Conditions: Corticosteroid Refractory Acute Graft vs Host Disease
Keywords: GvHD (Graft versus Host Disease) INC424 ruxolitinib best available therapy (BAT) corticosteroid-refractory acute graft vs. host disease allogeneic stem cell transplantation steroid refractory acute graft vs. host disease Janus Kinase (JAK) inhibitor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 310
Healthy volunteers: no

Brief summary:
Assess the efficacy and safety of ruxolitinib compared to Best Available Therapy (BAT) in patients with corticosteroid-refractory acute graft vs. host disease (aGvHD) after allogeneic stem cell transplantation.

Detailed description:
This randomized, phase III, open-label study investigated the efficacy and safety of ruxolitinib vs. BAT added to the patient's immunosuppressive regimen in adults and adolescents (≥ 12 years old) with grade II-IV Steroid-refractory Acute Graft vs. Host Disease (SR-aGvHD). During the screening period, patients were monitored for a diagnosis of SR-aGvHD, which was defined as patients who had high-dose systemic corticosteroids (methylprednisolone 2 mg/kg/day \[or equivalent prednisone dose 2.5 mg/kg/day\]), given alone or combined with CNI, who either:

1. Progressed based on organ assessment after at least 3 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD, OR
2. Failed to achieve at a minimum a partial response based on organ assessment after 7 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD, OR
3. Failed corticosteroid taper defined as fulfilling either one of the following criteria:

   * Requirement for an increase in the corticosteroid dose to methylprednisolone ≥ 2 mg/kg/day (or equivalent prednisone dose ≥ 2.5 mg/kg/day) OR
   * Failure to taper the methylprednisolone dose to \<0.5 mg/kg/day (or equivalent prednisone dose \<0.6 mg/kg/day) for a minimum 7 days.

Patients meeting eligibility criteria were randomized 1:1 to receive either ruxolitinib or BAT stratifying on aGvHD grade at the time of randomization (Grade II vs III vs IV).

Study treatment began on Day 1 (no later than 72 hours after randomization) followed by regular visits for assessments of efficacy and safety. Study treatment was administered until the patient met any of the criteria for discontinuation of study treatment or, in responders (i.e. patients achieving PR or CR) until the dosing schedule for ruxolitinib or BAT was completed.

All responders were to be tapered off during the treatment period by, first tapering from corticosteroids, followed by CNI and ruxolitinib. A slow tapering extending beyond 24 weeks was permitted for ruxolitinib at Investigator's discretion rather than an abrupt cessation, as the latter could result in an aGvHD flare.

During the Treatment Period, patients randomized to BAT could have crossed over to ruxolitinib between Day 28 and Week 24 if they:

* Failed to meet the primary endpoint response definition (CR or PR) at Day 28 OR
* Lost the response thereafter and met criteria for progression, mixed response, or no response, necessitating new additional systemic immunosuppressive treatment for aGvHD.

AND

\- Did not have signs/symptoms of chronic Graft vs. Host Disease (cGvHD) (overlap syndrome, progressive, or de novo cGvHD)

Patients who crossed over to ruxolitinib were followed until completion of treatment with ruxolitinib and received the same treatment and tapering schedule as patients randomized to ruxolitinib treatment.

The End of Treatment (EOT) visit occurred when the patient completed the study treatment period or earlier if the patient met any of the criteria for discontinuation of study treatment.

Patient's treatment period was up to 6 months (Week 24). However, ruxolitinib taper could be delayed up to 2 years from randomization due to an aGvHD flare or other safety concerns.

Arms:
arm 1: These patients were administered Ruxolitinib orally twice per day (b.i.d) at a dose of 10 mg bid, as two 5-mg tablets. Ruxolitinib was taken without regards to food. arm 2: These patients were administered BAT per the Investigator's best judgement based on a specific list of BAT.

Interventions: intervention 1: Ruxolitinib (RUX) intervention 2: Best Available Therapy (BAT)
Intervention descriptions: intervention 1: Ruxolitinib was provided as 5 mg tablets for oral use. intervention 2: BAT was based on the investigator's best judgment, taking into account the manufacturer's instructions, labeling, patient's medical condition, and institutional guidelines for any dose adjustment. The BAT in this study was identified by the investigator prior to patient randomization among the following treatments currently used in this setting: anti-thymocyte globulin (ATG), extracorporeal photopheresis (ECP), mesenchymal stromal cells (MSC), low-dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR inhibitors (everolimus or sirolimus), etanercept, or infliximab. No other types or combinations of BAT were permitted.

Protocol document:
Prot_000.pdf: 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 12 
Amendment 2 (21-Jun-2018) ............................................................................................ 13 
Amendment 1 (31-May-2017) ........................................................................................... 18 
Protocol Summary ............................................................................................................. 25 
1 
Background ........................................................................................................................ 28 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 28 
1.2 
Introduction to investigational treatment(s) and other study treatment(s)............. 30 
1.2.1 
Overview of ruxolitinib ......................................................................... 30 
2 
Rationale ............................................................................................................................ 35 
2.1 
Study rationale and purpose................................................................................... 35 
2.2 
Rationale for the study design ............................................................................... 35 
 
 38 
2.3 
Rationale for dose and regimen selection .............................................................. 38 
2.4 
Rationale for choice of combination drugs ............................................................ 39 
2.5 
Rationale for choice of comparators drugs ............................................................ 39 
2.6 
Risks and benefits .................................................................................................. 39 
3 
Objectives and endpoints ................................................................................................... 42 
4 
Study design ...................................................................................................................... 47 
4.1 
Description of study design ................................................................................... 47 
4.2 
Timing of interim analyses and design adaptations ............................................... 51 
4.3 
Definition of end of study ...................................................................................... 52 
4.4 
Early study termination.......................................................................................... 52 
5 
Population .......................................................................................................................... 52 
5.1 
Patient population .................................................................................................. 52 
5.2 
Inclusion criteria .................................................................................................... 53 
5.3 
Exclusion criteria ................................................................................................... 54 
6 
Treatment ........................................................................................................................... 56 
6.1 
Study treatment ...................................................................................................... 56 
6.1.1 
Dosing regimen ..................................................................................... 56 
6.1.2 
Ancillary treatments .............................................................................. 58 
6.1.3 
Rescue medication ................................................................................ 58 


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6.1.4 
Guidelines for continuation of treatment .............................................. 58 
6.1.5 
Treatment duration ................................................................................ 58 
6.2 
Dose escalation guidelines ..................................................................................... 61 
6.3 
Dose modifications ................................................................................................ 61 
6.3.1 
Dose modification and dose delay ........................................................ 61 
6.3.2 
Anticipated risks and safety concerns of the study treatment ............... 70 
6.4 
Concomitant medications ...................................................................................... 70 
6.4.1 
Permitted concomitant therapy ............................................................. 70 
6.4.2 
Permitted concomitant therapy requiring caution and/or action ........... 71 
6.4.3 
Prohibited concomitant therapy ............................................................ 71 
6.5 
Patient numbering, treatment randomization ......................................................... 72 
6.5.1 
Patient numbering ................................................................................. 72 
6.5.2 
Treatment randomization ...................................................................... 72 
6.5.3 
Treatment blinding ................................................................................ 73 
6.6 
Study drug preparation and dispensation ............................................................... 73 
6.6.1 
Study treatment packaging and labeling ............................................... 73 
6.6.2 
Drug supply and storage ........................................................................ 74 
6.6.3 
Study drug compliance and accountability ........................................... 74 
6.6.4 
Disposal and destruction ....................................................................... 75 
7 
Visit schedule and assessments ......................................................................................... 75 
7.1 
Study flow and visit schedule ................................................................................ 75 
7.1.1 
Molecular pre-screening ........................................................................ 91 
7.1.2 
Screening ............................................................................................... 91 
7.1.3 
Run-in period ........................................................................................ 94 
7.1.4 
Treatment period ................................................................................... 94 
7.1.5 
Discontinuation of study treatment ....................................................... 95 
7.1.6 
Withdrawal of Consent ......................................................................... 96 
7.1.7 
Follow-up for Safety Evaluations ......................................................... 97 
7.1.8 
Lost to follow-up ................................................................................... 98 
7.2 
Assessment types ................................................................................................... 98 
7.2.1 
Efficacy assessments ............................................................................. 98 
7.2.2 
Safety and tolerability assessments ..................................................... 100 
7.2.3 
Pharmacokinetics ................................................................................ 105 
 
 108 
 
 112 
7.2.6 
Patient reported outcomes ................................................................... 112 


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8 
Safety monitoring and reporting ...................................................................................... 113 
8.1 
Adverse events ..................................................................................................... 113 
8.1.1 
Definitions and reporting .................................................................... 113 
8.1.2 
Laboratory test abnormalities .............................................................. 114 
8.1.3 
Adverse events of special interest ....................................................... 115 
8.2 
Serious adverse events ......................................................................................... 115 
8.2.1 
Definitions ........................................................................................... 115 
8.2.2 
Reporting ............................................................................................. 116 
8.3 
Emergency unblinding of treatment assignment ................................................. 117 
8.4 
Pregnancies .......................................................................................................... 117 
8.5 
Warnings and precautions.................................................................................... 117 
8.6 
Data Monitoring Committee ................................................................................ 117 
8.7 
Steering Committee ............................................................................................. 118 
9 
Data collection and management ..................................................................................... 118 
9.1 
Data confidentiality ............................................................................................. 118 
9.2 
Site monitoring .................................................................................................... 118 
9.3 
Data collection ..................................................................................................... 119 
9.4 
Database management and quality control .......................................................... 119 
10  Statistical methods and data analysis .............................................................................. 119 
10.1 
Analysis sets ........................................................................................................ 120 
10.1.1 
Full Analysis Set ................................................................................. 120 
10.1.2 
Safety set ............................................................................................. 120 
10.1.3 
Per-Protocol set ................................................................................... 120 
10.1.4 
Dose-determining analysis set ............................................................. 120 
10.1.5 
Pharmacokinetic analysis set ............................................................... 120 
10.1.6 
Other analysis sets ............................................................................... 121 
10.2 
Patient demographics/other baseline characteristics ........................................... 121 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ..................... 121 
10.4 
Primary objective ................................................................................................. 122 
10.4.1 
Variable ............................................................................................... 122 
10.4.2 
Statistical hypothesis, model, and method of analysis ........................ 122 
10.4.3 
Handling of missing values/censoring/discontinuations ..................... 123 
10.4.4 
Supportive and Sensitivity analyses .................................................... 123 
10.5 
Secondary objectives ........................................................................................... 123 
10.5.1 
Key secondary objective(s) ................................................................. 124 
10.5.2 
Other secondary efficacy objectives ................................................... 124 


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10.5.3 
Safety objectives ................................................................................. 126 
10.5.4 
Pharmacokinetics ................................................................................ 128 
 
 130 
 
 130 
10.5.7 
Patient-reported outcomes ................................................................... 131 
 
. 131 
 
 131 
10.7 
Interim analysis .................................................................................................... 132 
10.8 
Sample size calculation........................................................................................ 133 
10.9 
Power for analysis of key secondary variables .................................................... 133 
11  Ethical considerations and administrative procedures .................................................... 134 
11.1 
Regulatory and ethical compliance ...................................................................... 134 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ....................................... 134 
11.3 
Informed consent procedures ............................................................................... 134 
11.4 
Discontinuation of the study ................................................................................ 134 
11.5 
Publication of study protocol and results............................................................. 135 
11.6 
Study documentation, record keeping and retention of documents ..................... 135 
11.7 
Confidentiality of study documents and patient records ..................................... 136 
11.8 
Audits and inspections ......................................................................................... 136 
11.9 
Financial disclosures ............................................................................................ 136 
12  Protocol adherence .......................................................................................................... 136 
12.1 
Amendments to the protocol ................................................................................ 137 
13  References (available upon request) ................................................................................ 138 
14  Appendices ...................................................................................................................... 141 
14.1 
Appendix 1: Acute GvHD Staging Criteria (Harris 2016) .................................. 141 
14.2 
Appendix 2: Infection Severity Grading.............................................................. 142 
14.3 
Appendix 3: Grading of Chronic GvHD (NIH Criteria) ..................................... 146 
14.4 
Appendix 4: Hematologic Disease Relapse/Progression definitions ................... 149 
14.5 
Appendix 5: HCT Specific Comorbidity Index Score ......................................... 151 
14.6 
Appendix 6: CIMBTR classification ................................................................... 152 
14.7 
Appendix 7: List of CYP3A4 inhibitors and inducers ........................................ 166 
14.8 
Appendix 8:  FACT-BMT (Version 4) ................................................................ 167 
14.9 
Appendix 9: EQ-5D-5L Health Questionnaire .................................................... 174 
  


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List of tables 
Table 3-1 
Objectives and related endpoints .......................................................... 44 
Table 6-1 
Dose and treatment schedule ................................................................. 57 
Table 6-2 
Treatment management based on patient response at Day 28 .............. 59 
Table 6-3 
Criteria for interruption and re-initiation of ruxolitinib treatment 
for adverse events suspected to be drug-related .................................... 64 
Table 6-4 
Dose reduction steps for ruxolitinib ...................................................... 69 
Table 6-5 
Dose re-escalation levels for ruxolitinib ............................................... 69 
Table 6-6 
Packaging and labeling ......................................................................... 74 
Table 6-7 
Supply and storage of study treatments ................................................ 74 
Table 7-1 
Visit evaluation schedule ...................................................................... 76 
Table 7-2 
Visit evaluation schedule for Cross-Over patients ................................ 84 
Table 7-3 
Local Clinical laboratory parameters collection plan ......................... 101 
Table 7-4 
Ruxolitinib Pharmacokinetic blood collection log for extensive PK 
(First 25 adult patients and all adolescents) ........................................ 106 
Table 7-5 
Ruxolitinib Pharmacokinetic blood collection log for sparse PK 
sampling (all other adult patients) ....................................................... 107 
 
 109 
Table 10-1 
Noncompartmental pharmacokinetic parameters ................................ 129 
Table 14-1 
Acute GvHD Staging Criteria (Harris 2016) ...................................... 141 
Table 14-2 
Severity grading table and recurrence interval definitions ................. 142 
Table 14-3 
Four age groups relevant to HCT ........................................................ 145 
Table 14-4 
HCT-Specific Comorbidity Index Score ............................................. 151 
Table 14-5 
CIBTMR disease risk index ................................................................ 153 
Table 14-6 
List of CYP3A4 inhibitors and inducers ............................................. 166 
 
List of figures 
Figure 4-1 
Schematic Study Design ....................................................................... 51 


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List of abbreviations 
ACS 
All Crossover Subjects 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
aGvHD 
Acute Graft vs. Host Disease 
alloSCT 
Allogeneic Stem Cell Transplantation 
ALL 
Acute Lymphoblastic Leukemia 
ALP 
Alkaline Phosphatase 
AML 
Acute Myeloid Leukemia 
ANC 
Absolute Neutrophils Count  
AP 
Alkaline phosphatase 
APC 
Antigen-Presenting Cells 
APTT 
Activated partial thromboplastin time 
ARDS 
Acute Respiratory Distress Syndrome 
ASBMT 
American Society for Blood and Marrow Transplantation 
ATC 
Anatomical Therapeutic Chemical 
ATG 
Anti-Thymocyte Globulin 
BID 
bis in diem/twice a day 
BAT 
Best Available Therapy 
BCC 
Basal Cell Carcinoma 
BCS 
Biopharmaceutical Classification System 
BLQ 
Below the Limit of Quantitation 
BM 
Bone Marrow 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
BP 
Blood pressure 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CAS 
Cross over Analysis Set 
CBC 
Complete blood count 
cGvHD 
chronic Graft vs. Host Disease 
CIBMTR 
Center for International Blood and Marrow Transplant Research 
CLcr 
Creatinine clearance 
CLL 
Chronic Lymphocytic Leukemia 
CMH 
Cochran–Mantel–Haenszel 
CMML 
Chronic Myelomonocytic Leukemia 
CMO & PS 
Chief Medical Office and Patient Safety 
CMV 
Cytomegalovirus 
CNI 
Calcineurin Inhibitor 
CNS 
Central Nervous System 
CR 
Complete response 
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or Paper 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CSR 
Clinical Study Report 
CT 
Computerized Tomography 


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CTCAE 
Common Terminology Criteria for Adverse Events 
CTD 
Connective Tissue Disease 
Ctrough 
Minimum concentration 
CYP3A 
Cytochrome P450, family 3, subfamily A 
CYP450 
Cytochrome P450 
DILI 
Drug-Induced Liver Injury 
DLI 
Donor Lymphocyte Infusion 
DLT 
Dose Limiting Toxicity 
DMC 
Data Monitoring Committee 
DOR 
Duration of Response 
EBMT 
European Bone Marrow Transplant 
EBV 
Epstein-Barr Virus 
ECP 
Extracorporeal Photopheresis 
eCRF 
Electronic Case Report/Record Form 
EDC 
Electronic Data Capture 
EDTA 
Ethylenediaminetetraacetic acid 
EFS 
Event-Free Survival 
EOS 
End of Study 
EOT 
End of treatment 
ET 
Essential Thrombocythemia 
EU 
European Union 
FACT-BMT 
Functional Assessment of Cancer Therapy - Bone Marrow Transplantation 
FAS 
Full Analysis Set 
FFS 
Failure-Free Survival 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
GGT 
Gamma-Glutamyl Transferase 
GI 
Gastro-Intestinal 
GM-CSF 
Granulocyte Macrophage Colony Stimulating Factor 
GvHD 
Graft vs. Host Disease 
GvL 
Graft vs. Leukemia 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HCT 
Hematopoietic Cell Transplantation 
HDL 
High Density Lipoprotein 
 
 
HHV-6 
Human Herpes Virus 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HSCT 
Hematopoietic stem cell transplantation 
HSV 
Herpes Simplex Virus 
HU 
Hydroxyurea 
IB 
Investigator Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
 
 
 
IEC 
Independent Ethics Committee 


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IFN 
Interferon 
IL 
Interleukin 
IN 
Investigator Notification 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System 
ITT 
Intention To Treat 
IUD 
Intra-Uterine Device 
IUS 
Intra-Uterine System 
JAK 
Janus kinase 
JAK STAT 
Janus kinase Signal Transducers and Activators of Transcription 
LC-MS/MS 
liquid chromatography-tandem mass spectrometry 
LDL 
Low Density Lipoprotein 
LDH 
Lactate dehydrogenase 
LFS 
Leukemia-Free Survival 
LFT 
Liver Function Tests 
LLN 
Lower limit of normal 
LLOQ 
Lower limit of quantification 
LPLV 
Last Patient Last Visit 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MDS 
Myelodysplastic Syndromes 
MEDRA 
Medical dictionary for regulatory activities 
MF 
Myelofibrosis 
MM 
Multiple Myeloma 
MM 
Malignant Melanoma 
MMF 
Mycophenolate mofetil 
MPNs 
Myeloproliferative Neoplasms 
MR 
Malignancy Relapse/Progression 
mPBSC 
mobilized Peripheral Blood Stem Cells 
MSC 
Mesenchymal Stromal Cells 
MTD 
Maximum Tolerated Dose 
mTOR 
Mammalian Target of Rapamycin 
MTX 
Methotrexate 
NCA 
Non-compartmental analysis 
NHL 
Non-Hodgkin lymphoma 
NIH 
National Institutes of Health 
NK 
Natural killer 
NMSC 
Non-Melanoma Skin Cancer 
NOS 
Not Otherwise Specified 
NR 
No Response 
NRM 
Non Relapse Mortality 
NSAID 
Nonsteroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
o.d. 
omnia die/once a day 


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OR 
Overall Response 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PAC 
Post-Approval Commitment 
PAS 
Pharmacokinetic analysis set 
PET 
Positron emission tomography 
PD 
Pharmacodynamics 
PHI 
Protected Health Information 
PK 
Pharmacokinetics 
PLL 
Prolymphocytic leukemia 
PLT 
Platelets  
PML 
Progressive Multifocal Leuko-Encephalopathy 
PPS 
Per-Protocol Set 
PR 
Partial response  
PRBC 
Packed red blood cells 
PRO 
Patient Reported Outcomes 
PTT 
Partial thromboplastin time 
PV 
Polycythemia Vera 
QD 
quaque die, once a day 
QOL 
Quality of Life 
RAEB 
Refractory anemia with excess blasts 
RAEB-T 
Refractory Anemia with Excess Blasts in Transformation 
RAP 
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses 
RARS 
Refractory Anaemia with Ring Sideroblasts 
RBC 
Red Blood Cell 
RDC 
Remote Data Capture 
RDI 
Relative Dose Intensity 
REB 
Research Ethics Board 
RoW 
Rest of the World 
RSV 
Respiratory Syncytial Virus 
 
R Value 
ALT/ALP in x ULN 
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
SC 
Steering Committee 
SCC 
Squamous Cell Carcinoma 
SCT 
Stem cell transplantation 
SD 
Stable disease 
SoC 
Standard of Care 
SOS 
Sinusoidal Obstructive Syndrome 
SR-aGvHD 
Steroid Refractory acute Graft vs. Host Disease 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TB 
Tuberculosis 
TBIL 
Total Bilirubin 
TNF 
Tumor Necrosis Factor 
TYK2 
Tyrosine kinase 2 


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UCB 
Umbilical Cord Blood 
US 
United States of America 
VOD 
Veno-Occlusive Disease 
VZV 
Varicella Zoster 
WBC 
White Blood Cells 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study patient  
Control drug 
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 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.)  
Enrollment 
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol) 
Investigational drug 
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous 
with “investigational new drug.” 
Investigational treatment 
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). This 
also includes approved drugs used outside of their indication/approved 
dosage, or that are tested in a fixed combination. Investigational treatment 
generally does not include other study treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used in within approved indication/dosage 
Medication number 
A unique identifier on the label of each study treatment package which is 
linked to one of the treatment groups of a study 
Other study treatment 
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment 
Subject Number (Subject No.) 
A unique identifying number assigned to each patient who enrolls in the 
study 
Period 
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc. 
Personal Data 
Subject information collected by the Investigator is transferred to Novartis 
for the purpose of the clinical trial. This data includes subject identifier 
information, study information and biological samples 
Randomization number 
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
Stage related to study timeline 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc. 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when 
study treatment was discontinued whichever is later 
Study treatment 
Includes any drug or combination of drugs in any study arm administered to 
the patient as part of the required study procedures, including placebo and 
active drug run-ins. 
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-investigational 
treatments in combination. 
Study treatment discontinuation 
Point/time when patient permanently stops taking study treatment for any 
reason 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints 
Withdrawal of consent 
Withdrawal of consent from the study occurs only when a patient does not 
want to participate in the study any longer, and does not allow any further 
collection of personal data  


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Amendment 2 (21-Jun-2018) 
Study Status 
As of 21-Jun-2018, a total of 384 patients have been screened and 175 patients randomized. 
Amendment rationale: 
 The main purpose of the amendment is to allow for more flexibility in the tapering of 
corticosteroids, calcineurin inhibitors (CNI) and ruxolitinib; and if needed, for this taper to 
be completed safely beyond Week 24. This change includes clarification that institutional 
guidelines for the tapering of corticosteroids and CNI may be followed. Additionally, the 
physician can tailor the tapering strategy to each patient’s condition, including stopping 
ruxolitinib more slowly in case of an acute Graft vs. Host Disease (aGvHD) flare or other 
safety concerns which may prevent the taper from being completed by Week 24.  
 Patients who meet the protocol criteria for treatment discontinuation will not be eligible to 
continue receiving ruxolitinib within the study. However, as part of Novartis “Post-trial 
access” commitment, patients who meet all of the following criteria : 
 responded to ruxolitinib at Day 28 (or Cross-Over Day 28),  
 met study discontinuation criteria, other than safety reasons,  
 are assessed by the Investigator to still be deriving clinical benefit from ruxolitinib, 
will be given the possibility to continue ruxolitinib outside the study, if requested; they will 
then not enter the Long-Term Follow-Up period.  
 Similarly, patients who are still receiving ruxolitinib at their end of study (approximately 2 
years from randomization), and deriving clinical benefit from ruxolitinib as assessed by 
the Investigator, will also be given the possibility to continue ruxolitinib outside the study 
from another source, where permitted by and in accordance to local laws and regulations.  
 To align with medical practices in managing adolescent patients, other systemic 
medications for aGvHD prophylaxis in addition to CNI can now be maintained after 
randomization for all patients. To be allowed, these additional prophylactic medications 
start date must precede the diagnosis date of aGvHD. While this change is anticipated to 
primarily improve adolescent enrolment, its impact on overall patient homogeneity is 
limited.  
 The pharmacokinetic (PK) sampling schedule was simplified following the completion of 
a preliminary analysis, conducted on a subset of 22 adult and 1 adolescent patients from 
the present study, with extensive PK sampling after the administration of repeated doses 
of ruxolitinib at 10 mg twice a day (BID). The results suggested that there was no 
substantial difference in terms of PK parameters (apparent clearance, apparent volume of 
distribution) between patients with aGvHD and historical data in healthy volunteers and 
other indications.  
 The secondary endpoint Best Overall Response (BOR) was added to align with aGvHD 
publications.  
 A Data Monitoring Committee (DMC) has been added to address the Study Steering 
Committee’s request to be informed on the balance of safety events between treatment 
arms. The DMC was added to maintain the Study Steering Committee blinding during 


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their review of pooled safety data, in order to preserve the integrity of the trial. No 
efficacy or safety data from the study were considered in the decision to add a DMC.   
 Finally, the amendment includes updates to align with the ruxolitinib Investigator 
Brochure and current Development Safety Update Report. These updates are not expected 
to impact the design or conduct of the current study. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
The following key changes were made and applied to the respective sections of the protocol: 
Change #1: Revisions to the tapering guidelines in Sections 2.2, 4.1, Figure 4-1, Sections 
6.1.1.1, 6.1.5, 6.1.5.1, Table 7-1, Table 7-2, Sections 7.1.4 and 
: 
 For corticosteroids and CNIs: clarification that taper should follow institutional guidelines. 
 For ruxolitinib:  
 Addition that ruxolitinib taper is optional per Investigator’s judgment however it must 
be initiated no later than Week 24 (or Cross-Over Week 24). 
 Addition of the possibility to complete ruxolitinib taper after Week 24 (or Cross-
Over-Week 24) in some cases.  
 Revision that several ruxolitinib taper attempts are allowed up to the patient’s end of 
study.  
Change #2: Clarifications to patient management rules in Sections 4.1, 4.3, 6.1.1.2, 6.1.5, 
7.1.4 and 7.1.5: 
 Additions and revisions to clarify the patient management rules, depending on their 
response, treatment arm and/or tapering strategy. 
 Clarification that responding patients (i.e. obtaining a Complete Response [CR] or Partial 
Response [PR]) completing the dosing schedule for ruxolitinib or for their assigned Best 
Available Therapy (BAT) at any time as per standard of care before Week 24 (or Cross-
Over Week 24) must continue to be assessed as per the applicable schedule of assessments 
until Week 24 (or Cross-Over Week 24). 
 Addition that patients who responded to ruxolitinib at Day 28 (or Cross-Over Day 28) and 
are assessed by the Investigator to still be deriving clinical benefit from ruxolitinib, 
despite meeting protocol criteria for treatment discontinuation, will be given the 
possibility to continue ruxolitinib outside the study.  
 Addition that patients still receiving ruxolitinib at their end of study (approximately 2 
years from randomization), and benefitting from ruxolitinib, may be transitioned to an 
alternative solution to receive ruxolitinib. 
Change #3: Revision of the “End of study definition” to include possible prolonged 
ruxolitinib taper in Section 4.3. 
Change #4: Allow continuation of systemic medications for aGvHD prophylaxis after 
randomization in Sections 4.1, 6.1, 6.1.1.2, 6.1.5, 6.4.1 and 7.1.2. 


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Change #5: Revisions to the Pharmacokinetic (PK) sampling schedule in Sections 6.1.1.1, 
Table 7-1, Table 7-2, Section 7.2.3.1, Tables 7-4 and 7-5 
Change #6: Clarifications on the Safety Follow-Up visit and Long-Term Follow-Up period 
in Sections 4.1 and 7.1.7. 
Change #7: Clarifications to the timing for cross-over between Day 28 and Week 24 in 
Section 4.1, Figure 4-1, and Section 7.1.4. 
Change #8: Clarifications to the timing for further analyses after the primary and key 
secondary endpoint analysis in Sections 2.2, 4.3, 10 and 10.7. 
Change #9: Clarifications on the addition of new systemic immunosuppressive therapy in 
Sections 2.2, 6.1.1.1, 6.1.5, 6.1.5.1, 6.4.1, 6.4.3 and 7.1.5: 
 Clarification that addition of new systemic immunosuppressive therapy is considered a 
treatment failure, and is a criterion for study treatment discontinuation.  
 Removal that patients randomized to ruxolitinib may be treated with new systemic therapy 
in case of ruxolitinib lack of efficacy. This is to be consistent with the study design as this 
is a study treatment discontinuation criterion. These patients may use other systemic 
treatment for aGvHD per Investigator’s assessment only outside of the study Treatment 
Period.  
 Change #10: Addition of a DMC in Section 8.6. 
Other changes: 
 Sections 1.2.1 and 1.2.1.2: Update to the number of patients who have received ruxolitinib 
treatment in Novartis- and Incyte-sponsored investigational clinical trials. 
 Section 3:  
 Clarification of baseline for aGvHD response assessment in cross-over patients. 
 Removal of timeframe for aGvHD and chronic Graft vs. Host Disease (cGvHD) 
assessments to align with the assessment schedule in the protocol.  
 Table 3-1: Addition of the secondary efficacy endpoint BOR. Addition of minimum 
concentration (Ctrough) to the list of PK parameters and “other relevant endpoints” 
for exposure-response relationship assessments.  
 Sections 4.1 and 6.1.5, Table 7-1: Addition of “Day 1 is the day of randomization”, and 
correction of the timing for the Safety Follow-Up visit to “last dose + 30 days”, to align 
with other protocol sections.  
 Section 5.3: Exclusion criteria revision with limited impact on patient’s homogeneity:  
 Exclusion criterion #15: Revision to allow for heparin or low-molecular-weight-
heparin to be used at sub-therapeutic doses with no restrictions on the reason for 
administration (sinusoidal obstructive syndrome [SOS]/veno-occlusive disease of the 
liver [VOD] prophylaxis is now only cited as an example). Similar revision was made 
to section 6.4.3.  
 Exclusion criterion #18: Revision to the required time without any investigational 
treatment agent amended, from 30 days prior to screening, to 30 days prior to 
randomization. 






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Amendment 1 (31-May-2017) 
Study Status 
As of 30 May 2017, a total of 38 patients have been screened and 8 patients randomized. 
Amendment rationale: 
The main purpose of the amendment is to clarify exclusion criterion #5 and other eligibility 
criteria to follow standard medical practice as detailed below 
Clarification of exclusion criterion #5 
The revision of exclusion criterion #5 is to follow standard medical practice in determining the 
presence of active viral infection. This determination is based on the treating physician’s clinical 
assessment according to local institutional guidelines at the time of randomization including but 
not limited to vital signs, physical examination, laboratory and relevant radiologic studies and 
viral load testing results when available. The investigator will assess at time of randomization 
if the patient is presenting with a viral infection or not based on his/her medical judgement and 
without waiting for viral load test results for CMV, EBV, HHV-6, HBV, HCV performed at 
screening in order not to delay the initiation of aGvHD treatment in this life threatening 
condition.  
Moreover, evidence of an uncontrolled viral infection at time of randomization renders the 
patient ineligible. However, a patient is eligible for enrollment into this study if she/he has been 
treated with appropriate anti-viral therapy in the setting of an active viral infection and has 
responded to treatment such that the viral infection is considered  well-controlled by the 
investigator.  Furthermore, as peripheral blood serology for CMV, EBV, HHV-6 are not reliable 
to detect acute phase antibody response in allogeneic transplant patients rendered B cell aplastic 
with administered high dose chemo-radiotherapy conditioning and aGvHD immunosuppressive 
treatment (Tomblyn M 2009), the protocol is amended to no longer require peripheral blood 
viral serologies for CMV, EBV and HHV-6 as a screening procedure in this protocol. Peripheral 
blood nucleic acid (viral load) testing can better support medical assessment of the presence of 
viral replication in patients rendered B cell aplastic with dose intensive conditioning. This 
testing will be performed routinely during screening and at regular (monthly) intervals during 
treatment in this trial.  
Clarification of exclusion criterion # 1 
Exclusion criterion # 1 is revised to clarify that there is no restriction on previous prophylaxis 
received for aGvHD prior to screening or randomization, and that the limitation resides in 
excluding any patient who has received more than one systemic treatment for steroid resistant 
aGVHD other than corticosteroids with or without concurrent administration of a calcineurin 
inhibitor. 
Clarification of exclusion criterion # 15 
Patients with aGvHD often receive heparin or low-molecular-weight heparin at sub-therapeutic 
low dosing as prophylaxis of sinusoidal obstructive syndrome/veno-occlusive disease 
(SOS/VOD) of the liver.  


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This sub-therapeutic dose does not increase the bleeding risk in the patients. Accordingly, 
exclusion criteria #15 was modified to allow patients to be treated with low-dose heparin as 
prophylaxis before and during the study treatment period (Section 6.4.3). 
Clarification of inclusion criterion # 8 
The timeframe of 48 hours of SR-aGvHD prior to study treatment start was removed for 
clarification because all patients who are confirmed steroid refractory aGvHD prior to 
randomization are eligible in regards to inclusion criteria 8.  
Acute GvHD patient progressing after 3 days of high dose systemic corticosteroids are 
considered SR aGvHD, according to EBMT guidelines. Therefore the time window of inclusion 
criterion 8-A was changed from “after 5 days” to “after at least 3 days” to ensure such patients 
are eligible in the trial. 
A lower steroid dose threshold is set in this amendment to define steroid taper failure, e.g. 
methylpredisolone dose <0.5 mg/kg/day reduced from <1 mg/kg/day (for a minimum of 7 days). 
This lower steroid dose threshold is set based on standard medical practice aiming to provide 
additional immunosuppression beyond systemic corticosteroids +/- calcineurin inhibitor to 
avoid more prolonged required systemic steroids with associated risk of infection and 
malignancy relapse. Therefore, any patient who fails steroid taper at a methylprednisolone dose 
of 0.5 mg/kg/day or higher (for 7 days duration) would be eligible for enrollment and could 
start prompt additional immunosuppressive therapy after randomization to either ruxolitinib or 
investigator choice best available therapy. Similarly, the definition of steroid taper failure is 
aligned during study treatment and the corticosteroid thresholds dosing are revised in 
corresponding sections of study protocol. 
Finally, the amendment includes updates to align with the ruxolitinib investigator’s brochure 
and current Development Safety Update Report. These updates are not expected to impact the 
design or conduct of the current study.  
The amendment also includes other revisions and administrative changes for clarification 
purposes.  
Detailed listing of changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
The following sections of the protocol have been changed: 
 Section 1.2.1: To update the numbers according to the Development Safety Update report 
2017. 
 Section 3: Revision of corticosteroid dose thresholds to align with the revised 
corticosteroid taper failure definition in case of aGvHD flare during corticosteroids taper.   
 Section 3, Table 3.1: Removal of Time point Day 56 for ORR assessment to align the 
secondary endpoint ORR assessment with the study design (i.e. patients not CR/PR from 
Day 28 will be discontinued or started in cross over if eligible) so ORR assessment at D56 
was not accurate. 
 Section 3, Table 3.1: Pharmacokinetic parameters updated with omitted information. 


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 Section 4.1: Revision of corticosteroid dose thresholds for methylprednisolone and 
prednisolone to align with the new aGvHD steroid refractory definition for patients who 
failed corticosteroid taper at time of eligibility assessment. 
 Section 4.1: Addition aGvHD prophylaxis treatment to be stopped prior to randomization 
to clarify that all aGvHD treatment including prophylaxis are to be stopped prior to 
randomization 
 Section 4.1: Revision of Study treatment start up to 72 hours from randomization at the 
latest. To allow more flexibility in the initiation of BAT after randomization as some local 
institution may require more than 24 hours obtaining the selected BAT and initiating 
patient’s treatment. 
 Section 5.2, inclusion criterion # 8:  
 Removal of timeframe confirmed aGvHD within 48 hours from study treatment start. 
To allow all patients to be enrolled into the trial as long as patient was confirmed SR 
aGvHD prior to randomization. 
 Revision of steroid treatment duration to align SR aGvHD definition with EBMT 
guidelines in progressing patients. 
 Revision of corticosteroid dose thresholds for methylprednisolone and prednisolone to 
align with the new aGvHD steroid refractory definition for patients who failed 
corticosteroid taper at time of eligibility assessment and ensure timely initiation of 
treatment. 
 Section 5.3, exclusion criterion #1: Addition of “steroid refractory” and removal of the 
rest of the sentence to clarify that eligible patients may have received no more than one 
SR aGvHD treatment but that there is no restriction to prior aGvHD prophylaxis therapy 
or steroids +/-CNI received as aGvHD treatment or prophylaxis. 
 Section 5.3, exclusion criterion #5:  
 Addition of “uncontrolled” viral infection and “based on assessment by the treating 
physician”. To clarify that no patient with uncontrolled viral infection is eligible 
based on treating physician assessment. And to revise that viral load testing is 
performed as a screening procedure whereas patient may be randomized (treated with 
ruxolitinib/BAT) in a timely manner if all other eligibility criteria are met. 
 Removal of the 2 last sentences including the confirmation of viral load results prior 
to randomization. To remove serology testing for CMV, EBV, HHV6 as results are 
not reliable in aGvHD patients under immunosuppression. 
 Section 5.3, exclusion criterion #9: Addition of a note for patients who have received a 
scheduled DLI as part of their transplant procedure and not for management of 
malignancy relapse. To clarify those patients who received unscheduled DLI for 
malignancy relapse are not eligible. 
 Section 5.3, exclusion criterion #14: Revision of prednisolone dose 1.5 mg/kg/day 
replaced by 1.25 mg/kg/day. To correct a typographical error in the equivalent dosing of 
prednisolone. 
 Section 5.3, exclusion criterion #15: Addition of a note that a patient who received a sub- 
therapeutic dose of heparin or low molecular weight heparin when used as prophylaxis of 
liver VOD/SOS is eligible. 


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 Section 6.1.5.1: Revision of corticosteroid dose thresholds for methylprednisolone and 
prednisolone to align with the revised corticosteroids taper failure definition in case of 
aGvHD flare during corticosteroids taper. 
 Section 6.4.1: Revision of corticosteroid dose thresholds for methylprednisolone and 
prednisolone to align with the revised corticosteroids taper failure definition in case of 
aGvHD flare during corticosteroids taper. 
 Section 6.4.3:  
 Addition of a note that patients who received a sub-therapeutic dose of heparin or low 
molecular weight heparin when used as prophylaxis of liver VOD/SOS can be 
maintained in the trial 
 Addition “Non-scheduled” DLI to clarify that only “non-scheduled” DLI is prohibited 
during the trial 
 Section 6.6.4: Addition of an alternative to study drug supply destruction to reflect the 
different options for study supply destruction in participating countries according to 
Novartis standard operational procedures and local regulations. 
 Section 7.1, table 7-1: Addition of IRT contact “monthly” and HBV and HCV serology 
tests to correct omitted information part of initial protocol 
 Section 7.1, table 7-2:  
 Addition of IRT contact “monthly” to correct omitted information part of initial 
protocol. 
 Correction of week number visits for cross-over visits W1- W8 to correct a 
typographical error. 
 Section 7.1.2: Addition of body weight and laboratory examination retests required (CMC 
Chemistry tests and coagulation) if available results are older than 24 hours from study 
treatment start. To ensure to have the most accurate values for safety assessment, when 
patient starts study treatment beyond 24 hours from randomization. 
 Section 7.1.2.2: Addition of aGvHD overall grade and organ staging to be recorded in 
CRF at time of screening. To record aGvHD overall grading and organ staging in CRF at 
time of screening for all patients including screening failure patients to better understand 
current aGvHD population characteristics. 
 Section 7.1.2.3:  
 Revision of screening period time-frame definition to incorporate assessments made 
at Day 1 but before start of study treatment. 
 Addition of a window of 48 hours between Screening and Day 1 visits for vital sign 
examinations and urinalysis tests and 7 days between Screening and Day 1 for viral 
load assessments. To avoid unnecessarily repeated examinations needed to confirm 
eligibility criteria, when Screening and Day1 visits occur up to 48 hours apart. 
 Addition of body weight, CBC, Chemistry and coagulation retests to be performed 
within 24 hours prior to start of study treatment. 
 Section 7.1.4:  
 Revision of Day 1 definition to the day of randomization to clarify the definition of 
Day 1 as the day of randomization and not necessarily the first day of study treatment. 


