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Clinical Trial Results:
Randomized, open label, multicenter phase III study of efficacy and safety in polycythemia vera subjects who are resistant to or intolerant of hydroxyurea: JAK inhibitor INC424 tablets versus best available care (The RESPONSE Trial) Due to EudraCT system limitations, which EMA is aware of, results of crossover studies and data using 999 as data points are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results

Summary
EudraCT number	2010-020807-57
Trial protocol	BE DE ES GB IT NL HU
Global end of trial date	09 Feb 2018

Results information
Results version number	v1(current)
This version publication date	24 Feb 2019
First version publication date	24 Feb 2019
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

CINC424B2301 (INC424, INCB018424)

ISRCTN number

-

US NCT number

NCT01243944

WHO universal trial number (UTN)

-

Sponsor organisation name

Novartis PharmaMA, AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

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

Scientific contact

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

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

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

09 Feb 2018

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

09 Feb 2018

Was the trial ended prematurely?

No

Main objective of the trial

The primary objective was to compare the efficacy of ruxolitinib to Best Available Therapy (BAT) as assessed by both the absence of phlebotomy eligibility and reduction in spleen volume.

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

27 Oct 2010

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 4

Country: Number of subjects enrolled

Australia: 11

Country: Number of subjects enrolled

Belgium: 11

Country: Number of subjects enrolled

Canada: 5

Country: Number of subjects enrolled

China: 3

Country: Number of subjects enrolled

France: 11

Country: Number of subjects enrolled

Germany: 25

Country: Number of subjects enrolled

Hungary: 15

Country: Number of subjects enrolled

Italy: 43

Country: Number of subjects enrolled

Japan: 18

Country: Number of subjects enrolled

Korea, Democratic People's Republic of: 4

Country: Number of subjects enrolled

Netherlands: 3

Country: Number of subjects enrolled

Russian Federation: 7

Country: Number of subjects enrolled

Spain: 13

Country: Number of subjects enrolled

Thailand: 1

Country: Number of subjects enrolled

Turkey: 6

Country: Number of subjects enrolled

United Kingdom: 7

Country: Number of subjects enrolled

United States: 35

Worldwide total number of subjects

222

EEA total number of subjects

128

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

155

From 65 to 84 years

66

85 years and over

1

Subject disposition

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Recruitment details

Participants may be treated beyond 256 weeks due to the 14 day visit window.

Screening details

Although 222 were centrally randomized to ruxolitinib and BAT arms (110 patients were in the ruxolitinib arm and 112 patients were in the BAT arm I patient in the BAT was not treated.

Period 1 title

Treatment Period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Ruxolitinib

Arm description

Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg once a day (QD) to 25 mg BID based on safety and efficacy

Arm type

Experimental

Investigational medicinal product name

INC424

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Starting dose of 10 mg bid on study Day 1. A standardized dosing paradigm was used to determine dose adjustments for safety and efficacy so that each patient was titrated to their most appropriate dose.

Best Available Therapy (BAT)

Arm description

Best Available Therapy (BAT) will be selected by the Investigator for each subject. BAT may not include experimental agents (i.e. those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements.

Arm type

Active comparator

Investigational medicinal product name

Best Available Therapy (BAT)

Investigational medicinal product code

Other name

BAT could include: Hydroxyurea, IFN/PEG-IFN, Pipobroman, Anagrelide, Lenalidomide, Pomalidomide, Observation only

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

selected by the Investigator for each subject

Number of subjects in period 1	Ruxolitinib	Best Available Therapy (BAT)
Started	110	112
Completed	65	61
Not completed	45	51
Adverse event, serious fatal	2	3
Physician decision	2	7
Disease progression	12	11
Adverse event, non-fatal	15	13
Subject decision	10	15
Lost to follow-up	2	1
Protocol deviation	1	1
non-compliance with study treatment	1	-

Baseline characteristics

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Reporting group title

Ruxolitinib

Reporting group description

Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg once a day (QD) to 25 mg BID based on safety and efficacy

Reporting group title

Best Available Therapy (BAT)

Reporting group description

Best Available Therapy (BAT) will be selected by the Investigator for each subject. BAT may not include experimental agents (i.e. those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements.

Reporting group values	Ruxolitinib	Best Available Therapy (BAT)	Total
Number of subjects	110	112	222
Age Categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	69	86	155
From 65-84 years	40	26	66
85 years and over	1	0	1
Age Continuous
Units: years
arithmetic mean (standard deviation)	61.1 ± 10.48	59.1 ± 10.25	-
Gender Categorical
Units: Subjects
Female	44	32	76
Male	66	80	146
Race/ethnicity
Units: Subjects
White/Caucasian	98	96	194
Black/African American	1	0	1
Asian	11	16	27

End points

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Reporting group title

Ruxolitinib

Reporting group description

Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg once a day (QD) to 25 mg BID based on safety and efficacy

Reporting group title

Best Available Therapy (BAT)

Reporting group description

Best Available Therapy (BAT) will be selected by the Investigator for each subject. BAT may not include experimental agents (i.e. those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements.

