Clinical trial NCT02292446
Conditions: Polycythemia Vera
Keywords: Polycythemia Vera Hematologic Diseases Myeloproliferative Disorders INC424 Ruxolitinib hydroxyurea resistant adult
Sponsor: Novartis Pharmaceuticals
Start date: 2014-11-21; Completion date: 2017-12-29
Enrollment: 161 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this open-label, single arm, multi-center Expanded Treatment Protocol (ETP) was to provide early access to ruxolitinib and evaluate safety information in patients with polycythemia vera (PV) who were hydroxyurea (HU) resistant or intolerant and who had no other standard treatment option, nor did they qualify for another clinical study for PV

Detailed description:

Arms: arm 1: All patients will receive ruxolitinib at a starting dose of 10 mg twice daily which could be titrated to most appropriate dose. Dose was not to exceed 25 mg bid nor be less than 5 mg once a day
Interventions: intervention 1: Ruxolitinib
Intervention descriptions: intervention 1: supplied as 5 mg, 10 mg and 20 mg tablets to be taken orally

Protocol documents:
Prot_000.pdf: 
Clinical Development
INC424/ruxolitinib/Jakavi®
Protocol CINC424B2001X / NCT02292446
An open-label, multi-center, Expanded Treatment Protocol 
(ETP) of ruxolitinib in patients with Polycythemia Vera who 
are Hydroxyurea resistant or intolerant and for whom no 
treatment alternatives are available.
Authors
Document type
Amended Protocol Version
EUDRACT number
2014-001309-42
Version number
01 (Clean)
Development phase
Phase IIIb
Document status
Final
Release date
11-Mar-2016
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................9
Protocol summary:.............................................................................................................10
Amendment 1 ....................................................................................................................12
1
Background........................................................................................................................16
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............16
1.2
Introduction to investigational treatment(s) and other study treatment(s).............17
1.2.1
Overview of ruxolitinib.........................................................................17
2
Rationale............................................................................................................................21
2.1
Study rationale and purpose...................................................................................21
2.2
Rationale for the study design ...............................................................................22
2.3
Rationale for dose and regimen selection..............................................................22
2.4
Rationale for choice of combination drugs............................................................22
2.5
Rationale for choice of comparators drugs............................................................22
3
Objectives and endpoints...................................................................................................23
4
Study design ......................................................................................................................23
4.1
Description of study design ...................................................................................23
4.2
Timing of interim analyses and design adaptations...............................................24
4.3
Definition of end of the study................................................................................24
4.4
Early study termination..........................................................................................24
5
Population..........................................................................................................................24
5.1
Patient population..................................................................................................24
5.2
Inclusion criteria ....................................................................................................25
5.3
Exclusion criteria...................................................................................................25
6
Treatment...........................................................................................................................27
6.1
Study treatment......................................................................................................27
6.1.1
Dosing regimen .....................................................................................27
6.1.2
Ancillary treatments..............................................................................28
6.1.3
Rescue medication ................................................................................28
6.1.4
Guidelines for continuation of treatment ..............................................28
6.1.5
Treatment duration................................................................................28
6.2
Dose escalation guidelines.....................................................................................28
6.3
Dose modifications ................................................................................................28


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6.3.1
Dose escalations due to inadequate efficacy.........................................28
6.3.2
Dose reductions due to hematological changes ....................................29
6.3.3
Restarting or increasing dose after hematological decline....................30
6.3.4
Ruxolitinib starting dose for patients with platelets less than 
100x109/L..............................................................................................31
6.3.5
Dose modification for renal impairment...............................................31
6.3.6
Dose reduction for non-hematological safety .......................................31
6.3.7
Dose reduction for concomitant CYP inhibitor use..............................31
6.3.8
Optional dose tapering strategy in the event of discontinuation...........31
6.4
Concomitant medications ......................................................................................32
6.4.1
Permitted concomitant therapy .............................................................32
6.4.2
Permitted concomitant therapy requiring caution and/or action...........32
6.4.3
Prohibited concomitant therapy ............................................................33
6.5
Patient numbering, treatment assignment or randomization .................................33
6.5.1
Patient numbering .................................................................................33
6.5.2
Treatment assignment ...........................................................................33
6.5.3
Treatment blinding................................................................................34
6.6
Study drug preparation and dispensation...............................................................34
6.6.1
Study drug packaging and labeling.......................................................34
6.6.2
Drug supply and storage........................................................................34
6.6.3
Study drug compliance and accountability ...........................................34
6.6.4
Disposal and destruction .......................................................................35
7
Visit schedule and assessments .........................................................................................35
7.1
Study flow and visit schedule................................................................................35
7.1.1
Screening...............................................................................................38
7.1.2
Treatment period ...................................................................................39
7.1.3
End of treatment visit including study completion and premature 
withdrawal.............................................................................................39
7.1.4
Follow up period ...................................................................................41
7.2
Assessment types...................................................................................................41
7.2.1
Efficacy assessments.............................................................................41
7.2.2
Safety and tolerability assessments.......................................................41
7.2.3
Biomarkers ............................................................................................43
7.2.4
Resource utilization...............................................................................43
7.2.5
Patient reported outcomes.....................................................................43
8
Safety monitoring and reporting........................................................................................44
8.1
Adverse events.......................................................................................................44


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8.1.1
Definitions and reporting ......................................................................44
8.1.2
Laboratory test abnormalities................................................................45
8.2
Serious adverse events...........................................................................................46
8.2.1
Definitions.............................................................................................46
8.2.2
Reporting...............................................................................................46
8.3
Emergency unblinding of treatment assignment ...................................................47
8.4
Pregnancies............................................................................................................47
8.5
Warnings and precautions......................................................................................48
8.6
Data Monitoring Committee..................................................................................48
8.7
Steering Committee ...............................................................................................48
9
Data collection and management.......................................................................................48
9.1
Data confidentiality ...............................................................................................48
9.2
Site monitoring ......................................................................................................49
9.3
Data collection.......................................................................................................50
9.4
Database management and quality control............................................................50
10 Statistical methods and data analysis ................................................................................50
10.1
Analysis sets ..........................................................................................................51
10.1.1
Full Analysis Set ...................................................................................51
10.1.2
Safety Set ..............................................................................................51
10.1.3
Per-Protocol Set ....................................................................................51
10.1.4
Dose-determining analysis set...............................................................51
10.1.5
Pharmacokinetic analysis set.................................................................51
10.1.6
Other analysis sets.................................................................................51
10.2
Patient demographics/other baseline characteristics .............................................51
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................51
10.4
Primary objective...................................................................................................52
10.4.1
Variable.................................................................................................52
10.4.2
Statistical hypothesis, model, and method of analysis..........................52
10.4.3
Handling of missing values/censoring/discontinuations.......................52
10.4.4
Supportive analyses...............................................................................52
10.5
Secondary objectives .............................................................................................52
10.5.1
Key secondary objective(s)...................................................................52
10.5.2
Other secondary efficacy objectives .....................................................52
10.5.3
Safety objectives ...................................................................................52
10.5.4
Pharmacokinetics ..................................................................................54
10.5.5
Resource utilization...............................................................................54


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10.5.6
Patient-reported outcomes.....................................................................54
10.6
Exploratory objectives...........................................................................................54
10.7
Interim analysis......................................................................................................54
10.8
Sample size calculation..........................................................................................54
10.9
Power for analysis of key secondary variables......................................................54
11 Ethical considerations and administrative procedures ......................................................55
11.1
Regulatory and ethical compliance........................................................................55
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................55
11.3
Informed consent procedures.................................................................................55
11.4
Discontinuation of the study..................................................................................55
11.5
Publication of study protocol and results...............................................................56
11.6
Study documentation, record keeping and retention of documents.......................56
11.7
Confidentiality of study documents and patient records .......................................57
11.8
Audits and inspections...........................................................................................57
11.9
Financial disclosures..............................................................................................57
12 Protocol adherence ............................................................................................................57
12.1
Amendments to the protocol..................................................................................57
13 References (available upon request)..................................................................................58
14 Appendices ........................................................................................................................60
14.1
Appendix 1: The 2008 World Health Organization diagnostic criteria for 
polycythemia vera..................................................................................................60
14.2
Appendix 2: Eastern Cooperative Oncology Group Performance Status..............61
14.3
Appendix 3: New York Heart Association (NYHA) Functional Classification....62
14.4
Appendix 4: 2008 WHO classification for Myelodysplastic Syndromes (MDS)
...............................................................................................................................63
14.5
Appendix 5: IWG-MRT recommended criteria for post-PV MF..........................64
14.6
Appendix 6: Myeloproliferative Neoplasm Symptom Assessment Form Total 
Symptom Score (MPN-SAF TSS).........................................................................65
14.7
Appendix 7: Restricted medications......................................................................66


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List of tables
Table 3-1
Objectives and related endpoints ..........................................................23
Table 6-1
Dose and treatment schedule.................................................................27
Table 6-2
Ruxolitinib allowed dose escalation due to inadequate efficacy ..........29
Table 6-3
Dose modifications for hematologic toxicity........................................30
Table 6-4
Ruxolitinib maximum allowable dose levels after dose interruption 
or reduction due to hematological decline ............................................30
Table 6-5
Preparation and dispensing ...................................................................34
Table 7-1
Visit evaluation schedule ......................................................................36
Table 7-2
Local clinical laboratory parameters.....................................................42
Table 14-1
Eastern Cooperative Oncology Group Performance Status..................61
Table 14-2
New York Heart Association (NYHA) Functional Classification........62
Table 14-3
2008 WHO classification for Myelodysplastic Syndromes (MDS)......63
Table 14-4
IWG-MRT recommended criteria for post-PV MF ..............................64
Table 14-5
List of CYP3A4 inhibitors and inducers...............................................66


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List of abbreviations
AE
Adverse Event
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
ANC
Absolute Neutrophil Count
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
AUC
Area Under the Concentration-Time Curve
b.i.d.
bis in diem/twice a day
BAT
Best Available Treatment
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
cm
Centimeter
Cmax
Maximum plasma concentration
Cmin
Pre-dose (trough) plasma concentration
CRF
Case Report/Record Form; the term CRF may be applied to either EDC or Paper
CRO
Contract Research Organization
CSR
Clinical study report
CSR addendum
An addendum to Clinical Study Report (CSR) that captures all the additional information that 
is not included in the CSR
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P
DS&E
Drug Safety and Epidemiology
ECG
Electrocardiogram
ECLAP
European Collaboration on Low-Dose Aspirin in Polycythemia Vera
ECOG
Eastern Cooperative Oncology Group
ELN
European Leukemia Net
EOT
End of Treatment
ET
Essential Thrombocythemia
GCP
Good Clinical Practice
GI
Gastrointestinal
Hb
Hemoglobin
hCG
Human Chorionic Gonadotropin
Hct
Hematocrit
HDL
High Density Lipoproteins
HIV
Human Immunodeficiency Virus
HU
Hydroxyurea
IB
Investigators Brochure
IC50
Inhibitory Concentration of 50%
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IN
Investigator Notification
IRB
Institutional Review Board
IRT
Interactive Response Technology: includes Interactive Voice Response System and 
Interactive Web Response System
IWG-MRT
International Working Group for Myelofibrosis Research and Treatment
IU
International Unit


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IUD
Intrauterine Device
IUS
Intrauterine System
JAK
Janus Kinase
kg
Kilogram
LDL
Low Density Lipoproteins
MAP
Master Analysis Plan documents project standards in the statistical methods which will be 
used within the individual clinical trial RAP documentation
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MDRD-eGFR
Modification of Diet in Renal Disease - estimate glomerular filtration rate
MF
Myelofibrosis
mg
Milligram
mL
milliliter
MPD
Myeloproliferative Diseases
MPN
Myeloproliferative Neoplasm
MPN-SAF TSS
Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score
NYHA
New York Heart Association
PD
Pharmacodynamic(s)
PEG-IFN
Pegylated-Interferon
PK
Pharmacokinetic(s)
PHI
Protected Health Information
PLT
Platelets
PML
Progressive multifocal leukoencephalopathy
PT (INR)
Prothrombin Time (International normalized ratio) 
PTT
Partial Thromboplastin Time
PV
Polycythemia Vera
qd
Every Day (Latin: Quaque die)
RAP
Reporting and Analysis Plan
RBC
Red Blood Count
REB
Research Ethics Board
RESPONSE
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 
SAE
Serious Adverse Event
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TEAE
Treatment Emergent Adverse Event
ULN
Upper Limit of Normal
WBC
White Blood Count
WHO
World Health Organization


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Dose level
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment
Point/time of patient entry into the study; the point at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with “investigational 
new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes approved 
drugs used outside of their indication/approved dosage, or that are tested in a fixed 
combination. Investigational treatment generally does not include other study 
treatments administered as concomitant background therapy required or allowed by 
the protocol when used in within approved indication/dosage
Medication number
A unique identifier on the label of each study treatment package which is linked to one 
of the treatment groups of a study
Other study treatment
Any drug administered to the patient as part of the required study procedures that 
was not included in the investigational treatment
Patient Number 
A unique identifying number assigned to each patient/subject/healthy volunteer who 
enrolls in the study
Premature patient 
withdrawal
Point/time when the patient exits from the study prior to the planned completion of all 
study treatment administration and/or assessments; at this time all study treatment 
administration is discontinued and no further assessments are planned, unless the 
patient will be followed for progression and/or survival
Stage related to study 
timeline
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures, including placebo and 
active drug run-ins.
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this case 
refers to the investigational and non-investigational treatments in combination.
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for any reason; 
may or may not also be the point/time of premature patient withdrawal
Variable
Identifier used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified timepoints


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Protocol summary:
Protocol number
CINC424B2001X Version 01
Title
An open-label, multi-center, Expanded Treatment Protocol (ETP) of ruxolitinib in 
patients with Polycythemia Vera (PV) who are Hydroxyurea (HU) resistant or intolerant 
and for whom no treatment alternatives are available
Brief title
Expanded Treatment Protocol of ruxolitinib in Polycythemia Vera patients who are HU 
resistant or intolerant. 
Sponsor and Clinical 
Phase
Novartis
Phase: IIIb
Investigation type
Drug
Study type
Interventional 
Purpose and 
rationale
To provide early treatment access and evaluate the safety of ruxolitinib in patients with 
Polycythemia Vera who are intolerant or resistant to Hydroxyurea.
Primary Objective(s) 
To evaluate the safety of ruxolitinib
Secondary 
Objectives
To evaluate change in hematocrit levels
To evaluate change in spleen length
To evaluate change in MPN-SAF TSS score
Study design
A global, open-label, single arm, multicenter, expanded treatment protocol with 
ruxolitinib.
Population
Approximately 500 Polycythemia Vera patients who are hydroxyurea resistant or 
intolerant and for whom no other standard treatment options are available. 
Inclusion criteria
●
Male or female patients aged ≥18 years of age.
●
Confirmed diagnosis of PV according to the 2008 WHO criteria.
●
HU resistant or intolerant
●
Peripheral blood blast count of 0% at screening
●
ECOG score of 0, 1 or 2 at baseline
●
Must have recovered or stabilized sufficiently from adverse drug reactions 
associated with any prior treatments before beginning ruxolitinib 
●
Does not have access to a comparable or satisfactory alternative treatment
●
Is not eligible for participation in any of the ruxolitinib ongoing clinical trials or has 
recently completed a clinical trial that has been terminated 
●
Is not being transferred from an ongoing clinical trial for which they are still eligible.
Exclusion criteria
●
Subjects with known hypersensitivity to ruxolitinib or any of its excipients
●
Patients with severely impaired renal function defined by:
●
Serum creatinine > 2 mg/dL (> 176.8µmol/L).
●
Patients with inadequate liver function defined by any of these:
●
Total bilirubin ≥ 2.5 x ULN and subsequent determination of direct bilirubin ≥ 2.5 
x ULN; 
●
Alanine aminotransferase (ALT) > 2.5 x ULN; Aspartate aminotransferase
(AST) > 2.5 x ULN.
●
Platelet count < 50 ×109/L or an ANC of < 1 × 109/L
●
Being treated concurrently with a potent systemic inhibitor or inducer of CYP3A4 at 
the time of Screening.
●
Clinically significant bacterial, fungal, parasitic or viral infection which requires 
therapy
●
History of progressive multifocal leukoencephalopathy (PML)
●
Any concurrent condition that, in the Investigator’s opinion would jeopardize the 
safety of the patient.
Investigational and 
reference therapy
ruxolitinib 10 mg bid 


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Efficacy assessments
Hematocrit, spleen length
Safety assessments
Adverse Events, vital signs, hematology 
Other assessments
PRO: MPN SAF 
Data analysis
Data will be summarized with respect to demographic and baseline characteristics and 
safety observations and measurements. Categorical data will be presented as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 
minimum, and maximum will be presented.
Key words
Polycythemia Vera, Hydroxyurea resistant or intolerant, ruxolitinib, INC424, 
myeloproliferative neoplasm, myeloproliferative disorder, blood disorder


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Amendment 1
Study Status
The study is ongoing with 65 patients enrolled.
The primary intent of the amendment is to harmonize the standard language for a matter of 
consistency among all Novartis sponsored clinical studies. In this regards, the overview of 
ruxolitinib has been updated, including the ruxolitinib approval status for the new indication 
Polycythemia vera.
The changes to the protocol are summarized in the table below:
Changes to the Protocol are listed below. Changes to specific sections of the protocol are 
shown in the track changes version of the protocol using strike-through red font for deletions, 
and red and bold for insertions:
Protocol summary:

This section has been updated with the sample size (number of patients), revised to 500 
from 1500 based on a number of countries declining participation due to an earlier 
approval of the Polycythemia Vera indication.