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 Revision of Study treatment start up 24 hours to 72 hours from randomization at the 
latest. To allow more flexibility in the initiation of BAT after randomization as some 
local institution may require more than 24 hours obtaining the selected BAT and 
initiating patient’s treatment. 
 Section 7.2.2.2: Addition of a window of 48 hours between Screening and Day 1 visits for 
physical examination. To avoid unnecessarily repeated examinations needed to confirm 
eligibility criteria when Screening and Day1 visits occur up to 48 hours apart. 
 Section 7.2.2.3: Addition of a retest for the body weight to ensure the most accurate value 
is reported before start of study treatment when the patient starts study treatment beyond 
24 hours from randomization.  
 Section 7.2.2.4, Table 7-3:  
 Addition of “OR” between PPT and aPTT to clarify that one of the two coagulation 
parameter is required for the study. 
 Update to serology and viral load requirements for HBV and HCV. To clarify that 
serology assessment and viral load sampling are required for HBV and HCV as 
screening procedures whereas viral load will also be required during study treatment 
period. 
 Replacement of footnotes by notes in “Urinalysis”, “Hepatitis markers” and 
“Additional viral testing”. To clarify the requirement for respective sections and align 
with clarification made to exclusion criteria #5 
 Addition of viral load collection not to be repeated at Day 1 if it was  performed 
within 7 days prior to randomization 
 Section 7.2.2.4.1: Addition of required laboratory examination retests if available results 
are older than 24 hours at the time of study treatment start. To ensure that most accurate 
values are collected when the patient starts study treatment beyond 24 hours from 
randomization. 
 Section 7.2.2.4.2: Addition of required laboratory examination retests if available results 
are older than 24 hours at the time of study treatment start. To ensure that most accurate 
values are collected when the patient starts study treatment beyond 24 hours from 
randomization. 
 Section 7.2.2.4.3: Addition of a window of 48 hours between Screening and Day 1 visits 
to avoid unnecessarily repeated urinalysis examination to confirm eligibility criteria when 
Screening and Day1 visits occur up to 48 hours apart. 
 Section 7.2.2.4.4:  
 Addition of “OR” between PPT and aPTT to clarify that one of the two coagulation 
parameter is required for the study. 
 Addition of required laboratory examination retests if available results are older than 
24 hours at the time of study treatment start. To ensure that most accurate values are 
collected when the patient starts study treatment beyond 24 hours from 
randomization.  
 Section 7.2.2.4.9: Update of requirements for serology and viral load to clarify for 
serology and viral load testing requirements at baseline and during the treatment period in 
alignment with the revised exclusion criteria #5 




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patient has CR/PR and maintains the response, he/she will continue the on-treatment 
assessments schedule after the last dose of BAT. Therefore the duration of response will 
not be censored based on a short BAT administration per standard of care. 
 Section 10.5.3.2: Revision of definitions for on-randomized and on-cross over treatment 
periods and the post-treatment period. To clarify that the end of treatment period is 30 
days after last dose study medication (randomized or crossover) or end of treatment per 
End of Treatment Disposition eCRFs (randomized or crossover), whichever comes last. 
 Section 10.5.4: Addition of Racc and AUC Tau, to add omitted information. 
 Section 10.7: Addition of early PK analysis plan to reflect the early PK analysis defined in 
study analysis plan prior to study start but not described in initial study protocol. 
IRB/IEC 
A copy of  this  amended  protocol  will  be  sent to  the  Institutional  Review  
Board(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol are considered substantial and do require 
IRB/IEC approval prior to implementation. In addition, if the changes herein affect the 
Informed Consent, sites are required to update and submit for approval a revised Informed 
Consent that takes into account the changes described in this amended protocol. 


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Protocol Summary 
Title 
A phase III randomized open-label multi-center study of ruxolitinib versus best 
available therapy in patients with corticosteroid-refractory acute graft vs. host 
disease after allogeneic stem cell transplantation 
Brief title 
Study of efficacy and safety of ruxolitinib vs. best available therapy (BAT) in 
patients with Grade II-IV steroid-refractory acute graft vs. host disease  
Sponsor and Clinical 
Phase 
Novartis: Phase 3  
Investigation type 
Drug (INC424/ruxolitinib) 
Study type 
Interventional 
Purpose and rationale 
The purpose of the study is to assess the efficacy of ruxolitinib when added to 
immunosuppression therapy in patients with Grade II-IV steroid refractory acute 
graft vs. host disease. Specifically, the study will test if ruxolitinib will result in 
higher rates of disease response compared with currently used second line 
treatment modalities, and further that this response will be sustained during 
steroid taper. The rationale of the study is based on current knowledge of acute 
graft vs. host disease pathophysiology and published studies that show that 
ruxolitinib impairs antigen presenting cell function, inhibits donor T cell 
proliferation, suppresses adverse cytokine production, and improves survival and 
disease manifestations in GvHD mouse models. Further, published data has 
shown that ruxolitinib has evidence of clinical efficacy when added to 
immunosuppressive therapy in patients with steroid refractory acute graft vs. 
host disease. 
Primary Objective(s) and 
Key Secondary Objective 
Primary objective: to compare the efficacy of ruxolitinib vs. Investigator’s choice 
Best Available Therapy in patients with Grade II-IV steroid refractory-acute Graft 
vs. Host Disease assessed by Overall Response Rate (ORR) at Day 28. ORR at 
Day 28 after randomization is defined as the proportion of patients in each arm 
demonstrating a complete response or partial response without requirement for 
additional systemic therapies for an earlier progression, mixed response or non-
response. Scoring of response will be relative to the organ stage at the time of 
randomization. 
Key secondary objective: to compare the rate of durable ORR at Day 56 
between ruxolitinib and Best Available Therapy. ORR at Day 56 is defined as the 
proportion of all patients in each arm who achieve a complete response (CR) or 
partial response (PR) at Day 28 and maintain a CR or PR at Day 56. 
Secondary Objectives 
● To estimate ORR at Day 14 
● To assess Duration of response 
● To assess the cumulative steroid dose until Day 56 
● To assess Overall Survival (OS) 
● To assess Event-Free Survival (EFS) 
● To assess Failure-Free survival (FFS) 
● To assess Non Relapse Mortality (NRM) 
● To assess incidence of Malignancy Relapse/Progression (MR)   
● To measure the incidence of cGvHD 
● To assess Best Overall Response (BOR) 
● To assess Pharmacokinetics (PK) of ruxolitinib in SR-aGvHD patients 
● To assess exposure-response relationship of ruxolitinib in SR-aGvHD 
● To evaluate changes in Patient Reported Outcomes (PROs) 
● To evaluate the safety of ruxolitinib and Best Available Therapy  
Study design 
This trial is a randomized (1:1) phase III open label study of ruxolitinib compared 
to Investigator choice Best Available Therapy (BAT) in allogeneic stem cell 
transplant recipients with Grade II-IV steroid refractory acute graft vs. host 
disease. Patients randomized to the BAT arm are allowed to cross-over to the 
ruxolitinib arm if they do not demonstrate complete or partial response at Day 28 
or if they lose their response thereafter and meet criteria for progression, mixed 
response, or no response, necessitating new additional systemic 
immunosuppressive treatment for aGvHD. 


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Population 
The study will enroll 308 adults and adolescents ≥12 years old who have 
undergone allogeneic stem cell transplantation and have developed Grade II-IV 
steroid refractory acute graft vs. host disease. 
Inclusion Criteria 
(Please refer to section 5 
for full list of inclusion 
criteria) 
1. Male or female patients aged 12 or older  
2. Able to swallow tablets 
3. Have undergone alloSCT from any donor source (matched unrelated donor, 
sibling, haplo-identical) using bone marrow, peripheral blood stem cells, or cord 
blood. Recipients of non- myeloablative, myeloablative, and reduced intensity 
conditioning are eligible 
4. Clinically diagnosed Grades II to IV acute GvHD as per standard criteria 
(Appendix 1) occurring after alloSCT requiring systemic immune suppressive 
therapy. Biopsy of involved organs with aGvHD is encouraged but not required 
for study screening. 
5. Evident myeloid and platelet engraftment (confirmed within 48h prior to study 
treatment start): 
 
● absolute neutrophil count (ANC) > 1000/mm3 AND  
 
● platelets ≥ 20,000/ mm3 
Note: Use of growth factor supplementation and transfusion support is allowed. 
6. Confirmed diagnosis of steroid refractory aGvHD defined as patients 
administered high-dose systemic corticosteroids (methylprednisolone 2 
mg/kg/day [or equivalent prednisone dose 2.5 mg/kg/day]), given alone or 
combined with calcineurin inhibitors (CNI) and either: 
 
A. Progressing based on organ assessment after at least 3 days compared to 
organ stage at the time of initiation of high-dose systemic steroid +/- CNI for the 
treatment of Grade II-IV aGvHD,  
 
OR 
 
B. Failure to achieve at a minimum partial response based on organ 
assessment after 7 days compared to organ stage at the time of initiation of 
high-dose systemic steroid +/- CNI for the treatment of Grade II-IV aGvHD, 
 
OR  
 
C. Patients who fail corticosteroid taper defined as fulfilling either one of the 
following criteria: 
 
 
1. Requirement for an increase in the corticosteroid dose to 
methylprednisolone ≥2 mg/kg/day (or equivalent  prednisone dose ≥2.5 
mg/kg/day), OR    
 
 
2. Failure to taper the methylprednisolone dose to <0.5 mg/kg/day (or 
equivalent prednisone dose <0.6 mg/kg/day) for a minimum 7 days 
Exclusion criteria 
(Please refer to section 5 
for full list of exclusion 
criteria) 
1. Has received more than one systemic treatment for steroid refractory aGvHD.  
2. Clinical presentation resembling de novo chronic GvHD or GvHD overlap 
syndrome with both acute and chronic GvHD features (as defined by Jagasia, et 
al. 2015). 
3. Failed prior alloHSCT within the past 6 months.  
4. Presence of an active uncontrolled infection including significant bacterial, 
fungal, viral or parasitic infection requiring treatment. Infections are considered 
controlled if appropriate therapy has been instituted and, at the time of 
screening, no signs of progression are present. Progression of infection is 
defined as hemodynamic instability attributable to sepsis, new symptoms, 
worsening physical signs or radiographic findings attributable to infection. 
Persisting fever without other signs or symptoms will not be interpreted as 
progressing infection. 
5. Evidence of uncontrolled viral infection including CMV, EBV, HHV-6, HBV, or 
HCV based on assessment by the treating physician. 
6. Presence of relapsed primary malignancy, or who have been treated for 
relapse after the alloHSCT was performed, or who may require rapid immune 
suppression withdrawal as pre-emergent treatment of early malignancy relapse. 
7. Previous participation in a study of any investigational treatment agent within 
30 days of randomization or within 5 half-lives of the investigational treatment 
agent, whichever is greater. 




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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
Allogeneic stem cell transplantation (alloSCT) is a curative immunotherapy for patients with 
blood-related malignancies including leukemia, lymphoma, and myeloma. AlloSCT also 
provides normal hematopoietic function in patients with non-malignant hematologic disorders, 
including severe aplastic anemia, inherited metabolic disorders, and hemoglobinopathies 
(Copelan 2006). Graft vs. Host Disease (GvHD) is a major limitation to the success of alloSCT 
and occurs when donor-derived immune cells in a bone marrow or stem cell graft  recognize 
the transplant recipient (the host) as foreign, thereby initiating an adverse immune reaction 
leading to an inflammatory cascade with resultant tissue damage, organ failure, or even death. 
Risk factors for GvHD include donor/recipient Human Leukocyte Antigen (HLA) mismatch, 
use of peripheral blood stem cells/bone marrow from an HLA matched unrelated or HLA 
mismatched related donor, multiparous female donor to male recipient, and advanced age of the 
donor or the recipient. GvHD presents as 2 distinct entities, namely acute GvHD (aGvHD) and 
chronic GVHD (cGvHD) with distinct clinical manifestations and separation by time of 
occurrence. Approximately 32,000 alloSCT procedures are performed world-wide annually 
with approximately 19,000 patients experiencing either aGvHD or cGvHD or both 
(Niederwieser 2016).  
aGvHD is characterized by high levels of pro-inflammatory cytokines (e.g. tumor necrosis 
factor [TNF]-α, interleukin [IL]-1β, IL-6, and interferon [IFN]-γ) which enhance activation and 
proliferation of donor effector T cells (Ferrara 2009). aGvHD occurs in 30-50% of HLA 
matched related alloSCT and in 50-70% of HLA matched unrelated alloSCT recipients with 
signs and symptoms observed generally within 100 days after infusion of allogeneic grafts 
including donor bone marrow (BM), mobilized peripheral blood stem cells (mPBSC), or 
umbilical cord blood (UCB). This fairly high incidence of aGvHD is seen despite prophylaxis 
with two or more immunosuppressive agents such as calcineurin inhibitors (cyclosporine, 
tacrolimus), short-course methotrexate, mycophenolate mofetil, high-dose cyclophosphamide 
post-transplant, and anti-thymocyte globulin (ATG).  
aGvHD target organs include the skin, liver, upper and lower GI tract, with signs and symptoms 
including the following: maculopapular skin rash, erythroderma, nausea, vomiting, secretory 
diarrhea, cholestasis, hyperbilirubinemia, and/or jaundice. aGvHD severity is scored by 
standard criteria that incorporate severity of individual organ signs and symptoms as well as 
number of organs affected.  Grading systems have evolved over 40 years of alloSCT with the 
initial widely adopted Glucksberg grading system  (Glucksberg 1974) updated by the NIH 
consensus group adding upper GI involvement to the overall GvHD grading (Przepiorka 1995). 
In addition, further refinement of the NIH consensus grading has been widely adopted that 
allows either measurement of the frequency of stools or the stool volume in staging lower GI 
involvement in aGvHD (Harris 2016). The extent of individual organ staging and overall grade 
of aGvHD is assessed at presentation as this is an important prognostic indicator. Biopsies of 
affected organs are often obtained in attempt to rule out non-GvHD etiologies. Histologic 
evaluations of affected organs are highly specific with however very low sensitivity (<60%), 
and as such aGvHD remains a clinical diagnosis based on careful integration of all available 


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clinical information (Ross 2012). Please refer to Appendix 1 for NIH consensus aGvHD organ 
staging and overall grading criteria. 
With the introduction of reduced intensity conditioning in the early 1990s, two subcategories 
of aGvHD emerged. The first, termed classic aGvHD, occurs in the majority (~90%) of patients 
within 100 days after transplantation or donor leukocyte infusion (DLI), and the second, termed 
persistent, recurrent, or late aGvHD, occurs beyond 100 days after transplantation or DLI for 
an additional 4 to 8 weeks. Both subgroups occur without the presence of cGvHD 
manifestations, termed overlap syndrome (Pavletic 2012). These observations have set the basis 
for current aGvHD grading that defines clinical manifestations, rather than time after 
transplantation, to define aGvHD.  
GvHD is a disease of adults and pediatric patients. In fact, a large proportion of pediatric 
patients undergo alloSCT for treatment of malignancy and a rising number receive alloSCT for 
non-malignant 
diseases 
including 
bone 
marrow 
failure, 
immunodeficiency, 
hemoglobinopathies, and inherited metabolic disorders.  The incidence of Grade II-IV aGvHD 
in adolescent patients aged 12-18 years approximates 5% of that observed in adults >18 years 
(CIBMTR data). As 32,000 alloSCT procedures are performed each year (Niederwieser 2016), 
approximately 1,600 adolescent patients aged 12-18 years develop Grade II-IV aGvHD with up 
to 800 of these patients considered at risk for the development of Steroid-Refractory aGvHD 
(SR-aGvHD) annually. All Grade III-IV aGvHD adult and pediatric patients regardless of 
frontline corticosteroids have high mortality risk (< 20% EFS at 5 years) (Holtan 2015). 
Effective treatment for aGvHD represents a high unmet medical need, particularly in patients 
with Grade II-IV. While long-term survival following Grade I aGvHD is >90%, it is 80%, 30%, 
and <10% for Grades II, III, and IV, respectively (Cahn 2005).  Systemic corticosteroids are 
standard of care (SOC) in initial stages of the disease in patients with Grade II-IV aGvHD. 
Corticosteroids are started with methylprednisolone 2 mg/kg/day (or equivalent prednisone 
dose 2.5 mg/kg/day) per European Bone Marrow Transplant (EBMT) guidelines (Ruutu 2014), 
and are tapered as soon as clinical improvement is observed. Calcineurin inhibitor (CNI) 
prophylaxis, either cyclosporine or tacrolimus, is continued during aGvHD treatment and is 
tapered off by 6 months after transplantation in responding patients. A flare of aGvHD often 
occurs after steroid tapering begins. If the flare is determined to be cGvHD with overlap 
syndrome, standard treatment of cGvHD with immunosuppressive therapy is initiated.  If 
cGvHD is not present, the steroid doses are increased to treat aGvHD and the taper resumed 
once the aGvHD is controlled. Treatment is continued until all signs of aGvHD have resolved.  
As systemic high-dose corticosteroids are immunosuppressive, patients with aGvHD are at a 
very high risk for life-threatening opportunistic infections that account for one third of deaths 
after alloSCT (Young 2008). This has prompted development and validation of a grading 
system based on severity of infection that is predictive of mortality in alloSCT patients 
(Cordonnier 2006). Administration of high-dose systemic corticosteroids for aGvHD is 
associated with an increased risk of bacteremia, viral reactivation including cytomegalovirus 
(CMV), Epstein Barr virus (EBV), human herpes virus 6 (HHV-6), hepatitis B (HBV) and C 
(HCV), herpes zoster virus, invasive aspergillosis, and mold infection–related death. Treatment 
of aGvHD therefore includes rapid taper of corticosteroids when response is observed, to 
minimize the risk of life-threatening infections. Aggressive antimicrobial prophylaxis is also 
standard of care for patients with aGvHD receiving systemic steroid therapy as signs and 


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symptoms of infection are often masked. Prophylactic or pre-emptive antiviral therapy or both 
are used to avoid viral diseases. Patients are closely monitored for any evidence of active viral 
infection by testing peripheral blood viral copy number (e.g. viral load by DNA titer) rather 
than just reliance on viral serologies that do not provide information as to whether an active 
viral infection is present. Peripheral blood DNA titer is therefore used to guide prophylaxis and 
pre-emptive therapy, including EBV, HBV, HHV-6, HCV, and CMV. 
Approximately 50% of Grade II-IV aGvHD patients do not show adequate response to initial 
treatment with high dose systemic corticosteroids and are termed Steroid Refractory (SR) (Jamil 
2015). The European Bone Marrow Transplant (EBMT) group has established clear guidelines 
for the definition of SR-aGvHD (no response to systemic corticosteroids after 7 days or clear 
progression after at least 3 days of treatment). SR-aGvHD is nearly always fatal, either from 
organ damage or from opportunistic infection as a consequence of high dose steroid treatment. 
Second line treatments that are currently used for Grade II-IV SR-aGVHD are mostly off-label 
and although they demonstrate initial responses in approximately 50% of patients, they are 
associated with aGvHD flare during attempted steroid taper. These second line treatments 
include the following: anti-thymocyte globulin (ATG), extracorporeal photopheresis (ECP), 
mesenchymal stromal cells (MSC), low-dose methotrexate (MTX), mycophenolate mofetil 
(MMF), mTOR inhibitors (everolimus or sirolimus), etanercept, or infliximab. Management of 
aGvHD flare necessitates administration of further high dose systemic corticosteroids over a 
more prolonged time period and/or additional new systemic immunosuppressive therapy 
leading to life-threatening infections, and/or malignancy recurrence, with resultant two year 
survival rates ranging only approximately 20-30% (Martin 2012).  
No standard second line treatment has been established for SR-aGvHD and of the systemic 
therapies that have been investigated in this setting spanning four decades, no specific agent 
has been shown to exert superior efficacy (Martin 2012). As a result, the selection of a second 
line treatment is therefore made based on physician preference, taking into account the effects 
of prior treatments, desired toxicity profile, considerations for drug interactions, convenience 
and cost. As such, the development of novel treatments that are associated not only with high 
response rates, but also durable control of aGvHD to allow successful steroid taper, would be 
highly beneficial for patients with SR-aGvHD.   
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.2.1 
Overview of ruxolitinib 
Ruxolitinib (INCB018424 phosphate, INC424, ruxolitinib phosphate) is a potent, selective 
inhibitor of JAK1 (Janus kinase 1) (inhibition concentration 50% [IC50]=3.3 ± 1.2 nM) and 
JAK2 (IC50=2.8 ± 1.2 nM) with modest to marked selectivity against TYK2 (tyrosine kinase 
2) (IC50=19 ± 3.2 nM) and JAK3 (IC50=428 ± 243 nM), respectively. Ruxolitinib interferes 
with the signaling of a number of cytokines and growth factors that are important for 
hematopoiesis and immune function. 
Dysregulated JAK-STAT signaling, via upregulation of JAK1 and JAK2 or gain of function 
mutations such as JAK2V617F, has been implicated as a driver of BCR-ABL-negative 
myeloproliferative neoplasms (MPNs), namely myelofibrosis (MF), polycythemia vera (PV) 


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and essential thrombocythemia (ET). Ruxolitinib, which is jointly developed in hematology/ 
oncology and Graft-vs-Host Disease indications by Novartis Pharma AG (Switzerland) and 
Incyte Corporation (USA), specifically binds to and inhibits JAK1, JAK2 and mutated 
JAK2V617F, leading to inhibition of growth factor-mediated cell signaling and tumor cell 
proliferation. Given this mechanism of action of ruxolitinib as a JAK inhibitor and the role 
played by dysregulation of the JAK pathway in the pathogenesis of MPNs, the primary clinical 
development plan for ruxolitinib initially focused on studies to support regulatory approval in 
these disorders. Ruxolitinib has been granted marketing authorization approval for the treatment 
of patients with myelofibrosis including primary MF, post PV-MF or post ET-MF and for the 
treatment of patients with PV who are resistant to or intolerant of hydroxyurea.  
Of relevance to aGvHD, inhibition of JAK1/2 signaling results in reduced proliferation of donor 
effector T cells, suppression of pro-inflammatory cytokine production in response to 
alloantigen, as well as impairment of antigen presenting cells in vitro and in vivo (Betts 2011). 
In vivo JAK1/2 inhibition by ruxolitinib has been shown to improve survival of mice developing 
aGvHD and to reduce histopathologic GvHD grading, serum levels of pro-inflammatory 
cytokines, and expansion of allo-reactive luc-transgenic T cells (Spoerl 2014). Furthermore, 
ruxolitinib impairs differentiation of CD4 T cells into IFN-gamma– and IL17A-producing cells; 
both T-cell phenotypes are linked to aGvHD pathophysiology (Parampalli 2015).  Importantly, 
Graft-vs-Leukemia (GvL) effects have been shown to be maintained in mice treated with 
ruxolitinib in two different MHC-mismatched alloSCT models and using two different murine 
leukemia models (both lymphoid and myeloid) (Choi 2014). 
Based on the review of the long term safety profile for MF and PV patients, there is no evidence 
for long latency adverse drug reactions (ADRs). The mean duration of patient exposure in the 
MF clinical development program was 30.8 months (SD 21.0) with a maximum of 68 months. 
The mean duration of patient exposure in the PV clinical development program was 19.6 
months (SD 15.7) with a maximum of 66.7 months. Therefore, potential adverse drug reactions 
(ADR) that have a longer latency than > 30 months could have been observed. 
As of 22 Feb 2018, approximately 13,730 patients have received ruxolitinib treatment in 
Novartis- and Incyte-sponsored investigational clinical trials.  
1.2.1.1 
Non-clinical experience 
Ruxolitinib has been evaluated in non-clinical investigations in pharmacology, safety 
pharmacology, repeat-dose toxicity, genotoxicity, reproductive toxicity studies, and 
carcinogenicity studies. Ruxolitinib was observed to be efficacious in mouse models of 
Philadelphia chromosome negative MPNs. Efficacy was also observed in rodent models of 
cytokine-dependent inflammation.  Effects noted in multiple-dose toxicity studies in mice (up 
to 4 weeks), rats (up to 6 months), and dogs (up to 12 months) were primarily those associated 
with the mechanism of action of ruxolitinib, a potent and reversible inhibitor of JAK/STAT 
signaling. Decreases in red blood cells, reticulocytes, eosinophils and lymphocytes have been 
observed along with lymphoid depletion in bone marrow and lymphoid organs. In a 
cardiovascular evaluation of ruxolitinib in dogs, electrocardiogram (ECG) parameters were 
unaffected at all doses.   


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Ruxolitinib was not mutagenic or clastogenic, nor did it demonstrate potential for 
carcinogenicity in a 6-month study in Tg.rasH2 mice or in the 2-year rat study. In embryo-fetal 
assessments in rat and rabbit, maternal toxicity and minimal embryo-fetal toxicity were noted 
at the highest doses evaluated. Ruxolitinib was not teratogenic in either rat or rabbit. In an 
evaluation of fertility and early embryonic development, no effects were noted on reproductive 
performance or fertility in male or female rats. Increases in post-implantation loss were noted 
at the higher doses. 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. More detailed information 
on the pharmacology of ruxolitinib, single and multiple dose pharmacokinetic (PK) studies 
conducted in multiple species and nonclinical safety evaluations can be found in the Investigator 
Brochure (IB). 
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. Ruxolitinib has also been administered to 
32 subjects with various degrees of renal impairment, 24 subjects with various degrees of 
hepatic impairment, and 50 patients with rheumatoid arthritis. As of 22 Feb 2018, 
approximately 13,730 patients have received ruxolitinib treatment in Novartis- and Incyte-
sponsored investigational clinical trials cumulatively since the Development IBD (DIBD). 
(Refer to Investigator Brochure for details).  
1.2.1.2.1 Clinical Pharmacology 
Fifteen Phase I, nine Phase II and three Phase III registration/pivotal studies 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, multiple myeloma (MM), or rheumatoid arthritis (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 


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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 pharmacodynamic 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 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. 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 studies led to a conclusion of no meaningful ethnic differences in 
exposure. 
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. 
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 Investigational Brochure for details on pharmacokinetics and 
pharmacodynamics. 
1.2.1.2.2 Summary of Clinical Efficacy and Safety Data 
The results from two phase III registration 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 
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 assessed spleen 
volume reduction at a different time point (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).Additionally, COMFORT-I met two out of 
three key secondary endpoints: 1) 50% decrease in total symptom score as defined by the MF 
symptom assessment form (response rate of 46% in the ruxolitinib arm vs. 5% with placebo) 
(p<0.0001), and 2) Mean change from baseline in MF symptom assessment form (-8.6 with 


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ruxolitinib from baseline of 18 vs. + 3.2 with placebo from baseline of 16.5). COMFORT-II 
exploratory endpoints related to symptom improvement and Quality of Life (QOL) were 
consistent with and supportive of the results from COMFORT-I. Grade 3-4 laboratory findings 
of anemia and thrombocytopenia were reported with ruxolitinib at rates of 38.3% and 8.3%, 
respectively, compared with 20.6% and 6.8% on BAT (COMFORT-II); and with ruxolitinib at 
rates of 45.2% and 12.9%, respectively, compared with 19.2% and 1.3% on placebo 
(COMFORT-I). Thrombocytopenia and anemia were predictable and manageable with dose 
modifications. 
Long term outcomes such as OS, Leukemia-Free Survival (LFS), duration of response and 
safety were reassessed at different time points, most recently in 2015 (5-year follow up report),  
comparing the patients originally randomized to the ruxolitinib arm to those that were 
randomized to the control arm. The 5-year follow-up report for COMFORT-I suggested longer 
survival for patients randomized to ruxolitinib versus control arm patients, with a hazard ratio 
of 0.693 (95% confidence interval [CI]:  0.503, 0.956, p = 0.0245). In COMFORT-II, long term 
follow-up also suggested a survival advantage with ruxolitinib treatment compared with BAT. 
There was a 33% reduction in the risk of death for patients treated with ruxolitinib compared 
with that for patients treated with BAT (hazard ratio [HR] = 0.67; 95% CI, 0.44-1.02). The 
estimated survival probability at 5.0 years was 56% (95%CI: 0.40, 0.62) in the ruxolitinib arm 
and 44% (95%CI: 0.31, 0.56) in the BAT arm. Safety profile in the two studies remained 
broadly unchanged. There were no new or unexpected safety signals that occurred with the 
longer treatment exposure and follow-up period.  
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. Significantly more patients randomized to ruxolitinib than patients randomized to 
BAT met the primary endpoint (hematocrit control and at least 35% spleen volume reduction) 
at Week 32: 23% vs 0.9%, respectively (p < 0.0001). More patients randomized to ruxolitinib 
achieved hematocrit control at Week 32 when compared to patients randomized to BAT: 60.0% 
(95% CI: 50.2, 69.2) vs 18.75% (95% CI: 12.7, 28.2), respectively. More patients randomized 
to ruxolitinib achieved at least 35% spleen volume reduction at Week 32 when compared to 
patients randomized to BAT: 40% (95% CI: 29.1, 47.9) vs 0.9% (95% CI: 0.0, 4.9), 
respectively. The great majority of these responses in the ruxolitinib arm were also durable at 
Week 48. Furthermore, significantly more patients randomized to ruxolitinib achieved the key 
secondary endpoint of complete hematological remission (hematocrit control, platelet count ≤ 
400×109/L, and WBC count ≤ 10×109/L) at Week 32 when compared to patients randomized to 
BAT: 23.6% vs 8.0%, respectively (p=0.0028, when adjusted for baseline platelet and WBC 
status). The study is still ongoing and will continue for a total of 5 years.   
In GvHD, two recent independent publications have reported encouraging early clinical data 
with ruxolitinib in SR-aGvHD and SR-cGvHD. The first included data from 6 SR-aGvHD 
patients who received an initial ruxolitinib dose of 5 mg BID that was advanced to 10 mg BID 
after 3 days when no side effects were observed (Spoerl 2014). Responses to ruxolitinib 
treatment in terms of improved GvHD grades and reduction of required corticosteroids were 
observed in all patients; no patient experienced GvHD flare during steroid taper requiring 
additional systemic therapy. Further early clinical experience with ruxolitinib in patients with 
SR-aGvHD was recently reported in a retrospective study that gathered experience in 95 SR-


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GvHD patients from 19 stem cell transplant centers (Zeiser 2015). In this study, 54 patients 
with SR-aGvHD (all severe Grade III/IV) who had received a median of 3 previous GvHD 
therapies (range 1-7) received a ruxolitinib dose of 5-10 mg BID. Dose reductions were 
generally not required for worsening cytopenias after initiation of ruxolitinib therapy. The 
Overall Response Rate (ORR) in SR-aGvHD was 81.5% which included 46.3% of patients 
demonstrating complete remission (CR). Median time to response was 1.5 weeks (range 1-11). 
Flare of aGvHD was observed in only 6.8% (3/44) of ruxolitinib-responsive patients during 
steroid taper.  GvL was maintained with only 5 of 54 patients (9.3%) demonstrating relapse of 
the underlying malignancy. The 6-month survival estimate was 79% (67.3-90.7% CI). Safety 
profile of ruxolitinib in SR-aGvHD was generally favorable. Although cytopenias were 
observed in 55.5% of SR-aGvHD patients, cytopenias preceded ruxolitinib administration in 
51.8% of these patients. CMV reactivation was observed in 30% of SR-aGvHD patients treated 
with ruxolitinib. This incidence rate compares favorably with that reported with other second 
line aGvHD agents including MMF, alemtuzumab, and others where CMV reactivation ranges 
from 70 to 80% (Rager 2011). 
2 
Rationale 
2.1 
Study rationale and purpose 
The scientific rationale for this study of ruxolitinib in adults and adolescents with Grade II-IV 
SR-aGvHD is based on current knowledge of aGvHD pathophysiology that begins with 
activation of host antigen-presenting cells (APC) by danger signals expressed by damaged 
tissues and/or pathogens. Activated host APC then present host antigens to donor immune cells, 
leading to donor T-cell proliferation and inflammatory cytokine production. These 
inflammatory cytokines then recruit and induce proliferation of additional immune effector 
cells, thereby perpetuating an adverse cycle of allo-reactive tissue injury and inflammation 
(Paczesny 2010). Ruxolitinib has been shown to lower pro-inflammatory cytokines in MF 
patients. In addition, pre-clinical data support the mechanism of action of ruxolitinib in GvHD 
to: i.) impair APC function, ii.) inhibit donor T cell proliferation,  iii.) suppress adverse cytokine 
production, and iv.) improve survival and disease manifestations in GvHD mouse models 
(Parampalli 2015, Heine 2013, Spoerl 2014).  This, in addition to the recently published data in 
which ruxolitinib was shown to have evidence of clinical efficacy when added to 
immunosuppressive therapy in patients with SR-aGvHD (Zeiser 2015; Spoerl 2014), provides 
strong rationale to test the hypothesis that ruxolitinib added to immunosuppression therapy for 
SR-aGvHD patients will provide higher rates of disease response compared with currently used 
second line systemic treatment modalities, and further that this response will be sustained during 
steroid taper.  
2.2 
Rationale for the study design 
This trial is designed as a randomized (1:1) phase III open label design to investigate the 
efficacy and safety of ruxolitinib vs. Investigator choice Best Available Therapy (BAT) added 
to the patient’s immunosuppressive regimen in adults and adolescents ≥12 years old with Grade 
II-IV SR-aGvHD.  


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Very few prospective comparative studies have been carried out to assess the efficacy and safety 
of currently used second-line therapy for aGvHD. A randomized study is necessary to determine 
whether administration of ruxolitinib in patients with SR-aGvHD provides better efficacy when 
compared to BAT and whether control of the underlying hematologic disease for which alloSCT 
is performed is maintained during steroid taper.  
In addition, as SR-aGvHD is associated with a very high mortality rate, including early 
mortality (i.e. within 30 days) attributable primarily to infection, hematologic disease 
progression or recurrence during prolonged administration of high dose systemic 
corticosteroids, and clinically meaningful longer term outcomes such as non-relapse mortality, 
event free survival, malignancy relapse and overall survival will be followed in each study arm. 
Investigator choice BAT is chosen as comparator as currently no treatment for SR-aGvHD is 
approved in either the United States of America (US) or European Union (EU) and practices 
vary as to the selection of various systemic therapies since to date no improvement in the high 
mortality rates has been documented despite treatment with these agents. Patients will be 
randomized 1:1 to receive either ruxolitinib or BAT, stratifying on GvHD grade (Grade II vs. 
III vs. IV). The choice of BAT will be decided by the Investigator before randomization in this 
study. The open label design of this study is necessary to accommodate the variety of treatments 
for Grade II-IV SR-aGvHD that may be considered as Investigator’s choice BAT, as these vary 
from administered tablets to cellular therapy and photopheresis, as well as the necessity of using 
frequent additional new immunosuppressive treatments, modifications, and dose adjustments 
in these therapies depending on the patient’s response. This design is well established in the 
alloSCT field and in SR-aGvHD, particularly.  
Grade II-IV SR-aGvHD adult and adolescent patients age ≥12 years are included in this study 
as mortality rates are unacceptably high for these patients. Furthermore, data from a phase I 
study in pediatric patients show that safety of ruxolitinib was generally favorable and their PK 
data comparable to adults (Loh 2015), hence the same ruxolitinib dosing approach would be 
used.  
Adolescents age ≥12 years comprise approximately 5% of the adult and pediatric aGvHD 
population (CIBMTR data) and standard treatment does not differ between adolescents and 
adults. Mortality risks for all adults and adolescents with SR-aGvHD are a continuum, with no 
age breakpoint, with only approximately 49% of all patients surviving beyond 6 months after 
alloSCT (Martin 2012). This high mortality risk represents a significant unmet medical need 
not only for adult patients but also adolescents. Pediatrics patients <12 years of age will be 
considered for future studies following discussion and agreement with the Paediatric Committee 
(PDCO) using ruxolitinib liquid formulation currently under development.   
The rationale to stratify patients at the time of enrollment and randomization is based on the 
fact that response rates are variable in patients with different GVHD grades. Grade II vs. Grade 
III vs. Grade IV disease severity by standard grading criteria also correlates with long-term 
survival. In a recent randomized Phase II study of aGvHD, the relative risk of non-relapse 
mortality (NRM) was 1.72 (95% confidence interval 1.13–2.59) for patients with Grade III–IV 
compared to patients with aGvHD Grade II or lower (Levine 2010). 
Multiple measures will be used in this study to reduce bias. First, addition of new systemic 
immunosuppressive therapy for patients meeting progression, mixed response, or no response 


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criteria, or aGvHD flare failure in either of the two treatment arms is considered a treatment 
failure, in order to prevent subjective addition of new therapy in either of the two treatment 
arms.. Second, the primary and key secondary endpoints of the trial will be based on objective 
measures of body surface area aGvHD skin rash, stool volumes or frequency per 24h time 
period, and serum bilirubin levels, and these objective measures are delineated by standard 
criteria (Harris 2016). Third, in order to minimize the potential for differential steroid tapering 
of BAT and ruxolitinib, recommendations for dose increases of systemic corticosteroids to 
manage aGvHD flares as well as steroid dose tapering per standard guidelines in the field are 
provided.  
A Screening period is planned to start at the time of Grade II-IV aGvHD diagnosis to allow 
sufficient time to obtain results of required tests and ensure that all eligibility criteria are met. 
Confirmation of eligibility during Screening allows rapid enrollment of patients in the event 
that steroid refractory status is documented (e.g. no response to standard doses of systemic 
corticosteroids after 7 days or clear progression after at least 3 days). This approach allows 
rapid randomization and initiation of study treatment required for these patients, which is 
critical to management of rapidly progressive SR-aGvHD.  
The study’s primary endpoint, overall response rate (ORR) without requirement for addition of 
new systemic immunosuppressive treatment will be assessed after 28 days of therapy, as Day 
28 ORR has been shown to correlate best with subsequent long-term survival (Levine 2010). A 
key secondary endpoint is to compare the ORR at Day 56 after randomization between 
ruxolitinib vs. BAT, in order to assess the durability of the primary response.  
The treatment phase will allow assessment of patient benefit and risk in terms of: i.) 
improvement or resolution of aGvHD manifestations, ii.) reduction or cessation of required 
systemic corticosteroids, iii.) any progression or recurrence of the underlying hematologic 
disease for which the alloSCT has been performed including malignancy progression or relapse 
(refer to Appendix 4), iv.) occurrence of any life-threatening infections, v.) occurrence of any 
graft failure, vi.) occurrence of chronic GvHD, vii.) occurrence of bleeding, viii.) duration of 
hospitalization and frequency of hospital readmissions for management of aGvHD and/or 
infections, and ix.) patient-reported quality of life (QoL). 
Analysis of primary and key secondary endpoints will occur when all patients have completed 
the Day 56 visit or discontinued study treatment. This analysis will be assessed and considered 
for regulatory filing. No interim analysis or design adaptations are planned. Further analyses on 
safety and efficacy endpoints will be performed when all patients have completed 
approximately 6 months treatment after randomization or discontinued earlier. Patients will be 
followed long-term to assess survival, NRM, EFS, hematologic disease progression or relapse, 
graft failure, occurrence of cGvHD, and occurrence of any second primary malignancies up to 
24 months after randomization. A final study report will be written when all patients have 
completed the study or discontinued from the study. 
Collection of PK data will be implemented in this study in order to assess exposure data and 
determine how it compares with data from previous studies, and explore its relationship with 
efficacy and safety parameters. 