Primary: The Percentage of Subjects Achieving a Primary Response at Week 32

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End point title

The Percentage of Subjects Achieving a Primary Response at Week 32

End point description

Primary response was defined as having achieved hematocrit control (the absence of phlebotomy eligibility beginning at the Week 8 visit and continuing through Week 32) and Spleen Volume Reduction (a greater than or equal to 35% reduction from baseline in spleen volume at Week 32).

End point type

Primary

End point timeframe

32 Weeks

End point values	Ruxolitinib	Best Available Therapy (BAT)
Number of subjects analysed	110	112
Units: Percentage of subjects
number (confidence interval 95%)	22.7 (15.3 to 31.7)	0.9 (0.0 to 4.9)

Group Comparison - Primary endpoint

Comparison groups

Ruxolitinib v Best Available Therapy (BAT)

Number of subjects included in analysis

222

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Log odds ratio

Point estimate

32.67

Confidence interval

level

95%

sides

2-sided

lower limit

5.04

upper limit

1337

Secondary: The Percentage of Subjects Achieving a Durable Primary Response at Week 48

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End point title

The Percentage of Subjects Achieving a Durable Primary Response at Week 48

End point description

Durable Primary Response was defined as any subject who achieved the primary outcome measure and who maintained their response up to 48 weeks after randomization.

End point type

Secondary

End point timeframe

48 Weeks

End point values	Ruxolitinib	Best Available Therapy (BAT)
Number of subjects analysed	110	112
Units: Percentag e of subjects
number (confidence interval 95%)	20.0 (13.0 to 28.7)	0.9 (0.0 to 4.9)

Group Comparison - 48 weeks

Comparison groups

Ruxolitinib v Best Available Therapy (BAT)

Number of subjects included in analysis

222

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

28.01

Confidence interval

level

95%

sides

2-sided

lower limit

4.24

upper limit

1144

Secondary: The Percentage of Subjects Achieving Complete Hematological Remission at Week 32

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End point title

The Percentage of Subjects Achieving Complete Hematological Remission at Week 32

End point description

Complete Hematological Remission at Week 32 was defined as any subject who achieved hematocrit control with a platelet count less than or equal to 400 X 10^9/L and a white blood cell count less than or equal to 10 X 10^9/L.

End point type

Secondary

End point timeframe

32 Weeks

End point values	Ruxolitinib	Best Available Therapy (BAT)
Number of subjects analysed	110	112
Units: Percentage of subjects
number (confidence interval 95%)	23.6 (16.1 to 32.7)	8.0 (3.7 to 14.7)

Group comparison - 32 Weeks

Comparison groups

Ruxolitinib v Best Available Therapy (BAT)

Number of subjects included in analysis

222

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0016

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

3.57

Confidence interval

level

95%

sides

2-sided

lower limit

1.5

upper limit

9.06

Secondary: The Percentage of Subjects Who Achieved a Durable Complete Hematological Remission at Week 48

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End point title

The Percentage of Subjects Who Achieved a Durable Complete Hematological Remission at Week 48

End point description

Durable Complete Hematological Remission was defined as any subject who achieved Complete Hematological Remission at Week 32 and maintained their response up to 48 weeks after randomization.

End point type

Secondary

End point timeframe

48 Weeks

End point values	Ruxolitinib	Best Available Therapy (BAT)
Number of subjects analysed	110	112
Units: Percentage of subjects
number (confidence interval 95%)	20.9 (13.7 to 29.7)	0.9 (0.0 to 4.9)

No statistical analyses for this end point

Secondary: The Percentage of Subjects Who Achieved a Durable Hematocrit Control at Week 48

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End point title

The Percentage of Subjects Who Achieved a Durable Hematocrit Control at Week 48

End point description

Durable Hematocrit Control was defined as any subject who achieved phlebotomy eligibility independence from Week 8 to Week 32 and maintained hematocrit control up to 48 weeks after randomization.

End point type

Secondary

End point timeframe

48 Weeks

End point values	Ruxolitinib	Best Available Therapy (BAT)
Number of subjects analysed	110	112
Units: Percentage of subjects
number (confidence interval 95%)	54.5 (44.8 to 64.1)	1.8 (0.2 to 6.3)

No statistical analyses for this end point

Secondary: The Percentage of Subjects Who Achieved Durable Spleen Volume Reduction at Week 48

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End point title

The Percentage of Subjects Who Achieved Durable Spleen Volume Reduction at Week 48

End point description

Durable Spleen Volume Reduction was defined as a subject who achieved at least 35% reduction from baseline in spleen volume at Week 32 and maintained that response 48 weeks after randomization.

End point type

Secondary

End point timeframe

48 Weeks

End point values	Ruxolitinib	Best Available Therapy (BAT)
Number of subjects analysed	110	112
Units: Percentage of subjects
number (confidence interval 95%)	37.3 (28.2 to 47.0)	0.9 (0.0 to 4.9)

No statistical analyses for this end point

Secondary: Estimated Duration of the Primary Response

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End point title

Estimated Duration of the Primary Response ^[1]

End point description

Duration of the primary response is defined as the time from the first occurrence when both components of the primary endpoint are met until the date of the first documented disease progression (end of response). Kaplan-Meier estimates are provided for duration of primary response.