This section has been updated as per the new program standard language issued in Sep 
2015.
Section 1.2.1 Overview of Ruxolitinib:

This section has been updated as per the new program standard language issued in Sep 
2015.
Section 1.2.1.3.3 Phase III:

This section has been updated as per the IB update version 14 with latest information from 
clinical trials.
Section 5.2 Inclusion criteria:

The Inclusion criterion #3, requiring a treatment history for PV that meets the definition of 
resistance or intolerance to hydroxyurea has been removed 

Inclusion criterion #2 has been updated to the following requirement: Confirmed diagnosis 
of PV according to the revised WHO criteria (see Appendix 1), with resistance or 
intolerance to hydroxyurea.

The reference of Barosi et al. 2009 has been removed as this is not anymore relevant as 
PV is now approved.

The inclusion criterion requiring palpable spleen has been removed. This criterion will 
allow patients without splenomegaly to enter the trial.
Section 5.3 Exclusion criteria:

All the exclusion criteria #1 to #18 have been changed according to the new program 
standard language issued in Sep 2015.


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
Updated of the pregnancy language as per the new program standard language issued in 
Sep 2015 and as per the new guideline on prevention of Pregnancies in Participants in 
Clinical Trials issued in 2015.
Section 6.3.2 Dose reductions due to hematological changes:

This section has been updated as per the new program standard language issued in Sep 
2015.
Table 6-3 Dose modifications for hematologic toxicity:

The table including the title has been fully updated to reflect the changes recommended as 
per the new program standard language issued in Sep 2015.
Section 6.3.4 Ruxolitinib starting dose for patients with platelets less than 100x109/L :

This section has been updated as per the new program standard language issued in Sep 
2015.
Section 6.3.5 Dose modification for renal impairment:

This section has been added as per the new program standard language issued in Sep 2015. 
Section 6.3.6 Dose reduction for non-hematological safety:

This section has been added as per the new program standard language issued in Sep 2015.
Section 6.3.7 Dose reduction for concomitant CYP inhibitor use:

Administrative change in this section: change from Section 6.3.5 to Section 6.3.7 for a 
matter of clarity.
Section 6.3.8 Optional dose tapering strategy in the event of discontinuation:

Administrative change in this section: change from Section 6.3.6 to Section 6.3.8 for a 
matter of clarity.
Section 6.4 Concomitant medications:

This section has been updated as per the new program standard language issued in Sep 
2015.
Section 6.4.2 Permitted concomitant therapy requiring caution and/or action

Higher Aspirin dose has been left in this section however it has been added in the Section 
6.4.3 Prohibited concomitant therapy.

Update of the Section 6.3.8 instead of Section 6.3.6 for the optional dose tapering strategy 
in the event of discontinuation.
Section 6.4.3 Prohibited concomitant therapy

This section has been updated to be aligned with program standard language issued in Sep 
2015.


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Table 7-1 Visit evaluation schedule

Pregnancy serum test has been added at the EOT to align with the program standard 
language issued in Sep 2015. 

Pregnancy urine test has been removed at EOT.
Section 7.2.2.5 Laboratory evaluations

Hemoglobin parameter has added in the laboratory assessment. This parameter is judged 
as important to assess safety. 

The serum pregnancy test has been added to align with the program standard language 
issued in Sep 2015.
Section 7.2.2.5.1 Pregnancy and assessments of fertility

The serum pregnancy test has been added at the EOT as per the new guidance.
Table 7-2 Local clinical laboratory parameters

Hemoglobin parameter has added in the laboratory assessment 

Pregnancy serum test has been added at EOT.

Abbreviations have been clarified.
Section 8.1.1 Safety

The paragraph “Progression of malignancy (including fatal outcomes), if documented by 
use of appropriate method (for example, as per RECIST criteria for solid tumors or as per 
Cheson's guidelines for hematological malignancies), should not be reported as a serious 
adverse event” has been removed.

This paragraph was removed to align with the trial reporting goals.
Section 8.4 Pregnancies:

The paragraph “Pregnancy outcomes must be collected for the female partners of any 
males who took study treatment in this study. Consent to report information regarding 
these pregnancy outcomes should be obtained from the mother” has been removed as per 
the new guideline on prevention of Pregnancies in Participants in Clinical Trials issued in 
2015.
Section 10.8 Sample size calculation

The sample size (number of patients) has been revised to 500 from 1500.

This is due to a number of countries declining participation due to an earlier approval of 
the Polycythemia Vera indication.
Section 13 References

The reference of Barosi et al. 2009 has been removed as this is not anymore relevant as 
PV indication is now approved.
Section 14.1 Appendix 1 Guidelines for hydroxyurea resistance and intolerance

This appendix has been removed as this is not relevant anymore as the PV indication is 
now approved, and the references to this appendix have been removed from the protocol.


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Section 14.7 Appendix 7 Restricted medications:

The Table 14-5 has been updated based on the new protocol standard language.
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Polycythemia Vera (PV) is classified as a myeloproliferative neoplasm (MPN) along with two 
other BCR-ABL-negative MPNs, myelofibrosis (MF) and essential thrombocythemia (ET) 
(Vardiman et al 2009). PV is characterized by clonal stem cell proliferation of the erythroid, 
myeloid, and megakaryocytic lines, and while its predominant characteristic is an increase in 
red cell mass, increased white blood cell and platelet counts are common (Spivak 2002). The 
increase in red blood cell mass results in hyperviscosity of the blood, significant morbidity, 
and a shortened life expectancy (Passamonti et al 2004).
The association between mutations in the Janus Kinase 2 (JAK2) enzyme and MPNs has 
added a genetic dimension to the diagnosis (Levine and Werning 2006). Virtually all patients 
with PV have a mutation in JAK2, and more than 95% carry the V617F allele. This 
observation is reflected in the 2008 revision to the WHO criteria for diagnosis for PV which 
includes “presence of JAK2V617F or other functionally similar mutation such as JAK2 exon 
12 mutation” as one of the two major criteria for diagnosis (Vardiman et al 2009).
Most symptoms noted in the early stages of PV are the consequence of hyperviscosity of the 
blood and may include headaches, fatigue, hypertension, visual and hearing symptoms, skin 
reddening from microvascular disturbances, and severe pruritus which are difficult to treat 
and impair the quality of life (Mesa 2007, Tefferi 2003, Mesa 2009). With disease progression, 
symptomatic splenomegaly and severe constitutional symptoms are often observed (Finazzi 
2007, Spivak 2002). The natural history of PV has been prospectively studied in the European 
Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) trial (Marchioli et al 
2005). Over time patients may develop cardiovascular complications (especially venous or 
arterial thrombo-embolic events), acute myeloid leukemia or myelodysplasia, or MF. Survival 
curves for PV and MF patients converge after 20 years of follow-up, with an 18% survival 
rate for PV and 13% for MF, underscoring the poor long-term prognosis in PV patients 
(Vaidya et al 2009).
The current therapeutic approach in PV focuses on lowering the risk for thrombotic events 
without exposing patients to increased risk of leukemic transformation (Finazzi and Barbui 
2008). While phlebotomy and low dose aspirin are accepted as the standard of care for initial 
therapy, cytoreductive therapy is recommended to aid in the control of erythrocytosis in the 
presence of poor tolerance to phlebotomy, symptomatic or progressive splenomegaly, or 
evidence of high thrombotic risk (Finazzi and Barbui 2007). Despite continued uncertainty 
about its leukemogenic potential, hydroxyurea (HU) remains the myelosuppressive agent of 
first choice. HU treatment is associated with cytopenias and often unsatisfactory 
hematological control over time, aphthous and leg ulcers, multiple other toxicities, and a 
potential risk of leukemia estimated at up to 10% at the 13th year (Tefferi 2003, Najean 1997).
Therapeutic options in the second-line setting, beyond HU, are limited (pipobroman, busulfan, 
chlorambucil, Peginterferon/interferon alpha, 32P, anagrelide), and as a consequence, it is 


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estimated that up to 20 - 60% of patients may continue on HU even though response is less 
than satisfactory (RESPONSE internal data, Najean and Rain 1997).
This trial will allow Polycythemia Vera (PV) patients who are HU resistant or intolerant and 
have no other treatment options available to them, nor are they eligible for an ongoing clinical 
trial in PV, the opportunity to obtain ruxolitinib based on the treating physician’s opinion that 
the patient could benefit from treatment while allowing collection of safety and efficacy data. 
1.2
Introduction to investigational treatment(s) and other study
treatment(s)
1.2.1
Overview of ruxolitinib
Dysregulated JAK-STAT signaling, via upregulation of JAK1 and JAK2 or gain of function 
mutations such as JAK2V617F, has been implicated as drivers of BCR-ABL-negative 
myeloproliferative neoplasms (MPN), namely myelofibrosis (MF), polycythemia vera (PV) 
and essential thrombocythemia (ET). Ruxolitinib, which is jointly developed in hematology 
and oncology indications by Novartis Pharma AG (Switzerland) and Incyte Corporation 
(USA), specifically binds to and inhibits JAK1, JAK2 and mutated JAK2V617F, leading to 
inhibition of growth factor-mediated cell signaling and tumor cell proliferation. Given this 
mechanism of action of ruxolitinib as a JAK inhibitor and the role played by dysregulation of 
the JAK pathway in the pathogenesis of MPNs, the primary clinical development plan for 
ruxolitinib focused on studies to support regulatory approval in these disorders. 
Ruxolitinib is currently approved under the trade name of ‘Jakavi’ in over 90 countries for the 
treatment of disease-related splenomegaly or symptoms in adult patients with (primary 
myelofibrosis) PMF, post-polycythemia vera myelofibrosis (PPV-MF) and post-essential 
thrombocythemia myelofibrosis (PET-MF). The use of ruxolitinib to treat polycythemia vera 
(PV) patients who are resistant to or intolerant of hydroxyurea is currently under re gulatory 
review worldwide based on the results from the RESPONSE study. So far approval in this 
second indication was granted in more than 45 countries including EU and Switzerland. 
Ruxolitinib is also approved in the USA under the trade name of ‘Jakafi’ and is indicated for 
the treatment of patients with intermediate or high risk myelofibrosis, including PMF, PPV-
MF and PET-MF and for the treatment of PV patients who have had an inadequate response 
to or are intolerant of hydroxyurea.
1.2.1.1
Non-clinical experience
Ruxolitinib inhibited the splenomegaly and morbidity/mortality in mice resulting from 
intravenous inoculation of cells expressing the same mutated JAK2 (V617F) implicated in the 
pathogenesis of the majority of Philadelphia chromosome negative MPNs. INC424 inhibited 
erythroid colony formation from mononuclear cells derived from PV patients (IC50 of 223 
nM compared to 407 nM for normal donors). Growth factor independent colony formation, a 
unique characteristic of PV and other MPNs, was inhibited more potently with an IC50 of 67 
nM for INC424 in cells bearing the JAK2V617F mutation compared to cells bearing the wild-
type JAK2.
Effects of INC424 noted in 6 month rat and 12 month dog repeat dose toxicology studies were 
primarily myelosuppressive in nature and are believed to be associated with the mechanism of 


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action of INC424 (inhibitor of JAK-STAT signaling). Genetic toxicology assessments 
(evaluations of INC424 in the bacterial mutagenicity assay, in vitro chromosome aberration 
assay, and in vivo micronucleus assay) in rats were negative. In safety pharmacology 
evaluations, an adverse decrease in minute volume in a respiratory study in female rats only 
was noted at the highest dose. In a cardiovascular evaluation of INC424 in dogs, 
electrocardiogram (ECG) parameters and ventricular repolarization were unaffected at all 
doses; whereas the compound lowered blood pressure and increased heart rate compared to 
vehicle control at the highest dose evaluated. In embryo-fetal assessments in rat and rabbit, 
maternal toxicity and minimal embryo-fetal toxicity were noted at the highest doses evaluated.
Ruxolitinib was not teratogenic in either rat or rabbit. No effects were noted on reproductive 
performance or fertility in male or female rats. Increases in post-implantation loss were noted 
at the higher doses.
More detailed information on pharmacology of ruxolitinib, single and multiple dose 
pharmacokinetic (PK) studies conducted in multiple species and nonclinical safety evaluations 
can be found in the IB.
1.2.1.2
Clinical pharmacokinetics and pharmacodynamics
Ruxolitinib exhibits near complete oral absorption, achieving maximal plasma concentration 
Cmax at approximately 1-2 h post-dose with linear PK over a dose range of 5-200 mg. 
Ruxolitinib is mainly eliminated by metabolism via CYP3A4 with minor contributions of 
CYP2C9 with a terminal elimination half-life of approximately 3 h. Administration with food 
did not affect ruxolitinib’s overall exposure. Ruxolitinib may be administered without regard 
to meals.
Ruxolitinib is metabolized in the liver by the cytochrome (CYP) P450 metabolizing enzyme 
system, predominantly by the 3A4 isozyme. The effects of the potent CYP3A4 inhibitor 
ketoconazole on the pharmacokinetics (PK) and pharmacodynamics (PD) of ruxolitinib 
administered as single oral doses shows that with concomitant dosing of ketoconazole, the 
observed AUC increase is approximately 2-fold, with a similar effect on the PD effect 
(cytokine-induced STAT3 phosphorylation). Thus, a dose reduction of approximately 50% for 
ruxolitinib is appropriate for subjects who take ketoconazole or other potent CYP3A4 
inhibitors as concomitant medication.
Ruxolitinib was given as a single 25 mg dose to subjects with varying degrees of renal 
function ([INCB 18424-142]), including normal, mild, moderate and severe (ClCr < 30 
mL/min) renal impairment as well as end stage renal impairment disease (ESRD). There was 
no statistically significant effect of mild, moderate or severe impairment of renal function on 
the PK or PD parameters; ESRD subjects requiring dialysis showed prolonged PD activity. In 
a hepatic impairment study, the PK of ruxolitinib was assessed following a single ruxolitinib 
dose of 25 mg [INCB 18424-137]. The mean AUC for ruxolitinib was increased by 87%, 28% 
and 65%, respectively, in subjects with mild, moderate and severe hepatic impairment 
compared to subjects with normal hepatic function, indicating no clear relationship to the 
degree of hepatic impairment based on Child-Pugh scores. The terminal elimination half-life 
was prolonged in subjects with hepatic impairment compared to healthy controls (4.1-5.1 h 
versus 3 h). Hepatic impairment, in general, decreased the plasma Cmax, but not the AUC 


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values, of ruxolitinib metabolites, and no rank correlation was observed between the change 
in the PK parameters of the metabolites and the degree of hepatic impairment.
The pharmacodynamics of ruxolitinib was characterized by an ex vivo whole-blood assay that 
involves quantification of phosphorylated STAT3 following IL-6 stimulation. Following 
single or multiple oral dose administrations, ruxolitinib demonstrated dose-dependent 
inhibition of cytokine-induced pSTAT3 with maximal inhibition occurring 1-2 h after 
administration. The pharmacodynamic-time profile (i.e., cytokine-induced pSTAT3 change 
over time) coincided with peak ruxolitinib plasma and trough concentrations. Additional 
details regarding the clinical pharmacology of ruxolitinib can be found in the IB.
1.2.1.3
Clinical experience
INCB 18424-256 is an uncontrolled open label dose-ranging Phase II study to determine the 
safety and efficacy of ruxolitinib in patients with advanced PV or ET refractory to or 
intolerant of HU. Following an initial 8-week phase in which three dose regimens (10 mg 
b.i.d., 25 mg b.i.d., or 50 mg q.d.) were evaluated in each patient population (n=6-8/dose), 
starting doses of 10 mg b.i.d. in PV patients and 25 mg b.i.d. in ET patients were selected, 
based on efficacy and tolerability, to explore in an expansion cohort. Dose modifications were 
allowed with the objective of normalizing hematocrit (Hct), platelet and WBC counts in each 
individual subject while avoiding hematologic toxicity. Primary endpoints include defined 
ranges for Hct, platelet and WBC counts for each disease; reduction in palpable spleen length; 
improvement in disease-related symptoms; reduction in the need for phlebotomy (PV only); 
and safety/tolerability. Thirty-four PV patients and 39 ET patients have been enrolled with a 
median time from diagnosis at study start of approximately 115 months for PV and 88 months 
for ET patients.
The first patient was enrolled in this study on 29-Aug-2008. The data were extracted from the 
clinical study report, 10-March-2011. The following information relates to the PV patients 
only.
1.2.1.3.1 Efficacy in INCB 18424-256
In total, 56% of PV subjects achieved an overall confirmed response after 8 weeks of 
ruxolitinib treatment (protocol-specified responder analyses). Unconfirmed response rates 
were higher, 62% in PV. These overall response rates were driven almost entirely by protocol-
defined partial responses. Over the duration of the study, unconfirmed complete response was 
achieved with low frequency (18% PV), while partial response rates were achieved with 
greater frequency (91% PV).
Findings from specific and ad hoc analyses conducted for PV indicate normalization of Hct 
(<45%) was achieved rapidly with ruxolitinib and was sustained in all responding subjects in 
the absence of phlebotomy for the duration of their available follow-up. After 36 weeks of 
treatment, 97% of PV subjects achieved Hct control without the aid of phlebotomy and 
complete hematologic remission was achieved in 45% of subjects.
Within 12 weeks of treatment, 62% of PV subjects with splenomegaly at baseline achieved 
absence of palpable splenomegaly. Improvement of palpable splenomegaly, based on ≥ 50% 
reduction from baseline in palpated spleen size was achieved in 81% of subjects after 36 