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Ruxolitinib may be taken without regard to food except on days when PK samples are drawn; 
on those days patients are instructed to fast and refrain from taking ruxolitinib until PK samples 
are collected. 
Patients may have dose reductions or modifications of ruxolitinib during the course of treatment 
based on adverse events, clinical evaluation, and laboratory assessments. See Section 6.3 for 
ruxolitinib dose modifications. 
2.4 
Rationale for choice of combination drugs  
Not applicable. 
2.5 
Rationale for choice of comparators drugs  
This will be an open label study of ruxolitinib versus Best Available Therapy as selected by the 
Investigator. BAT is chosen as comparator as there is currently no broadly approved, or 
uniformly used standard second line therapy in SR-aGvHD. A BAT control arm is required to 
ensure an adequately controlled duration to assess the primary endpoint of the study as well as 
ruxolitinib comparative safety. The BAT in this study will be selected by the Investigator prior 
to patient randomization among the following standard systemic treatments: anti-thymocyte 
globulin (ATG), extracorporeal photopheresis (ECP), mesenchymal stromal cells (MSC), low-
dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR inhibitors (everolimus or 
sirolimus), etanercept, or infliximab.  No other BAT will be allowed. 
2.6 
Risks and benefits  
Appropriate eligibility criteria, as well as specific dose modification and stopping rules, are 
included in this protocol. Recommended guidelines for prophylactic or supportive management 
of study-drug induced adverse events are provided in Section 6.1.5.1 and Section 6.3. The risk 
to patients in this trial may be minimized by compliance with the eligibility criteria and study 
procedures, as well as, close clinical monitoring, and, protocol-defined ruxolitinib dose 
modifications guidelines and treatment discontinuation criteria. There may be unforeseen risks 
with ruxolitinib which could be serious. Refer to the most recent Investigator’s Brochure. 
The curative potential of alloSCT for patients with life-threatening hematologic disorders is 
significantly limited by aGvHD that occurs in a large proportion (>60%) of alloSCT recipients 
despite administration of multi-agent prophylactic immunosuppressive therapy. SR-aGvHD is 
associated with a very high mortality risk and available second line therapies have not been 
shown to reduce mortality. Potential benefit of ruxolitinib for alloSCT patients with SR-aGvHD 
is based on published pre-clinical and encouraging early clinical data.  
Important identified and potential risks from ruxolitinib MPN clinical development and post-
authorization experience to date include: i.) myelosuppression (thrombocytopenia, anemia and 
leukopenia), ii.) infections (including opportunistic infections), iii.) tuberculosis, iv.) use in 
patients with hepatic impairment, v.) use in patients with moderate or severe renal failure or end 
stage renal failure requiring hemodialysis, vi.) elevated transaminases, vii.) bleeding, viii.) 
progressive multifocal leukoencephalopathy, ix.) increased systolic blood pressure, x.) non-
melanoma skin cancer, xi.) hepatitis B reactivation, xii.) developmental toxicity, xiii.) 
overexposure with concomitant strong CYP3A4 inhibitors or fluconazole, xiv.) use with 


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CYP3A4 inducers such as rifampicin and xv.) pharmacodynamic interaction between 
ruxolitinib and hematopoietic growth factors or combination with cytoreductive therapies.  
These identified and potential risks will be monitored closely and mitigated throughout this 
study in patients randomized to receive ruxolitinib vs. BAT as these risks are also common in 
the alloSCT setting particularly patients with SR-aGvHD. 
Myelosuppression: Myelosuppression is a common occurrence in alloSCT patients with 
incidence higher at earlier time points when SR-aGvHD occurs, e.g. first 6 weeks after graft 
infusion. Myelosuppression is observed prior to and during early donor engraftment, and in the 
setting of CMV reactivation as well as HHV-6 infection.  In addition, medications used to treat 
these viral infections, particularly gancyclovir, are associated with myelosuppression. Case 
series in acute and chronic GvHD have identified worsening of myelosuppression in 
approximately 10-20% of GvHD patients treated with ruxolitinib at doses ranging 5-10 mg 
orally BID spanning several months (Zeiser 2015). This was managed with dose reduction of 
ruxolitinib to 5 mg orally BID and required holding ruxolitinib in some patients whose ANC 
dropped below 500/mm3. 
Myelosuppression is manageable in SR-aGvHD patients by keeping the starting dose 
comparatively lower than in MF (10 mg orally BID) and not allowing dose escalation above 
this starting dose. Dose adjustment or dose holding is based on ANC and platelet count (see 
Table 6-3). Patients will also be closely monitored for any evidence of secondary graft failure 
defined as initial whole blood or marrow donor chimerism >5% declining to <5% on subsequent 
measurements. In the Phase III clinical protocols in MPN patients, the concurrent use of 
hematopoietic growth factors was discouraged, but not prohibited. These same guidelines apply 
to this study as potential benefit of hematopoietic growth factors may exceed any risk. 
Administration of hematopoietic growth factors will be allowed per Investigator judgement.   
Bleeding:  Hemostatic disturbances are common in patients undergoing alloSCT and have a 
significant impact on morbidity and mortality. aGvHD correlates strongly with the incidence 
and severity of bleeding episodes. Ruxolitinib dose adjustment or dose holding will be based 
on platelet count (see Table 6-3) and platelet transfusions may be given as clinically indicated.  
Use in patients with hepatic impairment: As the liver is a target organ in aGvHD 
pathophysiology, elevated liver function tests including bilirubin and AST/ALT cannot be used 
as a parameter to exclude SR-aGvHD patients or determine starting dose. Diagnostic evaluation 
and management of hepatic impairment in SR-aGvHD patients treated on this study will follow 
institutional guidelines. The ruxolitinib starting dose in SR-aGvHD patients is relatively low, 
e.g. 10 mg orally BID, and patients will be closely monitored for any signs of ruxolitinib-
associated hepatic toxicities. For patients with myeloproliferative disorders with hepatic 
impairment treated with ruxolitinib, the recommended starting dose, based on platelet count, is 
generally reduced by approximately 50%. However in patients with SR-aGvHD the starting 
ruxolitinib dose will not be reduced, as the dose is already low, and there is a need to ensure an 
adequate dose is administered to effectively treat SR-aGvHD that is immediately life-
threatening. 
Use in patients with renal impairment: Renal impairment is a common occurrence in patients 
with SR-aGvHD due to episodes of mild dehydration attributable to GI involvement in the 
outpatient setting causing decreased oral intake as well as concurrent administration of CNI. 


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AlloSCT patients with severely impaired renal function are excluded from enrollment.  
Diagnostic evaluation and management of renal impairment in SR-aGvHD patients will follow 
institutional guidelines.  
Infections: Serious bacterial, mycobacterial, fungal, viral and other infections have occurred in 
MPN patients treated with ruxolitinib. Actions to minimize the risk of serious infections in SR-
aGvHD patients will follow standard alloSCT guidelines including close monitoring of clinical 
signs and symptoms of infection, their prompt recognition and treatment. Patients with positive 
serologies pre-transplant for CMV, EBV, HHV-6, HBV, HCV require peripheral blood viral 
load (viral copies/mL) to rule out presence of active viral infection as eligibility requirement. 
As CMV reactivation with ruxolitinib therapy has been observed in SR-aGvHD patients (Zeiser 
2015), this will be monitored closely in this trial. Management of any active viral infection and 
viral prophylaxis will follow transplant program guidelines and viral load titer data will be 
documented.  
Patients are ineligible for enrollment if they have an active uncontrolled infection. Any 
bacterial, fungal, viral, parasitic, and non-microbiologically defined infection will be managed 
per institutional guidelines and severity graded by standard alloSCT criteria including 
recurrence intervals (see Appendix 2: Severity Grading Table & Recurrence Interval 
Definitions). This protocol will use, in addition to standard CTCAE grading, the infection 
grading system developed and validated for alloSCT patients as this grading system is 
predictive of mortality (Cordonnier 2006). All Grade 2 and 3 microbiologically documented 
infections occurring after initiation of therapy will be reported by site of disease, date of onset, 
pathogen, and grade.  
Tuberculosis: Tuberculosis (TB) is very rare in alloSCT patients as all patients are carefully 
screened prior to the transplant procedure and are not allowed to undergo alloSCT if TB is 
present. SR-aGvHD patients in both the ruxolitinib and BAT arms will be monitored for any 
clinical signs and symptoms of active TB infection, and appropriate treatment provided. Skin 
testing for TB will not be performed in this study of alloSCT patients as this assessment is non-
informative due to anergy. Ruxolitinib therapy will not be administered in any patient with an 
active TB infection.  
Progressive Multifocal Encephalopathy: Progressive multifocal leukoencephalopathy (PML) 
is a rare complication in alloSCT recipients. The median time from transplantation to symptom 
onset has been reported as 11 months, while median time to symptom onset has been notably 
shorter in other viral encephalitis in this population. These other viral entities, including HHV-
6, HSV, EBV, CMV, HBV, HCV and VZV, have been reported with a median time to symptom 
onset post-HCT of between 3 and 8 months, respectively. The incidence of PML in the HCT 
population is significantly less than in patients with HIV, with comparative incidence rates of 
35.4 vs. 130 per one-hundred thousand person years, respectively (Kaufman 2013).  Actions to 
minimize the risk of PML in SR-aGvHD patients will follow standard alloSCT guidelines 
including close monitoring of any clinical signs of progressive focal neurological symptoms, 
with prompt diagnostic work up and treatment.  
Long-Term Follow-Up: Non melanoma skin cancers: Non-melanoma skin cancers 
(NMSCs), including basal cell, squamous cell, and Merkel cell carcinoma have been reported 
in MPN patients treated with ruxolitinib. Skin cancer incidence is increased in alloSCT patients 


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vs. the general population, including increased risk of basal cell carcinoma (BCC), squamous 
cell carcinoma (SCC), and malignant melanoma (MM) occurring late, generally 10-15 years 
after transplant (Omland 2016). Any occurrence of skin cancers will be monitored throughout 
this study. 
Long-Term Follow Up: Long-term side effects after alloSCT include nonmalignant organ or 
tissue dysfunction, changes in quality of life, infections related to abnormal immune 
reconstitution and secondary cancers. Different categories of secondary malignancies can occur 
after alloSCT, including: post-transplant lymphoproliferative disorders, donor-type secondary 
leukemia/other malignancy and de novo solid tumors (Mohty 2011). Second primary 
malignancy rates for SR-aGvHD patients in both the ruxolitinib and BAT arms will be assessed 
during long-term follow-up after transplant and will be compared with relevant epidemiologic 
data.  
Safety in pediatric patients:  In a Phase I study, ruxolitinib with BID continuous oral dosing 
in children aged 2.4–21.4 (median 14.4) years with refractory/recurrent solid tumors (ST) and 
hematologic malignancies was well tolerated and showed similar pharmacokinetics to those in 
adults. No maximum tolerated dose was reached and the recommended dose for continuous 
BID oral administration was 50 mg/m2/dose (Loh 2015). 
3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 
Efficacy assessments:  
aGvHD response assessment will be made with respect to the organ stage at the time of 
randomization and, in patients entering the Cross-Over Treatment Period, with respect to the 
last available organ stage prior to or at the time of cross-over: 
 Complete response is defined as a score of 0 for the aGvHD grading in all evaluable 
organs that indicates complete resolution of all signs and symptoms of aGvHD in all 
evaluable organs without administration of additional systemic therapy for any earlier 
progression, mixed response or non-response of aGvHD.   
 Partial response is defined as improvement of 1 stage in 1 or more organs involved with 
aGvHD signs or symptoms without progression in other organs or sites without 
administration of additional systemic therapy for an earlier progression, mixed response or 
non-response of aGvHD.   
 Lack of response is defined as no response, mixed response, or progression. 
 No response is defined as absence of improvement in any organ involved by aGvHD, 
without worsening in any involved organ.  
 Mixed response is defined as improvement of at least 1 stage in the severity of 
aGvHD in one organ accompanied by progression in another organ or development of 
signs or symptoms of aGvHD in a new organ. 
 Progression is defined as worsening in 1 or more organs by 1 or more stages without 
improvement in any involved organ.   
Patients requiring additional systemic therapy for aGvHD will be classified as non-responders.  


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aGvHD Flare is defined as any increase in signs or symptoms of  aGvHD that is sustained 
for >24h after an initial response (CR or PR) and requires re-escalation of immunosuppressive 
therapy (e.g. corticosteroid, CNI, BAT and/or ruxolitinib dosing). While all aGvHD flares will 
be captured on study whether occurring during steroid, CNI, BAT, or ruxolitinib taper, only 
flares that fulfil either one the following criteria will be considered a failure of treatment: 
1. Addition of new systemic therapy for aGvHD due to inability to taper corticosteroids 
below methylprednisolone 0.5 mg/kg/day (or equivalent <0.6 mg/kg/day of prednisone) 
for a minimum 7 days,  
OR  
2. Addition of new systemic therapy for aGvHD due to re-escalation of corticosteroids to 
methylprednisolone >2 mg/kg/day (or equivalent >2.5 mg/kg/day of prednisone).  
aGvHD assessments will be performed by the treating team according to standard criteria 
(Harris 2016) as described in Appendix 1. Disease assessments must be performed per the 
schedule of visits after randomization, unless the patient meets any of the criteria for 
discontinuation of study treatment (see Section 7.1.5), withdraws consent, dies, or is lost to 
follow up. 
After randomization, signs and symptoms of cGvHD may be observed. cGvHD signs and 
symptoms may occur in up to 50% of patients based on published literature. Patients will be 
evaluated for any signs or symptoms of cGvHD and scored using NIH Consensus Criteria (Lee 
2015) as described in Appendix 3. Development of cGvHD signs or symptoms is not considered 
a treatment failure of aGvHD. Treatment of cGvHD will follow institutional standards of 
procedure and Investigator preference. Ruxolitinib will not be administered for treatment of 
cGvHD. For patients receiving ruxolitinib at the time of onset of cGvHD, ruxolitinib taper will 
follow guidelines per Section 6.1.5.1. 
Objectives and related endpoints are described in Table 3-1 below. 


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Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
Refer to Section 10.4 
To compare the efficacy of ruxolitinib vs. Investigator’s 
choice Best Available Therapy (BAT) in patients with 
Grade II-IV SR-aGvHD assessed by Overall Response 
Rate (ORR) at Day 28 
Overall response rate (ORR) at Day 28 after 
randomization, defined as the proportion of patients in 
each arm demonstrating a complete response (CR) or 
partial response (PR) without requirement for 
additional systemic therapies for an earlier 
progression, mixed response or non-response. 
Scoring of response will be relative to the organ stage 
at the time of randomization. 
CMH analyses, stratified by aGvHD grade 
Key secondary endpoint 
 
Refer to Section 10.5.1 
To compare the rate of durable ORR at Day 56 
between ruxolitinib and BAT 
Proportion of all patients in each arm who achieve a 
complete response (CR) or partial response (PR) at 
Day 28 and maintain a CR or PR at Day 56. 
CMH analyses, stratified by aGvHD grade 
Other secondary endpoints 
 
Refer to Section 10.5.2 
To estimate ORR at Day 14 
Proportion of patients who achieved OR (CR+PR) at 
Day 14.  
 
To assess Duration of response 
Duration of response (DOR) is assessed for 
responders only and is defined as the time from first 
response until aGvHD progression or the date of 
additional systemic therapies for aGvHD. Onset of 
chronic GvHD, or death without prior observation of 
aGvHD progression are considered as competing 
risks. 
 
To assess the cumulative steroid dose until Day 56 
Weekly cumulative steroid dose for each patient up to 
Day 56 or end of treatment will be calculated.  
 
To assess Overall Survival (OS) 
Overall survival, defined as the time from the date of 
randomization to the date of death due to any cause.  
Probability of overall survival at Months 1, 2, 6, 12, 18 
& 24 will be estimated from the Kaplan-Meier curves 
for each arm. 
To assess Event-Free Survival (EFS) 
Event-free survival, defined as the time from the date 
of randomization to the date of hematologic disease 
relapse/progression, graft failure, or death due to any 
cause.  
Probability of EFS at Months 1, 2, 6, 12, 18 & 24 will 
be estimated from the Kaplan-Meier curves for each 
arm. 


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Objective 
Endpoint 
Analysis 
To assess Failure-Free Survival (FFS) 
Failure-free survival, defined as the time from the date 
of randomization to date of hematologic disease 
relapse/progression, non-relapse mortality, or addition 
of new systemic aGvHD treatment.   
Cumulative incidence of FFS at Months 1, 2, 6, 12, 18 
& 24 will be estimated, considering each event as a 
competing risk for the other two.  Onset of chronic 
GvHD is considered as a competing risk.  
To assess Non Relapse Mortality (NRM) 
Non-relapse mortality (NRM), defined as the time from 
date of randomization to date of death not preceded 
by hematologic disease relapse/progression.  
Cumulative incidence of NRM at Months 1, 2, 6, 12, 18 
& 24 will be estimated, considering hematologic 
disease relapse/progression as competing events. 
To assess incidence of Malignancy 
Relapse/Progression (MR)  
Malignancy Relapse/Progression (MR) (refer to 
Appendix 4), defined as the time from date of 
randomization to hematologic malignancy 
relapse/progression. Calculated for patients with 
underlying hematologic malignant disease. 
Cumulative incidence of MR at Months 1, 2, 6, 12, 18 
& 24 will be estimated, considering deaths not 
preceded by hematologic malignancy 
relapse/progression as competing events. 
To measure the incidence of cGvHD  
cGvHD, defined as the diagnosis of any cGvHD 
including mild, moderate, severe.   
Cumulative incidence of cGvHD at Months 1, 2, 6, 12, 
18 & 24 will be estimated, considering hematologic 
disease relapse/progression and death without prior 
cGvHD as competing events. 
To estimate the rate of Best Overall Response (BOR) 
Proportion of patients who achieved OR (CR+PR) at 
any time point up to and including Day 28 and before 
the start of additional systemic therapy for aGvHD. 
 
To assess Pharmacokinetics (PK) of ruxolitinib in SR-
aGvHD patients 
Pharmacokinetic parameters of ruxolitinib after a 
single dose and at steady state. Cmax, AUClast, 
AUCinf, Ctrough, Racc and AUCtau. Other PK 
parameters are CL/F, Vz/F, Tmax and T1/2. 
 
To assess exposure-response relationship of 
ruxolitinib in SR-aGvHD 
Pharmacokinetics (exposure) and efficacy (ORR, OS, 
or other relevant endpoints) relationship.  
Pharmacokinetics (exposure) and safety (AEs) 
relationship. 
 
To evaluate changes in Patient Reported Outcomes 
(PROs) 
Change in FACT-BMT from baseline to each visit 
where measured. 
Change in EQ-5D-5L from baseline to each visit where 
measured. 
 
To evaluate the safety of ruxolitinib and Best Available 
Therapy 
Safety and tolerability including myelosuppression, 
infections, and bleeding will be assessed by 
monitoring the frequency, duration and severity of 
Adverse Events including occurrence of any second 
 




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4 
Study design 
4.1 
Description of study design 
This randomized, Phase III, open-label study will investigate the efficacy and safety of 
ruxolitinib vs. BAT added to the patient’s immunosuppressive regimen in adults and 
adolescents (≥12 years old) with SR-aGvHD.  
The randomization target for this study is 308 patients. 
The study is comprised of 4 defined periods, as outlined below: 
 Screening Period (Day -28 to Day -1) 
To facilitate rapid randomization and initiation of treatment once patients are diagnosed as 
steroid refractory, screening activities and assessment of inclusion and exclusion criteria should 
begin once the patient has been diagnosed with aGvHD and has signed the Screening Informed 
Consent. Any occurrence of Steroid-Refractory aGvHD will be monitored closely. 
Steroid-Refractory aGvHD is defined as patients administered high-dose systemic 
corticosteroids (methylprednisolone 2 mg/kg/day [or equivalent prednisone dose 2.5 
mg/kg/day]), given alone or combined with calcineurin inhibitors (CNI) either: 
A. Progressing based on organ assessment after at least 3 days compared to organ stage at the 
time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade 
II-IV aGvHD,  
OR 
B. Failure to achieve at a minimum partial response based on organ assessment after 7 days 
compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- 
CNI for the treatment of Grade II-IV aGvHD, 
OR 
C. Patients who fail corticosteroid taper defined as fulfilling either one of the following 
criteria: 
1. Requirement for an increase in the corticosteroid dose to methylprednisolone ≥2 
mg/kg/day (or equivalent prednisone dose ≥2.5 mg/kg/day)  
OR 
2. Failure to taper the methylprednisolone dose to <0.5 mg/kg/day (or equivalent 
prednisone dose <0.6 mg/kg/day) for a minimum 7 days.  
Note: Patients will receive systemic corticosteroids +/- continued CNI +/- other systemic 
treatment for aGvHD per standard of care by the Investigator during the Screening period. 
Systemic medications for aGvHD other than corticosteroids +/- CNI may be continued after 
randomization only if used for aGvHD prophylaxis (i.e. started before the diagnosis of 
aGvHD). 
Patients meeting all eligibility criteria including one of the above criteria for Steroid-Refractory 
aGvHD (SR-aGvHD), may be consented to the Study Informed Consent. The Investigator must 
identify Investigator choice BAT prior to randomization.  


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Please refer to Section 7 for details on Screening Assessments including assessments to be 
performed during Screening and those to be performed after obtaining the study written 
informed consent.  
Patients meeting all inclusion and exclusion criteria will be randomized 1:1 to receive either 
ruxolitinib or BAT stratifying on aGvHD grade at the time of randomization (Grade II vs. III 
vs. IV). 
 Treatment Period (Day 1 to Week 24 / EOT) 
Study treatment will begin on Day 1, following randomization (preferably on the same day but 
no later than 72 h after randomization). Day 1 is the day of randomization.  
Study visits will occur per the following schedule to monitor tolerability and efficacy of the 
study treatments during the Treatment period: 
 Weekly visits from Day 1 up to Day 56; 
 4-weekly visits (every 28 days) beyond Day 56 and until Week 24.  
 The End of Treatment (EOT) visit will occur at Week 24, or earlier in case the patient 
meets any of the criteria for discontinuation of study treatment (see Section 7.1.5).  
 Responding patients (i.e. obtaining a CR or PR) completing the dosing schedule 
for ruxolitinib or their assigned BAT at any time as per standard of care before 
Week 24 must continue to be assessed for all scheduled visits until Week 24.  
While these patients will have their EOT visit at Week 24, they must also have assessments 
performed within 7 days of the last dose, either at a scheduled visit per Table 7-1 (if within 7 
days) or as an unscheduled visit. The list of required assessments is detailed in Section 7.1.4. 
 Should an aGvHD flare or other safety concerns prevent ruxolitinib taper from being 
completed by Week 24, the patient must continue to be assessed until the taper of 
ruxolitinib is complete, i.e. the EOT visit may be delayed until Week 96 at the latest. 
In this case, taper follow-up visits will occur every 8 weeks from Week 24 to Week 
48, and every 12 weeks thereafter, as applicable. 
Patients may be treated up to approximately 6 months (see Section 6 for Study Treatment details 
and permitted/prohibited concomitant therapies), or up to approximately 2 years from 
randomization, in case the end of ruxolitinib taper is delayed due to an aGvHD flare or other 
safety concerns.During the Treatment Period, patients randomized to BAT may be eligible to 
cross-over and receive ruxolitinib between Day 28 and Week 24 if they: 
 Fail to meet the primary endpoint response definition (CR or PR) at Day 28  
OR 
 Lose the response thereafter AND meet criteria for progression, mixed response, or no 
response, necessitating new additional systemic immunosuppressive treatment for 
aGvHD.  
AND 
 
Do not have signs/symptoms of cGvHD (overlap syndrome, progressive, or de novo 
cGvHD) 


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Patients who have crossed over from the BAT to the ruxolitinib arm between Day 28 and Week 
24 will be followed until completion of treatment with ruxolitinib and will follow the same 
treatment and taper schedule as patients originally randomized to ruxolitinib treatment. Weekly 
assessments will be required for 56 days after initiation of ruxolitinib and 4-weekly assessments 
thereafter until Cross-Over Week 24. 
 The Cross-Over EOT visit will occur at Cross-Over Week 24, or earlier in case the patient 
meets any of the criteria for discontinuation of study treatment (see Section 7.1.5).  
 Responding patients (i.e. obtaining a CR or PR) completing the dosing schedule for 
ruxolitinib at any time before Cross-Over Week 24 must continue to be assessed for 
all scheduled visits until Cross-Over Week 24.  
 While these patients will have their Cross-Over EOT visit at Cross-Over Week 
24, they must also have assessments performed within 7 days of the last dose, 
either at a scheduled visit per Table 7-2 (if within 7 days) or as an unscheduled 
visit. The list of required assessments is detailed in Section 7.1.4. 
 Should an aGvHD flare or other safety concerns prevent ruxolitinib taper from being 
completed by Cross-Over Week 24, the patient must continue to be assessed until the taper 
of ruxolitinib is complete, i.e. the Cross-Over EOT visit may be delayed until Cross-Over 
Week 96, or 2 years from randomization, whichever occurs first. In this case, taper follow-
up visits will occur every 8 weeks from Cross-Over Week 24 to Cross-Over Week 48, and 
every 12 weeks thereafter as applicable. 
Patients who meet cross-over criteria above and receive ruxolitinib are allowed to continue 
corticosteroids and CNI for aGvHD treatment as per standard of care, with cessation required 
of any other systemic immunosuppressive treatment prior to cross-over, unless used for aGvHD 
prophylaxis (i.e. started before the diagnosis of aGvHD).  
Please refer to Section 7 for assessment details. 
 Safety Follow-Up (last dose + 30 days) 
A 30-day Safety Follow-Up visit will be done for all patients after the last dose of ruxolitinib 
or BAT at the end of the Treatment Period.  
Note: for patients randomized to the BAT arm and crossing over to ruxolitinib, the Safety 
Follow-Up visit will only occur once, i.e. 30 days after the last dose of ruxolitinib in the Cross-
Over Treatment Period. 
Please refer to Section 7 for assessment details. 
 Long-Term Follow-Up Period (From EOT to Month 24) 
Recognizing that SR-aGvHD is a complication of alloSCT that often leads to death within 2 
years after the procedure, and that assessment of long-term safety and durable efficacy is 
clinically meaningful, all patients (responders and non-responders in both arms, regardless of 
when treatment was discontinued) will be followed to collect long term data including: survival,  
any relapse/progression of the underlying hematologic disease for which the alloSCT procedure 
was performed (refer to Appendix 4), NRM, any occurrence of graft failure, EFS, any 
occurrence of cGvHD, and occurrence of any second primary malignancies. 


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Visits will be performed after EOT or Cross-Over EOT, at 6, 9, 12, 18, and 24 months from 
randomization (Day 1), as applicable, once the Treatment Period is completed. 
It is anticipated that unscheduled visits may be needed throughout the trial for evaluation and 
management of any aGvHD flare, worsening cytopenias, occurrence of serious infections, non-
hematologic toxicities, graft failure, hematologic disease progression or relapse. 
Please refer to Section 7 for assessment details. 




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4.3 
Definition of end of study 
End of Study (EoS) will occur when all patients have reached Month 24 (2 years from 
randomization), unless the patient withdraws consent.  
The primary analysis including the analysis on primary and key secondary endpoints will be 
performed after all patients have completed Day 56 or discontinued from study participation 
earlier. The primary analysis data will be summarized in the primary clinical study report 
(CSR). 
Further analyses on secondary endpoints will be performed when all patients have completed 
approximately 6 months treatment or discontinued from study participation earlier.  
The final analysis will occur once all patients have completed the study (up to 24 months from 
randomization). All available data from all patients up to EoS, inclusive of OS, will be reported 
in a final CSR. 
Patients who are still receiving ruxolitinib at their end of study (approximately 2 years from 
randomization), and deriving clinical benefit from ruxolitinib as assessed by the Investigator, 
will be given the possibility to continue ruxolitinib outside the study from another source, where 
permitted by and in accordance to local laws and regulations.  
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 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. 
 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 IRBs and/or ECs of the early termination of the 
trial. 
5 
Population 
5.1 
Patient population 
The patient population will include male or female patients aged 12 or older, who have 
undergone alloSCT, have evidence of myeloid and platelet engraftment (ANC >1,000/mm3 
AND platelet count >20,000/mm3), and have been diagnosed with aGvHD requiring systemic 
treatment (Grade II-IV) which is determined to be steroid-refractory (Appendix 1).  


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This trial will have a two-step enrollment process as defined in Section 4: 
1. Enrollment into the Screening segment will occur after a diagnosis of aGvHD requiring 
systemic treatment (Grade II-IV) and after the Screening informed consent form is signed 
2. Randomization will occur when any one criterion for steroid-refractory disease is met, and 
the patient has signed the Study informed consent form. 
The Investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are randomized and started on treatment in the study. 
5.2 
Inclusion criteria 
Patients eligible for inclusion in the study must meet all of the following criteria: 
1. Written Screening informed consent and/or assent from the patient, parent, or guardian at 
the time of Screening, i.e. at the time of aGvHD Grade II-IV diagnosis. 
2. Written Study informed consent and/or assent from the patient, parent, or guardian    
once SR-aGvHD is confirmed.  
3. Male or female patients aged 12 or older at the time of Screening informed consent 
4. Able to swallow tablets. 
5. Have undergone alloSCT from any donor source (matched unrelated donor, sibling, haplo-
identical) using bone marrow, peripheral blood stem cells, or cord blood. Recipients of 
non-myeloablative, myeloablative, and reduced intensity conditioning are eligible. 
6. Clinically diagnosed Grades II to IV acute GvHD as per standard criteria (Appendix 1) 
occurring after alloSCT requiring systemic immune suppressive therapy. Biopsy of 
involved organs with aGvHD is encouraged but not required for study screening.  
7. Evident myeloid and platelet engraftment (confirmed within 48h prior to study treatment 
start): 
 Absolute neutrophil count (ANC) > 1000/mm3  
AND  
 Platelets ≥ 20,000/ mm3 
Note: Use of growth factor supplementation and transfusion support is allowed. 
8. Confirmed diagnosis of steroid-refractory aGvHD defined as patients administered high-
dose systemic corticosteroids (methylprednisolone 2 mg/kg/day [or equivalent  prednisone 
dose 2.5 mg/kg/day]), given alone or combined with calcineurin inhibitors (CNI) and 
either: 
A. Progressing based on organ assessment after at least 3 days compared to organ stage at 
the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of 
Grade II-IV aGvHD,  
OR 
B. Failure to achieve at a minimum partial response based on organ assessment after 7 
days compared to organ stage at the time of initiation of high-dose systemic 
corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD, 
OR 
C. Patients who fail corticosteroid taper defined as fulfilling either one of the following 
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1. Requirement for an increase in the corticosteroid dose to methylprednisolone ≥2 
mg/kg/day (or equivalent  prednisone dose ≥2.5 mg/kg/day)  
OR 
2. Failure to taper the methylprednisolone dose to <0.5 mg/kg/day (or equivalent 
prednisone dose <0.6 mg/kg/day) for a minimum 7 days. 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Has received more than one systemic treatment for steroid-refractory aGvHD,  
2. Clinical presentation resembling de novo chronic GvHD or GvHD overlap syndrome with 
both acute and chronic GvHD features (as defined by Jagasia, et al. 2015) 
3. Failed prior alloHSCT within the past 6 months.  
4. Presence of an active uncontrolled infection including significant bacterial, fungal, viral or 
parasitic infection requiring treatment. Infections are considered controlled if appropriate 
therapy has been instituted and, at the time of screening, no signs of progression are 
present.  Progression of infection is defined as hemodynamic instability attributable to 
sepsis, new symptoms, worsening physical signs or radiographic findings attributable to 
infection. Persisting fever without other signs or symptoms will not be interpreted as 
progressing infection. 
5. Evidence of uncontrolled viral infection including CMV, EBV, HHV-6, HBV, or HCV 
based on assessment by the treating physician.  
6. Evidence of active tuberculosis (clinical diagnosis per local practice; skin testing is not 
required as not informative due to anergy). 
7. Known human immunodeficiency virus infection (HIV). 
8. Presence of relapsed primary malignancy, or who have been treated for relapse after the 
alloHSCT was performed, or who may require rapid immune suppression withdrawal as 
pre-emergent treatment of early malignancy relapse. 
9. SR-aGvHD occurring after non-scheduled DLI administered for pre-emptive treatment of 
malignancy recurrence. Note: Patients who have received a scheduled DLI as part of their 
transplant procedure and not for management of malignancy relapse are eligible.  
10. Significant respiratory disease including patients who are on mechanical ventilation or 
who have resting O2 saturation <90% by pulse-oximetry.  
11. Presence of severely impaired renal function defined by serum creatinine > 2 mg/dL (> 
176.8μmol/L), renal dialysis requirement, or have estimated creatinine clearance <30 
mL/min measured or calculated by Cockroft Gault equation (confirmed within 48h prior 
to study treatment start). 
12. Clinically significant or uncontrolled cardiac disease including any of the following: 
 Acute myocardial infarction within 6 months from Day 1 of study treatment 
administration 
 Uncontrolled hypertension 
 New York Heart Association Class III or IV congestive heart failure 
 Unstable angina within last 6 months from screening 


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 Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker, circulatory collapse requiring vasopressor or inotropic support, or 
arrhythmia requiring therapy). 
13. Cholestatic disorders, or unresolved sinusoidal obstructive syndrome/veno-occlusive 
disease of the liver (defined as persistent bilirubin abnormalities not attributable to 
aGvHD and ongoing organ dysfunction). 
14. Any corticosteroid therapy for indications other than aGvHD at doses > 1 mg/kg/day 
methylprednisolone (or equivalent prednisone dose 1.25 mg/kg/day) within 7 days of 
Screening. Routine corticosteroids administered during conditioning or cell infusion is 
allowed. 
15. Current therapy with medications that interfere with coagulation or platelet function 
including but not limited to aspirin and related drugs, heparin, and warfarin (to minimize 
risk of bleeding). Note: Heparin or Low Molecular Weight Heparin (LMWH) is allowed if 
used at sub-therapeutic dose (e.g. for prophylaxis of sinusoidal obstructive syndrome/veno-
occlusive disease of the liver). 
16. History of progressive multifocal leuko-encephalopathy (PML). 
17. Patients who received JAK inhibitor therapy for any indication after initiation of current 
alloSCT conditioning. 
18. Previous participation in a study of any investigational treatment agent within 30 days of 
randomization or within 5 half-lives of the investigational treatment agent, whichever is 
greater. 
19. Any condition that would, in the Investigator's judgment, interfere with full participation 
in the study, including administration of study treatment and attending required study 
visits; pose a significant risk to the patient; or interfere with interpretation of study data. 
20. Known allergies, hypersensitivity, or intolerance to systemic immunosuppressive therapy. 
21. Pregnant or nursing (lactating) women 
22. Female patients randomized to ruxolitinib, ≥ 12 and < 18 years of age and of childbearing 
potential (e.g. are menstruating) who do not agree to abstinence or, if sexually active, do 
not agree to the use of highly effective contraception as defined below, throughout the 
study and for up to 90 days after stopping treatment, 
OR 
Female patients randomized to ruxolitinib, ≥ 18 years of age and of child-bearing potential, 
defined as all women physiologically capable of becoming pregnant, unless they are using 
highly effective methods of contraception as defined below, throughout the study and for 
up to 90 days after stopping treatment.  
Highly effective contraception methods include: 
 Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation   
methods) and withdrawal are not acceptable methods of contraception. 
 Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 


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study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment. 
 Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that patient.  
 Use of oral, injected or implanted hormonal methods of contraception. Placement of 
an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception (in case of oral contraception, 
patients should have been using the same pill on a stable dose for a minimum of 3 
months before Screening). 
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), 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. 
OR 
Female patients randomized to BAT who do not agree to follow locally approved BAT 
label or guidance for contraception requirements. 
23. Male patients randomized to BAT who do not agree to follow locally approved BAT label 
or guidance for contraception requirements. 
6 
Treatment 
6.1 
Study treatment 
The study treatment will consist of ruxolitinib or Investigator choice BAT administered in an 
open label manner following randomization of the patient on study Day 1. 
Patients will be randomized 1:1 to receive assigned study treatment (either ruxolitinib or BAT) 
stratifying on aGvHD grade (Grade II vs. III vs. IV) until Day 28. Further study treatment 
duration and management up to Week 24 / EOT are described for ruxolitinib and BAT, 
respectively, in Section 6.1.1.1 and Section 6.1.1.2, as well as in Section 6.1.5.1. 
In addition to assigned ruxolitinib or BAT, patients may receive standard alloSCT supportive 
care including anti-infective medications and transfusion support. Continued use of systemic 
corticosteroids, calcineurin inhibitors (CNI) (cyclosporine or tacrolimus), and topical 
corticosteroid therapy per institutional guidelines is permitted. Other systemic medications for 
aGvHD may be continued after randomization only if used for aGvHD prophylaxis (i.e. started 
before the diagnosis of aGvHD). Permitted concomitant therapies are described in Section 
6.4.1.  
6.1.1 
Dosing regimen 
The Investigator will instruct the patient to take the study treatment as per protocol.  


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All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record Case Report Form (CRF). 
Table 6-1 
Dose and treatment schedule  
Study treatments 
Pharmaceutical form and 
route of administration 
Dose 
Frequency and/or 
Regimen 
Ruxolitinib (INC424) 
5-mg tablet for oral use 
10 mg BID 
(2 tablets orally BID) 
Daily  
BAT 
Will vary depending upon Investigator’s choice identified prior to randomization. Dose 
and frequency will depend on label (where approved) and institutional guidelines for 
various BAT. 
6.1.1.1 
Ruxolitinib 
Ruxolitinib will be administered to all patients randomized to the ruxolitinib arm, orally twice 
per day at a dose of 10 mg BID, given as two 5-mg tablets. Ruxolitinib should be taken orally, 
approximately 12 hours apart (morning and night) without regards to food. Ruxolitinib will be 
administered by hospital personnel in an inpatient setting, or self-administered by the patient in 
an outpatient setting. 
Patients should be instructed not to make up for missed doses. A missed dose is defined as a 
case when a dose is not taken within 8 hours after the approximate time of the usually daily 
dosing. The missed dose should be omitted and the patient should continue treatment with the 
next scheduled dose. If vomiting occurs during the course of treatment, patients should not take 
the study drug again before the next scheduled dose. 
Within the first 28 days, patients meeting criteria of aGvHD disease progression, mixed 
response, no response, can move to new systemic treatment per Investigator choice. 
Requirement for initiation of this new systemic treatment will be considered a treatment failure. 
In this case, the patient must discontinue study treatment (see Section 7.1.5). 
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record CRF. 
Patients should be instructed not to take study treatment at home on Day 1 and Day 7 (PK 
sampling 
) and at Weeks 2, 4, 8 and 24 on the day of the scheduled pre-
dose blood collection (Section 7). Dosing will be administered post-blood collection at these 
visits. 
Patients responding to treatment may be tapered off ruxolitinib as needed, starting no earlier 
than Day 56. The dose tapering strategy should be based on evaluation of the condition of the 
patient, current dosing regimen and the clinical judgment of the Investigator. 
 If a taper of ruxolitinib is considered appropriate, the taper should be completed by no 
later than Week 24 (or Cross-Over Week 24) unless prolonged tapering is indicated due to 
an aGvHD flare or other safety concerns. In such case, the taper of ruxolitinib must be 
initiated no later than Week 24 (or Cross-Over Week 24) and completed by no later than 
the patient’s end of study (up to approximately 2 years from randomization). Guidelines 
for the tapering of ruxolitinib and of immunosuppression (corticosteroids and CNI) are 
provided in Section 6.1.5.1. 


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 Should a tapering strategy not be in the best interest of the patient, or should the taper be 
completed prior to Week 24 (or Cross-Over Week 24, as applicable), the patient must still 
follow the assigned Visit Evaluation Schedule in Table 7-1 Randomized Treatment (or 
Table 7-2 Cross-Over Treatment), including all safety and efficacy assessments, until 
Week 24 (or Cross-Over Week 24, as applicable), as detailed in Section 4.1 and Section 
7.1.4. 
6.1.1.2 
Best Available Therapy 
Patients will receive Best Available Therapy based on Investigator’s best judgment, taking into 
account the manufacturer’s instructions, labeling, patient’s medical condition, and institutional 
guidelines for any dose adjustment. The BAT in this study will be identified by the Investigator 
prior to patient randomization among the following treatments currently used in this setting: 
anti-thymocyte globulin (ATG), extracorporeal photopheresis (ECP), mesenchymal stromal 
cells (MSC), low-dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR inhibitors 
(everolimus or sirolimus), etanercept, or infliximab. No other types or combinations of BATs 
are permitted in this study.  
Note: Medications used for aGvHD prophylaxis (i.e. started before the diagnosis of aGvHD) 
which have failed to prevent aGvHD in a patient prior to randomization must not be chosen as 
BAT in this same patient. 
Within the first 28 days, patients meeting criteria of disease progression, mixed response, no 
response, can move to treatment with another BAT within the Treatment Period of the study. 
Requirement for initiation of this new systemic treatment will be considered a failure of initial 
BAT.The dose and administration schedule may be changed at any time based on the judgment 
of the Investigator and in accordance with accepted medical practices. 
The EOT visit will occur at Week 24, or earlier in case the patient meets any of the criteria for 
discontinuation of study treatment (see Section 4.1, Section 7.1.4 and Section 7.1.5). 
Guidelines for the tapering of immunosuppression (corticosteroids and CNI) in the BAT arm  
are provided in Section 6.1.5.1. 
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 
The planned duration of aGvHD treatment is approximately 6 months.  


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The Treatment Period will begin for each patient on the day of randomization (Day 1) and 
continue on assigned treatment arm (ruxolitinib or BAT) until the patient reaches the Week 24 
visit from randomization, unless the patient meets any of the criteria for discontinuation of study 
treatment (see Section 7.1.5).  
During the Treatment Period, and beyond Day 28, patient’s treatment will be managed 
according to their response as described in Table 6-2: 
Table 6-2 
Treatment management based on patient response at Day 28 
Patients 
meeting the 
primary 
endpoint at 
Day 28 
Patients responding to ruxolitinib will continue ruxolitinib until Day 56. These patients may 
be tapered off ruxolitinib as needed, starting no earlier than Day 56. The dose tapering 
strategy should be based on evaluation of the condition of the patient, current dosing regimen 
and the clinical judgment of the Investigator. 
 