End point type

Secondary

End point timeframe

Through study completion, analysis was conducted when all patients had completed the Week 80 visit or discontinued the study

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: Duration of the Response was done only on the study drug.

End point values	Ruxolitinib
Number of subjects analysed	110
Units: Probability
number (confidence interval 95%)
16 Weeks	1.00 (0.99 to 999)
32 Weeks	1.00 (0.99 to 999)
48 Weeks	0.92 (0.72 to 0.98)
64 Weeks	0.92 (0.72 to 0.98)
80 Weeks	0.92 (0.72 to 0.98)
96 Weeks	0.88 (0.67 to 0.96)
112 Weeks	0.84 (0.62 to 0.94)
128 Weeks	0.84 (0.62 to 0.94)
144 Weeks	0.84 (0.62 to 0.94)
160 Weeks	0.79 (0.57 to 0.91)
176 Weeks	0.79 (0.57 to 0.91)
192 Weeks	0.74 (0.51 to 0.88)
208 Weeks	0.74 (0.51 to 0.88)
224 Weeks	0.74 (0.51 to 0.88)
240 Weeks	999 (999 to 999)
256 Weeks	999 (999 to 999)

No statistical analyses for this end point

Secondary: The Percentage of Subjects Who Achieved Overall Clinicohematologic Response at Week 32

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End point title

The Percentage of Subjects Who Achieved Overall Clinicohematologic Response at Week 32

End point description

Overall Clinicohematologic Response is defined as any subject who achieved a complete or partial clinicohematologic response per the European LeukemiaNet modified criteria for response in polycythemia vera (PV). A Complete Response (CR) is defined as: hematocrit control, spleen volume reduction at least 35% from baseline, platelet count less than or equal to 400 x 10(9)/L, and white blood cell count less than or equal to 10 x 10(9)/L. A Partial Response (PR) is defined as hematocrit control or response in all 3 of the other criteria.

End point type

Secondary

End point timeframe

32 Weeks

End point values	Ruxolitinib	Best Available Therapy (BAT)
Number of subjects analysed	110	112
Units: Percentage of subjects
number (not applicable)
Complete response rate	8.2	0.9
Partial response rate	54.5	18.8

No statistical analyses for this end point

Secondary: The Percentage of Subjects Achieving a Durable Complete or Partial Clinicohematologic Response at Week 48

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End point title

The Percentage of Subjects Achieving a Durable Complete or Partial Clinicohematologic Response at Week 48

End point description

Durable Complete or Partial Clinicohematologic Response was defined as any subject who achieved complete or partial clinicohematologic response per the European LeukemiaNet modified criteria for response in polycythemia vera at Week 32 and maintained that response 48 weeks after randomization.

End point type

Secondary

End point timeframe

48 Weeks

End point values	Ruxolitinib	Best Available Therapy (BAT)
Number of subjects analysed	110	112
Units: Percentage of subjects
number (not applicable)
Complete response rate	7.3	0.9
Partial response rate	50.9	0.9

No statistical analyses for this end point

Secondary: Estimated Duration of the Complete Hematological Remission

Top of page

End point title

Estimated Duration of the Complete Hematological Remission ^[2]

End point description

Duration of the complete hematological remission is defined as the time from the first occurrence of complete hematological remission until the date of the first documented progression (end of response). Kaplan-Meier estimates are provided for duration of complete hematological remission.

End point type

Secondary

End point timeframe

Through study completion, analysis was conducted when all patients had completed the Week 80 visit or discontinued the study

Notes
[2] - 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: Estimated Duration of the Complete Hematological Remission was done only on the study drug.

End point values	Ruxolitinib
Number of subjects analysed	110
Units: Probability
number (confidence interval 95%)
16 Weeks	1.00 (0.99 to 999)
32 Weeks	1.00 (0.99 to 999)
48 Weeks	0.88 (0.66 to 0.96)
64 Weeks	0.83 (0.61 to 0.93)
80 Weeks	0.74 (0.51 to 0.87)
96 Weeks	0.74 (0.51 to 0.87)
112 Weeks	0.69 (0.46 to 0.84)
128 Weeks	0.69 (0.46 to 0.84)
144 Weeks	0.65 (0.41 to 0.81)
160 Weeks	0.65 (0.41 to 0.81)
176 Weeks	0.55 (0.32 to 0.73)
192 Weeks	0.55 (0.32 to 0.73)
208 Weeks	0.55 (0.32 to 0.73)
224 Weeks	0.55 (0.32 to 0.73)
240 Weeks	999 (999 to 999)
256 Weeks	999 (999 to 999)

No statistical analyses for this end point

Secondary: Duration of Reduction in Spleen Volume

Top of page

End point title

Duration of Reduction in Spleen Volume ^[3]

End point description

Duration of spleen volume reduction is defined as the time from the first occurrence of a >=35% reduction from baseline in spleen volume until the date of the first documented progression.

End point type

Secondary

End point timeframe

256 Weeks

Notes
[3] - 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: Duration of Reduction in Spleen Volume was done only on the study drug.

