Conditions: Myelofibrosis With High Molecular Risk Mutations
Keywords: Early Myelofibrosis high molecular risk mutations. Ruxolitinib INC424 High molecular risk mutations HMR
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 49
Healthy volunteers: no

Brief summary:
Myelofibrosis patients with high molecular risk mutations have an intrinsically aggressive disease with increased risk of leukemic transformation and reduced overall survival. As there are no therapies currently established in the subset of high molecular risk patients with early myelofibrosis, the study aimed to evaluate ruxolitinib in this patient population.

Detailed description:

Arms:
arm 1: Two tablets of ruxolitinib 5 mg were administered orally twice per day. arm 2: Two tablets of 5mg placebo were administered orally twice per day.

Interventions: intervention 1: Ruxolitinib intervention 2: Ruxolitinib Placebo
Intervention descriptions: intervention 1: 5 mg tablet for oral use intervention 2: 5 mg placebo tablet for oral use

Protocol document:
Prot_000.pdf: 
Clinical Development
INC424/Ruxolitinib/JAKAVI
Protocol CINC424A2353 / NCT02598297
A randomized, double blind, placebo-controlled, multi-
center, Phase III study investigating the efficacy and safety 
of ruxolitinib in Early Myelofibrosis patients with high 
molecular risk mutations
Authors
 
Document type
Oncology Clinical Trial Protocol
EUDRACT number
2014-004928-21
Version number
00 (Original Protocol)
Development phase
III
Document status
Final
Release date
29-Sep-2015
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Template version 17-Nov-2014


Novartis
Confidential
Page 2
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................6
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Protocol summary:.............................................................................................................11
1
Background........................................................................................................................13
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............13
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 comparators drugs............................................................23
2.5
Risks and Benefits .................................................................................................23
3
Objectives and endpoints...................................................................................................24
4
Study design ......................................................................................................................27
4.1
Description of study design ...................................................................................27
4.2
Timing of interim analyses and design adaptations...............................................29
4.3
Definition of end of the study................................................................................29
4.4
Early study termination..........................................................................................30
5
Population..........................................................................................................................30
5.1
Patient population..................................................................................................30
5.2
Inclusion criteria ....................................................................................................30
5.3
Exclusion criteria...................................................................................................31
6
Treatment...........................................................................................................................33
6.1
Study treatment......................................................................................................33
6.1.1
Dosing regimen.....................................................................................33
6.1.2
Ancillary treatments..............................................................................34
6.1.3
Rescue medication ................................................................................34
6.1.4
Guidelines for continuation of treatment ..............................................34
6.1.5
Treatment duration................................................................................34
6.2
Dose escalation guidelines.....................................................................................34
6.3
Dose modifications................................................................................................34


Novartis
Confidential
Page 3
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
6.3.1
Dose modification and dose delay ........................................................34
6.3.2
Follow-up for toxicities.........................................................................39
6.3.3
Anticipated risks and safety concerns of the study drug.......................40
6.4
Concomitant medications ......................................................................................40
6.4.1
Permitted concomitant therapy .............................................................40
6.4.2
Permitted concomitant therapy requiring caution and/or action...........41
6.4.3
Prohibited concomitant therapy ............................................................41
6.5
Patient numbering, treatment assignment or randomization .................................41
6.5.1
Patient numbering .................................................................................41
6.5.2
Treatment assignment or randomization...............................................42
6.5.3
Treatment blinding................................................................................42
6.6
Study drug preparation and dispensation...............................................................43
6.6.1
Study drug packaging and labeling.......................................................43
6.6.2
Drug supply and storage........................................................................44
6.6.3
Study drug compliance and accountability ...........................................44
6.6.4
Disposal and destruction .......................................................................44
7
Visit schedule and assessments .........................................................................................45
7.1
Study flow and visit schedule................................................................................45
7.1.1
Molecular pre-screening........................................................................57
7.1.2
Screening...............................................................................................57
7.1.3
Run-in period ........................................................................................59
7.1.4
Treatment Period...................................................................................59
7.1.5
Discontinuation of Study Treatment .....................................................59
7.1.6
Withdrawal of Consent .........................................................................60
7.1.7
Follow up for Safety Evaluations..........................................................61
7.1.8
Lost to follow-up...................................................................................61
7.2
Assessment types...................................................................................................62
7.2.1
Efficacy assessments.............................................................................62
7.2.2
Safety and tolerability assessments.......................................................64
7.2.3
Pharmacokinetics ..................................................................................67
68
7.2.5
Patient reported outcomes.....................................................................69
8
Safety monitoring and reporting........................................................................................71
8.1
Adverse events.......................................................................................................71
8.1.1
Definitions and reporting ......................................................................71
8.1.2
Laboratory test abnormalities................................................................72


Novartis
Confidential
Page 4
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
8.2
Serious adverse events...........................................................................................73
8.2.1
Definitions.............................................................................................73
8.2.2
Reporting...............................................................................................73
8.3
Emergency unblinding of treatment assignment ...................................................74
8.4
Pregnancies............................................................................................................75
8.5
Warnings and precautions......................................................................................75
8.6
Data Monitoring Committee..................................................................................75
8.7
Steering Committee ...............................................................................................75
9
Data collection and management.......................................................................................76
9.1
Data confidentiality ...............................................................................................76
9.2
Site monitoring ......................................................................................................76
9.3
Data collection.......................................................................................................77
9.4
Database management and quality control............................................................77
10 Statistical methods and data analysis ................................................................................78
10.1
Analysis sets ..........................................................................................................78
10.1.1
Full Analysis Set ...................................................................................78
10.1.2
Safety Set ..............................................................................................78
10.1.3
Per-Protocol Set ....................................................................................78
10.1.4
Pharmacokinetic analysis set.................................................................78
10.2
Patient demographics/other baseline characteristics .............................................79
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................79
10.4
Primary objective...................................................................................................79
10.4.1
Variable.................................................................................................79
10.4.2
Statistical hypothesis, model, and method of analysis..........................80
10.4.3
Handling of missing values/censoring/discontinuations.......................80
10.4.4
Supportive analyses...............................................................................81
10.4.5
Sensitivity analyses ...............................................................................81
10.5
Secondary objectives .............................................................................................81
10.5.1
Secondary efficacy objectives...............................................................82
10.5.2
Safety objectives ...................................................................................84
10.5.3
Pharmacokinetics ..................................................................................85
86
10.5.5
Resource utilization...............................................................................87
10.5.6
Patient-reported outcomes.....................................................................87
88


Novartis
Confidential
Page 5
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
 
88
88
88
88
10.7
Interim analysis......................................................................................................89
10.8
Sample size calculation..........................................................................................90
10.9
Power for analysis of key secondary variables......................................................91
10.10 Design adaptation ..................................................................................................91
11 Ethical considerations and administrative procedures ......................................................92
11.1
Regulatory and ethical compliance........................................................................92
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................92
11.3
Informed consent procedures.................................................................................93
11.4
Discontinuation of the study..................................................................................93
11.5
Publication of study protocol and results...............................................................93
11.6
Study documentation, record keeping and retention of documents.......................93
11.7
Confidentiality of study documents and patient records .......................................94
11.8
Audits and inspections...........................................................................................94
11.9
Financial disclosures..............................................................................................94
12 Protocol adherence ............................................................................................................95
12.1
Amendments to the protocol..................................................................................95
13 References (available upon request)..................................................................................96
14 Appendices ........................................................................................................................97
Appendix 1 ........................................................................................................................97
Appendix 2 ........................................................................................................................98
Appendix 3 ........................................................................................................................99
Appendix 4 ......................................................................................................................100


Novartis
Confidential
Page 6
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
List of figures
Figure 1-1
Prognostically detrimental ‘HMR’ mutations and survival in PMF: 
Kaplan Meier Plots................................................................................15
Figure 4-1
Schematic study design.........................................................................28
List of tables
Table 3-1
Objectives and related endpoints ..........................................................25
Table 6-1
Starting Doses of INC424 based on platelet counts (Treatment 
Period 2)................................................................................................33
Table 6-2
Dose and treatment schedule.................................................................33
Table 6-3
Dose and treatment schedule.................................................................34
Table 6-4
Dose reductions and interruptions due to hematological changes –
Treatment Period 1................................................................................35
Table 6-5
Dose modifications for abnormal liver function tests...........................36
Table 6-6
Packaging and labeling .........................................................................43
Table 7-1
Visit evaluation schedule ......................................................................46
Table 7-2
Central Clinical laboratory parameters collection plan.........................65
Table 7-3
Pharmacokinetic blood collection log (Group 1)..................................68
Table 7-4
Pharmacokinetic blood collection log (Group 2)..................................68
69
Table 10-1
Simulated probabilities to stop for futility at the interim or final 
PFS-1 analysis.......................................................................................89
Table 10-2
Time to progression based on IPSS risk group .....................................91
Table 14-1
List of CYP3A4 inhibitors and inducers...............................................97
Table 14-2
European Consensus on the grading of myelofibrosis (adapted 
from literature) ......................................................................................98
Table 14-3
Eastern Cooperative Oncology Group performance status...................99


Novartis
Confidential
Page 7
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
List of abbreviations
AE
Adverse Event
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
APTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
BAT
Best available therapy
BCR-ABL
Breakpoint cluster region Abelson
BCS
Biopharmaceutical Classification System
BID
bis in diem/twice a day
BP
Blood pressure
BUN
Blood Urea Nitrogen
Clcr
Creatinine Clearance
CNS
Central Nervous System
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRP
C-Reactive Protein
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DIPSS
Dynamic International Prognostic Scoring System
DMC
Data Monitoring Committee
DS&E
Drug safety and epidemiology
EC
Ethics committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EOT
End Of Treatment
EQ-5D
EuroQol-5D-5L
ET
Essential Thrombocythemia
FA
Final Analysis
FAS
Full Analysis Set
GI
Gastrointestinal
Hb
Hemoglobin
hCG
Human chorionic gonadotropin
HDL
High Density Lipoprotein
hERG
human ether-à-go-go related gene
HIV
Human Immunodeficiency Virus
HMR
High Molecular Risk
HR
Hazard Ratio
IA
Interim Analysis
ICF
Informed Consent Form
IEC
Independent Ethics Committee 
IL
Interleukin
IN
Investigator notification


Novartis
Confidential
Page 8
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
INR
International normalized ratio
IPSS
International Prognostic Scoring System
IRB
Institutional review board
IRT
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System
IUD
Intrauterine device
IUS
Intrauterine system
IWG-MRT
International Working Group for Myelofibrosis Research and Treatment
JAK
Janus kinase
JAK-STAT
Janus Kinase-Signal Transducer & Activator of Transcription
LC-MS
Liquid chromatography-tandem mass spectrometry
LDL
Low Density Lipoprotein
LLOQ
Lower limit of quantification
LMR
Lower molecular risk
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MedDRA
Medical dictionary for regulatory activities
MF
Myelofibrosis
MF-7
Myelofibrosis 7 Item Symptom Scale 
MM
Multiple Myeloma
MPN
Myeloproliferative Neoplasm
MRI
Magnetic Resonance Imaging
NYHA
New York Heart Association
PAS
Pharmacokinetic Analysis Set
PD
Progressive disease
PET-MF
Post-essential Thrombocythemia Myelofibrosis
PFS
Progression Free Survival
PHI
Protected health information
PK
Pharmacokinetic(s)
PLT
Platelet
PMF
Primary Myelofibrosis
PML
progressive multifocal leuko-encephalopathy
PPS
Per Protocol Set
PPV-MF
Post-polycythemia vera Myelofibrosis
PRO
Patient Reported Outcome
PT
Prothrombin Time
PTT
Partial Prothrombin Time
PV
Polycythemia Vera
QALY
Quality-adjusted life years
QoL
Quality of life
RA
Rheumatoid Arthritis
RAP
Report and Analysis Plan
RBC
Red Blood Cell
RDC
Remote data capture
REB
Research Ethics Board


Novartis
Confidential
Page 9
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
RU
Resource Utilization
SAE
Serious Adverse Event
SAWP
Scientific advice working party
SC
Steering Committee
SEC
Safety Event Categories
SmPC
Summary of product characteristics
SUSAR
Suspected Unexpected Serious Adverse Reactions
TNF-α
Tumor necrosis factor alpha
TTP
Time to progression
TTPPS
Time to progressive palpable splenomegaly
TTSP
Time to symptomatic progression
ULN
Upper Limit Normal
VAS
Visual analogue scale
WBC
White Blood Cell


Novartis
Confidential
Page 10
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Glossary of terms
Assessment
A procedure used to generate data required by the study
One week
Equates to 7 calendar days
Control drug (Placebo)
A study treatment used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug.
Baseline Period / Baseline 
Data Collection
The initial period /initial collection of data, prior to randomization and 
pre-dose, that serves as the reference for all statistical analyses 
investigating (potential) changes occurred while on study treatment.
Study treatment
(ruxolitinib /Placebo)
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.
INC424
Refers to ruxolitinib
HMR+ EMF
Early myelofibrosis patients positive for high molecular risk mutations 
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
MF-7
Myelofibrosis 7 Item symptom scale 
MF-7 score
Computed as the sum of the observed scores in the individual 
symptom items to achieve a 0-to-70 score
Subject Number
A unique identifying number assigned to each patient/subject/healthy 
volunteer who participates 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 End 
of Treatment visit should occur. 
Randomization number
A unique treatment identification code assigned to each randomized 
patient, corresponding to a specific treatment arm assignment
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 
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
Treatment Period 1
Period of treatment with blinded study treatment (ruxolitinib or 
placebo)
Treatment Period 2
Period of treatment with ruxolitinib (post progression on blinded 
treatment)
Variable
Identifier used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified time points


Novartis
Confidential
Page 11
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Protocol summary:
Title
A randomized, double blind, placebo-controlled, multi-center, Phase III study 
investigating the efficacy and safety of ruxolitinib in Early Myelofibrosis patients 
with high molecular risk mutations
Brief title
Phase III study investigating the efficacy and safety of ruxolitinib in Early 
Myelofibrosis patients with high molecular risk mutations.
Sponsor and
Clinical Phase
Novartis
Phase 3
Investigation type
Drug
Study type
Interventional
Purpose and rationale
Myelofibrosis patients with high molecular risk mutations have an intrinsically 
aggressive disease with increased risk of leukemic transformation and reduced 
overall survival. As there are no therapies currently established in the subset of 
high molecular risk patients with early myelofibrosis, the study aims to evaluate 
ruxolitinib in this patient population.
Primary Objective
To evaluate the effect of ruxolitinib in delaying progression of MF from early 
disease to more advanced disease stages
Secondary Objectives
To evaluate time to disease progression of MF with or without ruxolitinib
To evaluate the changes in spleen volume with or without ruxolitinib
To assess the changes in symptoms using MF-7, EuroQol-5D-5L (EQ-5D)
To assess the safety and tolerability of ruxolitinib
To evaluate the effect of ruxolitinib on overall survival
To assess the pharmacokinetics of ruxolitinib
To evaluate the efficacy of ruxolitinib post progression
Study design
Randomized, double blinded, placebo controlled (1:1) study with treatment until 
disease progression or patient discontinuation.
Population
Patients must have a confirmed diagnosis of MF; exhibit minimally symptomatic 
early MF disease and should also be positive for the HMR mutational status
Inclusion criteria
●
Confirmed diagnosis of MF with bone marrow fibrosis of at least Grade 1; 
irrespective of JAK2 mutational status
●
Patients with at least one mutation in one of the five HMR genes (ASXL1, 
EZH2, SRSF2 and IDH1/2)
●
Patients with non-palpable spleen or spleen palpable ≤ 5 cm from the left costal 
margin to the point of greatest splenic protrusion
●
Patients with MF-7 score of ≤ 15, with each individual symptom score of ≤ 3
Exclusion criteria
●
Patients with prior treatment with ruxolitinib or other JAK inhibitors.


Novartis
Confidential
Page 12
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Investigational and 
reference therapy
Ruxolitinib or Placebo
Efficacy assessments
●
Spleen volume determination by MRI/CT
●
Laboratory assessments confirming disease progression (Hb decrease, WBC 
count and peripheral blood blast count)
●
Bone marrow biopsy and aspirate for leukemic transformation
●
Symptom assessment using MF-7, EQ-5D
Safety assessments
Physical examination, laboratory assessments, ECG
Other assessments
●
Assessment and characterization of the pharmacokinetics of ruxolitinib
 
Data analysis
An interim analysis will be performed once 45 PFS-1 events are documented. The 
primary analysis of study data will be conducted once 90 PFS-1 events are
documented.
Key words
Ruxolitinib; INC424; early myelofibrosis; High molecular risk mutations; HMR.


Novartis
Confidential
Page 13
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Myelofibrosis (MF) is a clonal hematologic neoplastic disease characterized by the presence 
of megakaryocyte proliferation and atypia, usually accompanied by either reticulin and/or 
collagen fibrosis (Tefferi 2008), splenomegaly, anemia, and debilitating constitutional 
symptoms that include fatigue, weight loss, pruritus, night sweats, fever, and bone, muscle, or 
abdominal pain (Mesa et al 2007, Abdel-Wahab, Levine 2009). MF can either be primary in 
origin (primary myelofibrosis, or PMF) or result from progression of polycythemia vera or 
essential thrombocythemia vera (Tefferi 2008). The median age at diagnosis of MF is 
approximately 65 years. Patients with myelofibrosis have shortened survival that ranges from 
a median of approximately 2 years to 11 years depending on the presence of certain risk 
factors that define their risk category including age, anemia, leukocytosis, etc.
Several prognostic risk scores that are based on survival outcomes have been developed in 
MF to better define treatment choices for physicians and therefore improve patient 
management. The International Prognostic Scoring System (IPSS) was developed by the 
International Working Group for Myeloproliferative Neoplasms Research and Treatment 
(IWG-MRT) (Cervantes et al 2009). The IPSS is used at diagnosis and employs five 
hematologic and clinical variables (age, leukocytosis, anemia, peripheral blood blasts and 
constitutional symptoms) to stratify patients in a low, intermediate-1, intermediate-2 and high-
risk category. The dynamic IPSS (DIPSS) was subsequently developed to be used for patients 
evaluated after MF diagnosis (Gangat et al 2011). The DIPSS relies upon the same five 
variables as IPSS but utilizes the predictive value of selected cytogenetic abnormalities. These 
scoring systems are expected to facilitate categorizing patients to different risk groups, and 
thus assist physicians in recommending optimal treatment management plans.
All currently available pharmacologic treatments are either directed towards the management 
of MF-originated anemia or the treatment of MF-symptoms including splenomegaly. As these 
treatments do not cure or modify the disease progression of MF, they are mostly used to treat 
patients in the higher risk categories. MF patients in the lower risk categories (IPSS Low and 
Int-1), by virtue of a relatively asymptomatic disease and an indolent disease course, are 
managed through active surveillance or a ‘watch and wait’ approach until appearance of 
bothersome symptoms or the definitive progression to the higher risk groups. Allogeneic stem 
cell transplantation is the only curative option, but it is often associated with a high rate of 
mortality and morbidity (Kroger 2008). Other available treatments include splenectomy, 
involved field radiotherapy, erythropoiesis stimulating agents, androgen preparations, 
thalidomide and its analogs, hydroxyurea. More recent advancements in MF treatment include 
the discovery of ruxolitinib, a Janus Kinase (JAK)1 and JAK2 inhibitor. Ruxolitinib is one of 
the first treatments in MF that has demonstrated rapid and durable reductions in MF- related 
splenomegaly, improvement in disease-related symptoms and offers a distinct survival benefit 
(Vannucchi et al 2015).


Novartis
Confidential
Page 14
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
The recent years have witnessed major advances in the molecular understanding of MF, first 
with the identification of JAK2 and MPL mutations (Kilpivaara, Levine 2008) and more 
recently the calreticulin (CALR) gene (Klampfl T et al 2013), all of which are associated with 
an activation of the Janus Kinase-Signal Transducer & Activator of Transcription (JAK-
STAT) pathway. In addition, as also shown in other myeloid malignancies, mutations in a 
multiplicity of other genes involved in the epigenetic and spliceosome regulatory machineries 
have been reported in MF across IPSS risk categories and shown to have a negative 
prognostic impact.
A recent study evaluated 879 PMF patients to determine the individual and combinatorial 
prognostic relevance of somatic mutations. Analysis was performed in 483 European patients 
and the seminal observations were validated in 396 Mayo Clinic patients. Samples from the 
European cohort, collected at the time of diagnosis, were analyzed for mutations in ASXL1, 
SRSF2, EZH2, TET2, DNMT3A, CBL, IDH1, IDH2, MPL and JAK2 (Vannucchi et al 2013a). 
A specific sub-group of mutations were identified (ASXL1, EZH2, SRSF2 and IDH) that may 
be predictive of PMF patients who are at risk for premature death or leukemic transformation. 
These mutations are classified as the ‘high molecular risk’ category (HMR) in PMF based on 
the presence of at least one of the five prognostically detrimental mutated genes.
[Guglielmelli et al.] further evaluated the additional prognostic value of the number of 
mutated genes. A total of 797 patients were recruited from Europe (n=537) and the Mayo 
Clinic (n=260). In the European cohort, 167 (31%) patients were categorized as HMR: 127 
(23.6%) had one and 40 (7.4%) had two or more mutated genes. The presence of two or more 
mutations predicted the worst survival: median 2.6 years (hazard ratio (HR) 3.8, 95% 
confidence interval (CI) 2.6–5.7) vs 7.0 years (HR 1.9, 95% CI 1.4–2.6) for one mutation vs 
12.3 years for no mutations (Figure 1-1, Ref – Guglielmelli et al 2014a). The presence of two 
or more mutations was also associated with shortened leukemia-free survival (HR 6.2, 95% 
CI 3.5–10.7). Overall, the recent studies demonstrate that patients with PMF harboring 
mutations in any one of the five prognostically detrimental genes (ASXL1, EZH2, SRSF2 and 
IDH1/2) constitute an IPSS/DIPSS-plus independent HMR category with shorter survival and 
greater risk of acute myeloid leukemia (AML) progression compared with the low molecular 
risk (LMR) patients. These findings therefore identify a clinically relevant subgroup of MF 
patients with HMR mutations, who despite being minimally symptomatic (including less 
severe splenomegaly) and thus categorized to harbor a lower risk disease through the IPSS or 
DIPSS scoring systems, may require earlier intervention with treatments that would prevent or 
delay their disease progression and leukemic transformation and potentially improve their 
survival. The majority of HMR positive patients with minimally symptomatic disease (Early 
MF) are currently not treated until symptoms present more aggressively. These HMR positive 
early MF (HMR+ EMF) patients are in need of therapy that can delay progression and 
therefore have an unmet medical need.
Currently, ruxolitinib is the only treatment that has shown evidence through prospective 
randomized trials to not only reduce symptom burden and splenomegaly but also confer a 
longer 
term 
survival 
advantage 
and 
delay 
time 
to 
leukemia 
transformation 
(Vannucchi et al 2015). A retrospective analysis conducted by Guglielmelli et al in the 
COMFORT II study, showed that HMR status did not affect the likelihood of obtaining a 
treatment benefit with ruxolitinib, suggesting that the clinical efficacy and survival 


Novartis
Confidential
Page 15
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
improvement observed with ruxolitinib in MF patients may occur independently of the 
underlying molecular pattern. These observations were however confined to patients in the 
higher risk categories (IPSS Int-2 and High) and therefore currently not established in the 
lower risk categories. This study will investigate the effect of JAK inhibition with ruxolitinib 
in a patient population with earlier MF disease harboring HMR mutations. It is to be noted 
that the selection of patients with HMR mutations is solely intended to identify a subset of 
patients with an intrinsically aggressive MF disease, with poor prognosis and hence an unmet 
medical need for appropriate therapeutic intervention. The HMR test in the study is not 
intended for preselecting patients who are more likely to respond to ruxolitinib or tolerate the 
treatment.
Figure 1-1
Prognostically detrimental ‘HMR’ mutations and survival in PMF: 
Kaplan Meier Plots


Novartis
Confidential
Page 16
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
a – Overall survival stratified by zero, one and two/more prognostically detrimental mutations (HMR).
b – Overall survival for IPSS low risk categories (Low and intermediate-1) stratified by number of HMR 
mutations.
c - Overall survival for IPSS high risk categories (intermediate-2 and high) stratified by number of HMR 
mutations.