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weeks and was maintained in all responding subjects for the duration of their available follow-
up. Enrolled patients demonstrated rapid, marked and durable reductions in patient-reported 
symptom scores for pruritus, night sweats and bone pain. These responses paralleled positive 
changes in the EORTC QLQ-C30 instrument.
1.2.1.3.2 Safety and tolerability in study INCB 18424-256
The overall risk-benefit of ruxolitinib in the PV population is favorable. The most frequently 
reported treatment emergent adverse events (TEAEs) were, respectively, anemia (73.5%), 
thrombocytopenia (32.4%), and diarrhea (20.6%). Of these most frequently reported TEAEs, 
relatively few were Grade 3 in severity: the percentage of subjects with Grade 3 anemia was 
3%, Grade 3 thrombocytopenia 5.9% and no subject had Grade 3 diarrhea.
TEAEs in PV subjects were thrombocytopenia and pneumonia, each reported by two subjects 
(5.9%).
Few PV (2; 5.9%) subjects permanently discontinued study medication due to an AE. Few PV 
subjects (5; 14.7%) reported SAEs. Pneumonia was reported in two subjects with PV, and all 
other SAEs were reported only once (Verstovsek et al, 2014).
1.2.1.3.3 Phase III
The [CINC424B2301] study (RESPONSE Trial) is a global, randomized, open label pivotal 
study comparing ruxolitinib (starting dose of 10 mg b.i.d.) with BAT (Best Available 
Treatment: HU, pipobroman, immunomodulatory drugs, pegylated interferon or interferon, 
anagrelide, observation only) in PV patients. The protocol is designed for patients, either 
resistant or intolerant to HU, with evidence of need for phlebotomy for Hct control and 
presence of splenomegaly. The primary endpoint is a composite one with hematocrit control 
(Hct < 45% in the absence of phlebotomy from Week 8 to 32) and reduction in spleen volume 
by MRI (or CT if MRI is clinically contraindicated) of at least 35% measured at 32 weeks. 
Two key secondary endpoints include durability of the primary endpoint and complete 
hematologic remission. There are multiple, non-key secondary endpoints including modified 
clinico-hematologic response (overall response rate, durability and duration), as defined by 
the European Leukemia Net (ELN). Enrollment was completed in the study with 222 patients 
enrolled. 
The trial met its primary endpoint. 
The primary efficacy objective was based on a composite endpoint consisting of hematocrit 
control (absence of phlebotomy eligibility) and of at least 35% spleen volume reduction as 
assessed by central radiologic evaluation.
Significantly more patients randomized to ruxolitinib met the primary endpoint at Week 32 
when compared to patients randomized to BAT, 22.7% vs. 0.9%, respectively (p<0.0001).
Additionally at Week 32, a higher proportion of patients randomized to ruxolitinib achieved 
either of the individual components of the primary composite endpoint (95% CI are non -
overlapping):

60.0% (95% CI: 50.2, 69.2) vs. 19.6% (95% CI: 12.7, 28.2) of the patients achieved 
hematocrit control (absence of phlebotomy eligibility) in the ruxolitinib arm vs. the BAT 


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arm, respectively. This difference was also reflected in the high proportion of patients 
randomized to ruxolitinib who had no phlebotomy from Week 8 to Week 32 (80.2%) 
when compared to patients randomized to BAT (37.6%)

40.0% (95% CI: 30.8, 49.8) vs. 0.9% (95% CI: 0.0, 4.9) of the patients achieved at least a 
35% reduction in spleen volume from baseline in the ruxolitinib arm vs. the BAT arm, 
respectively.
Overall, 77.3% of the patients randomized to ruxolitinib met at least one component of the 
primary endpoint.
The safety profile of ruxolitinib was generally consistent with previous studies based on initial 
review of the data. .
2
Rationale
2.1
Study rationale and purpose
When cytoreduction is clinically indicated in PV patients, hydroxyurea (HU) is the preferred 
cytoreductive agent in the first line setting (Finazzi and Barbui 2007). However, HU treatment 
is associated with cytopenias and often unsatisfactory hematological control over time, 
aphthous and leg ulcers, multiple other toxicities, and a potential risk of leukemia estimated at 
up to 10% at the 13th year (Tefferi 2003, Najean 1997 For patients who do not tolerate or are 
resistant to HU, therapeutic options remain limited. The different available cytoreductive 
agents have been rarely compared in a randomized fashion and their use is supported by little 
prospective evidence. The most commonly used second-line therapies include pipobroman, 
anagrelide, Peginterferon/interferon alpha, 32P and alkylating agents (Marchioli 2005). Imids 
have shown clinical activity in the MPDs, most specifically in Primary Myelofibrosis and 
post-ET/PV myelofibrosis (Barosi 2001).
Ruxolitinib is an inhibitor of the Janus kinase family of protein tyrosine kinases (JAKs) that is 
currently under development for treatment of myeloproliferative neoplasms (MPNs) and 
advanced hematologic malignancies. A causal role for JAK2 has recently been proposed for 
PV patients possess the JAK2 V617F mutation. As described in Section 1.2, data from the 
Phase II Study (INCB 18424-256) in PV patients refractory or intolerant to HU have 
demonstrated that treatment with ruxolitinib is effective and well tolerated, and can result in 
normalization of Hct, white blood cell count, and platelet count while eliminating the need for 
phlebotomy. When present, splenomegaly is markedly improved by ruxolitinib treatment as 
evidenced by the rapid and durable decreases in palpable spleen length with therapy. The 
symptomatic burden of enrolled patients, namely pruritus, bone pain, fever and night sweats, 
are improved by ruxolitinib as reported by patient-reported symptom assessments.
In addition, a global phase III CINC424B2301 study (RESPONSE Trial), randomized, open 
label comparing ruxolitinib (starting dose of 10 mg b.i.d.) with BAT in PV patients either 
resistant or intolerant to HU, with evidence of need for phlebotomy for Hct control and 
presence of splenomegaly has met its primary endpoint. The safety profile of ruxolitinib was 
generally consistent with previous studies based on initial review of the data.  The results of 
this trial have been submitted to the upcoming ASCO and EHA 2014 meetings.Taken together, 


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the emerging efficacy and safety profile for ruxolitinib supports further access in PV patients 
who demonstrate resistance or intolerance to HU therapy.  
2.2
Rationale for the study design
2.3
Rationale for dose and regimen selection
The purpose of this open-label, single arm, multi-center Expanded Treatment Protocol (ETP) 
is to provide early access to ruxolitinib and evaluate safety information in patients with PV, 
who are HU resistant or intolerant and who have no other standard treatment option, nor do 
they qualify for another clinical study for PV.
The available data from Study INCB 18424-256 established 10 mg bid starting dose of 
ruxolitinib as an active, safe and well tolerated dose in patients with PV. Primary endpoints 
include defined ranges for Hct, platelet and WBC counts; reduction in palpable spleen length; 
improvement in disease-related symptoms; reduction in the need for phlebotomy; and 
safety/tolerability. Thirty-four PV patients were enrolled. Section 1.2.1.3 provides more 
information on the safety and efficacy results from this study that support the use of a 10 mg 
bid starting dose in the PV patient population.
In this study, all patients will be initiated at a dose of 10 mg bid (see Section 6.3.4 and Section 
6.3.7 for exceptions). Dose levels of ruxolitinib will be adjusted based on safety and efficacy 
so that each patient is titrated to their optimal dose, and the starting ruxolitinib dose will likely 
not be the final dose for many patients. In addition, the global phase III ([CINC424B2301] or 
the RESPONSE Trial) confirmed that a starting dose of 10 mg b.i.d, is an a ctive and well 
tolerated dose. 
The highest ruxolitinib dose allowed in study INCB 18424-256 and CINC424B2301 was 25 
mg bid.  This dose has been established as the maximally tolerated dose in healthy volunteers, 
and has been safe and well tolerated in MF and PV when the dose level has been implemented 
as part of individualized dose titration.
See the IB for more information on ruxolitinib PV clinical study findings.
2.4
Rationale for choice of combination drugs
Not applicable.
2.5
Rationale for choice of comparators drugs
Not applicable.


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3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.
Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
To evaluate the safety of 
ruxolitinib
AEs, Grade 3&4 AEs & SAEs, events of special 
interest, AEs leading to discontinuation, and deaths.
Evaluate changes in hematology."
Secondary
Efficacy
Refer to Section 10.5.2
To evaluate change in 
hematocrit levels
Change in Hct levels from Baseline to each visit 
where measured 
To evaluate change in spleen 
length
Change in spleen length from Baseline to each visit 
where measured.
Patient Reported Outcome
Refer to Section 10.5.6
To evaluate change in MPN-
SAF TSS score
Change in MPN-SAF TSS score from baseline to 
each visit where measured.
4
Study design
4.1
Description of study design
This is a global, single arm, open-label, multi-center protocol designed to provide early access 
and evaluate the safety of ruxolitinib in patients with polycythemia vera who are HU resistant 
or intolerant and who have no other standard treatment options. Efficacy and patient reported 
outcomes will also be assessed. 
There are limited therapeutic options in this disease setting. Ruxolitinib will be provided until 
it becomes commercially available for this indication in each participating country or until 31 
December 2017, whichever date occurs first.
Screening/baseline phase

Screening/baseline assessments will be performed within 35 days prior to the first dose of 
ruxolitinib treatment (e.g., labs including hematology, blood chemistry, urine, and 
pregnancy tests, physical examination including spleen palpation, vital signs, and ECOG 
Performance Status).

If all screening lab assessments are received, reviewed, and within protocol parameters 
and patient meets all inclusion and none of the exclusion criteria, the screening labs may 
be used as baseline and patient may continue to Day 1 within 14 days of the screen after 
the eligibility checklist has been completed in the IRT system.
Treatment phase/duration of treatment 

Patients who are eligible will receive ruxolitinib at a starting dose of 10 mg bid (see 
Sections 6.3.4 and Section 6.3.7 for exceptions). The first dose of ruxolitinib treatment is 


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administered on Day 1. Patients will have clinic visits every 4 weeks until Week 24 and 
every 12 weeks thereafter. The dose of drug may be adjusted during the study based on 
efficacy and safety to a maximum of 25mg bid (see Sections 6.3 for guidance). Clinical 
suspicion of disease progression to MF, MDS, or AML (see Appendix 4and Appendix 5
for definitions) or the occurrence of a Grade 3 or 4 events at any time requires a physical 
examination to assess disease status. This examination is to be performed promptly rather 
than waiting for the next scheduled visit.

Patients may continue to receive ruxolitinib treatment until disease progression, (see 
Appendix 4and Appendix 5), as determined by the local investigator, unacceptable 
toxicity, death, withdrawal of consent for protocol specified procedures, or discontinuation 
from the treatment for any other reason until the drug becomes commercially available in 
each participating country or until 31 December 2017, whichever occurs first.
4.2
Timing of interim analyses and design adaptations
Not applicable.
4.3
Definition of end of the study
The study will end for each country 3 months after the drug is commercially available in the 
country or by 31 December 2017, whichever occurs first. The entire study will end when all 
countries have completed participation.
Should ruxolitinib not be available to patients after the drug is commercially available in the 
country, Novartis Country Pharma Organization will have a transition plan in place to ensure 
that patients have access without delays in treatment. 
4.4
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible (for a prematurely withdrawn patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator 
will be responsible for informing IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
The patient population will consist of male or female individuals, aged 18 years or older who 
have been diagnosed with Polycythemia Vera (PV, see Appendix 1), and who are 
hydroxyurea (HU) resistant or intolerant and have no other treatment options or are not 
eligible for a clinical study with an investigational medicinal product for PV.
Patients in the study may not participate in any other interventional clinical studies of other 
investigational agents or devices. Patients who have discontinued the study may not be re-
enrolled for a second course of treatment.


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The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Written informed consent must be obtained prior to any screening procedures.
Patients eligible for inclusion in this study have to meet all of the following criteria at 
screening:
1. Male or female aged 18 or over,
2. Confirmed diagnosis of PV according to the revised World Health Organization (WHO) 
criteria (see Appendix 1), with resistance or intolerance to hydroxyurea.
3. ECOG performance status of 0, 1, or 2 at Baseline,
4. Peripheral blood blast count of 0% at screening,
5. Must have recovered or stabilized sufficiently from adverse drug reactions associated with 
any prior treatments before beginning treatment with ruxolitinib,
6. Does not have access to a comparable or satisfactory alternative treatment (i.e., 
comparable or satisfactory treatment is not available or does not exist),
7. Is not eligible for participation in any of the ruxolitinib ongoing clinical trials or has 
recently completed a clinical trial that has been terminated and, after considering other 
options (e.g., trial extensions, amendments, etc.), the clinical team has determined that 
treatment is necessary and there are no other feasible alternatives for the patient),
8. Is not being transferred from an ongoing clinical trial for which he/she is still eligible.
5.3
Exclusion criteria
Patients eligible for this study should not meet any of the following criteria at screening:
Lab and Clinical Abnormalities
1. Subjects with known hypersensitivity to ruxolitinib or any of its excipients
2. Patients with severely impaired renal function defined by:
Serum creatinine > 2 mg/dL (> 176.8µmol/L)
3. Patients with inadequate liver function defined by any of these:

Total bilirubin ≥ 2.5 x ULN and subsequent determination of direct bilirubin ≥ 2.5 x 
ULN; 

Alanine aminotransferase (ALT) > 2.5 x ULN; Aspartate aminotransferase (AST) > 
2.5 x ULN.
4. Platelet counts < 50 ×109/L or an Absolute Neutrophil Count (ANC) < 1 × 109/L at 
screening.
Concurrent Diseases / Medication History
5. Patients being treated concurrently with a strong (potent) systemic inhibitor or inducer of 
CYP3A4 (refer to Appendix 7) at the time of Screening.
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7. Known history of human immunodeficiency virus (HIV) infection or other 
immunodeficiency syndromes such as X-linked agammaglobulinemia and common 
variable immune deficiency
8. Acute viral hepatitis or active chronic hepatitis B or C infection.
9. History of progressive multifocal leuko-encephalopathy (PML).
10. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of ruxolitinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome, small bowel resection).
11. History or current diagnosis of uncontrolled or significant cardiac disease, including any 
of the following:

Myocardial infarction within last 6 months 

Uncontrolled congestive heart failure

Unstable angina within last 6 months

Clinically significant  (symptomatic) cardiac arrhythmias (e.g., sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker)
12. Significant concurrent, uncontrolled medical condition which, in the investigator’s opinion,
would jeopardize the safety of the patient or compliance with the protocol.
13. Subjects undergoing treatment with another investigational medication or having been 
treated with an investigational medication within 30 days or 5 half-lives (whichever is 
longer) prior to the first dose of study drug.
14. Patients with a history of malignancy in the past 3 years except for treated, early-stage 
squamous or basal cell carcinoma.
15. Receiving PEG-IFN-alpha-2a within 5 weeks of first dose.
Ability to comply with Protocol
16. Patients who are unable to comprehend or unwilling to sign an informed consent form 
(ICF).
Pregnancy and Birth Control
17. Pregnant or nursing (lactating) women
18. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
throughout the study duration inclusive of 30 day safety follow up. Highly effective 
contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening).  The vasectomized male 
partner should be the sole partner for that subject.


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
Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception (in case of oral contraception you 
should have been using the same pill on a stable dose for a minimum of 3 months 
before screening)
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment is she considered not of child bearing potential.
6
Treatment
6.1
Study treatment
INC424/ruxolitinib tablets will be the only investigational drug in this study. 
6.1.1
Dosing regimen
The starting dose of ruxolitinib will be 10 mg bid (see Section 6.3.4 and Section 6.3.7 for 
exceptions). A standardized dosing paradigm will be used to determine dose adjustments for 
safety and efficacy so that each patient is titrated to their most appropriate dose (see Section 
6.3.1 of the protocol). The ruxolitinib dose should not exceed 25 mg bid and should not be 
less than 5 mg once a day unless there is an adverse event that warrants interruption.
Patients may self-administer daily ruxolitinib tablets qd or bid (see Section 6.3.4 and Section 
6.3.7 for exceptions) orally, without regard to food, in an outpatient setting in accordance with 
the specified dosing schedule provided by the investigator. 
Patients who miss a dose should be counseled to take the next dose as scheduled and not to 
take double the dose.
Table 6-1
Dose and treatment schedule
Study 
treatments
Pharmaceutical form and 
route of administration
Dose
Frequency and/or 
Regimen
INC424/
ruxolitinib
Tablet for oral use
Starting dose 10 mg bid (approximately 12 
hours apart: morning and night), to be 
increased or decreased (5 mg steps) per 
standardized dosing paradigm and not to 
exceed 25 mg bid (see Section 6.1.1)
Daily, unless 
instructed to 
temporarily withhold 
dosing for safety
The investigator will instruct the patient to take the study drug as per protocol. All dosages 
prescribed and dispensed to the patient and all dose changes during the study should be 
recorded on the Dosage Administration Record eCRF.