End point values	Ruxolitinib
Number of subjects analysed	110
Units: Probability
number (confidence interval 95%)
16 Weeks	1.00 (0.99 to 9.99)
32 Weeks	1.00 (0.99 to 9.99)
48 Weeks	1.00 (0.99 to 9.99)
64 Weeks	1.00 (0.99 to 9.99)
80 Weeks	1.00 (0.99 to 9.99)
96 Weeks	0.98 (0.84 to 1.00)
112 Weeks	0.95 (0.82 to 0.99)
128 Weeks	0.95 (0.82 to 0.99)
144 Weeks	0.95 (0.82 to 0.99)
160 Weeks	0.93 (0.79 to 0.98)
176 Weeks	0.93 (0.79 to 0.98)
192 Weeks	0.93 (0.79 to 0.98)
208 Weeks	0.87 (0.66 to 0.95)
224 Weeks	0.72 (0.34 to 0.91)
240 Weeks	999 (999 to 999)
256 Weeks	999 (999 to 999)

No statistical analyses for this end point

Secondary: Duration of The Overall Clinicohematologic Response

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End point title

Duration of The Overall Clinicohematologic Response ^[4]

End point description

Duration of the overall clinicohematologic response was defined as the time from the first occurrence of complete response (CR) or partial response (PR) until the date of the first documented disease progression.

End point type

Secondary

End point timeframe

256 Weeks

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Duration of The Overall Clinicohematologic Response was done only on the study drug.

End point values	Ruxolitinib
Number of subjects analysed	110
Units: Probability
number (confidence interval 95%)
16 Weeks	1.00 (0.99 to 999)
32 Weeks	0.99 (0.90 to 1.0)
48 Weeks	0.96 (0.87 to 0.99)
64 Weeks	0.91 (0.81 to 0.96)
80 Weeks	0.88 (0.78 to 0.94)
96 Weeks	0.88 (0.78 to 0.94)
112 Weeks	0.85 (0.74 to 0.92)
128 Weeks	0.82 (0.71 to 0.89)
144 Weeks	0.82 (0.71 to 0.89)
160 Weeks	0.80 (0.69 to 0.88)
176 Weeks	0.75 (0.63 to 0.84)
192 Weeks	0.70 (0.57 to 0.80)
208 Weeks	0.67 (0.54 to 0.77)
224 Weeks	0.67 (0.54 to 0.77)
240 Weeks	0.67 (0.54 to 0.77)
256 Weeks	0.67 (0.54 to 0.77)

No statistical analyses for this end point

Secondary: Duration of the Absence of Phlebotomy Eligibility

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End point title

Duration of the Absence of Phlebotomy Eligibility ^[5]

End point description

Duration of the absence of phlebotomy eligibility is defined as the time from the first occurrence of absence of phlebotomy eligibility until the date of the first documented progression.

End point type

Secondary

End point timeframe

256 Weeks

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: Duration of absence of Phlebotomy was done only on the study drug.

End point values	Ruxolitinib
Number of subjects analysed	110
Units: Probability
number (confidence interval 95%)
16 Week	1.00 (0.99 to 999.99)
32 Weeks	1.00 (0.99 to 999.99)
48 Weeks	0.97 (0.88 to 0.99)
64 Weeks	0.92 (0.82 to 0.97)
80 Weeks	0.91 (0.80 to 0.96)
96 Weeks	0.91 (0.80 to 0.96)
112 Weeks	0.87 (0.76 to 0.93)
128 Weeks	0.84 (0.72 to 0.91)
144 Weeks	0.84 (0.72 to 0.91)
160 Weeks	0.82 (0.70 to 0.90)
176 Weeks	0.79 (0.66 to 0.87)
192 Weeks	0.77 (0.64 to 0.86)
208 Weeks	0.73 (0.60 to 0.83)
224 Weeks	0.73 (0.60 to 0.83)
240 Weeks	0.73 (0.60 to 0.83)
256 Weeks	0.73 (0.60 to 0.83)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

This timeframe defines the comparative phase of the study where majority of the subjects remained on their original randomized assignment. Exposure between ruxolitinib & BAT was similar. Data, inclusive of end of study was reported up to Week 256.

Adverse event reporting additional description

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

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

Ruxolitinib (RUX)

Reporting group description

RUX = subjects randomized to INC424, and continued the treatment till week 256

Reporting group title

BATWEEK256

Reporting group description

BATWeek256 = subjects randomized to BAT, and crossed over to INC424 after week 32, and continued the treatment till week 256

Reporting group title

Best Available Therapy (BAT)