Novartis
Confidential
Page 17
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
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, have been implicated as drivers of Breakpoint Cluster Region 
Abelson (BCR-ABL)-negative Myeloproliferative neoplasms (MPN), namely myelofibrosis, 
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, as well as JAK2 and 
mutated JAK2V617F, leading to inhibition of growth factor-mediated cell signaling and 
tumor cell proliferation. 
 
 
 
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 regulatory 
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 was evaluated in non-clinical investigations in pharmacology, safety 
pharmacology, repeat-dose toxicity, genotoxicity, reproductive toxicity studies and 
carcinogenicity studies. Ruxolitinib was efficacious in mouse models of Philadelphia 
chromosome negative MPNs and in additional preclinical tumor models representing both 
hematological and solid tumors expressing wild-type JAKs or a clinically relevant 
constitutively active mutant JAK2. Efficacy was also observed in rodent models of cytokine-
dependent inflammation. Effects noted in multiple-dose toxicity studies in mice, rats, and 
dogs were primarily those associated with the mechanism of action of ruxolitinib, a potent and 
reversible inhibitor of JAK/STAT signaling. In these studies, expected consequences of the 
pharmacology of JAK inhibition, were noted. In a respiratory safety pharmacology study, an 
adverse decrease in minute volume was noted in female but not in male rats at the highest 
dose, 150 mg/kg. In a cardiovascular evaluation of ruxolitinib in dogs, electrocardiogram 
(ECG) parameters were unaffected at all doses. Administration of ruxolitinib at the highest 
dose evaluated (30 mg/kg) resulted in an adverse lowering of blood pressure along with an 
increase in heart rate compared to vehicle control. The IC50 for the human ether-à-go-go 
related gene (hERG) ion channel was determined to be 131.6 µM. Ruxolitinib was not 


Novartis
Confidential
Page 18
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
mutagenic, clastogenic or teratogenic, nor did it demonstrate potential for carcinogenicity or 
in studies involving animal models and embryo-fetal assessments. Increases in post-
implantation loss were noted at the higher doses. In a pre- and post-natal development and 
maternal function study in rats there were no adverse findings for fertility indices or for 
maternal and embryo-fetal survival, growth, and developmental parameters. Ruxolitinib 
passed into the milk of lactating rats with an exposure that was 13-fold higher than maternal 
plasma exposure.
Please refer to the [Investigator Brochure] for further information.
1.2.1.2
Clinical experience
Ruxolitinib has been administered to approximately 430 healthy volunteers as single, repeat 
single, or multiple doses for up to 10 days’ duration, 32 subjects with various degrees of renal 
impairment, and 24 subjects with various degrees of hepatic impairment. Up to 22 February 
2015, ruxolitinib has been administered to approximately 8240 subjects in Novartis and Incyte 
sponsored investigational trials and 5033 subjects in third party sponsored trials (Refer to 
[Investigator Brochure] for details).
1.2.1.2.1 Clinical Pharmacology
Fifteen Phase I, nine Phase II and three Phase III clinical studies (two in MF, one in PV) 
provided clinical pharmacology data on ruxolitinib in healthy volunteers and in patients with 
MF, ET, PV, as well as in subjects with renal or hepatic impairment, prostate cancer, 
pancreatic cancer, MM or RA. Oral absorption of ruxolitinib is rapid and nearly complete, 
with ≥95% absorption indicating high in vivo permeability in the human gastrointestinal tract, 
consistent with a Biopharmaceutical Classification System (BCS) Class I compound. Mean 
peak plasma concentrations (Cmax) is achieved 1-2 h post-dose.
The effect of food on ruxolitinib exposure is minimal and is not expected to be clinically 
significant; as a result, the drug may be administered either with or without food. Dose
proportional exposure is observed between 5 and 200 mg dose range with linear 
pharmacokinetics (PK).
Plasma protein binding is approximately 97% in vitro. There is moderate distribution to 
organs and tissues with no long-term retention of drug-related material in preclinical species 
and limited drug penetration into the central nervous system (CNS) or across the blood-brain 
barrier. There is >95% [14C] drug recovery in a mass balance study with 74% and 22% of the 
dose excreted in urine and feces of healthy subjects, respectively. Less than 1% of the 
administered dose is recovered in urine and feces as unchanged parent drug. The mean 
terminal elimination half-life (t1/2) is ~3 h with no appreciable accumulation of either parent 
or metabolites with twice daily dosing. Metabolism is predominantly via the cytochrome P450 
isozyme CYP3A4 to yield oxygenated and subsequent conjugated metabolites. Oxidative 
metabolites of ruxolitinib retain pharmacological activity albeit with one half to one fifth of 
the activity of the parent compound. Ex vivo pharmacokinetic/pharmacodynamic analysis 
indicates that the total of 8 active metabolites contribute to 18% of the overall 
pharmacodynamics activity of ruxolitinib. When administering ruxolitinib with strong 
CYP3A4 inhibitors, the total daily dose should be reduced by approximately 50%. No dose 
adjustment is necessary when co-administering ruxolitinib with strong CYP3A4 inducers. No 


Novartis
Confidential
Page 19
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
dose adjustment is necessary when co-administering ruxolitinib with CYP3A4 substrates. 
Ruxolitinib did not decrease the exposure of a fixed dose oral contraceptive metabolized via 
the CYP3A4 pathway, thus demonstrating lack of CYP3A4 induction potential.
In patients with severe renal impairment [creatinine clearance (Clcr) < 30 mL/min], the 
recommended starting dose based on platelet count should be reduced by approximately 50% 
to be administered twice a day. Patients on hemodialysis should initiate ruxolitinib with a 
single dose of 15 mg or 20 mg (or two doses of 10 mg given 12 hour apart) based on platelet 
counts on day of hemodialysis with subsequent doses only on hemodialysis days and 
following each hemodialysis session. Ruxolitinib doses should be titrated based on individual 
safety and efficacy.
In patients with mild, moderate or severe hepatic impairment, the recommended starting dose 
based on platelet count should be reduced by approximately 50% with subsequent dose 
titration based on individual safety and efficacy.
Ruxolitinib PK in healthy volunteers was largely comparable between Japanese, Chinese and 
Western subjects and did not lead to a conclusion of meaningful ethnic differences.
Baseline elevations in inflammatory markers such as tumor necrosis factor alpha (TNFα), 
interleukin (IL)-6, and C-reactive protein (CRP) noted in patients with MF were associated 
with constitutional symptoms such as fatigue, pruritus, and night sweats. Decreases were 
observed in these markers over the 24 weeks of treatment with ruxolitinib, with no evidence 
that patients became refractory to the effects of ruxolitinib treatment.
Please refer to the [Investigator Brochure] for additional details on pharmacokinetics and 
pharmacodynamics.
1.2.1.2.2 Summary of Clinical Efficacy data
The results from two Phase III studies in myelofibrosis (COMFORT-I, COMFORT-II) 
demonstrate the effectiveness of ruxolitinib in patients with PMF, PPV-MF and PET-MF. The 
results of these two studies were consistent, demonstrating statistically significant (p < 
0.0001) differences in rates of ≥35% spleen volume reduction compared with either placebo 
or an investigator’s selection of best available therapy (BAT). Although each study measures 
spleen volume reduction at different time points (Weeks 24 and 48 for COMFORT-I and 
COMFORT-II, respectively), the mean reduction in spleen volume is similar at Week 24 
(31.6% vs. 29.2%, COMFORT-I and COMFORT-II, respectively).
Consistent with its activity in myelofibrosis, ruxolitinib demonstrated in the RESPONSE 
pivotal study its efficacy in polycythemia vera patients who are resistant to or intolerant of 
hydroxyurea. A significantly greater proportion of patients who were randomized to 
ruxolitinib met the primary endpoint of the study, which was a composite endpoint of 
hematocrit control in the absence of phlebotomy and spleen volume reduction ≥ 35% when 
compared to patients randomized to BAT (20.9% vs. 0.9%, p < 0.0001). Of the patients 
meeting the primary endpoint at Week 32, 94% maintained their response at Week 48.


Novartis
Confidential
Page 20
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
1.2.1.2.3 Summary of Clinical safety data
In the randomized period of the two pivotal studies in MF, COMFORT-I and COMFORT-II 
discontinuation due to adverse events, regardless of causality was observed in 11.3% of 
patients. The most frequently reported adverse drug reactions were thrombocytopenia and 
anemia. Hematological adverse reactions (any Common Terminology Criteria for Adverse 
Events [CTCAE]
Grade) included anemia (82.4%), thrombocytopenia (69.8%) and 
neutropenia (16.6 %). Anemia, thrombocytopenia and neutropenia are dose related effects. 
The three most frequent non-hematological adverse reactions were bruising (21.6%), 
dizziness (15.3%) and headache (14.0%). The three most frequent non-hematological 
laboratory abnormalities were raised alanine aminotransferase (27.2%), raised aspartate 
aminotransferase (18.6%) and hypercholesterolemia (16.9%).
Long-term follow-up in patients with MF in the phase I/II study INCB 18424-251 and the 
COMFORT studies has shown that as expected, the numbers and proportions of adverse 
events (AEs) and serious adverse events (SAEs) have increased; however, no new safety 
signals have emerged. Additionally in patients with MF, the dose optimization strategy of 
dose reduction and occasional dose interruption for thrombocytopenia was successful in 
maintaining patients on therapy with only one patient on the ruxolitinib arm of each study 
discontinuing for thrombocytopenia; platelet transfusions occurred with low frequency, 
comparable to the control arms in the Phase III studies.
Overall, the safety profile of ruxolitinib in the PV population treated with ruxolitinib is 
generally consistent with what was observed in the MF population. Ruxolitinib was generally 
well tolerated in patients with PV and only a small proportion of patients discontinued 
ruxolitinib due to AEs (3.6%). Most of the AEs have been managed by dose adjustments. 
Hematological toxicities were less frequent and less severe in patients with PV as compared to 
those observed in patients with MF.
No new safety signals emerged from a study in pancreatic cancer in combination with 
capecitabine.
The AE profile of ruxolitinib has also been assessed in 198 healthy volunteers, subjects with 
various degrees of renal (n=32) or hepatic (n=24) impairment, and in patients with RA (n=59) 
receiving ruxolitinib: AEs were, in general, mild and resolved without interventions.
A thorough QT study was conducted in 50 healthy subjects. There was no indication of a 
QT/QTc prolonging effect of ruxolitinib in single doses up to a supra-therapeutic dose of 200 
mg indicating that ruxolitinib has no effect on cardiac repolarization.
Please refer to the [Investigator Brochure] for further information.


Novartis
Confidential
Page 21
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
2
Rationale
2.1
Study rationale and purpose
Ruxolitinib is currently indicated for the treatment of disease related splenomegaly or 
symptoms in adult patients with primary myelofibrosis, post polycythemia vera myelofibrosis 
or post essential thrombocythemia myelofibrosis. This approval was based on the results of 
the COMFORT I & COMFORT II registration studies conducted in symptomatic MF patients 
and demonstrating significant improvements in MF related splenomegaly and symptoms, with 
acceptable safety and long term tolerability. Ruxolitinib was also shown to delay disease 
progression, time to leukemic transformation and prolong survival as compared to placebo 
and best available therapies (BAT) (Verstovsek – ASH 2013, Abstract 396; Cervantes, Blood 
2013).
Recent advances in genetic profiling of MF and the discovery of high molecular risk (HMR) 
mutations have distinguished a biological sub-group of patients who, independently of their 
MF symptoms at presentation, have a more aggressive course of the disease. Genetic profiling 
of MF has led to the establishment of a set of genes, namely ASXL1, EZH2, SRSF2 and 
IDH1/ IDH2, mutations in one or more of which indicate an intrinsically aggressive MF 
disease (Guglielmelli et al, Leukemia 2014). The prognostic value of these mutations was 
evaluated based on data from 797 patients (inclusive of test and validation cohorts) and 
confirmed that patients harboring mutations in any one of these ‘high molecular risk’ (HMR) 
genes have shortened OS (Hazard ratio [HR] of 2.29; 95% confidence interval [CI] 1.65–3.19)
and a higher risk of transformation to AML (HR of 2.96; 95% CI 1.85–4.76) compared with 
patients without the HMR genes. These findings are of significant clinical relevance as they 
allow the identification of a subgroup of patients with an intrinsically aggressive disease. 
Although patients without overt splenomegaly or disease related symptoms are currently not 
chosen for immediate commencement of active therapies, it is assessed, that the sub-group of 
patients with HMR status, by virtue of harboring a more aggressive disease, may be 
candidates requiring immediate therapeutic intervention.
Stem cell transplantation is the only intervention that has currently produced evidence for 
potential cure with prolongation of survival in MF. However, stem cell transplantation is 
limited by donor availabilities and is associated with considerable mortality and morbidity 
(Kroger 2008). This group of patients is therefore not currently considered as transplant 
candidate and is assessed to currently have an unmet medical need for therapies that would 
improve their clinical outcomes.
With ruxolitinib establishing its efficacy both in terms of alleviating disease symptoms, spleen 
burden and improving survival in advanced MF patients (IPSS int-2 and high risk patients), 
this study will investigate the benefits of ruxolitinib in patients with less advanced MF 
(patients with spleen ≤ 5 cm below left costal margin, hemoglobin (Hb) > 10 g/dl and 
symptoms by Myelofibrosis 7 Item symptom scale [MF-7] ≤ 15), who harbor at least one 
HMR mutation, and for whom ruxolitinib is currently not indicated for use or not actually 
used in countries with less restrictive labels.


Novartis
Confidential
Page 22
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
2.2
Rationale for the study design
The study intends to investigate the potential of ruxolitinib in delaying progression of disease 
in MF patients with no/minimal splenomegaly or symptoms and harboring HMR mutations.
The trial will consist of a double blind, placebo-controlled, randomized (1:1) study design 
with treatment administered until disease progression or premature discontinuation of patient 
(Section 6.1.5) (Figure 4-1). Given that ruxolitinib is currently indicated for the treatment of 
disease related splenomegaly or symptoms in adult patients with MF, patients who progress 
during the blinded study period due to splenomegaly or symptoms and are candidates for 
treatment with ruxolitinib (as per investigators decision) will be treated at the approved 
starting doses of 5mg, 15mg or 20 mg BID, based on platelet counts at the time of treatment 
initiation (Refer to Section 6.1).
The study will evaluate the primary endpoint of progression free survival as a primary 
efficacy measure. The study is designed in line with IWG-MRT group recommendation of 
using a ‘time to event’ endpoint in phase III studies investigating treatment options in early 
MF (Barosi 2014). The study will primarily investigate the potential of ruxolitinib in delaying 
progression of MF from the less advanced stages (Early MF) to more advanced stages. 
Assessment of disease progression will be performed utilizing criteria for clinical responses
recommended by the IWG-MRT in MPN patients (Tefferi et al 2013). This will be based on 
events including progressive splenomegaly, emergence or worsening of cytopenia, blasts in 
the peripheral blood, deterioration in the severity of disease symptoms, leukemic 
transformation and death. Additionally, the study will evaluate longer term treatment benefits 
with ruxolitinib through evaluation of 
 
 overall survival as efficacy measures. Furthermore, the study will include the 
assessment of second progression (i.e. following progression of disease into advanced MF) on 
subsequent treatment with currently approved doses of ruxolitinib. The study will include an
interim analysis for futility.
Disease progression in the blinded treatment Period 1 will be referred to as progression free 
survival-1 (PFS-1) event; while progression in the ruxolitinib treatment Period 2 will be 
referred to as progression free survival-2 (PFS-2) event.
2.3
Rationale for dose and regimen selection
The dose of ruxolitinib at 10 mg BID (twice a day) to be used in this study was selected based 
on assessment of data from COMFORT studies and the disease severity in the target 
population, alongside consultation with experts in the MF disease area.
Observations from the two pivotal COMFORT studies indicated that the incidence of 
hematological AEs were relatively lower and less severe at ruxolitinib 10 mg BID as 
compared to the higher dose of 15 mg BID. The ruxolitinib starting dose of 10 mg BID has 
also been shown to be well tolerated in patients with lower platelet counts (75,000 to 
100,000/µL) than those originally enrolled in COMFORT studies (>100,000/µL) 
(Boekhorst et al, ASH 2014). Although relatively better spleen responses were observed in 
patients with higher dose intensities, the 10 mg BID dose was able to provide improvements 
in MF related symptoms that are significant and comparable to the higher doses. In the current 
study, eligible patients are expected to have an indolent MF disease at its earliest stages with 


Novartis
Confidential
Page 23
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
minimal or no splenomegaly and symptoms. Since large reductions in spleen sizes is not the 
mainstay of the expected benefit from treatment in the study target population, 10 mg BID 
dose was assessed to adequately maintain the small spleen size and minimal symptom burden, 
alongside a relatively better tolerability profile. The 10 mg BID dose is also consistent with 
the dose used in studies investigating ruxolitinib in other less severe MPNs such as PV.
Treatment with ruxolitinib following the first progression will be at the currently approved 
doses of 5 mg, 15 mg or 20 mg BID, depending on platelet counts at treatment initiation
(Section 6.1).
2.4
Rationale for choice of comparators drugs
There is no standard therapy established in the management of patients with HMR positive 
early MF that is proven to delay their disease progression. Stem cell transplantation is the only 
intervention that is currently available for such patients but is very rarely used due to limited 
donor availabilities and the associated mortality and morbidity. As such, placebo will be used 
as the comparator of choice in the blinded period (Treatment Period 1), which will also ensure 
that there is no bias introduced in the assessment of the primary endpoint.
There will be no comparator used during Treatment Period 2.
2.5
Risks and Benefits
As the study is placebo-controlled and is conducted in a patient population that currently has 
no established treatment options, associated risks and benefits are limited to the use of 
ruxolitinib.
Dose-dependent, reversible thrombocytopenia and anemia are primary adverse effects that are 
observed with ruxolitinib. A theoretical risk of neutropenia exists, although only a few 
examples of Grade 3 or 4 neutropenia have been observed in MF patients in previous studies, 
generally in subjects who entered the study with baseline ANC levels near the lower limit of 
laboratory normal. Commonly occurring adverse events besides thrombocytopenia, anemia
and neutropenia include bruising, urinary tract infection, hypercholesterolemia or 
hypertriglyceridemia, dizziness, headache, weight gain and abnormal liver function tests. The 
above events could increase the risk of infection, including pneumonia and bronchitis, 
possibility of developing anemia, bleeding, fatigue, and/or shortness of breath. Common 
toxicities in patients (affecting between 1 and 10 in every 100 patients) with myelofibrosis 
include herpes zoster, flatulence, constipation and hypertension which may also be the cause 
of dizziness and headache. Tuberculosis has been infrequently reported in patients receiving 
ruxolitinib to treat myelofibrosis (<1/100 patients). The symptoms of tuberculosis include 
chronic cough with blood-tinged sputum, fever, night sweats, and weight loss. There may be 
risks associated with rapid discontinuation of ruxolitinib. Patients with myelofibrosis, 
particularly those who have stopped taking ruxolitinib suddenly, have reported symptoms that 
are associated with inflammation, including anxiety, insomnia or weakness, and recurrence of 
the signs and symptoms of myelofibrosis.
The effect of ruxolitinib on viral replication in patients with chronic hepatitis B virus is 
unknown. A rare disease called progressive multifocal leuko-encephalopathy (PML), has been 
reported in one patient treated with ruxolitinib. It is important to note that PML and infections 


Novartis
Confidential
Page 24
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
are complications associated with MF that has been previously described in the absence of 
ruxolitib. Additionally, non-melanoma skin cancers (NMSCs), including basal cell, squamous 
cell, and a rare and aggressive type of skin cancer called Merkel Cell Carcinoma has been 
reported in patients who took ruxolitinib, it is unknown whether this was due to ruxolitinib 
treatment.
Ruxolitinib has previously demonstrated marked reductions in disease related spleen sizes and 
symptom improvements in patients with advanced MF. Although the inclusive population in 
the current study have relatively early disease with minimal or no splenomegaly or disease 
related symptoms, it is hypothesized that ruxolitinib would delay progression of underlying 
disease and therefore benefit patients by delaying the time to acquiring these bothersome 
disease related events. It is anticipated that ruxolitinib will also be associated with reductions 
in inflammatory cytokine levels.
In summary, while early institution of treatment in the studied population and the expectant 
duration of treatment may increase the likelihood of some adverse events, the lower dose of 
ruxolitinib used in the study, the relatively better general physical status of the patients at 
study entry and the anticipated benefit of maintaining this status over prolonged periods, is 
expected to confer participating patients with an overall therapeutic advantage with acceptable 
tolerability.
Please refer to the study-specific informed consent form for further information.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


Novartis
Confidential
Page 25
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
To evaluate the effect of ruxolitinib in delaying progression 
of MF from early disease to advanced disease 
Progression free survival (PFS-1) from date of randomization until the 
occurrence of any of the criteria for disease progression (See Section 10.4.1 for 
details on criteria and required confirmation):
●
Progressive splenomegaly
●
Circulating peripheral blast counts > 10%
●
Leukemic transformation
●
Hb < 10g/dl with absolute decrease of at least 3 g/dl from baseline
●
White blood cell (WBC) counts > 25 x 103/ μL
●
MF-7 score ≥ 30
●
Death from any cause
Refer to Section 10.4.1
Secondary
Refer to Section 10.5
To evaluate time to disease progression of MF with or 
without ruxolitinib
Time to primary progression
To evaluate the changes in spleen volume with or without 
ruxolitinib
Time to first progressive splenomegaly as determined by spleen volume (by 
MRI/CT)
Change in spleen volume (by MRI/CT) from baseline
To assess the changes in symptoms using MF-7, EuroQol-
5D-5L (EQ-5D)
Time to first symptomatic progression as determined by MF-7
Quality-adjusted life years using EQ-5D
Changes in symptoms using MF-7 and EQ-5D from baseline
To assess the safety and tolerability of ruxolitinib
Monitoring the frequency, duration, and severity of adverse events including 
abnormalities in vital signs, laboratory parameters and ECG data
To evaluate the effect of ruxolitinib on overall survival
Overall survival 
To assess the pharmacokinetics (PK) of ruxolitinib
Plasma ruxolitinib concentrations. Characterize PK by utilizing a Population PK 
approach
To evaluate the efficacy of ruxolitinib post PFS-1
Progression free survival (PFS-2) assessed by 25% increase over new baseline 
of PFS-1 in any of the following (See Section 10.5.1 for details):
●
Progressive splenomegaly
●
25 % increase in MF-7 score with absolute score ≥ 30


Novartis
Confidential
Page 26
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Objective
Endpoint
Analysis


Novartis
Confidential
Page 27
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
4
Study design
4.1
Description of study design
This is a double blind, randomized placebo-controlled study of ruxolitinib in patients with 
HMR positive early MF (HMR+ EMF). The study consists of a screening period, Treatment 
Period 1 and Treatment Period 2.
Screening:
Patients will be pre-screened for the determination of HMR mutation status after obtaining the 
molecular pre-screening informed consent. Only patients who are centrally confirmed to be 
HMR+ will be eligible to enter the screening phase. Patients should be consented to the main 
study informed consent as soon as HMR positivity is confirmed (recommended within 28 
days). Patients will be randomized in a 1:1 ratio to ruxolitinib or placebo on Day 1 following 
confirmation of eligibility, including confirmed bone marrow fibrosis grading during the 40 
day screening period.
Treatment Period 1
Blinded study treatment will begin on Day 1 following randomization. Visits will be every 4 
weeks up to Week 24 to monitor tolerability and efficacy with the study treatment. After 
Week 24, visits will be every 8 weeks until Week 48, and then every 12 weeks thereafter. 
Blinded study treatment
will be administered until disease progression or patient 
discontinuation. A 30-day safety follow up visit will be done after the last dose of blinded 
study drug (except if entering Treatment Period 2). Patients who discontinue for reasons other 
than disease progression will enter the post treatment follow up. Patients will be followed for 
survival after end of Treatment Period 1 or post-treatment follow up every 3 months until the 
termination of study by the sponsor.
Treatment Period 2
Patients who progress due to splenomegaly or symptoms and are candidates for treatment 
with currently approved doses of ruxolitinib (as per investigators decision) will be treated 
with ruxolitinib at 5mg, 15mg or 20 mg BID, based on platelet counts at the time of treatment 
initiation (Section 6.1). These patients will continue on the same schedule of assessments as in 
‘Treatment Period 1’ (Table 7-1). A 30-day safety follow up visit will be performed after the 
last dose of study drug. Patients will be followed for survival after end of Treatment Period 2
every 
3 
months 
until 
the 
termination 
of 
study 
by 
the 
sponsor 
(Figure 4-1).