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6.1.2
Ancillary treatments 
All patients should receive low dose aspirin (75-150 mg/day), as standard of care for PV 
patients, unless medically contraindicated. In this case, other prophylactic antithrombotic 
agents may be used. Higher doses of aspirin (> 150 mg/day) should not be used except when 
medically indicated per the treating physician.
Aspirin and other antithrombotic use will be documented in the eCRF.
6.1.3
Rescue medication 
Not applicable.
6.1.4
Guidelines for continuation of treatment 
Not applicable.
6.1.5
Treatment duration
Patients may continue ruxolitinib treatment until they experience any of the following:

Disease progression determined by the local investigator (see Appendix 4 and Appendix 
5),

Unacceptable toxicity that precludes further treatment,

Start of a new anti-cancer therapy,

Pregnancy,

Treatment is discontinued at the discretion of the investigator or patient,

Lost to follow-up or withdrawn consent,

Death,

Study terminated by the sponsor,

Study is completed (see definition below).
Treatment duration is considered “completed” three months after ruxolitinib becomes 
commercially available in the patients participating country or by 31 December 2017, 
whichever comes first, and the patient should be transitioned to commercial product. Study 
sites should stop all patients’ study participation on the ETP at this time.
6.2
Dose escalation guidelines
Not applicable to the study.
6.3
Dose modifications
6.3.1
Dose escalations due to inadequate efficacy
The initial dose of ruxolitinib will be 10 mg bid up to Week 4 (see Section 6.3.4 and Section 
6.3.7 for exceptions). Based upon hematology and spleen palpation results, the dose of 
ruxolitinib may be increased by 5 mg bid from the previous 4 weeks in patients who meet the 
following conditions: 
1. Inadequate efficacy as demonstrated by one or more of the following:


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a.
Hct > 45%,
b. WBC > upper limit of normal range,
c.
A clinically relevant increase in palpable spleen as determined by the investigator. 
AND
2. The patient should have demonstrated adequate safety to increase the dose with all of the 
following: 
a.
Platelet count  ≥ 140 x 109/L,
b. Hemoglobin ≥12 g/dL
c.
ANC ≥ 1.5 x 109/L.
d. No treatment-related toxicity must have occurred with the current dose level, resulting 
in treatment reduction or interruption in the previous 28 days.
The total dose should never exceed 25 mg bid. 
Table 6-2
Ruxolitinib allowed dose escalation due to inadequate efficacy
Week of Study
Maximum Dose
Based on (no potent CYP3A4 inhibitor use)
1 to 4
10 mg bid
Eligibility for study
5 to 8
15 mg bid
Hematology, spleen palpation, AEs
9 to 12
20 mg bid
Hematology,  spleen palpation,  AEs
13 to EoT
25 mg bid
Hematology, spleen palpation, AEs
6.3.2
Dose reductions due to hematological changes
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. Dose reductions or 
interruptions for hematological changes are described in Table 6-3.
The objective of the ruxolitinib dose adjustment rules is to optimize response for each 
individual patient (namely achieve and maintain Hct < 45% and normalize WBC and PLT 
counts) while avoiding specific Grade 2 or higher cytopenias.
Doses may be titrated based on safety. Treatment should be interrupted for platelet counts less 
than 50 x 109/L or absolute neutrophil counts less than 0.5 x 109/L.
The treatment should also be interrupted when hemoglobin is below 8 g/dL (80 g/L).
Dose reductions should be considered if the platelet counts decrease below 100 x 109/ L with 
the goal of avoiding dose interruptions for thrombocytopenia. The dose reduction should also 
be considered if hemoglobin decreases below 12 g/dL (120 g/L) and is recommended if 
hemoglobin decreases below 10 g/dL (100 g/L). 
After dose interruption, when blood counts recover, dosing may be restarted at 5 mg twice 
daily and gradually increased based on careful monitoring of blood cell counts.
All dose changes should be recorded on the Dosage Administration Record eCRF.
The following guidelines should be applied: 


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Table 6-3
Dose modifications for hematologic toxicity
Hematology Parameters
Reduction or Interruption
Platelet count < 100 x 109/L
Dose reduction should be considered.
Platelet count < 50 x 109/L  
Treatment should be interrupted. 
Absolute neutrophil count < 0.5 x 109/L
Treatment should be interrupted.
Hemoglobin <  12 g/dL (120 g/L) 
Dose reduction should be considered 
Hemoglobin <  10 g/dL (100 g/L)
Dose reduction is recommended
Hemoglobin < 8 g/dL (80 g/L)
Treatment should be interrupted.
6.3.3
Restarting or increasing dose after hematological decline
Dosing may be restarted or increased following recovery of the hematologic parameter(s) to 
acceptable levels. Table 6-4 illustrates the maximum allowable dose that may be used after 
restarting or increasing doses following a previous interruption or dose decrease. 
Table 6-4
Ruxolitinib maximum allowable dose levels after dose interruption or 
reduction due to hematological decline
Current Hb (g/dL)
Maximum allowable dose
< 8 
Continue hold
8 to < 10
5 mg bid for at least 2 weeks, if stable may increase to 10 mg bid
10 to < 12
10 mg bid for at least 2 weeks, if stable may increase to 15 mg bid
≥ 12
15 mg bid for at least 2 weeks, if stable may increase to 20 mg bid
Current PLT (x 109/L)
Maximum allowable dose
< 50
Continue hold
50 to < 75
5 mg bid for at least 2 weeks, if stable may increase to 10 mg bid
75 to < 100
10 mg bid for at least 2 weeks, if stable may increase to 15 mg bid
≥ 100
15 mg bid for at least 2 weeks, if stable may increase to 20 mg bid
Current ANC (x 109/L)
Maximum allowable dose
< 1.0
Continue hold
1.0 to < 1.5
5 mg bid for at least 2 weeks, if stable may increase to 10 mg bid
1.5 to < 2.0
10 mg bid for at least 2 weeks, if stable may increase to 15 mg bid
≥  2.0
15 mg bid for at least 2 weeks, if stable may increase to 20 mg bid
Dose increases should be in increments of 5 mg bid and should not occur more often than 
every 2 weeks.
When restarting ruxolitinib after dose interruption, the Hb, PLT, and ANC levels must be 
considered to determine the restart dose, regardless of which level caused the dose 
interruption.  The lowest calculated dose per Table 6-4 should be used. The restart dose 
should be at least 5 mg LESS that the dose that resulted in the interruption. 
Patients who required dose interruption while receiving a dose of 5 mg bid may resume at a 
dose of 5 mg bid or 5 mg qd, but never higher, once: 

Hb is ≥10 g/dL

PLT is ≥ 75 x 109/L,

and ANC is ≥ 1.5 x109/L


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6.3.4
Ruxolitinib starting dose for patients with platelets less than 
100x109/L
Patients who enter the study with a platelet value between 50 x 109/L and <100x109/L should 
start ruxolitinib with a starting dose of 5mg bid. It is recommended that these patients’ platelet 
values are monitored more frequently per Table 6-3.
6.3.5
Dose modification for renal impairment
No specific dose adjustment is needed in patients with mild or moderate renal impairment
while receiving ruxolitinib.
Patients diagnosed with severe renal impairment while receiving ruxolitinib should be 
carefully monitored and need to have their doses reduced to avoid adverse drug reactions 
(ADRs).
6.3.6
Dose reduction for non-hematological safety
Study drug MUST be permanently discontinued upon the occurrence of a clinically significant 
Grade 3 or Grade 4 laboratory or non-laboratory abnormality attributed to ruxolitinib if fails 
to resolve to Grade 2 or better within 8 weeks or if a lower re-start dose or administration 
schedule is either not available or likely to be clinically ineffective. 
6.3.7
Dose reduction for concomitant CYP inhibitor use
Ruxolitinib is metabolized in the liver by the cytochrome (CYP) P450 metabolizing enzyme 
system, predominantly by the CYP 3A4 isozyme. With concomitant dosing of potent 
CYP3A4 inhibitors such as systemic ketoconazole, plasma exposure of ruxolitinib increases 
by approximately 2-fold. Thus, a dose reduction of ~ 50% for ruxolitinib is appropriate for 
patients who take systemic ketoconazole or other potent CYP3A4 inhibitors systemically as 
concomitant medication (see Appendix 7).
Potent inhibitors of CYP3A4 include systemic ketoconazole, clarithromycin, itraconazole, 
nefazodone and telithromycin. The use of these agents on Study Day 1 will require that 
patients initiate ruxolitinib therapy at 10 mg qd. 
NOTE: once the course of therapy using a potent CYP3A4 inhibitor has been completed, the 
patient may resume his/her prior bid dose regimen of ruxolitinib beginning the next day.
6.3.8
Optional dose tapering strategy in the event of discontinuation
When a decision is made to permanently discontinue ruxolitinib therapy for reasons other than 
for hematologic safety, a dose tapering strategy may be considered, based on evaluation of the 
condition of the patient, the current dosing regimen and the clinical judgment of the
investigator. If considered to be medically necessary, the investigator may use any treatment 
to manage withdrawal from ruxolitinib including a gradual tapering of the study drug dosage 
or use of other medications to manage events occurring after discontinuation. 
Short-term courses of corticosteroids have been used in patients with MF and may be 
considered as part of a tapering strategy. Corticosteroids may be started prior to, or concurrent 
with, ruxolitinib tapering. When a decision has been made to discontinue the patient utilizing 


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a tapering strategy, routine study visits and study assessments should continue to be 
completed per the protocol schedule (see Table 7-1) until the patient completes the ruxolitinib 
tapering, regardless of any concomitant medications. The follow-up phone call (30 days post 
last dose) should also occur as scheduled. 
6.4
Concomitant medications 
The patient must be told to notify the investigational site about any new medication s he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy, and herbal/natural medications) administered 
during the study must be listed on the Concomitant Medications/Significant Non-Drug 
Therapies of the eCRF. All prior medications used to treat Polycythemia vera will be recorded. 
Patients will be instructed not to take any additional medications (including over-the-counter 
products) during the course of the study without consultation with the investigator.
6.4.1
Permitted concomitant therapy
6.4.1.1
Hormonal contraception
Females of childbearing potential will be allowed to use oral, injectable or implanted 
contraceptives that have been determined to be at least 99% effective as indicated in 
Exclusion Criterion (see Section 5.3). 
6.4.2
Permitted concomitant therapy requiring caution and/or action
The following medications have restrictions on use, dose, or require changes to the way in 
which ruxolitinib is administered during the study: 

Systemic corticosteroid doses greater than the equivalent of 10 mg prednisolone per day is 
not permitted, unless used as part of a ruxolitinib-dose tapering strategy (see Section 6.3.8
Optional dose tapering strategy in the event of discontinuation)

Low dose aspirin (75-150 mg/day) and non-steroidal anti-inflammatory agents 
(acetaminophen, ibuprofen) may be used. Higher doses of aspirin (> 150 mg/day) should 
not be used except when medically indicated and recommended by the treating physician. 

When concomitant administration of an anticoagulant/antiplatelet medication is required 
for patient management, the platelet count history, and any observations of 
thrombocytopenia during the study while on study drug should be considered. 

Granulocyte growth factors are not allowed while study medication is being administered 
but may be used for severe neutropenia at the Investigator’s discretion while study 
medication is being withheld. 

Inducers or inhibitors of the metabolizing enzyme CYP3A4 (Refer to Appendix 7):

When concomitant administration of a strong (potent) systemic inhibitor of CYP3A4 
metabolizing enzymes or dual CYP2C9/CYP3A4 inhibitors (see Appendix 7) is required
for patient management, the dose of study treatment must be reduced by approximately 
50% to be administered twice daily by decreasing the twice daily dose or by decreasing 
the frequency of dosing to the corresponding once daily dose when twice daily dosing is 
not practical.


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Note: No dose adjustment of ruxolitinib is needed for use with topical ketoconazole. 
Note: More frequent monitoring of hematology parameters and clinical signs and 
symptoms of ruxolitinib related adverse reactions is recommended upon initiation of a 
strong (potent) CYP3A4 inhibitor.

No dose adjustment will be made when moderate systemic CYP3A4 inducers (See 
Appendix 7) are co-administered with study treatment.
6.4.3
Prohibited concomitant therapy
The following medications are prohibited during the study until treatment discontinuation:
a.
Any investigational medication (other than ruxolitinib) that is not approved for any 
indication. Use of such medications within 30 days or 5 half-lives, whichever is longer, 
prior to the first dose of study drug and during the study through the Safety Follow-up 
Visit is prohibited.
b. Use of PEG-IFN-alpha-2a within the 5 weeks prior to Study Day -1 is prohibited.
c.
Use of any medication to treat PV disease (except for low-dose aspirin) is prohibited once 
dosing with ruxolitinib begins on or after Study Day 1.
d. Use of 32P prior to or during the study until treatment discontinuation at any time is 
prohibited. 
e.
Use of busulfan or chlorambucil during the study until treatment discontinuation at any 
time is prohibited. 
Aspirin in doses exceeding 150 mg per day is prohibited unless medically indicated.
6.5
Patient numbering, treatment assignment or randomization
6.5.1
Patient numbering
Each patient is identified in the study by a Patient Number that is assigned when the patient is 
first enrolled for screening and is retained as the primary identifier for the patient throughout 
his/her entire participation in the trial. The Patient No. consists of the Center Number (Center 
No., as assigned by Novartis to the investigative site) with a sequential patient number 
suffixed to it, so that each patient is numbered uniquely across the entire database. Upon 
signing the informed consent form, the patient is assigned to the next sequential Patient No.
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Patient Number 
must not be reused for any other patient and the Patient Number for that individual must not 
be changed, even if the patient is re-screened. If the patient fails to be dosed, the reason will 
be entered into the Screening Log page. 
6.5.2
Treatment assignment 
Prior to dosing, all patients who fulfill all entry criteria will be assigned to treatment via IRT. 
The investigator or his/her delegate will contact the IRT and confirm that the patient fulfills 
the protocol’s entry criteria.


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6.5.3
Treatment blinding
Not applicable.
6.6
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF
Table 6-5
Preparation and dispensing
Study treatment
Dispensing
Preparation
INC424/ruxolitinib
Tablets including instructions for administration are dispensed by study 
personnel on an outpatient basis.
Patients will be provided with adequate supply of study drug for self-
administration at home until their next scheduled study visit.
Not applicable
6.6.1
Study drug packaging and labeling
INC424/ruxolitinib can be provided as global supply or as local commercial material where 
appropriate and per local regulation. If INC424/ruxolitinib is sourced and labeled in-country, 
the locally approved form and packaging will be used.
Medication labels will be in the local language and comply with the legal and regulatory
requirements of each country. Labels will include storage conditions for the drug but no 
information about the patient.
6.6.2
Drug supply and storage
INC424/ruxolitinib treatments must be received by designated personnel at the study site, 
handled and stored safely and properly, and kept in a secured location to which o nly the 
investigator and designated site personnel have access. Upon receipt, the study treatment
should be stored according to the instructions specified on the drug labels and in the 
Investigator’s Brochure. 
6.6.3
Study drug compliance and accountability
6.6.3.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
patient visit.
Sites should counsel patients if patient compliance falls below 80% of the prescribed dose.
6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 


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monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
6.6.3.3
Handling of other study treatment
Not applicable.
6.6.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation.
All visits are to be scheduled according to the appropriate number of calendar days from Day 
1 of ruxolitinib drug administration. There is a visit window of +/- 7 for visits up to Week 24 
and +/- 14 days for visits after.
Note: If treatment with ruxolitinib is withheld at any time, all study visits, and safety 
assessments should continue according to the appropriate number of calendar days from 
Day 1 as per the schedule of assessments.
All data obtained from these assessments must be supported in the patient’s source 
documentation. No eCRF will be used as a source document except for the MPN-SAF TSS.
The table indicates which assessments produce data to be entered into the database (D) or 
remain in the source documents (S).