Reporting group description

BAT = subjects randomized to BAT, and continued the treatment till week 32

Serious adverse events	Ruxolitinib (RUX)	BATWEEK256	Best Available Therapy (BAT)
Total subjects affected by serious adverse events
subjects affected / exposed	44 / 110 (40.00%)	43 / 98 (43.88%)	10 / 111 (9.01%)
number of deaths (all causes)	2	4	0
number of deaths resulting from adverse events	1	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute leukaemia
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute myeloid leukaemia
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Adenocarcinoma gastric
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	3 / 110 (2.73%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 3	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Carcinoma in situ of skin
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic myeloid leukaemia
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colon neoplasm
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Hairy cell leukaemia
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Invasive ductal breast carcinoma
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Keratoacanthoma
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mediastinum neoplasm
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to central nervous system
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastasis
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastatic squamous cell carcinoma
subjects affected / exposed	2 / 110 (1.82%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myelofibrosis
subjects affected / exposed	1 / 110 (0.91%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myxofibrosarcoma
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neoplasm malignant
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Oropharyngeal squamous cell carcinoma
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Polycythaemia vera
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	1 / 110 (0.91%)	2 / 98 (2.04%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectosigmoid cancer
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	4 / 110 (3.64%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	3 / 9	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of lung
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	2 / 110 (1.82%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 110 (0.00%)	0 / 98 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypovolaemic shock
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Chest pain
subjects affected / exposed	2 / 110 (1.82%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Hyperthermia
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Pyrexia
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Endometrial hyperplasia
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 110 (0.00%)	2 / 98 (2.04%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 110 (0.00%)	2 / 98 (2.04%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Pulmonary arterial hypertension
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 110 (0.00%)	0 / 98 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vocal cord cyst
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Attention deficit/hyperactivity disorder
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Personality change
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Forearm fracture
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural haematoma
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	1 / 110 (0.91%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Splenic rupture
subjects affected / exposed	1 / 110 (0.91%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 110 (0.00%)	0 / 98 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 110 (0.00%)	0 / 98 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	3 / 110 (2.73%)	1 / 98 (1.02%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 110 (0.00%)	0 / 98 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Central nervous system haemorrhage
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Cerebral infarction
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolic encephalopathy
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neurological symptom
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 110 (0.00%)	2 / 98 (2.04%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Disseminated intravascular coagulation
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Splenomegaly
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Blindness
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cataract
subjects affected / exposed	1 / 110 (0.91%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Glaucoma
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retinal detachment
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 110 (0.00%)	2 / 98 (2.04%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anal fistula
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anal haemorrhage
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dental necrosis
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Gastric varices haemorrhage
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Incarcerated inguinal hernia
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Large intestinal stenosis
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	2 / 110 (1.82%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Varices oesophageal