Novartis
Confidential
Page 28
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Figure 4-1
Schematic study design
A) Screening
Pre-Screening:
Molecular  Informed Consent obtained
Blood sample for: HMR mutation status/Genetic mutations in 
pathogenesis of MF
Screening: (Day -40 to -1)
Inclusion/Exclusion
Screening procedures
Patient 
eligible
HMR+
Randomization: Day 1
Screening


Novartis
Confidential
Page 29
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
B) Treatment Period
4.2
Timing of interim analyses and design adaptations
The study will have one interim analysis (IA) and one final analysis (FA). The intent of the 
interim analysis is to stop for futility. It is planned once at least 45 PFS-1 events are
documented.
4.3
Definition of end of the study
The End of Study will occur after approximately 1 year after the 90th PFS-1 event on blinded 
study treatment has been confirmed & the primary analysis reported (estimated study duration
5.5 - 6 years). Following the primary analysis, if the primary objective is met and a need for 
longer term follow up of patients is assessed, the study may continue for an extended period 
of up to 5 years from LPFV. Patients will be discontinued at the end of study including any 
follow up for post treatment assessments and survival.
At the end of the study, every effort will be made to continue provision of study treatment 
outside this study through an alternative setting to patients who in the opinion of the 
Investigator are still deriving clinical benefit.


Novartis
Confidential
Page 30
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis or by a regulatory 
authority based on the occurrence of any of the following.

New side effects unknown in respect to their nature, severity, and duration or the
unexpected incidence of known side effects

Medical or ethical reasons that affect the continued performance of the study

Further development of the study drug has been permanently discontinued due to safety
reasons

Data from interim analyses demonstrating futility (Refer to Section 4.2)

Other reasons that are not known at this time
Should this be necessary, the patient should be seen as soon as possible and the same 
assessments should be performed as described in Section 7.1.5 for a discontinued or
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 institutional review boards (IRB)
and/or ethics committees (EC) of the early termination of the trial.
5
Population
5.1
Patient population
Patient population will include approximately 320 male or female adults (age 18 or over) with 
a confirmed diagnosis of MF. Patients must exhibit minimally symptomatic early MF disease 
and must also be positive for the HMR mutational status. Patients will be pre-screened after 
obtaining a molecular screening consent for HMR status. The determination of HMR status 
will be performed at a Novartis accredited central laboratory with a targeted next generation 
sequencing assay. Those subjects harboring one or more mutations in the following genes; 
ASXL1, EZH2, SRSF2 and IDH1/ IDH2 will be determined HMR positive. Only patients with 
a centrally confirmed HMR positive mutational status should sign the main informed consent 
form and enter the main screening period (Section 7).
The investigator or designee must ensure that only patients who meet all of the following 
inclusion and none of the exclusion criteria at screening are randomized to receive treatment 
in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria at 
screening:
Written informed consent must be obtained prior to any screening procedures.
1. Male or Female aged 18 or over.
2. Confirmed diagnosis of MF with bone marrow fibrosis of at least Grade 1 (Appendix 2); 
irrespective of JAK2 mutational status.


Novartis
Confidential
Page 31
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
3. Patients with at least one mutation in one of the five HMR genes (ASXL1, EZH2, SRSF2 
and IDH1/2).
4. Patients with non-palpable spleen or spleen palpable ≤ 5 cm from the left costal margin to 
the point of greatest splenic protrusion.
5. Patients with MF-7 score of ≤ 15, with each individual symptom score of ≤ 3.
6. Patients with a peripheral blood blast count percentage of < 1%.
7. Patients with Hemoglobin > 10g/dL.
8. Patients with platelet counts ≥ 75,000/µL.
9. Patients with Absolute neutrophil count (ANC) ≥ 1000/μL.
10. Patients with WBC ≤ 15 x 103/ μL.
11. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 
or 2.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria at screening:
1. Patients with prior treatment with ruxolitinib or other JAK inhibitors.
2. Patients with known hypersensitivity to ruxolitinib or any of its excipients.
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. Patients with severely impaired renal function defined by:
Serum creatinine > 2 mg/dL.
5. Patients with active bacterial, fungal, parasitic, or viral infection which requires therapy.
6. 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).
7. Known history of human immunodeficiency virus (HIV) infection or other 
immunodeficiency syndromes such as X-linked agammaglobulinemia and common 
variable immune deficiency.
8. Active hepatitis A, B or C infection, which requires treatment.
9. History of progressive multifocal leuko-encephalopathy (PML).
10. 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)


Novartis
Confidential
Page 32
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
11. Significant concurrent, uncontrolled medical condition, which in the investigator’s opinion 
would jeopardize the safety of the patient or compliance with the protocol.
12. Patients being treated concurrently with a strong (potent) systemic inhibitor or inducer of 
CYP3A4 (Appendix 1) at the time of Screening.
13. Patients under ongoing 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 treatment.
14. Patients with a history of malignancy in the past 3 years, except for well-controlled early 
stage squamous or basal cell carcinoma in situ.
15. Patients eligible for stem cell transplantation.
16. Pregnant or nursing (lactating) women.
17. 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 
screening. 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.

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 use of oral 
contraception women should have been stable on the same pill 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), total 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.
18. Subjects who are unable to comprehend or are unwilling to sign an informed consent form 
(ICF).


Novartis
Confidential
Page 33
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
6
Treatment
6.1
Study treatment
Treatment Period1:
The study treatment will consist of INC424 (ruxolitinib) or matching placebo administered in 
a blinded manner following randomization of the patient on study Day 1.
Treatment Period 2:
INC424 (ruxolitinib) administered as per Table 6-1.
Table 6-1
Starting Doses of INC424 based on platelet counts (Treatment Period
2)
INC424
Platelet count (x 109/L)
5 mg BID
50 – <100
15 mg BID
100 – 200
20 mg BID
>200
6.1.1
Dosing regimen
Table 6-2
Dose and treatment schedule
Treatment Period 1 (INC424/Placebo - Blinded)
Study treatments
Pharmaceutical form and 
route of administration
Dose
Frequency and/or 
Regimen
INC424/ Placebo
Tablet for oral use
10 mg BID
(2 tablets of INC424 
5mg/placebo BID)
Daily
Study treatment will be administered orally twice per day at a dose of 10 mg BID, given as 2 
tablets of INC424 5mg / placebo (Table 6-2). Study treatment should be taken orally twice 
daily, approximately 12 hours apart (morning and night) without regards to food. Study 
treatment will be self-administered by the patient in an outpatient setting, and each 
investigator should instruct the patient to take the study drug as per protocol. All dosages 
taken by the patient must be recorded on the Dosage Administration Record case report form 
(CRF).
Patients should be instructed not to take study treatment at Week 12, Week 24 and Week 48 
visit (and every 12 weeks thereafter) on the day of the scheduled pre-dose blood collection 
(Section 7). Dosing will be administered post blood collection at these visits.


Novartis
Confidential
Page 34
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Treatment Period 2 (INC424)
Once the patient progresses in Treatment Period 1 by splenomegaly or symptoms, the patient 
will start treatment with INC424 (ruxolitinib) 5/15/20 mg BID based on platelet count as per 
approved label (Table 6-1 and Table 6-3).
Table 6-3
Dose and treatment schedule
Treatment Period 2 (INC424)
Study treatments
Pharmaceutical form and 
route of administration
Dose
Frequency and/or 
Regimen
INC424
Tablet for oral use
5/15/20 mg BID
Daily
6.1.2
Ancillary treatments
Not applicable.
6.1.3
Rescue medication
Not applicable.
6.1.4
Guidelines for continuation of treatment
Refer to Section 6.3 on dose modifications and follow up for toxicities for guidelines for 
continuation of treatment.
6.1.5
Treatment duration
Patient may continue treatment with the study drug until patient experiences unacceptable 
toxicity, disease progression and/or treatment is discontinued at the discretion of the 
investigator or patient.
6.2
Dose escalation guidelines
Not applicable.
6.3
Dose modifications
6.3.1
Dose modification and dose delay
6.3.1.1
Dose modification for hematologic toxicity
Treatment Period 1
Dose reductions or interruptions for hematological changes are permitted in order to allow the 
patient to continue on the study treatment. The maximum allowed doses for different ranges 
of cytopenia is described in Table 6-4. The objective of the dose adjustment rules is to 
optimize treatment response for each individual patient while avoiding significant cytopenia. 
Dosing may be restarted or increased following recovery of the hematologic parameter(s) to 
acceptable levels. Any patient requiring dose interruption continuously for more than 4 weeks 


Novartis
Confidential
Page 35
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
due to decreases in ANC or platelet (PLT) counts must be permanently discontinued from 
treatment. Hb levels decreasing below 8g/dL with an absolute drop of 3g/dL from baseline, 
will constitute a marker of progressive MF disease, if Hb levels fail to recover ≥ 8g/dL 
following treatment interruption for two consecutive weeks. Such patients must permanently 
discontinue study treatment.
Table 6-4
Dose reductions and interruptions due to hematological changes –
Treatment Period 1
Current Hb (g/dL)
Maximum allowable dose
< 8
Interrupt dosing (HOLD)
8 to < 10
Reduce total daily dose to 5 mg BID
Current PLT (x 109/L)
< 50
Interrupt dosing (HOLD)
50 to < 75
Reduce total daily dose to 5 mg BID
Current ANC (x 109/L)
< 0.5
Interrupt dosing (HOLD)
0.5 to < 0.75
Reduce total daily dose to 5 mg BID
All dose changes must be recorded on the Dosage Administration Record CRF.
Patients whose dose has been interrupted for more than 4 weeks for any reason are 
recommended to be permanently discontinued from study treatment.
Treatment Period 2
Dose reductions and interruptions for ruxolitinib treatment during ‘Treatment Period 2’ can be 
performed in accordance with the local label requirements. In countries where ruxolitinib is 
not currently approved, treatment should be discontinued for platelet counts less than 50 x 
109/L or absolute neutrophil counts less than 0.5 x 109/L. After recovery of blood counts 
above these levels, dosing may be re-started at 5 mg twice daily and gradually increased based 
on careful monitoring of complete blood cell count, including a white blood cell count 
differential.
6.3.1.2
Dose modification for non-hematological toxicity (Treatment Period 1 
and 2)
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 it 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. Specific recommendations 
that are to be followed in the event of abnormal liver function tests are provided in Table 6-5.


Novartis
Confidential
Page 36
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Table 6-5
Dose modifications for abnormal liver function tests
Isolated Elevation of Total Bilirubin
> ULN – 1.5 x ULN
Maintain dose level
>1.5x baseline AND > 1.5 - 3.0 x ULN 
Omit dose with weekly monitoring of LFTsa, or more frequently if clinically indicated, until resolved to ≤ 1.5 
x ULN or baseline levels
- If resolved in ≤ 14 days, then maintain dose level
- If resolved in > 14 days, then ↓ 1 dose leveld
> 3.0 - 10.0 x ULN 
Omit dose with weekly monitoring of LFTsa, or more frequently if clinically indicated, until resolved to ≤ 1.5 
x ULN or baseline levels
- If resolved in ≤ 14 days, then ↓ 1 dose leveld
- If resolved > 14 days, discontinue patient from study drug treatment. The patient should be monitored 
weekly (including LFTsa), or more frequently if clinically indicated, until total bilirubin have resolved to 
baseline levels or have remained stable over 4 weeks.
> 10.0 x ULN
Discontinue patient from study drug treatment. The patient should be monitored weekly (including LFTsa), 
or more frequently if clinically indicated, until total bilirubin have resolved to baseline levels or have 
remained stable over 4 weeks.


Novartis
Confidential
Page 37
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Isolated AST or ALT elevation
> ULN - 3.0 x ULN
Maintain dose level
> 3.0 - 5.0 x ULN
Maintain dose level. Repeat LFTsa as soon as possible, preferably within 48-72 hours from awareness of 
the abnormal results; if abnormal lab values are confirmed upon the repeat test, then monitor LFTsa
weekly, or more frequently if clinically indicated, until resolved to ≤ 3.0 x ULN
> 5.0 - 10.0 x ULN
●
For patients with baseline value ≤ 3.0 x ULN
●
For patients with baseline value > 3.0 -5.0 x ULN
Omit dose. Repeat LFTsb as soon as possible, preferably within 48-72 hours from awareness of the 
abnormal results; monitor LFTsb weekly, or more frequently if clinically indicated, until resolved to ≤ 3.0 x 
ULN Then
- If resolved in ≤ 14 days, maintain dose level
- If resolved in > 14 days, ↓ 1 dose level
Maintain dose level. Repeat LFTsb as soon as possible, preferably within 48-72 hours from awareness of 
the abnormal results; if abnormal lab values are confirmed upon the repeat test, then monitor LFTsb, 
weekly, or more frequently if clinically indicated, until resolved to ≤ 5.0 x ULN
> 10.0 - 20.0 x ULN 
Omit dose. Repeat LFTsb as soon as possible, preferably within 48-72 hours from awareness of the 
abnormal results; monitor LFTsb weekly, or more frequently if clinically indicated, until resolved to ≤ 
baseline. Then↓1 dose level.
> 20.0 x ULN
Discontinue patient from study drug treatment
AND
Repeat LFTsa as soon as possible, preferably within 48-72 hours from awareness of the abnormal results; 
monitor LFTsa weekly, or more frequently if clinically indicated, until resolved to baseline levels or have 
remained stable over 4 weeks.


Novartis
Confidential
Page 38
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Combinedb elevations of AST or ALT and total bilirubin
For patients with normal baseline ALT or AST or total 
bilirubin value:
AST or ALT >3.0xULN combined with total bilirubin >2.0 x 
ULN without evidence of cholestasisc
OR
[AST or ALT>2x baseline AND > 3.0 xULN] OR [AST or 
ALT > 8.0 xULN], whichever is lower, combined with [total 
bilirubin >2x baseline AND >2.0 xULN without evidence of 
cholestasisc
Permanently discontinue patient from study drug treatment;
AND
Repeat LFTsa as soon as possible, preferably within 48 hours from awareness of the abnormal results,
then with weekly monitoring of LFTsa), or more frequently if clinically indicated, until AST, ALT, or bilirubin
have resolved to baseline or have remained stable over 4 weeks. Refer to Section 6.3.2.1 for additional 
follow-up evaluations as applicable.
a. Core LFTs consist of ALT, AST, GGT, total bilirubin (fractionated [direct and indirect], if total bilirubin > 2.0 x ULN), and alkaline phosphatase (fractionated 
[quantification of isoforms], if alkaline phosphatase > 2.0 x ULN.)
b. “Combined” defined as: total bilirubin increase to the defined threshold concurrently with ALT/AST increase to the defined threshold
If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the instructions for isolated elevation of total bilirubin and 
isolated elevation of AST/ALT, and take a conservative action based on the degree of the elevations (e.g. discontinue treatment at the situation when omit dose is needed 
for one parameter and discontinue treatment is required for another parameter). After all elevations resolve to the defined thresholds that allow treatment re-initiation, re-
start the treatment either at the same dose or at one dose lower if meeting a criterion for dose reduction
c. “Cholestasis” defined as: ALP elevation (>2xULN and R value <2 ) in patients without bone metastasis, or elevation of ALP liver fraction in patients with bone 
metastasis
Note : The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for both values. It denotes the relative pattern of ALT and/or ALP elevation is 
due to cholestatic or hepatocellular liver injury
d. Total daily dose 10 mg (5 mg BID) lower than the previous dose


Novartis
Confidential
Page 39
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
6.3.1.3
Optional dose tapering strategy in the event of study treatment 
discontinuation
Following interruption or discontinuation of ruxolitinib, symptoms of myelofibrosis may 
return over a period of approximately one week. There have been cases of patients 
discontinuing ruxolitinib who sustained more severe events, particularly in the presence of 
acute intercurrent illness. It has not been established whether abrupt discontinuation of 
ruxolitinib contributed to these events. Unless abrupt discontinuation is required, gradual 
tapering of the study treatment dose may be considered, although the utility of the tapering is 
unproven.
6.3.2
Follow-up for toxicities
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or clinically significant laboratory value, must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts such as ophthalmologist, endocrinologist, 
dermatologist, psychiatrists etc. should be consulted as deemed necessary. All patients must 
be followed up for adverse events and serious adverse events for 30 days following the last 
dose of study treatment.
6.3.2.1
Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events.
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT or AST or TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], whichever is lower, 
combined with [TBIL > 2 x baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as: ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or 
elevation of ALP liver fraction in patients with bone metastasis.
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes the relative pattern of ALT and/or ALP elevation is due to 
cholestatic or hepatocellular liver injury)
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from 
the awareness of the abnormal results. The evaluation should include laboratory tests, detailed 


Novartis
Confidential
Page 40
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.

Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase.

A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.

Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g., biliary 
tract) may be warranted.

Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is 
performed in the study.

Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the 
term “potential drug-induced liver injury”. All events should be followed up with the outcome 
clearly documented.
6.3.3
Anticipated risks and safety concerns of the study drug
Appropriate eligibility criteria as well as specific dose modification and stopping rules are 
included in this protocol. Refer to preclinical toxicity and/or clinical data found in the 
[Investigator’s Brochure].
6.4
Concomitant medications
All concomitant medications and treatments must be recorded on the appropriate eCRF. Any 
prior medication received up to 30 days prior to the first dose of study drug will be recorded 
in the CRF. Any prior anti-neoplastic medications used to treat hematological disease will 
also 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
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy, herbal/natural medications and blood 
transfusions) administered during the study must be listed on the Concomitant Medications or 
the Procedures and Significant Non-Drug Therapies CRF.


Novartis
Confidential
Page 41
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
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 study treatment is administered during the study:

Systemic corticosteroid doses greater than the equivalent of 10 mg prednisolone per day 
are prohibited at any time during the study until treatment discontinuation.

Inducers or inhibitors of the metabolizing enzyme CYP3A4 (Appendix 1):

When concomitant administration of a strong (potent) systemic inhibitor of CYP3A4 
metabolizing enzymes or dual CYP2C9/CYP3A4 inhibitors 
(see Appendix 1) 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.
Note: No dose adjustment of study treatment 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 CYP3A4 inducers 
(See Appendix 1) are co-administered with study treatment.

Granulocyte growth factors are not allowed while study treatment is being administered 
but may be used for severe neutropenia at the Investigator’s discretion while study 
medication is being withheld.
6.4.3
Prohibited concomitant therapy
The following therapies are prohibited at any time during the study until treatment 
discontinuation:

Concomitant use of another JAK inhibitor.

Any investigational medication (other than study treatment) 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 treatment and until treatment discontinuation is prohibited.

Any use of known drugs treating the investigated underlying disease is not permitted at 
any time during the study until treatment discontinuation.

Use of strong (potent) systemic CYP3A4 inducers is prohibited (See Appendix 1).

Aspirin in doses exceeding 150 mg per day is prohibited unless medically indicated.

Stem cell transplantation is prohibited.
6.5
Patient numbering, treatment assignment or randomization
6.5.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned 
when the patient is first enrolled for molecular pre-screening and is retained as the primary 
identifier for the patient throughout his/her entire participation in the trial. The Subject No. 


Novartis
Confidential
Page 42
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
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 subject is numbered uniquely 
across the entire database. Upon signing the informed consent form, the patient is assigned to 
the next sequential Subject No. available to the investigator through the Oracle Clinical RDC 
interface.
At molecular pre-screening, the patient will be assigned a subject number (as assigned by 
Novartis to the investigative site). Once the subject enters the screening phase, 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 Subject No. must 
not be reused for any other subject and the Subject No. for that individual must not be 
changed, even if the patient is re-screened. If the patient fails to be randomized the reason will 
be entered into the Screening Disposition page and indicated in the Interactive Response 
Technology (IRT) system.
6.5.2
Treatment assignment or randomization
Treatment Period 1
Patients will be assigned to one of the “2” treatment arms (Section 4.1 and Section 6.1) in a 
ratio of 1:1 (ruxolitinib or placebo).
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers.
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms. The investigator or his/her delegate will log on to the IRT 
and confirm that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign a 
randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the first package of study treatment to be 
dispensed to the patient. The randomization number will not be communicated to the caller.
Treatment Period 2
Patients entering Treatment Period 2 will be assigned to receive ruxolitinib by the IRT. Sites 
must enter all required information including dosage (5/15/20 mg) in the IRT to ensure 
ruxolitinib medication assignment.
6.5.3
Treatment blinding
This is a double-blind study in Treatment Period 1. Patients, investigator, site personnel, and 
data analysts will remain blinded to the identity of the treatment administered in Treatment 
Period 1 from the time of randomization until database lock. There will be no unblinding of 
Treatment Period 1 even as patients enter Treatment Period 2. Randomization data are kept 
strictly confidential until the time of unblinding, and will not be accessible by anyone else 


Novartis
Confidential
Page 43
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
involved in the study. This information will not be accessible with the following exceptions: 
bio analyst and pharmacokineticist to avoid the unnecessary analysis of placebo samples, 
independent biostatistician who will perform the interim analysis. The identity of the 
treatments will be concealed by the use of study treatments that are all identical in packaging, 
labeling, schedule of administration, appearance.
Unblinding will only occur in the case of patient emergencies (Section 8.3), at the time of the 
interim analysis (see Section 10.7), by designated personnel for a data monitoring committee 
(DMC) (Section 8.6), for regulatory reporting purposes and at the conclusion of the study.
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.
6.6.1
Study drug packaging and labeling
Treatment Period 1
The study medication packaging has a 2-part label. A unique medication number is printed on 
each part of this label. Responsible site personnel will identify the study treatment package(s) 
to dispense to the patient by using the IRT and obtaining the medication number(s). Site 
personnel will add the patient number on the label. Immediately before dispensing the 
package to the patient, site personnel will detach the outer part of the label from the packaging 
and affix it to the source document (Drug Label Form) for that patient’s unique patient 
number.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the drug and the medication number
but no information about the patient.
Treatment Period 2
The study medication will have the same labeling and dispensing procedure as described for 
Treatment Period 1. The medication will be assigned appropriately by the IRT and dispensed 
to the patient.
Table 6-6
Packaging and labeling
Study treatments
Packaging
Labeling (and dosing frequency)
INC424 or placebo
Tablets in HDPE bottles
INC424/placebo (BID)


Novartis
Confidential
Page 44
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
6.6.2
Drug supply and storage
Study 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 only 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.
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 
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.


Novartis
Confidential
Page 45
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists 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.
No CRF will be used as a source document.
(S) is defined as ‘source’ and (D) as ‘data based’.
Assessments noted as (D) in the category column will remain in the clinical database, except 
the following which will be part of the central database – 1) Eligibility checklist in IRT and 2) 
contact IRT system.


