHD

Secondary: Cumulative Incidence of cGvHD

Secondary: Graft Failure

Secondary: Graft Failure

Secondary: Questionnaire on acceptability and palatability

Secondary: Questionnaire on acceptability and palatability

Secondary: PK parameter - maximum serum concentration (Cmax) versus efficacy

Secondary: PK parameter - maximum serum concentration (Cmax) versus efficacy

Secondary: PK parameter: Minimum serum concentration (Ctrough) versus safety

Secondary: PK parameter: Minimum serum concentration (Ctrough) versus safety

Secondary: PK parameter: Cmax versus safety

Secondary: PK parameter: Cmax versus safety

Secondary: PK parameter: AUClast versus efficacy

Secondary: PK parameter: AUClast versus efficacy

Secondary: PK parameter: Ctrough versus efficacy

Secondary: PK parameter: Ctrough versus efficacy

Secondary: PK parameter: AUClast versus PD biomarkers

Secondary: PK parameter: AUClast versus PD biomarkers

Secondary: PK parameter: Cmax versus PD biomarkers

Secondary: PK parameter: Cmax versus PD biomarkers

Secondary: Percentage of patients who achieved Best Overall Response (BOR) up to Day 28

Secondary: Percentage of patients who achieved Best Overall Response (BOR) up to Day 28

Secondary: PK parameter: Ctrough versus PD biomarkers

Secondary: PK parameter: Ctrough versus PD biomarkers

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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