If a taper of ruxolitinib is considered appropriate, the taper should be completed by 
no later than Week 24 unless prolonged tapering is indicated due to an aGvHD flare or 
other safety concerns. In such case, the taper of ruxolitinib must be initiated no later than 
Week 24 and completed by no later than Week 96. Guidelines for the tapering of 
ruxolitinib are provided in Section 6.1.5.1. 
 
Should a tapering strategy not be in the best interest of the patient, or should the 
taper be completed prior to Week 24, the patient must still follow the assigned Visit 
Evaluation Schedule (Table 7-1), including all safety and efficacy assessments, until 
Week 24. 
Patients responding to BAT will be managed as per institutional practices. These patients 
may further cross-over to the ruxolitinib treatment arm between Day 28 and Week 24 if they 
meet cross-over criteria after an initial response.  
 
Responding patients (i.e. obtaining a CR or PR) completing the dosing schedule for their 
assigned BAT at any time as per standard of care before Week 24 must continue to be 
assessed for all scheduled visits until Week 24.  
Patients not 
meeting the 
primary 
endpoint at 
Day 28 
Patients who are randomized to ruxolitinib, will discontinue study treatment, and be 
treated per Investigator’s judgement. These patients will then enter the Long-Term Follow-Up 
period. 
Patients who are randomized to BAT and who do not meet cross-over criteria at Day 28 
will have their EOT visit, Safety Follow-Up visit and enter the Long-Term Follow-Up period. 
Patients who are randomized to BAT, and who meet cross-over criteria at or after Day 
28, may cross-over to the ruxolitinib treatment arm. 
Patients who cross-over at Day 28 or thereafter will follow the same treatment duration and 
taper schedule as patients originally randomized to ruxolitinib treatment. Corticosteroids and 
CNI for aGvHD treatment is allowed to be continued, with cessation required of any other 
systemic immunosuppressive treatment prior to cross-over, unless used for aGvHD 
prophylaxis (i.e. started before the diagnosis of aGvHD). 
 
Patients not achieving a CR or PR at Cross-Over Day 28 will discontinue treatment with 
ruxolitinib and will be treated per Investigator’s judgement. These patients will then enter 
the Long-Term Follow-Up period. 
 
If a taper of ruxolitinib is considered appropriate, the taper should be started no 
earlier than Cross-Over Day 56 and completed by no later than Cross-Over Week 24 
unless prolonged tapering is indicated due to an aGvHD flare or other safety concerns. 
In such case, the taper of ruxolitinib must be initiated no later than Cross-Over Week 24 
and completed by no later than Cross-Over Week 96, or 2 years from randomization, 
whichever occurs first. Guidelines for the tapering of ruxolitinib are provided in Section 
6.1.5.1. 


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 
Should a tapering strategy not be in the best interest of the patient, or should the 
taper be completed prior to Cross-Over Week 24, the patient must still follow the 
assigned Visit Evaluation Schedule (Table 7-2), including all safety and efficacy 
assessments, until Cross-Over Week 24. 
Patients in both arms responding to treatment will be tapered off immunosuppression 
(corticosteroids and CNI) as described in Section 6.1.5.1.  
Addition of any new systemic immunosuppressive therapy after randomization may be decided 
by the Investigator for patients meeting aGvHD criteria for progression, mixed response, or no 
response criteria, or aGvHD flare failure as defined in Section 3. Requirement for initiation of 
such treatment will be considered a treatment failure. In this case, the patient must discontinue 
study treatment (see Section 7.1.5).  
All patients, responders and non-responders, will be followed up for long-term observation up 
to 24 months from randomization. 
6.1.5.1 
Tapering guidelines 
Tapering of immunosuppression will follow 2 steps: first taper of corticosteroids, followed with 
taper of CNI and/or ruxolitinib in responding patients. During the Treatment Period in both the 
ruxolitinib and BAT arms, immunosuppression taper guidelines are as follows: 
 Corticosteroids: the taper of corticosteroids in patients demonstrating a PR or CR as 
observed by the Investigator must not be initiated earlier than Day 7, and should then be 
performed per institutional guidelines (e.g. 10% dose reduction every 5 days, beginning no 
earlier than Day 7 and continuing to approximately Day 56 to allow 7-8 week taper). 
 CNI (cyclosporine or tacrolimus): CNI taper is allowed in patients demonstrating a PR 
or CR, once off corticosteroids, and should then be performed per institutional guidelines 
(e.g. 25% dose reduction per month).  
 Ruxolitinib: ruxolitinib taper is allowed in patients demonstrating a PR or CR, once off 
corticosteroids, and must not start earlier than Day 56. The following guidance may be 
followed based on evaluation of the condition of the patient, current dosing regimen and 
the clinical judgement of the Investigator: a 50% dose reduction every 2 months (56 days) 
i.e. initial dose reduction to 5 mg orally BID and, if sustained aGvHD stable disease is 
observed, patient is further tapered by a second 50% dosage reduction to 5 mg orally QD 
for an additional 56 days, prior to cessation (see Section 6.3.1.1.3) 
It is expected that the taper of corticosteroids, CNI, and ruxolitinib will be completed by Week 
24. Should an aGvHD flare or other safety concerns prevent taper from being completed by 
then, the dose of ruxolitinib may be maintained until Week 24. In such case, ruxolitinib taper 
must be initiated no later than Week 24 and must be completed by no later than Week 96. 
Similarly, patients receiving ruxolitinib after cross-over may have their taper initiated no later 
than Cross-Over Week 24 and completed by no later than Cross-Over Week 96, or 2 years from 
randomization, whichever occurs first. 
If aGvHD flare occurs during the taper of immunosuppressive medications prior to Day 56,  the 
dose of corticosteroids may be re-escalated at the Investigator's discretion and will not be 
considered treatment failure, as long as criteria defined below and in Section 3 are not met. The 


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taper of corticosteroids should be attempted again once the patient demonstrates a PR or CR. In 
these circumstances the taper of corticosteroids may be extended beyond Day 56, delaying the 
initiation of CNI and/or ruxolitinib taper. If aGvHD flare requires addition of a new systemic 
therapy due to inability to taper corticosteroids below methylprednisolone 0.5 mg/kg/day (or 
equivalent <0.6 mg/kg/day of prednisone) for a minimum 7 days, OR due to re-escalation of 
corticosteroids to methylprednisolone >2 mg/kg/day (or equivalent >2.5 mg/kg/day of 
prednisone), the patient will be considered to have experienced an aGvHD flare failure per 
protocol, and new systemic treatment is indicated per Investigator’s judgement. Patients 
requiring new systemic treatment for aGvHD must discontinue study treatment (see Section 
7.1.5).  
If aGvHD flare occurs during ruxolitinib taper after Day 56, patients may have their ruxolitinib 
dose increased to the prior dose level (maximum 10 mg BID), their response monitored, and 
ruxolitinib taper attempted again as needed until the patient’s end of study (up to approximately 
2 years from randomization). The patient will be considered to have experienced an aGvHD 
flare failure when further treatment is indicated per Investigator’s judgment including: starting 
a new systemic treatment. Patients requiring new systemic treatment for aGvHD must 
discontinue study treatment (see Section 7.1.5). 
If cGVHD signs and symptoms including overlap syndrome, de novo, or progressive disease 
develop during the taper of ruxolitinib, clinical management of cGvHD follows standard 
institutional guidelines. Ruxolitinib tapering schedule may be maintained for patient’s safety to 
avoid aGvHD flare. Ruxolitinib will not be administered for the treatment of cGvHD including 
overlap syndrome. 
6.2 
Dose escalation guidelines 
Not applicable. 
6.3 
Dose modifications  
6.3.1 
Dose modification and dose delay 
A standardized dosing paradigm will be used to determine dose adjustments for safety and 
efficacy so that each patient is titrated to their most appropriate dose. 
These changes must be recorded on the Dosage Administration Record eCRF. 
6.3.1.1 
Dose adjustments for ruxolitinib safety 
For patients who do not tolerate the protocol-specified dosing schedule, dose reductions and/or 
interruptions are either recommended or mandated in order to allow the patients to continue the 
study treatment and maintain ruxolitinib dosing for optimal treatment of SR-aGvHD. The 
objective of ruxolitinib dose adjustment rules described below is to optimize response for each 
individual patient (namely rapid resolution of aGvHD) while avoiding clinically relevant 
toxicities attributed to study drug. Deviations to mandatory dose interruptions and/or reductions 
are not allowed. Permanent treatment discontinuation is mandatory for specific events indicated 
as such in Table 6-3 or listed in Section 7.1.5.  
The ruxolitinib dose will not exceed 10 mg orally BID and will not be less than 5 mg QD.  


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6.3.1.1.1 Dose adjustments of ruxolitinib for hematologic safety 
Dose reductions or interruptions for worsening cytopenias attributed to ruxolitinib are permitted 
in order to allow the patient to continue on the study treatment. Doses adjustments for different 
ranges of cytopenias are described in Table 6-3. The objective of the dose adjustment rules is 
to optimize treatment response for each individual patient while avoiding significant 
cytopenias.   
For any patient who develops severe worsening cytopenias necessitating abrupt interruption of 
ruxolitinib, flare of aGvHD is expected to occur. To avoid significant aGvHD flare during 
abrupt ruxolitinib interruption, the patient’s corticosteroid dose should be maintained or 
increased to ≥ 0.4 mg/kg/day methylprednisolone (or equivalent prednisone to ≥ 0.5 mg/kg/day) 
for a minimum 7 days after abrupt cessation of ruxolitinib. 
Ruxolitinib dosing may be restarted or increased following recovery of the hematologic 
parameter(s) to acceptable levels. The objective for restarting or escalating after a reduction for 
hematologic safety is to find the highest safe dose regimen of ruxolitinib for each patient that is 
necessary to obtain a clinical response, with increases in dose not more than in increments of 5 
mg BID and not more often than every 2 weeks. Please refer to Table 6-5. 
Treatment with ruxolitinib may be delayed up to 14 days to allow for resolution of toxicity.  
Patients may resume treatment if no medical condition or other circumstance exists that, in the 
opinion of the Investigator, would make the patient unsuitable for further participation in the 
study. The Investigator should contact the sponsor medical monitor to discuss cases where 
treatment has been delayed for more than 14 days before restarting treatment. 
6.3.1.1.2 Dose adjustments of ruxolitinib for non-hematologic safety 
Dose reductions or interruptions for non-hematologic toxicity are permitted in order to allow 
the patient to continue on the study treatment. Dose adjustments for different ranges of non-
hematologic toxicity are described in Table 6-3. The objective of the dose adjustment rules is 
to optimize treatment response for each individual patient while avoiding significant non-
hematologic toxicities.   
As organ toxicities are relatively common in alloSCT patients, any AE must be assessed to 
determine whether it is suspected to be related to ruxolitinib treatment. Ruxolitinib dose 
adjustments are only required for AEs that are suspected to be related to the study drug. This 
has particular relevance in evaluation of elevated creatinine, as elevations related to CNI 
administration are often seen. Dose adjustment of CNI will follow institutional guidelines and 
investigator judgement, with CNI dose reductions anticipated if rising creatinine noted, to 
potentially alleviate the need for ruxolitinib dose reductions. 
Ruxolitinib must be permanently discontinued upon any one of the following AE attributed to 
study drug that fails to resolve to Grade 2 or better within 14 days, or if a lower re-start dose or 
administration schedule subsequent to any of the following non-hematologic toxicities is either 
not available or likely to be clinically ineffective: 
 The occurrence of a Grade 4 laboratory or non-laboratory abnormality attributable to 
ruxolitinib; 


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 The occurrence of a Grade 3 laboratory or non-laboratory abnormality attributable to 
ruxolitinib that remains at Grade 3 or worse for greater than 14 days. 
If any one or more of the treatment discontinuation criteria outlined above are met prior to Day 
28, the patient will be considered to be a non-responder in terms of the Day 28 primary endpoint. 
Subsequent to Day 28, if any one or more of the treatment discontinuation criteria outlined 
above are met, the patient will be considered to be a non-responder in terms of the Day 56 
secondary endpoint. 
In the event that any patients permanently discontinues the study treatment, regardless of 
reason, reasonable efforts should be made to have the patient return for an early termination 
visit and have the End of Treatment evaluations completed as described in Section 7. All 
patients completing/discontinuing study treatment at any time point after randomization will be 
followed in the Long-term follow-up period until they reach 2 years from randomization.  
The date any patient discontinued the study treatment and the specific reason for discontinuation 
will be recorded in the eCRF.  


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The instructions provided in this table and the criteria for dose reduction / interruption are used to determine a protocol deviation 
Table 6-3 
Criteria for interruption and re-initiation of ruxolitinib treatment for adverse events suspected to be drug-related 
Dose modifications for ruxolitinib for adverse events suspected to be drug-related 
Worst toxicity 
 
Investigations (Hematologic) 
Neutropenia (ANC) 
Grade 1 (ANC < LLN - 1500/mm3) 
Recommendation: Maintain dose level 
Grade 2 (ANC < 1500 - 1000/mm3) 
Recommendation: Maintain dose level 
Grade 3 (ANC < 1000 - 750/mm3) 
Recommendation: Maintain dose level 
Grade 3 (ANC < 750 - 500/mm3) 
Mandatory:   1 dose level (see Table 6-4), monitor ANC daily until resolved to ≤ Grade 2, then resume 
initial dose level 
Grade 4 (ANC < 500/mm3) 
Mandatory: Hold dose, monitor ANC daily until resolved to ≤ Grade 3, then resume  1 dose level.  If 
resolves to ≤ Grade 2, can resume initial dose level. If not resolved in ≤14 days the patient must be 
discontinued. 
Febrile neutropenia (ANC < 750/mm3, fever ≥ 38.5°C) 
Mandatory: Hold dose until resolved, then restart at  1 dose level 
Thrombocytopenia  
Grade 1 (PLT < LLN-75,000/mm3) 
Recommendation: Maintain dose level 
Grade 2 (PLT< 75,000 - 50,000/mm3)   
Recommendation: Maintain dose level 
Grade 3 (PLT< 50,000 - 25,000/mm3)  
Recommendation: Maintain dose level 
Grade 4 (PLT< 25,000 - 20,000/mm3) 
Recommendation: Maintain dose level 
Grade 4 (PLT< 20,000 - 15,000/mm3)  
Mandatory:  1 dose level until resolved to ≥20,000/mm3 
If resolved in ≤ 7 days, then resume initial dose level 
If resolved in > 7 days, then maintain  1 dose level 
Grade 4 (PLT < 15,000/mm3) 
Mandatory: Hold dose until resolved to ≥20,000/mm3, then resume at  1 dose level.  If resolves to ≤ 
Grade 3, can resume initial dose level. If not resolved in ≤14 days the patient must be discontinued. 


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Dose modifications for ruxolitinib for adverse events suspected to be drug-related 
Worst toxicity 
 
Investigations (Renal) 
Serum creatinine  
Grade 1 (> ULN - 1.5 x ULN) 
Recommendation: Maintain dose level 
Grade 2 (> 1.5 - 3.0 x ULN) 
Mandatory:  1 dose level until resolved to ≤ Grade 1 or baseline, then resume initial dose level 
Grade 3 (> 3.0 - 6.0 x ULN) 
Mandatory: Hold dose until resolved to ≤ Grade 2, then restart at  1 dose level.  If resolves to ≤ Grade 1 
can resume initial dose level. 
Grade 4 (> 6.0 x ULN) 
Mandatory: Hold dose and discontinue patient from study treatment  
Investigations (Hepatic)  
Total Bilirubin elevation  
> ULN – 1.5 x ULN 
Recommendation: Maintain dose level 
> 1.5 - 3.0 x ULN  
Recommendation: Maintain dose level 
> 3.0 - 5.0 x ULN*  
 
Mandatory:  1 dose level until resolved to ≤ 3.0.  Monitor LFTsb weekly, or more frequently if clinically 
indicated, until resolved to ≤ 3.0 x ULN: 
If resolved in ≤ 14 days, then increase by one dose level  
If resolved in > 14 days, then maintain the decreased dose level  
> 5.0 - 10.0 x ULN*  
 
Mandatory: Hold dose.  Monitor LFTsb weekly, or more frequently if clinically indicated, until resolved to ≤ 
3.0 x ULN: 
If resolved in ≤ 14 days, then resume same dose level  
If resolved in > 14 days, then resume at  1 dose level 
> 10.0 x ULN* 
Mandatory: Hold dose.  Monitor  LFTsb  weekly, or more frequently if clinically indicated, until resolved to ≤ 
3.0 x ULN: 
If resolved in ≤ 14 days, then resume at↓ 1 dose level  
If resolved in > 14 days, then discontinue patient from study treatment.  The patient should be monitored 
weekly (including LFTsb), or more frequently if clinically indicated, until total bilirubin has resolved to 
baseline or stabilization over 4 weeks. 
AST or ALT elevation  
> ULN - 3.0 x ULN 
Recommendation: Maintain dose level 
> 3.0 - 5.0 x ULN  
For patients with baseline value ≤ 3.0 x ULN 
 
 
 
 
 
Recommendation: 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,  1 
dose level until resolved to ≤ 3.0 x ULN.  Monitor LFTsb weekly, or more frequently if clinically indicated, 
until resolved to ≤ 3.0 x ULN: 
If resolved in ≤ 14 days, then then increase by one dose level  


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Dose modifications for ruxolitinib for adverse events suspected to be drug-related 
Worst toxicity 
 
 
 
For patients with baseline value  > 3.0 -5.0 x ULN 
If resolved in > 14 days, then continue at the  1 dose level  
 
Recommendation: Maintain dose level.  Monitor LFTsb weekly, or more frequently if clinically indicated, 
until resolved to ≤ baseline   
> 5.0 - 10.0 x ULN 
Mandatory: Hold 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 ≤ 
5.0 x ULN  Then: 
If resolved in ≤ 14 days, then resume same dose level 
If resolved in > 14 days, then resume at↓ 1 dose level 
> 10.0 - 20.0 x ULN  
Mandatory: Hold 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 ≤ 
5.0 x ULN. Then resume at↓ 1 dose level.  
> 20.0 x ULN 
For patients deriving clinical benefit upon 
Investigator’s judgement 
 
 
 
 
For all other patients 
 
Mandatory: Hold 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 
x ULN (or ≤ 5 x ULN for patients with baseline value  > 3.0 -5.0 x ULN), then resume treatment at ↓ 1 
dose level. Only 1 dose reduction is allowed; if reoccurs at > 5 x ULN, discontinue patient from study 
treatment. 
 
Mandatory: Discontinue patient from study treatment  
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 or stabilization 
over 4 weeks. 


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Dose modifications for ruxolitinib for adverse events suspected to be drug-related 
Worst toxicity 
 
Investigation (metabolic) 
Asymptomatic amylase and/or lipase elevation 
Grade 1 (> ULN - 1.5 x ULN) 
Recommendation:  Maintain dose level 
Grade 2 (> 1.5 - 2.0 x ULN) 
Recommendation:  Maintain dose level 
Grade 3 (> 2.0 - 5.0 x ULN) 
Recommendation: Hold dose of until resolved to Grade ≤ 2, then: 
If resolved in ≤ 7 days,  then resume same dose level 
If resolved in > 7 days, then resume at↓ 1 dose level 
Grade 4 (> 5.0 x ULN) 
Recommendation: Hold dose and discontinue patient from study treatment. 
Vascular disorders 
Hypertension 
CTCAE Grade 3 
Recommendation:  1 dose level until resolved to ≤ Grade 2, then increase by one dose level 
CTCAE Grade 4 
Mandatory: Hold dose and discontinue patient from study treatment 
Gastro intestinal 
Pancreatitis 
Grade 2 
Recommendation: Maintain dose level 
Grade ≥ 3 
Mandatory: Hold dose and discontinue patient from study treatment 
Diarrhea*** 
Grade 1 
Recommendation:  Maintain dose level. May initiate anti-diarrhea treatment 
Grade 2 
Recommendation:  Maintain dose level. May initiate anti-diarrhea treatment 
Grade 3 
Recommendation:  1 dose level until resolved to ≤ Grade 2, then increase by one  dose level 
Grade 4 
Mandatory: Hold dose. Discontinue patient from study treatment 
Skin and subcutaneous tissue disorders 
Rash/photosensitivity  
Grade 1 
Recommendation:  Maintain dose level 
Grade 2 
Recommendation:  Maintain dose level 
Grade 3 
Recommendation:  1 dose level until resolved to ≤ Grade 2, then: 
If resolved in ≤ 7 days, then increase by one dose level 
If resolved in > 7 days, then maintain the  dose level 
Grade 4 
Mandatory: Hold dose. Discontinue patient from study treament 
Other adverse events  
Grade 1 or 2 
Recommendation:  Maintain dose level 


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Dose modifications for ruxolitinib for adverse events suspected to be drug-related 
Worst toxicity 
 
Grade 3 
Recommendation:  1 dose level until resolved to ≤ Grade 2 
Recommendation: Hold dose for ≥ Grade 3 vomiting or Grade 3 nausea only if the vomiting or nausea 
cannot be controlled with optimal antiemetic (as per local practice) 
Grade 4 
Recommendation: Hold dose and then discontinue from study treatment 
All dose modifications should be based on the worst preceding toxicity. 
For dose level refer to Table 6-4 and Table 6-5 
a Common Toxicity Criteria for Adverse Events (CTCAE Version 4.03) 
b 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.) 
* Note: If total bilirubin > 3.0 x ULN is due to the indirect (non-conjugated) component only, and hemolysis as the etiology has been ruled out as per institutional 
guidelines (e.g., review of peripheral blood smear and haptoglobin determination), then ↓ 1 dose level and continue treatment at the discretion of the Investigator. 
** Note: A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be performed within 1 week of the first occurrence of any ≥ Grade 3 of 
amylase and/or lipase. If asymptomatic Grade 2 elevations of lipase and/or amylase occur again at the reduced dose, patients will be discontinued permanently from 
study treatment. 
*** Note: antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt diarrhea 


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Table 6-4 
Dose reduction steps for ruxolitinib 
Current Dose 
First Dose Reduction 
Second Dose Reduction 
10 mg BID 
5 mg BID 
5 mg QD 
5 mg BID 
5 mg QD 
Discontinue 
Patients who have had a dose reduction of ruxolitinib in order to manage toxicity may resume 
treatment at the previous dose if hematologic/non-hematologic parameters meet the required 
threshold(s).   
Dose re-escalation levels of ruxolitinib are described in Table 6-5. Dose increases may not 
exceed 10 mg BID, with increments of 5 mg BID and not more often than every 2 weeks. 
Table 6-5 
Dose re-escalation levels for ruxolitinib 
Current Dose 
First Dose Escalation 
Second Dose Escalation 
5 mg QD 
5 mg BID 
10 mg BID 
5 mg BID 
10 mg BID 
- 
6.3.1.1.3 Optional dose tapering strategy in the event of study treatment 
discontinuation 
When a decision is made to permanently discontinue ruxolitinib therapy for reasons other than 
for hematologic/non-hematologic safety (e.g. when aGvHD complete response is observed), a 
dose tapering strategy may be followed, based on evaluation of the condition of the patient, 
current dosing regimen and the clinical judgment of the Investigator. 
Following any abrupt interruption or discontinuation of ruxolitinib, symptoms of aGvHD flare 
are expected. If considered to be medically necessary, the Investigator may use any treatment 
to manage withdrawal from ruxolitinib including a gradual tapering of the study drug dosage or 
use of other medications including corticosteroid as minimum dosage ≥0.4 mg/kg/day 
methylprednisolone (or equivalent prednisone ≥0.5 mg/kg/day) to manage aGvHD flare 
anticipated after abrupt ruxolitinib discontinuation.  
When a decision has been made to discontinue the patient with utilization of a tapering strategy, 
regardless of the use of concomitant medications, safety data will continue to be assessed in 
accordance with the protocol for a period of time at least through the continued administration 
on ruxolitinib and until the safety follow-up visit is completed (30 days from last ruxolitinib 
dose intake) for AEs monitoring. 
6.3.1.1.4 Dose modification for ruxolitinib when combined with CYP450 modulators 
In all cases when ruxolitinib is co-administered with CYP450 modulators, patients should be 
closely monitored and dose titrated based on safety (see Section 6.3.1.1.1 and Section 6.3.1.1.2).  
See Appendix 7 for a list of cytochrome P450 3A4 (CYP3A4) inhibitors and inducers. 
Strong CYP3A4 inhibitors 
A dose reduction of ruxolitinib (e.g. by 50%) should be considered when using strong CYP3A4 
inhibitors. No dose adjustment of ruxolitinib is needed for use with topical ketoconazole. See 
Section 6.4.2. 


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Mild or moderate CYP3A4 inhibitors 
No dose adjustment is recommended when ruxolitinib is co-administered with mild or moderate 
CYP3A4 inhibitors. 
Dual CYP2C9 and CYP3A4 inhibitors 
A dose reduction of ruxolitinib (e.g. by 50%) should be considered when using medicinal 
products which are dual inhibitors of CYP2C9 and CYP3A4 enzymes (e.g. fluconazole). The 
concomitant use of ruxolitinib with fluconazole doses greater than 200 mg daily is prohibited. 
CYP3A4 inducers 
No dose adjustment is recommended when ruxolitinib is co-administered with CYP3A4 
inducers.  
6.3.2 
Anticipated risks and safety concerns of the study treatment 
Please refer to Section 2.6. Risks and Benefits 
6.4 
Concomitant medications  
6.4.1 
Permitted concomitant therapy 
Supportive treatments per institutional guidelines for management of alloSCT patients with SR-
aGvHD are allowed. The patient must be told to notify the investigational site about any new 
medications he/she takes after randomization and the start of treatment.  
In addition to assigned ruxolitinib or BAT, patients may receive standard alloSCT supportive 
care including anti-infective medications and transfusion support. Continued use of systemic 
corticosteroids, calcineurin inhibitors (CNI) (cyclosporine or tacrolimus), and topical 
corticosteroid therapy per institutional guidelines is permitted. Other systemic medications for 
aGvHD may be continued after randomization only if used for aGvHD prophylaxis (i.e. started 
before the diagnosis of aGvHD). 
Corticosteroids may be taken or administered without regard to food except on days when PK 
samples are drawn; on those days, patients should be instructed to fast and refrain from taking 
corticosteroids until after PK samples are collected. See Section 7 for additional information. 
Doses of methylprednisolone will be converted to prednisone equivalents by multiplying the 
methylprednisolone dose by 1.25. Prednisone doses for each patient are converted to 
mg/kg/day.  For patients that weigh over 100 kg, maximal starting dose of prednisone will be 
200 mg (or 2 mg/kg/day based on a modified starting weight of 100 kg). For calculation of 
subsequent prednisone doses/kg on subsequent measures, the modified starting weight of 100 
kg will be used.  
It is recommended that any patient receiving a CNI at study entry will remain on the same CNI 
as needed while being in the study treatment period.  
Patients who undergo alloSCT are at risk for a variety of infections based on the degree of 
immunosuppression induced by the conditioning regimen prior to transplant. As such, it is 
considered routine practice to utilize antibiotics, anti-infectives, and immunizations as 
prophylactic therapies (Tomlyn 2009). In cases where post-transplant anti-infective prophylaxis 


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measures are necessary, ongoing therapy may continue at Investigator's discretion per 
institutional guidelines. This includes any viral prophylaxis indicated based on pre-alloSCT 
serologies.  
Additional supportive care measures (e.g., use of anti-emetics and anti-motility agents for 
diarrhea management) are permitted at Investigator's discretion.  
All medications (other than ruxolitinib and BAT) 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, Surgeries and Procedures CRFs. Relevant 
prior medication received up to 30 days prior to the first dose of ruxolitinib/BAT will also be 
recorded in the appropriate CRF. 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. 
6.4.2 
Permitted concomitant therapy requiring caution and/or action 
SR-aGvHD patients receiving ruxolitinib with concomitant medications provided per standard 
institutional guidelines for management after alloSCT including: anti-emetics, calcineurin 
inhibitors, azole fungal prophylaxis, broad spectrum antibiotics in the event of fever (either 
semi-synthetic penicillin or third generation cephalosporin with vancomycin, gentamycin or 
equivalent), acyclovir prophylaxis, G-CSF, steroid pre-meds prior to RBC/plt transfusions, 
narcotics, and sedatives, warrant close monitoring of potential drug-drug interactions effects of 
these concurrent drugs. 
Ruxolitinib dose adjustments may be required, particularly in patients treated with CYP450 
modulators (See Section 6.3.1.1.4). 
Upon initiation of a strong CYP3A4 inhibitor or a dual CYP3A4/CYP2C9 inhibitor including 
fluconazole up to a dose of 200 mg, the dose of ruxolitinib may be reduced (e.g. by 50%), and 
more frequent monitoring of hematology parameters and clinical signs and symptoms of 
ruxolitinib related adverse events is recommended. The patient and the Investigator should be 
aware of potential signs of overdose of the concomitant medications and in the event of 
suspected study drug related toxicity; administration of ruxolitinib should be dose reduced or 
held according to guidelines (See Table 6-3) and Investigator judgment, with appropriate 
corticosteroid immunosuppression provided to avoid aGvHD flare. 
6.4.3 
Prohibited concomitant therapy 
The following therapies are prohibited at any time during the study until treatment 
discontinuation: 
 Due to the high risk of bleeding in alloSCT patients with SR-aGvHD, aspirin, NSAIDs, 
and related medications that would expectedly reduce platelet function and/or heparin, 
warfarin or related medication that would adversely affect blood coagulation are 
prohibited. Note: Heparin or LMWH is allowed if used at sub-therapeutic dose (e.g. for 
prophylaxis of sinusoidal obstructive syndrome/veno-occlusive disease of the liver). 
 Concomitant use of another JAK inhibitor. 
 Any investigational medication (other than ruxolitinib or BAT) that is not approved for 
any indication. Use of such medications within 30 days or 5 half-lives, whichever is 


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longer, prior to the first dose of study treatment and until treatment discontinuation is 
prohibited. 
 Use of chemotherapeutic agents and/or non-scheduled DLI for malignancy 
progression/relapse prophylaxis after alloSCT is not permitted. If required for patient 
management, the patient is discontinued from study treatment. 
 Any pre-emergent intervention related to graft failure or hematologic disease 
relapse/progression including but not limited to: stem cell graft boost, additional 
conditioning chemotherapy or anti-T cell therapy, non-scheduled DLI, and/or abrupt 
cessation/taper immunosuppression is not permitted. If required for patient management, 
the patient is discontinued from study treatment. 
 Administration of fluconazole at daily doses higher than 200 mg is prohibited (Section 
6.3.1.1.4). 
 Addition of any new systemic immunosuppressive therapy after randomization may be 
decided by the Investigator for patients meeting aGvHD criteria for progression, mixed 
response, or no response criteria, or in case of aGvHD flare, due to inability to taper 
corticosteroids below methylprednisolone 0.5 mg/kg/day (or equivalent <0.6 mg/kg/day of 
prednisone) for a minimum 7 days, or due to  re-escalation of corticosteroids to 
methylprednisolone >2 mg/kg/day (or equivalent >2.5 mg/kg/day of prednisone). 
Requirement for initiation of such treatment will be considered a treatment failure per 
protocol. In this case, the patient must discontinue study treatment (see Section 7.1.5).  
6.5 
Patient numbering, treatment 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 screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential patient 
number suffixed to it, so that each patient is numbered uniquely across the entire database. Upon 
signing the informed consent form, the patient is assigned to the next sequential Subject No. 
available to the investigator through the Oracle Clinical RDC interface. 
At Screening, the investigator or designated staff will contact the Interactive Response 
Technology (IRT) system 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 
patient 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 or start treatment for any reason, the reason will 
be entered into the Screening Disposition page and indicated in the IRT system. 
IRT must be notified within 2 days that the patient was not randomized. 
6.5.2 
Treatment randomization 
Patients will be randomized to one of the “2” treatment arms (Section 4.1 and Section 6.1) in a 
ratio of 1:1 (ruxolitinib or BAT). 
Randomization will be stratified by aGvHD grade (Grade II vs. III vs. IV). 


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The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased. 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 call or 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 on the ruxolitinib arm. The randomization number will not be 
communicated to the caller. 
6.5.3 
Treatment blinding 
Not applicable 
6.6 
Study drug preparation and dispensation 
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record CRF. 
6.6.1 
Study treatment packaging and labeling 
Study treatment, ruxolitinib, will be provided as global clinical open supply and will be packed 
and labeled under the responsibility of Novartis, Global Clinical Supply.  
The study medication packaging has a 2-part label (base plus tear-off 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. 
Study treatment labels will comply with the legal requirements of each country and will include 
storage conditions, a unique medication number (corresponding to study treatment and 
strength). Responsible site personnel will identify the study treatment package(s) to dispense 
by the medication number(s) assigned by IRT to the patient. Site personnel will add the patient 
number on the label. If the label has 2-parts (base plus tear-off label), immediately before 
dispensing the package to the patient, site personnel will detach the outer part of the label from 
the package and affix it to the patient’s source document. 


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Table 6-6 
Packaging and labeling  
Study treatments 
Packaging 
Labeling (and dosing frequency) 
INC424 
Tablets in HDPE bottles 
INC424  (BID) 
BAT  
Refer to local product information 
Refer to local product information 
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, ruxolitinib should be stored according to the 
instructions specified on the drug label and in the Investigator’s Brochure.  
Table 6-7 
Supply and storage of study treatments  
Study treatments 
Supply 
Storage 
INC424 
Centrally supplied by Novartis 
Refer to study treatment label 
BAT  
Locally 
Refer to local product information 
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 ruxolitinib 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 
ruxolitinib and packaging on a regular basis, at the end of the study or at the time of ruxolitinib 
discontinuation. 
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused ruxolitinib, 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 
In the context of this aGvHD protocol, the following non-investigational treatment will be taken 
by the patient as per standards of care but will be monitored specifically because dose 
adjustment of these non-investigational treatments may contribute to the efficacy assessment: 
 CNI 
 Systemic Corticosteroids  
All dosages prescribed to the patient and all dose changes during the study must be recorded on 
the Dosage Administration Record CRF Details will be described in the monitoring plan. 


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6.6.4 
Disposal and destruction 
The study drug supply (ruxolitinib) can be destroyed at the local Novartis facility, Drug Supply 
group, third party, or at the site only if permitted by local regulations and authorized by Novartis 
in a prior agreement as appropriate. 
7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1 and Table 7-2 Visit evaluation schedule for Cross-Over patients list all of the 
assessments and indicate 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.  


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Table 7-1 
Visit evaluation schedule  
 
Category 
Protocol 
Section 7.2 
Screening 
Treatment Period 
From Day 1 (randomization) to Week 24 / End of Study Treatment (EOT), 
whichever occurs first 
Taper follow-up visits from Week 24 (as applicable) 
Safety Follow-
up Visit 
 
Long-Term Follow-up 
Visits at Month 6, 9, 12, 18, 24 
from randomization 
Visit Name 
 
 
Screening 
Day 1 
Week 1- 
Week 8 (weekly) 
Week 12- 
Week 20 (4-weekly) 
Taper follow-up (as 
applicable) 
EOT (premature 
treatment 
discontinuation, 
or Week 24, or 
end of ruxolitinib 
taper if delayed 
[Week 96 max.]) 
Safety Follow-up 
Visit 
Month 6 
Month 9 
Month 12 
Month 18 
Month 24 
Week 24 
Taper - 
Week 48 
Taper 
(8-weekly) 
Week 60 
Taper - 
Week 84 
Taper 
(12-weekly) 
Weeks of treatment 
 
 
 
 
1-8 
12-20 
24-48 (max.) 
60-84 (max.) 
Week 24 or last 
dose (Week 96 
max.) 
 
 
 
 
 
 
Day 
 
 
-28 
to 
-1 
1 
7-56 
84-140 
168-336 
(max.) 
420-588 
(max.) 
168 or last dose 
(672 max.) 
Last 
Dose + 
30d 
182 
273 
365 
546 
730 
Visit window 
 
 
 
 
+/- 3d 
+/- 7d 
+/- 14d 
+/- 28d 
+/- 7d (Week 24) 
+7d 
+/- 
28d 
+/- 
28d 
+/- 
28d 
+/- 
28d 
+/- 
28d 
Screening Informed 
Consent 
D  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study Informed 
Consent 
D  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / 
Exclusion criteria 
D  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Disease history 
(alloSCT  and aGvHD 
history, CIBMTR risk 
assessment) 
D  
X 
 
 
 
 
 
 
 
 
 
 
 
 


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Category 
Protocol 
Section 7.2 
Screening 
Treatment Period 
From Day 1 (randomization) to Week 24 / End of Study Treatment (EOT), 
whichever occurs first 
Taper follow-up visits from Week 24 (as applicable) 
Safety Follow-
up Visit 
 
Long-Term Follow-up 
Visits at Month 6, 9, 12, 18, 24 
from randomization 
Visit Name 
 
 
Screening 
Day 1 
Week 1- 
Week 8 (weekly) 
Week 12- 
Week 20 (4-weekly) 
Taper follow-up (as 
applicable) 
EOT (premature 
treatment 
discontinuation, 
or Week 24, or 
end of ruxolitinib 
taper if delayed 
[Week 96 max.]) 
Safety Follow-up 
Visit 
Month 6 
Month 9 
Month 12 
Month 18 
Month 24 
Week 24 
Taper - 
Week 48 
Taper 
(8-weekly) 
Week 60 
Taper - 
Week 84 
Taper 
(12-weekly) 
Weeks of treatment 
 
 
 
 
1-8 
12-20 
24-48 (max.) 
60-84 (max.) 
Week 24 or last 
dose (Week 96 
max.) 
 
 
 
 
 
 
Day 
 
 
-28 
to 
-1 
1 
7-56 
84-140 
168-336 
(max.) 
420-588 
(max.) 
168 or last dose 
(672 max.) 
Last 
Dose + 
30d 
182 
273 
365 
546 
730 
HCT-Specific Co-
Morbidity Index Score 
D  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Intended BAT 
treatment  in case of 
SR-aGvHD 
D  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
D  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Other relevant 
Medical History 
D  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
D  
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Blood Component 
Transfusions (pRBC  
PLT and 
Cryoprecipitate, 
Fresh frozen plasma) 
D  
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 


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Category 
Protocol 
Section 7.2 
Screening 
Treatment Period 
From Day 1 (randomization) to Week 24 / End of Study Treatment (EOT), 
whichever occurs first 
Taper follow-up visits from Week 24 (as applicable) 
Safety Follow-
up Visit 
 
Long-Term Follow-up 
Visits at Month 6, 9, 12, 18, 24 
from randomization 
Visit Name 
 
 
Screening 
Day 1 
Week 1- 
Week 8 (weekly) 
Week 12- 
Week 20 (4-weekly) 
Taper follow-up (as 
applicable) 
EOT (premature 
treatment 
discontinuation, 
or Week 24, or 
end of ruxolitinib 
taper if delayed 
[Week 96 max.]) 
Safety Follow-up 
Visit 
Month 6 
Month 9 
Month 12 
Month 18 
Month 24 
Week 24 
Taper - 
Week 48 
Taper 
(8-weekly) 
Week 60 
Taper - 
Week 84 
Taper 
(12-weekly) 
Weeks of treatment 
 
 
 
 
1-8 
12-20 
24-48 (max.) 
60-84 (max.) 
Week 24 or last 
dose (Week 96 
max.) 
 
 
 
 
 
 
Day 
 
 
-28 
to 
-1 
1 
7-56 
84-140 
168-336 
(max.) 
420-588 
(max.) 
168 or last dose 
(672 max.) 
Last 
Dose + 
30d 
182 
273 
365 
546 
730 
IRT (Registration 
Randomization, 
Cross-over, EOT) 
D  
X 
X 
X 
(4-
weekly) 
X 
X 
X 
X 
 
 
 
 
 
 
Physical 
examination 
S 7.2.2.1 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Height 
D 7.2.2.3  
X 
 
 
 
X (Week 48: 
adolescents) 
 
X (adolescents)  
 
 
 
 
 
 
Weight 
D 7.2.2.3   
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Vital signs 
D 7.2.2.2   
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Laboratory 
assessments 
 
7.2.2.4   
 
Hematology 
D 7.2.2.4.1   X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Chemistry 
D 7.2.2.4.2   X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Coagulation  
D 7.2.2.4.4   X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 


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Category 
Protocol 
Section 7.2 
Screening 
Treatment Period 
From Day 1 (randomization) to Week 24 / End of Study Treatment (EOT), 
whichever occurs first 
Taper follow-up visits from Week 24 (as applicable) 
Safety Follow-
up Visit 
 
Long-Term Follow-up 
Visits at Month 6, 9, 12, 18, 24 
from randomization 
Visit Name 
 
 
Screening 
Day 1 
Week 1- 
Week 8 (weekly) 
Week 12- 
Week 20 (4-weekly) 
Taper follow-up (as 
applicable) 
EOT (premature 
treatment 
discontinuation, 
or Week 24, or 
end of ruxolitinib 
taper if delayed 
[Week 96 max.]) 
Safety Follow-up 
Visit 
Month 6 
Month 9 
Month 12 
Month 18 
Month 24 
Week 24 
Taper - 
Week 48 
Taper 
(8-weekly) 
Week 60 
Taper - 
Week 84 
Taper 
(12-weekly) 
Weeks of treatment 
 
 
 
 
1-8 
12-20 
24-48 (max.) 
60-84 (max.) 
Week 24 or last 
dose (Week 96 
max.) 
 