Novartis
Confidential
Page 46
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Table 7-1
Visit evaluation schedule
A) Treatment Period 1 (Blinded)
Visit Name
Category
Protocol Section
Molecular Pre-screening
Screening 
Treatment Period 1 (Blinded)
End of treatment (EOT)
Progressive disease (PD) confirmation
Safety Follow up 30 days after last 
dose
Post treatment follow up (See Section 
7.1.7)
Survival Follow up (Every 3 months)
Day 1
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 32
Week 36 (MRI / CT)
Week 40
Week 48+ (every 12 weeks until 
EOT)
Day
-40 to -1
1
28
56
84
112
140
168
224
252
280
336+
Visit window 
(Study day)
+/-3
+/-3
+/-3
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
+/-7
Obtain Molecular
pre-screening ICF
D
7.1.1
x
Blood collection 
(Genetic mutations 
impacting 
pathogenesis of MF 
including HMR)
D
7.2.4
x
x
x 
(every 
24 
weeks)
x
Obtain Informed 
Consent
D
7.1.2
x 
(centrally 
confirmed 
HMR+ 
status)


Novartis
Confidential
Page 47
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Visit Name
Category
Protocol Section
Molecular Pre-screening
Screening 
Treatment Period 1 (Blinded)
End of treatment (EOT)
Progressive disease (PD) confirmation
Safety Follow up 30 days after last 
dose
Post treatment follow up (See Section 
7.1.7)
Survival Follow up (Every 3 months)
Day 1
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 32
Week 36 (MRI / CT)
Week 40
Week 48+ (every 12 weeks until 
EOT)
Day
-40 to -1
1
28
56
84
112
140
168
224
252
280
336+
Visit window 
(Study day)
+/-3
+/-3
+/-3
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
+/-7
Inclusion/Exclusion
D
5
x
Eligibility checklist 
in IRT
D
7.1.2.1
x
Patient history
7.1.2
Demography
D
x
Medical History 
D
x
Disease diagnosis
D
x
Prior Anti-neoplastic 
therapy medication 
(Hematologic 
disease)
D
x
Prior/concomitant 
medications
D
x
x (at every visit)


Novartis
Confidential
Page 48
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Visit Name
Category
Protocol Section
Molecular Pre-screening
Screening 
Treatment Period 1 (Blinded)
End of treatment (EOT)
Progressive disease (PD) confirmation
Safety Follow up 30 days after last 
dose
Post treatment follow up (See Section 
7.1.7)
Survival Follow up (Every 3 months)
Day 1
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 32
Week 36 (MRI / CT)
Week 40
Week 48+ (every 12 weeks until 
EOT)
Day
-40 to -1
1
28
56
84
112
140
168
224
252
280
336+
Visit window 
(Study day)
+/-3
+/-3
+/-3
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
+/-7
Physical 
examination
S
7.2.2.1
x
x
x
x
x
x
x
x
x
x
x
x
Performance status
D
7.2.2.4
x
x
x
x
x
x
x
x
x
x
x
x
Height 
D
7.2.2.3
x
Weight
D
7.2.2.3
x
x
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
x
x
Spleen 
measurement 
(length)
D
7.2.2.1
x
x
x
x
x
x
x
x
x
x
x
x
Laboratory 
assessments
7.2.2.5
Hematology
D
7.2.2.5.1
x
x
x
x
x
x
x
x
x
x
x
x
x (Refer 
to PD 
guidance)
x
Chemistry
D
7.2.2.5.2
x
x
x
x
x
x
x
x
x
x
x
x


Novartis
Confidential
Page 49
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Visit Name
Category
Protocol Section
Molecular Pre-screening
Screening 
Treatment Period 1 (Blinded)
End of treatment (EOT)
Progressive disease (PD) confirmation
Safety Follow up 30 days after last 
dose
Post treatment follow up (See Section 
7.1.7)
Survival Follow up (Every 3 months)
Day 1
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 32
Week 36 (MRI / CT)
Week 40
Week 48+ (every 12 weeks until 
EOT)
Day
-40 to -1
1
28
56
84
112
140
168
224
252
280
336+
Visit window 
(Study day)
+/-3
+/-3
+/-3
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
+/-7
Coagulation
D
7.2.2.5.4
x
x (To be performed as clinically indicated)
x
Urinalysis
D
7.2.2.5.3
x
x
Pregnancy test
D
7.2.2.5.5
x
x
x
x
x
x
x
x
x
x
x
x
Hepatitis test
D
7.2.2.5
x
Imaging
7.2.1
ECG
D
7.2.2.6.1
x
x (Every 48 weeks)
x
MRI/CT
D
7.2.1
x (-7 to -
1)
x
x
x
x
x
x
Safety
7.2.2
Adverse events
D
x
x (at every visit)


Novartis
Confidential
Page 50
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Visit Name
Category
Protocol Section
Molecular Pre-screening
Screening 
Treatment Period 1 (Blinded)
End of treatment (EOT)
Progressive disease (PD) confirmation
Safety Follow up 30 days after last 
dose
Post treatment follow up (See Section 
7.1.7)
Survival Follow up (Every 3 months)
Day 1
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 32
Week 36 (MRI / CT)
Week 40
Week 48+ (every 12 weeks until 
EOT)
Day
-40 to -1
1
28
56
84
112
140
168
224
252
280
336+
Visit window 
(Study day)
+/-3
+/-3
+/-3
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
+/-7
Bone Marrow 
biopsy and aspirate
D
7.2.1
x
x (every 2 years)
x
x


Novartis
Confidential
Page 51
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Visit Name
Category
Protocol Section
Molecular Pre-screening
Screening 
Treatment Period 1 (Blinded)
End of treatment (EOT)
Progressive disease (PD) confirmation
Safety Follow up 30 days after last 
dose
Post treatment follow up (See Section 
7.1.7)
Survival Follow up (Every 3 months)
Day 1
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 32
Week 36 (MRI / CT)
Week 40
Week 48+ (every 12 weeks until 
EOT)
Day
-40 to -1
1
28
56
84
112
140
168
224
252
280
336+
Visit window 
(Study day)
+/-3
+/-3
+/-3
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
+/-7
Patient reported 
Outcomes (PRO)
7.2.5
MF-7
D
x
x
x
x
x
x
x
x
x
x
x
x
x (Refer 
to PD 
guidance)
x
x
EQ-5D
D
x
x
x
x
x
x
x
x
x
x
x
x
x
Study Drug 
administration
D
6.1
x
x
x
x
x
x
x
x
x
x
PK sampling
7.2.3
x
x
Contact IRT system
D
x
x (at every dispensing visit)
x
x
Survival
D
7.1.7
x


Novartis
Confidential
Page 52
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Visit Name
Category
Protocol Section
Molecular Pre-screening
Screening 
Treatment Period 1 (Blinded)
End of treatment (EOT)
Progressive disease (PD) confirmation
Safety Follow up 30 days after last 
dose
Post treatment follow up (See Section 
7.1.7)
Survival Follow up (Every 3 months)
Day 1
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 32
Week 36 (MRI / CT)
Week 40
Week 48+ (every 12 weeks until 
EOT)
Day
-40 to -1
1
28
56
84
112
140
168
224
252
280
336+
Visit window 
(Study day)
+/-3
+/-3
+/-3
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
+/-7
Leukemic 
transformation
D
7.1.7
x
Anti-neoplastic 
therapy after 
discontinuation of 
study treatment
D
7.1.7
x
x
x


Novartis
Confidential
Page 53
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
B) Treatment Period 2 (Ruxolitinib) for patients progressing due to splenomegaly or symptoms (MF-7 score)
Visit Name
Category
Protocol Section
Treatment Period 2 (Ruxolitinib)
End of treatment (EOT)
Progressive disease (PD) confirmation
Safety Follow up 30 days after last dose
Survival Follow up (Every 3 months) 
First dose – Ruxolitinib
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 32
Week 36 (MRI / CT)
Week 40
Week 48+ (every 12 weeks until EOT)
Day
28
56
84
112
140
168
224
252
280
336+
Visit window (Study day)
+/-3
+/-3
+/-3
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
+/-7
Prior/concomitant medications
D
x (at every visit)
Physical examination
S
7.2.2.1
x
x
x
x
x
x
x
x
x
x
Performance status
D
7.2.2.4
x
x
x
x
x
x
x
x
x
x
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 measurement (length)
D
7.2.2.1
x
x
x
x
x
x
x
x
x
x


Novartis
Confidential
Page 54
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Visit Name
Category
Protocol Section
Treatment Period 2 (Ruxolitinib)
End of treatment (EOT)
Progressive disease (PD) confirmation
Safety Follow up 30 days after last dose
Survival Follow up (Every 3 months) 
First dose – Ruxolitinib
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 32
Week 36 (MRI / CT)
Week 40
Week 48+ (every 12 weeks until EOT)
Day
28
56
84
112
140
168
224
252
280
336+
Visit window (Study day)
+/-3
+/-3
+/-3
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
+/-7
Laboratory assessments
7.2.2.5
Hematology
D
7.2.2.5.1
x
x
x
x
x
x
x
x
x
x
Chemistry
D
7.2.2.5.2
x
x
x
x
x
x
x
x
x
x
Coagulation
D
7.2.2.5.4
(To be performed as clinically indicated)
x
Urinalysis
D
7.2.2.5.3
x
Pregnancy test
D
7.2.2.5.5
x
x
x
x
x
x
x
x
x
x
Imaging
7.2.1
ECG
D
7.2.2.6.1
x (Every 48 weeks)
x
MRI/CT
D
7.2.1
x
x
x
x
x
Safety
7.2.2
Adverse events
D
x (at every visit)


Novartis
Confidential
Page 55
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Visit Name
Category
Protocol Section
Treatment Period 2 (Ruxolitinib)
End of treatment (EOT)
Progressive disease (PD) confirmation
Safety Follow up 30 days after last dose
Survival Follow up (Every 3 months) 
First dose – Ruxolitinib
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 32
Week 36 (MRI / CT)
Week 40
Week 48+ (every 12 weeks until EOT)
Day
28
56
84
112
140
168
224
252
280
336+
Visit window (Study day)
+/-3
+/-3
+/-3
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
+/-7
Bone Marrow biopsy and 
aspirate
D
7.2.1
x (every 2 years)
x
Patient reported Outcomes 
(PRO)
7.2.5
MF-7
D
x
x
x
x
x
x
x
x
x
x
x (Refer 
to PD 
guidance)
x
EQ-5D
D
x
x
x
x
x
x
x
x
x
x
x
Study Drug administration
D
6.1
x
x
x
x
x
x
x
x
x
x
Contact IRT system
D
x (at every dispensing visit)
x
x


Novartis
Confidential
Page 56
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Visit Name
Category
Protocol Section
Treatment Period 2 (Ruxolitinib)
End of treatment (EOT)
Progressive disease (PD) confirmation
Safety Follow up 30 days after last dose
Survival Follow up (Every 3 months) 
First dose – Ruxolitinib
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 32
Week 36 (MRI / CT)
Week 40
Week 48+ (every 12 weeks until EOT)
Day
28
56
84
112
140
168
224
252
280
336+
Visit window (Study day)
+/-3
+/-3
+/-3
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
+/-7
Survival
D
7.1.7
x
Leukemic transformation
D
7.1.7
x
Anti-neoplastic therapy after 
discontinuation
D
7.1.7
x
x


Novartis
Confidential
Page 57
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
7.1.1
Molecular pre-screening
Molecular pre-screening will be done for all patients after the molecular informed consent 
form is obtained. Subject will sign the molecular pre-screening informed consent form and 
will have blood sample tested for genetic mutations impacting pathogenesis of MF including 
HMR by a Novartis accredited central laboratory. Only subjects who show the presence of 
any of the HMR mutations will be eligible to enter screening and sign the main informed 
consent form. Molecular pre-screening is mandatory for all patients to enter into the screening 
phase.
7.1.2
Screening
Patients will be consented to the main study informed consent after obtaining a central 
confirmation of HMR positivity. There will be a 40 day screening period (Day -40 to –Day -
1). Screening procedures are outlined in the visit evaluation schedule (Table 7-1 [A]).
Upon completion of all routine screening procedures and all other eligibility criteria including 
patient history, laboratory assessments, and symptom score assessments should be performed.
A bone marrow biopsy should be performed, unless adequate archival tissue is available for 
the patient from a procedure performed within the last 6 months prior to randomization. 
Biopsy specimen and marrow aspirate must be sent to a Novartis designated laboratory for 
central analysis. Upon receipt of the bone marrow biopsy grade confirming patient eligibility, 
the investigator must perform the MRI (or CT for applicable patients) scan and send to the 
central imaging laboratory for assessment the same day as the scan. MRI/CT should be 
performed within 7 days prior to randomization.
A patient who has a laboratory test result(s) that does not satisfy the entrance criteria may 
have the test(s) repeated. These tests may be repeated as soon as the investigator believes the 
retest result is likely to be within the acceptable range to satisfy the entrance criteria, but 
should be completed within 40 days of the original screening visit date. In this case, the 
subject will not be required to sign another ICF, and the original patient ID number assigned 
by the investigator will be used. In the event that the laboratory test(s) cannot be performed 
within 40 days of the original screening visit, or the retest(s) do not meet the entrance criteria 
or the patient’s medical condition has change significantly during the screening phase so that 
the inclusion/exclusion criteria are no longer met, the patient is considered a screen failure.
A new ICF will need to be signed if the investigator chooses to re-screen the patient after a 
patient has screen failed. The subject number will remain unchanged and patient will be 
entered in the IRT as re-screen. All required screening activities must be performed when the 
patient is rescreened for participation in the study. An individual patient may only be 
rescreened once for the study.


Novartis
Confidential
Page 58
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
7.1.2.1
Eligibility screening
Patients must meet all inclusion and exclusion criteria at screening in order to be eligible to 
proceed to the Treatment Period of the study.
Investigative staff will capture patient eligibility within source documents maintained at the 
site. Additionally the sites will enter patient information into the eCRF. Eligibility information 
in source documents will be made available during planned interim monitoring visits and 
compared against the clinical database for accuracy. The site will also be asked to confirm 
eligibility with the IRT system. Following registering in IRT for screening, patient eligibility
data will be verified once all screening procedures are completed. The eligibility check will be 
embedded in the IRT system. Please refer and comply with detailed guidelines in the IRT 
manual. Only when eligibility data has been confirmed with the IRT system will the IRT 
assign study treatment.
7.1.2.2
Information to be collected on screening failures
Subject who signed an Informed Consent Form but failed to be randomized for any reason 
will be considered a screen failure. Both subjects who signed a molecular pre-screening ICF 
but are considered ineligible after molecular pre-screening, as well as subjects who are found 
not eligible after signing the main study consent will be considered as screening failures, and 
data will be handled in the same manner.
The reason for not being started on treatment for molecular pre-screening failure or screening 
failure 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 subjects. Additionally, data for genetic mutations affecting MF 
pathogenesis including HMR will be available. No other data will be entered into the clinical 
database for subjects who are screen failures, unless the subject experienced a Serious 
Adverse Event during the Screening Phase (see Section 8 for SAE reporting details). For 
molecular pre-screening failures, only SAEs possibly related to a study procedure will be 
reported.
If the patient in the screening phase fails to be randomized, the IRT should be notified.
7.1.2.3
Patient demographics and other baseline characteristics
Patients will have the following assessments performed at screening:

Review of medical history, prior anti-neoplastic therapy related to hematologic disease, 
prior concomitant medications and adverse events

Disease diagnosis confirmed by a Novartis designated laboratory (Section 7.1.2) using a 
bone marrow biopsy and aspirate

Physical examination including height, weight, performance status, vital signs and 
measurement of spleen length by palpation (Section 7.2.2)

Laboratory assessments – Hematology, serum chemistry, coagulation, urinalysis, 
pregnancy test (if applicable) and hepatitis test (Section 7.2.2)

Patient reported outcomes – MF-7, EQ-5D and 
 questionnaires


Novartis
Confidential
Page 59
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353

Electrocardiogram (ECG)

MRI/CT of the spleen to determine spleen volume by central imaging laboratory
The investigator must confirm all the inclusion and exclusion criteria prior to contacting IRT 
for randomization of the patient. Once the patient’s eligibility is confirmed, the patient must 
have baseline assessments performed on Day 1 prior to randomization and treatment initiation 
(Table 7-1).
7.1.3
Run-in period
Not applicable.
7.1.4
Treatment Period
Treatment Period 1
Blinded study treatment will be initiated on Day 1 after randomization and treatment 
assignment by IRT system. Day 1 is defined as the first day of study treatment. After day 1, 
visits will occur at the following frequency as specified in Table 7-1.

Every 4 weeks until week 24 (+/- 3 days)

Every 8 weeks until week 48 (+/- 7 days)
Note: Week 36 visit is required only for MRI/CT of the spleen.

Every 12 weeks until the end of treatment (+/- 7 days)
Blinded treatment will be administered until disease progression or patient discontinuation.
Treatment Period 2
Patients progressing due to splenomegaly or symptom (MF-7 score) in Treatment Period 1 
will enter the ruxolitinib Treatment Period 2. All patients are required to have an End of 
Treatment Period 1 assessment prior to entering Treatment Period 2. All End of Treatment 
Period 1 assessments should be performed within 2 weeks prior to the first dose of ruxolitinib 
in Treatment Period 2. The End of treatment bone marrow biopsy and MRI/CT assessments 
should follow the schedule as per Section 7.2.1.1. The schedule of assessments for patients 
entering Treatment Period 2 will continue from when the patient discontinued in Treatment 
Period 1 (Table 7-1 [B]).
7.1.5
Discontinuation of Study Treatment
Patients may voluntarily discontinue from the study treatment for any reason at any time. If
a patient decides to discontinue from the study treatment, the investigator should make a 
reasonable effort (e.g. telephone, e-mail, letter) to understand the primary reason for this
decision and record this information in the patient’s chart and on the appropriate CRF pages.
They may be considered withdrawn if they state an intention to withdraw, fail to return for
visits, or become lost to follow-up for any other reason.
The investigator should discontinue study treatment for a given patient if, he/she believes that
continuation would be detrimental to the patient’s well-being.
Study treatment must be discontinued under the following circumstances:


Novartis
Confidential
Page 60
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353

Disease progression in Treatment Period 1 (except if entering Treatment Period 2) (Refer 
to Section 10.4.1)

Disease Progression in Treatment Period 2 (Refer to Section 10.5.1)

Dose modifications to study treatment leading to discontinuation (Section 6.3)

Protocol deviations that results in a significant risk to the patient’s safety

Pregnancy

New therapy for study indication
The appropriate personnel from the site and Novartis will assess whether study treatment
should be discontinued for any patient whose treatment code has been broken inadvertently for 
any reason. Refer to Section 8.3 on emergency unblinding.
Patients who discontinue study treatment should NOT be considered withdrawn from the
study. They should return for assessments as specified at the end of treatment visit in 
Table 7-1. The patients will then undergo safety follow up visit and then enter the follow-up 
period (Section 7.1.7). If they fail to return for these assessments for unknown reasons, every
effort (e.g. telephone, email, letter) should be made to contact them as specified in Section 
7.1.8. The investigator must also contact the IRT to register the patient’s discontinuation from 
study treatment.
Patients who permanently discontinue study treatment in Treatment Period 1 due to reasons 
other than progressive disease must continue to return for post-treatment follow up 
assessments as described in Section 7.1.7 until progressive disease is evident or a new therapy 
for MF is commenced. Upon progressive disease or starting a new therapy the patients will be 
followed for survival (Section 7.1.7).
7.1.5.1
Replacement policy
Patients who discontinue prematurely will not be replaced on this study. Enrollment of new 
patients will be considered if the PFS event rate is not met based on statistical assumptions.
7.1.6
Withdrawal of Consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not want any 
further study related contact.
Novartis will continue to retain and use all research results that have already been collected 
for the study evaluation. All biological samples that have already been collected may be 
retained and analyzed at a later date (or as required by local regulations).
If a patient withdraws consent, the investigator should make a reasonable effort (e.g.
telephone, e-mail, letter) to understand the primary reason for this decision and record this 
information.
Study treatment must be discontinued and no further assessments conducted.
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up.


Novartis
Confidential
Page 61
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
7.1.7
Follow up for Safety Evaluations
All patients must have a follow-up visit for safety evaluations 30 days following the last dose 
of study drug based on discontinuation from Treatment Period 1 or 2. At this visit adverse 
events and anti-neoplastic therapies after treatment discontinuation will be reviewed and 
patient reported outcomes will be collected. Refer to Table 7-1 for a complete list of 
assessments at the 30 day safety follow up visit.
7.1.7.1
Survival Follow up
Patients who discontinue study treatment due to disease progression (as outlined below) will 
be followed for survival every 3 months:

Disease progression in Treatment Period 1 (except if entering Treatment Period 2)

Disease progression in Treatment Period 2
Patients will be contacted by the site for information on survival, leukemic transformation and 
anti-neoplastic therapy after treatment discontinuation (Table 7-1). Data collected should be 
entered in the appropriate CRF.
7.1.7.2
Post Treatment Follow Up Assessments
Patients who permanently discontinue study treatment in Treatment Period 1 due to reasons 
other than progressive disease must continue to return for hematological laboratory 
assessments, spleen volume assessments via MRI/CT and MF-7 assessments. Data for new 
MF therapy after treatment discontinuation will also be collected. The assessments in the post-
treatment follow up phase should follow the same visit schedule as described in
Table 7-1 until progressive disease is evident or a new anti-neoplastic therapy is commenced. 
Upon progressive disease or starting a new therapy the patients will enter the survival follow 
up period.
7.1.8
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF.


Novartis
Confidential
Page 62
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
7.2
Assessment types
7.2.1
Efficacy assessments
7.2.1.1
Assessments for primary efficacy endpoint (progression free survival
– PFS-1)
The criteria for disease progression (PFS-1) will be assessed for determination of the primary 
endpoint of progression free survival in accordance with Section 10.4.1. For patients meeting 
the progressive disease criteria the Investigator must review according to the guidance below,
and confirm the relevant criterion. The data should be entered in the appropriate CRF and IRT 
notified.
Guidance for progressive disease criterion assessment:

Earliest confirmed single disease progression criterion should be entered.

If more than one criterion are confirmed on the same date, time or visit (+ 14 days from 
the date of first confirmed criterion); progressive disease should be assessed using the
single criterion based on the hierarchy below:
1. Death
2. Leukemic transformation
3. Splenomegaly
4. Symptom (MF-7 score)
5. Hematologic criteria. Note: In the case of more than one hematologic criteria, the 
investigator should assess the key contributing criterion to declare disease progression
The following assessments will be utilized to assess and confirm disease progression.
1. Spleen volume determination by MRI/CT:
Evaluation of progressive splenomegaly will be performed by regular assessments of spleen 
volumes via Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) where MRI 
is contraindicated to ensure an objective and unbiased assessment. MRI (or CT) of the spleen 
will be performed at screening (within 7 days prior to randomization), every 12 weeks and at 
the end of treatment (Table 7-1). An end of treatment MRI (or CT) assessment is only
required for patients who discontinue treatment due to disease progression if a MRI (or CT) 
scan was not performed within 6 weeks of study treatment discontinuation. Patients who enter 
the post treatment follow up phase after study treatment discontinuation for reasons other than 
disease progression should have their assessments performed as per the visit schedule at the 
time of discontinuation.
A designated central imaging laboratory will be used to collect all imaging data; perform 
quality check and provide read-out for the study. The scans from an individual patient will be 
read by a central reader upon transfer from the site radiologist. Results from the central 
evaluations will be used for primary analyses.
MRI is the preferred method for obtaining spleen volume data. However, CT scans may be 
performed at the visits where MRI would be conducted if the patient is not a candidate for 
MRI (because of the presence of metal clips in the body, or because of claustrophobia, for 


Novartis
Confidential
Page 63
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
example), or if MRI is unavailable to the study site. CT scans will be similarly processed by a 
Central Laboratory. Procedure specific training for scanning and image capture will be 
provided by the vendor. NOTE: Generally, the same method (MRI or CT) should be used for 
all visits for a given patient unless a new contraindication to the use of MRI (e.g., pacemaker 
insertion) occurs. Please contact the sponsor if a modality change is required.
2. Laboratory assessments confirming disease progression (Hb decrease, WBC count and 
peripheral blood blast count):
Assessments involving specific laboratory parameters should be confirmed in accordance with 
Section 10.4.1 if they meet criteria for progressive disease. Description of laboratory 
assessments is outlined in Section 7.2.2.5.
3. Bone marrow biopsy and aspirate for leukemic transformation and 
:
Bone marrow fibrosis will be measured in grades (see Appendix 2) from samples obtained for 
patients at screening, every 2 years and at the end of treatment. An end of treatment biopsy 
and aspirate is not required if a biopsy from a previous assessment is within 6 months of study 
treatment discontinuation.
A paraffin embedded core bone marrow biopsy block (1/2 of the core biopsy sample) and 3 
unstained bone marrow aspirate slides are required to be sent to a Novartis designated central 
lab for central analysis for all patients. If per local SOP the paraffin embedded core bone 
marrow biopsy block sample cannot be sent to the central lab, six unstained slides of the bone 
marrow biopsy block may be sent. Please refer to the vendor manual for additional 
instructions.
A centrally confirmed grading of bone marrow fibrosis is required for patient eligibility 
(Section 7.1.2). The central lab will notify the site of results at the time of screening and when
results meet the protocol definition of progressive disease criteria for leukemic transformation
(Section 10.4.1). Results from the central evaluations will be used for primary 
 
analyses.
4. Symptom assessment using MF-7:
MF-7 symptom score assessment will be used to determine the primary endpoint in 
accordance with Section 10.4.1. Details regarding the use of patient reported outcomes and 
specific time points are outlined in Section 7.2.5.
7.2.1.2
Assessments for secondary efficacy endpoints
Assessments for secondary endpoints will be done in accordance with Section 10.5.1.
1. Time to primary progression, time to first progressive splenomegaly and time to first 
symptomatic progression:
Refer to Section 10.5.1 for details on time to progression for specific parameters.
2. Changes in spleen volume by MRI/CT:
Refer to Section 7.2.1.1 for detailed description of assessments.
3. Changes in symptoms using MF-7, EQ-5D, Quality adjusted life years:
Assessments for patient reported outcomes as detailed in Section 7.2.5 will be used to 
determine the secondary endpoints.