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Volvulus
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder disorder
subjects affected / exposed	0 / 110 (0.00%)	0 / 98 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephrotic syndrome
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion
subjects affected / exposed	3 / 110 (2.73%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 110 (0.00%)	2 / 98 (2.04%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spondylolisthesis
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 110 (0.91%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis viral
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 110 (0.91%)	2 / 98 (2.04%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 1	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 110 (0.91%)	1 / 98 (1.02%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 110 (0.00%)	0 / 98 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatitis B reactivation
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 110 (0.91%)	2 / 98 (2.04%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	1 / 1	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nasal abscess
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	5 / 110 (4.55%)	6 / 98 (6.12%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	2 / 5	1 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0
Sepsis
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tooth abscess
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 110 (0.91%)	2 / 98 (2.04%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Varicella zoster virus infection
subjects affected / exposed	0 / 110 (0.00%)	2 / 98 (2.04%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vulvovaginitis trichomonal
subjects affected / exposed	1 / 110 (0.91%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	2 / 110 (1.82%)	0 / 98 (0.00%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gout
subjects affected / exposed	0 / 110 (0.00%)	0 / 98 (0.00%)	1 / 111 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 110 (0.00%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Ruxolitinib (RUX)	BATWEEK256	Best Available Therapy (BAT)
Total subjects affected by non serious adverse events
subjects affected / exposed	108 / 110 (98.18%)	89 / 98 (90.82%)	93 / 111 (83.78%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	16 / 110 (14.55%)	5 / 98 (5.10%)	1 / 111 (0.90%)
occurrences all number	19	7	1
Myelofibrosis
subjects affected / exposed	8 / 110 (7.27%)	5 / 98 (5.10%)	0 / 111 (0.00%)
occurrences all number	8	5	0
Squamous cell carcinoma of skin
subjects affected / exposed	7 / 110 (6.36%)	4 / 98 (4.08%)	0 / 111 (0.00%)
occurrences all number	9	6	0
Vascular disorders
Haematoma
subjects affected / exposed	11 / 110 (10.00%)	6 / 98 (6.12%)	3 / 111 (2.70%)
occurrences all number	13	6	3
Hypertension
subjects affected / exposed	17 / 110 (15.45%)	15 / 98 (15.31%)	4 / 111 (3.60%)
occurrences all number	19	15	4
General disorders and administration site conditions
Asthenia
subjects affected / exposed	16 / 110 (14.55%)	13 / 98 (13.27%)	12 / 111 (10.81%)
occurrences all number	22	18	12
Chest pain
subjects affected / exposed	4 / 110 (3.64%)	7 / 98 (7.14%)	1 / 111 (0.90%)
occurrences all number	4	7	1
Fatigue
subjects affected / exposed	22 / 110 (20.00%)	13 / 98 (13.27%)	17 / 111 (15.32%)
occurrences all number	31	15	17
Oedema
subjects affected / exposed	7 / 110 (6.36%)	2 / 98 (2.04%)	1 / 111 (0.90%)
occurrences all number	7	2	1
Oedema peripheral
subjects affected / exposed	9 / 110 (8.18%)	5 / 98 (5.10%)	7 / 111 (6.31%)
occurrences all number	11	5	7
Pyrexia
subjects affected / exposed	17 / 110 (15.45%)	10 / 98 (10.20%)	5 / 111 (4.50%)
occurrences all number	22	15	7
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	20 / 110 (18.18%)	12 / 98 (12.24%)	6 / 111 (5.41%)
occurrences all number	26	17	8
Dyspnoea
subjects affected / exposed	19 / 110 (17.27%)	10 / 98 (10.20%)	2 / 111 (1.80%)
occurrences all number	23	11	3
Epistaxis
subjects affected / exposed	9 / 110 (8.18%)	7 / 98 (7.14%)	3 / 111 (2.70%)
occurrences all number	12	11	6
Psychiatric disorders
Insomnia
subjects affected / exposed	11 / 110 (10.00%)	11 / 98 (11.22%)	6 / 111 (5.41%)
occurrences all number	15	13	8
Investigations
Alanine aminotransferase increased
subjects affected / exposed	7 / 110 (6.36%)	6 / 98 (6.12%)	1 / 111 (0.90%)
occurrences all number	8	8	1
Aspartate aminotransferase increased
subjects affected / exposed	7 / 110 (6.36%)	5 / 98 (5.10%)	0 / 111 (0.00%)
occurrences all number	7	10	0
Blood cholesterol increased
subjects affected / exposed	6 / 110 (5.45%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences all number	7	1	0
Blood lactate dehydrogenase increased
subjects affected / exposed	4 / 110 (3.64%)	8 / 98 (8.16%)	2 / 111 (1.80%)
occurrences all number	4	8	2
Gamma-glutamyltransferase increased
subjects affected / exposed	9 / 110 (8.18%)	8 / 98 (8.16%)	3 / 111 (2.70%)
occurrences all number	12	8	4
Haemoglobin decreased
subjects affected / exposed	1 / 110 (0.91%)	7 / 98 (7.14%)	1 / 111 (0.90%)
occurrences all number	1	15	1
Weight increased
subjects affected / exposed	26 / 110 (23.64%)	14 / 98 (14.29%)	1 / 111 (0.90%)
occurrences all number	32	15	1
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	6 / 110 (5.45%)	3 / 98 (3.06%)	5 / 111 (4.50%)
occurrences all number	8	3	6
Fall
subjects affected / exposed	3 / 110 (2.73%)	6 / 98 (6.12%)	2 / 111 (1.80%)
occurrences all number	3	7	2