 
 
 
 
 
Day 
 
 
-28 
to 
-1 
1 
7-56 
84-140 
168-336 
(max.) 
420-588 
(max.) 
168 or last dose 
(672 max.) 
Last 
Dose + 
30d 
182 
273 
365 
546 
730 
Hepatitis viral 
serology testing 
(HBV, HCV) 
D 7.2.2.8   
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis viral load 
testing (HBV, HCV)  
D 7.2.2.8   
X 
X 
X (4-
weekly) 
X 
X 
X 
X 
X 
 
 
 
 
 
Testing for CMV, 
EBV, HHV-6 viral 
load  
D 7.2.2.8   
X 
X 
X (4-
weekly) 
X 
X 
X 
X 
X 
 
 
 
 
 
Urinalysis   
D 7.2.2.4.3   X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Pregnancy test 
(serum) 
D 7.2.2.4.5   X 
 
 
 
 
 
X 
 
 
 
 
 
 
Pregnancy test 
(urine) 
D 7.2.2.4.5    
X 
X (4-weekly) 
X 
X 
 
 
 
 
 
 
 
acute GvHD 
assessment 
D 7.2.1.1   
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 


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Category 
Protocol 
Section 7.2 
Screening 
Treatment Period 
From Day 1 (randomization) to Week 24 / End of Study Treatment (EOT), 
whichever occurs first 
Taper follow-up visits from Week 24 (as applicable) 
Safety Follow-
up Visit 
 
Long-Term Follow-up 
Visits at Month 6, 9, 12, 18, 24 
from randomization 
Visit Name 
 
 
Screening 
Day 1 
Week 1- 
Week 8 (weekly) 
Week 12- 
Week 20 (4-weekly) 
Taper follow-up (as 
applicable) 
EOT (premature 
treatment 
discontinuation, 
or Week 24, or 
end of ruxolitinib 
taper if delayed 
[Week 96 max.]) 
Safety Follow-up 
Visit 
Month 6 
Month 9 
Month 12 
Month 18 
Month 24 
Week 24 
Taper - 
Week 48 
Taper 
(8-weekly) 
Week 60 
Taper - 
Week 84 
Taper 
(12-weekly) 
Weeks of treatment 
 
 
 
 
1-8 
12-20 
24-48 (max.) 
60-84 (max.) 
Week 24 or last 
dose (Week 96 
max.) 
 
 
 
 
 
 
Day 
 
 
-28 
to 
-1 
1 
7-56 
84-140 
168-336 
(max.) 
420-588 
(max.) 
168 or last dose 
(672 max.) 
Last 
Dose + 
30d 
182 
273 
365 
546 
730 
aGvHD Response 
assessment 
D 7.2.1.1   
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Chronic GvHD 
assessment 
D 7.2.1.2   
 
 
X (4-
weekly) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Graft failure 
assessment 
D 7.2.1.3   
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematologic 
disease 
relapse/progression 
assessment 
D 7.2.1.4   
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Second primary 
malignancy 
assessment 
 
7.2.2.9   
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chimerism 
D 7.2.1.3.1   X 
 
X (4-
weekly) 
 
 
 
 
 
 
 
 
 
 


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Category 
Protocol 
Section 7.2 
Screening 
Treatment Period 
From Day 1 (randomization) to Week 24 / End of Study Treatment (EOT), 
whichever occurs first 
Taper follow-up visits from Week 24 (as applicable) 
Safety Follow-
up Visit 
 
Long-Term Follow-up 
Visits at Month 6, 9, 12, 18, 24 
from randomization 
Visit Name 
 
 
Screening 
Day 1 
Week 1- 
Week 8 (weekly) 
Week 12- 
Week 20 (4-weekly) 
Taper follow-up (as 
applicable) 
EOT (premature 
treatment 
discontinuation, 
or Week 24, or 
end of ruxolitinib 
taper if delayed 
[Week 96 max.]) 
Safety Follow-up 
Visit 
Month 6 
Month 9 
Month 12 
Month 18 
Month 24 
Week 24 
Taper - 
Week 48 
Taper 
(8-weekly) 
Week 60 
Taper - 
Week 84 
Taper 
(12-weekly) 
Weeks of treatment 
 
 
 
 
1-8 
12-20 
24-48 (max.) 
60-84 (max.) 
Week 24 or last 
dose (Week 96 
max.) 
 
 
 
 
 
 
Day 
 
 
-28 
to 
-1 
1 
7-56 
84-140 
168-336 
(max.) 
420-588 
(max.) 
168 or last dose 
(672 max.) 
Last 
Dose + 
30d 
182 
273 
365 
546 
730 
Pulmonary Function 
Test 
S 7.2.2.5   
 
 
X (as clinically indicated) 
 
 
 
 
 
 
Safety 
D 8. 
 
Adverse events  
D 8.1   
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Infection, Bleeding 
monitoring 
D 7.2.2.6, 
7.2.2.7 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 


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Category 
Protocol 
Section 7.2 
Screening 
Treatment Period 
From Day 1 (randomization) to Week 24 / End of Study Treatment (EOT), 
whichever occurs first 
Taper follow-up visits from Week 24 (as applicable) 
Safety Follow-
up Visit 
 
Long-Term Follow-up 
Visits at Month 6, 9, 12, 18, 24 
from randomization 
Visit Name 
 
 
Screening 
Day 1 
Week 1- 
Week 8 (weekly) 
Week 12- 
Week 20 (4-weekly) 
Taper follow-up (as 
applicable) 
EOT (premature 
treatment 
discontinuation, 
or Week 24, or 
end of ruxolitinib 
taper if delayed 
[Week 96 max.]) 
Safety Follow-up 
Visit 
Month 6 
Month 9 
Month 12 
Month 18 
Month 24 
Week 24 
Taper - 
Week 48 
Taper 
(8-weekly) 
Week 60 
Taper - 
Week 84 
Taper 
(12-weekly) 
Weeks of treatment 
 
 
 
 
1-8 
12-20 
24-48 (max.) 
60-84 (max.) 
Week 24 or last 
dose (Week 96 
max.) 
 
 
 
 
 
 
Day 
 
 
-28 
to 
-1 
1 
7-56 
84-140 
168-336 
(max.) 
420-588 
(max.) 
168 or last dose 
(672 max.) 
Last 
Dose + 
30d 
182 
273 
365 
546 
730 
Patient Reported 
Outcomes 
D 7.2.6   
 
FACT-BMT  
(patients ≥ 18 only) 
D 7.2.6   
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
EQ-5D-5L 
D 7.2.6   
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 


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Category 
Protocol 
Section 7.2 
Screening 
Treatment Period 
From Day 1 (randomization) to Week 24 / End of Study Treatment (EOT), 
whichever occurs first 
Taper follow-up visits from Week 24 (as applicable) 
Safety Follow-
up Visit 
 
Long-Term Follow-up 
Visits at Month 6, 9, 12, 18, 24 
from randomization 
Visit Name 
 
 
Screening 
Day 1 
Week 1- 
Week 8 (weekly) 
Week 12- 
Week 20 (4-weekly) 
Taper follow-up (as 
applicable) 
EOT (premature 
treatment 
discontinuation, 
or Week 24, or 
end of ruxolitinib 
taper if delayed 
[Week 96 max.]) 
Safety Follow-up 
Visit 
Month 6 
Month 9 
Month 12 
Month 18 
Month 24 
Week 24 
Taper - 
Week 48 
Taper 
(8-weekly) 
Week 60 
Taper - 
Week 84 
Taper 
(12-weekly) 
Weeks of treatment 
 
 
 
 
1-8 
12-20 
24-48 (max.) 
60-84 (max.) 
Week 24 or last 
dose (Week 96 
max.) 
 
 
 
 
 
 
Day 
 
 
-28 
to 
-1 
1 
7-56 
84-140 
168-336 
(max.) 
420-588 
(max.) 
168 or last dose 
(672 max.) 
Last 
Dose + 
30d 
182 
273 
365 
546 
730 
Study Drug 
Treatment 
administration 
(ruxolitinib or BAT) 
D  
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
PK sampling 
D 7.2.3   
 
X 
X 
(Weeks 
1, 2, 4, 8) 
 
X 
(Week 24) 
 
X 
(Week 24) 
 
 
 
 
 
 
Survival Follow-up 
D  
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Disposition 
D  
X 
 
 
 
 
 
X 
 
 
 
 
 
 


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Table 7-2 
Visit evaluation schedule for Cross-Over patients 
 
Category 
Protocol 
Section 7.2 
Cross-Over (CO) Treatment Period 
From CO Day 1 to CO Week 24 / CO EOT, whichever occurs firstTaper follow-up 
visits from Cross-Over Week 24 (as applicable) 
Safety 
Follow-up 
Visit 
Long-Term 
Follow-up 
Visits at Month 6, 
9, 12 18, 24 from 
randomization 
Visit Name  
 
 
CO Day 1 
CO Week 1 – CO 
Week 8 (weekly) 
CO Week 12 – CO 
Week 20 (4-weekly) 
Taper follow-up (as 
applicable) 
CO EOT 
(premature 
treatment 
discontinuation, 
or CO Week 24,  
or end of 
ruxolitinib taper if 
delayed [CO 
Week 96 max.]) 
Safety Follow-Up 
Visit 
 
CO Week 24 
Taper - 
CO Week 48 
Taper 
(8-weekly) 
CO Week 60 
Taper - 
CO Week 84 
Taper 
(12-weekly) 
Weeks of treatment 
 
 
 
1-8 
12-20 
24-48 (max.) 
60-84 
(max.) 
CO Week 24 or 
last dose (CO 
Week 96 max.) 
 
Day from Cross-
Over 
 
 
1 
7-56 
84-140 
168-336 
(max.) 
420-588 
(max.) 
168 or last dose 
(672 max.) 
Last 
Dose 
+ 30d 
Time window 
 
 
 
+/- 3d 
+/- 7d 
+/- 14d 
+/- 28d 
+/- 7d 
+7d 
Please refer to Table 7-1 
Eligibility for Cross-
Over 
D 
 
X 
 
 
 
 
 
 
Contact IRT system 
D 
 
X 
X (4-
weekly) 
X 
X 
X 
X 
 
Concomitant 
medications 
D 
 
X 
X 
X 
X 
X 
X 
X 
Blood Component 
Transfusions (pRBC, 
PLT ,Cryoprecipitate, 
Fresh frozen plasma) 
D 
 
X 
X 
X 
X 
X 
X 
X 
Physical 
examination 
S 
7.2.2.1   
X 
X 
X 
X 
X 
X 
X 


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Category 
Protocol 
Section 7.2 
Cross-Over (CO) Treatment Period 
From CO Day 1 to CO Week 24 / CO EOT, whichever occurs firstTaper follow-up 
visits from Cross-Over Week 24 (as applicable) 
Safety 
Follow-up 
Visit 
Long-Term 
Follow-up 
Visits at Month 6, 
9, 12 18, 24 from 
randomization 
Visit Name  
 
 
CO Day 1 
CO Week 1 – CO 
Week 8 (weekly) 
CO Week 12 – CO 
Week 20 (4-weekly) 
Taper follow-up (as 
applicable) 
CO EOT 
(premature 
treatment 
discontinuation, 
or CO Week 24,  
or end of 
ruxolitinib taper if 
delayed [CO 
Week 96 max.]) 
Safety Follow-Up 
Visit 
 
CO Week 24 
Taper - 
CO Week 48 
Taper 
(8-weekly) 
CO Week 60 
Taper - 
CO Week 84 
Taper 
(12-weekly) 
Weeks of treatment 
 
 
 
1-8 
12-20 
24-48 (max.) 
60-84 
(max.) 
CO Week 24 or 
last dose (CO 
Week 96 max.) 
 
Day from Cross-
Over 
 
 
1 
7-56 
84-140 
168-336 
(max.) 
420-588 
(max.) 
168 or last dose 
(672 max.) 
Last 
Dose 
+ 30d 
Height 
D 
7.2.2.3   
X 
 
 
X (CO Week 
48: 
adolescents) 
 
X (adolescents) 
 
Weight 
D 
7.2.2.3   
X 
X 
X 
X 
X 
X 
X 
Vital signs 
D 
7.2.2.2   
X 
X 
X 
X 
X 
X 
X 
Laboratory 
assessments 
 
7.2.2.4   
 
Hematology 
D 
7.2.2.4.1   
X 
X 
X 
X 
X 
X 
X 
Chemistry 
D 
7.2.2.4.2   
X 
X 
X 
X 
X 
X    
X 
Coagulation 
D 
7.2.2.4.4  
X  
X 
X 
X 
X 
X 
X 
Hepatitis testing 
(HBV, HCV) viral 
load 
D 
7.2.2.8  
X 
X (4-
weekly) 
X 
X 
X 
X 
X 


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Category 
Protocol 
Section 7.2 
Cross-Over (CO) Treatment Period 
From CO Day 1 to CO Week 24 / CO EOT, whichever occurs firstTaper follow-up 
visits from Cross-Over Week 24 (as applicable) 
Safety 
Follow-up 
Visit 
Long-Term 
Follow-up 
Visits at Month 6, 
9, 12 18, 24 from 
randomization 
Visit Name  
 
 
CO Day 1 
CO Week 1 – CO 
Week 8 (weekly) 
CO Week 12 – CO 
Week 20 (4-weekly) 
Taper follow-up (as 
applicable) 
CO EOT 
(premature 
treatment 
discontinuation, 
or CO Week 24,  
or end of 
ruxolitinib taper if 
delayed [CO 
Week 96 max.]) 
Safety Follow-Up 
Visit 
 
CO Week 24 
Taper - 
CO Week 48 
Taper 
(8-weekly) 
CO Week 60 
Taper - 
CO Week 84 
Taper 
(12-weekly) 
Weeks of treatment 
 
 
 
1-8 
12-20 
24-48 (max.) 
60-84 
(max.) 
CO Week 24 or 
last dose (CO 
Week 96 max.) 
 
Day from Cross-
Over 
 
 
1 
7-56 
84-140 
168-336 
(max.) 
420-588 
(max.) 
168 or last dose 
(672 max.) 
Last 
Dose 
+ 30d 
Testing for CMV, 
EBV, HHV-6 viral 
load  
D 
7.2.2.8  
X 
X (4-
weekly) 
X 
X 
X 
X 
X 
Urinalysis  
D 
7.2.2.4.3  
X 
X 
X 
X 
X 
X 
X 
Pregnancy test 
(serum) 
D 
7.2.2.4.5  
X 
 
 
 
 
X 
 
Pregnancy test 
(urine) 
D 
7.2.2.4.5   
 
X (4-weekly) 
X 
X 
 
 
Acute GvHD 
assessment 
D 
7.2.1.1   
X 
X 
X 
X 
X 
X 
 
aGvHD Response 
assessment 
D 
7.2.1.1 
X 
X 
X 
X 
X 
X 
 
Chronic GvHD 
assessment 
D 
7.2.1.2   
X 
X 
X 
X 
X 
X 
X 


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Category 
Protocol 
Section 7.2 
Cross-Over (CO) Treatment Period 
From CO Day 1 to CO Week 24 / CO EOT, whichever occurs firstTaper follow-up 
visits from Cross-Over Week 24 (as applicable) 
Safety 
Follow-up 
Visit 
Long-Term 
Follow-up 
Visits at Month 6, 
9, 12 18, 24 from 
randomization 
Visit Name  
 
 
CO Day 1 
CO Week 1 – CO 
Week 8 (weekly) 
CO Week 12 – CO 
Week 20 (4-weekly) 
Taper follow-up (as 
applicable) 
CO EOT 
(premature 
treatment 
discontinuation, 
or CO Week 24,  
or end of 
ruxolitinib taper if 
delayed [CO 
Week 96 max.]) 
Safety Follow-Up 
Visit 
 
CO Week 24 
Taper - 
CO Week 48 
Taper 
(8-weekly) 
CO Week 60 
Taper - 
CO Week 84 
Taper 
(12-weekly) 
Weeks of treatment 
 
 
 
1-8 
12-20 
24-48 (max.) 
60-84 
(max.) 
CO Week 24 or 
last dose (CO 
Week 96 max.) 
 
Day from Cross-
Over 
 
 
1 
7-56 
84-140 
168-336 
(max.) 
420-588 
(max.) 
168 or last dose 
(672 max.) 
Last 
Dose 
+ 30d 
Graft failure 
assessment 
D 
7.2.1.3   
X 
X 
X 
X 
X 
X 
X 
Hematologic 
disease 
relapse/progression 
assessment 
D 
7.2.1.4   
X 
X 
X 
X 
X 
X 
X 
Second Primary 
Malignancy 
assessment 
D 
7.2.2.9 
X 
X 
X 
X 
X 
X 
X 
Chimerism 
D 
7.2.1.3.1 
 
X (CO 
Week 1 
only) 
 
 
 
 
 
Pulmonary Function 
Test 
S 
7.2.2.5   
 
X (as clinically indicated) 
 
Safety 
 
8 
 


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Category 
Protocol 
Section 7.2 
Cross-Over (CO) Treatment Period 
From CO Day 1 to CO Week 24 / CO EOT, whichever occurs firstTaper follow-up 
visits from Cross-Over Week 24 (as applicable) 
Safety 
Follow-up 
Visit 
Long-Term 
Follow-up 
Visits at Month 6, 
9, 12 18, 24 from 
randomization 
Visit Name  
 
 
CO Day 1 
CO Week 1 – CO 
Week 8 (weekly) 
CO Week 12 – CO 
Week 20 (4-weekly) 
Taper follow-up (as 
applicable) 
CO EOT 
(premature 
treatment 
discontinuation, 
or CO Week 24,  
or end of 
ruxolitinib taper if 
delayed [CO 
Week 96 max.]) 
Safety Follow-Up 
Visit 
 
CO Week 24 
Taper - 
CO Week 48 
Taper 
(8-weekly) 
CO Week 60 
Taper - 
CO Week 84 
Taper 
(12-weekly) 
Weeks of treatment 
 
 
 
1-8 
12-20 
24-48 (max.) 
60-84 
(max.) 
CO Week 24 or 
last dose (CO 
Week 96 max.) 
 
Day from Cross-
Over 
 
 
1 
7-56 
84-140 
168-336 
(max.) 
420-588 
(max.) 
168 or last dose 
(672 max.) 
Last 
Dose 
+ 30d 
Adverse events 
D 
8.1   
X 
X 
X 
X 
X 
X 
X 
Infection, Bleeding 
monitoring 
D 
7.2.2.6, 
7.2.2.7 
X 
X 
X 
X 
X 
X 
X 


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Category 
Protocol 
Section 7.2 
Cross-Over (CO) Treatment Period 
From CO Day 1 to CO Week 24 / CO EOT, whichever occurs firstTaper follow-up 
visits from Cross-Over Week 24 (as applicable) 
Safety 
Follow-up 
Visit 
Long-Term 
Follow-up 
Visits at Month 6, 
9, 12 18, 24 from 
randomization 
Visit Name  
 
 
CO Day 1 
CO Week 1 – CO 
Week 8 (weekly) 
CO Week 12 – CO 
Week 20 (4-weekly) 
Taper follow-up (as 
applicable) 
CO EOT 
(premature 
treatment 
discontinuation, 
or CO Week 24,  
or end of 
ruxolitinib taper if 
delayed [CO 
Week 96 max.]) 
Safety Follow-Up 
Visit 
CO Week 24 
Taper - 
CO Week 48 
Taper 
(8-weekly) 
CO Week 60 
Taper - 
CO Week 84 
Taper 
(12-weekly) 
Weeks of treatment 
 
 
 
1-8 
12-20 
24-48 (max.) 
60-84 
(max.) 
CO Week 24 or 
last dose (CO 
Week 96 max.) 
 
Day from Cross-
Over 
 
 
1 
7-56 
84-140 
168-336 
(max.) 
420-588 
(max.) 
168 or last dose 
(672 max.) 
Last 
Dose 
+ 30d 
Patient Reported 
Outcomes 
 
7.2.6   
 
FACT-BMT (patients 
≥ 18) 
D 
7.2.6   
X 
X 
X 
X 
X 
X 
X 
EQ-5D-5L 
D 
7.2.6   
X 
X 
X 
X 
X 
X 
X 


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Category 
Protocol 
Section 7.2 
Cross-Over (CO) Treatment Period 
From CO Day 1 to CO Week 24 / CO EOT, whichever occurs firstTaper follow-up 
visits from Cross-Over Week 24 (as applicable) 
Safety 
Follow-up 
Visit 
Long-Term 
Follow-up 
Visits at Month 6, 
9, 12 18, 24 from 
randomization 
Visit Name  
 
 
CO Day 1 
CO Week 1 – CO 
Week 8 (weekly) 
CO Week 12 – CO 
Week 20 (4-weekly) 
Taper follow-up (as 
applicable) 
CO EOT 
(premature 
treatment 
discontinuation, 
or CO Week 24,  
or end of 
ruxolitinib taper if 
delayed [CO 
Week 96 max.]) 
Safety Follow-Up 
Visit 
 
CO Week 24 
Taper - 
CO Week 48 
Taper 
(8-weekly) 
CO Week 60 
Taper - 
CO Week 84 
Taper 
(12-weekly) 
Weeks of treatment 
 
 
 
1-8 
12-20 
24-48 (max.) 
60-84 
(max.) 
CO Week 24 or 
last dose (CO 
Week 96 max.) 
 
Day from Cross-
Over 
 
 
1 
7-56 
84-140 
168-336 
(max.) 
420-588 
(max.) 
168 or last dose 
(672 max.) 
Last 
Dose 
+ 30d 
Study Drug 
administration 
(ruxolitinib) 
D 
 
X 
X 
X 
X 
X 
 
 
PK sampling 
D 
7.2.3   
X 
X (CO 
Weeks 1, 
2, 4, 8) 
 
X (CO Week 
24) 
 
X (CO Week 24) 
 
Disposition 
D 
 
 
 
 
 
 
X 
 
 
 


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7.1.1 
Molecular pre-screening  
Not Applicable 
7.1.2 
Screening 
Patients will be proposed to enroll in the Screening period of the study once diagnosed with 
aGvHD (grades II-IV) after alloSCT.  
The Screening period will begin once the patient has signed the Screening Informed Consent 
and will be a maximum of 28 days (Day -28 to Day -1). 
Screening procedures are outlined in the visit evaluation schedule (Table 7-1) including blood 
sample tested as needed, and assessment of inclusion and exclusion criteria.  
These Screening assessments performed during the Screening period will be reported in source 
notes, however the corresponding data will only be fully reported in the eCRF for patients 
diagnosed with SR-aGvHD during the Screening period and who signed the Study Informed 
Consent. Limited information on screening failures will be reported in the clinical database, as 
described in Section 7.1.2.2. 
Patients will be treated for aGvHD with systemic corticosteroids +/- continued CNI +/- another 
systemic aGvHD treatment per standard of care by the Investigator during the Screening period. 
Any occurrence of Steroid Refractory aGvHD as defined in Section 4.1 will be also closely 
monitored by the Investigator to identify if the patient is eligible for this study as follows: 
Patients who develop SR-aGvHD, will be proposed to continue in the Study. 
Patients meeting all eligibility criteria including SR-aGvHD criteria, may be consented to the 
Study Informed Consent. The Investigator must ensure availability of laboratory assessments 
including CBC, chemistry, and coagulation studies not older than 48 hours prior to start of study 
treatment with remainder of laboratory assessments performed within 28 days before 
randomization. The Investigator must identify Investigator choice BAT prior to randomization. 
Note: Medications used for aGvHD prophylaxis (i.e. started before the diagnosis of aGvHD) 
which have failed to prevent aGvHD in a patient prior to randomization must not be chosen as 
BAT in this same patient. 
Continued use of systemic corticosteroids +/- CNI and topical corticosteroid therapy per 
institutional guidelines is permitted. Other systemic medications for aGvHD other than 
corticosteroids +/- CNI may be continued after randomization only if used for aGvHD 
prophylaxis (i.e. started before the diagnosis of aGvHD).  
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, and can be 
completed within 48 hours prior to study treatment start. In this case, the patient will not be 
required to sign another ICF, and the original patient ID number assigned by the investigator 
will be used. 


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If study treatment does not start within 24 hours after randomization, body weight, CBC, 
Chemistry and coagulation tests should be repeated to have laboratory assessments not older 
than 24 hours prior to study treatment start. 
A patient is considered a screen failure in the event that the laboratory test(s) cannot be available 
within 48 hours from treatment start, or the retest(s) do not meet the entrance criteria or the 
patient’s medical condition has changed significantly during the screening period so that the 
inclusion/exclusion criteria are no longer met, more details outlined on Section 7.1.2.1 
Patients who do not develop SR- aGvHD within the 28 days of the screening period will 
be considered a screen failure.  
If a patient fails corticosteroid taper after the 28 days from initial screening as per SR-aGvHD 
criteria outlined in Section 4.1, they may be considered for re-screening.  
A new Study Screening 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. 
Patients meeting all inclusion and exclusion criteria will be randomized 1:1 to receive either 
ruxolitinib or BAT stratifying on aGvHD grade at the time of randomization (Grade II vs. III 
vs. IV). 
7.1.2.1 
Eligibility screening   
Patients must meet all inclusion and exclusion criteria in order to be eligible to proceed to the 
Treatment Period of the study. 
Investigative staff will capture patient’s 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 by the 
investigator once all screening procedures are completed. The eligibility check will be 
embedded in the IRT system. Please refer to and comply with detailed guidelines in the IRT 
manual. Only when eligibility data has been confirmed with the IRT system will the IRT allow 
patient’s randomization and assign study treatment arm. 
7.1.2.2 
Information to be collected on screening failures 
Patients who sign the Screening informed consent and/or the Study informed consent, but fail 
to be started on study treatment for any reason will be considered a screen failure.  
The reason for not being started on treatment will be entered on the applicable Screening 
Disposition CRF pages.  


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The demographic information, informed consent, and Inclusion/Exclusion pages CRF page 
must also be completed for all Screen Failure patients. In addition, the aGvHD assessment at 
screening will also be recorded in the CRF with overall grade and staging to better characterize 
the aGvHD population screened for this trial. 
No other data will be entered into the clinical database for patients who are screen failures, 
unless the patient experienced a Serious Adverse Event during the Screening Period (see 
Section 8 for SAE reporting details). For Patients who signed a Screening ICF only and no 
Study informed consent, only SAEs possibly related to a study procedure will be reported. 
If the patient fails to be randomized, the IRT must be notified within 2 days of the screen fail 
that the patient was not randomized. 
7.1.2.3 
Patient demographics and other baseline characteristics 
Patient will have the following assessments performed before the start of study treatment: 
 Review of medical history including alloSCT and CIMBTR risk assessment at the time of 
the alloSCT (Appendix 6), aGvHD history and disease diagnosis 
 HCT Specific Comorbidity index score (Appendix 5) 
 Prior aGvHD therapy (drug and non-drug) and aGvHD prophylaxis 
 Intended BAT strategy in case of SR-aGvHD  prior to randomization 
 Prior/Concomitant medications and Blood transfusions,  adverse events including 
infections/second primary malignancy (Section 7.2)  
 Physical examination including height, weight, vital signs, (Section 7.2.2.1)  
 Laboratory assessments – Hematology, Chemistry, Coagulation, Urinalysis 
 Hepatitis serology (HBV and HCV) if applicable (Section 7.2.2.8) 
 CMV, EBV, HHV-6, HBV and HCV viral load tests. (Section 7.2.2.8) 
 Pregnancy test (if applicable) (Section 7.2.2.4.5) 
 aGvHD assessment as per standard criteria  (Appendix 1)   
 Chimerism if applicable (Section 7.2.1.3.1)  
 Hematologic underlying disease relapse/progression baseline assessment (Section 7.2.1.4) 
 Graft failure baseline assessment (Section 7.2.1.3) 
 Patient reported outcomes: FACT-BMT, EQ-5D-5L as applicable (Section 7.2.6) 
 
 
 
 
 The investigator must confirm all the inclusion and exclusion criteria prior to contacting 
IRT for randomization.  
Notes: 
 Vital signs and urinalysis assessments as detailed in Table 7-1 performed within 48 
hours prior to randomization do not need to be repeated at Day 1. 
 Viral load tests performed within 7 days from Day 1 do not need to be repeated at 
Day 1. 


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 If study treatment does not start within 24 hours after randomization, body weight, 
CBC, Chemistry and coagulation tests should be repeated to have laboratory 
assessments not older than 24 hours prior to study treatment start. 
7.1.3 
Run-in period  
Not Applicable 
7.1.4 
Treatment period 
 Study treatment will be initiated on Day 1 after randomization and treatment assignment 
by IRT system (or within 72 hours from randomization at the latest).  
 Day 1 is defined as the day of randomization.  
 Study treatment will be administered until the patient meets any of the criteria for 
discontinuation of study treatment (see Section 7.1.5) or, in responders (i.e. patients 
achieving PR or CR) until the dosing schedule for ruxolitinib or BAT is complete. Patients 
in the BAT arm may be eligible to cross-over between Day 28 and Week 24. 
 Patients in the randomized Treatment Period should follow the schedule of assessments in 
Table 7-1 and patients who cross-over to ruxolitinib should follow the schedule of 
assessments in Table 7-2. In addition, the frequency of visits and possible time-points for 
the EOT are detailed in Section 4.1. 
 All cross-over patients should complete the EOT CRF at the time of discontinuation of 
randomized treatment (BAT) and again at the time of discontinuation of cross-over 
treatment (ruxolitinib). Should the EOT visit and Cross-Over Day 1 visit be 3 days apart 
or less, assessments due at both visits do not need to be repeated. 
 Unscheduled visits may be performed as necessary. Additional assessments may be done 
as per institutional guidelines at investigator’s discretion at any time during the trial. 
aGvHD assessments performed at unscheduled visit and leading to a change in patient’s 
management or, during treatment period to a change in patient’s response should be 
recorded in the CRF, as well as any relevant safety assessment performed. 
Assessments required at the time of last dose if before Week 24, in responding patients: 
As noted in Section 4.1, responding patients (i.e. obtaining a CR or PR) completing the dosing 
schedule for ruxolitinib or their assigned BAT before Week 24, will have their EOT visit at 
Week 24 AND must also have assessments performed within 7 days of the last dose. These 
assessments will be performed: 
 At a scheduled visit (if planned within 7 days of last dose), 
OR 
 At an unscheduled visit. 
 In this case, assessments identified below, which are not part of the assessments for 
the scheduled visit, must be performed and recorded as unscheduled assessments, in 
addition to planned assessments.  
The same rules apply in the Cross-Over Treatment Period. 
The following assessments are required: 




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 Protocol deviation that results in a significant risk to the patient’s safety including use of 
prohibited treatment (refer to Section 6.4.3)  
The Investigator may opt for a dose tapering strategy in the event of ruxolitinib treatment 
discontinuation, e.g. in patients who develop cGvHD (see Section 6.3.1.1.3 and Section 
6.1.5.1). Patients with hematologic disease progression, graft failure, AE, patient safety, or 
pregnancy may require abrupt cessation of ruxolitinib study treatment per Investigator 
discretion.  Patients should return for assessments as specified at the end of treatment (EOT) 
visit in Table 7-1 (or Table 7-2 for cross-over patients).  
Patients who discontinue ruxolitinib study treatment should NOT be considered withdrawn 
from the study. After the EOT visit, they will still undergo the Safety Follow-Up visit and then 
enter the Long-Term 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.  
Patients who meet the protocol criteria for treatment discontinuation will not be eligible to 
continue receiving ruxolitinib within the study. However, as part of Novartis “Post-trial access” 
commitment, patients who meet all of the following criteria: 
 responded to ruxolitinib at Day 28 (or Cross-Over Day 28),  
 met study discontinuation criteria (Section 7.1.5), other than safety reasons, 
 are assessed by the Investigator to still be deriving clinical benefit from ruxolitinib,  
will be given the possibility to continue ruxolitinib outside the study, if requested; they will 
then not enter the Long-Term Follow-Up period. 
The Investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment. All patients who discontinue treatment for any reasons, must continue in the Long-
Term Follow-Up period with visits every 12 weeks in the 1st year from randomization (Day 1) 
and thereafter, every 6 months in the 2nd year from randomization and follow assessments as 
described in Section 7.1.7 unless discontinued from the study earlier. 
7.1.5.1 
Replacement policy 
Patients who discontinue prematurely will not be replaced on this study.  
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 from the study occurs only when a patient does not want to participate 
in the study any longer, does not allow further collection of personal data.  
In this situation, the Investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for patient’s decision to withdraw his/her consent and record 
this information. 
Study treatment must be discontinued and no further assessments conducted and the data that 
would have been collected at subsequent visits will be considered missing. 


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Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up.  
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law. 
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form.   
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.  
7.1.7 
Follow-up for Safety Evaluations 
 Safety Follow-Up visit 
All patients must have a follow-up visit for safety evaluations 30 days following the last dose of 
study treatment at the end of the Treatment Period.  
Note: for patients randomized to the BAT arm and crossing over to ruxolitinib, the Safety 
Follow-Up visit will only occur once, i.e. 30 days after the last dose of ruxolitinib in the Cross-
Over Treatment Period. 
At the Safety Follow-Up visit, adverse events and therapies after treatment discontinuation will 
be reviewed, physical examinations, laboratory assessment, patient reported outcomes 
 
 will be collected. Refer to Table 7-1 or Table 7-2 for a complete list of 
assessments at the 30-day Safety Follow-Up visit. 
 Long-Term Follow-Up 
All patients who discontinue study treatment (responders, non-responders, completing or 
prematurely discontinued from the Treatment Period for any reasons as outlined above) will 
enter in the Long-Term Follow-Up period which lasts up to 24 months from randomization. 
Visits are scheduled after EOT or Cross-Over EOT, at Month 6 (in case of premature 
discontinuation), Month 9, Month 12, Month 18 and Month 24 from randomization (Day 1).  
If visits on site are not possible during the Long-Term Follow-Up period, patients may be 
contacted by the site to collect similar information. 
Information to be collected is detailed (Table 7-1). Data collected should be entered in the 
appropriate CRF. Unscheduled visits may be performed as necessary. Additional assessments 
may be done as per institutional guidelines at investigator’s discretion at any time during the 
trial.  


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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. 
7.2 
Assessment types 
7.2.1 
Efficacy assessments  
7.2.1.1 
aGvHD assessment  
aGvHD grading will be performed by the Investigator at every visit during the treatment period 
and at EOT visit as outlined in Table 7-1 and Table 7-2.  
aGvHD will be performed using standard criteria (Harris 2016): measures of body surface area 
aGvHD skin rash, stool volumes or frequency per 24h time period, and serum bilirubin levels,  
staging by organ (skin; liver; upper GI; Lower GI) and overall grading at the time of the 
evaluation should be reported according to Appendix 1. 
In addition, biopsy of the organ involved may be performed per institutional practices at 
Investigator’s discretion for aGvHD management. If performed, the Investigator will indicate 
the results once available.  
Once randomized, response to study treatment will be assessed by the Investigator at every visit 
during the Treatment Period according to definitions outlined in this protocol (Section 3). 
Response assessment by the Investigator at Day 28 and at Day 56 will support respectively, the 
primary and key secondary endpoints assessments for this trial.  
Patients will be also monitored for occurrence aGvHD flares occurring during steroid, CNI, and 
ruxolitinib taper. 
Investigator should carefully record any action taken to manage aGvHD including start of 
tapering, initiation of any new systemic therapy, re-escalation of corticosteroids and the re-
escalated steroid dose, and steroid taper failure.  
The data should be entered in the appropriate CRFs. Worsening of aGvHD, including 
occurrence of GvHD flare will be reported on appropriate specific CRF and, not as an adverse 
event (Section 8.1.1). 
Note: Additional assessments may be done as per institutional guidelines at investigator’s 
discretion. aGvHD assessments performed at unscheduled visit and leading to a change in 
patient’s management including within 7 days from last dose of study treatment, or a change in 
patient’s response should be recorded in the CRF. 


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7.2.1.2 
Chronic GVHD Assessment 
Occurrence of definitive and possible manifestations of cGvHD will be assessed monthly from 
Day 1 to Day 56 and at every visits thereafter during the treatment period, at the time of last 
dose if before Week 24, in responding patients (see Section 7.1.4), and at EOT (or Cross-Over 
EOT).  
After EOT (or Cross-Over EOT), patients will be assessed for occurrence of cGvHD at the 
Safety Follow-Up visit, and at Month 6, at Month 9, at Month 12, at Month 18 and at Month 24 
during the Long-Term Follow-Up period (see Table 7-1 and Table 7-2). Occurrence of cGvHD 
will be reported on appropriate specific CRF and, not as an adverse event (Section 8.1.1). 
Ruxolitinib taper may be initiated or continued as outlined in Section 6.1.5.1 Tapering 
guidelines. 
Investigator will assess cGvHD as per NIH consensus guidelines for cGVHD (Appendix 3):  
overall grading (mild, moderate, severe) at the time of cGvHD diagnosis which will be reported 
in corresponding CRF.  
In addition, Investigator should indicate if a systemic treatment is initiated for cGvHD in 
appropriate CRF(s). 
7.2.1.3 
Graft failure monitoring  
Patients will also be monitored for any evidence of secondary graft failure at each visit from 
Day 1 during the Treatment, at the time of last dose if before Week 24, in responding patients 
(see Section 7.1.4), at EOT (or Cross-Over EOT), Safety Follow-Up if applicable, and Long-
Term Follow-Up periods.  
In addition, considering that graft failure is defined as initial whole blood or marrow donor 
chimerism >5% declining to <5% on subsequent measurements, donor chimerism will be also 
closely monitored (Section 7.2.1.3.1) 
If a patient experiences graft failure, Investigator should indicate any action taken to manage 
the graft  including rapid taper of immunosuppression, administration of non-scheduled DLI, 
stem cell boost, and/or chemotherapy or any other action taken. 
Occurrence of graft failure will be reported on appropriate specific CRF and also as an adverse 
event (Section 8.1.1). 
7.2.1.3.1 Chimerism 
Donor chimerism after a hematopoietic stem cell transplant involves identifying the genetic 
profiles of the recipient and of the donor pre-transplant, and then evaluating the ratio of donor 
to recipient cells in the recipient's blood, or bone marrow.  
Chimerism testing using peripheral blood mononuclear cells or bone marrow (or peripheral 
blood selected CD3+ T cells) will be performed during screening (prior to study treatment start), 
at Day 28 and at Day 56 as outlined in Table 7-1. If prior chimerism was performed as part of 
standard of care within 28 days from Day 1, results may be used for purposes of baseline and 
do not need to be repeated during the Screening Period. 


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In addition, for patients who cross-over from BAT to ruxolitinib, chimerism will be also 
performed at Cross-Over Week 1 only as described in Table 7-2. 
Note: chimerism may be performed at any time during study (Treatment and Long-Term 
Follow-Up period) at the treating investigator's discretion according to local institutional 
practice as indicated.  
In general, genomic polymorphisms should be assessed via polymerase chain reaction analysis 
of short tandem repeat loci from isolated lymphocytes or myeloid cells. Fluorescence in situ 
hybridization analysis may also be used in cases with sex-mismatched transplants (Thiede 2004; 
Matsuda 2004)). 
7.2.1.4 
Hematologic disease relapse/progression assessment 
Patients will be closely monitored for any evidence of underlying hematologic disease relapse 
or progression at each visit from Day 1 during the Treatment period, including during cross-
over period if applicable, at the time of last dose if before Week 24, in responding patients (see 
Section 7.1.4), at EOT (or Cross-Over EOT), Safety Follow-Up if applicable, and the Long-
Term Follow-Up period as outlined in Table 7-1 and Table 7-2. 
Investigator will assess relapse and progression of the underlying hematologic disease 
according definitions outlined in Appendix 4, and indicate if any therapy was instituted to treat 
persistent, progressive or relapsed hematologic disease, including the withdrawal of 
immunosuppressive therapy, chemotherapy administration, and/or donor lymphocyte infusion. 
Evaluation and/or evidence of malignancy relapse/progression will be conducted according to 
local institutional practices. Available information on the malignant hematologic disease 
progression/relapse will be documented in the appropriate CRF and, not as an adverse event 
(Section 8.1.1). 
7.2.2 
Safety and tolerability assessments 
Safety will be monitored by assessing physical examination, laboratory assessments, PROs, 
Adverse event data will be collected 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 during screening, all scheduled, 
study visits up to EOT during Treatment period (Table 7-1) including at the time of last dose if 
before Week 24, in responding patients (see Section 7.1.4). 
It will include the examination of general appearance and vital signs (Section 7.2.2.2). 
Significant findings that were present prior to the signing of Study informed consent must be 
included in the Medical History page on the patient’s CRF. Significant new findings that begin 
or worsen after Study informed consent must be recorded on the Adverse Event page of the 
patient’s CRF. 