Novartis
Confidential
Page 64
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
4. Overall survival:
Survival follow up will be done as per Table 7-1 for all patients after study treatment 
discontinuation. Detailed description is outlined in Section 7.1.7.
5. Progression free survival -2 (PFS-2)
The criteria for disease progression (PFS-2) will be assessed in accordance with 
Section 10.5.1. For patients meeting the progressive disease criteria the Investigator must 
review according to the guidance below, confirm the relevant criterion and enter data in the 
appropriate e CRF and notify IRT.
Guidance for progressive disease criterion assessment:
If more than one criterion are confirmed on the same date, time or visit (+ 14 days from the 
date of first confirmed criterion); progressive disease should be assessed using the single 
criterion based on the hierarchy below:
1. Splenomegaly
2. Symptom (MF-7 score)
The following assessments will be utilized to assess and confirm disease progression.
a. Spleen volume determination by MRI/CT:
Refer to Section 7.2.1.1 for detailed description of assessments.
b. Symptom assessment using MF-7:
MF-7 symptom score assessment will be used to determine the secondary endpoint in 
accordance with Section 10.5.1. Details regarding the use of patient reported outcomes 
and specific time points are outlined in Section 7.2.5.
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing physical examination, laboratory assessments, ECG, 
PROs as well as collecting of the adverse events at every visit. For details on AE collection 
and reporting, refer to Section 8.
7.2.2.1
Physical examination
A physical exam as per local standard of care will be performed at screening and all scheduled 
study visits up to the end of treatment (Table 7-1). It will include the examination of general 
appearance and vital signs (blood pressure [BP], respiratory rate, temperature and pulse).
Spleen size will be assessed by palpation and measured in centimeters using a soft ruler, from 
the coastal margin to the point of greatest splenic protrusion.
 
Significant findings that were present prior to the signing of informed consent and any 
ongoing conditions must be included in the Medical History page on the patient’s CRF. 
Significant new findings that begin or worsen after informed consent must be recorded on the 
Adverse Event page of the patient’s CRF.


Novartis
Confidential
Page 65
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
7.2.2.2
Vital signs
Vital signs (blood pressure, pulse, body temperature, and respiratory rate) will be collected as 
outlined in the Visit Schedule in Table 7-1. Vital signs will be taken with the patient in the 
sitting position after 5 minutes of rest. Body temperature may be measured orally or via ear.
7.2.2.3
Height and weight
Height in centimeters (cm) will be measured only at screening. Body weight in kilograms (to 
the nearest 0.1 kilogram (kg) in indoor clothing, but without shoes) will be measured 
according to Table 7-1. The CRFs include the following units e.g., height in cm or in and 
weight in kg or lb. and therefore, data may be collected in the units they are measured in.
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 (Appendix 3)
7.2.2.5
Laboratory evaluations
Table 7-2
Central Clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Mean corpuscular hemoglobin (MCH), Mean corpuscular hemoglobin 
concentration (MCHC), Mean corpuscular volume (MCV), Platelets, Red blood cells (RBC), 
White blood cells with Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils), Absolute neutrophil count [with bands]
Chemistry
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Calcium, Creatinine, Total 
Bilirubin*, Blood Urea Nitrogen (BUN) or Urea
Additionally, specified parameters are required at the following visits:
At screening only - Direct Bilirubin, Indirect Bilirubin
At screening, every 24 weeks and EOT - Total Cholesterol, Low density lipoprotein (LDL), High 
density lipoprotein (HDL), Total Protein, Triglycerides
Urinalysis
Macroscopic Panel** (Color, Bilirubin, Blood, Glucose, pH, Protein, Specific Gravity)
Coagulation
Prothrombin time (PT) or International normalized ratio (INR), Activated partial thromboplastin 
time (APTT)
Pregnancy test
At screening and EOT – Serum pregnancy test
All other time points – Urine pregnancy test
Hepatitis test
Screening only - Hepatitis A virus antibody; Hepatitis B surface antigen, Hepatitis
B surface antigen antibody, Hepatitis B core antibody, Hepatitis
C virus antibody
*Direct and indirect bilirubin tests may be performed centrally at any visit if clinically indicated.
**Any clinically significant findings will be followed with a microscopic evaluation centrally.
A central laboratory will be used for analysis of all specimens collected. Details on the collections, shipment of 
samples and reporting of results by the central laboratory are provided to investigators in the [Laboratory Manual].
7.2.2.5.1 Hematology
Hematocrit, hemoglobin, MCH, MCHC, MCV, platelet count, RBC count, WBC count with 
differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils) and Absolute 
neutrophil count [with bands] will be measured at screening, all scheduled visits during 
treatment and end of treatment as noted in Table 7-1.


Novartis
Confidential
Page 66
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
7.2.2.5.2 Clinical chemistry
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Calcium, Creatinine, Total 
Bilirubin and BUN or Urea will be measured at screening, all scheduled visits during 
treatment and end of treatment as noted in Table 7-1. Direct and indirect bilirubin will be 
measured only at screening. These tests may however be performed centrally at any visit if 
clinically indicated. Total Cholesterol, LDL, HDL, Total Protein and Triglycerides will be 
measured at screening, every 24 weeks and end of treatment.
7.2.2.5.3 Urinalysis
Urinalysis will be performed using macroscopic evaluation of color, bilirubin, blood, glucose, 
pH, protein, specific gravity. Any significant findings on the macroscopic panel will be 
followed up with a microscopic evaluation.
7.2.2.5.4 Coagulation
PT, INR, and aPTT will be measured at screening, all scheduled study visits during treatment 
and end of treatment.
7.2.2.5.5 Pregnancy and assessments of fertility
All pre-menopausal female patients, who are not surgically sterile must undergo a serum 
pregnancy test at screening to confirm eligibility in the trial, and at end of treatment. The 
patient will have urine pregnancy tests performed at all other scheduled visits as noted in 
Table 7-1.
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.
If local requirements mandate more frequent pregnancy testing, applicable sites must adhere 
to these requirements even if scheduled visits are less frequent. For women of child bearing 
potential, home pregnancy test kits should be provided by the site for the duration of study. 
The outcome of the home urinary test should be available at the site as part of the source 
documentation. The site must instruct the patient to contact the investigator immediately in 
case of a positive test.
7.2.2.6
Cardiac assessments
7.2.2.6.1 Electrocardiogram (ECG)
A standard 12 lead ECG will be performed at screening, every 48 weeks and at the end of 
treatment.
Interpretation of the tracing must be made by a qualified physician and documented on the 
ECG CRF page. Each ECG tracing should be labeled with the study number, patient initials 
(where regulations permit), patient number, date, and kept in the source documents at the 
study site. Clinically significant abnormalities present when the patient signed informed 
consent should be reported on the Medical History CRF page. Clinically significant findings 
must be discussed with Novartis prior to enrolling the patient in the study. New or worsened 


Novartis
Confidential
Page 67
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
clinically significant findings occurring after informed consent must be recorded on the 
Adverse Events CRF page.
7.2.3
Pharmacokinetics
Pharmacokinetic assessment is required only in Treatment Period 1 (Refer to Table 7-1 [A]). 
To explore PK characteristics of HMR positive Early MF patients, a subset of at least 80 (40 
ruxolitinib) patients are required to have a sampling scheme as described in Table 7-3. All 
early enrolling patients (referred to as ‘Group 1’ with an estimate of first 100 patients) must 
have one pre-dose on Week 12 (Day 84) and Week 24 (Day 168) and three (3) post dose PK 
samples collected on Week 24 (Day 168) for ruxolitinib concentration determination (Refer to 
Table 7-3). Once this requirement is fulfilled all sites will be notified. Subsequent patients
(referred to as ‘Group 2’) will have a total of two (2) pre-dose samples on Week 12 (Day 84) 
and Week 24 (Day 168) per Table 7-4.
Whole blood per sampling time as outlined in Table 7-3 and Table 7-4 will be obtained by 
either direct venipuncture or via an indwelling cannula from a peripheral vein into a tube 
containing di-potassium ethylenediaminetetraacetic acid
(EDTA). Immediately after 
collection the tube should be inverted several times to prevent clotting. Blood samples should 
be kept in an ice water bath at approximately 4°C until centrifugation. The tubes should be 
centrifuged within 30 minutes of collection at approximately 2000 x g at 4°C for 15 minutes 
to yield plasma. The plasma should be decanted and transferred into a polypropylene screw-
cap tube, the tube capped, and then immediately placed in a freezer at ≤ -60°C until shipment 
to sponsor and/or designated central laboratory. Refer to the [Laboratory Manual] for detailed 
instructions for the collection, handling, and shipment of PK samples.
All sampling is relative to the ingestion of ruxolitinib. 
 
The exact collection date and 
time of all samples must be documented on the PK blood collection CRF pages. The date and 
exact time of dosing, as well as the date and actual time of blood sampling must be recorded 
on the CRF.


Novartis
Confidential
Page 68
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Table 7-3
Pharmacokinetic blood collection log (Group 1)
Week
Day
Profile 
Day
Scheduled time-point
Dose reference 
ID
PK 
Sample 
No
Sample 
volume 
[mL]
Early enrolling
subjects
12
84
1
Pre-morning dose
1
101a
1
4
24
168
1
Pre-morning dose
2
201a
2
4
24
168
1
Post dose 0.5 h ± 15 min
2
-
3
4
24
168
1
Post dose 2.0 h ± 1h 
2
-
4
4
24
168
1
Post dose 4-12 h 
(suggested 5 h ± 1 h)
2
-
5
4
Unscheduled Sample
---
---
1001+ 
series
(4)
Total Sample Volume
20 mL
For the PK trough samples the actual date and time of administration of the previous dose of study medication 
should also be recorded with appropriate Dose reference IDs as indicated in the above table
a The first Dose reference ID is for current dose, while the second Dose reference ID is for the last dose the 
subject received prior to the collection of the PK sample.
Table 7-4
Pharmacokinetic blood collection log (Group 2)
Week
Day
Profile 
Day
Scheduled time-point
Dose reference 
ID
PK 
Sample 
No
Sample 
volume 
[mL]
In all subjects
12
84
1
Pre-morning dose
1
101a
1
4
24
168
1
Pre-morning dose
2
201a
2
4
Unscheduled Sample
---
---
1001+ 
series
(4)
Total Sample Volume
8 mL
For the PK trough samples the actual date and time of administration of the previous dose of study medication 
should also be recorded with appropriate Dose reference IDs as indicated in the above table.
a The first Dose reference ID is for current dose, while the second Dose reference ID is for the last dose the 
subject received prior to the collection of the PK sample.
7.2.3.1
Analytical method
The plasma samples from patients will be assayed for ruxolitinib concentrations using 
validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS). Values 
below the lower limit of quantification (LLOQ) of INC424 at approximately 0.50 ng/mL will 
be reported at 0.0 ng/mL. Missing values will be labeled accordingly.


Novartis
Confidential
Page 69
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
7.2.5
Patient reported outcomes
Patients with MF often experience significant symptoms that interfere with their quality of life 
(QoL) including, fatigue, early satiety, pruritus, weight loss, weakness and night sweats. The 
effect of ruxolitinib on patient symptoms and QoL will be measured using several assessment 
tools including the MF-7, the EQ-5D-5L 
 
 All questionnaires are patient-reported outcomes (PROs). The PRO questionnaires 


Novartis
Confidential
Page 70
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
provided electronically (ePRO) are to be completed by the patient. The site will review for 
completeness.
Instructions for all PROs will be provided as separate documents. Patients must complete the 
questionnaire(s) before other clinical assessments at any given visit. The PRO questionnaires 
should be completed in the same order at each visit to ensure that the patient is answering 
them as consistently as possible. The questionnaires should be given in the following order:
1. MF-7
2. EQ-5D-5L
Patient Reported Outcomes will be collected according to the Visit Schedule outlined in Table 
7-1. The patient should be given sufficient space and time to complete the PRO 
questionnaires. The site personnel should check the questionnaires for completeness and ask 
the patient to complete any missing responses. The original questionnaire will be kept with 
the patient’s file as the source document.
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.
MF-7
The Myelofibrosis 7 Item Symptom Scale (MF-7) (Appendix 4) is a disease specific 
questionnaire comprised of 7 items that measures the severity of seven of the most prevalent 
associated symptoms including: tiredness, early satiety, abdominal discomfort, night sweats, 
itching (pruritus), bone pain (diffuse not joint or arthritis) and pain under ribs on left side. 
Each item is scored on a scale ranging from 0 (absent) to 10 (worst imaginable). The MF-7
score is computed as the sum of the observed scores in the individual items to achieve a 0-to-
70 score. There would be one recall period of 24 hours used in this questionnaire.
EQ-5D-5L
EQ-5D-5L (Appendix 4) is a standardized instrument for measuring health outcomes in a 
wide range of health conditions and treatments. It consists of a descriptive system and a visual 
analogue scale (EQ VAS). The descriptive system comprises the following 5 dimensions: 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension 
has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme 
problems. The EQ VAS records the respondent’s self-rated health on a vertical, visual 
analogue scale where the endpoints are labeled ‘Best imaginable health state’ and ‘worst 
imaginable health state’. The EQ-5D scores can be summarized into a single index score that 
provides a simple measure of health for clinical and economic appraisal.


Novartis
Confidential
Page 71
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
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.
For patients who sign the molecular pre-screening ICF, AEs which occur after signature of 
this consent will only be captured if they meet the definition of serious as outlined in 
Section 8.2 and are reported to be causally related with study procedures (e.g. an invasive 
procedure such as biopsy). Once the main study ICF is signed, all AEs per the descriptions 
below will be captured in the Adverse Event CRF.
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 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.
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, 


Novartis
Confidential
Page 72
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
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) (add or Ongoing at End of Study for NOVDD)
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)
4. Action taken with respect to study or investigational treatment (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. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown) Delete for NOVDD Trials as outcome 
is not collected
7. 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.
Confirmation of progression of disease, based on criteria described in Section 10.4.1 should 
not be reported as adverse event. However death should be reported as SAE (Section 8.2).
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.
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.


Novartis
Confidential
Page 73
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

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

Requires inpatient hospitalization or prolongation of existing hospitalization,

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
Refer to Section 8.1 for details on protocol exempt AEs and SAEs.
8.2.2
Reporting
For patients who sign the molecular pre-screening ICF, SAE collection will start upon signing 
the molecular pre-screening ICF. SAEs will only be reported if the event is suspected to be 
causally related to a study procedure as assessed by the investigator (e.g. an invasive 
procedure such as biopsy). SAEs will be followed until resolution or until clinically relevant 
improvement or stabilization. If the main ICF is not signed (molecular screen failure), SAE 
collection ends 30 days after the last study related procedure.
For patients who sign the main study ICF, SAE collection starts at time of main study 
informed consent whether the patient is a screen failure or not.
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided main 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 


Novartis
Confidential
Page 74
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
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 
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
Emergency unblinding should only be undertaken when it is essential for effective treatment 
of the patient. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency code breaks are performed using the IRT. When the investigator 
contacts the IRT to unblind a patient, he/she must provide the requested patient identifying 
information and confirm the necessity to unblind the patient. The investigator will then 
receive details of the drug treatment for the specified patient. The system will automatically 
inform the Novartis monitor for the site and the Study Lead that the code has been broken.
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of emergency. The investigator will inform the patient how to contact 
his/her backup in cases of emergency when he/she is unavailable. The protocol number, study 
treatment name if available, patient number, and instructions for contacting the local Novartis 
CPO (or any entity to which it has delegated responsibility for emergency code breaks) will 


Novartis
Confidential
Page 75
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
be provided to the patient in case emergency unblinding is required at a time when the 
investigator and backup are unavailable. However, if a mechanism is already in place to 
ensure that the investigator and/or back-up can always be reached in case of emergency then 
the procedure above is not required.
If a patient is unblinded due to an emergency, he/she may continue to receive study treatment 
and followed up as described in the protocol if the investigator believes it is beneficial for the 
patient and after consultation with Novartis personnel.
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 the study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
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
This study will institute a data monitoring committee (DMC) which will function 
independently of all other individuals associated with the conduct of this clinical trial, 
including the site investigators participating in the study. The DMC will be constituted prior 
to the randomization of the first patient. Further details on the function and responsibilities of 
the data monitoring committee will be outlined in the DMC charter.
8.7
Steering Committee
A Steering Committee (SC) will be established for this study. Further details on the functions 
and responsibilities will be outlined in the Steering Committee charter.


Novartis
Confidential
Page 76
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
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

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).


Novartis
Confidential
Page 77
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
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.
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.
Samples and/or data that will be processed centrally will have results sent electronically to 
Novartis (or a designated CRO).
Randomization codes and data about all study treatments dispensed to the patient and all IRT 
assigned dosage changes 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).
At the conclusion of the study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies 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 the treatment codes will be unblinded 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.


Novartis
Confidential
Page 78
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
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
The data from all participating centers in this protocol will be combined. The interim analysis 
will be performed once 45 PFS-1 events have been documented. The primary analysis of 
study data will be conducted when approximately 90 PFS-1 events have been documented. 
This data will be summarized in the primary Clinical Study Report (CSR). All available data 
from all patients up to this cutoff date will be analyzed.
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been 
assigned by randomization. According to the intent to treat principle, patients will be analyzed 
according to the treatment they have been assigned to during the randomization procedure.
10.1.2
Safety Set
The Safety Set includes all patients who received at least one dose of study medication, where 
treatment received is defined as the randomized treatment if the patient takes at least one dose 
of that treatment or the first treatment received if the randomized treatment is never received.
10.1.3
Per-Protocol Set
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who have at least 
one post-baseline assessment for PFS and no major protocol deviations.
All major protocol deviations leading to exclusion from the PPS will be detailed in the 
analysis plan.
10.1.4
Pharmacokinetic analysis set
The pharmacokinetic Analysis Set (PAS) consists of all patients set who have received at least 
one dose of ruxolitinib and provided evaluable pharmacokinetic (PK) data.
Evaluable PK data must fulfill the following criteria:
1. Post-dose data must not be associated with a vomiting event within 4 hours of ruxolitinib 
dosing
2. Pre-dose sample must not be associated with vomiting within 4 hours of last dose.
3. Post-dose PK samples must be collected within the time window indicated in the PK 
collection log.
The PAS will be used for the Population PK analysis.


Novartis
Confidential
Page 79
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data (including disease characteristics) will be summarized 
descriptively by treatment group for the FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
The safety set will be used for the analyses below.
The actual dose and duration of ruxolitinib and placebo treatment as well as the dose intensity 
(computed as the ratio of total dose received and actual treatment duration) and the relative 
dose intensity (computed as the ratio of dose intensity and planned dose intensity), will be 
listed and summarized by treatment group. Dose reductions and dose interruptions (including 
the reasons for these) will be listed and summarized by treatment group.
Concomitant medications including prohibited medications, and significant non-drug 
therapies prior to and after the start of the study treatment will be summarized for all patients 
and by treatment group.
Duration of follow up will be summarized descriptively by treatment group.
10.4
Primary objective
The primary objective for this study is to evaluate the effect of ruxolitinib in delaying 
progression of MF from early disease to more advanced disease stages.
10.4.1
Variable
The primary endpoint is progression free survival (PFS-1) in Treatment Period 1 . It is 
defined as the time from date of randomization until earliest time for one of the following 
events:

Progressive splenomegaly as assessed by doubling of spleen volume (by MRI/CT); in 
addition to an absolute spleen volume of greater than 450 cm3.

Circulating peripheral blast counts > 10% (requires confirmation after 8 weeks)

Leukemic transformation defined by an increase in peripheral blood blast percentage to ≥ 
20% that is sustained for at least 8 weeks or a bone marrow blast count of ≥20%

Hb < 10g/dl with an absolute decrease of at least 3 g/dl from baseline levels (requires 
confirmation following 2 week of dose interruption/reductions to ensure this is not drug 
induced cytopenia. In case of Hb stabilizing following dose modification within the 2 
weeks, study drug can be re-escalated based on investigators discretion. See section 6.3 
for guidance on dosing modifications

WBC counts > 25 x 103/ μL


Novartis
Confidential
Page 80
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353

Confirmed MF-7 score of ≥ 30 in addition to an individual symptom score of ≥7 in at least 
one non-splenomegaly related symptom, i.e., tiredness, night sweats, itching (pruritus), 
bone pain (diffuse not joint pain or arthritis). (Confirmed on two consecutive weeks)

Death from any cause
As the proposed study intends to investigate the benefit of ruxolitinib in delaying the
emergence of MF associated symptoms, MF-7 is expected to objectively evaluate disease 
progression based on the worsening of symptoms through symptom scores. A clinically 
relevant threshold of ≥ 30 was set to capture the time point when the patient begins 
experiencing more symptomatic disease (disease progression) reflected by a minimum of 
doubling in the baseline MF-7 scores. Additionally, progression by symptom will also require 
an individual score of ≥7 in at least one non-splenomegaly related symptom, i.e., tiredness, 
night sweats, itching (pruritus), bone pain (diffuse not joint pain or arthritis).
10.4.2
Statistical hypothesis, model, and method of analysis
The primary efficacy analysis will be the comparison of PFS-1 between the two treatment 
groups using a log-rank test at one-sided 2.5% level of significance.
Assuming proportional hazards model for PFS, the following statistical hypotheses will be 
tested to address the primary efficacy objective:
H01: θ1 ≥ 0 vs. Ha1: θ1 < 0
where θ1 is the log-hazard ratio (test treatment arm vs. control treatment arm) of PFS.
The primary efficacy endpoint PFS-1 will be analyzed at the interim look and final look of a 
group sequential design based on the FAS population according to the treatment group 
patients were randomized. PFS will be estimated using the Kaplan-Meier method. The median 
PFS along with 95% confidence intervals (when applicable) will be presented by treatment 
group.
A Cox regression model will be used to estimate the hazard ratio of PFS, along with 95% 
confidence interval.
10.4.3
Handling of missing values/censoring/discontinuations
PFS will be censored if no PFS event is observed before the cut-off date or the date when a 
new anti-neoplastic therapy or another investigational treatment is started, whichever occurs 
earlier. The censoring date will be the date of last adequate assessment before either of these 
two dates. If a PFS event is observed after at least two consecutive missing assessments 
(corresponding to a minimum of 24 weeks), then PFS will be censored at the last adequate 
assessment prior to the first missing value. If a PFS event is observed after a single missing 
assessment, the actual date of event will be used and PFS will not be censored.
Since the definition of progression in this study is multimodal the term assessment 
corresponds to either spleen palpation, laboratory assessment of hematology parameters 
(hemoglobin, WBC, peripheral blast count) or MF-7 questionnaire. Adequate assessment 
requires non-missing assessment for all components of PFS.