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Table 7-1
Visit evaluation schedule
Visit Number 
Category
Protocol 
Section
Screening
Baseline
+/- 7 day window
Every 12 
Weeks 
(+/- 14 days)
End of 
study 
treatmen
t (EoT)
End of 
Study 
(EoS)
1
2
3
4
5
6
7
8
9
10, 11, 12, 
etc., 
(777)
30 day 
phone call
(778)
Week
--5 to -1
-1
1
4
8
12
16
20
24
36, 48, 60, ...
Day
-35 to -1
-14 to 
-1
1
28
56
84
112
140
168
252, 336, 
420...
Last
Obtain Informed Consent
D
7.1.1.
X
Patient History
Demography
D
7.1.1.3
X
Inclusion/exclusion criteria
D
7.1.1.1
X
Eligibility Screening Checklist in 
IRT
D
7.1.1.1
X
PV Disease History including 
phlebotomy history
D
7.1.1.3
X
Prior antineoplastic therapy 
(Hydroxyurea)
D
7.1.1.3
X
Prior antineoplastic therapy 
(Hematologic disease)
D
7.1.1.3
X
Smoking history
D
7.1.1.3
X
Prior/concomitant medications
D
7.1.1.3
X
X
continuous
X
Relevant medical history/current 
medical conditions 
D
7.1.1.3
X
Phlebotomy procedures
D
7.1.1.3
X
X
X
X
X
X
X
X
X
X
Physical examination
S
7.2.2.1
X
X
X
X
X
X
ECOG Performance status
D
7.2.2.4
X
X
X
X
X
X
Height 
D
7.2.2.3
X


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Visit Number 
Category
Protocol 
Section
Screening
Baseline
+/- 7 day window
Every 12 
Weeks 
(+/- 14 days)
End of 
study 
treatmen
t (EoT)
End of 
Study 
(EoS)
1
2
3
4
5
6
7
8
9
10, 11, 12, 
etc., 
(777)
30 day 
phone call
(778)
Week
--5 to -1
-1
1
4
8
12
16
20
24
36, 48, 60, ...
Day
-35 to -1
-14 to 
-1
1
28
56
84
112
140
168
252, 336, 
420...
Last
Weight
D
7.2.2.3
X
X
X
X
X
X
X
X
X
X
Vital signs
D
7.2.2.2
X
X
X
X
X
X
X
X
X
X
Spleen palpation
D
7.2.2.1
X
X
X
X
X
X
Patient Reported Outcome
MPN-SAF
D
7.2.5
X
X
X
X
X
Laboratory Assessments
Hematology
S/D
7.2.2.5
X
X
X
X
X
X
X
X
X
X
Chemistry
S
7.2.2.5
X
X
X
X
X
X
X
X
X
X
Coagulation
S
7.2.2.5
X
X
X
X
X
Urinalysis (macroscopic)
S
7.2.2.5
X
X
Pregnancy Test, Serum
D
7.2.2.5.1
X
X
Pregnancy test, Urine
D
7.2.2.5.1
X
X
X
X
X
X
X
X
Safety Assessments
Adverse Events
D
8.1
X
X
continuous
X
Study Drug administration 
D
7.1.2
X
X
X
X
X
X
X
X
End of Treatment Disposition
D
7.1.3.1
X
Disease Progression Status 
including diagnostic criteria
D
7.1.3.1
X
End of Study Disposition
D
7.1.3
X


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7.1.1
Screening
Written informed consent must be obtained before any study specific procedure is performed.
Screening assessments to confirm eligibility should be performed as per the schedule of 
assessments in Table 7-1.
All assessments should be completed within the 35 day screening period.
Re-screening of patients will be allowed, if all entry criteria are not met during the screening 
period (-35 days to -1 day).
7.1.1.1
Eligibility screening 
Patients must meet all inclusion (Section 5.2) and none of the exclusion (Section 5.3) criteria 
during the Screening phase in order to be eligible to proceed to the Treatment Phase of the 
study. Patient eligibility will be confirmed by using the following processes:

Investigative staff will capture patient eligibility within the source documents maintained 
at the site,

All screening assessment results must be received and reviewed by the 
investigator/designee to be within protocol required parameters before the patient starts 
study treatment,

Patient eligibility will be confirmed by the site within the IRT system. Following 
registering in IRT for screening, patient eligibility will be checked once all screening 
procedures are completed. The eligibility check will be embedded in the IRT system. An 
end of screening phase disposition will be completed. Please refer and comply with 
detailed guidelines in the IRT manual. Only when eligibility has been confirmed will the 
IRT system indicate patient can proceed with study treatment.
Additionally, sites will enter patient information into the eCRF, and automated queries will be 
generated for immediate resolution should patient eligibility be in question based on the 
patient information entered.
7.1.1.2
Information to be collected on screening failures
A patient who signs an informed consent but fails to satisfy all eligibility criteria for any 
reason will be considered a screen failure. The reason for not starting dosing will be entered 
on the Screening Phase Disposition Page. The demographic information, informed consent, 
and Inclusion/Exclusion pages must also be completed for Screen Failure patients. No other 
data will be entered into the clinical database for patients who are screen failures, unless the 
patient experienced a Serious Adverse Event during the Screening Phase (see Section 8 for 
SAE reporting details).
Patients who signed ICF but are considered ineligible after signing the study consent will be 
considered as screening failures, and data will be handled in the same manner.
The following eCRFs must be completed for screening failure patients:

Screening Phase Disposition page (including reason for not satisfying eligibility criteria 
and being started on treatment)


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
Informed consent

Demography

Adverse Events (only if an SAE occurs)

Inclusion/Exclusion Criteria
In order to be officially considered a screen failure, the IRT system should be notified, 
preferably within 2 days of the decision to screen fail the patient.
7.1.1.3
Patient demographics and other baseline characteristics
Data to be collected on patient characteristics at screening include:

Demography (including: date of birth, age, patient initials, gender, childbearing potential, 
race and ethnicity, or as allowed by local regulations)

Relevant medical history including: smoking history, previous cardiovascular and 
thromboembolic events. Any history of previous pre malignant or malignant cutaneous 
lesions should be collected.

PV diagnosis and extent of disease, including:

Date of diagnosis

Estimated number of phlebotomies in the past 52 weeks

Prior antineoplastic therapies including use of hydroxyurea

Prior and Concomitant Medications, surgical and medical procedures
All medications taken from screening must be recorded on the Prior and Concomitant 
medication eCRF page and updated on a continual basis if there is a new change to the 
medication.
7.1.2
Treatment period
Following completion of screening procedures and verifying patient eligibility, the patient 
will be approved for treatment via the IRT.
The study treatment phase begins on Day 1 with the first administration of ruxolitinib and will 
continue until disease progression (see Appendix 4 and Appendix 5), unacceptable toxicity, 
death, withdrawal of consent for protocol specified procedures, or discontinuation from the 
study for any other reason until the drug becomes commercially available in each 
participating country.
Patients will be assessed as per visit schedule in Table 7-1.
Visit windows of ± 7 days from scheduled study assessments will apply up to Week 24 and ± 
14 days for visits after Week 24.
7.1.3
End of treatment visit including study completion and premature 
withdrawal
At the time patients discontinue study treatments, a visit should be scheduled as soon as 
possible, at which time all of the assessments listed for the End of Treatment (EOT) visit will 


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be performed and an End of treatment CRF page will be completed giving the date and reason 
for stopping treatment.
At a minimum, all patients who discontinue treatment, including those who refuse to return 
for a final visit, will be contacted for safety evaluations 30 days following the last dose of 
treatment by phone.
Patients who discontinue treatment should be considered withdrawn after the final visit 
assessments are performed or when it is clear that the patient will not return for these 
assessments.
If a withdrawal occurs, or if the patient fails to return for visits, the investigator must 
determine the primary reason for a patient’s premature withdrawal from the study and record 
this information on the study Evaluation Completion CRF page.
7.1.3.1
Criteria for premature patient withdrawal
Patients may voluntarily withdraw from the ETP at any time.
Patient death will be considered as a withdrawal from the study. Patients may also be 
withdrawn (the physician may decide to remove the patient from any further study activity) if 
any of the following occur:

Adverse event(s) (see Section 8.1)

Major protocol deviation

Technical problems

Physician decision

Non-compliance with study treatment
Patients must be withdrawn if any of the following occur:

Lost to follow-up

Patient/guardian decision

Study terminated by sponsor

Pregnancy (Pregnancy will be followed for outcome)

Disease progression – sites should indicate type of progression and include information on 
the diagnostic bone marrow biopsy result if obtained as per diagnostic criteria (see 
Appendix 4 and Appendix 5).

Withdrawal of consent
Patients lost to follow up should be recorded as such on the eCRF. For patients who are lost to 
follow-up, the investigator should show “due diligence” by documenting in the source 
documents steps taken to contact the patient, e.g. dates of telephone calls, registered letters, 
etc.
Treatment duration is considered “completed” three months after the expanded treatment 
plan’s drug becomes commercially available for the PV indication in the patients participating 
country or by 31 Dec 2017, whichever comes first, and the patient should be transitioned to 
commercial product. Study sites should stop all patients’ study participation on the study at 
this time.


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7.1.3.2
Replacement policy 
Patients will not be replaced on study
7.1.4
Follow up period
All patients must have a follow up safety phone evaluation 30 days after the last dose of 
treatment (Study Evaluation Completion or EoS).
Patients lost to follow up should be recorded as such on the CRF. For patients who are lost to 
follow-up, the investigator should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc.
7.2
Assessment types
7.2.1
Efficacy assessments
Assessments for efficacy will consist of Hct measured locally, spleen by palpation, and MPN-
SAF TSS.

Samples for hematology assessments will be prepared and analyzed locally as indicated in
Table 7-1. Data for specific Hematology tests will be recorded in the eCRF as indicated in 
Table 7-2.
7.2.2
Safety and tolerability assessments
Safety will be monitored by the assessments described below as well as the collection of AEs 
at every visit. For details on AE collection and reporting, refer to. Significant findings that 
were present prior to the signing of informed consent must be included in the relevant medical 
history/current medical conditions page on the patient’s eCRF. Significant new findings that 
begin or worsen after informed consent must be recorded on the Adverse Event page of the 
patient’s eCRF.
7.2.2.1
Physical examination
Physical examinations will include an examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, and a basic nervous system evaluation. Information about the physical 
examination must be present in the source documentation at the center. For the assessment 
schedule refer to Table 7-1.
Spleen will be assessed by palpation at visits indicated in Table 7-1. If palpable, a soft ruler 
should be used to document the spleen size, rounded to the nearest centimeter, from the left 
costal margin to the point of greatest splenic protrusion Spleen size will be used to determine 
if dose increases for lack of efficacy should be considered at or subsequent to Week 4 and for 
routine patient management. Spleen length information will be documented in the eCRF.
Significant findings that were present prior to the signing of informed consent must be 
included in the Medical History page on the patient’s CRF. Significant new findings that 


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begin or worsen after informed consent must be recorded on the Adverse Event page of the 
patient’s CRF except for spleen length which will be documented in a separate eCRF page. 
7.2.2.2
Vital signs
Vital signs include body temperature and blood pressure. Blood pressure (systolic and 
diastolic) should be measured after the patient has been sitting for five minutes.
For the assessment schedule refer to Table 7-1
7.2.2.3
Height and weight
Height in centimeters (cm) will only be collected at screening. Body weight (to the nearest 0.1 
kilogram (kg) with indoor clothing on, but without shoes) will be measured at every study 
visit. 
7.2.2.4
Performance status
The performance status will be assessed per the schedule in Table 7-1 and according to the 
ECOG performance status scale (see Appendix 2). 
7.2.2.5
Laboratory evaluations
Local site laboratories will be used for the analysis of scheduled hematology, biochemistry, 
urine, and other blood specimens collected as part of safety monitoring. All unscheduled 
blood testing will be performed locally. The time windows granted for laboratory evaluations 
are identical to the corresponding visit time windows for each visit (refer to Section 7.1)
Laboratory abnormalities that are considered clinically significant, induce clinical signs or 
symptoms, require concomitant therapy or require changes in ruxolitinib treatment (see 
Section 8.1) constitute an adverse event (AE) and must be reported as an AE on the AE CRF 
page.
Laboratory values obtained at the screening visit will be used to assess eligibility to meet 
inclusion criteria. If patient meets all inclusion and no exclusion criteria, the screening labs 
can be used for baseline if patient is dosed within 14 days of the screening visit. If patient 
cannot be dosed within 14 days of screen, then the labs should be repeated the day before 
patient starts dosing (see baseline visit in Table 7-1).
Only Hematocrit (Hct), Hemoglobin (Hb), Platelet (Plt), White Blood Count (WBC), absolute
or % neutrophils and pregnancy values will be collected on the eCRF.
Table 7-2
Local clinical laboratory parameters
Test 
Category
Documentation
Test Name
Hematology 
eCRF
Hematocrit, Hemoglobin, Platelets, WBC, Absolute or % Neutrophils
Hematology
Source 
documents
Hematocrit, Hemoglobin, Mean Corpuscular Hemoglobin (MCH) , Mean 
Corpuscular Hemoglobin Concentration  (MCHC), Mean Corpuscular 
Volume (MCV), Platelets, Red blood cells, White blood cells, %Blasts, Red 
Blood Count (RBC), White Blood Cells with Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils)


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Test 
Category
Documentation
Test Name
Chemistry
Source 
Documents
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Bicarbonate, 
Calcium, Chloride, Creatinine, Creatine kinase, 
Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, Total Cholesterol, Low 
Density Lipoprotein (LDL), High Density Lipoprotein (HDL), Total Protein, 
Triglycerides, Blood Urea Nitrogen (BUN) or Urea, Uric Acid
Urinalysis
Source 
Documents
Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, Ketones, 
Leukocytes esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen)
Coagulation
Source 
Documents
Prothrombin time (PT) or International normalized ratio [INR]), Partial 
thromboplastin time (PTT), Activated partial thromboplastin time (APTT)
Pregnancy
eCRF
Serum at screening and End of Treatment (EOT); Urine - all other time 
points
7.2.2.5.1 Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have a serum hCG test at 
screening. Thereafter, the patients will have a urine pregnancy test. At the End of Treatment 
visit a serum hCG test will be done. A positive urine pregnancy test requires immediate 
interruption of study drug until serum hCG is performed and found to be negative. If positive, 
the patient must be discontinued from the study. All the urine pregnancy tests will be 
performed locally. See Section 5.3 for further information on required birth control methods.
The time windows granted for pregnancy testing are identical to the corresponding visit time 
windows for each visit. Refer to Table 7-1. If local requirements dictate otherwise, local 
regulations should be followed.
If a positive pregnancy test is performed in between visits, the patients must immediately 
notify the investigator.
7.2.2.6
Cardiac assessments
Not applicable.
7.2.3
Biomarkers
Not applicable.
7.2.4
Resource utilization
Not applicable.
7.2.5
Patient reported outcomes
Patient reported Outcomes will be collected through the MPN-SAF according to the Visit 
Schedule outlined in Table 7-1. 
The patient should be given sufficient space and time to complete the questionnaire. The site 
personnel should check the questionnaire for completeness and ask the patient to complete 
any missing responses. The original questionnaire will be kept with the patient’s file as the 
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Completed questionnaire(s) and any unsolicited comments written by the patient should be 
reviewed and assessed by the investigator for responses which may indicate potential AEs or 
SAEs before any clinical study examinations. This assessment should be documented in study 
source records. If AEs or SAEs are confirmed, study investigators should not encourage the 
patient to change responses reported in the completed questionnaires. Study investigators 
must follow reporting instructions outlined in Section 8 (e.g. reference “Adverse Events” 
section) of the study protocol. 
MPN-SAF
The MPN-SAF (Appendix 6) is a disease specific questionnaire comprised of 10 items that 
measures fatigue related to MPN disease and the severity of nine of the most prevalent 
associated symptoms including: early satiety, abdominal discomfort, inactivity, concentration, 
night sweats, itching, bone pain, fever and weight loss. There are three recall periods used in 
this questionnaire, they are 24 hours for fatigue, the past week for symptoms of early satiety, 
abdominal discomfort, inactivity, concentration, night sweats, itching, bone pain and fever, 
and the past 6 months for weight loss, Each item is scored on a scale ranging from 0 (no 
fatigue/absent) to 10 (As bad as you can imagine/worst imaginable). The MPN-SAF TSS is 
computed as the average of the observed items multiplied by 10 to achieve a 0-to-100 scale. 
The MPN-SAF TSS thus has a possible score range of 0 to 100.
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should 
be continued for at least 30 days (or 5 half-lives, whichever is longer) following the last dose 
of study treatment. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event.
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03.


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If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will 
not be used in this study; rather, information about deaths will be collected though a Death 
form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine:
1. The severity grade (CTCAE Grade 1-4)
2. Its duration (Start and end dates) 
3. Reasonable possibility that AE is related to ruxolitinib (no, yes) 
4. Action taken with respect to ruxolitinib (none, dose adjusted, temporarily interrupted, 
permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse 
Events should be followed until they have returned to normal or an adequate explanation of 
the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event.


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Laboratory abnormalities, that do not meet the definition of an adverse event, should not be
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:
1. Is fatal or life-threatening
2. Results in persistent or significant disability/incapacity
3. Constitutes a congenital anomaly/birth defect
4. Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above
5. Requires inpatient hospitalization or prolongation of existing hospitalization, 
6. Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition
Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above is 
not a serious adverse event
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 


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specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department.
The telephone and telefax number of the contact persons in the local department of Drug 
Safety and Epidemiology (DS&E), specific to the site, are listed in the investigator folder 
provided to each site. The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site.
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis Drug Safety and Epidemiology (DS&E) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries.
8.3
Emergency unblinding of treatment assignment
Not applicable. 
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to ruxolitinib of any pregnancy outcome. Any SAE experienced 
during pregnancy must be reported on the SAE Report Form.
The procedures that will be followed based on whether a pregnancy is confirmed by a positive 
serum or urine test result during the study or within 30 days of stopping study drug, are listed 
below:

Investigator and patient must notify each other immediately.


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
Investigator must notify the Sponsor/designee immediately (see Section 9.2).

Discontinue study drug immediately.

Perform the required End-of-treatment visit study evaluations.

Investigator must complete and submit the Pregnancy Initial and Follow-up report forms 
to the Sponsor.

A serum pregnancy test must be performed to confirm the urine test result. (The serum test 
should be performed at the investigative site to ensure the test will be performed promptly 
and the result available immediately for review.)