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7.2.2.2 
Vital signs 
Vital signs include blood pressure (supine or seated position), pulse measurement, and body 
temperature. Vital signs will be performed during screening, all scheduled study visits up to 
EOT during the Treatment Period (Table 7-1) including at the time of last dose if before Week 
24, in responding patients (see Section 7.1.4). 
Vital signs of screening visit performed within 48 hours prior randomization do not need to be 
repeated at Day 1. 
7.2.2.3 
Height and weight 
Height will be measured at screening for all patients, at the time of last dose if before Week 24, 
in responding patients (see Section 7.1.4) and at EOT (and Cross-Over EOT as applicable) in 
adolescents patients (<18 years old at screening) as specified in Table 7-1 and Table 7-2. 
Adolescent patients requiring prolonged ruxolitinib taper will also have their height measured 
at Week 48 or Cross-Over Week 48, as applicable. 
Body weight (in indoor clothing, but without shoes) will be measured at screening and at 
subsequent time points as specified in Table 7-1 and Table 7-2. 
If study treatment does not start at Day 1, body weight assessment may need to be repeated 
within 24 hours prior to start of study treatment. 
7.2.2.4 
Laboratory evaluations 
Table 7-3 
Local 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. RBC Morphology, Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils,  Absolute Neutrophil Count (ANC), Absolute 
Reticulocytes, Bands  
Chemistry 
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Gamma glutamyl transferase 
(GGT), Lactate Dehydrogenase (LDH), Bicarbonate, Calcium, Creatinine, Magnesium, 
Phosphorus,  Chloride, Sodium, Potassium, Total Bilirubin, Direct Bilirubin, (Indirect Bilirubin 
only if Total Bilirubin out of range), Blood Urea Nitrogen (BUN) or Urea, Creatine kinase, 
Total Cholesterol, Low Density Lipoprotein (LDL), High Density Lipoprotein (HDL), Total 
Protein, Triglycerides, Uric Acid, Amylase, Lipase, Glucose (fasting) 
Urinalysis 
Macroscopic Panel (Dipstick)* (Color, Bilirubin, Blood, Glucose, Ketones, Leukocytes 
esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen) 
Note: Any findings on dipstick will be followed up with a microscopic evaluation (Red Blood 
Cells, White Blood Cells, Casts, Crystals, Bacteria, Epithelial cells) 
Coagulation 
Prothrombin time (PT), International normalized ratio (INR), Partial thromboplastin time 
(PTT) or Activated partial thromboplastin time (APTT), D-Dimer, Fibrinogen 
Hepatitis 
markers 
Hepatitis B surface antigen, Hepatitis B surface antigen antibody, Hepatitis B core antibody 
(baseline) and HBV DNA-PCR (baseline and during treatment period)  
Hepatitis C virus antibody (baseline) and HCV RNA-PCR (baseline and during treatment 
period)  
Note : 
Prior HBV and HCV serology test results obtained as part of standard of care prior to 
alloSCT that confirm a patient is immune and not at risk for reactivation (i.e., hepatitis B or C 
surface antigen negative, surface antibody positive) within 28 days from Day 1 may be used 


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Test 
Category 
Test Name 
for purposes of eligibility and baseline serology tests do not need to be repeated during the 
Screening period 
Additional viral 
testing 
Cytomegalovirus(CMV), Epstein Barr Virus (EBV), and Human herpes Virus 6 (HHV-6) :  
viral load by PCR (screening, Day1 and during treatment period) 
Notes :  
● Patient must have baseline viral load assessments performed within 28 days prior to 
randomization. 
● Viral load collected during screening period (within 7 days from Day 1) does not  need to 
be repeated at Day1  
Pregnancy 
Test 
Serum at Screening and End of Treatment (EOT) 
Urine at all other time points 
7.2.2.4.1 Hematology 
Hematocrit, Hemoglobin, MCH, MCHC, MCV, Platelets, RBC, White blood cells with 
Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils), ANC[with 
bands] (ANC), Absolute Reticulocytes will be measured at screening, all scheduled visits 
during the treatment period up to EOT (or Cross-Over EOT as applicable), at the time of last 
dose if before Week 24, in responding patients (see Section 7.1.4) and at the Safety Follow-Up 
visit as noted in Table 7-1 and Table 7-2. 
If study treatment does not start at Day 1, CBC test may need to be repeated for safety 
assessment within 24 hours prior to start of study treatment. 
7.2.2.4.2 Clinical chemistry 
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), GGT, LDH, Calcium, Creatinine, 
Magnesium, Phosphorus,  Sodium, Potassium, Total Bilirubin, Direct Bilirubin, BUN or Urea, 
Creatine kinase, Total Cholesterol, LDL, HDL, Total Protein, Triglycerides, Uric Acid 
Amylase, Lipase, Glucose  will be measured at screening, all scheduled visits during treatment 
period up to EOT (or Cross-Over EOT as applicable), at the time of last dose if before Week 
24, in responding patients (see Section 7.1.4), and at Safety Follow-Up visit  as stated in Table 
7-1 and Table 7-2. 
Indirect Bilirubin will be measured only if Total Bilirubin is out of range. 
If study treatment does not start at Day 1, chemistry test may need to be repeated for safety 
assessment within 24 hours prior to start of study treatment. 
7.2.2.4.3 Urinalysis 
Urinalysis will be performed using macroscopic evaluation of color, bilirubin, blood, glucose, 
pH, protein, specific gravity will be measured at screening, scheduled visits during treatment 
period up to EOT (or Cross Over EOT as applicable), at the time of last dose if before Week 
24, in responding patients (see Section 7.1.4) and at Safety Follow-Up visit as outlined in Table 
7-1 and Table 7-2. 
Any significant findings on the macroscopic panel will be followed up with a microscopic 
evaluation. 


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Urinalysis assessment performed within 48 hours prior randomization does not need to be 
repeated at Day 1. 
7.2.2.4.4 Coagulation 
Prothrombin time (PT), International normalized ratio (INR), Partial thromboplastin time (PTT) 
or Activated partial thromboplastin time (APTT), D-Dimer, Fibrinogen will be measured at 
screening, scheduled visits during treatment period up to EOT (or Cross-Over EOT as 
applicable), at the time of last dose if before Week 24, in responding patients (see Section 7.1.4), 
and at Safety Follow-Up visit as outlined in Table 7-1 and Table 7-2. 
If study treatment does not start at Day 1, coagulation assessment may need to be repeated 
within 24 hours prior to start of study treatment. 
7.2.2.4.5 Pregnancy and assessments of fertility 
All female patients of child bearing potential including adult ≥ 18 years of age and patients ≥ 
12 and < 18 years of age and of childbearing potential (e.g. are menstruating), must undergo a 
serum pregnancy test at screening to confirm eligibility in the trial, at the time of last dose if 
before Week 24, in responding patients (see Section 7.1.4) and at end of treatment as noted in 
Table 7-1 and at Cross-Over Day 1 and Cross-Over EOT as applicable as noted in Table 7-2. 
These female patients will have urine pregnancy tests performed at the other scheduled visits 
(monthly) as outlined in Table 7-1 and Table 7-2. 
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 treatment period. 
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 treatment up to safety follow up period. 
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. 
7.2.2.5 
Pulmonary function test 
Pulmonary function test may be performed as clinically indicated during the treatment period 
at investigator's discretion according to local institutional practice.   
7.2.2.6 
Bleeding  
Bleeding complications are important identified and potential risks in the setting of alloSCT 
due to profound thrombocytopenia and/or coagulopathy and therefore will be monitored closely 
throughout the treatment period from Day 1 and, at every visit until EOT (Cross-Over EOT as 
applicable), at the time of last dose if before Week 24, in responding patients (see Section 7.1.4) 
and at the Safety Follow-Up visit as outlined in Table 7-1and Table 7-2.  


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Bleeding will be reported as an adverse event and the AE severity grade will be assessed 
according to CTCAE grading as defined in Section 8.1. 
During the Long Term Follow-Up period, monitoring of bleeding and management will be 
performed according to local institutional practice. 
7.2.2.7 
Infection monitoring  
Infections (including opportunistic infections) are important risks identified  with ruxolitinib 
and BAT aGvHD therapy and therefore will be monitored closely throughout the treatment 
period from Day 1 and, at every visit until EOT (Cross Over EOT as applicable), at the time of 
last dose if before Week 24, in responding patients (see Section 7.1.4) and at the Safety Follow-
Up visit as outlined in Table 7-1 and Table 7-2.  
Infections will be reported as adverse event and the AE severity grade will be assessed 
according to CTCAE grading as defined in Section 8.1.  
In addition, Investigator will detail type of infection as well as method of diagnosis and assess 
the event according to the Infection severity grading (Appendix 2). 
During the Long-Term Follow-Up period, monitoring of infections including any serology 
testing will be performed according to local institutional practice at the treating investigator's 
discretion in order to monitor any potential viral reactivation. 
7.2.2.8 
Viral reactivation monitoring 
Investigator must confirm patient is immune and not at risk for reactivation at screening based 
on medical assessment as defined in Exclusion criteria 5 and the rationale for amendment 1.  
The following viral serology testing should be performed during screening and peripheral blood 
nucleic acid (viral load) testing should be performed at Screening and Day 1 visits as baseline 
assessment:   
 Hepatitis B surface antigen, Hepatitis B AB (IgG) Hepatitis B Core Antibody (IgM) and, 
HBV viral DNA-PCR  
 Hepatitis C virus antibody and HCV RNA-PCR   
 EBV viral load 
 HHV-6 viral load  
 CMV DNA quantification  
Testing can be done once the patient has signed the Screening informed consent.  
However, serology Hepatitis test results for HBV and HVC obtained as part of standard of care 
prior to alloSCT that confirm a patient is immune and not at risk for reactivation (i.e., hepatitis 
B surface antigen negative, surface antibody positive, or HCV antibody) within 28 days from 
Day 1 may be used for purposes of eligibility and baseline serology tests do not need to be 
repeated during the Screening period. 
If viral load tests were collected during the screening period (within 7 days from Day 1), viral 
load tests do not need to be repeated at Day 1.  


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The results of the baseline viral load tests to assess CMV, EBV, HHV6, HCV and HBV 
performed during screening, may become available by the time of randomization or a later date 
as these specialized laboratory viral load tests may take up to several days. 
In the absence of international guidelines on validated nucleic acid testing methods to assess 
CMV, EBV, HHV6 viral copies/mL in the peripheral blood, no threshold is set in this study 
protocol. Definition of active infection is based on institutional guidelines and treating physician’s 
assessment. Once eligible patients are randomized, their viral load will be monitored for 
potential viral reactivation throughout the treatment period at Day 1(if applicable) and then on 
a monthly basis up to EOT (Cross-Over EOT as applicable), at the time of last dose if before 
Week 24, in responding patients (see Section 7.1.4) and at the Safety Follow-Up visit as outlined 
in Table 7-1 and Table 7-2. 
7.2.2.9 
Second primary malignancy monitoring 
Occurrence of any new malignancies other than the underlying hematologic disease, including 
non-melanoma skin cancer, will be monitored closely up to 24 months after randomization 
(from Day 1 throughout the treatment period including at the time of last dose if before Week 
24, in responding patients (see Section 7.1.4) and Long-Term Follow-Up period outlined in 
Table 7-1and Table 7-2.  
Second primary malignancy will be reported as adverse event as defined in Section 8.1.  
7.2.3 
Pharmacokinetics 
7.2.3.1 
Blood sampling schedules 
Blood sampling for PK of ruxolitinib will be performed in all patients enrolled in the study to 
explore PK characteristics of aGvHD patients (Refer to Table 7-4 as described in Table 7-1). 
Extensive PK sampling schedule  
Early enrolling patients randomized to ruxolitinib arm (or who crossed over from BAT to 
ruxolitinib) will follow an “extensive PK” sampling schedule as outlined in Table 7-4. 
Approximately the first twenty-five (25) adult patients and all adolescent patients enrolled are 
required to follow the “extensive PK” sampling schedule. Patients should be instructed to fast 
and refrain from taking corticosteroids until after PK samples are collected on “extensive PK” 
sampling days. 
The ‘Extensive PK’ sampling scheme includes a pre-dose and seven (7) post-dose samples on 
Day 1 and Day 7 thereafter, two (2) samples (1 pre-dose and 1 post-dose) per scheduled visit 
will be collected as outlined in Table 7-4. PK samples should be taken on the day of study visit 
as indicated on Table 7-4, or within the following visit windows indicated on Table 7-1 (i.e. ±3 
days up to Week 8, and ±7 days after Week 8). Every effort should be made to take the PK 
sample as scheduled. 
Sparse PK sampling schedule  
Once the requirement for “extensive PK sampling” is fulfilled for Day 1 and Day 7, all sites 
will be notified by the Sponsor. Subsequent adult patients randomized to ruxolitinib, and any 
patients crossing over from BAT to ruxolitinib after Day 28, will follow the “Sparse PK” 


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sampling schedule and will have a total of two (2) samples (1 pre-dose and 1 post-dose) per 
scheduled visit as outlined in Table 7-5. 
Table 7-4 
Ruxolitinib Pharmacokinetic blood collection log for extensive PK 
(First 25 adult patients and all adolescents) 
Treatment 
Period 
Week 
Day 
Scheduled  
timepoint 
PK collection 
number  
/ Dose reference ID  
PK 
Sample 
No 
Sample 
volume 
[mL] 
1 
1 
1 
Pre-dose 
Post-dose 0.5 hour  
(± 15 min) 
Post-dose 1 hour 
(± 15 min) 
Post-dose 1.5 hours 
(± 15 min) 
Post-dose 2 hours 
(± 15 min) 
Post-dose 4 hours 
(± 1 hr) 
Post-dose 6 hours 
(± 1 hr) 
Post-dose 9 hours 
(± 1 hr) 
1 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
-- 
-- 
 
-- 
 
-- 
 
-- 
 
-- 
 
-- 
 
-- 
1 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
2 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
1 
1 
7 
Pre-dose 
Post-dose 0.5 hour  
(± 15 min) 
Post-dose 1 hour 
(± 15 min) 
Post-dose 1.5 hours 
(± 15 min) 
Post-dose 2 hours 
(± 15 min) 
Post-dose 4 hours 
(± 1 hr) 
Post-dose 6 hours 
(± 1 hr) 
Post-dose 9 hours 
(± 1 hr) 
2 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
201a 
9 
10 
 
11 
 
12 
 
13 
 
14 
 
15 
 
16 
2 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
1 
2 
14 
Pre-dose 
Post-dose 2 hour 
(± 15 min) 
3 
3 
301a 
17 
18 
2 
2 
1 
4 
28 
Pre-dose 
Post-dose 2 hour 
(± 15 min) 
5 
5 
501a 
21 
22 
2 
2 
1 
8 
56 
Pre-dose 
Post-dose 2 hour 
(± 15 min) 
7 
7 
701a 
25 
26 
2 
2 
1 
24 
168 
Pre-dose 
Post-dose 2 hour 
(± 15 min) 
9 
9 
901a 
29 
30 
2 
2 
 
Unscheduled 
Sampleb 
--- 
--- 
1001+ 
2 


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Treatment 
Period 
Week 
Day 
Scheduled  
timepoint 
PK collection 
number  
/ Dose reference ID  
PK 
Sample 
No 
Sample 
volume 
[mL] 
a Dose reference IDs to collect previous dose information for PK trough samples. For the PK trough (pre-dose) 
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 
b Unscheduled PK sampling is required at the time of last dose in responding patients (i.e. obtaining a CR or 
PR) completing the dosing schedule for ruxolitinib at any time before Week 24, and continuing to be assessed 
until Week 24. Such patients will have a PK trough sample taken (“pre-dose” tube) if they still took a ruxolitinib 
dose approximately 12 hours prior to the visit. If the last dose of ruxolitinib is administered on the day of the 
visit, a second sample will be taken at post dose 2 hour (± 15 min). 
Table 7-5 
Ruxolitinib Pharmacokinetic blood collection log for sparse PK 
sampling (all other adult patients) 
Treatment 
Period 
Week 
Day 
Scheduled timepoint 
PK collection 
number  
/ Dose reference ID  
PK 
Sample No 
Sample 
volume 
[mL] 
1 
1 
1 
Pre-dose  
Post-dose 2 hours 
(± 15 min) 
10 
10 
-- 
-- 
101 
102 
2 
2 
1 
1 
7 
Pre-dose 
Post-dose 2 hours 
(± 15 min) 
20 
20 
2001a 
103 
104 
2 
2 
1 
2 
14 
Pre-dose 
Post-dose 2 hour 
(± 15 min) 
30 
30 
3001a 
105 
106 
2 
2 
1 
4 
28 
Pre-dose 
Post-dose 2 hour 
(± 15 min) 
50 
50 
5001a 
109 
110 
2 
2 
1 
8 
56 
Pre-dose 
Post-dose 2 hour 
(± 15 min) 
70 
70 
7001a 
113 
114 
2 
2 
1 
24 
168 
Pre-dose 
Post-dose 2 hour 
(± 15 min) 
90 
90 
9001a 
117 
118 
2 
2 
 
Unscheduled 
Sampleb 
--- 
--- 
1001+ 
2 
a Dose reference IDs to collect previous dose information for PK trough samples. For the PK trough (pre-dose) 
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 
b Unscheduled PK sampling is required at the time of last dose in responding patients (i.e. obtaining a CR or 
PR) completing the dosing schedule for ruxolitinib at any time before Week 24 (or Cross-Over Week 24, as 
applicable), and continuing to be assessed until Week 24 (or Cross-Over Week 24, as applicable). Such 
patients will have a PK trough sample taken (“pre-dose” tube) if they still took a ruxolitinib dose approximately 
12 hours prior to the visit. If the last dose of ruxolitinib is administered on the day of the visit, a second sample 
will be taken at post dose 2 hour (± 15 min). 
7.2.3.2 
Pharmacokinetic blood collection and handling 
Whole blood (2 mL) per sampling time as outlined in Table 7-4 and Table 7-5 will be obtained 
by either direct venipuncture or via an indwelling cannula from a peripheral vein into a tube 
containing di-potassium 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 




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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 Screening ICF only (and not Study 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 possibly related to  study procedures (e.g. an invasive procedure such as 
biopsy). Once the 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 or at least 30 days 
after the End of Treatment visit, whichever occurs last. 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. 
AEs will not be collected beyond 30 days after the End of Treatment visit, with the exception 
of any occurrence of second primary malignancy including non-melanoma skin cancer which 
will be captured under the AE form throughout the study, including the Long Term Follow-up 
period, as outlined in Section 8.1.3.  
Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. 
Grade 1 to 5 will be used to characterize the severity of the Adverse Event. If CTCAE grading 
does not exist for an adverse event, the severity of mild, moderate, severe, life-threatening and 
death due to the AE, corresponding respectively to Grades 1 - 5, will be used. Information about 
any deaths (related to an Adverse Event or not) will also be collected through a Death form. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine: 
1. The severity grade (CTCAE Grade 1-5) 


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2. Its duration (Start and end dates)  
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
4. Action taken with respect to study 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. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1 
and which seriousness criteria have been met. 
7. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown)  
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4.   
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. 
The following events, which are components of study endpoints: worsening of study indication 
(aGvHD) including occurrence of aGvHD flare as defined in Section 3,  occurrence of chronic 
GvHD, or progression/relapse of underlying hematologic disease (including fatal outcomes) as 
defined in Appendix 4, should not be reported as a serious adverse event and will be reported 
on specific CRFs other than AE CRF. 
Adverse events separate from the events listed above (example, deep vein thrombosis at the 
time of progression or hemoptysis concurrent with finding of disease progression) will be 
reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the study drug. 
8.1.2 
Laboratory test abnormalities 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an Adverse Event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event. 


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Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such. 
8.1.3 
Adverse events of special interest  
Adverse Events of Special Interest are defined on the basis of an ongoing review of the safety 
data. AESIs are discussed in detail in the Risks and Benefits (Section 2.6) and the most recent 
Investigator Brochure.  
AESI will include but may be not limited to: 
 Cytopenias 
 Infections 
 Bleeding 
 Hypertension 
 Second primary Malignancies including non-melanoma skin cancer   .  
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 study indication  
 Occurrence of chronic GvHD 
 Progression/relapse of underlying hematologic disease (including fatal outcomes), as 
defined in Appendix 4 
 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 
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8.2.2 
Reporting 
For patients who sign the Screening ICF, SAE collection will start upon signing the 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 
Study ICF is not signed (screen failure), SAE collection ends 30 days after the last study related 
procedure. 
For patients who sign the Study ICF, SAE collection starts at time of 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 Study informed consent and until at least 30 days after the patient has 
stopped study treatment or at least 30 days after the End of Treatment visit, whichever occurs 
last, must be reported to Novartis within 24 hours of learning of its occurrence. Any additional 
information for the SAE including complications, progression of the initial SAE, and recurrent 
episodes must be reported as follow-up to the original episode within 24 hours of the 
investigator receiving the follow-up information. An SAE occurring at a different time interval 
or otherwise considered completely unrelated to a previously reported one should be reported 
separately as a new event. 
Any SAEs experienced after the 30-day safety evaluation follow-up, or later than 30 days after 
the End of Treatment visit, whichever occurs last, should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. 
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 submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site. 
Follow-up information is submitted in the same way as the original SAE 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, and whether the patient 
continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure (new occurrence) and 
is thought to be related to the Novartis study treatment, a Chief Medical Office and Patient 
Safety (CMO & PS) 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. 


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8.3 
Emergency unblinding of treatment assignment 
Not Applicable 
8.4 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. Occurrence of Pregnancy 
should be monitored for 90 days after stopping treatment (i.e. End of treatment or Cross-Over 
End of treatment whichever comes last). 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. The follow-up to three months after delivery is mandatory for all reported 
pregnancy cases and in cases of live birth, the follow-up on any development issues or 
abnormality that would not be seen at birth. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Chief Medical Office and Patient Safety (CMO & PS). 
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. 
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment including best available therapy (BAT) in this study. Consent to report information 
regarding these pregnancy outcomes should be obtained from the mother. 
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 review safety data as outlined in a 
separate DMC charter that is established between the sponsor and the DMC.  
Specific details regarding composition, responsibilities, data monitoring and meeting 
frequency, and documentation of DMC reports, minutes, and conclusion will also be described 
in the DMC charter. There will be a meeting with the DMC describing their roles and 
responsibilities and discussing potential data format and process issues prior to the finalization 
of DMC charter and the dedicated analysis plan. 


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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. 
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 patients 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. 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 


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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. 
 PK samples and/or data will be processed centrally and the results will be sent 
electronically to Novartis (or a designated CRO). 
Randomization codes and data about 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, who will also manage the database. The data will be sent 
electronically to Novartis personnel (or designated CRO). 
The occurrence of any protocol violations will be determined. After these actions have been 
completed and the data has been verified to be complete and accurate, the database will be 
declared locked and made available for data analysis. Authorization is required prior to making 
any database changes to locked data, by joint written agreement between the Global Head of 
Biostatistics and Data Management and the Global Head of Clinical Development. 
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site. 
10 
Statistical methods and data analysis 
The primary efficacy and safety analysis will be conducted when all patients have completed 
the Day 56 visit or discontinued earlier. Prior to this analysis time, no summary reports by actual 


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treatment groups will be produced. Further analyses on secondary endpoints will be performed 
when all patients have completed approximately 6 months treatment or discontinued earlier. 
The final study report will be written once all patients have completed the study. An analysis 
cut-off date will be defined corresponding to these time points and all data captured in the study 
up to that cut-off will be reported. 
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 and strata, 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 treatment. 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 if the randomized treatment was never received. 
10.1.3 
Per-Protocol set 
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with the requirements of the clinical study protocol. 
The protocol deviations leading to exclusion from the PPS include: 
 Not steroid refractory aGvHD. 
 More than one prior systemic therapy for the treatment of aGvHD other than corticosteroids 
+/- CNI (prophylaxis or treatment). 
 Missing or incorrect aGvHD grade at randomization. 
 Taking any prohibited medication as specified in this protocol after start of study treatment 
and before end of study treatment. 
 Study treatment received is different from treatment arm assigned by randomization. 
10.1.4 
Dose-determining analysis set 
Not applicable. 
10.1.5 
Pharmacokinetic analysis set 
The Pharmacokinetic analysis set (PAS) includes all patients who provide at least one evaluable 
PK concentration. For a concentration to be evaluable, patients are required to: 
 
Take a dose of ruxolitinib prior to sampling. 
For pre-dose samples, do not vomit within 2 hours after the dosing of ruxolitinib prior to 
sampling; for post-dose samples, do not vomit within 2 hours after the dosing of ruxolitinib. 
The PAS will be used for NCA analysis for patients where extensive PK sampling is obtained.  


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This analysis set will also be used for any exposure-response analysis and/or exploratory 
exposure-biomarker analysis. 
10.1.6 
Other analysis sets 
The Crossover Analysis Set (CAS) comprises all patients randomized to and received BAT who 
then crossed over and received at least one dose of ruxolitinib. This analysis set will be used for 
all analyses for crossover patients. 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by treatment group. 
Baseline for safety endpoints (except adverse events), 
 patient reported 
outcomes is defined as the last assessment prior to or on the treatment start date.  
For evaluations after cross-over, the baseline is defined as the last assessment prior to or on the 
start date of crossover treatment. 
Baseline for efficacy endpoints is defined as the last assessment or procedure conducted prior 
to or on the date of randomization + 3 days, but no later than the treatment start date. 
10.3 
Treatments (study treatment, concomitant therapies, 
compliance) 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented.  
The duration of exposure in days to ruxolitinib and BAT will be summarized by means of 
descriptive statistics. The dose intensity (computed as the ratio of actual cumulative dose 
received and actual duration of exposure) for the ruxolitinib arm will be summarized.  
Patients randomized to Investigator’s choice of BAT will receive various different categories 
of therapy. Since the units for administration will differ depending on the treatment 
administered for BAT, dosage summaries will not be calculated for the BAT arm. 
The number of patients with dose adjustments and the reasons will be summarized for 
ruxolitinib arm and all dosing data will be listed. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group. 


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10.4 
Primary objective 
The primary objective is to compare the efficacy of ruxolitinib to BAT as assessed by overall 
response rate at Day 28. 
10.4.1 
Variable 
The primary variable is the overall response rate (ORR) at Day 28, defined as the proportion of 
patients with complete response (CR) or partial response (PR), according to standard criteria 
(Harris 2016). Note that response is relative to the assessment of aGvHD at randomization. 
 Complete response is defined as a score of 0 for the aGvHD grading in all evaluable 
organs that indicates complete resolution of all signs and symptoms of aGvHD in all 
evaluable organs without administration of additional systemic therapies for any earlier 
progression, mixed response or non-response of aGvHD.   
 Partial response is defined as improvement of 1 stage in 1 or more organs involved with 
aGvHD signs or symptoms without progression in other organs or sites without 
administration of additional systemic therapies for an earlier progression, mixed response 
or non-response of aGvHD.   
 Lack of response is defined as no response, mixed response, or progression. 
 No response is defined as absence of improvement in any organ involved by aGvHD, 
without worsening in any involved organ.   
 Mixed response is defined as improvement of at least 1 stage in the severity of 
aGvHD in at least one organ accompanied by progression in another organ or 
development of signs or symptoms of aGvHD in a new organ. 
 Progression is defined as worsening in 1 or more organs by 1 or more stages without 
improvement in any involved organ 
A flare in aGvHD is defined as any increase in signs or symptoms of aGvHD after an initial 
response (CR or PR). 
Only flares in GvHD that require new additional systemic therapy, will be considered aGvHD 
flare failure. Patients with missing baseline or Day 28 aGvHD response assessment will be 
considered as treatment non-responders. 
Acute GvHD will be assessed according to standard criteria (Harris 2016), as described in 
Appendix 1. Grade will be calculated based on the staging of the organs and recorded on the 
eCRF by the Investigator. The Investigator reported grade will be used for randomization and 
all analyses. Grade and response will be calculated by the sponsor for the purposes of data 
review and sensitivity analysis.  
10.4.2 
Statistical hypothesis, model, and method of analysis 
The following statistical hypotheses will be tested to address the primary efficacy objective:  
H0: ORRrux ≤ ORRBAT  vs.   H1: ORRrux > ORRBAT 
where ORRrux and ORRBAT are the overall response rates at Day 28 in the ruxolitinib and BAT 
groups, respectively. The Cochrane-Mantel-Haenszel chi-square test, stratified by the 


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randomization stratification factor (i.e., aGvHD Grade II vs III vs. IV), will be used to compare 
ORR between the two treatment groups, at the one-sided 2.5% level of significance.  
The primary efficacy variable, ORR at Day 28, will be analyzed at the time when all patients 
have completed their Day 56 visit or discontinued earlier. The primary analysis will be 
performed on FAS according to ITT principle. ORR and its 95% confidence interval will be 
presented by treatment group. P-value, odds ratio and 95% Wald confidence limits calculated 
from stratified Cochran-Mantel-Haenszel test will be also presented 
10.4.3 
Handling of missing values/censoring/discontinuations 
Patients with missing assessments that prevent the evaluation of the primary endpoint will be 
considered non-responders on that treatment arm. This includes aGvHD response assessments 
at baseline and Days 28, 56.  Patients who discontinue the randomized treatment prior to the 
completion of the Day 28 visit will be considered non-responders on that treatment arm.  
The analysis windows will be further defined in the analysis plan. 
Baseline assessment is the last aGvHD assessment prior to or on the date of randomization (Day 
1). A tolerance of up to 3 days from randomization will be considered in the analysis, but the 
baseline assessment will not be later than the date of treatment start. 
10.4.4 
Supportive and Sensitivity analyses 
As supportive analyses, the primary endpoint will also be evaluated with the same analysis 
conventions as for the primary efficacy analysis using all patients in PPS. 
If the primary analysis is statistically significant, subgroup analyses to assess the homogeneity 
of the treatment effect across demographic and baseline disease characteristics will be 
performed on the FAS. The subgroups include but may not be limited to: 
 Age group (12- <18 vs. 18-65 vs. >65) 
 Gender 
 Race 
 aGvHD grade (Grade II vs. III vs. IV)  
 Source of grafts 
 Criteria for SR-aGvHD (progression after at least 3 days, failure to achieve a response 
after 7 days, flare failure during taper) 
 Prior aGvHD therapy (steroid  +/- CNI vs. steroid +/- CNI +/- BAT)    
10.5 
Secondary objectives 
The secondary objectives in this study are durable overall response rate at Day 56, duration of 
response, overall survival (OS), non-relapse mortality (NRM), incidence of malignancy relapse 
and onset of chronic GvHD, pharmacokinetics (PK), patient reported outcomes (PROs), and 
safety.  
Durable ORR at Day 56 is identified as the key secondary endpoint. A hierarchical testing 
strategy will be used to control the overall type I error rate, where durable ORR at Day 56 will 


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only be formally tested and interpreted if the primary analysis of ORR at Day 28 is statistically 
significant. 
The other secondary estimates will be estimated for both treatment arms, ruxolitinib and BAT 
but no comparison or testing between arms will be performed. 
10.5.1 
Key secondary objective(s) 
The key secondary objective of the study is to compare the proportions of all patients in each 
arm who achieve a complete response (CR) or partial response (PR) at Day 28 and maintain a 
CR or PR at Day 56. A patient will not be considered a durable responder at Day 56 if any of 
the following events occurs prior to or at Day 56: 
 No CR or PR at Day 28 or at Day 56.  
 aGvHD progression or additional systemic therapy for aGvHD  
The following statistical hypotheses will be tested to address the key secondary efficacy 
objective:  
H0: DORRrux ≤ DORRBAT  vs.   H1: DORRrux > DORRBAT 
where DORRrux and DORRBAT are the durable overall response rates at Day 56 in the ruxolitinib 
and BAT groups, respectively. The Cochrane-Mantel-Haenszel chi-square test, stratified by the 
randomization stratification factor (i.e., aGvHD Grade II vs III vs. IV), will be used to compare 
the durable ORR between the two treatment groups, at the one-sided 2.5% level of significance, 
if the primary endpoint is significant.  
The key secondary efficacy variable, durable ORR at Day 56, will be analyzed at the time when 
all patients have completed their Day 56 visit or discontinued earlier. The analysis will be based 
on FAS according to ITT principle. Durable ORR and its 95% confidence interval will be 
presented by treatment group. P-value, odds ratio and 95% Wald confidence limits calculated 
from stratified Cochran-Mantel-Haenszel test will be also presented. 
As supportive analyses, the key secondary endpoint will also be evaluated with the same 
analysis conventions using the PPS.   
10.5.2 
Other secondary efficacy objectives 
All other secondary efficacy endpoint analyses are non-comparative in nature and will be 
analyzed using the full analysis set (FAS).  
 Overall Response Rate at Day 14, will be derived in the same way as the primary variable 
ORR at Day 28 and presented per treatment arm. 
 Duration of response (DOR) 
Duration of response will be calculated for patients whose overall response at Day 28 is 
complete response (CR) or partial response (PR) according to updated standard criteria (Harris 
2016). The start date is the date of first documented response of CR or PR (i.e., the start date of 
response), and the end date is defined as the date of progression or the date of addition of 
systemic therapies for aGvHD, since this constitutes a non-response. 


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Death without prior observation of aGvHD progression and onset of chronic GvHD are 
considered to be competing risks. 
Duration of response will be censored at the last response assessment prior to or at the analysis 
cut-off date, if no events/competing risk occurred before or at of cut-off date. 
DOR will be listed and summarized by treatment group for all patients in the FAS with overall 
response of CR or PR at Day 28.   
 Overall survival (OS)  
Overall survival 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 latest date the 
patient was known to be alive (on or before the cut-off date).  
OS will be analyzed according to the randomized treatment group and strata assigned at 
randomization (aGvHD grade: Grade II vs. III vs. IV). The OS distribution will be estimated 
using the Kaplan-Meier method, and the Kaplan-Meier curves, medians, 1, 2, 6, 12, 18 and 24 
month survival estimates and 95% confidence intervals will be presented for each treatment 
group. The hazard ratio for OS will be calculated, along with its 95% confidence interval, using 
a stratified Cox model.  
 Event Free Survival (EFS) 
Event-free survival is defined as the time from the date of randomization to the date of 
hematologic disease relapse/progression, graft failure or death due to any cause. If a patient is 
not known to have any event, then EFS will be censored at the latest date the patient was known 
to be alive (on or before the cut-off date). The EFS distribution will be estimated using the 
Kaplan-Meier method, and the Kaplan-Meier curves, medians, 1, 2, 6, 12, 18 and 24 month 
survival estimates and 95% confidence intervals will be presented for each treatment group.   
 Failure Free Survival (FFS) 
Failure-free survival is defined as the time from the date of randomization to date of 
hematologic disease relapse/progression, non-relapse mortality or addition of new systemic 
aGvHD treatment.  
Cumulative incidence of FFS at 1, 2, 6, 12, 18 and 24 months will be estimated, considering 
each event as a competing risk for the other two.  Onset of chronic GvHD is considered as a 
competing risk for all three types of failure. 
 Non-relapse mortality (NRM)  
Non-relapse mortality is defined as the time from date of randomization to date of death not 
preceded by hematologic disease relapse/progression. Hematologic disease relapse/progression 
is considered a competing risk for NRM with the date of hematologic disease 
relapse/progression being the earlier of documented hematologic disease relapse/progression or 
institution of therapy to treat potential hematologic disease relapse/progression. If a patient is 
not known to have died or to have relapsed/progressed, then NRM will be censored at the latest 
date the patient was known to be alive (on or before the cut-off date).  
NRM will be analyzed in the FAS population according to the randomized treatment group 
and strata assigned at randomization (aGvHD grade: Grade II vs. III vs. IV).  The cumulative 


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incidence curve for NRM as well as estimates at 1, 2, 6, 12, 18 and 24 months with 95% 
confidence intervals will be presented for each treatment group. 
 Incidence of Malignancy Relapse/Progression (MR) 
Malignancy relapse/progression is defined as the time from date of randomization to 
hematologic malignancy relapse/progression. Deaths not preceded by hematologic malignancy 
relapse/progression are competing risks. If a patient is not known to have event or competing 
risks, then MR will be censored at the latest date the patient was known to be alive (on or before 
the cut-off date). The cumulative incidence of MR will be estimated for patients with underlying 
hematologic malignant disease, accounting for NRM as the competing risk. 
In addition, the proportion of patients who had hematologic malignancy relapse/progression 
and its 95% confidence interval will be presented by treatment group for patients with 
underlying hematologic malignant disease. Odds ratio and 95% Wald confidence limits 
calculated from stratified Cochran-Mantel-Haenszel test will be also presented. 
 Best Overall Response (BOR) 
Best overall response rate, is defined as the proportion of patients with complete response (CR) 
or partial response (PR) at any time point (up to and including Day 28 and before the start of 
additional systemic therapy for aGvHD). 
 Cumulative steroid dosing until Day 56 
Overall and weekly cumulative steroid dose for each patient up to Day 56 or discontinuation of 
randomized treatment will be tabulated.  In addition the relative dose intensity (RDI), by week, 
will be calculated relative to the starting dose of corticosteroids and categorized as (1) Complete 
reduction where patients are tapered off corticosteroids by D56, (2) ≤ 50% RDI and (3) > 50% 
RDI. The proportion of patients in each category and corresponding 95% confidence intervals 
will be presented by treatment group.  
 Proportion of patients who developed cGvHD 
The cumulative incidence of cGvHD will be estimated, accounting for deaths without prior 
onset of cGvHD and hematologic disease relapse/progression as the competing risks. If a patient 
is not known to have event or competing risks, then the incidence of cGvHD will be censored 
at the latest date the patient was known to be alive (on or before the cut-off date). 
10.5.3 
Safety objectives 
10.5.3.1 Analysis set and grouping for the analyses 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group. For safety evaluations (except for AE), the last available assessment on or 
before the date of start of study treatment is taken as the “baseline” assessment. 
10.5.3.2 Adverse events (AEs) 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period (randomized or crossover), the treatment-emergent AEs.  