Novartis
Confidential
Page 81
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
For each assessment, the assessment date is calculated as the latest of all measurement dates 
(e.g. laboratory, MRI) if there is no progression. Otherwise, in case of progression the 
assessment date is calculated as the earliest date of all measurement dates at that evaluation 
number.
If a patient permanently discontinues study treatment for reason other than disease 
progression and progression event occurs between permanent discontinuation and start of new 
anti-neoplastic treatment then the PFS time will be censored at last adequate assessment date 
prior to discontinuation of study treatment.
10.4.4
Supportive analyses
A summary of first progression (PFS-1) events will be tabulated by treatment group.
A subgroup analysis of PFS will be performed by IPSS risk group, type & number of HMR 
mutations, presence of palpable splenomegaly and/or active symptoms as determined by MF-
7.
The analysis of PFS will be repeated for per protocol set.
10.4.5
Sensitivity analyses
If progression event occurs between two scheduled assessments then a date of next schedule 
assessment will be used as end date for PFS and the outcome will be an event.
If a progression event occurs after two or more missing assessments then date of next 
scheduled assessment will be used as end date for PFS and the outcome will be an event.
If a patient permanent discontinues study treatment for reason other than disease progression 
and progression event occurs between permanent discontinuation and start of new anti-
neoplastic treatment then the actual date of event will be used and PFS will not be censored.
An alternative definition of PFS excluding MF-7 from progression will be performed.
10.5
Secondary objectives
Secondary objectives related to efficacy include overall survival, time to progression, change 
in spleen length and volume from baseline, change in symptoms using MF-7 from baseline
and progression free survival (PFS-2) in the Treatment Period 2.
Another secondary objective is to assess the effect of ruxolitinib versus placebo on patient 
reported outcomes (PRO), including disease related symptoms, functioning, and health-related 
quality of life.
Additional objectives include evaluation of the safety profile of ruxolitinib versus placebo.


Novartis
Confidential
Page 82
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
10.5.1
Secondary efficacy objectives
Time to primary progression (TTP)
TTP is defined as time from randomization until disease progression as defined for PFS-1
excluding death as an event.
The TTP will be analyzed using log rank test on the FAS population according to the 
treatment group patients were randomized. TTP will be estimated using the Kaplan-Meier 
method. The median TTP along with 95% confidence intervals (when applicable) will be 
presented by treatment group.
The Cox regression model will be used to estimate the hazard ratio (HR) of TTP, along with 
95% confidence interval.
Time to first progressive splenomegaly (TTPS)
TTPS is defined as time from randomization until earliest time to progressive splenomegaly 
as assessed by doubling of spleen volume (by MRI/CT); in addition to an absolute spleen 
volume of greater than 450 cm3. Since this endpoint is a component of PFS the censoring 
rules are similar to PFS.
TTPS will be analyzed using log rank test on the FAS population according to the treatment 
group patients were randomized. TTPS will be estimated using the Kaplan-Meier method. The 
median TTPS along with 95% confidence intervals (when applicable) will be presented by 
treatment group.
A Cox regression model will be used to estimate the HR of TTPS, along with 95% confidence 
interval.
Time to first symptomatic progression (TTSP)
TTSP is defined as time from randomization until confirmed MF-7 scores of ≥ 30 with at least 
one symptom score ≥ 7 in at least one non-splenomegaly related symptom, i.e., tiredness, 
night sweats, bone pain (diffuse not joint pain or arthritis), itching (pruritus) (confirmed on 
two consecutive weeks). Since this endpoint is a component of PFS the censoring rules are 
similar to PFS-1.
TTSP will be analyzed using log rank test on the FAS population according to the treatment 
group patients were randomized. The time to symptomatic progression will be estimated using 
the Kaplan-Meier method. The median TTSP along with 95% confidence intervals (when 
applicable) will be presented by treatment group.
A Cox regression model will be used to estimate the hazard ratio (HR) of TTSP, along with 
95% confidence interval.


Novartis
Confidential
Page 83
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Quality-adjusted life years (QALY)
EQ-5D-5L health states will be converted into index values (utilities) from which the QALY 
will be calculated.
QALY will be summarized descriptively by treatment arm.
Change in symptoms using MF-7
See Section 10.5.6.
Change in EQ-5D from baseline
See Section 10.5.6.
Overall survival
OS is defined as the time from date of randomization to date of death due to any cause. If a 
patient is not known to have died, then OS will be censored at the last date the patient was 
known to be alive.
The analyses for OS will be based on the FAS population according to the randomized 
treatment group of the patients. OS will be estimated using the Kaplan-Meier method. The 
median OS along with 95% confidence intervals (when applicable) will be presented by 
treatment group. A Cox regression model will be used to estimate the HR of OS, along with 
95% confidence interval.
Progression free survival after primary progression (PFS-2)
Patients who experienced a first progression (PFS-1) event in either splenomegaly or 
symptoms (MF-7 score) will be followed for second progression events, defined below. All 
patients randomized in the study (FAS) will be included in the PFS-2 analysis. PFS-2 is 
defined as the time from date of randomization until second disease progression or death from 
any cause, whichever first. Patients alive and for whom a second disease progression has not 
been observed should be censored at the last time known to be alive and without second 
disease progression.
Second disease progression is the earliest time for one of the following events:

Spleen volume increases ≥ 25% over PFS-1 (new baseline) with an absolute volume > 450
cm3

MF-7 score ≥ 25% over PFS-1 (new baseline) with absolute scores ≥ 30, an individual 
symptom score of ≥7 in at least one non-splenomegaly related symptom, i.e., tiredness, 
night sweats, itching (pruritus), bone pain (diffuse not joint pain or arthritis) (Confirmed 
on two consecutive weeks)
The thresholds for evaluation of progression in the ruxolitinib Treatment Period 2 (≥25% 
over PFS-1 for both spleen volume increases and MF-7 score worsening) were defined to 
account for any lack of treatment effect in the post progression Treatment Period and prevent
premature discontinuation from treatment due to any transient and borderline worsening in the 


Novartis
Confidential
Page 84
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
symptoms (MF-7 score) and spleen sizes in the immediate post progression period while the 
patient is switching therapy.
In addition, the following post primary progression parameters assessed in Treatment Period 2
will be summarized descriptively.

Change in MF-7: Number of patients with 50% reduction in MF-7 score from PFS-1 will 
be tabulated.

Change in spleen volume and change in palpable spleen length below costal margin: 
Number of patients with 35% reduction from PFS-1 will be tabulated.
10.5.2
Safety objectives
10.5.2.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group.
The overall observation period will be divided into three 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. post-treatment period: starting at day 31 after last dose of study medication.
10.5.2.2 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 Common 
Terminology Criteria for Adverse Events [CTCAE] grades), type of adverse event, relation to 
study treatment by treatment group.
Serious adverse events, non-serious adverse events and adverse events of special interest 
(AESI) during the on-treatment period will be tabulated.
All deaths (on-treatment and post-treatment) will be tabulated.
10.5.2.3 Laboratory abnormalities
For laboratory tests covered by the CTCAE version 4.03 the study’s biostatistical and 
reporting team will grade laboratory data accordingly. For laboratory tests covered by 
CTCAE, a Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
Grade 5 will not be used.


Novartis
Confidential
Page 85
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
For some cases (e.g. white blood cell differentials) the lower limits of normal ranges used in 
CTCAE definition have to be replaced by a clinical 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.
A listing of laboratory values will be provided by laboratory test, patient, and study day. A 
separate listing will display notable laboratory abnormalities (i.e., newly occurring CTCAE 
grade 3 or 4 laboratory abnormalities).
The following by-treatment summaries will be generated separately for hematology and 
biochemistry laboratory tests:

frequency table for newly occurring on-treatment grades 3 or 4 (see below for details)

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,
 
 
10.5.2.4 Other safety data
Analyses will be performed on the safety set.
ECG

shift table baseline to worst on-treatment result for overall assessments

listing of ECG evaluations for all patients with at least one abnormality.
Vital signs

shift table baseline to worst on-treatment result

table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points.
10.5.3
Pharmacokinetics
Objective of the planned pharmacokinetic analyses is as follows:
1. To compare PK characteristics of HMR positive early MF patients with PK characteristics 
of patients from previous MF studies, and
2. To explore exposure-response relationship across major AEs/ efficacy measures and 
ruxolitinib exposure.
In order to assess any potential PK differences in this early MF population compared to the 
previously studied MF patients (Study 251 and 351), newly observed ruxolitinib plasma 
concentrations stratified into two strata – male and female - will be superimposed over the 5th, 


Novartis
Confidential
Page 86
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
50th, and 95th percentiles of simulated observations using the previous MF model and 10 mg 
BID. Observed ruxolitinib plasma concentrations blood concentrations (Ct in units ng/mL) 
will be adjusted to the dose (10 mg BID) by the equation: Ct,adj = 10 mg × Ct/(actual mg dose).
If the data suggests that there could be any relevant difference in PK compared to the 
previously studied MF population, then data from Study CINC424A2353 will be pooled with 
data from Studies 251 and 351. The population pharmacokinetics of study treatment is likely 
to be adequately described by one or two compartment structural pharmacokinetic model with
first order absorption model.
Plasma concentrations of ruxolitinib will be analyzed using non-linear mixed-effects approach 
in order to characterize the population pharmacokinetics of ruxolitinib and the associated 
inter-individual and intra-individual variability. After evaluation of adequacy of the data for 
the objective, additional analyses may be performed to identify and quantify the effects of 
covariates on the pharmacokinetic variability of ruxolitinib. The main covariate effects to 
examine are as follows:
1. effects of body weight on central volume and gender on clearance since these were 
incorporated in the earlier population PK model developed from Studies 251 and 351
2. effect of Study CINC424A2353 on clearance relative to Studies 251 and 351.
The addition of other covariates to the model, e.g., concomitant medications, will be guided 
by sample size of subpopulations, by exploratory plots of random effects representing inter-
individual variability versus covariates, and by the NONMEM objective function value. 
Covariates may be dropped from the model based on p-value (e.g., p>0.01), relative standard 
error (e.g., >30%), or reduction in inter-individual variability (e.g., no decrease in the 
coefficient of variation).
Average steady-state exposures will be computed by the POP PK model accounting for dose 
modifications or dose interruptions up to the day prior to the day of assessment (assessments 
include progressions, AE endpoints of interest such as Hg levels, platelet counts, laboratory 
values as needed). Graphical presentation of exposures presented as quartiles may be related 
to each response/safety end-point as permitted, Time to progression will be assessed by 
Kaplan-Meire plots by quartiles of average daily exposure. Incidence rates of Grade 3 or 4 
hematological or lab abnormalities will be plotted by average daily exposure quartiles.
During modeling of the pharmacokinetics of study treatment, the broad principles outlined in 
the FDA guidance will be followed (Guidance for Industry: Population Pharmacokinetics; 
http://.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm07
2137.pdf).


Novartis
Confidential
Page 87
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
10.5.5
Resource utilization
Not applicable.
10.5.6
Patient-reported outcomes
The Myeloproliferative Neoplasm-Symptom Assessment Form Total Symptom Score (MF-
7)and the EuroQol-5D-5L (EQ-5D) will be used to collect data on the impact of ruxolitinib 
treatment on the patient’s disease-related symptoms, functioning and overall quality of life. 
The MF-7 and the EQ-5D are identified as the key PRO variables of interest. 
 
The FAS will be used for analyzing PRO data. No formal statistical test will be performed. 
Analysis of time to symptomatic progression and QALY are described in Section 10.5.1. 
Percent change from Baseline in MF-7 total symptom score and 10 individual symptoms at 


Novartis
Confidential
Page 88
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
each visit will be summarized with descriptive statistics. A mixed effect repeated measures 
analysis model may be used to evaluate the treatment effect over time.
Descriptive statistics will be used to summarize the scored scales at each scheduled 
assessment time point for the
 and the EQ-5D. Additionally, change from baseline in the 
domain scores and individual items at the time of each assessment will be summarized for the 
EQ-5D. Patients with baseline score and at least one non-missing post-baseline score during 
the treatment period will be included in the change from baseline analyses. 
 
 
 
Missing items data in a PRO scale will be handled based on each instrument manual. All PRO 
analyses will include data as imputed according to the scoring manual. No imputation will be 
applied if the total or subscale scores are missing at a visit.


Novartis
Confidential
Page 89
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
10.7
Interim analysis
One interim analysis is planned at approximately 45 of the 90 targeted PFS-1 events (50% 
information fraction). The intent of the interim analysis is to stop early for lack of efficacy 
(futility). It is expected that 309 patients will be randomized when approximately 45 PFS-1 
events have occurred if H0 is true (HR=1).
The design accounts for one interim look under a 2-look group sequential design. A user-
defined gamma spending function (gamma= -2 , as implemented in EAST 5.4) is used as beta-
spending function to determine the non-binding futility boundary. The interim analysis is 
planned when 45 (50%) of the 90 PFS-1 events have been recorded. To conclude futility the
observed hazard ratio has to be over 0.89 (or the z-statistic is less than 0.388, or nominal p-
value ≥ 0.3489) if the interim analysis is based on exactly 45 events. EAST 5.4 was used for 
the calculations.
Since the observed number of events at the interim analysis may not be exactly equal to the 
planned 45 PFS-1 events, the futility boundary will need to be re-calculated using the pre-
specified β-spending function and based on the actual number of observed events at interim 
and the total number of targeted events to calculate the exact information fraction. The 
observed hazard ratio (or p-value, or Z-test statistic) at the interim analysis will then be 
compared against the re-calculated futility boundary.
If the study continues to the final PFS analysis, the final PFS-1 analysis will be performed 
when approximately 90 PFS-1 events have been documented. If exactly 45 events are 
observed at the interim analysis, the study continued and exactly 90 events are obtained at the 
final analysis, the observed p-value will have to be no more than 0.025.
Based on the stopping boundaries defined above and the timing of interim analysis at 50% 
information fraction the design has the following operational characteristics based on 
simulations in East 5.4.
Table 10-1
Simulated probabilities to stop for futility at the interim or final PFS-1 
analysis
Scenario
Look
# PFS-1 events
Simulated incremental 
probabilities (%)
Stop for futility
Under H0 (HR=1)
Interim
45
66%
Final
90
-
Under Ha (HR=0.50)
Interim
45
3%
Final
90
-
Under other Ha 
(HR=0.70)
Interim
45
21%
Note: Simulation is performed in East 5.4 with number of simulations = 10,000 and random seed =1234.
The interim analyses will be performed by an independent statistician (not involved with the 
conduct of the study). Further details will be described in the DMC charter. The results of the 
interim analyses will be provided to the DMC by the independent statistician.


Novartis
Confidential
Page 90
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
10.8
Sample size calculation
There are very limited published data available regarding the population under investigation 
in the study, MF patients harboring HMR mutations, with asymptomatic or minimally 
symptomatic disease. Additionally, there is no data that specifically describes the time to 
progression of disease from asymptomatic or minimally symptomatic disease to more 
symptomatic disease in myelofibrosis patients and this, likewise, applies to the subgroup of 
myelofibrosis patients harboring HMR mutations as well. The estimates for the time to 
progression of disease from early stage MF disease to more advanced stages were therefore 
extrapolated from survival data that is available by IPSS categories (Cervantes et al, Blood). 
As the acquisition of a new hematological abnormality or clinical symptom represents a shift 
in categorization from one risk group to the next higher one in the IPSS risk categorization 
tool, it was assessed that the difference in median survival between two consecutive IPSS risk 
groups, would represent the time taken to progress from one risk category to the next higher 
category. For instance if the median survival for patients in the low risk IPSS is ‘(X) years’ 
and the median survival for Int-1 risk IPSS is ‘(Y) years’, the time to progression from a low 
risk IPSS to Int-1 risk IPSS was estimated to be ‘(X – Y) years’. Since the markers of 
progressive disease in the study are largely based on the same components of prognosis that 
the IPSS uses, the above approach was expected to allow a reasonable estimate of time to 
progression of disease and thus PFS in MF patients. The PFS estimates in the lower IPSS risk 
groups (low risk and int-1 risk who have either none or one prognostic factor) were assessed 
as appropriate for the population under study. Table 10-1 depicts the estimation of the time to 
progression from one IPSS risk category to the next higher one.
The estimated PFS for MF patients in the various categories thus ranges between 21 and 47 
months. To enable a conservative estimate of PFS, the best case estimate of 47 months 
median PFS was considered. These observations are consistent with the survival estimates for 
HMR patients categorized by different risk groups conducted by Guglielmelli et al, Leukemia, 
2014, although this study categorizes patients into two broader risk groups rather than the four 
used by IPSS, i.e., lower risk group (IPSS low + Int-1) and higher risk groups (IPSS Int-2 + 
High). For statistical assumptions in the proposed study, a median PFS of approximately 50 
months was thus used.
Assuming exponential distribution for PFS, it was estimated that with the median PFS of 50 
months, around 60% of the patients in the control arm would remain progression free 
following 36 months of treatment. For the investigational arm, it was assumed that an 
additional 20% patients remaining progression free, i.e., 80% patients remaining progression 
free after 36 months of treatment would correspond to a median PFS of 100 months. In 
consultation with clinical experts involved in the care of MF patients, this improvement of 
treatment effect from the estimated median of 50 months (control) to a median of 100 months, 
corresponding to a HR of 0.5 was assessed as clinically relevant in this patient population 
with a clinically indolent but intrinsically aggressive MF disease.
The final analysis of PFS-1 will require 90 PFS-1 events, which is the number of PFS-1
events needed for a one-sided log-rank test at 2.5% significance level to have at least 90% 
power to show a statistically significant difference when the true hazard ratio is 0.50 
(corresponding to a median PFS-1 for ruxolitinib of 100 months and a median PFS-1 in 
placebo of 50 months). It is estimated that approximately 320 patients will have to be 


Novartis
Confidential
Page 91
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
randomized (1:1 ratio) into 2 treatment arms (160 patients in the ruxolitinib treatment arm and 
160 patients in placebo control arm) to observe 90 PFS events by approximately 48 months 
from the randomization date of the first patient in this trial if the accrual rate is constant at 13 
patients per month over the accrual period (24 months), assuming 15% cumulative dropout 
rate at month 48.
Table 10-2
Time to progression based on IPSS risk group
Risk group
Prognostic factors
Median survival 
(months)
Estimated PFS to next 
risk group (months)
Low
0
135
135-95 = 40
Int-1
1
95
95 - 48 = 47
Int-2
2
48
48 - 27 = 21
High
>2
27
N/A
10.9
Power for analysis of key secondary variables
Not applicable
10.10
Design adaptation
Considering the disease setting and limited data on the PFS endpoint from other studies, a 
blinded review of the confirmed PD events will be performed at about 25% information 
fraction or 24 months after first patient enrolled whichever comes first. This will allow 
assessing event accrual as per assumption and future prediction of anticipated timing for the 
IA/FA (Interim analysis/Final analysis). The potential outcome of this review could be either:

to increase the sample size and extend the accrual duration if
1. event rate is lower than per assumption;
2. accrual is within assumption;
3. dropout rate is within assumption of 15% by month 48.

to recommend the futility interim analysis proceed at month 48, based on calendar time
rather than number of events if
1. event rate is low;
2. accrual is low;
3. dropout rate is high, i.e. posterior predictive probability of observing 50% information 
fraction by month 48 is less than 40%.
Blinded sample size review
The blinded sample size review will be performed prior to the unblinded futility interim 
analysis. It will be conducted by blinded Novartis personnel using data pooled across 
treatment arms. No one with access to unblinded data, e.g. during the preparation of the 
futility interim analysis or unblinded safety DMC reports, will be involved in the sample size 
review. Prior to the completion of enrolment, a review of blinded progression data will be 
performed to re-assess the assumptions of the sample size calculation. With time-to-event data 
the information of a trial depends on the number of events and not on the number of patients 
enrolled. The study will be completed once a total of 90 patients with primary disease 


Novartis
Confidential
Page 92
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
progression are observed (90 PFS-1 events). The sole purpose of the blinded sample size 
review is to control the length of the trial with the aim to keep it as close as possible to the 
projected 48 months. The preplanned number of events will be kept at 90 and will not be 
changed in the sample size review.
Once 25% of events are accumulated or 24 months after first patient enrolled whichever 
comes first and while the enrollment is still ongoing, a review of blinded data will be 
performed to re-assess the assumptions regarding the nuisance parameters in the sample size 
calculation for the disease progression endpoint, i.e. the overall progression free survival time
and time-to-dropout pooled across the treatment arms. The overall time-to-event processes 
will be modeled (e.g. using exponential, piecewise exponential, or Weibull distributions). The 
assumption regarding the treatment effect will remain unchanged, i.e. proportional hazards 
with a hazard ratio of 0.50. Under this assumption the overall time-to-event processes can be 
split into two treatment groups to obtain treatment specific estimates under the assumed 
hazard ratio. For instance, assuming exponential distributions, the pooled hazard rate will be 
estimated by the total number of events divided by the time under risk aggregated over all 
patients. The overall rate across treatment arms is a weighted average of the treatment specific 
rates and therefore treatment specific rates can be calculated assuming a certain rate ratio. 
Based on the updated hazard rate and drop-out rate assumptions, the observed recruitment so 
far and the expected recruitment in the coming months, the sample size necessary to achieve a 
total of 90 progressions within 48 months is computed. If this calculation indicates that a 
sample size larger than the preplanned total of 320 patients is required, then the enrollment 
period (which will be still ongoing at the time of the sample size review) will be extended and 
the total sample size increased, so that, if feasible, the expected duration of the study will be 
about 48 months. The maximum sample size is set to 420 patients and if the recalculated 
sample size exceeds this maximum, an extension of the trial beyond 68 months will be 
considered or a decrease in power will be accepted. The final decision on a sample size 
increase will be made by the sponsor.
During the sample size review no unblinded data will be used and no adjustment of the 
significance level is necessary.
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 


Novartis
Confidential
Page 93
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
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 molecular informed 
consent form and a main 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.
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 


Novartis
Confidential
Page 94
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
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.
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.


Novartis
Confidential
Page 95
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
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.


Novartis
Confidential
Page 96
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
13
References (available upon request)
Abdel-Wahab, Levine (2009) Primary myelofibrosis: update on definition, pathogenesis, and 
treatment. Annu Rev Med;60:233-245.
Boekhorst et al (2014) A Phase 1b, Open-Label, Dose-Finding Study of Ruxolitinib in 
Patients With Myelofibrosis and Baseline Platelet Counts From 50 × 109/L to 99 × 109/L (the 
EXPAND Study). Poster Presentation at the 56th ASH Annual Meeting, December 6-9, 2014, 
San Francisco, California. (available upon request)
Cervantes et al (2009) New prognostic scoring system for primary myelofibrosis based on a 
study of the International Working Group for Myelofibrosis Research and Treatment. 
Blood;113:2895-2901.
Gangat et al (2011) DIPSS Plus: A Refined Dynamic International Prognostic Scoring System 
for Primary Myelofibrosis That Incorporates Prognostic Information From Karyotype, Platelet 
Count, and Transfusion Status. JCO February 1, 2011 vol. 29 no. 4 392-397.
Guglielmelli et al (2014a) The number of prognostically detrimental mutations and prognosis 
in primary myelofibrosis: an international study of 797 patients. Leukemia (2014), 1–7.
Guglielmelli et al (2014b) Impact of mutational status on outcomes in myelofibrosis patients 
treated with ruxolitinib in the COMFORT-II study. Blood, 3 April 2014 x Volume 123, 
Number 14: 2157-2160.
Kilpivaara, Levine (2008) JAK2 and MPL mutations in myeloproliferative neoplasms: 
discovery and science. Leukemia (2008) 22, 1813–1817.
Klampfl et al (2008) Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms. N 
Engl J Med 2013;369:2379-90.
Kroger (2008) Epigenetic Modulation and Other Options to Improve Outcome of Stem Cell 
Transplantation in MDS. Hematology 2008: 60-67.
Mesa et al (2007) The Burden of Fatigue and Quality of Life in Myeloproliferative Disorders 
(MPDs). An International Internet-Based Survey of 1179 MPD Patients. Cancer January 1, 
2007 / Volume 109 / Number 1.
Tefferi (2008) Epigenetic alterations and anti-epigenetic therapy in myelofibrosis. Leukemia 
& Lymphoma, December 2008; 49(12): 2231–2232.
Tefferi et al (2013) Revised response criteria for myelofibrosis: International Working Group-
Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European 
LeukemiaNet (ELN) consensus report. Blood. 2013;122(8):1395-1398.
Vannucchi et al (2013a) Mutations and prognosis in primary myelofibrosis. Leukemia (2013) 
27, 1861–1869.
Vannucchi et al (2015) A pooled analysis of overall survival in COMFORT-I and 
COMFORT-II, 2 randomized phase 3 trials of ruxolitinib for the treatment of myelofibrosis.
Haematologica June 11, 2015.


Novartis
Confidential
Page 97
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
14
Appendices
Appendix 1
Table 14-1
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 be 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.
a A 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.
b A 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/CYP3A4 inhibitor:
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).