Withdraw the patient from the study.

If a negative serum test does not confirm the urine test result, then: the investigator will 
use his/her expert judgment, based on an assessment of the potential benefit/risk to the 
patient, to determine if it is in the patients best interest to resume study drug and continue 
participation in the study.
The outcome of all such pregnancies (i.e., spontaneous miscarriage, elective termination, 
normal birth, or congenital abnormality) must be documented and followed-up on a form that 
will be provided by the Sponsor. The pregnancy will be followed to term and the outcome, 
including any premature termination, must be reported to the Sponsor. All live births must be 
followed for a minimum of 30 days or to the first well-baby visit. All reports of congenital 
abnormalities/birth defects and spontaneous abortions/miscarriages should be reported as an 
SAE for this study. Elective abortion procedures, without complications, should not be 
considered as AEs.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.6
Data Monitoring Committee 
Not applicable.
8.7
Steering Committee
Not applicable.
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study


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
Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements 
and to enable appropriate age-related normal ranges to be used in assessing laboratory test 
results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan.


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9.3
Data collection
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR 
Part 11 requirements, Investigator site staff will not be given access to the EDC system until 
they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs and, allow modification or verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner.
9.4
Database management and quality control
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the 
nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated 
investigator site staff are required to respond promptly to queries and to make any necessary 
changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology.
An inclusion/exclusion checklist will be tracked using an Interactive Response Technology. 
The system will be supplied by a vendor(s), who will also manage the database. The data will 
be sent electronically to Novartis personnel (or designated CRO).
The occurrence of any protocol violations will be determined. After these actions have been 
completed and the data has been verified to be complete and accurate, the database will be 
declared locked and made available for data analysis. Authorization is required prior to 
making any database changes to locked data, by joint written agreement between the Global 
Head of Biostatistics and Data Management and the Global Head of Clinical Development.
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site.
10
Statistical methods and data analysis
Novartis and/or a designated CRO will perform all analyses. Any data analysis carried out 
independently by the investigator should not be presented or published before the final 
analysis is completed. The data from all centers that participate will be combined in the 
analyses.
Final analyses will be performed when all patients have been followed for 30 days after they 
have either prematurely discontinued or been discontinued from the study after completing 
treatment as per protocol (i.e., until the drug is commercially available for this indication in 
each participating country).


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The data will be summarized with respect to demographic and baseline characteristics, and 
safety observations and measurements. Categorical data will be presented as frequencies and 
percentages. For continuous data, mean, standard deviation, median, minimum, and maximum 
will be presented.
10.1
Analysis sets
The following analysis sets will be used for statistical analysis and data reporting. 
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been 
assigned.
10.1.2
Safety Set
The Safety Set includes all patients who received at least one dose of study treatment.
10.1.3
Per-Protocol Set
Not applicable.
10.1.4
Dose-determining analysis set
Not applicable.
10.1.5
Pharmacokinetic analysis set
Not applicable.
10.1.6
Other analysis sets
Not applicable.
10.2
Patient demographics/other baseline characteristics
Demographic, disease characteristics and other baseline data will be summarized descriptively 
for the FAS.
10.3
Treatments (study treatment, concomitant therapies, compliance)
All analyses from this section will be performed on all patients from the safety set.
Duration of ruxolitinib treatment exposure and cumulative dose and dose intensity will be 
summarized. The number of patients with dose changes/interruptions will be presented, along 
with reasons for the dose change/interruption.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
treatment will be summarized by ATC code.


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10.4
Primary objective
The primary objective is to evaluate safety data in patients with PV who are hydroxyurea 
resistant or intolerant. The safety set will be used for the analysis of clinical safety data.
10.4.1
Variable
The analysis of the primary objective is described in Section 10.5.3.
10.4.2
Statistical hypothesis, model, and method of analysis
No statistical hypotheses will be tested.
10.4.3
Handling of missing values/censoring/discontinuations
No imputation will be applied for any missing data.
10.4.4
Supportive analyses
Not applicable. 
10.5
Secondary objectives
10.5.1
Key secondary objective(s)
Not applicable. 
10.5.2
Other secondary efficacy objectives
Secondary objectives are described in Section 3 and corresponding efficacy endpoints are 
outlined in detail in Table 3-1.
Only descriptive statistics will be presented for all secondary efficacy endpoints.
Change from Baseline in Hct and spleen length, to different scheduled visits will be 
summarized with descriptive statistics. 
If multiple assessments are taken within the window of the visit, the assessment used to 
evaluate a visit will be the one closest to that visit that occurs within the window allowable for 
the assessment and that is evaluable.
10.5.3
Safety objectives
10.5.3.1
Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. 
The overall observation period will be divided into mutually exclusive segments:
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication
3. If applicable, post-treatment period: starting at day 31 after last dose of study medication.


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10.5.3.2
Adverse events (AEs)
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
and type of adverse event.
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event.
Specific safety event categories (SEC) will be considered. Such categories consist of one or 
more well-defined safety events which are similar in nature and for which there is a specific 
clinical interest in connection with the study treatment(s).
For each specified SEC, number and percentage of patients with at least one event part of the 
SEC will be reported.
10.5.3.3
Laboratory abnormalities
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03, the study’s biostatistical and reporting team will grade laboratory data 
accordingly.
In cases of the white cell differentials the lower limits of normal ranges used in CTCAE 
definition have to be replaced by a clinically meaningful limit expressed in absolute counts.
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.
The following summaries will be generated separately for hematology, biochemistry and 
urinary laboratory tests:

shift tables using CTCAE grades to compare baseline to the worst on-treatment value

for laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high)

listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges.
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the MAP and/or RAP.
10.5.3.4
Other safety data
Other safety data (including vital signs and weight) will be summarized and listed, notable 
values will be flagged, and any other information collected will be listed as appropriate.


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10.5.3.5
Supportive analyses for secondary objectives
Not applicable.
10.5.3.6
Tolerability
Tolerability will be studied in terms of dose reductions or dose interruption due to an AE.
Number and percentage of patients who have a dose modification due to a treatment related 
Adverse Event will be summarized by type of dose modification (interruption, dose reduction, 
and permanent discontinuation).
10.5.4
Pharmacokinetics
Not applicable.
10.5.5
Resource utilization
Not applicable.
10.5.6
Patient-reported outcomes
The MPN-SAF will be used to collect data on the patient’s disease-related symptoms. No 
formal statistical test will be performed.
Missing items data in a scale will be handled based on each instrument manual. No imputation 
will be applied if the total or subscale scores are missing at a visit. 
Descriptive statistics (e.g., mean, median) will be used to summarize the scored scales at each 
scheduled assessment time point for the MPN-SAF TSS. Additionally, change from baseline 
in the domain scores at the time of each assessment will be summarized. Patients with an 
evaluable baseline score and at least one evaluable post baseline score during the treatment 
period will be included in the change from baseline analyses. 
10.6
Exploratory objectives
Not applicable.
10.7
Interim analysis
No interim analysis is planned.  Analyses may be performed if needed to fulfill regulatory 
requests or for publication purposes. 
10.8
Sample size calculation
The planned sample size of approximately 500 patients was chosen based on the expected 
accrual rates and the planned duration of the trial. It was not based on any statistical 
consideration.  The actual sample size may differ from this planned number.
10.9
Power for analysis of key secondary variables
Not applicable. 


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11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study 
in accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their CRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in 
Section 4.4.


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11.5
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported 
on the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF 
should be dated, initialed, and explained (if necessary) and should not obscure the original 
entry. For electronic CRFs an audit trail will be maintained by the system. The investigator 
should retain records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.


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11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis should be notified of this action and the IRB/IEC at the study 
site should be informed according to local regulations (e.g. UK requires the notification of 
urgent safety measures within 3 days) but not later than 10 working days.


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13
References (available upon request)
Barosi G, Birgegard G, Finazzi G, et al. (2009b) Response criteria for essential 
thrombocythemia and polycythemia vera: result of a European LeukemiaNet consensus 
conference. Blood.;113:4829-4833. (B).
Barosi G, Grossi A, Comotti B, et al. (2001) Safety and efficacy of thalidomide in patients 
with myelofibrosis with myeloid metaplasia Br. J. Haematol. 114 (1):78-83.
Barosi G, Mesa R, Finazzi G, et al. (2013) Revised response criteria for polycythemia vera 
and essential thromobythemia: a ELN and IWG-MRT consensus project. Blood.; 121: 4778-
4781.
Barosi, G Mesa, R, Thiele, J, et al. (2008) Proposed criteria for the diagnosis of post-
polycythemia vera nd post-essential thrombocythemia myelofibrosis: a consensus statement 
from the international working group for myelofibrosis research and treatment. Leukemia.; 22 
(2):437-438.
Finazzi G, Barbui T (2007) How I treat patients with polycythemia vera. Blood.;109:5104-
5111.
Finazzi G, Barbui T (2008) Evidence and expertise in the management of polycythemia vera 
and essential thrombocythemia. Leukemia.; 22:1494-1502.
Landolfi R, Di Gennaro L, et al. (2007) Leukocytosis as a major thrombotic risk factor in 
patients with polycythemia vera. Blood.; 109:2446-2452.
Levine RL, Wernig G (2006) Role of JAK-STAT Signaling in the Pathogenesis of 
Myeloproliferative Disorders. Hematology Am Soc Hematol Educ Program.;233-239.
Marchioli R, Finazzi G, Landolfi R, et al. (2005) Vascular and neoplastic risk in a large cohort 
of patients with polycythemia vera. J Clin Oncol.;23:2224-2232.
Marchioli R, Finazzi G, Specchia G, et al. (2013) Cardiovascular Events and Intensity of 
Treatment in Polycythemia Vera. The New England Journal of Medicine.; 368: 22-33.
Mesa RA (2009) Itchy mast cells in MPNs. Blood. ;113:5697-5698.
Mesa RA, Niblack J, Wadleigh M, et al. (2007) The Burden of Fatigue and Quality of Life in 
Myeloproliferative Disorders (MPDs). Cancer;109:68-76.
Najean Y, Rain JD (1997) Treatment of polycythemia vera: The use of hydroxyurea and 
pipobroman in 292 patients under the age of 65 years. Blood.;90:3370-3377.
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events v4.0 
(CTCAE) online at the NCI website, ctep.cancer.gov/reporting/ctc.html.
Oken MM, Creech RH, Tormey DC, et al. (1982) Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol.;5:649-655.
Passamonti F, Rumi E, Pungolino E, et al. (2004) Life expectancy and prognostic factors for 
survival in patients with polycythemia vera and essential thrombocythemia. Am J Med.;117: 
755-761.


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Quintas-Cardama A, Vaddi K, Liu P, et al. (2010) Preclinical characterization of the selective 
JAK1/JAK2 inhibitor INCB018424: implications for the treatment of myeloproliferative 
neoplasms. Blood.; Epub ahead of print.
Spivak JL (2002) Polycythemia vera: myths, mechanisms, and management. 
Blood.;100:4272-4290.
Tefferi A (2003) Polycythemia vera: a comprehensive review and clinical recommendations. 
Mayo Clin Proc.;78:174-94.
Tefferi A, Thiele J, Orazi A, et al. (2007) Proposals and rationale for revision of the World 
Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia and 
primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood.; 
110:1092-1097.
Tefferi A, Vardiman JW (2008) Classification and diagnosis of myeloproliferative neoplasms: 
The 2008 World Health Organization criteria and point-of-care diagnostic algorithms. 
Leukemia.; 22:14-22.
Tefferi A, Vardiman JW (2009) Myelodysplastic Syndromes. The New England Journal of 
Medicine; 361:1872-1885.
The Criteria Committee of the New York Heart Association (1994) Nomenclature and Criteria 
for Diagnosis of Diseases of the Heart and Great Vessels. Boston, Mass: Little, Brown & Co; 
9th ed.:253-256
Thiele J, Kvasnicka HM (2009) The 2008 WHO Diagnostic Criteria for Polycythemia Vera, 
Essential Thromobcythemia, and Primary Myelofibrosis. Current Hematologic Malignancy 
Reports; 4:33-40.
Trussell J (2004) Contraceptive failure in the United States. Contraception.;70:89–96. 
Vaidya R, Gangat N, Siragusa S, et al. (2009) Long-Term Survival in 652 Patients with 
Primary Myelofibrosis or Polycythemia Vera – Trends in Recent Years. Blood.;114:22:1137.
Vardiman JW, Thiele J, Arber DA, et al. (2009) The 2008 revision of the World Health 
Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and 
important changes. Blood;114:937-951.
Verstovsek S, Passamonti F, Rambaldi A, Barosi G, Rosen P J, Rumi E, Gattoni E, Pieri L, 
Guglielmelli P, Elena C, He S, Contel N, Mookerjee B, Sandor V, Cazzola M, Kantarjian HM, 
Barbui T, and Vannucchi A M. (2014), A phase 2 study of ruxolitinib, an oral JAK1 and 
JAK2 inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant 
to hydroxyurea. Cancer; 120:513–520. doi: 10.1002/cncr.28441
World Medical Association Declaration of Helsinki Ethical Principles for Medical Research 
Involving Human Subjects. Adopted by the 18th WMA General Assembly, Helsinki, Finland, 
June 1964, and amended by the 29th WMA General Assembly, Tokyo, Japan, October 1975, 
35th WMA General Assembly, Venice, Italy, October 1983, 41st WMA General Assembly, 
Hong Kong, September 1989, 48th WMA General Assembly, Somerset West, Republic of 
South Africa, October 1996, and the 52nd WMA General Assembly, Edinburgh, Scotland, 
October 2000. Note of Clarification on Paragraph 29 added by the WMA General Assembly, 
Washington 2002. Note of Clarification on Paragraph 30 added by the WMA General 
Assembly, Tokyo 2004. Available at wma.net/e/policy/b3.htm.


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14
Appendices
14.1
Appendix 1: The 2008 World Health Organization diagnostic 
criteria for polycythemia vera
Diagnosis requires meeting both major criteria and one minor criterion or the first major 
criterion and two minor criteria.
Major criteria
1. Hemoglobin > 18.5 g/dL in men, 16.5 g/dL in women or other evidence of increased red 
cell volume.*
2. Presence of JAK2V617F or other functionally similar mutation such as JAK2 exon 12 
mutation.
Minor criteria
1. Bone marrow biopsy showing hypercellularity for age with trilineage growth 
(panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation.
2. Serum erythropoietin level below the reference range for normal.
3. Endogenous erythroid colony formation in vitro.
*Hemoglobin or Hct > 99th percentile of method-specific reference range for age, sex, and 
altitude of residence; or hemoglobin > 17 g/dL in men, 15 g/dL in women if associated with a 
documented and sustained increase of at least 2 g/dL from an individual’s baseline value that 
cannot be attributed to correction of iron deficiency; or elevated red cell mass > 25% above 
mean normal predicted value.
(Thiele and Kvasnicka 2009 as adapted from Tefferi et al 2007, Tefferi and Vardiman 2008)


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14.2
Appendix 2: Eastern Cooperative Oncology Group Performance 
Status
Table 14-1
Eastern Cooperative Oncology Group Performance Status
Grade
Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more 
than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
(Oken et al 1982)


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14.3
Appendix 3: New York Heart Association (NYHA) Functional 
Classification
Table 14-2
New York Heart Association (NYHA) Functional Classification
Class
Symptoms
I
No symptoms and no limitation in ordinary physical activity, e.g. shortness of breath when walking, 
climbing stairs etc.
II
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity.
III
Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. walking short 
distances (20-100 m). Comfortable only at rest.
IV
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients.
(The Criteria Committee of the New York Heart Association 1994)


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14.4
Appendix 4: 2008 WHO classification for Myelodysplastic 
Syndromes (MDS)
Table 14-3
2008 WHO classification for Myelodysplastic Syndromes (MDS)
Auer Rods
Peripheral Blood 
Blasts ≥ 1%
Bone Marrow Blasts ≥ 
5%
Isolated 
del(5q)
RAEB-2
Yes
No
No
No
RAEB-2
No
Yes (5-19%)
No
No
RAEB-2
No
No
Yes (10-19%)
No
RAEB-1
No
Yes (2-4%)
No
No
RAEB-1
No
No
Yes (5-9%)
No
MDS-del(5q)
No
No
No
Yes
No Auer Rods, Blood Blasts, Bone Marrow Blasts, Isolated del(5q)
Multilineage 
dysplasia
Unilineage 
dysplasia
≥ 15% Ring 
sideroblasts
Not fitting 
elsewhere
RCMD
Yes
No
No
No
RCUD
No
Yes
No
No
RARS
No
Yes
Yes
No
MDS-U
No
No
No
Yes
Minimal criteria for MDS = Presence of ≥ 10% dysplastic cells in bone marrow with a specific myeloid lineage 
Exclude:
AML (≥ 20% peripheral blood or bone marrow blasts) 
CMML (monocyte count >1x109/L)

AML - acute myeloid leukemia

CMML- chronic myelomonocytic leukemia

RAEB-1 - Refractory anemia with excess blasts-1 

RAEB-2 - Refractory anemia with excess blasts-2

MDS del(5q) - MDS associated with isolated del(5q) 