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For reporting of AEs, the overall observation period will be divided into mutually exclusive 
categories, including the on-treatment period as defined below. 
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of randomized study medication 
2. on-randomized treatment period: from day of first dose of randomized study medication to 
30 days after last dose of randomized study medication or end of randomized treatment 
per End of Randomized Treatment Disposition eCRF, whichever is later; for those 
patients who cross-over from BAT to ruxolitinib, the period is from day of first dose of 
randomized study medication to earlier of (i) 30 days after last dose of randomized study 
medication, or end of randomized treatment per End of Randomized Treatment 
Disposition eCRF, whichever is later (ii) the day before first dose of crossover treatment  
3. on-crossover treatment period: from day of first dose of crossover study medication to 30 
days after last dose of crossover study medication or end of crossover treatment per End 
of Crossover Treatment Disposition eCRF, whichever is later. 
4. post-treatment period: starting at Day 31 after last dose of study medication or the day 
after end of study treatment per end of treatment disposition eCRFs, whichever is later 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment.  
Serious adverse events, non-serious adverse events and adverse events of special interest 
(AESI) such as worsening cytopenias, infections, etc. during the on-treatment period will be 
tabulated.  
All deaths (on-treatment and post-treatment) will be summarized.  
All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged.  
The proportion of patients developing Grade 2 to 3 infections using infection severity 
(Appendix 2) during the aGvHD treatment period Day 1 to Day 56 will be summarized in 
addition to standard CTC grading. In addition, proportion of patients developing second 
primary malignancies will be summarized based on the entire study period.  
10.5.3.3 Laboratory abnormalities 
Grading of laboratory 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. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher.  
For laboratory tests where grades are not defined by CTCAE v4.03, results will be categorized 
as low/normal/high based on laboratory normal ranges. 
The following summaries will be generated separately for hematology, and biochemistry tests: 












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10.8 
Sample size calculation 
The study with a total of 308 patients and 1:1 randomization (ruxolitinib vs. BAT) stratified on 
aGvHD grade (Grade II vs. Grade III vs. Grade IV) has 90% power to test for the primary 
endpoint (ORR at Day 28) and approximately 90% power to test for the key secondary endpoint 
(durable ORR at Day 56). The family wise α-level will be controlled at 0.025 overall for the 
two comparisons. Specifically, this study will claim to have achieved the efficacy objective 
when the primary endpoint ORR at Day 28 shows a significant treatment effect at one-sided α 
= 0.025. Conditional on significance of the primary endpoint, the key secondary endpoint 
durable ORR at Day 56 will be tested at one-sided α = 0.025.  
The sample size calculation is based on the primary variable ORR at Day 28. The hypotheses 
to be tested and details of the testing strategy are described in Section 10.4.2 and Section 10.8.  
Based on Martin P. et al BBMT 2013, the ORR at Day 28 in the BAT arm is expected to be 
58%. The stratum specific rates (Grade II 69%, Grade III 59%, Grade IV 50%) are obtained 
assuming that the ratio of aGvHD Grade II: III: IV is 0.2:0.4:0.4. It is expected that treatment 
with ruxolitinib will result in an 18% increase in the ORR, i.e., an expected odds ratio of 2.25 
(which corresponds to an increase in ORR to 75%). Power for the CMH test, stratifying on 
aGvHD grade, was calculated using software package East V6. In order to ensure 90% power 
a total sample size of 308 patients are needed.  
With a sample size of 154 patients in each treatment arm, an observed odds ratio greater than 
or equal to 1.63 would achieve statistical significance for the primary endpoint. Assuming that 
the observed response rates in Grades II/III/IV in BAT arm are 69%/59%/50% (overall 57%), 
observed response rates ≥ 78%/70%/62% (overall 68%) in the ruxolitinib arm would achieve 
statistical significance. 
10.9 
Power for analysis of key secondary variables 
Durable ORR at Day 56, as the key secondary variable, will be formally statistically tested, 
provided that the primary endpoint ORR at Day 28 is statistically significant. The hypotheses 
to be tested and details of the testing strategy are provided in Section 10.5.1. Based on (Van 
Groningen 2016), the durable ORR at Day 56 in the BAT arm is expected to be approximately 
35%. The stratum specific rates (Grade II 45%, Grade III 36%, Grade IV 30%) are obtained 
assuming that the ratio of aGvHD Grade II: III: IV is 0.2:0.4:0.4. It is expected that treatment 
with ruxolitinib will result in a 20% increase in the ORR, i.e., an expected odds ratio of 2.25 
(which corresponds to an increase in durable ORR to 55%). With these assumptions and sample 
size of 308 patients, the power for the key secondary endpoint is at least 90%. 
With sample size 154 patients in each treatment arm, an observed odds ratio greater than or 
equal to 1.59 for durable ORR at Day 56 would achieve statistical significance. Assuming that 
the observed durable response rates in Grades II/III/IV in BAT arm are 45%/36%/30% (overall 
35%), observed durable response rates ≥ 57%/47%/41% (overall 47%) in the ruxolitinib arm 
would achieve statistical significance. 


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


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11.5 
Publication of study protocol and results 
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome.  Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. www.clinicaltrials.gov before study 
start. . In addition, results of interventional clinical trials in adult patients are posted  on 
www.novartisclinicaltrials.com,  a publicly accessible database of clinical study results within 
1 year of  study completion (i.e., LPLV), those for interventional clinical trials involving 
pediatric patients within 6 months of study completion.  
Novartis follows the ICMJE authorship guidelines (www.icmje.org) and other specific 
guidelines of the journal or congress to which the publication will be submitted  
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency.  Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations. 
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable. 
According to Novartis policy, authors of publication will not receive remuneration for their 
writing of a publication, either directly from Novartis or through the professional medical 
writing agency.  Author(s) may be requested to present poster or oral presentation at scientific 
congress; however, there will be no honorarium provided for such presentations. 
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to www.novartis.com. 
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 patients. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patients’ 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 


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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. 
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. 


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12.1 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC at the study site should be informed 
according to local regulations (e.g. UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days. 


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13 
References (available upon request) 
Bercovitz RS, O'Brien SH. (2012) Measuring bleeding as an outcome in clinical trials of 
prophylactic platelet transfusions. Hematology Am Soc Hematol Educ Program; 2012: 157-
60. 
Betts BC1, Abdel-Wahab O, Curran SA, et al. (2011) Blood; 118(19):5330-9. 
Brooks, R (1996). EuroQol: The current state of play. Health policy; 1(37): 53-72 
Cahn JY, Klein JP, Lee SJ,et al. (2005) Dana Farber Cancer Institute; International Bone 
Marrow Transplant Registry. Prospective evaluation of 2 acute graft-versus-host (GVHD) 
grading systems: a joint Société Française de Greffe de Moëlle et Thérapie Cellulaire (SFGM-
TC), Dana Farber Cancer Institute (DFCI), and International Bone Marrow Transplant 
Registry (IBMTR) prospective study.  Blood; 106(4): 1495-500. 
Choi J, Cooper ML, Alahmari B, et al (2014) Pharmacologic blockade of JAK1/JAK2 reduces 
GvHD and preserves the graft-versus-leukemia effect.  PLoS; 9(10): 1-6. 
Copelan E.A. (2006) Hematopoietic stem-cell transplantation. N Engl J Med; 354(17): 1813-
26. 
Cordonnier C, Maury S, Ribaud P, et al (2006) A grading system based on severity of 
infection to predict mortality in allogeneic stem cell transplant recipients.  Transplantation; 
82(1): 86-92. 
Ferrara JL, Levine JE, Reddy P, et al (2009) Graft-versus-host disease. Lancet 373(9674): 
1550-61. 
Glucksberg H, Storb R, Fefer A, et al (1974) Clinical manifestations of graft-versus-host 
disease in human recipients of marrow from HL-A-matched sibling donors.  Transplantation 
18(4): 295-304. 
Harris AC, Young R, Devine S, et al. (2016) International, Multicenter Standardization of 
Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai 
Acute GVHD International Consortium. Biol Blood Marrow Transplant; 22(1): 4-10. 
Heine A, Held SA, Daecke SN, et al (2013) The JAK-inhibitor ruxolitinib impairs dendritic 
cell function in vitro and in vivo. Blood; 122(7):1192-202 
Herdman M, Gudex C, Lloyd A et al (2011).Development and preliminary testing of the new 
five-level version of EQ-5D(EQ-5D-5L).Qual Life Res; 20:1727-1736 
Holtan SG, DeFor TE, Lazaryan A, et al (2015 Composite end point of graft-versus-host 
disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation.  Blood 
125(8): 1333-8. 
Jagasia MH, Greinix HT, Arora M, et al (2015) National Institutes of Health Consensus 
Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. 
The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant; 
21(3): 389-401. 
Jamil MO, Mineishi S (2015) State-of-the-art acute and chronic GVHD treatment.  Int J 
Hematol.; 101(5): 452-66. 




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Pavletic SZ, Fowler DH. (2012) Are we making progress in GVHD prophylaxis and 
treatment?  Hematology Am Soc Hematol Educ Program.  2012: 251-64. 
Przepiorka D, Weisdorf D, Martin P, et al (1995) 1994 Consensus Conference on Acute 
GVHD Grading.  Bone Marrow Transplant; 15(6): 825-8. 
Rager A1, Frey N, Goldstein SC, et al (2011) Inflammatory cytokine inhibition with 
combination daclizumab and infliximab for steroid-refractory acute GVHD. Bone Marrow 
Transplant; 46(3): 430-5. 
Ross WA, Alousi AM. (2012) Making the diagnosis of gastrointestinal GVHD: is evaluation 
of the ileum necessary? Bone Marrow Transplant; 47(3): 321-2. 
Ruutu T, Gratwohl A, de Witte T, et al (2014) Prophylaxis and treatment of GVHD: EBMT-
ELN working group recommendations for a standardized practice.  Bone Marrow Transplant; 
49(2): 168-73. 
Sorror ML, Maris MB, Storb R, et al: Hematopoietic cell transplantation (HCT)-specific 
comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 106(8): 
2912-9, 2015 
Spoerl S, Mathew NR, Bscheider M, et al (2014) Activity of therapeutic JAK 1/2 blockade in 
graft-versus-host disease.  Blood; 123(24): 3832-42. 
Thiede C1, Bornhäuser M, Ehninger G. (2004) Strategies and clinical implications of 
chimerism diagnostics after allogeneic hematopoietic stem cell transplantation. Acta 
Haematol; 112(1-2):16-23 
Tomblyn M1, Chiller T, Einsele H, et al (2009) Center for International Blood and Marrow 
Research; National Marrow Donor program; European Blood and MarrowTransplant Group; 
American Society of Blood and Marrow Transplantation; Canadian Blood and Marrow 
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Epidemiology of America; Association of Medical Microbiology and Infectious Disease 
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complications among hematopoietic cell transplantation recipients: a global perspective.  Biol 
Blood Marrow Transplant; 15(10): 1143-238. 
van Groningen, LF, Liefferink AM, de Haan AF,et al (2016) Combination Therapy with 
Inolimomab and Etanercept for Severe Steroid-Refractory Acute Graft-versus-Host Disease 
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Verstovsek S, Kantarjian H, Mesa RA, et al (2010) Safety and efficacy of INCB018424, a 
JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med; 363(12): 1117-27. 
Young JA. (2008) Infectious complications of acute and chronic GVHD. Best Pract Res Clin 
Haematol.; 21(2): 343-56. 
Zeiser R, Burchert A, Lengerke C, et al (2015) Ruxolitinib in corticosteroid-refractory graft-
versus-host disease after allogeneic stem cell transplantation: a multicenter survey.  
Leukemia; 29(10): 2062-8. 


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14 
Appendices 
14.1 
Appendix 1: Acute GvHD Staging Criteria (Harris 2016) 
Organ staging will be performed according to updated NIH criteria as described by Harris et al 
in Table 14-1. 
Table 14-1 
Acute GvHD Staging Criteria (Harris 2016) 
Stage  
Skin 
(Active Erythema Only) 
Liver 
(Bilirubin) 
Upper GI 
Lower GI 
(stool output/day) 
Stage 0 
No active (erythematous)  
GVHD rash 
< 2mg/dL 
No or 
intermittent 
nausea, 
vomiting, or 
anorexia 
Adult: <500mL/day or < 3 
episodes/day 
Child: <10mL/kg/day or < 4 
episodes/day 
Stage 1 
Maculopapular rash  
< 25% BSA 
2 – 3 mg/dL 
Persistent 
nausea, 
vomiting, or 
anorexia 
Adult: 500-999 mL/day or 3-4 
episodes/day 
Child: 10-19.9 mL/kg/day or 4-6 
episodes/day 
Stage 2 
Maculopapular rash < 25-
50% BSA 
3.1 – 6 
mg/dL 
 
Adult: 1000-1500mL/day or 5-7 
episodes/day 
Child: 20-30mL/kg/day or 7-10 
episodes/day 
Stage 3 
Maculopapular rash > 50% 
BSA 
6.1 – 15 
mg/dL 
 
Adult: >1500mL/day or > 7 
episodes/day 
Child: >30mL/kg/day or > 10 
episodes/day 
Stage 4 
Generalized erythrodema 
(>50% BSA) plus bullous 
formation and 
desquamation > 5% BSA 
> 15 mg/dL 
 
Severe abdominal pain with or 
without ileus or grossly bloody 
stool (regardless of stool 
volume) 
Overall clinical grade (based on most severe target organ involvement): 
Grade 0: No stage 1-4 of any organ. 
Grade I: Stage 1-2 skin without liver, upper GI or lower GI involvement. 
Grade II: Stage 3 rash and/or stage 1 liver and/or stage 1 upper GI and/or stage 1 lower GI.  
Grade III: Stage 2-3 liver and/or stage 2-3 lower GI with stage 0-3 skin and/or stage 0-1 upper GI. 
Grade IV: Stage 4 skin, liver or lower GI involvement, with stage 0-1 upper GI. 


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14.2 
Appendix 2: Infection Severity Grading 
Table 14-2 
Severity grading table and recurrence interval definitions 
Type of Infection/ 
Severity Grade 
Grade 1 
Grade 2 
Grade 3 
Bacterial infections 
Bacterial focus NOS 
requiring no more than 
14 days of therapy for 
treatment (e.g urinary 
tract infection) 
Bacteremia (except 
CoNS) without severe 
sepsis *** 
Bacteremia with deep 
organ involvement (e.g. 
with new or worsening 
pulmonary infiltrates; 
endocarditis) 
Coag Neg Staph (S. epi), 
Corynebacterium, or 
Proprioniobacterium 
bacteremia 
Bacterial focus with 
persistent signs, 
symptoms or persistent 
positive cultures requiring 
greater than 14 days of 
therapy 
Severe sepsis with 
bacteremia. 
Cellulitis responding to 
initial therapy within 14 
days 
Cellulitis requiring a 
change  in therapy d/t 
progression  
Localized or diffuse 
infections requiring 
incision with or without 
drain placement 
Fasciitis requiring 
debridement 
 
Any pneumonia 
documented or presumed 
to be bacterial 
Pneumonia requiring 
intubation 
 
 
Brain abscess or 
meningitis without 
bacteremia 
C. Difficile toxin positive 
stool with diarrhea < 1L 
without abdominal pain 
(child < 20 mL/kg) 
C. Difficile toxin positive 
stool with diarrhea > 1L 
(child > 20 mL/kg) or with 
abdominal pain   
C. Difficile toxin positive 
stool with toxic dilatation 
or renal insufficiency 
with/without diarrhea 
Fungal infections 
Superficial candida 
infection (e.g. oral thrush, 
vaginal candidiasis) 
Candida esophagitis 
(biopsy proven). 
Fungemia including 
Candidemia 
 
 
 
Proven or probable 
fungal sinusistis 
confirmed radiologically 
without orbital, brain or 
bone involvement. 
Proven or probable 
invasive fungal infections 
(e.g., Aspergillus, Mucor, 
Fusarium, 
Scedosporium). 
Fungal infections 
(continued) 
 
 
Disseminated infections 
(defined as multifocal 
pneumonia, presence of 
urinary or blood antigen, 
and/or CNS involvement) 
with Histoplasmosis, 
Blastomycosis, 
Coccidiomycosis, or 
Cryptococcus. 
 
 
 
Pneumocystis jiroveci 
pneumonia (regardless of 
PaO2 level) 
Viral infections 
Mucous HSV infection 
 
 


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Type of Infection/ 
Severity Grade 
Grade 1 
Grade 2 
Grade 3 
 
Dermatomal Zoster 
VZV infection with 3 or 
more  dermatomes 
Severe VZV infection 
(coagulopathy or organ 
involvement) 
 
Asymptomatic CMV 
viremia untreated or a 
CMV viremia with viral 
load decline by at least 
2/3 of the baseline value  
after 2 weeks of therapy 
Clinically active CMV 
infection (e.g. symptoms, 
cytopenias) 
or CMV Viremia not 
decreasing by at least 2/3 
of the baseline value 
after 2 weeks of therapy 
CMV end-organ 
involvement 
(pneumonitis, enteritis, 
retinitis) 
 
EBV reactivation not 
treated with rituximab 
EBV reactivation 
requiring institution of 
therapy with rituximab 
EBV PTLD 
 
Adenoviral conjunctivitis 
asymptomatic viruria, 
asymptomatic stool 
shedding and viremia not 
requiring treatment 
Adenoviral upper 
respiratory infection, 
viremia, or symptomatic 
viruria requiring treatment 
Adenovirus with end-
organ involvement 
(except conjunctivitis and 
upper respiratory tract) 
 
Asymptomatic HHV-6 
viremia untreated or an 
HHV-6 viremia with a 
viral load decline by at 
least 0.5 log after 2 
weeks of therapy 
Clinically active HHV-6 
infection (e.g. symptoms, 
cytopenias) or HHV-6 
viremia without viral load 
decline 0.5 log after 2 
weeks of therapy 
 
 
BK viremia or viruria with 
cystitis not requiring 
intervention 
BK viremia or viruia with 
clinical consequence  
requiring prolonged 
therapy and/or surgical 
intervention 
 
Viral infections 
(continued) 
 
Enterocolitis with enteric 
viruses 
 
 
 
Symptomatic upper tract 
respiratory virus 
Lower tract respiratory 
viruses 
 
Viremia (virus not 
otherwise specified) not 
requiring therapy 
Any viremia (virus not 
otherwise specified) 
requiring therapy 
Any viral encephalitis or 
meningitis 
Parasitic infections 
 
 
CNS or other organ 
toxoplasmosis 
 
 
 
Strongyloides 
hyperinfection 
Nonmicrobiologically 
defined infections 
Uncomplicated fever with 
negative cultures 
responding within 14 
days 
 
 
 
Clinically documented 
infection not requiring 
inpatient management 
Pneumonia or 
bronchopneumonia not 
requiring mechanical 
ventilation 
Any acute pneumonia 
requiring mechanical 
ventilation 
 
 
Typhlitis 
 
 
 
 
Severe sepsis*** without 
an identified organism 
*Concomitant or multimicrobial infections are graded according to the grade of the infection with the 
higher grade of severity. 


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**Therapy includes both PO and IV formulations 
***Severe Sepsis:   
Adults: 
Hypotension 
 A systolic blood pressure of <90 mm Hg or a reduction of >40 mm hg from baseline in the 
absence of other causes for hypotension 
Multiple Organ Dysfunction Syndrome 
 2 or more of the following: Renal failure requiring dialysis, respiratory failure requiring 
bipap or intubation, heart failure requiring pressors, liver failure 
Pediatrics: 
 Pediatric SIRS definition and suspected or proven infection and cardiovascular 
dysfunction or ARDS or TWO or MORE other organ dysfunctions 
Pediatric SIRS definition: 
Two or more of the following, one of which must be abnormal temperature or leukocyte count 
1) 
Core temperature >38.5C or < 36C 
2) 
Tachycardia, otherwise unexplained persistent in absence of external stimulus, chronic 
drugs or painful stimuli. or bradycardia, in < 1 year old, otherwise unexplained persistent. 
3) 
Tachypnea or mechanical ventilation for an acute process not related to underlying 
neuromuscular disease or general anesthesia 
4) 
Leukocytosis or leukopenia for age (not secondary to chemotherapy) or >10% bands 
Pediatric organ dysfunction criteria: 
Cardiovavascular: despite administration of fluid bolus >40 ml/kg in 1 hour: 
 Hypotension <5th percentile for age (or per Table 14-3)  
 Pressors at any dose  
 Two of the following:  
 Capillary refill > 5 secs  
 Core to peripheral temperature gap > 3oC  
 Urine output < 0.5 mL/kg/hr  
 Unexplained metabolic acidosis (Base deficit > 5.0 mEq/L)  
 Blood lactate > 2 x ULN  
Respiratory: 
 ARDS or  
 Intubated or  
 >50% FiO2 to maintain SaO2 > 92%  
Neurological: 
 Glasgow Coma Score < 11 or  


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 Acute change in mental status with a decrease in GSC >3 pts from abnormal baseline  
Renal: 
 Serum creatinine > 2 x ULN for age or 2-fold increase in baseline creatinine  
Hepatic: 
 Total bilirubin > 4 mg/dL or  
 ALT >2 x ULN for age 
Table 14-3 
Four age groups relevant to HCT 
Age 
Tachycardia 
(bpm) 
Bradycardia 
(bpm) 
Tachypnea 
(breaths/min) 
Leukocytosis / 
Leukopenia 
(WBC) 
Hypotension 
Systolic BP 
mmHg 
1 mo to 1 yr 
>180 
<90 
>34 
>17.5 to <5.0 
<100 
2 yr to 5 yr 
>140 
NA 
>22 
>15.5 to <6.0 
<94 
6 yr to 12 yr 
>130 
NA 
>18 
>13.5 to <4.5 
<105 
13 yr to < 18 yr 
>110 
NA 
>14 
>11 to <4.5 
<117 
Disseminated Infections:  
1. Two or more non-contiguous sites with the SAME organism 
2. A disseminated infection can occur at any level of severity, but most will be grade 2 or 3. 
Recurrence Intervals to Determine Whether an Infection is the Same or New: 
1. CMV, HSV, EBV, HHV6: 2 months (< 60 days) 
2. VZV, HZV: 2 weeks (< 14 days) 
3. Bacterial, non-C. difficile: 1 week (< 7 days) 
4. Bacterial, C. difficile: 1 month (< 30 days) 
5. Yeast: 2 weeks (< 14 days) 
6. Molds: 3 months (< 90 days) 
7. Helicobacter: 1 year (< 365 days) 
8. Adenovirus, Enterovirus, Influenza, RSV, Parainfluenza, Rhinovirus: 2 weeks (< 14 days) 
9. Polyomavirus (BK virus): 2 months (< 60 days) 
For infections coded as “Disseminated” per the Infection Form, any previous infection with the 
same organism but different site within the recurrence interval for that organism will be counted 
as part of the disseminated infection. 


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14.3 
Appendix 3: Grading of Chronic GvHD (NIH Criteria) 
Grading of chronic GvHD as described by Jagasia et al. should be performed as described 
below.  
 
 
Organ scoring of chronic GVHD. ECOG indicates Eastern Cooperative Oncology Group; KPS, 
Karnofsky Performance Status; LPS, Lansky Performance Status; BSA, body surface area; 
ADL, activities of daily living; LFTs, liver function tests; AP, alkaline phosphatase; ALT, 
alanine aminotransferase; ULN, normal upper limit. *Weight loss within 3 months. Skin scoring 
should use both percentage of BSA involved by disease signs and the cutaneous features scales. 
When a discrepancy exists between the percentage of total body surface (BSA) score and the 
skin feature score, OR if superficial sclerotic features are present (Score 2), but there is impaired 


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mobility or ulceration (Score 3), the higher level should be used for the final skin scoring. To 
be completed by specialist or trained medical providers. **Lung scoring should be performed 
using both the symptoms and FEV1 scores whenever possible. FEV1 should be used in the final 
lung scoring where there is discrepancy between symptoms and FEV1 scores. 
 
 


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14.4 
Appendix 4: Hematologic Disease Relapse/Progression 
definitions 
Malignancy relapse/progression is defined as follows:  
Relapse is defined by either morphological or cytogenetic evidence of acute leukemia or MDS 
consistent with pre-transplant features, or radiologic evidence of lymphoma, documented or not 
by biopsy.  Progression of disease applies to patients with lymphoproliferative diseases 
(lymphoma or chronic lymphocytic leukemia) not in remission prior to transplantation.  The 
event is defined as increase in size of prior sites of disease or evidence of new sites of disease, 
documented or not by biopsy.  
Acute leukemia and MDS – Relapse will be diagnosed when there is: 
Reappearance of leukemia blast cells in the peripheral blood; or, 
>5% blasts in the bone marrow, not attributable to another cause (e.g. bone marrow 
regeneration) 
The appearance of previous or new dysplastic changes (MDS specific) within the bone marrow 
with or without falling donor chimerism; or  
The development of extramedullary leukemia or leukemic cells in the cerebral spinal fluid or 
The reappearance of cytogenetic abnormalities present prior to transplantation 
Lymphoproliferative Diseases – Relapse or progression will be diagnosed when there is: 
Appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, 
even if other lesions are decreasing in size.  Increased FDG uptake in a previously unaffected 
site will only be considered relapsed or progressive disease after confirmation with other 
modalities. In patients with no prior history of pulmonary lymphoma, new lung nodules 
identified by CT are mostly benign.  Thus, a therapeutic decision should not be made solely on 
the basis of the PET without histologic confirmation. 
At least a 50% increase from nadir in the sum of the product diameters of any previously 
involved nodes, or in a single involved node, or the size of other lesions (e.g., splenic or hepatic 
nodules).  To be considered progressive disease, a lymph node with a diameter of the short axis 
of less than 1.0 cm must increase by > 50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm 
in the long axis.  
Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was 
PET positive before therapy unless the lesion is too small to be detected with current PET 
systems (<1.5 cm in its long axis by CT). 
In addition to the criteria above, patients with CLL who present in complete remission prior to 
transplantation may fulfill the relapse definition if there is reappearance of circulating malignant 
cells that are phenotypically characteristic of CLL.  
Non-Malignant Hematologic Disease progression is defined as follows:  
Sickle Cell Disease- Progression will be diagnosed when there is: 


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Recurrent signs/symptoms of disease in the setting of graft failure and autologous recovery 
including but not limited to: recurrence of painful crises, ongoing hemolysis, chest syndrome, 
stroke, and/or progression of sickle nephropathy, 
Thalassemia (including beta, alpha, epsilon)- Progression will be diagnosed when there is: 
Recurrent signs/symptoms of disease in the setting of graft failure and autologous recovery 
including but not limited to: severe hemolytic anemia requiring ongoing RBC transfusion 
support.   
Severe Aplastic Anemia- Progression will be diagnosed when there is: 
Recurrent signs/symptoms of disease in the setting of graft failure and autologous recovery 
including but not limited to: severe pancytopenia requiring ongoing RBC/platelet transfusion 
support.   
*Institution of any therapy to treat persistent, progressive or relapsed hematologic 
disease, including the withdrawal of immunosuppressive therapy, chemotherapy 
administration, or donor lymphocyte infusion, will be considered evidence of 
relapse/progression regardless of whether the criteria described above were met. 


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14.5 
Appendix 5: HCT Specific Comorbidity Index Score 
The HCT-Specific Comorbidity Index Score is described in Table 14-4 below. 
Table 14-4 
HCT-Specific Comorbidity Index Score 
Comorbidities 
Definition 
Score 
Migraine/headache 
 
0 
Osteoporosis 
 
0 
Osteoarthritis 
 
0 
Hypertension 
 
0 
Gastrointestinal 
Including inflammatory bowel disease 
0 
Mild pulmonary 
DLCO and/or FEV1 > 80% or 
Dyspnea on moderate activity 
0 
Mild renal 
Serum creatinine 1.2-2 mg/dL 
0 
Endocrine 
 
0 
Bleeding 
 
0 
Coagulopathy 
Deep venous thrombosis or pulmonary embolism 
0 
Asthma 
 
0 
Arrhythmia 
 
1 
Myocardial 
Coronary artery disease, congestive heart failure, history of medically 
documented myocardial infarction, EF ≤50% 
1 
Mild hepatic 
Chronic hepatitis, bilirubin > ULN to 1.5 x ULN, or AST/ALT > ULN to 2.5 
x ULN 
1 
Cerebro-vascular 
accident 
History of transient ischemic attack or cerebro-vascular accident 
1 
Morbid obesity 
 
1 
Diabetes 
Requiring treatment 
1 
Depression/anxiety 
 
1 
Infection 
Requiring continuation of treatment after day 0 
1 
Rheumatologic 
SLE, RA, polymyositis, mixed CTD, polymyalgia rheumatica 
2 
Moderate pulmonary 
DLCO and/or FEV1 66% - 80% or 
Dyspnea on slight activity 
2 
Peptic ulcer 
Patients who have required treatment 
2 
Moderate-severe 
renal 
Serum creatinine > 2 mg/dl, on dialysis, or prior renal transplantation 
2 
Valvular heart 
disease 
Except mitral valve prolapse 
3 
Prior solid tumor 
Requiring treatment with chemotherapy 
3 
Moderate-severe 
hepatic 
Liver cirrhosis, Bilirubin > 1.5 x ULN, or AST/ALT > 2.5 x ULN 
3 
Severe pulmonary 
DLCO and/or FEV1 ≤ 65% or 
Dyspnea at rest or requiring oxygen 
3 
Total score is the sum of all comorbidities present at time of transplantation. 
AST: aspartate aminotransferase; ALT; alanine aminotransferase; CTD: connective tissue 
disease; DLCO: diffusing capacity of the lung for carbon monoxide; EF: ejection fraction; 
FEV1: forced expiratory volume in 1 second; RA: rheumatoid arthritis; SLE: systemic lupus 
erythematosus; ULN: upper limit of normal.  


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Source: Sorror ML, Maris MB, Storb R, et al: Hematopoietic cell transplantation (HCT)-
specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 
106(8): 2912-9, 2015 
14.6 
Appendix 6: CIMBTR classification 
CIBMTR risk assessment should be performed as described in Table 14-5. 


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Table 14-5 
CIBTMR disease risk index 
ASBMT Diagnosis Category   
ASBMT RFI Classification 
CIBMTR Classification^ 
AML and ALL 
precursor B-lymphoblastic 
lymphoma/leukemia {per W.H.O. 
reclassified from lymphoma} 
precursor T-lymphoblastic 
lymphoma/leukemia 
Low risk: 
CR 1 
First complete remission (CR1):A treatment response where all of the following criteria are met for 
at least four weeks*†: 
Hematological: no blast cells in the peripheral blood, < 5% blasts in the bone marrow, no blasts with 
Auer rods (AML only), normal maturation of all cellular components in the marrow, normal CBC and 
ANC of > 1,000/µL 
Platelets ≥ 100,000/µL*† 
Transfusion independent 
No other signs or symptoms of disease, including extramedullary disease(e.g., central nervous 
system or soft tissue involvement) 
Include recipients with persistent cytogenetic abnormality who otherwise meet all the criteria of CR. 
CIBMTR collects information about cytogenetic and molecular testing for those in CR (hematologic 
CR), however these are only relevant for RFI reporting in as much as the center’s judge importance 
of residual cytogenetic abnormalities in determining current status beyond the hematic criteria. 
*In some cases, there may not be a four-week interval between the completion of treatment for 
disease and the disease assessment immediately prior to the HSCT. If this is the case, CR should 
still be reported as the status at transplantation. Although this is an exception to the general 
condition that CR is “durable” beyond four weeks, the status of CR represents the “best 
assessment” prior to HSCT. Similarly, sufficient time may not have elapsed to allow for platelet 
recovery to normal levels and physician judgment is required to interpret whether residual low 
platelet counts may reflect residual disease. 
NOTE: Recipients with MDS that transformed to AML 
If the recipient has residual MDS following treatment for AML, report the AML 
disease status as either PIF or relapse (i.e., the recipient cannot be in an AML CR if there is 
evidence of MDS at the time of assessment). 
AML and ALL (con‟t) 
Intermediate risk: 
CR2, CR3+ 
Complete remission 2nd or greater (CR2/+)†: Recipient achieved CR as defined above, relapsed 
and achieved CR again. Final pre-HSCT status must be CR. 


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ASBMT Diagnosis Category   
ASBMT RFI Classification 
CIBMTR Classification^ 
AML and ALL (con‟t) 
High risk (not in remission): 
Never treated 
 
 
Primary Induction Failure (PIF)  
Relapse 
Never treated: The recipient was diagnosed with acute leukemia and never treated.  
For example, this disease status may be appropriate if MDS was initially diagnosed and treated, the 
MDS then transformed into AML, and a decision was made to proceed immediately to transplant 
instead of treating the AML with therapy. 
 
Primary Induction Failure (PIF): The recipient was treated for acute leukemia but 
never achieved durable* complete remission with any therapy (*including relapsed <1 mo from CR1 
determination). The term “PIF” is not limited to the number of treatments used unsuccessfully. 
 
Relapse: Recurrence of disease after CR. Relapse is defined as: 
≥ 5% blasts in the marrow 
Extramedullary disease 
Reappearance of cytogenetic abnormalities and/or molecular markers associated with the diagnosis 
that, in the judgement of a physician, are at a level representing relapse. 
Although CIBMTR collects information upon the number of the relapse, this information is not 
needed for the ASBMT RFI 
CML 
Low risk: 
Hematologic CR1 
CP1 
 
Hematologic CR 1 deriving from first Chronic Phase (never in AP or BP).  
A treatment response where all of the following criteria are met: 
White blood count is less than 10 x 109/L, without immature granulocytes and with less than 5% 
basophils 
Platelet count less than 450 x 109/L 
Non-palpable spleen 
 First chronic phase (CP1): Recipient was in chronic phase from diagnosis to the start of  the 
preparative regimen, never in AP or BP. Characterized by: 
Relatively few blasts (<10%) present in the blood and bone marrow. 
Symptoms are often not present. 
The chronic phase may last several months to years depending on the individual recipient and the 
treatment received. 
Although CIBMTR collects additional information regarding cytogenetic and molecular response, 
this information is not needed to complete the RFI. 
CML (con’t) 
Intermediate risk: 
CP2  
Hematologic CR2 
Hematologic CR deriving from 
AP or BP 
AP1 
Second chronic phase (CP2): Recipient had one AP or BP (see BP definition in high 
risk group) and was treated back into CP or hematologic CR. 
Hematologic CR2: A hematologic CR occurring after treatment for progression from a first 
hematologic CR (eg hematologic CR, progress to CP/AP or BP, then treated back into hematologic 
CR). 
Hematologic CR deriving from AP or BP: Hematologic CR occurring after treatment for a single 
previous episode of AP or BP. 


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ASBMT Diagnosis Category   
ASBMT RFI Classification 
CIBMTR Classification^ 
Accelerated phase 1 (AP1): One or more of the following must be present (WHO 
definition): 
10-19% blasts in blood or marrow 
≥ 20% basophils in peripheral blood 
Clonal cytogenetic abnormalities in addition to the single Philadelphia chromosome (clonal evolution) 
Increasing spleen size, unresponsive to therapy 
Increasing WBC, unresponsive to therapy 
Thrombocytopenia (platelets < 100,000) unrelated to therapy 
Thrombocytosis (platelets > 1,000,000) unresponsive to therapy 
CML (con’t) 
High risk: 
CP3/+, 
Hematologic CR3/+ AP2/+ 
BP (Blast phase) 
 
Third chronic phase (CP3): Recipients had two or more AP/BP and was treated back 
into CP or hematologic CR 
Hematologic CR3: Recipients who have achieved two prior hematologic CRs, progressed, and 
achieved a third hematologic CR after treatment. 
Second accelerated phase (AP2/+): e.g. 1) recipient was in BP and treated back into 
AP. 2) CP1->AP1->CP2->AP2, 3) CP1->AP1->CP2->AP2->CP3. 
Blast Phase/Crisis (BP): 
≥ 20% blasts (formerly ≥ 30%) in the peripheral blood or bone marrow 
Extramedullary blastic infiltrates (i.e., myeloid sarcoma, granulocytic sarcoma, or chloroma) 
CLL (includes PLL) 
(report Hairy Cell Leukemia as 
„other‟, see last row of table) 
Low risk: 
CR (includes CR2 or 
subsequent CR) 
nPR 
Complete remission (CR): The disease is completely absent and no relapse occurred prior to the 
preparative regimen. Requires all the following: 
 No lymphadenopathy 
 No organomegaly 
 Neutrophils > 1.5 x 109/L 
 Platelets > 100 x 109/L 
 Hemoglobin 11g/dL 
 Lymphocytes < 4 x 109/L/L 
 Bone marrow < 30% lymphocytes 
 Absence of constitutional symptoms 
 
Nodular Partial Remission (nPR) complete response with persistent lymphoid nodules in bone 
marrow. 
CLL (con’t) 
Intermediate risk: 
PR 
Never treated 
Relapse (untreated) 
Partial remission(PR): Reduction of more than 50% in the disease burden regardless 
of the number of lines of therapy received. Requires all of the following: 
50% decrease in peripheral blood lymphocyte count from pretreatment value 
50% reduction in lymphadenopathy if present pretreatment 
50% reduction in liver and spleen size if enlarged pretreatment 


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ASBMT Diagnosis Category   
ASBMT RFI Classification 
CIBMTR Classification^ 
AND one or more of the following: 
Neutrophils ≥ 2.5x109/L or 50% above baseline 
Platelets > 100x109/L or 50% improvement over baseline 
Hemoglobin > 11.0 g/dL or 50% improvement over baseline 
 
Never Treated: The recipient was diagnosed with leukemia and never treated. 
 
Relapse (untreated): The re-appearance of disease after complete recovery (previous 
CR). Relapse should be determined by one or more diagnostic tests. 
CLL (con‟t) 
High risk: 
NR/SD  
Progression 
No Response/Stable disease (NR/SD): No change OR Less than 50% change in 
disease.Not complete response, partial response, or progressive disease. 
 
Progression: Increase in disease burden or new sites of disease. Requires one or more of the 
following: 
≥ 50% increase in the sum of the products of ≥ 2 lymph nodes (≥ 1 node must be ≥ 2 cm) or new 
nodes 
≥ 50% increase in liver or spleen size, or new hepatomegaly or splenomegaly 
≥ 50% increase in absolute lymphocyte count to ≥ 5 x 109/L 
Transformation to a more aggressive histology, e.g. transform to diffuse large 
B-cell lymphoma known as Richter’s transformation. 
MDS 
(Note all MPD are reported as 
“other‟. JMML has its own 
category on the ASBMT RFI 
Outcomes Data table) 
Low risk: 
RA  
RARS  
RCMD  
RCMD/RS 
MDS Unclassifiable isolated 
5q- syndrome 
RA/RARS/RCMD/RS/ MDS-NOS and <5% blasts, isolated 5q-syndrome/ 
MDS (con’t) 
 
High risk: 
RAEB 
RAEB-T  
RAEB-1 
RAEB-2 
CMML 
RAEB/RAEB-T/RAEB-1/RAEB-2/ CMML 
 
NOTE: RAEB and RAEB-T have been replaced in current WHO nomenclature by 
RAEB-1 or RAEB-2 


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ASBMT Diagnosis Category   
ASBMT RFI Classification 
CIBMTR Classification^ 
Hodgkin Disease/Hodgkin 
Lymphoma† 
Low Risk: 
CR1 
CRU1 
CR1 Confirmed: Complete disappearance of all known disease for ≥ 4 weeks†. The 
term “confirmed” is defined as a laboratory and/or pathological or radiographic determination. 
 
CR1 Unconfirmed (CRU1): Complete disappearance of all known disease for ≥ 4 weeks with the 
exception of persistent scan abnormalities of unknown significance†.  
The term “unconfirmed” is defined as scan abnormalities of unknown significance that are not 
biopsied or otherwise evaluated.  
Hodgkin Disease/Hodgkin 
Lymphoma†  (con’t) 
Intermediate risk: 
CR2/+  
CRU2/+ 
PR without prior CR (PR1) 
PR with prior CR (PR2+) 
(includes any sensitive 
relapse) 
CR2+ Confirmed: The recipient relapsed, then achieved complete absence of disease for at least 
one month without radiographic evidence of disease†. 
 
 
CR2+ Unconfirmed (CRU2+): The recipient has achieved a second or subsequent complete 
response but has persistent radiographic abnormalities of unknown significance 
 
 
Partial remission- (PR): Reductions of ≥ 50% in greatest diameter of all sites of known disease and 
no new sites. 
Partial response may be represented as PR1, PR2, etc. There are differing interpretations of what 
the number after “PR” represents. To avoid confusion, distinguish the type of PR with the following: 
“without prior CR” and “with prior CR”. This includes any relapse that is sensitive to chemotherapy, 
which by definition is achievement of at least a PR to therapy. 
Hodgkin Disease/Hodgkin 
Lymphoma† (con’t) 
High risk: 
Never treated 
Primary Refractory (PIF res) 
Relapse untreated (any 
number) 
Relapse resistant (any 
number) 
Never Treated: The recipient was diagnosed with lymphoma and never treated. 
 
Primary refractory (less than partial response to initial therapy or PR not maintained at time of 
HSCT). The response of the lymphoma to treatment is less than in a partial response (PR). This 
status would also include recipients who achieved a prior PR (but never CR) but are not currently in 
PR. 
 
Relapse: The recipient obtained CR/CRU, but relapsed (any sensitivity, includes PR with prior CR). 
Recurrence of disease after CR. This may involve an increase in size of known disease or new sites 
of disease. Patients who have any relapse AND have resistant or untreated or unknown sensitivity to 
chemotherapy. 
NHL (Indolent/ Low Grade) † 
Includes the following diseases: 
splenic marginal zone B-cell 
lymphoma, extranodal marginal 
Low risk: 
CR1 
CRU1 
CR1 Confirmed: Complete disappearance of all known disease for ≥ 4 weeks†. The 
term “confirmed” is defined as a laboratory and/or pathological or radiographic 
determination. 
 


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ASBMT Diagnosis Category   
ASBMT RFI Classification 
CIBMTR Classification^ 
zone B-cell lymphoma of MALT 
type, 
nodal marginal zone B-cell 
lymphoma, follicular lymphoma 
(Grade I-III and 
unknown) 
Waldenstrom 
macroglobulinemia 
(lymphoplasmacytic 
lymphoma) should be reported 
as ‘Other’ 
CR1 Unconfirmed (CRU1): Complete disappearance of all known disease for ≥ 4 weeks with the 
exception of persistent scan abnormalities of unknown significance†. The term “unconfirmed” is 
defined as scan abnormalities of unknown significance that are not biopsied or otherwise evaluated. 
 