Novartis
Confidential
Page 98
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Appendix 2
Table 14-2
European Consensus on the grading of myelofibrosis (adapted from 
literature)
Grading
Description*
MF - 0
Scattered linear reticulin with no intersections (cross-overs) corresponding to normal 
bone marrow
MF - 1
Loose network of reticulin with many intersections, especially in perivascular areas
MF - 2
Diffuse and dense increase in reticulin with extensive intersections, occasionally with 
only focal bundles of collagen and/or focal osteosclerosis
MF - 3
Diffuse and dense increase in reticulin with extensive intersections with coarse bundles 
of collagen, often associated with significant osteosclerosis
*Fiber density should be assessed in hematopoietic (cellular) areas.
Adapted from: Thiele J et al. 2005; Haematologica ; 90:1128-1132 (European consensus on grading 
bone marrow fibrosis and assessment of cellularity).


Novartis
Confidential
Page 99
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Appendix 3
Table 14-3
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, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead


Novartis
Confidential
Page 100
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
Appendix 4
Patient reported outcomes – Questionnaires
MF-7 Myelofibrosis 7 Item Symptom Scale
Myelofibrosis 7 Item Symptom Scale (MF-7)
Symptom
0 to 10 Ranking
Select the one number that describes the worst severity you have experienced with each of the 
following in the past 24 hours
Tiredness
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)
Filling up quickly when you eat
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)
Abdominal discomfort
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)
Night Sweats
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)
Itching (pruritus)
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)
Bone pain (diffuse not joint pain or 
arthritis)
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)
Pain under ribs on left side
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)


Novartis
Confidential
Page 101
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353
EQ-5D-5L Health Questionnaire


Novartis
Confidential
Page 102
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353


Novartis
Confidential
Page 103
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353


Novartis
Confidential
Page 104
Oncology Clinical Trial Protocol (v00)
Protocol No. CINC424A2353

SAP_001.pdf: 
Clinical Development
INC424 / Ruxolitinib / JAKAVI®
CINC424A2353 / NCT02598297
A randomized, double blind, placebo-controlled, multi-
center, Phase III study investigating the efficacy and safety 
of ruxolitinib in Early Myelofibrosis patients with high 
molecular risk mutations
Statistical Analysis Plan (SAP) – Amendment 1
TEMPLATE VERSION AND DATE: Final 1.0 24-Sep-2015, Effective 31-Oct-2015
Author:
Document type:
SAP Documentation
Document status:
Final 1.0
Release date:
25-July-2017
Number of pages:
30
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


Novartis
For business use only
Page 2
Statistical analysis plan
CINC424A2353 (ReTHINK)
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
29-Jan-
2016
Prior 
to DB 
lock
Creation of 
final version
N/A - First version
NA
19-Jul-
2017
Prior 
to DB 
lock
Creation of 
amendment
1 due to 
study 
premature
termination
Change to the ultimate goal of the 
early termination study: To present 
the efficacy, safety and 
 
data of interest.
Introduction 
section 1.2
Specified that primary endpoint 
PFS, and other time to event 
endpoints will not be derived.
Introduction 
section 1.2
Removed Per-Protocol Set and PK 
Set, and Subgroup of interest.
Analysis sets 
Section 2.2
Treatment period 1 data will be 
tabulated, Treatment period 1 and
period 2 data will be listed.
Sections 2.3, 2.4, 
2.5, 2.7, 2.8
Specified that no analysis for 
primary endpoint is planned. The 
early terminated study aims to 
present data collected for the 
endpoints of interest, including 
change in spleen volume and 
length from baseline, change in 
symptoms using MF-7 and EQ-5D 
from baseline (see patient reported 
outcomes section), safety 
endpoints, 
 
Descriptive statistics will be used 
to summarize the endpoints of 
interest and the FAS will be used 
for analyzing the data.
Analysis of the 
primary objective 
section 2.5
Specified that no sufficient data 
were collected to assess the effect 
of ruxolitinib versus placebo on 
overall survival and time to 
progression, so that no secondary 
Analysis of the 
secondary 
objectives section 
2.7


Novartis
For business use only
Page 3
Statistical analysis plan
CINC424A2353 (ReTHINK)
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
efficacy analysis will be performed 
in this study.
AESI is not planned for this 
prematurely terminated study.
Section 2.8.1.1
Add text to AE of clinical trial 
safety disclosure.
Section 2.8.1.2
No formal PK analysis is planned. 
Individual 
plasma 
ruxolitinib 
concentration data will only be 
listed for the Full analysis set. 
PK Section 2.9


Novartis
For business use only
Page 4
Statistical analysis plan
CINC424A2353 (ReTHINK)
Table of contents
Table of contents .................................................................................................................4
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints .............................................................................10
2
Statistical methods.............................................................................................................10
2.1
Data analysis general information .........................................................................10
2.1.1
General definitions................................................................................11
2.1.2
Date of first administration of study treatment in treatment period 1...11
2.1.3
Date of last administration of study treatment in treatment period 1....11
2.1.4
Date of first administration of open label ruxolitinib in treatment 
period 2..................................................................................................11
2.1.5
Date of last administration of open label ruxolitinib in treatment 
period 2..................................................................................................12
2.1.6
Last date of study treatment ..................................................................12
2.1.7
Study day...............................................................................................12
2.1.8
Baseline.................................................................................................12
2.1.9
Last contact date....................................................................................13
2.1.10
Windows for multiple assessments .......................................................13
2.2
Analysis sets ..........................................................................................................14
2.2.1
Full Analysis Set ...................................................................................14
2.2.2
Safety Set ..............................................................................................14
2.2.3
Per-Protocol Set ....................................................................................14
2.2.4
Pharmacokinetic analysis set.................................................................15
2.2.5
Subgroup of interest ..............................................................................15
2.2.6
Withdrawal of Informed Consent..........................................................15
2.3
Patient disposition, demographics and other baseline characteristics ...................15
2.3.1
Patient disposition.................................................................................15
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................16
2.4.1
Study treatment / compliance................................................................17
2.4.2
Prior, concomitant and post therapies ...................................................18
2.5
Analysis of the primary objective..........................................................................18
2.6
Analysis of the key secondary objective ...............................................................19
2.7
Analysis of secondary efficacy objective(s) ..........................................................19


Novartis
For business use only
Page 5
Statistical analysis plan
CINC424A2353 (ReTHINK)
2.8
Safety analyses.......................................................................................................19
2.8.1
Adverse events (AEs)............................................................................20
2.8.2
Deaths....................................................................................................21
2.8.3
Laboratory data .....................................................................................21
2.8.4
Other safety data ...................................................................................22
2.9
Pharmacokinetic endpoints....................................................................................23
23
2.11
Patient-reported outcomes .....................................................................................23
24
2.13
Bone marrow biopsy and aspirate..........................................................................24
25
2.15
Interim analysis......................................................................................................25
3
Sample size calculation .....................................................................................................25
4
Change to protocol specified analyses ..............................................................................25
5
Appendix ...........................................................................................................................25
5.1
Imputation rules.....................................................................................................25
5.1.1
Study drug .............................................................................................25
5.1.2
AE date imputation ...............................................................................25
5.1.3
Concomitant medication date imputation .............................................26
5.2
AEs coding/grading ...............................................................................................27
5.3
Laboratory parameters derivations ........................................................................28
6
Reference...........................................................................................................................30


Novartis
For business use only
Page 6
Statistical analysis plan
CINC424A2353 (ReTHINK)
List of abbreviations
AE
Adverse event
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
bid
bis in diem/twice a day
CSR
Clinical Study Report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee 
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
IRT
Interactive Response Technology that includes Interactive Voice Response System 
and Interactive Web Response System
MedDRA
Medical Dictionary for Drug Regulatory Affairs
NCI
National Cancer Institute
o.d.
Once Daily
OS
Overall Survival
PFS
Progression-Free Survival
PK
Pharmacokinetics
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
qd
Qua’que di’e / once a day
QoL
Quality of Life
RAP
Report and Analysis Process
RECIST
Response Evaluation Criteria in Solid Tumors 
SAP
Statistical Analysis Plan
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization


Novartis
For business use only
Page 7
Statistical analysis plan
CINC424A2353 (ReTHINK)
1
Introduction
The purpose of the Statistical Analysis Plan (SAP) is to describe the implementation of the 
statistical analysis planned in the protocol for the abbreviated clinical study report (CSR) and 
potential publications.
The study is terminated prematurely due to unresolvable recruitment issues. Descriptive 
statistics and listings of safety, efficacy and biomarker data of interest is planned for reporting 
CINC424A2353. No formal statistical analyses for progression free survival (PFS) are 
planned as the number of patients enrolled in the study is insufficient to perform confirmative 
analysis. 
The latest MedDRA version by the time of DBL should be used for the CSR. 
1.1
Study design
This is a double blind, randomized placebo-controlled study of ruxolitinib in patients with 
HMR positive early MF (HMR+ EMF). The study consists of a screening period, Treatment 
Period 1 and Treatment Period 2.
Details of the discontinuation from study/treatment, unblinding, planning of the EOT 
assessment and safety monitoring are documented in the Premature Termination Plan. 
Screening:
Patients will be pre-screened for the determination of HMR mutation status after obtaining the 
molecular pre-screening informed consent. Only patients who are centrally confirmed to be 
HMR+ will be eligible to enter the screening phase. Patients should be consented to the main 
study informed consent as soon as HMR positivity is confirmed (recommended within 28 
days). Patients will be randomized in a 1:1 ratio to ruxolitinib or placebo on Day 1 following 
confirmation of eligibility, including confirmed bone marrow fibrosis grading during the 40 
day screening period.
Treatment Period 1
Blinded study treatment will begin on Day 1 following randomization. Visits will be every 4 
weeks up to Week 24 to monitor tolerability and efficacy with the study treatment. After 
Week 24, visits will be every 8 weeks until Week 48, and then every 12 week s thereafter. 
Blinded study treatment
will be administered until disease progression or patient 
discontinuation. A 30-day safety follow up visit will be done after the last dose of blinded 
study drug (except if entering Treatment Period 2). Patients who discontinue for reasons other 
than disease progression will enter the post treatment follow up. Patients will be followed for 
survival after end of Treatment Period 1 or post-treatment follow up every 3 months until the 
termination of study by the sponsor.


Novartis
For business use only
Page 8
Statistical analysis plan
CINC424A2353 (ReTHINK)
Treatment Period 2
Patients who progress due to splenomegaly or symptoms and are candidates for treatment 
with currently approved doses of ruxolitinib (as per investigators decision) will be treated 
with ruxolitinib at 5mg, 15mg or 20 mg BID, based on platelet counts at the time of treatment 
initiation. These patients will continue on the same schedule of assessments as in ‘Treatment 
Period 1’. A 30-day safety follow up visit will be performed after the last dose of study drug. 
Patients will be followed for survival after end of Treatment Period 2 every 3 months until the 
termination of study by the sponsor (Figure 1-1).
Figure 1-1
Schematic study design
A) Screening
Pre-Screening:
Molecular  Informed Consent obtained
Blood sample for: HMR mutation status/Genetic mutations in 
pathogenesis of MF
Screening: (Day -40 to -1)
Inclusion/Exclusion
Screening procedures
Patient 
eligible
HMR+
Randomization: Day 1
Screening


Novartis
For business use only
Page 9
Statistical analysis plan
CINC424A2353 (ReTHINK)
B) Treatment Period
Randomization
Patients will be assigned to one of the two treatment arms in a ratio of 1:1 (ruxolitinib or 
placebo).
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers.
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms. The investigator or his/her delegate will log on to the IRT 
and confirm that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign a 
randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the first package of study treatment to be 
dispensed to the patient. The randomization number will not be communicated to the caller.
Randomization is not stratified.


Novartis
For business use only
Page 10
Statistical analysis plan
CINC424A2353 (ReTHINK)
Interim analysis
The study is terminated prior to initial planned interim analysis due to unresolvable 
recruitment issue. Hence, one final analysis is planned for the abbreviated CSR and no interim 
analysis will be performed.
1.2
Study objectives and endpoints
Table 3-1 of CINC424A2353 study protocol specifies the study objectives and endpoints. The 
initial plan of efficacy evaluation and safety assessment of ruxolitinib cannot be implemented 
due to early termination of the study. The number of patients randomized and the study 
duration by termination were minimal and they did not provide sufficient information to 
perform formal comparison specified in the original analysis plan.
To present the efficacy, safety and 
 data of interest is the ultimate goal of the early 
termination study. The key endpoints of interest are listed in Table 1-1below.
Table 1-1 Endpoints of Interest
Endpoint
Change in spleen volume (by MRI/CT) from baseline
Change in spleen size (by palpation) from baseline
Changes in symptoms using MF-7 and EQ-5D from baseline
The frequency, duration, and severity of adverse events including abnormalities in vital 
signs, laboratory parameters and ECG data
Plasma ruxolitinib concentrations
2
Statistical methods
This section contains information that will be used to draft CSR Section 9.7 on statistical 
analysis.
2.1
Data analysis general information
Data analysis for the clinical study report will be performed by Novartis personnel, 
Biostatistics and Statistical Programming department.. SAS version 9.4 or later will be used to 
produce statistical outputs. One final analysis will be performed for efficacy assessments and 
safety endpoints using data collected up to the cut-off date. The cut-off date is determined by 
the study termination date.
Only data with an assessment or event start date (e.g., vital sign assessment date or start date 
of an AE) prior to or on the cut-off date will be included in the analysis. For example: if cut-
off date is 15-Jun-2014 then an AE starting on 13-Jun-2014 will be reported, whereas an AE 
with start date on 17-Jun-2014 will not be reported. 
All events with start date before or on the cut-off date and end date after the cut-off date will 
be flagged as ‘continuing at the cut-off date’. The same rule will be applied to events starting 


Novartis
For business use only
Page 11
Statistical analysis plan
CINC424A2353 (ReTHINK)
before or on the cut-off date and not having documented end date.  This approach applies, in 
particular, to adverse event and concomitant medication reports. For these events, the end date 
will not be imputed and therefore will not appear in the listings. However, for any analysis of 
duration of AE, the cut-off date will be used for censoring of this event which was ongoing at 
time of cut-off.  
Data post cut-off will not be included in the analysis datasets and not listed.
All participating study centers will be combined for the analysis unless otherwise specified.  
In general, no center effect will be assessed due to expected small patient enrollment size of 
centers. 
Since the randomization in this study is not stratified, no stratification factors are present.
Categorical data or qualitative characteristics of a subject (e.g., gender, race, subject 
disposition, etc.) will be summarized by frequency count (number of subjects) and 
percentages. Percentages will be calculated using the number of subjects in the relevant 
population or subgroup as the denominator.
Continuous data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (mean, standard deviation, median, minimum, and maximum).
2.1.1
General definitions
Investigational drug refers to ruxolitinib and study treatment refers to ruxolitinib or 
placebo.
2.1.2
Date of first administration of study treatment in treatment period 1
The date of first administration of study treatment is defined as the first date when a nonzero 
dose of study treatment was administered and recorded on DAR TRT1 eCRF. The date of first 
administration of study treatment in period 1 will also be referred as the start date of study 
treatment.
2.1.3
Date of last administration of study treatment in treatment period 1
The date of last administration of study treatment is defined as the last date when a nonzero 
dose of study drug was administered and recorded on DAR TRT1 eCRF.
2.1.4
Date of first administration of open label ruxolitinib in treatment period 
2
The date of first administration of open label ruxolitinib in treatment period 2 is defined as the 
first date when a nonzero dose of open label ruxolitinib was administered and recorded on 
DAR TRT2 (ruxolitinib) eCRF. 


Novartis
For business use only
Page 12
Statistical analysis plan
CINC424A2353 (ReTHINK)
2.1.5
Date of last administration of open label ruxolitinib in treatment period 
2
The date of last administration of open label ruxolitinib in treatment period 2 is defined as the 
last date when a nonzero dose of study drug was administered and recorded on DAR TRT2 
eCRF.
2.1.6
Last date of study treatment
The last date of study treatment is defined as (1) the date of last administration of study 
treatment in treatment period 1 if the patient never went to treatment period 2 or (2) the date 
of last administration of study treatment in treatment period 2 if the patient went to treatment 
period 2.
2.1.7
Study day
The term assessment will be used to represent an evaluation, a measurement or an event (e.g. 
AE onset, laboratory abnormality occurrence, disease progression, etc)
The study day for efficacy assessments will be calculated as follows:
Study day  =  date of assessment – randomization date + 1 
if date of assessment is after the randomization date. 
Study day  =  date of assessment – randomization date 
if date of assessment is before the randomization date.
The study day for safety assessments will be calculated as follows:
Study day  =  date of assessment – start date of study treatment + 1 
if date of assessment is after the randomization date. 
Study day  =  date of assessment – start date of study treatment
if date of assessment is before the randomization date.
For any assessment or events such as baseline disease characteristics or medical history (e.g., 
time since diagnosis of disease) that is supposed to occur prior to randomization/start date of 
the study treatment, study day will be negative. There is no Day 0 defined. 
Time unit
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If 
duration is reported in months, duration in days will be divided by 30.4375.  If duration is 
reported in years, duration in days will be divided by 365.25.
2.1.8
Baseline
Baseline values for safety and non-safety evaluations are defined as below unless specified 
otherwise in the RAP. 
For safety evaluations (e.g. laboratory and vital signs), the last assessment available before or 
on the start date of study treatment in period 1 (only if such assessment are pre-dose) is taken 
as a “baseline” assessment. 


Novartis
For business use only
Page 13
Statistical analysis plan
CINC424A2353 (ReTHINK)
For efficacy and other non-safety evaluations (e.g. MRI / CT scan), the last available 
assessment before or on the day of randomization is taken as the “baseline” value or 
“baseline” assessment. Multiple assessments on the same day are not expected.
If patients have no assessments as defined above, the baseline result will be missing.
2.1.9
Last contact date
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the latest complete date among the following:

Date of randomization

Last contact date/last date patient was known to be alive from the Survival Follow-up 
page (if patients status is alive)

Assessment dates (i.e. vital signs assessment, performance status assessment, and 
assessment date for spleen imaging, central laboratory, completed PROs)

Start/end dates from drug administration records and for further antineoplastic therapies 

Adverse events dates including the start and stop date of AEs

Date of discontinuation from ‘End of Treatment’ eCRF
The last contact date is defined as the latest complete date from the above list on or before the 
cut-off date. The cut-off date will not be used for last contact date, unless the patient was seen 
or contacted on that date. No date post cut-off date will be used. 
2.1.10
Windows for multiple assessments 
In order to summarize data collected over time (including unscheduled visits), the assessments 
will be time slotted. The following general rule will be applied in creating the assessment 
windows: If more than one assessment is done within the same time window, the assessment
performed closest to the target date will be used. If 2 assessments within a time window are 
equidistant from the target date, then the later of the 2 assessments will be used. Data from all 
assessments (scheduled and unscheduled), including multiple assessments, will be listed. 
Table 2-1
Time windows for imaging assessments
Time Window
Planned Visit Timing 
Time Window Definition
Screening
Study Days -7 to -1*
Study Days -7-1
Week 12
Study Day 84
Study Days 81-87
Week 24
Study Day 168
Study Days 161-175
Week 36
Study Day 252
Study Days 245-259
Week 48
Study Day 336
Study Days 329-343
Every 12 weeks thereafter
Week y=48+12*k
(with k = 1, 2, …)
Study Day (48+12*k)*7
Study Day 
Study Day (48+12*k)*7 – 7 to 
Study Day (48+12*k)*7 + 7 
Note: EOT data visit are 
included if obtained within 30 
days of last non-zero dose 


Novartis
For business use only
Page 14
Statistical analysis plan
CINC424A2353 (ReTHINK)
intake.
*Study Day 1 = randomization date
The visits and time windows apply to treatment period 1, 2 and post-treatment follow up, i.e. 
week 48 visit will be in the same window of 329-343 days in all these periods.
Table 2-2
Time windows for laboratory and spleen palpation assessments
Time Window
Planned Visit Timing 
Time Window Definition
Baseline (Day 1)
On Study Day 1*
Study Days -40-1
Week 4
Study Day 28
Study Days 25-31
Week 8
Study Day 56
Study Days 49-63
Week 12
Study Day 84
Study Days 81-87
Week 16
Study Day 112
Study Days 105-119
Week 20
Study Day 140
Study Days 133-147
Week 24
Study Day 168
Study Days 161-175
Week 32
Study Day 224
Study Days 217-231
Week 36
Study Day 252
Study Days 245-259
Week 48
Study Day 336
Study Days 329-343
Every 12 weeks thereafter
Week y=48+12*k
(with k = 1, 2, …)
Study Day (48+12*k)*7
Study Day 
Study Day (48+12*k)*7 – 7 to 
Study Day (48+12*k)*7 + 7 
Note: EOT data visit are 
included if obtained within 30 
days of last non-zero dose 
intake.
2.2
Analysis sets
2.2.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been 
assigned by randomization. According to the intent to treat principle, patients will be analyzed 
according to the treatment they have been assigned to during the randomization procedure.
2.2.2
Safety Set
The Safety Set includes all patients who received at least one dose of study medication...
Patients will be analyzed according to the study treatment received, where treatment received 
is defined as the randomized treatment if the patient took at least one dose of that treatment or 
the first treatment received in the randomized treatment was never received.
2.2.3
Per-Protocol Set
Not Applicable for this prematurely terminated study. 


Novartis
For business use only
Page 15
Statistical analysis plan
CINC424A2353 (ReTHINK)
2.2.4
Pharmacokinetic analysis set
Not Applicable for this prematurely terminated study.
2.2.5
Subgroup of interest
Not Applicable for this prematurely terminated study.
2.2.6
Withdrawal of Informed Consent
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis data sets.  The date on 
which a patient withdraws full consent will be recorded in the eCRF. 
Death events in some countries can be reported if the death event can be confirmed to be 
captured from public records (registers).  If confirmed, the events will be included in the 
analysis.
Third party data e.g. PK, 
 etc., collected in the clinical database without having 
obtained consent for collection will not be included in the analysis data sets. These data will 
be excluded by the presence of the appropriate protocol deviation criterion.
2.3
Patient disposition, demographics and other baseline 
characteristics
Demographic and other baseline data (including disease characteristics) will be summarized 
descriptively by treatment group for the FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented.
Demographic characteristics to be summarized: age, sex, race, ethnicity, weight, height, BMI, 
and ECOG performance status.
Disease characteristics: type of MF, baseline spleen size and volume, MF-7 score, prior MF 
treatment, JAK2 mutation status, CALR mutation status, MPL mutation status, HMR 
mutation status, number of individual mutations,  baseline hemoglobin level (as continuous 
variable and relative to 10g/dL), platelet count (as continuous variable and relative to 
75,000/µL), absolute neutrophil count (ANC) (continuous variable and relative to 1000/μL), 
white blood count (continuous variable and relative to WBC > 15 x 103/ μL).
2.3.1
Patient disposition
The number of patients who had molecular pre-screening, number of screened patients and 
number of patients randomized will be tabulated. This summary will be produced for all pre -
screened patients.  Reasons for screening failure will be summarized and listed.
Patient disposition will be tabulated for the treatment period 1.  FAS will be used for these 
summaries. The summary will include the number of patients who were randomized, treated, 
ongoing, permanently discontinued from treatment period 1 and went to treatment period 2. 
Patient disposition for both treatment period 1 and treatment period 2 will be listed.