RCMD - Refractory cytopenia with multilineage dysplasia

RCUD - Refractory cytopenia with unilineage dysplasia

RARS - Refractory anemia with ringed sideroblasts

MDS-U - Myelodysplastic syndrome, unclassified
Tefferi A, Vardiman, J (2009)


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14.5
Appendix 5: IWG-MRT recommended criteria for post-PV MF
Table 14-4
IWG-MRT recommended criteria for post-PV MF
Required criteria:
1
Documentation of a previous diagnosis of polycythemia vera as defined by the WHO criteria1
2
Bone marrow fibrosis grade 2–3 (on 0–3 scale)3 or grade 3–4 (on 0–4 scale)4,a
Additional criteria (two are required):
1
Anemiab or sustained loss of requirement of either phlebotomy (in the absence of cytoreductive therapy) or 
cytoreductive treatment for erythrocytosis
2
A leukoerythroblastic peripheral blood picture
3
Increasing splenomegaly defined as either an increase in palpable splenomegaly of 5 cm or more (distance 
of the tip of the spleen from the left costal margin) or the appearance of a newly palpable splenomegaly
4
Development of 1 or more of three constitutional symptoms: >10% weight loss in 6 months, night sweats, 
unexplained fever (>37.5°C)
(Barosi et al 2008)


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14.6
Appendix 6: Myeloproliferative Neoplasm Symptom Assessment 
Form Total Symptom Score (MPN-SAF TSS)


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14.7
Appendix 7: Restricted medications
Table 14-5
List of CYP3A4 inhibitors and inducers
Category
Drug Names
Strong inhibitorsa of 
CYP3A
boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir, 
eltegravir/ritonavir, grapefruit juice1, idelalisib, indinavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, LCL161, mibefradil, nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, sequinavir/ritonavir,  telaprevir, telithromycin, voriconazole, 
indinavir/ritonavir, tipranoavir/ritonavir, troleandomycin,
Moderate inhibitorsb of 
CYP3A
amprenavir, aprepitant, atazanavir, atazanavir/ritonavir,, casopitant, cimetidine, 
ciprofloxacin, crizotinib, cyclosporin, duranavir, darunavir/ritonavir, diltiazem, 
dronedarone, erythromycin, faldaprevilr, fluconazole2, fosamprenavir, grapefruit 
juice1, imatinib, lomitapide, netupitant,nilotinib, schisandra sphenanthera3, tofisopam, 
verapamil
Strong inducersc of 
CYP3A
avasimibe, carbamazepine, enzalutamide, mitotane,phenytoin, rifampin, St. John’s 
wort3, rifabutin, phenobarbital, 
Moderate inducersd of 
CYP3A
bosentan, efavirenz, etravirine, genistein3, lersivirine, lopinavir, modafinil, nafcillin, 
ritonavir, semagacestat4, talviraline4, thioridazine, tipranavir, , 
The list of CYP inhibitors and inducers was compiled from the FDA’s “Guidance for Industry, Drug Interaction 
Studies;” from the Indiana University School of Medicine’s “Clinically Relevant” Table and from the University of 
Washington’s Drug Interaction Database. Note that this may not an exhaustive list. Please refer to footnotes.
1. Effect seems to be due to CYP2C19 inhibition by ethinyl estradiol.
2. Fluconazole is a dual CYP3A4 and CYP2C9 inhibitor. Fluconazole is a strong CYP2C9 inhibitor based on the 
AUC ratio of omeprazole, which is also metabolized by CYP3A; fluconazole is a moderate CYP3A inhibitor. 
3. Herbal product.
4. Drugs not available in the US Market.
aA strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for 
that CYP by equal or more than 5-fold. 
bA moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate 
for that CYP by less than 5-fold but equal to or more than 2-fold
c A strong inducer for a specific CYP is defined as an inducer that decreases the AUC of a sensitive substrate for 
that CYP by equal or more than 80%.
d A moderate inducer for a specific CYP is defined as an inducer that decreases the AUC of a substrate for that 
CYP by 50-80%.
Dual CYP2C9 and CYP3A4 inhibitors:
Fluconazole: Avoid the concomitant use of ruxolitinib with fluconazole doses ≥ 200 mg daily; 
if clinically necessary to use doses ≥ 200 mg daily consultation with Sponsor is required. 
Please refer to Section 6.4.2 Permitted concomitant therapy requiring caution and/or action.

SAP_001.pdf: 
Clinical Development
INC424/Ruxolitinib/Jakavi@
CINC424B2001X / NCT02292446
An open-label, multi-center, Expanded Treatment Protocol 
(ETP) of ruxolitinib in patients with Polycythemia Vera who 
are Hydroxyurea resistant or intolerant and for whom no 
treatment alternatives are available
RAP Module 3 – Detailed Statistical Methodology
Author:
 
Document type:
SAP Documentation
Document status:
Final; Amendment1
Release date:
15-Mar-2018
Number of pages:
22
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous version of RAP module 3.
Version
Date
Changes
First Version
18-Feb-2015
NA
Amendment 1
13-Mar-2018
Table of Contents: 2.5.2 and 2.5.3 are included by changing the 
heading style from 4 to 3. 
Section 2.4.1, “Listings will be provided for disposition, informed 
consent, inclusion/exclusion criteria and the screening logs” was 
changed to “Listings will be provided for disposition, 
inclusion/exclusion criteria and the screening logs” since informed 
consent listing is deleted from TFL shells Amendment 1. 
Section 2.4.7, “Concomitant medications and significant non-drug 
therapies after the start of the study treatment and up to 30 days 
after the last dose date will be summarized by WHO drug class and 
WHO drug term for the Safety Set” was changed to “Concomitant 
medications and significant non-drug therapies after the start of the 
study treatment and up to 30 days after the last dose date will be 
summarized by ATC code the Safety Set”. In “These summaries 
will include medications starting on or after the start of study 
treatment or medications starting prior to the start of study 
treatment and continuing after the start of study treatment”, “and 
continuing after the start of study treatment” was removed. Both 
sentences are changed to be consistent with Protocol Section 10.3. 
Sectin 2.8, “three mutually exclusive segments” was changed to 
“mutually exclusive segments” and “post-treatment period” was 
changed to “If applicable, post-treatment period” to keep consistent 
with protocol Section 10.5.3.1.
Section 2.8.1, “SAEs adjusted for patient-year exposure, regardless 
of study drug relationship” was added as the last bullet point as this 
is newly added in TFL shells Amendment1 Table 14.3.1-1.11: 
Serious adverse events adjusted for patient-year exposure, 
regardless of study drug relationship, by primary system organ 
class, preferred term, maximum grade and treatment group (Safety 
Set)
Section 2.8,2, “Boxplots will be presented for selected hematology 
and biochemistry parameters over time using Safety set” was 
changed to “Boxplots will be presented for selected hematology 
parameters over time using Safety set” since biochemistry 
parameters are not collected. 
Section 2.9.1, sample size was changed from 1,500 to 500 to keep 
consistent with Protocol Amendment 1 Section 10.8.


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Table of contents
Table of contents .................................................................................................................3
1
Introduction .........................................................................................................................5
1.1
Document content....................................................................................................5
1.2
References................................................................................................................5
2
CSR Section 9.7 - Statistical methods planned in the protocol and determination of 
sample size...........................................................................................................................5
2.1
CSR Section 9.7.1 Statistical and analytical plans ..................................................5
2.2
Data included in the analysis ...................................................................................6
2.3
Analysis sets ............................................................................................................6
2.4
Patients and treatments ............................................................................................6
2.4.1
Patient disposition...................................................................................6
2.4.2
Patient demographics and other baseline characteristics ........................6
2.4.3
Protocol deviations..................................................................................7
2.4.4
Antineoplastic therapy ............................................................................7
2.4.5
Date of first/last administration of study drug ........................................7
2.4.6
Extent of exposure...................................................................................7
2.4.7
Concomitant Medications .......................................................................9
2.5
Analysis for the primary objective ..........................................................................9
2.5.1
Variable...................................................................................................9
2.5.2
Statistical hypothesis, model and method of analysis.............................9
2.5.3
Handling of missing values.....................................................................9
2.6
Analysis of the key secondary objective .................................................................9
2.7
Analysis of the secondary efficacy objectives.........................................................9
2.7.1
Analysis for secondary efficacy objectives.............................................9
2.7.2
Patient-reported outcomes.....................................................................10
2.7.3
Biomarkers............................................................................................10
2.7.4
Resource utilization...............................................................................10
2.8
Safety evaluation ...................................................................................................10
2.8.1
Adverse events ......................................................................................10
2.8.2
Laboratory values..................................................................................11
2.8.3
ECG analysis.........................................................................................12
2.8.4
Analysis of vital signs ...........................................................................12
2.9
CSR Section 9.7.2 – Sample size and power considerations.................................13
2.9.1
Sample size............................................................................................13
2.9.2
Power for analysis of key secondary variables .....................................13


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3
Appendix 16.1.7 Randomization scheme and codes.........................................................14
3.1
Randomization scheme and codes .........................................................................16
3.2
Treatment assignment............................................................................................16
3.3
Treatment blinding.................................................................................................16
4
Appendix 16.1.9 Documentation of statistical methods....................................................18
4.1.1
Study day...............................................................................................18
4.2
Analysis populations..............................................................................................18
4.3
Safety evaluations..................................................................................................18
4.3.1
Baseline.................................................................................................18
4.3.2
Multiple assessments within post-baseline visits..................................18
4.4
Handling of missing or partial dates......................................................................18
4.4.1
AE date imputation ...............................................................................19
4.4.2
Incomplete date of initial diagnosis of cancer and date of most
recent recurrence ...................................................................................21
4.4.3
Incomplete date for anti-neoplastic therapies .......................................21
4.4.4
Incomplete date for death ......................................................................21
4.4.5
Incomplete dates for last dose of INC424 .............................................21


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1
Introduction
1.1
Document content
This RAP module describes the planned statistical methods for all safety and efficacy analyses. 
It is structured as

a draft of Section 9.7 (Statistical methods planned in the protocol and determination of 
sample size).

a draft of Appendix 16.1.7 (Randomization scheme and codes) of the clinical study report 
(CSR).

a draft of Appendix 16.1.9 (Documentation of statistical methods) of the CSR.
It is written in future tense. It will be reviewed and updated (including conversion to past tense) 
for entry into the clinical study report after the analysis has taken place.
1.2
References
Please refer to the following documents:

CSR template (Full Clinical Study Report)

Guidelines for content of Statistical Appendices of the Clinical Study Report
2
CSR Section 9.7 - Statistical methods planned in the 
protocol and determination of sample size
2.1
CSR Section 9.7.1 Statistical and analytical plans
The statistical analysis of these data will be performed by Novartis personnel in accordance 
with the data analysis section, Section 10, of the study protocol which is available in Appendix 
16.1.1 of the CSR. Important information is given in the following sections and details are 
provided, as applicable, in Appendix 16.1.9 of the CSR. SAS version 9.4 will be used in all 
analyses.
This is a global, single arm, open-label, multi-center trial designed to provide early access and 
evaluate the safety of ruxolitinib in patients with polycythemia vera who are HU resistant or 
intolerant and who have no other standard treatment options. Efficacy and patient reported 
outcomes will also be assessed.
Final analyses will be performed when all patients have been followed for 30 days after they
have either prematurely discontinued or been discontinued from the study after completing
treatment as per protocol (i.e., until the drug is commercially available for this indication in
each participating country).
It is planned that the data from all centers that participate in this trial will be pooled and 
analyzed.  Unless otherwise specified, qualitative data will be described using frequency and
percentages, while quantitative data, will be described using descriptive statistics: n, mean,
standard deviation, median, minimum, and maximum.  


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No interim analysis is planned, and the final analysis will be performed after all patients have
either completed the study or have been prematurely discontinued from the study. 
2.2
  Data included in the analysis
All data reported in the database (scheduled, repeat and unscheduled visits) up to the cut-off 
date will be included in the analyses.
2.3
Analysis sets 
The following analysis sets, or populations, will be considered in the data analyses:
Full analysis set (FAS) comprises all patients to whom study treatment has been assigned.
Demographics, baseline characteristics, and patient disposition will be presented using the 
FAS. Furthermore, all efficacy data will be analyzed using the FAS.
The Safety set includes all patients who received at least one dose of study treatment. All 
safety data will be analyzed using the Safety Set.
2.4
Patients and treatments
2.4.1
Patient disposition
Patient disposition will be summarized using the Full analysis set (FAS).The following will 
be tabulated:

Number (%) of patients screened;

Number (%) of patients enrolled;

Number (%) of patients, who remained in the trial at the time of data cut-off;

Number (%) of patients who discontinued the treatment;

Number (%) of patients with primary reason for  end of treatment (based on patient 
status entered in the ‘END OF TREATMENT DISPOSITION’ page);

Number (%) of patients with primary reason for end of study (based on completion of 
‘STUDY EVALUATION COMPLETION’ page);
Listings will be provided for disposition, inclusion/exclusion criteria and the screening logs.
2.4.2
Patient demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be summarized 
descriptively using the FAS. Demographic data will include age, age categories (≤60, >60 
years), sex, race, ethnicity, weight, and height. Baseline characteristics will include 
polycythemia vera history including bone marrow biopsy, any prior medication for PV
(yes/no), frequency of phlebotomy within 52 weeks prior to screening (1, 2, >2), frequency of 
patients with thromboembolic events; frequency of patients with pre-malignant or non-
melanoma malignant skin lesion (NMSC), HU resistance or intolerance, Hct (<45%, ≥45-
≤50%, >50%), WBC counts [(≤10, >10-≤15, >15) x109/L] and platelet counts at baseline 
[(<100, ≥100-<400, ≥400-<600, ≥600) x 109/L]. Baseline characteristics will also include 


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splenectomy history due to PV (yes/ no); previously treated with ruxolitinib (yes/no) and 
patient received ruxolitinib on a clinical trial (yes/no), palpable spleen at screening (yes/no and 
Eastern Cooperative Oncology Group (ECOG) Performance Status (0, 1, 2).
Listings including smoking history will be provided using FAS.
2.4.3
Protocol deviations
Protocol deviations will be categorized into the following categories per ICH guidelines for 
CSR-reportable protocol deviations:

Patient developed study/treatment withdrawal criteria during the study, but was not 
withdrawn

Patient received the wrong treatment or incorrect dose

Patient took an excluded concomitant medication

Patient did not satisfy the entry criteria
Other important deviations may also be identified and summarized, as necessary, which may 
impact the scientific value of the trial.
All protocol deviations, including protocol deviations leading to exclusion from any analysis 
population will be specified in the study Validation and Planning (VAP) document. 
The number and percentage of patients in the Full Analysis Set (FAS) with any protocol 
deviation will be tabulated by the CSR-reportable deviation categories.  
All protocol deviations will be listed using FAS.
2.4.4
Antineoplastic therapy
Prior antineoplastic medications for hematologic disease, including PV, will be listed and
summarized by preferred terms using the FAS. Duration of prior antineoplastic use will be 
summarized descriptively. The reason for discontinuation of therapy will also be summarized 
categorically. 
All data related to prior antineoplastic medication will be listed by patients using FAS.
2.4.5
Date of first/last administration of study drug
The start date of study drug is defined as the first date when a non-zero dose of study drug 
was administered and recorded on the Dosage Administration Record (DAR) eCRF. 
The date of last administration of study drug is defined as the last date when a non-zero dose of 
study drug was administered and recorded on DAR eCRF. 
2.4.6
Extent of exposure
All exposure analyses will be performed on Safety set.


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2.4.6.1
Dose intensity and exposure
Definitions of duration of exposure, cumulative dose, average daily dose, actual dose intensity 
(DI), planned dose intensity (PDI), relative dose intensity (RDI), percentage of days dosed, 
percentage of days the planned/intended dose was received, as well as intermediate 
calculations, include:

Duration of exposure (days):
last date of study drug − first date of study drug + 1

Cumulative dose (mg):
total dose of study drug taken by a patient in the study

Number of dosing days (days): duration of exposure − number of zero dose days 

% Days dosed:
100 x number of dosing days / duration of exposure 
(days)

% Days with planned dose:
100 x number of days with planned dose / duration of 
exposure (days)

Average daily dose (mg/day):
cumulative dose (mg) / number of dosing days (days)

DI (mg/day):
cumulative dose (mg) / duration of exposure (days)

PDI (mg/day):
cumulative planned dose (mg) / duration of exposure 
(day)

RDI (%):
100 x DI (mg/day) / PDI (mg/day)
Duration of exposure to study drug, actual cumulative dose, percentage of actual days dosed, 
percentage of days the planned dose was received, average daily dose, DI and RDI (including 
categories: <70, 70-90, >90) will be summarized descriptively. In addition, the duration of 
exposure to study drug will be categorized into time intervals; frequency counts and percentages 
of patients with exposure in each time interval will be presented. 
The derived parameters above will also be listed using Safety set.
2.4.6.2
Dose changes
The number and percentage of patients with dose interruption, reduction and increase will
be summarized in the safety set. Dose interruption, reduction and increase are defined as
follows:

Interruption is defined as any period of zero total daily dose followed by a non-zero 
dose.

Reduction is defined as any decrease from the immediate prior non-zero total daily 
dose. Zero daily doses are not regarded as reductions.