Nervous system disorders
Dizziness
subjects affected / exposed	17 / 110 (15.45%)	20 / 98 (20.41%)	11 / 111 (9.91%)
occurrences all number	26	22	13
Headache
subjects affected / exposed	25 / 110 (22.73%)	17 / 98 (17.35%)	21 / 111 (18.92%)
occurrences all number	38	29	26
Hypoaesthesia
subjects affected / exposed	6 / 110 (5.45%)	7 / 98 (7.14%)	1 / 111 (0.90%)
occurrences all number	6	9	1
Neuralgia
subjects affected / exposed	6 / 110 (5.45%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences all number	6	1	0
Neuropathy peripheral
subjects affected / exposed	6 / 110 (5.45%)	2 / 98 (2.04%)	5 / 111 (4.50%)
occurrences all number	8	3	5
Paraesthesia
subjects affected / exposed	7 / 110 (6.36%)	7 / 98 (7.14%)	7 / 111 (6.31%)
occurrences all number	13	8	9
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	38 / 110 (34.55%)	29 / 98 (29.59%)	4 / 111 (3.60%)
occurrences all number	64	42	4
Leukocytosis
subjects affected / exposed	4 / 110 (3.64%)	7 / 98 (7.14%)	3 / 111 (2.70%)
occurrences all number	4	11	3
Thrombocytopenia
subjects affected / exposed	19 / 110 (17.27%)	4 / 98 (4.08%)	12 / 111 (10.81%)
occurrences all number	34	6	17
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	9 / 110 (8.18%)	5 / 98 (5.10%)	3 / 111 (2.70%)
occurrences all number	11	5	3
Vertigo
subjects affected / exposed	7 / 110 (6.36%)	4 / 98 (4.08%)	4 / 111 (3.60%)
occurrences all number	10	4	4
Eye disorders
Cataract
subjects affected / exposed	1 / 110 (0.91%)	6 / 98 (6.12%)	0 / 111 (0.00%)
occurrences all number	1	7	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	6 / 110 (5.45%)	1 / 98 (1.02%)	4 / 111 (3.60%)
occurrences all number	6	1	4
Abdominal pain
subjects affected / exposed	16 / 110 (14.55%)	8 / 98 (8.16%)	13 / 111 (11.71%)
occurrences all number	19	10	13
Abdominal pain upper
subjects affected / exposed	12 / 110 (10.91%)	6 / 98 (6.12%)	5 / 111 (4.50%)
occurrences all number	12	7	6
Constipation
subjects affected / exposed	14 / 110 (12.73%)	15 / 98 (15.31%)	3 / 111 (2.70%)
occurrences all number	15	18	3
Diarrhoea
subjects affected / exposed	30 / 110 (27.27%)	12 / 98 (12.24%)	9 / 111 (8.11%)
occurrences all number	38	12	10
Dyspepsia
subjects affected / exposed	7 / 110 (6.36%)	3 / 98 (3.06%)	1 / 111 (0.90%)
occurrences all number	8	3	1
Nausea
subjects affected / exposed	15 / 110 (13.64%)	7 / 98 (7.14%)	4 / 111 (3.60%)
occurrences all number	19	10	4
Vomiting
subjects affected / exposed	6 / 110 (5.45%)	7 / 98 (7.14%)	4 / 111 (3.60%)
occurrences all number	8	9	4
Skin and subcutaneous tissue disorders
Ecchymosis
subjects affected / exposed	2 / 110 (1.82%)	7 / 98 (7.14%)	1 / 111 (0.90%)
occurrences all number	3	7	1
Night sweats
subjects affected / exposed	13 / 110 (11.82%)	6 / 98 (6.12%)	9 / 111 (8.11%)
occurrences all number	16	8	9
Pruritus
subjects affected / exposed	30 / 110 (27.27%)	20 / 98 (20.41%)	24 / 111 (21.62%)
occurrences all number	42	25	28
Purpura
subjects affected / exposed	2 / 110 (1.82%)	5 / 98 (5.10%)	0 / 111 (0.00%)
occurrences all number	2	6	0
Rash
subjects affected / exposed	4 / 110 (3.64%)	7 / 98 (7.14%)	5 / 111 (4.50%)
occurrences all number	4	7	6
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	24 / 110 (21.82%)	11 / 98 (11.22%)	8 / 111 (7.21%)
occurrences all number	32	14	8
Back pain
subjects affected / exposed	17 / 110 (15.45%)	18 / 98 (18.37%)	5 / 111 (4.50%)
occurrences all number	21	21	5
Bone pain
subjects affected / exposed	4 / 110 (3.64%)	4 / 98 (4.08%)	6 / 111 (5.41%)
occurrences all number	6	4	6
Muscle spasms
subjects affected / exposed	22 / 110 (20.00%)	11 / 98 (11.22%)	7 / 111 (6.31%)
occurrences all number	28	12	8
Musculoskeletal pain
subjects affected / exposed	7 / 110 (6.36%)	6 / 98 (6.12%)	4 / 111 (3.60%)
occurrences all number	10	7	4
Myalgia
subjects affected / exposed	7 / 110 (6.36%)	3 / 98 (3.06%)	8 / 111 (7.21%)
occurrences all number	9	3	9
Osteoarthritis
subjects affected / exposed	6 / 110 (5.45%)	4 / 98 (4.08%)	0 / 111 (0.00%)
occurrences all number	7	4	0
Pain in extremity
subjects affected / exposed	10 / 110 (9.09%)	11 / 98 (11.22%)	4 / 111 (3.60%)
occurrences all number	13	16	5
Infections and infestations
Bronchitis
subjects affected / exposed	14 / 110 (12.73%)	13 / 98 (13.27%)	5 / 111 (4.50%)
occurrences all number	17	17	5
Gastroenteritis
subjects affected / exposed	2 / 110 (1.82%)	5 / 98 (5.10%)	1 / 111 (0.90%)
occurrences all number	2	5	1
Herpes zoster
subjects affected / exposed	19 / 110 (17.27%)	12 / 98 (12.24%)	0 / 111 (0.00%)
occurrences all number	26	12	0
Influenza
subjects affected / exposed	13 / 110 (11.82%)	9 / 98 (9.18%)	2 / 111 (1.80%)
occurrences all number	14	9	2
Nasopharyngitis
subjects affected / exposed	19 / 110 (17.27%)	14 / 98 (14.29%)	9 / 111 (8.11%)
occurrences all number	30	32	10
Pharyngitis
subjects affected / exposed	6 / 110 (5.45%)	1 / 98 (1.02%)	0 / 111 (0.00%)
occurrences all number	7	1	0
Sinusitis
subjects affected / exposed	3 / 110 (2.73%)	6 / 98 (6.12%)	1 / 111 (0.90%)
occurrences all number	7	9	1
Upper respiratory tract infection
subjects affected / exposed	10 / 110 (9.09%)	8 / 98 (8.16%)	5 / 111 (4.50%)
occurrences all number	17	14	5
Urinary tract infection
subjects affected / exposed	10 / 110 (9.09%)	8 / 98 (8.16%)	0 / 111 (0.00%)
occurrences all number	18	11	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	9 / 110 (8.18%)	5 / 98 (5.10%)	6 / 111 (5.41%)
occurrences all number	9	6	6
Hypercholesterolaemia
subjects affected / exposed	5 / 110 (4.55%)	5 / 98 (5.10%)	0 / 111 (0.00%)
occurrences all number	6	6	0