Novartis
For business use only
Page 16
Statistical analysis plan
CINC424A2353 (ReTHINK)
The following summaries will be provided: % based on the total number of FAS patients:

Number (%) of patients who were randomized (based on data from IRT system)

Number (%) of patients who were randomized but not treated (based on ‘DAR’ eCRF 
page not completed for any study treatment component)

Primary reason for not being treated (based on “End of Treatment Phase Completion” 
eCRF page) 

Number (%) of patients who were treated (based on ‘DAR’ eCRF pages of each study 
treatment component completed with non-zero dose administered)

Number (%) of patients who are still on-treatment (based on the ‘End of Treatment Phase’ 
page not completed); 

Number (%) of patients who discontinued the study treatment phase (based on the ‘End of 
Treatment Phase’ page) 

Primary reason for study treatment phase discontinuation (based on the ‘End of Treatment 
Phase’ page)

Number (%) of patients who have entered the post-treatment follow-up (based on the ‘End 
of Treatment Phase’ page);

Number (%) of patients who have discontinued from the post-treatment follow-up (based 
on the Study Evaluation Completion/ End of Post-treatment follow-up  page);

Reasons for discontinuation from the post-treatment follow-up (based on Study Evaluation 
Completion/ End of Post-treatment follow-up page);

Number (%) of patients who have entered the survival follow-up (based on the ‘End of 
Treatment Phase’ or ‘End of Post-treatment follow-up’ page).
Protocol deviations
The number (%) of patients in the FAS with any protocol deviation will be tabulated by 
deviation category (as specified in the study Data Handling Plan) overall and by treatment 
group for the FAS. Major protocol deviations leading to exclusion from analysis sets will be 
tabulated separately overall and by treatment group. All protocol deviations will be listed.
Analysis sets
The number (%) of patients in each analysis set will be summarized by treatment group.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
The safety set will be used for the analyses below.
The average daily dose, cumulative dose, duration of exposure in treatment period 1 to 
ruxolitinib or placebo, dose intensity will be listed and summarized by treatment group. 
Duration of exposure and duration of follow up will be categorized into time intervals; 
frequency counts and percentages will be presented for the number (%) of subjects in each 
interval. The number (%) of subjects who have dose reductions or interruptions, and the 
reasons, will be summarized by treatment group.


Novartis
For business use only
Page 17
Statistical analysis plan
CINC424A2353 (ReTHINK)
The dose administration records for both treatment period 1 and treatment period 2 will be 
listed, including the duration of exposure for patients who will enter treatment period 2. 
Concomitant medications including prohibited medications, and significant non-drug 
therapies prior to and after the start of the study treatment will be summarized for all patients 
and by treatment group.
2.4.1
Study treatment / compliance
Duration of exposure in treatment period 1 is considered by taking into account the 
duration of exposure to ruxolitinib or placebo.
Duration of exposure in treatment period 1 (days) = (date of last administration of study 
treatment in treatment period 1) – (date of first administration of study treatment in treatment 
period 1) + 1.
Duration of exposure in treatment period 2 is considered by taking into account the 
duration of exposure to open label ruxolitinib.
Duration of exposure in treatment period 2 (days) = (date of last administration of study 
treatment in treatment period 2) – (date of first administration of study treatment in treatment 
period 2) + 1.
Summary of duration of exposure in treatment period 1 of study treatment in appropriate time 
units will include categorical summaries and continuous summaries (i.e. mean, standard 
deviation etc) using appropriate units of time.
Duration of follow up is defined as last contact date – randomization date + 1.
The average daily dose refers to the actual daily dose administered.
The cumulative dose in treatment period 1 refers to the total actual dose administered, over 
the duration exposure in treatment period 1.
Dose intensity in treatment period 1 (DI1) for subjects with non-zero duration of exposure 
in treatment period 1 is defined as follows: 
DI1 (mg/day) = Actual Cumulative dose in treatment period 1 (mg) / Duration of exposure to 
study treatment in treatment period 1 (days).
The number of subjects who have dose reductions, permanent discontinuations or 
interruptions, and the reasons, will be summarized separately for each of the study treatment
components. 
‘Dose changed’, ‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the 
Dosage Administration CRF pages (DAR) will be used to determine the dose reductions, dose 
interruptions, and permanent discontinuations, respectively.
The corresponding fields ‘Reason for dose change/dose interrupted’ and ‘Reason for 
permanent discontinuation’ will be used to summarize the reasons.
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption that are entered on consecutive days with different reasons will be counted as 


Novartis
For business use only
Page 18
Statistical analysis plan
CINC424A2353 (ReTHINK)
separate interruptions. However, if the reason is the same in this block of entries, then it will 
be counted as one interruption.
The protocol allows use of dose tapering strategy for patients who permanently discontinue 
study treatment and a separate summary will be produced with the number of patients for 
whom dose tapering will be recorded in treatment period 1 and treatment period 2.
2.4.2
Prior, concomitant and post therapies
Prior MF therapy
Prior medications to treat MF will be listed and summarized by ATC class, preferred term, 
overall and by treatment group by means of frequency counts and percentages using FAS.
Post treatment anti-cancer therapy
Anti-neoplastic therapies since discontinuation of study treatment will be listed and 
summarized by ATC class, preferred term, overall and by treatment group by means of 
frequency counts and percentages using FAS.
Concomitant medications
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a patient coinciding with the study treatment 
period. Concomitant therapy include medications (other than study drugs) starting on or after 
the start date of study treatment or medications starting prior to the start date of study 
treatment and continuing after the start date of study treatment. 
Concomitant medications will be coded using the <World Health Organization (WHO) Drug 
Reference  Listing  (DRL)  dictionary  that  employs  the  WHO  Anatomical  Therapeutic 
Chemical (ATC) classification system and summarized by lowest ATC class and preferred 
term using frequency counts and percentages. Surgical and medical procedures will be coded 
using MedDRA and summarized by SOC and preferred term. These summaries will include:
1. Medications starting on or after the start of study treatment but no later than 30 days 
after start of last dose of study treatment and
2. Medications starting prior to start of study treatment and continuing after the start of 
study treatment.
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior 
to the start of study treatment or starting more than 30 days after the last date of study 
treatment will be flagged in the listing. The safety set will be used for all concomitant 
medication tables and listings.
2.5
Analysis of the primary objective
The study was terminated prematurely with insufficient sample size and study duration to 
evaluate the effect of ruxolitinib in delaying progression of MF from early disease to more 
advanced disease stages. Therefore, the initial primary end point, progression free survival 


Novartis
For business use only
Page 19
Statistical analysis plan
CINC424A2353 (ReTHINK)
(PFS), will not be derived and no statistical hypothesis will be tested. Consequently, no 
supportive analysis for per protocol set is planned.
The early terminated study aims to present data collected for the endpoints of interest, 
including change in spleen volume and length from baseline, change in symptoms using MF-7 
and EQ-5D from baseline (see patient reported outcomes section), safety endpoints
 
 Descriptive statistics will be used to summarize the endpoints of interest and the 
FAS will be used for analyzing the data. Change in spleen volume and palpable spleen length 
below costal margin
Regular assessments of spleen volumes via Magnetic Resonance Imaging (MRI) or Computed 
Tomography (CT) are performed to evaluate progressive splenomegaly. Spleen size is 
assessed by palpation and measured in centimeters using a soft ruler, from the coastal margin 
to the point of greatest splenic protrusion. 
Spleen volume, spleen length, absolute change and percentage change in spleen volume by 
MRI/CT and palpable spleen length below costal margin will be summarized descriptively by 
treatment for each assessment timepoints. 
2.6
Analysis of the key secondary objective
There are no key secondary objectives in this study.
2.7
Analysis of secondary efficacy objective(s)
No sufficient data were collected to assess the effect of ruxolitinib versus placebo on overall 
survival and time to progression, so that no secondary efficacy analysis will be performed in 
this study. 
2.8
Safety analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group.
The overall observation period will be divided into four mutually exclusive segments:
pre-treatment period: from day of patient’s informed consent (molecular pre-screen or main 
study informed consent) to the day before the first administration of study 
treatment
on-treatment period 1: from day of start of study treatment to minimum of (1) 30 days 
following the last date of study treatment in period 1 and (2) start of open label 
ruxolitinib in treatment period 2:
[Start date of study treatment; min(last date of study treatment  in treatment 
period 1 + 30 days, start date of open label ruxolitinib in treatment period 2 –
1 day)]. 
on-treatment period 2: from start day of open label ruxolitinib to 30 days following the last 
date of study treatment in period 2:
[Start date of open label ruxolitinib in treatment period 2; last date of open label 
ruxolitinib in treatment period 2 + 30 days]. 
post-treatment period: starting at day 31 after last dose of study treatment.


Novartis
For business use only
Page 20
Statistical analysis plan
CINC424A2353 (ReTHINK)
On-treatment assessment is defined as any assessment reported in the on-treatment period 1 or 
2. 
Safety summaries (tables, figures) include data from the pre-treatment period (to display the 
baseline status) and the on-treatment period 1. Data from the on-treatment period 2 (if 
provided) and the post-treatment period (if provided) with the exception of deaths should not 
be included.
In particular, summary tables for adverse events (AEs) will summarize only on-treatment 
events, with a start date during the on-treatment period 1, the so-called treatment-emergent
AEs for period 1.  
However, all safety data (including those from the post-treatment period if provided) will be 
listed and those collected during the pre-treatment, treatment period 2 and post-treatment 
period will be flagged.
2.8.1
Adverse events (AEs)
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 Common 
Terminology Criteria for Adverse Events] grades, using CTCAE version 4.03), type of 
adverse event, relation to study treatment by treatment group.
Serious adverse events and non-serious adverse events during the on-treatment period will be 
tabulated.
All deaths (on-treatment and post-treatment) will be tabulated.
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT)
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event.
In AE summaries the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order 
for the preferred term will be based on their frequency in the ruxolitinib arm.
The following adverse event summaries will be produced by treatment; overview of adverse 
events and deaths (number and % of subjects who died, with any AE, any SAE, any dose 
reductions/interruptions), AEs by SOC and PT, summarized by relationship (all AEs and AEs 
related to study treatment), seriousness (SAEs and non-SAEs), leading to treatment 
discontinuation, leading to dose interruption/adjustment, requiring additional therapy and 
leading to fatal outcome. In addition, for the summary of serious and non-serious adverse 
events the number of occurrences will be produced (an occurrence is defined as >1 day 
between start and prior end date of record of same preferred term
2.8.1.1
Adverse events of special interest / grouping of AEs
Not planned for this premature termination study.


Novartis
For business use only
Page 21
Statistical analysis plan
CINC424A2353 (ReTHINK)
2.8.1.2
Adverse events of clinical trial safety disclosure
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on adverse 
events which are not serious adverse events with an incidence greater than 5% and on serious 
adverse events and SAE suspected to be related to study treatment will be provided by system 
organ class and preferred term on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective of study treatment relationship will be provided by SOC and PT.
2.8.2
Deaths
Separate summaries for on-treatment and all deaths (on-treatment and post-treatment) will be 
produced by treatment arm, system organ class and preferred term. All deaths will be listed, 
post treatment deaths will be flagged.
2.8.3
Laboratory data
Laboratory, data summaries will include all assessments available for the lab parameter 
collected no later than 30 days after the last study treatment administration date, using data 
from all sources (central and local laboratories). All laboratory assessments will be listed and 
those collected later than 30 days after the last study treatment date will be flagged in the 
listings.
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. The criteria to assign CTCAE grades are given in <Novartis internal 
criteria for CTCAE grading of laboratory parameters>. The latest available version of the 
document based on the underlying CTCAE version 4.03 at the time of analysis will be used. 
The Novartis internal CTCAE grading document will be added as appendix to the CSR.
For laboratory tests where grades are not defined by CTCAE v4.03, results will be graded by 
the low/normal/high (or other project-specific ranges, if more suitable) classifications based 
on laboratory normal ranges.
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 will not be used. For laboratory tests that are graded for both low and high values, 


Novartis
For business use only
Page 22
Statistical analysis plan
CINC424A2353 (ReTHINK)
summaries will be done separately and labelled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia.
In rare cases where multiple lab measurements meet the baseline definition, with no further 
flag or label that can identify the chronological order then the following rule should be 
applied: If values are from central and local laboratories, the value from central assessment 
should be considered as baseline. If multiple values are from the same laboratory (local or 
central) then the value with the last sequence/repeat number should be considered as baseline.
A listing of laboratory values will be provided by laboratory test, patient, and study day. A 
separate listing will display notable laboratory abnormalities (i.e., newly occurring CTCAE 
grade 3 or 4 laboratory abnormalities).
The following by-treatment summaries will be generated separately for hematology and 
biochemistry 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.

Boxplots of hematological parameters (hemoglobin and platelet count) over time
2.8.4
Other safety data
Analyses will be performed on the safety set.
2.8.4.1
ECG and cardiac imaging data
A standard 12 lead ECG will be performed at screening, every 48 weeks and at the end of
Treatment, read and interpreted locally per protocol specifications. The ECG data will be 
listed. 
2.8.4.2
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm), weight (kg), body temperature (°C), heart 
rate (beats per minute), systolic and diastolic blood pressure (mmHg), and respiratory rate 
(per minute).
Data handling
Vital signs collected during on-treatment will be summarized. Values measured outside of on-
treatment period will be flagged in the listings.
Data analysis
For analysis of vital signs the notable criteria are provided in Table 7-1 below.


Novartis
For business use only
Page 23
Statistical analysis plan
CINC424A2353 (ReTHINK)
Table 2-3
Notable Criteria for vital signs
Vital sign (unit)
Notable high value 
Notable low value
Weight (kg)
increase >= 10% from baseline
decrease  >= 10% from baseline
Systolic blood 
pressure (mmHg)
>=180 and 
increase from baseline of >=20
<=90 and
decrease from baseline of >=20
Diastolic blood 
pressure (mmHg)
>=105 and 
increase from baseline of >=15 
<=50 and 
decrease from baseline of >=15
Pulse rate (bpm)
>=100 and 
increase from baseline of >25%
<=50 and 
decrease from baseline of >25%
Body temperature
( o C)
>= 39.1 
--
Summary table will be produced for vital signs. The table will include descriptive statistics at 
baseline, one or several post-baseline time points and change from baseline to this/these post-
baseline time points.
A listing of all vital sign assessments will be produced by treatment arm and notable values 
will be flagged. In the listing, the assessments collected outside of on-treatment period will be 
flagged as well as assessments made in treatment period 2.
2.9
Pharmacokinetic endpoints
All individual plasma ruxolitinib concentration data will be listed for the Full analysis set.
Handling of PK data below LLOQ or missing 
All concentration values below the lower limit of quantitation (LLOQ) (0.50 ng/mL) are set to 
zero by the Bioanalyst, and will be displayed in the listings as zero and flagged. Missing 
values for any PK data will not be imputed and will be treated as missing.
2.11
Patient-reported outcomes
There are several patient reported outcomes measured in the study, including the 
Myeloproliferative Neoplasm-Symptom Assessment Form (MF-7) Total Symptom Score, the 
EQ-5D and 
. The FAS will be used for analyzing PRO data. No formal 
statistical test will be performed. 
Change in symptoms using MF-7
The MF-7 total symptom score is among the key patient reported outcome variables of 
interest. It will be used to collect data on the impact of ruxolitinib treatment on the patient’s 
disease-related symptoms, functioning and overall quality of life. No formal statistical test 


Novartis
For business use only
Page 24
Statistical analysis plan
CINC424A2353 (ReTHINK)
will be performed. Percent change from Baseline in MF-7 total symptom score and 7
individual symptoms at each visit will be summarized with descriptive statistics.
Missing items data in a PRO scale will be handled based on each instrument manual. All PRO 
analyses will include data as imputed according to the scoring manual. No imputation will be 
applied if the total or subscale scores are missing at a visit.
Change in EQ-5D from baseline
The EQ-5D is among the key PRO variables of interest. EQ-5D profiles for each of the five 
dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) will be 
tabulated by each level (no problems, slight problems, moderate problems, severe problems, 
and extreme problems) at baseline and each scheduled assessment.  
EQ visual analogue scale (VAS) values will be summarized descriptively by arm for each 
scheduled visit.
The EQ VAS self-rating records of the respondent’s own assessment on their health status. 
The EQ VAS scores are anchored on 100=the best health you can imagine and 0=worst health 
you can imagine.
Imputation: There should be only ONE response for each dimension.   Missing values will be
coded as ‘9’. Ambiguous values (e.g. 2 boxes are ticked for a single dimension) will be 
treated as missing values.
2.13
Bone marrow biopsy and aspirate
The bone marrow biopsy and aspirate assessments data collected at baseline and end of 
treatment (if available) will be presented in listing. The bone marrow fibrosis is graded
according to the IWG consensus criteria for treatment response (Tefferi 2013) and bone 
marrow blast count in percentage is measured for leukemic transformation.


Novartis
For business use only
Page 25
Statistical analysis plan
CINC424A2353 (ReTHINK)
2.15
Interim analysis
Not applicable.
3
Sample size calculation
Not applicable.
4
Change to protocol specified analyses
Not applicable.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
Any partial dates or gaps between dates should be resolved. The end date of study drug is 
derived by using the last non-zero dose end date from the dose administration record CRF 
page. 
If after DBL the partial dates still exist for end date, the imputation rule is as below:
If Month and Year is present, but day is missing, set the end date to be the first day of the 
month. If after imputation of day, study medication end date is earlier then study medication
start date set study medication end date to study medication start date.
5.1.2
AE date imputation
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 post-treatment period) will be listed and those collected during the 
pre-treatment and after 30 days of post- treatment period are to be flagged.
Any missing onset date, causality, or severity must be queried for resolution. Unsolved 
missing values will be imputed according to the following:

An unsolved missing causality will be left as missing.

An unsolved missing severity will be left as missing in the AE tables. For AEs listed by 
highest severity, AE terms with missing severity will be excluded.

An unsolved missing onset date will be imputed by the date of Day 2, which will force the 
AE to be treatment emergent, with the following exceptions:

If the stop/resolution date is prior to Study Day 1, the AE will then be considered as 
not being treatment-emergent.


Novartis
For business use only
Page 26
Statistical analysis plan
CINC424A2353 (ReTHINK)

If both the month and day of the onset date are missing, and the last day of the year is 
prior to Study Day 1, the AE will then be considered as not being treatment-emergent. 

If only the day of the onset date is missing, and the last day of the month is prior to 
Study Day 1, then the AE will be considered as not being treatment-emergent.

If only the day of the onset date is missing, and the 1st day of the month is after Study 
Day 1, the AE will then be considered as being treatment-emergent, and the 
incomplete date will be imputed as the 1st of the month.

If the non-missing stop/resolution date is equal to Study Day 1, the AE will then be 
considered as not being treatment-emergent.
5.1.3
Concomitant medication date imputation
The start/stop dates recorded in the electronic case report form (eCRF) will be used to identify 
when a concomitant medication or a significant non-drug therapy was taken during the study.
Concomitant medications and significant non-drug therapies after the start of the study 
treatment will be listed and summarized by ATC class and standardized medication term for 
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 and continuing after the 
start of study treatment. Any prior medications and significant non-drug therapies starting and 
ending prior to the start of study treatment will be listed. These analyses will be based on 
Safety Set.
Any missing start date will be queried for resolution. For any unsolved missing start dates, the 
following rules in the following order will be applied to decide if a concomitant medication or 
a significant non-drug therapy was taken after the start of the study treatment and to decide if 
the data should be included in the summary table. Originally collected start date will be listed 
in listings.

If the date is completely missing, the Day 1 date will be used as the missing start date.

If only the day is missing, and the last day of the month is prior to Study Day 1, the 
concomitant medication will be then considered as starting prior to Day 1. 

If only the day is missing, and the 1st day of the month is after the 1st dosing date on Day 1, 
the concomitant medication will then be considered as starting after Day 1.

If only the day is missing, and the month is equal to the month of the 1st dosing date on 
Day 1, Study Day 2 will be used as the missing day.

If both the month and day are missing, and the last day of the year is prior to Study Day 1, 
the concomitant medication will then be considered as starting prior to Day 1.
No rule will be applied to any missing stop date. If Start/Stop will be the start/stop date of a 
concomitant medication, Date1 will be the date of first INC dose, the concomitant medication 
will then be allocated to 1 or more summary groups according to the following algorithm as 
shown in Table 5-1.
Table 5-1
Allocation of concomitant medications
If
Prior 
Medication
Treatment 
Phase


Novartis
For business use only
Page 27
Statistical analysis plan
CINC424A2353 (ReTHINK)
If
Prior 
Medication
Treatment 
Phase
Stop≤Date1
X
Start≤Date1 and Stop=missing and ongoing
X
X
Start<=Date1<=Stop
X
X
Start>Date1 
X
5.1.3.1
Prior therapies date imputation
Partial end date of prior therapies date imputation rules are as below: 
If only day missing then impute to be 15th of month but should be seven days prior to the start 
date of study drug. If month and day missing then impute last month and day of year but 
should be seven days prior to the start date of study drug. If entire date is missing then leave 
as missing.
5.1.3.2
Post therapies date imputation
Start date: 

If Day is missing, then impute to the max (reference start date, first day of the month). 

Day and month are missing then impute to the max(reference start date, Jan 1) 

Reference start date will be last date of study treatment administration + 1. 
End date: No imputation
5.1.3.3
Other imputations
Missing death date
For cases when either day is missing or both month and day are missing for the date of death, 
the following imputation rules will be implemented:

If only day is missing, then impute max [(1 mmm-yyyy), min(last contact date+1 , cutoff 
date)]. 
If both day and month are missing, then impute max [(1 Jan-yyyy, min (last contact date +1, 
cutoff date)].
5.2
AEs coding/grading
Adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. AEs are graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03.
The CTCAE represents a comprehensive grading system for reporting the acute and late 
effects of cancer treatments. CTCAE grading is by definition a 5-point scale generally 
corresponding to mild, moderate, severe, life threatening, and death. This grading system 
inherently places a value on the importance of an event, although there is not necessarily 
proportionality among grades (a grade 2 is not necessarily twice as bad as a grade 1). The 


Novartis
For business use only
Page 28
Statistical analysis plan
CINC424A2353 (ReTHINK)
CTCAE grade of 5 (death) is not used; rather, ‘fatal’ is collected as AE outcome and death 
information is also collected on a separate (e)CRF page.
5.3
Laboratory parameters derivations
All laboratory values will be converted into SI units and the severity grade calculated using 
appropriate common toxicity criteria (CTC).
As CTC only grades lab values as grade 1-4, grade 0 will be used when lab value is normal. A 
severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 will not be used. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labelled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia.
If sites report WBC differential counts in percentage (%) with corresponding lab normal 
ranges in terms of %, the % differentials will be converted to absolute differentials as:
Absolute value = [Value (%)/100] x WBC.
However, the normal ranges will no longer be applicable after conversion. For such cases, 
then for CTC grading reporting purposes, the <Novartis internal criteria for CTCAE grading 
of laboratory parameters>will be referenced to determine the CTC grade.


Novartis
For business use only
Page 29
Statistical analysis plan
CINC424A2353 (ReTHINK)
Table 5-2
Visit evaluation schedule in respect to the components of the primary endpoint
A) Treatment Period 1 (Blinded)
Visit Name
Category
Molecular Pre-
screening
Screening
Treatment Period 1 (Blinded)
End of treatment 
(EOT)
Progressive 
disease (PD) 
confirmation
Safety Follow up 
30 days after last 
dose
Post treatment 
follow up
Survival Follow up 
(Every 3 months)
Day 1
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 32
Week 36 (MRI / 
CT)
Week 40
Week 48+ 
(every 12 
weeks until 
EOT)
Day
-40 to -1
1
28
56
84
112
140
168
224
252
280
336+
Visit window (Study 
day)
+/-3
+/-3
+/-3
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
+/-7
Hematology
D
x
x
x
x
x
x
x
x
x
x
x
x
x
x
MRI/CT
D
x (-7 to -
1)
x
x
x
x
x
x
Bone Marrow biopsy 
and aspirate
D
x
x (every 2 years)
x
x
MF-7
D
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
B) Treatment Period 2 (Ruxolitinib) for patients progressing due to splenomegaly or symptoms (MF-7 score)
Visit Name
Category
Treatment Period 2 (Ruxolitinib)
End of treatment 
(EOT)
Progressive 
disease (PD) 
confirmation
Safety Follow up 30 
days after last dose
Survival Follow up 
(Every 3 months)
First dose –
Ruxolitinib
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 32
Week 36 (MRI / 
CT)
Week 40
Week 48+ 
(every 12 weeks 
until EOT)
Day
28
56
84
112
140
168
224
252
280
336+
Visit window (Study day)
+/-3
+/-3
+/-3
+/-3
+/-3
+/-7
+/-7
+/-7
+/-7
+/-7
MRI/CT
D
x
x
x
x
x
MF-7
D
x
x
x
x
x
x
x
x
x
x
x 
x


Novartis
For business use only
Page 30
Statistical analysis plan
CINC424A2353 (ReTHINK)
6
Reference
Tefferi et al (2013) Revised response criteria for myelofibrosis: International Working Group-
Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European  
LeukemiaNet (ELN) consensus report. Blood. 2013;122(8):1395-1398.