Increase is defined as any increase from the immediate prior non-zero total daily 
dose.
The number and percentage of patients with dose interruption, reduction and increase, along
with reasons for dose change or dose delay will be summarized using Safety set.
The duration of dose changes (days) will be summarized.


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Listings of all doses of the study drug along with dose reduction, increase and interruption and 
reasons for dose change or dose delay will be presented. The derived parameters above will also 
be listed using Safety set.
2.4.7
Concomitant Medications
Concomitant medications and significant non-drug therapies after the start of the study 
treatment and up to 30 days after the last dose date will be summarized by ATC code the Safety 
Set. These summaries will include medications starting on or after the start of study treatment 
or medications starting prior to the start of study treatment. All concomitant medications and 
significant non-drug therapies will be listed using Safety set, including any prior medications 
and significant non-drug therapies starting and ending prior to the start of study treatment. 
2.5
Analysis for the primary objective
The primary objective is to evaluate safety data in patients with PV who are hydroxyurea-
resistant or -intolerant. The safety set will be used for the analysis of clinical safety data.
2.5.1
Variable 
Refer to section 2.8.1.
2.5.2
Statistical hypothesis, model and method of analysis
No statistical hypotheses will be tested in this ETP.
2.5.3
Handling of missing values
Missing/partial dates for prior anti-neoplastic therapy, adverse event, death and dosing record 
will be imputed. Details imputation rules for missing dates are described in section 4.4.
2.6
Analysis of the key secondary objective
Not applicable. 
2.7
Analysis of the secondary efficacy objectives
2.7.1
Analysis for secondary efficacy objectives
There will be three secondary efficacy endpoints (i-iii). All three endpoints will be 
summarized descriptively by visit using the FAS. No formal statistical hypotheses will be 
tested.
i.
Change in Hct levels from Baseline to each visit 
ii. Change in spleen length from Baseline to each visit
iii. Change in MPN-SAF TSS score from Baseline to each visit
In addition to change from baseline analyses, descriptive statistics by visit in terms of n, mean, 
median, SD (standard deviation), min and max will also be provided for each of the secondary 
efficacy variables. Patients with an evaluable baseline score and at least one evaluable post 


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baseline score during the treatment period will be included in the change from baseline analyses.
In addition to the secondary efficacy objectives, number of phlebotomies patients received since 
their last visit will be summarized by visit.
A listing for each secondary variable will also be provided by patient using FAS.
2.7.1.1
Handling of missing values
No imputation will be applied for missing value.
2.7.2
Patient-reported outcomes
The MPN-SAF TSS will be used to collect data on the patient’s disease-related symptoms. No 
formal statistical test will be performed. The details on the questionnaire as well as the 
derivation of raw and standardized scores are provided.
Patients with an evaluable baseline score and at least one evaluable post baseline score during 
the treatment period will be included in the change from baseline analyses. Missing data items 
in a scale will be handled based on the instrument manual. No imputation will be applied if 
the total or subscale scores are missing at a visit.
2.7.3
Biomarkers 
Not applicable
2.7.4
Resource utilization
Not applicable 
2.8
Safety evaluation
The overall observation period will be divided into mutually exclusive segments:
We have 
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication
3. If applicable, post-treatment period: starting at day 31 after last dose of study medication.
2.8.1
Adverse events
Adverse events (AE) will be coded using the MedDRA dictionary that provides the system 
organ class and preferred term information. CTCAE version 4.03 or higher will be used for
reporting AE severity. Treatment-emergent AEs starting on or after the date of first study
medication (including AEs that start within 30 days after the discontinuation of the study
medication) will be reported.
All AE will be summarized (frequency counts and percentages) by system organ class and/or
preferred term, and maximum severity grades, except where otherwise noted. A patient with 


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multiple CTC grades for an AE will be summarized under the maximum CTC grade recorded 
for the event.
The following selection of AEs will be listed and summarized separately using Safety set. All 
these AEs will be summarized for all grades and for grade 3 or 4 side-by-side.

AEs regardless of study drug related

AEs suspected to be study drug related

On-treatment deaths, by primary system organ class and preferred term

All deaths, by primary system organ class and preferred term

SAEs regardless of study drug relationship

SAEs suspected to be study drug related

AEs leading to discontinuation of study drug
AEs leading to discontinuation of study drug that are suspected to be study drug related 
AEs requiring dose adjustment or study drug interruption
AEs requiring concomitant medication or non-drug therapy. 
Adverse events which are not serious adverse events, regardless of study drug 
relationship
AEs of Specific safety event categories (SEC)
SAEs adjusted for patient-year exposure, regardless of study drug relationship
Specific safety event categories (SECs) include hematopoietic thrombocytopenia (SMQ), 
hematopoietic erythropenia (SMQ) and hematopoietic leukopenia (SMQ), hemorrhage (SMQ) 
and infections (SOC). The naming of SMQs and grouping of preferred terms into corresponding 
SMQs will be based on the MedDRA version 17.0.or higher. When discussing these SECs in 
the CSR, the clinical review will be undertaken to ensure the correct interpretation on the 
analysis results based on SMQs.
The number (%) of patients with specific safety event categories will be summarized using the 
Safety set. Exposure (patient-years)-adjusted summaries will also be generated for these 
specific safety event categories.
Deaths which occurred during the study treatment or within 30 days after discontinuation of
the study treatment will be listed and Safety set will be used. All deaths will also be listed 
using Safety set.
Note that patients will be discontinued from the study if dose is interrupted more than 8 weeks 
due to AE.
2.8.2
Laboratory values
Laboratory values will be converted to SI units and analyzed using NCI CTCAE grades
version 4.03 or later.  


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For laboratory tests where grades are not defined by CTCAE, results will be graded by the    
low/normal/high classifications based on laboratory normal ranges.
The following by-visit summaries will be generated separately for hematology:

shift tables using CTCAE grades to compare baseline to the worst on-treatment value,

for laboratory tests where CTCAE grades are not defined, shift tables using the
low/normal/high/(low and high) classification to compare baseline to the worst on
treatment value

Listing of all laboratory data with values flagged to show the corresponding CTCAE
grades and the classifications relative to the laboratory normal ranges.
Boxplots will be presented for selected hematology over time using Safety set.
Listing for serum and urine pregnancy data will also be provided by patients where available 
using Safety set. 
2.8.3
ECG analysis
Not applicable
2.8.4
Analysis of vital signs
Vital sign assessments will be performed in order to characterize basic body function. The
parameters collected are weight (kg), body temperature (°C), sitting systolic and diastolic 
blood pressure (mmHg).
Clinically notable elevated values are defined as:

Systolic BP:  160 mmHg and an increase 20 mmHg from baseline

Diastolic BP:  100 mmHg and an increase 15 mmHg from baseline

Body temperature: 39.1°C

Weight: increase from baseline of 10%
Clinically notable below normal values are defined as:

Systolic BP: 90 mmHg and a decrease 20 mmHg from baseline

Diastolic BP: 50 mmHg and a decrease 15 mmHg from baseline

Body temperature: 35°C

Weight: decrease from baseline of 10%
Vital signs shift table based on values classified as notable low, normal, notable high or 
notable (high and low) at baseline and worst post-baseline will be produced for weight, body 
temperature and sitting diastolic and systolic BP using Safety set.
Vital signs data (weight, body temperature, pulse rate, sitting systolic blood pressure and 
diastolic blood pressure) will be summarized by visit and Safety set will be used. 


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Descriptive statistics will be tabulated for baseline and change from baseline at each post-
baseline time point for each vital sign measure using Safety set.
Patients with clinically notable vital sign abnormalities will be listed using Safety set. All vital 
sign assessments will be listed by patient and vital sign parameter. In the listings, clinically 
notable values will be flagged.
2.9
CSR Section 9.7.2 – Sample size and power considerations
2.9.1 Sample size
The planned sample size of approximately 500 patients was chosen based on the expected 
accrual rates and the planned duration of the trial. It was not based on any statistical 
consideration. The actual sample size may differ from this planned number.
2.9.2 Power for analysis of key secondary variables
Not applicable


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3
Appendix 16.1.7 Randomization scheme and codes
This section of the RAP document presents a short account of the randomization procedures.


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Clinical
Development
INC424
INC424B2401
Appendix 16.1.7: Randomization scheme and
codes
Document type:
Clinical Study Report - Appendix 16.1.7
Property of 
Novartis
Confidential
May not be used, divulged, published or otherwise
disclosed without the consent of Novartis


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3.1
Randomization scheme and codes
Each patient is identified in the study by a Patient Number that is assigned when the patient is
first enrolled for screening and is retained as the primary identifier for the patient throughout
his/her entire participation in the trial. The Patient No. consists of the Center Number (Center
No., as assigned by Novartis to the investigative site) with a sequential patient number suffixed 
to it, so that each patient is numbered uniquely across the entire database. Upon signing the 
informed consent form, the patient is assigned to the next sequential Patient No.
Since this is an open label single arm study, no randomization will be needed; however, IRT
(Interactive Response Technology) will be used to assign patient numbering. The investigator 
or designated staff will contact the IRT and provide the requested identifying information for 
the patient to register them into the IRT. Once assigned, the Patient Number must not be reused 
for any other patient and the Patient Number for that individual must not be changed, even if 
the patient is re-screened. If the patient fails to be dosed, the reason will be entered into the 
Screening Log page.
3.2
Treatment assignment
Prior to dosing, all patients who fulfill all entry criteria will be assigned to treatment via IRT.
The investigator or his/her delegate will contact the IRT and confirm that the patient fulfills 
the protocol’s entry criteria.
3.3
Treatment blinding
Not applicable


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Clinical
Development
INC424
INC424B2401
Appendix 16.1.9: Documentation of statistical methods
Document type:
Clinical Study Report - Appendix 16.1.9
Property of 
Novartis
Confidential
May not be used, divulged, published or otherwise
disclosed without the consent of Novartis


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4
Appendix 16.1.9
Documentation of statistical methods
The statistical methods used to perform the analyses presented in the clinical study report
will be described in Section 9.7. Section 16.1.9 will provide further details of the
statistical methods not already provided in Section 9.7.
4.1.1
Study day
Definitions will be applied for all situations:

Study day for post-randomization event = event date – first dose date + 1

Study day for pre-randomization  event = randomization date - event date
The first day of study drug is study day 1. 
If duration is to be reported in weeks, duration in days will be divided by 7, likewise if in months, 
then duration in days will be divided by 30.4375 and if in years, duration in days will be divided 
by 365.25.
4.2
Analysis populations
The populations are detailed in Section 9.7.1 of the Clinical Study Report.
4.3
Safety evaluations
The text below gives more detailed instructions and rules needed for programming of the 
analyses described in Section 2.8.1.
4.3.1 Baseline
The last available assessment before or on the start date of study drug is defined as “baseline” 
value or “baseline” assessment. If an assessment is planned to be performed prior to the first 
dose of study drug in the protocol and the assessment is performed on the same day as the first 
administration of study drug, it will be assumed that it was performed prior to study drug 
administration, if assessment time point is not collected or is missing. If assessment time 
points are collected, the observed time point will be used to determine pre-dose on study day 
1 for baseline calculation. Unscheduled assessments will be used in the determination of 
baseline.
Patients who will start treatment and discontinue from the study on the same day may have 2 
different sets of data collected on study day 1, one being reported to day 1 visit, the other 
reported to the end of treatment (EOT) visit. Data reported at the EOT visit are not eligible for 
baseline selection.
4.3.2 Multiple assessments within post-baseline visits
For all analyses regarding abnormal assessments or analyses based on worst post-baseline 
value (vital signs, ECOG performance status), all post-baseline values will be included 
(scheduled, unscheduled, repeat). All unscheduled and repeat measurements will be included 
in listings.
4.4
Handling of missing or partial dates
For patients not known to have died prior to the cut-off date:


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
All events with start date before or on the cut-off date, and with end date missing or 
after the cut-off date will be reported as “continuing at the cut-off date”.

This approach applies, in particular, to AEs and concomitant medication reports. For 
these events, the end date will not be imputed and therefore will not appear in the listings.
For patients known to have died prior to or on the cut-off date:

All events with start date before or on the cut-off date, and with end date missing or 
after the cut-off date will have the end date imputed to the death date.

This approach applies, in particular, to AEs and concomitant medication reports. For 
these events, the imputed end date will not appear in the listings.
4.4.1 AE date imputation
Date imputation is the creation of a new, complete date from a partial one according to an 
agreed and acceptable algorithm. Missing date for AE will be handled according to rules 
specified below. A partial date is simply an incomplete date e.g. DDOCT2001: the days are 
missing from this DDMMMYYYY date.
Partial AE start dates, if left partial, would ultimately mean the following:
It would not be possible to place the AE in time. Therefore the treatment/dosage at the time of 
the event would be unknown. So the event could not be reported/summarized appropriately –
if at all.
Therefore it is important to perform date imputation to ensure that as many data events are 
represented as correctly as possible. Of course partial and/or missing dates should also be 
caught as edit checks and passed back to the investigator for resolution.
There will be no attempt to impute the following:

Missing AE start dates

AE start dates missing the year

Partial/missing AE end dates
   Table 4-2      AE/treatment date abbreviations
Day
Month
Year
Partial AE start date
<not used>
AEM
AEY
Treatment start date (TRTSTD)
<not used>
TRTM
TRTY
The following matrix Table 4-3 describes the possible combinations and their associated 
imputations. In the light grey boxes the upper text indicates the imputation and the lower text 
the relationship of the AE start date to the treatment start date (TRTSTD).
Table 4-3
AE partial date imputation algorithm
AEM Missing
AEM < TRTM
AEM = TRTM
AEM > TRTM


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AEY Missing
NC
Uncertain
(D)
NC
Uncertain
(C)
NC
Uncertain
(C)
NC
Uncertain
(C)
AEY < TRTY
Before TRTSTD
(B)
Before TRTSTD
(C)
Before TRTSTD
(B)
Before TRTSTD
(A)
AEY = TRTY
Uncertain
(E)
Before TRTSTD
(A)
Uncertain
(A)
After TRTSTD
(A)
AEY > TRTY
After TRTSTD
(E)
After TRTSTD
(A)
After TRTSTD
(B)
After TRTSTD
(A)
Table 4-4       AE/treatment date relationship and imputation legend     
Relationship
Before TRTSTD
Indicates AE start date prior to Treatment Start Date 
After TRTSTD
Indicates AE start date after Treatment Start Date
Uncertain
Insufficient to determine the relationship of AE start date to 
Treatment Start Date
Imputation Calculation
NC/Blank 
No convention/imputation
(A)
01MONYYYY
(B)
TRTSTD+1
(C)
15MONYYYY
(D)
01JULYYYY
(E)
01JANYYYY
The following Table 4-5 gives a few examples.
Table 4-5      AE imputation example scenarios
Partial AE start 
date
Treatment start 
date
Relationship
Imputation 
calculation
Imputed date
12mmyyyy
20OCT2001
Uncertain
NC
<blank>
ddmmm2000
20OCT2001
Before
(D)
01JUL2000
ddmmm2002
20OCT2001
After
(E)
01JAN2002
ddmmm2001
20OCT2001
Uncertain
(B)
21OCT2001
ddSEP2001
20OCT2001
Before
(C)
15SEP2001
ddOCT2001
20OCT2001
Uncertain
(B)
21OCT2001
ddNOV2001
20OCT2001
After
(A)
01NOV2001


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4.4.2
Incomplete date of initial diagnosis of cancer and date of most recent 
recurrence
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 
01-Jan.
4.4.3 Incomplete date for anti-neoplastic therapies
Prior therapies
Start date:
The same rule which is applied to the imputation of AE/concomitant medication start date 
will be used with the exception that for scenario (B) will be replaced to 
be ‘start date of study drug -1’.
End date:
Imputed date = min (start date of study drug, last day of the month), if day is
missing; Imputed date = min (start date of study drug, 31DEC), if month and day are
missing.
If the end date is not missing and the imputed start date is after the end date, use the
end date as the imputed start date.
If both the start date and the end date are imputed and if the imputed start date is after
the imputed end date, use the imputed end date as the imputation for the start date.
Post therapies
Start date
  Imputed date = max (last date of study drug + 1, first day of the month), if day is missing;
  Imputed date = max (last date of study drug + 1, 01JAN), if day and month are missing.
4.4.4 Incomplete date for death
All dates must be completed with day, month and year.
If the day or month is missing, death will be imputed to the maximum of the last contact date 
(excluding the date of death) and the following:

Missing day:                    15th of the month and year of death

Missing day and month:  July 1st of the year of death  
4.4.5 Incomplete dates for last dose of INC424
Scenario 1
If the last date of study drug is after the cut-off date or is completely missing and there is no 
end of treatment eCRF page and no death date the patient should be considered to be on-going 
and use the cutoff date for the analysis as the last dosing date
Scenario 2
If the last date of study drug is completely or partially missing and there is EITHER an end
of treatment eCRF page OR a death date available then imputed last dose date:


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= 31DECYYYY, if only Year is available and Year < Year of min (EOT visit date,
death date)
= Last day of the month, if both Year and Month are available and Year = Year of min
(EOT visit date, death date) and Month < the month of min (EOT visit date, death date)
= min (EOT visit date, death date), for all other cases
The imputed date will be compared with start date of study drug.
If the imputed date < start date of study drug, then last date of study drug is set to start 
date of study drug; otherwise, use the imputed date.