More information

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Were there any global substantial amendments to the protocol? Yes

23 Aug 2011

Protocol amendment 1, issued after 30 patients had been randomized, introduced the following main changes: • Some inclusion criteria were re-evaluated and revised: • The inclusion criteria were revised from requiring a palpable spleen length of > 5 cm to requiring palpable splenomegaly confirmed by imaging (volume ≥ 450 cm3) at Screening. Patients with palpable spleen were to be considered eligible if MRI (or CT if applicable) confirmed a spleen volume of ≥ 450 cm3 (i.e. approximately twice the upper limit of a normal spleen volume). • The inclusion criterion that required patients to have a leukocytosis > 15x109/L and/or thrombocytosis > 600x109/L at Screening were removed • The definition of unacceptable non-hematological toxicities in HU intolerant patients was extended to include events reflecting severe/very severe toxicities leading to treatment discontinuation or interruption, and hospitalization • The phlebotomy requirement prior to study entry was extended from 12 to 16 weeks between the last phlebotomy and screening, for patients with hematocrit > 45% at screening for the evidence of phlebotomy dependence • The definition of durable response for the primary endpoint and key secondary endpoints was changed to 48 weeks after randomization, however, the definition of duration of primary response was maintained as time from initial response. • Bone marrow biopsy was mandated in the event of suspected development of MF or acute leukemia • Sample size was reduced from 300 to 200 patients and the assumption on response rate for durable primary endpoint was modified accordingly

13 Apr 2012

Protocol amendment 2, issued after 98 patients had been randomized (no patients had reached the Week 80 visit), introduced the following main changes: • The treatment period of patients receiving ruxolitinib at Week 80 (end of treatment in the current protocol) was extended by 128 week from Week 80 to Week 208. This period was defined as the Extended Treatment Phase • The PV patients benefitting from ruxolitinib at Week 80 were offered enrollment onto a 128-week Extended Treatment Phase

25 Jun 2013

Protocol amendment 3, issued after all (n=222) patients had been randomized but 6 months prior to database lock for the primary analysis, introduced the following main changes: • The analysis window for MRI/CT scans was extended from ±7 days to ±28 days. • The analysis windows for hematocrit, WBC and platelets were specified in greater detail for individual study visits, and the use of multiple assessments available within an analysis window was defined, in order to minimize missing data, remove any ambiguity and optimize the use of available assessments.

13 Nov 2014

The rationale for the amendment is as follows: • To collect long-term safety and efficacy data, treatment duration will be extended by additional 48 weeks, to a total of 256 weeks (5 years). • Hydroxyurea resistance/intolerance has recently been shown to be associated with significantly reduced overall survival, attributed in part to lack of effective second-line therapies (Alvarez-Larran, 2012). In the current study, ruxolitinib demonstrated superiority to BAT in hematocrit control, reduction in splenomegaly and complete hematologic remission in hydroxyurea resistant or intolerant patients. To evaluate whether these benefits translate into an improved survival, overall survival will be added as an exploratory endpoint to the study. Survival follow-up after treatment discontinuation will be conducted in all patients until Last Patient Last Visit. • Thromboembolic events and transformation to acute leukemia or myelofibrosis (MF) are the major causes of morbidity and mortality in PV patients (Tefferi et al, 2013). Tight hematocrit control with a target of ≤ 45% leads to a 4-fold reduction in the risk of thrombosis (Marchioli et al, 2013). In the current study, week 32 analysis demonstrated that hematocrit control without phlebotomy was achieved in 60% of patients in the ruxolitinib arm, compared to 20% in the BAT arm. The number of thromboembolic adverse events up to week 32 was lower in the ruxolitinib arm (N=1) compared to the BAT arm (N=6). The number of transformation events up to week 32 was too low to draw any conclusions (MF, N=2 on ruxolitinib vs N=1 on BAT; AML, N=1 on ruxolitinib vs N=0 on BAT). To assess long-term impact of ruxolitinib, the rate of thrombosis and transformation-free survival will be added as exploratory endpoints to the study.

16 Feb 2016

To remove the requirement for contraception for male participants since there were no effects of INC424 on reproductive performance or fertility in male rats. While INC424 was not measured in semen of humans or any animal species studied, the estimated dose to the woman (based on INC424 exposure in males and estimated amount expected in semen) was approximately 333’333 times smaller than the embryo-fetal NOEL. This dose would present no increased risk to the embryo-fetus. Therefore, it was not expected that INC424 would lead to any adverse reaction in women whose partner was treated by INC424. This supports the removal of the requirement for male contraception; To update the contraception requirements for female participants; To clarify that Survival Follow Up was only applicable for patients who complete/discontinue study treatment prior to Week 256 and only continues until the time when the individual Week 256 visit from randomization would have been reached; To clarify that samples for pharmacodynamic assessments must be collected at the end of study treatment in the extended treatment phase (early termination or Week 256 visit); To clarify that EORTC QLQ-C30 & Pruritus Symptom Impact Scale questionnaires must be collected at the end of study treatment in the extended treatment phase (early termination or Week 256 visit); To clarify that serum pregnancy test must be performed at the end of study treatment in the extended treatment phase; To add new information on dual inhibitors of CYP2C9 & CYP3A4 (e.g. , fluconazole). The concomitant use of INC424 and fluconazole doses of ≥ 200 mg daily should be avoided if clinically necessary to use doses ≥ 200 mg daily consultation with Sponsor was required; To clarify that aPTT assessment was also allowed as equivalent of PTT; To make admin. changes: clarified throughout the protocol that Survival Follow Up visits can be performed approximately every 3 months, corrected internal hyperlinks, typos, updated list of abbrevs.

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, results of crossover studies and data using 999 as data points are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results

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