Intermediate risk: 
CR2/+,  
CRU2/+ 
PR with prior CR 
PR without prior CR (includes 
any sensitive relapse) 
Never Treated 
CR2+ Confirmed: The recipient relapsed, then achieved complete absence of disease for at least 
one month without radiographic evidence of disease†. 
 
CR2+ Unconfirmed (CRU2+): The recipient has achieved a second or subsequent 
complete response but has persistent radiographic abnormalities of unknown significance. 
 
Partial remission- (PR): Reductions of ≥ 50% in greatest diameter of all sites of 
known disease and no new sites. 
Partial response may be represented as PR1, PR2, etc. There are differing interpretations of what 
the number after “PR” represents. To avoid confusion, distinguish the type of PR with the following: 
“without prior CR” and “with prior CR”. This includes any relapse that is sensitive to chemotherapy, 
which by definition is achievement of at least a PR to therapy. 
 
Never Treated: The recipient has never been treated for NHL. No chemotherapy was given within 
the 6 months prior to the preparative regimen (disease untreated, REL unt). 
NHL (Indolent/Low Grade) 
(con’t) 
High risk: 
Primary Refractory 
Relapse untreated (any 
number) 
Relapse resistant (any 
number) 
Primary refractory (less than partial response to initial therapy or PR not maintained at time of 
HSCT). The response of the lymphoma to treatment is less than 
in a partial response (PR). This status would also include recipients who achieved a prior PR (but 
never CR) but are not currently in PR. 
 
Relapse: The recipient obtained CR/CRU, but relapsed (any sensitivity, includes PR with prior CR). 
Recurrence of disease after CR. This may involve an increase in size of known disease or new sites 
of disease. Patients who have any relapse AND have resistant or untreated or unknown sensitivity to 
chemotherapy. 


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ASBMT Diagnosis Category   
ASBMT RFI Classification 
CIBMTR Classification^ 
NHL (Aggressive/ Intermediate 
andHigh Grade) 
Includes the following diseases: 
mantle cell lymphoma, diffuse 
large B-cell lymphoma, Burkitt’s 
lymphoma/Burkitt cell leukemia, 
high grade B-cell lymphoma, 
Burkitt- like (provisional entity), 
adult T-cell lymphoma/leukemia 
(HTLV1+), aggressive NK-cell 
leukemia, extranodal NK/T-cell 
lymphoma  lymphoma, 
hepatosplenic gamma- 
delta T-cell lymphoma, 
subcutaneous panniculitis T-cell 
lymphoma, anaplastic large-cell 
lymphoma – T/null cell – primary 
cutaneous type, peripheral T-cell 
lymphoma unspecified, 
angioimmunoblastic T- cell 
lymphoma (AILD), anaplastic 
large cell T/null cell–primary 
systemic type, large T-cell 
granular lymphocytic leukemia, 
mycosis fungoides/Sezary 
syndrome and other T-NK cell 
lymphoma.– nasal type, 
enteropathy type T-cell 
Low risk: 
CR1 
CRU1 
CR1 Confirmed: Complete disappearance of all known disease for ≥ 4 weeks†. The 
term “confirmed” is defined as a laboratory and/or pathological or radiographic determination. 
 
CR1 Unconfirmed (CRU1): Complete disappearance of all known disease for ≥ 4 weeks with the 
exception of persistent scan abnormalities of unknown significance†. The term “unconfirmed” is 
defined as scan abnormalities of unknown significance that are not biopsied or otherwise evaluated. 
NHL (Aggressive/ Intermediate 
and High Grade) 
(con’t) 
Intermediate risk: 
CR2/+,  
CRU2/+ 
PR with prior CR 
PR without prior CR (includes 
any sensitive relapse) 
CR2+ Confirmed: The recipient relapsed, then achieved complete absence of disease for at least 
one month without radiographic evidence of disease†. 
 
CR2+ Unconfirmed (CRU2+): The recipient has achieved a second or subsequent complete 
response but has persistent radiographic abnormalities of unknown significance 
 
Partial remission- (PR): Reductions of ≥ 50% in greatest diameter of all sites of 
known disease and no new sites. 
Partial response may be represented as PR1, PR2, etc. There are differing interpretations of what 


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CIBMTR Classification^ 
the number after “PR” represents. To avoid confusion, distinguish the type of PR with the following: 
“without prior CR” and “with prior CR”. This includes any relapse that is sensitive to chemotherapy, 
which by definition is achievement of at least a PR to therapy. 
NHL (Aggressive/ Intermediate 
and High Grade) 
(con’t) 
High risk: 
Primary refractory 
Relapse untreated (any 
number) 
Relapse resistant (any 
number) 
Never Treated 
Primary refractory (less than partial response to initial therapy or PR not maintained at time of 
HSCT). The response of the lymphoma to treatment is less than 
in a partial response (PR). This status would also include recipients who achieved a prior PR (but 
never CR) but are not currently in PR. 
 
Relapse: The recipient obtained CR/CRU, but relapsed (any sensitivity, includes PR 
with prior CR). Recurrence of disease after CR. This may involve an increase in size of known 
disease or new sites of disease. Patients who have any relapse AND have resistant or untreated   or 
unknown sensitivity to chemotherapy. 
 
Never Treated: The recipient has never been treated for NHL. No chemotherapy was given within 
the 6 months prior to the preparative regimen (disease untreated, REL unt). 
Multiple Myeloma 
(report plasma cell leukemia, 
solitary plasmacytoma, primary 
amyloidosis or other plasma cell 
disorders as „other‟) 
Low risk: 
CR1 (includes first sCR) VGPR 
1 (eg VGPR without prior CR) 
PR1 (eg PR without prior CR) 
CR1, (CR) A treatment response where all of the following criteria are met: 
Negative immunofixation on serum and urine samples 
Disappearance of any soft tissue plasmacytomas 
 < 5% plasma cells in the bone marrow (confirmation with repeat bone marrow biopsy not needed) 
CR requires two consecutive assessments† made at any time before the institution of any new 
therapy, and no known evidence of progressive or new bone lesions if radiographic studies were 
performed; radiographic studies are not required to satisfy CR requirements. 
Stringent Complete Remission (sCR) Follow criteria for CR as defined above PLUS Normal free light 
chain ratio AND 
Absence of clonal cells in the bone marrow by immunohistochemistry or immunoflourescence 
(confirmation with repeat bone marrow biopsy not needed). (An abnormal kappa/lambda ratio by 
immunohistochemistry and or immunofluorescence requires a minimum of 100 plasma cells for 
analysis. An abnormal ration reflecting the presence of an abnormal clone is kappa/lambda of >4:1 or 
< 1:2) 
 
 
Very Good Partial Response (VGPR) Serum and urine M protein detectable by immunofixation but 
not on electrophoresis, or >= 90% reduction in serum M-protein and urine M protein level < 100 
mg/24h 
PR without prior CR (PR1) 
Both of the following must be present: 
    ≥ 50% reduction in serum M-protein 


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CIBMTR Classification^ 
    Reduction in 24-hour urinary M-protein by ≥ 90% or to < 200 mg/24 hours. 
If the serum and urine M-protein are not measurable (i.e., do not meet any of the following criteria: 
    Serum M-protein ≥ 1 g/dL, 
    Urine M-protein ≥ 200 mg/24 hours; 
Then a ≥ 50% decrease in the difference between involved and uninvolved free light chain levels is 
required in place of the M-protein criteria (provided the serum-free light chain assay shows involved 
level ≥ 10 mg/dL and the serum-free light chain ratio is abnormal). 
Multiple Myeloma (con’t) 
 
Low risk: (con’t) 
CR1 (includes first sCR)  
VGPR 1 (eg VGPR without 
prior CR) 
PR1 (eg PR without prior CR) 
If serum and urine M-protein and serum-free light chains are not measurable, a ≥50% reduction in 
plasma cells is required in place of M-protein, provided the baseline bone marrow plasma cell 
percentage was ≥ 30%. 
In addition to the above listed criteria, a ≥ 50% reduction in the size of soft tissue plasmacytomas is 
also required, if present at baseline. 
VGPR and PR requires two consecutive assessments† made at any time before the institution of 
any new therapy, and no known evidence of progressive or new bone lesions if radiographic 
studies were performed; radiographic studies are not required to satisfy PR requirements. 
For recipients otherwise meeting the criteria for CR, but with no documented marrow with <5% 
plasma cells , status must be classified as PR. 
Multiple Myeloma (con’t) 
High risk: 
Relapse from CR (untreated) 
CR2/+ 
sCR2/+ 
VGPR2/+  
PR2/+ (with prior CR) 
SD  
Progression  
Never treated  
PR2/+ 
Relapse from CR (untreated) Requires one or more of the following: 
Reappearance of serum or urine M-protein by immunofixation or electrophoresis 
Development of ≥ 5% plasma cells in the bone marrow (relapse from CR has a 5% cutoff vs. 10% for 
other categories of relapse) 
Appearance of any other sign of progression (e.g., new plasmacytoma, lytic bone lesion, 
hypercalcemia) 
Relapse requires two consecutive assessments made at any time before classification as 
relapse, and/or the institution of any new therapy† 
 
CR2/+: Same criteria as „Myeloma low risk CR‟, except a relapse must have occurred and recipient 
was treated back into CR. 
 
sCR2/+: see sCR definition for MM, except a relapse must have occurred and recipient was treated 
back into sCR 
 
VGPR2/+: See VGPR definition. 
PR2/+ (with prior CR): 
Same criteria as ‘Myeloma low risk PR’, except a relapse must have occurred and treatment back 
into PR. 


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ASBMT Diagnosis Category   
ASBMT RFI Classification 
CIBMTR Classification^ 
Multiple Myeloma (con’t) 
High risk (Con’t): 
Relapse from CR (untreated) 
CR2/+ 
sCR2/+VGPR2/+ PR2/+ 
(with prior CR) 
SD Progression Never treated 
PR2/+ 
SD: 
Does not meet the criteria for CR, VGPR, PR, or PD. 
 
SD requires two consecutive assessments made at any time before the institution of any new 
therapy, and no known evidence of progressive or new bone lesions if radiographic studies were 
performed; radiographic studies are not required to satisfy SD requirements 
 
Progression: Requires one or more of the following: 
Increase of ≥ 25% from the lowest response value achieved: 
Serum M-component (including an absolute increase ≥ 0.5 g/dL) (for 
progressive disease, serum M-component increases of ≥ 1 g/dL are sufficient 
to define relapse if the starting M-component is ≥ 5 g/dL) 
Urine M-component with an absolute increase ≥ 200 mg/24 hours 
For recipients without measurable serum and urine M-protein levels: the difference between involved 
and uninvolved free light chain levels with an absolute increase > 10 mg/dL 
Bone marrow plasma cell percentage with absolute percentage ≥ 10% 
Definite development of new bone lesions or soft tissue plasmacytomas, or definite increase in the 
size of any existing bone lesions or soft tissue plasmacytomas 
Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 
2.65 mmol) that can be attributed solely to the plasma cell proliferative disorder 
PD requires two consecutive assessments made at any time before classification as disease 
progression, and/or the institution of any new therapy†. 
Solid Tumors: 
Adult Includes: breast cancer, 
Ewings sarcoma, germ cell 
cancers, neuroblastoma, ovarian 
cancer, rhabdomyosarcoma, 
testicular cancer, renal cell 
carcinoma and any other solid 
tumors 
All clinical status at HCT 
 
Solid Tumors: 
Pediatric 
Neuroblastoma 
Intermediate Risk 
CR1 
CRU1 
VGPR1 
PR1 (PR without prior CR)  
Adjuvant 
Note addition of RECIST criteria. RECIST criteria are based on the sum of the 
longest diameter of measured lesions, rather than product of two dimensions of measured 
lesions. 
 
First Complete remission (CR1): The recipient has achieved complete absence of disease. 
RECIST adds: Disappearance of all target lesions for a period of at least one month. Adjuvant 
treatment is excluded from this definition 


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ASBMT Diagnosis Category   
ASBMT RFI Classification 
CIBMTR Classification^ 
 
First Complete Response Unconfirmed (CRU1) Disappearance of all signs and symptoms of 
disease with normalization of all biochemical and radiologic parameters, but with persistent, 
unchanging imaging abnormalities of unknown significance. RECIST: Complete response with 
persistent imaging abnormalities of unknown significance (CRU) 
 
First very good partial response (VGPR): The recipient has obtained a reduction of more than 
90% in the disease burden after only one line of therapy. 
 
First Partial response: (Note 1st PR would include any first VGPR) No prior CR, reduction of more 
than 50% in the disease burden regardless of the number of lines of therapy received. Decrease of 
≥ 50% in total tumor load of the lesions that have been measured for at least 4 weeks RECIST: 
Partial response (PR) – At least 30% decrease in the sum of the longest diameter of measured 
lesions (target lesions) taking as reference the baseline sum of longest diameters 
 
Adjuvant: High dose treatment with transplantation delivered in the absence of any known residual 
disease with an adjuvant intent. Metastatic recipients (any status) should never be considered as 
adjuvant. Treatment given after the primary cancer treatment to increase the chances of a cure. 
Adjuvant cancer therapy may include chemotherapy, radiation therapy, hormone therapy, or 
biological therapy. 
Solid Tumors: 
Pediatric 
Neuroblastoma (con’t) 
High Risk 
 CR2/+  
CRU2/+ 
PR2/+ (with prior CR) 
NR/SD 
PD 
Relapse (untreated)  
Never treated 
Note CR definitions for Neuroblastoma above. 
 
2nd Partial response or more (PR with prior CR, any number): (Note includes VGPR after prior CR) 
One prior CR, reduction of more than 50% in the disease burden regardless of the number of lines of 
therapy received after relapse Decrease of ≥50% in total tumor load of the lesions that have been 
measured for at least 4 weeks.  
RECIST: Partial response (PR) – At least 30% decrease in the sum of the longest diameter of 
measured lesions (target lesions) taking as reference the baseline sum of longest diameters 
 
Progressive Disease (PD) Increase of ≥ 25% in the size of one or more measurable lesions, or the 
appearance of new lesions. RECIST: At least a 20% increase in the sum of the longest diameter 
of measured lesions (target lesions), taking as reference the smallest sum of the longest 
diameters recorded since the treatment started or the appearance of one or more new lesions 
 
Relapse (untreated) The reappearance of disease after complete recovery. Should be determined 
by one or more diagnostic tests. 
 
Never Treated (upfront): Recipient has not received any treatment for Neuroblastoma prior to the 


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ASBMT Diagnosis Category   
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CIBMTR Classification^ 
preparative regimen. This disease status at transplant should rarely be used 
 
No Response/Stable Disease (NR/SD) Disease has been treated and the size of one or more lesions 
has neither increased 25% or more in the size of one or more lesions, nor has total tumor size 
decreased 50% or more. RECIST: Stable disease (SD) – Neither sufficient shrinkage to qualify for 
PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest 
diameters since the treatment started 
All Other Solid Tumors – 
Pediatrics 
Includes all other solid tumors 
except neuroblastoma 
Intermediate Risk – same as 
Neuroblastoma (above) 
CR1 
CRU1 
VGPR1 
PR1 (PR without prior CR)  
Adjuvant 
See Neuroblastoma above. 
All Other Solid Tumors – 
Pediatrics (con’t) 
Includes all other solid tumors 
except neuroblastoma 
High Risk – same as 
Neuroblastoma (above) 
CR2/+ CRU2/+ 
PR with prior CR NR/SD 
PD Relapse Never treated 
See Neuroblastoma above. 
Non-Malignant Disease – Adults 
Includes: severe aplastic anemia, and any other non-malignant 
diseases 
 
Non-Malignant Disease - Pediatrics 
Includes: histiocytic disorders, 
Immunodeficiencies, Inborn errors of 
metabolism, congenital bone marrow failure, 
acquired aplastic anemia, thalassemia major, 
sickle cell anemia and any other non-
cancerous diseases 
 
 
Other 
Includes any hematologic disorder or solid 
tumor not included in above (e.g. other 
plasma cell disorders, amyloidosis, plasma 
cell leukemia, hairy cell leukemia, 
myeloproliferative diseases) 
 
 


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2014 and 2015 Update: 
No substantive changes from the 2011 through 2014 documents. 
2011 Update: 
No changes from the 2010 document. 
2010 Updates: 
† Several diseases (eg AML, MM, NHL and HL) require an observation period of response of at least 4 weeks or two independent assessments in order to 
strictly be considered to have achieved that level of response. However, in many cases, transplantation is conducted before this time has fully elapsed, or 
subsequent assessment can be completed. In these circumstances, the best response determined before the transplantation or based upon the last 
assessment before transplantation should be used. 
^ CIBMTR has included instructions from the CIBMTR TED manual for reference, along with the CIBMTR “matching” disease classifications in bold 
font 
 
2009 and 2010 Updates: 
General updates to align ASBMT risk categories with disease status collected on CIBMTR TED forms 
Matching disease text to the revised TED Forms per W.H.O. criteria (e.g. precursor B-lymphoblastic lymphoma/leukemia moved to ALL from Lymphoma) 
Matching response text to the revised TED Forms 
Preparative regimen replaces conditioning 
Referring to revised CIBMTR Disease Forms for detailed criteria  
Distinguishing PR1/1st PR to PR without prior CR and PR2/2nd PR to PR with prior CR 
Waldenstrom macroglobulinemia moved to “Other‟ from Plasma Cell Disorders, and better description of diseases fitting into “Other” category. 
Moved mycosis fungoides/Sezary syndrome to the aggressive/intermediate diagnosis category. 
Adding Response Evaluation Criteria in Solid Tumors (RECIST) criteria for solid tumors  
Added details from the CIBMTR TED instruction manual. 
 
Date created: 3/4/03  
Date(s) of Revision: 2/27/04; 12/1/04; 11/17/05; 10/23/06; 11/15/07; 9/26/09; 10/18/10, 11/23/11, 11/4/12, 12/3/13; 1/13/14, 2/16/15, 3/23/16.  
Copyright 2016, American Society for Blood and Marrow Transplantation 


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14.7 
Appendix 7: List of CYP3A4 inhibitors and inducers 
Table 14-6 
List of CYP3A4 inhibitors and inducers 
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). 
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%. 


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14.8 
Appendix 8:  FACT-BMT (Version 4) 
Below is a list of statements that other people with your illness have said are important. Please 
circle or mark one number per line to indicate your response as it applies to the past 7 days. 














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14.9 
Appendix 9: EQ-5D-5L Health Questionnaire 
 


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SAP_001.pdf: 


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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)


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Table of contents
Table of contents .................................................................................................................3
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints ...............................................................................9
2
Statistical methods.............................................................................................................13
2.1
Data analysis general information .........................................................................13
2.1.1
General definitions................................................................................13
2.2
Analysis sets ..........................................................................................................18
2.2.1
Subgroup of interest ..............................................................................19
2.3
Patient disposition, demographics and other baseline characteristics ...................21
2.3.1
Patient disposition.................................................................................22
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................23
2.4.1
Study treatment / compliance................................................................23
2.4.2
Prior, concomitant and post therapies...................................................26
2.5
Analysis of the primary objective..........................................................................28
2.5.1
Primary endpoint...................................................................................28
2.5.2
Statistical hypothesis, model, and method of analysis..........................29
2.5.3
Handling of missing values/censoring/discontinuations.......................30
2.5.4
Supportive analyses for ORR at Day 28 ...............................................30
2.5.5
ORR at Crossover Day 28.....................................................................32
2.6
Analysis of the key secondary objective ...............................................................32
2.6.1
Key secondary endpoint........................................................................32
2.6.2
Statistical hypothesis, model, and method of analysis..........................33
2.6.3
Handling of missing values/censoring/discontinuations.......................33
2.6.4
Durable ORR at Crossover Day 56.......................................................33
2.7
Analysis of secondary efficacy objective(s)..........................................................34
2.7.1
Secondary efficacy endpoints ...............................................................34
2.7.2
Statistical hypothesis, model, and method of analysis..........................35
2.7.3
Handling of missing values/censoring/discontinuations.......................38
2.8
Safety analyses.......................................................................................................38
2.8.1
Adverse events (AEs)............................................................................39
2.8.2
Deaths....................................................................................................40
2.8.3
Laboratory data .....................................................................................40
2.8.4
Other safety data ...................................................................................41


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2.9
Pharmacokinetic endpoints....................................................................................42
2.10
PD and PK/PD analyses.........................................................................................45
2.11
Patient-reported outcomes .....................................................................................46
47
48
2.14
Interim analysis......................................................................................................49
3
Sample size calculation .....................................................................................................49
3.1
Primary analysis.....................................................................................................49
3.2
Power for analysis of key secondary variables......................................................50
4
Change to protocol specified analyses ..............................................................................50
5
Appendix ...........................................................................................................................50
5.1
Imputation rules.....................................................................................................50
5.1.1
Study drug.............................................................................................50
5.1.2
AE, ConMeds and safety assessment date imputation..........................51
5.2
AEs coding/grading ...............................................................................................52
5.3
Laboratory parameters derivations ........................................................................53
5.4
Statistical models...................................................................................................54
5.4.1
Primary analysis....................................................................................54
5.4.2
Key secondary analysis.........................................................................55
5.4.3
Other secondary analysis.......................................................................55
6
Reference...........................................................................................................................57


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List of abbreviations
AE
Adverse event
AESI
Adverse Event of Special Interest
aGvHD
Acute Graft vs. Host Disease
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
BAT
Best Available Therapy
bid
bis in diem/twice a day
BMI
BOR
Body Mass Index
Best Overall Response
BSA
Body Surface Area
cGvHD
chronic Graft vs. Host Disease
CIBMTR
Center for International Blood and Marrow Transplant Research
CMH
Cochran–Mantel–Haenszel
CMV
Cytomegalovirus
CR
Complete Response
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DAR
Dose Administration Record
DMC
Data Monitoring Committee 
eCRF
Electronic Case Report Form
EFS
Event-Free Survival
FACT-BMT
Functional Assessment of Cancer Therapy - Bone Marrow Transplantation
FAS
Full Analysis Set
FFS
Failure-Free Survival
GvHD
Graft vs. Host Disease
HCT
Hematopoietic Cell Transplantation
IRT
Interactive Response Technology that includes Interactive Voice Response
System and Interactive Web Response System
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
NRM
Non Relapse Mortality
ORR
Overall Response Rate
OS
Overall Survival
PAS
Pharmacokinetic analysis set
PD
Pharmacodynamics
PK
Pharmacokinetics
PPS
Per-Protocol Set
PR
Partial response 
PRO
Patient-reported Outcomes
QoL
Quality of Life
RAP
Report and Analysis Process


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RPSFT
Rank-Preserving Structure Failure Time
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
WBC
White Blood Cells
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the Clinical Study Report 
(CSR) of study CINC424C2301, a phase III, randomized, open-label, multi-center study of 
ruxolitinib versus best available therapy in patients with corticosteroid-refractory acute graft vs. 
host disease (aGvHD Grade II-IV) after allogeneic stem cell transplantation.
The content of this SAP is based on protocol CINC424C2301 version 02. All decisions 
regarding final analysis, as defined in the SAP document, have been made prior to database 
lock of the study data.
1.1
Study design
This is a phase III, randomized, open-label, multi-center study of ruxolitinib versus best 
available therapy in patients with corticosteroid-refractory acute graft vs. host disease after 
allogeneic stem cell transplantation. Approximately 308 patients will be  randomized to one of 
the following treatment arms in 1:1  ratio:

Ruxolitinib

BAT
Randomization will be stratified by the aGvHD grade (Grade II vs. Grade III vs. Grade IV).
Overall response rate (ORR) at Day 28, as assessed by local investigators’ review of aGvHD
response and using standard criteria [Harris 2016], is the primary endpoint in this study. Durable 
overall response rate at Day 56 is the key secondary endpoint. 
The primary analysis including the analysis on primary and key secondary endpoints was
performed with the cut-off date as 25-Jul-2019 after all patients have completed their Day 56 
visit or have discontinued study. The primary analysis data were summarized in the primary 
clinical study report (CSR). 
Further analyses on secondary endpoints was performed with the cut-off date as 06-Jan-2020 
when all patients have completed 6 months treatment or discontinued from study participation 
earlier.
The final analysis will occur once all patients have completed the study (up to 24 months from 
randomization). All available data from all patients up to end of study, inclusive of OS, will be 
reported in a final CSR.
No formal interim efficacy analysis is planned in this study. 




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1.2
Study objectives and endpoints
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 2.5
To compare the efficacy of ruxolitinib vs. 
Investigator’s choice Best Available Therapy 
(BAT) in patients with Grade II-IV SR-aGvHD 
assessed by Overall Response Rate (ORR) at 
Day 28
Overall response rate (ORR) at Day 28 after 
randomization, defined as the proportion of 
patients in each arm demonstrating a complete 
response (CR) or partial response (PR) without 
requirement for additional systemic therapies for 
an earlier progression, mixed response or non-
response. Scoring of response will be relative to 
the organ stage at the time of randomization.
CMH analyses, stratified by aGvHD grade
Key secondary endpoint
Refer to Section 2.6
To compare the rate of durable ORR at Day 56 
between ruxolitinib and BAT
Proportion of all patients in each arm who achieve 
a complete response (CR) or partial response 
(PR) at Day 28 and maintain a CR or PR at Day 
56.
CMH analyses, stratified by aGvHD grade
Other secondary endpoints
Refer to Sections 2.7, 2.8, 2.9, 2.10, 2.11
To estimate ORR at Day 14
Proportion of patients who achieved ORR 
(CR+PR) at Day 14. 
To assess Duration of response
Duration of response (DOR) is assessed for 
responders only and is defined as the time from 
first response until aGvHD progression or the date 
of additional systemic therapies for aGvHD. Onset 
of chronic GvHD, or death without prior 
observation 
of 
aGvHD 
progression 
are 
considered as competing risks.


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Objective
Endpoint
Analysis
To assess the cumulative steroid dose until Day 
56
Weekly cumulative steroid dose for each patient 
up to Day 56 or end of treatment will be calculated. 
To assess Overall Survival (OS)
Overall survival, defined as the time from the date 
of randomization to the date of death due to any 
cause. 
Probability of overall survival at Months 1, 2, 6, 12, 
18 & 24 will be estimated from the Kaplan-Meier 
curves for each arm.
To assess Event-Free Survival (EFS)
Event-free survival, defined as the time from the 
date of randomization to the date of hematologic 
disease
relapse/progression, graft failure, or 
death due to any cause. 
Probability of EFS at Months 1, 2, 6, 12, 18 & 24 
will be estimated from the Kaplan-Meier curves for 
each arm.
To assess Failure-Free Survival (FFS)
Failure-free survival, defined as the time from the 
date of randomization to date of hematologic 
disease 
relapse/progression, 
non-relapse 
mortality, or addition of new systemic aGvHD 
treatment.  
Cumulative incidence of FFS at Months 1, 2, 6, 
12, 18 & 24 will be estimated, considering each 
event as a competing risk for the other two.  Onset 
of chronic GvHD is considered as a competing 
risk. 
To assess Non Relapse Mortality (NRM)
Non-relapse mortality (NRM), defined as the time 
from date of randomization to date of death not 
preceded 
by 
hematologic 
disease 
relapse/progression. 
Cumulative incidence of NRM at Months 1, 2, 6, 
12, 18 & 24 will be estimated, considering 
hematologic disease relapse/progression as 
competing events.
To
assess 
incidence 
of 
Malignancy 
Relapse/Progression (MR) 
Malignancy Relapse/Progression (MR) (refer to 
protocol Appendix 4), defined as the time from 
date of randomization to hematologic malignancy 
relapse/progression. Calculated for patients with 
underlying hematologic malignant disease.
Cumulative incidence of MR at Months 1, 2, 6, 12, 
18 & 24 will be estimated, considering deaths not 
preceded 
by 
hematologic 
malignancy 
relapse/progression as competing events.
To measure the incidence of cGvHD 
cGvHD, defined as the diagnosis of any cGvHD 
including mild, moderate, severe.  
Cumulative incidence of cGvHD at Months 1, 2, 6, 
12, 18 & 24 will be estimated, considering 
hematologic disease relapse/progression and
death without prior cGvHD as competing events.
To estimate the rate of Best Overall Response 
(BOR)
Proportion of patients who achieve OR (CR+PR) 
at any time point up to and including Day 28 and 






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2
Statistical methods
2.1
Data analysis general information
The final analysis will be performed by Novartis. SAS version 9.4 or later and/or R version 
3.0.2 or later will be used to perform all data analyses and to generate tables, figures and listings.
Data included in the analysis
The analysis cutoff date for the final analysis of study data will be established when all patients 
have completed the study.All statistical analyses will be performed using all data collected in
the database up to the data cutoff date. All data with an assessment date or event start date (e.g. 
vital sign assessment date or start date of an adverse event) prior to or on the cut-off date will 
be included in the analysis. Any data collected beyond the cut-off date will not be included in 
the analysis and will not be used for any derivations.All events with start date before or on the 
cut-off date and end date after the cut-off date will be reported as ‘ongoing’. The same rule will 
be applied to events starting 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.
General analysis conventions
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of patients enrolled at centers, no center effect 
will be assessed. 
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables
by treatment group; a missing category will be included as applicable. Percentages will be
calculated using the number of patients in the relevant population or subgroup as the
denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate
descriptive statistics (i.e. mean, standard deviation, median, minimum, and maximum) by 
treatment group.
2.1.1
General definitions
Investigational drug and study treatment
Investigational drug, will refer to the ruxolitinib only. Whereas, study treatment will refer to 
ruxolitinib and BAT. 
Randomized treatment will refer to the study treatment received during the randomized 
treatment period. Up to Day 28 visit, more than one BAT regimen may be initiated as study 
treatment. These regimens reported on the Dosage Administration Record (DAR) eCRF are 
considered randomized treatment. Crossover treatment will refer to the study treatment 
received during the crossover treatment period.


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Date of first administration of randomized treatment
The date of first administration of randomized treatment is derived as the first date when a 
nonzero dose of randomized treatment was administered as per the DAR eCRF. The date of 
first administration of randomized treatment will also be referred as start of randomized
treatment.
Date of first administration of crossover treatment 
The date of first administration of crossover treatment is derived as the first date when a nonzero 
dose of crossover treatment was administered as per the DAR eCRF. The date of first 
administration of crossover treatment (ruxolitinib) will also be referred as start of crossover
treatment.
Date of last administration of randomized treatment 
The date of last administration of randomized treatment is defined as the last date when a 
nonzero dose of randomized treatment was administered as per DAR eCRF. 
Date of last administration of crossover treatment 
The date of last administration of crossover treatment is defined as the last date when a nonzero 
dose of crossover treatment (ruxolitinib) was administered as per DAR eCRF. 
Study day
The study day, describes the day of the event or assessment date, relative to the reference start 
date. 
The study day is defined as:
The date of the event (visit date, onset date of an event, assessment date etc.) −reference 
start date + 1 if event is on or after the reference start date;

The date of the event (visit date, onset date of an event, assessment date etc.) − reference 
start date if event precedes the reference start date.
The reference start date for safety assessments (e.g. adverse event onset, laboratory abnormality
occurrence, vital sign measurement, dose interruption, PK, etc.), 
 and PRO is the
start of randomized treatment.
The reference start date for all other, non-safety assessments (i.e., aGvHD assessment, survival, 
aGvHD progression, aGvHD response, underlying hematologic disease relapse/progression, 
etc.) is the date of randomization.
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative.
Crossover study day
The crossover study day, describes the day of the event or assessment date, relative to the start 
of crossover treatment.


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Crossover study day = date of event – start of crossover treatment + 1, if event is on or after the 
start of crossover treatment
Crossover study day = date of event – start of crossover treatment, if event precedes the start of 
crossover treatment
The crossover study day will be displayed in the data listings if an event starts on or after the 
start of crossover treatment.
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.
Baseline
Baseline for safety endpoints (except adverse events), 
 and patient reported 
outcomes is defined as the last assessment prior to or on the treatment start date. 
For evaluations after cross over, the baseline is defined as the last assessment prior to or on the 
start date of crossover treatment.
Baseline for efficacy endpoints is defined as the last assessment or procedure conducted prior 
to or on the date of randomization date + 3 days, but no later than the treatment start date.
If patients have no value as defined above, the baseline result will be missing.
On-treatment assessment/event and observation periods
For adverse event reporting the overall observation period will be divided into four mutually 
exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent at screening to the day 
before first administration of study treatment
2. on-randomized-treatment period: from date of first administration of randomized
treatment to 30 days after date of last actual administration of randomized treatment
(including start and stop date), or end of randomized treatment per End of Randomized 
Treatment Disposition eCRF, whichever is later; for those patients who cross over from 
BAT to ruxolitinib, the period is from date of first administration of randomized 
treatment to earlier of (i) 30 days after date of last actual administration of randomized 
treatment, or end of randomized treatment per End of Randomized Treatment 
Disposition eCRF, whichever is later, (ii) the day before the date of first administration 
of crossover treatment. Up to Day 28 visit, more than one BAT regimen may be initiated
as study treatment. In this case, the last actual administration of randomized treatment
refers to the last actual administration of the last BAT regimen reported on the DAR 
eCRF.  
3. on-crossover-treatment period: from date of first administration of crossover treatment 
to 30 days after date of last administration of crossover treatment (including start and 


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stop date), or end of crossover treatment per End of Crossover Treatment Disposition 
eCRF, whichever is later.
4. post-treatment period: starting at Day 31 after last administration of study treatment, or 
the day after end of study treatment per end of treatment disposition eCRFs, whichever 
is later.
If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period cannot 
be made, then the respective data will be assigned to the on-randomized-treatment period.  
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). The data on-randomized-treatment period and on-crossover-treatment 
period will be summarized separately. In addition, a separate summary for death including on-
treatment and post-treatment deaths will be provided.  In particular, summary tables for adverse 
events (AEs) will summarize only on-treatment events, with a start date during the on-treatment 
period (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 post-treatment period will be flagged.
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 two assessments within a time window are 
equidistant from the target date, then the later of the two  assessments will be used. If multiple 
assessments on the same date then the worst case will be used.  Data from all assessments 
(scheduled and unscheduled), including multiple assessments, will be listed.
The following time windows are defined for descriptive summary on aGvHD assessment, 
 PROs and safety (Table 2-1) by visit. The end of treatment assessment will be 
mapped into the time points if collected within 7 days of the last dose intake.  
Table 2-1
Time windows for aGvHD assessment, 
PROs and safety 
assessment (lab, vital sign, etc.)
Time Window
Planned Visit Timing 
Time Window Definition
On treatment
Baseline1
Study Day 11
≤Study Days 1+3, no later 
than treatment start date
Baseline2
On or before Study Day 12
≤ Study Day 1 
Week 1
Study Day 7
Study Days 4 – 10
Week 2
Study Day 14
Study Days 11 – 17
Week 3  
Study Day 21
Study Days 18 – 24
Week 4
Study Day 28
Study Days 25 – 31
Week 5 
Study Day 35
Study Days 32 – 38
Week 6  
Study Day 42
Study Days 39 – 45


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Week 7
Study Day 49
Study Days 46 – 52
Week 8 
Study Day 56
Study Days 53 – 59
Week 12
Study Day 84
Study Days 71 – 98 
Week 16
Study Day 112
Study Days 99 – 126 
Week 20
Study Day 140
Study Days 127 – 154 
Week 24
Study Day 168
Study Days 155 – 182 
Safety follow-up
30 days after last dose
Last dose date + 30
Baseline1 for aGvHD assessment (efficacy); 
Baseline2 for PROs, safety assessments 
(safety);
Study Day 11 = randomization date;
Study Day 12 = start date of randomized treatment;
Crossover Study Day 1 = start date of crossover treatment
EOT (randomized treatment or crossover treatment) assessments are mapped to the time 
points.
Safety follow-up is a separate time point for PROs and safety assessments.
Last contact date 
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the last complete date among the following:
Table 2-2
Last contact date data sources
Source data
Conditions
Date of Randomization 
No Condition
Last date patient was known to be alive from 
Survival Follow-up page 
Patient status is reported to be alive, lost to 
follow-up or unknown.
Start/End dates from further aGvHD therapy
Non-missing medication/procedure term.
Start/End* dates from drug administration record 
Non-missing dose. Doses of 0 are allowed.
End of treatment date from end of treatment page
No condition.
- aGvHD assessment date
- any specific efficacy assessment date if 
available (e.g., cGvHD assessment, graft failure 
assessment, hematologic disease 
relapse/progression assessment)
Evaluation is marked as ‘done’.
Laboratory/PK collection dates/
 
Sample collection marked as ‘done’. 
Vital signs date
At least one non-missing parameter value
Start/End dates of AE 
Non-missing verbatim term


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The last contact date is defined as the latest complete date from the above list on or before the 
data 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. Completely imputed
dates (e.g. the analysis cut-off date programmatically imputed to replace the missing end date
of a dose administration record) will not be used to derive the last contact date. Partial date 
imputation is allowed for event (death)/censoring coming from ‘Survival information’ eCRF. 
The last contact date will be used for censoring of patients in the analysis of overall survival.
2.2
Analysis sets
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 and strata, they have been assigned to during the randomization procedure.
Per-Protocol Set 
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with requirements of the clinical study protocol.
The following list of protocol deviations will lead to exclusion of the patient from the Per-
Protocol Set:

Not steroid refractory aGvHD (PDID: INCL09 per SSD v22.0)

More than one prior systemic therapy for the treatment of aGvHD other than corticosteroids 
+/- CNI (prophylaxis or treatment) (PDID: EXCL01 per SSD v22.0)

Missing or incorrect aGvHD grade at randomization (PDID: OTH02, INCL07 per SSD 
v22.0)

Taking any prohibited medication as specified in this protocol after start of study treatment 
and before end of study treatment (PDID: COMD01, COMD02 per SSD v22.0)

Study treatment received different from treatment arm assigned by randomization (PDID: 
TRT02 per SSD v22.0)
Safety Set
The Safety Set includes all patients who received at least one dose of study treatment. 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 if the randomized treatment was never received during the randomized 
treatment period.
Crossover Analysis Set
The Crossover Analysis Set (CAS) comprises all patients randomized to and received BAT who 
then crossed over and received at least one dose of ruxolitinib.  This analysis set will be used 
for all analyses for crossover patients.




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The primary efficacy endpoint will be summarized by the following subgroups to examine the 
homogeneity of treatment effect provided that the primary efficacy analysis based on the FAS 
is statistically significant : 

Age group (12- <18, 18-65, >65 years)

Gender

Race

Region (Europe, Australia and Canada), Japan, Asia excluding Japan)

Acute GvHD grade (Grade II, III, IV) 

Source of grafts (related, not related)

Criteria for SR-aGvHD (progression after at least 3 days, failure to achieve a response 
after 7 days, flare failure during taper)

Prior aGvHD therapy (steroid  +/- CNI, steroid +/- other systemic aGvHD treatment, 
steroid +/- CNI +/- other systemic aGvHD treatment, )

Conditioning regimen type (myeloablative, non-myeloablative, reduced intensity)

Stem cell type (bone marrow, peripheral blood, single cord blood)

Donor HLA status (match, mismatch)

Note: HLA status Match score means that 1:1 match, e.g. 10/10, 8/8, 6/6, 12/12. 
Mismatch will be all the other scores.  

Donor gender match (F/F, M/M, F/M, M/F)

Donor CMV status (negative, positive)

Donor source/HLA match status (related and matched, related and mismatched, not related 
and matched, not related and mismatched)

aGvHD organ involvement at randomization (skin, liver, upper GI, lower GI)
No formal statistical test of hypotheses will be performed for the subgroups, only point estimate 
of the treatment effect and 95% confidence intervals will be provided (see Section 2.5 for further 
analysis details). The objective of the efficacy subgroup analysis is to demonstrate homogeneity 
of treatment effect in the above subgroups. 
Safety
Key safety analyses will be repeated on the Safety Set in the following subgroups:

Age group (12- <18, 18-65, >65 years)

Gender

Race

Region (Europe, Australia and Canada), Asia excluding Japan, Japan)

aGvHD organ involvement at randomization (skin, liver, upper GI, lower GI)    
The objective for carrying out these subgroup analyses is to identify potential safety issues 
that may be limited to or more commonly observed in a subgroup of patients.  The following 
summaries will be presented by subgroup:


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
AEs, irrespective of causality, by primary system organ class and preferred term

AEs with suspected relationship to study treatment, by primary system organ class and 
preferred term

Serious AEs, irrespective of causality, by primary system organ class and preferred term

Serious AEs with suspected relationship to study treatment, by primary system organ class 
and preferred term

On-treatment deaths, by primary system organ class and preferred term
Adolescent patients
In order to be able to make a separate risk/benefit assessment for the adolescent patients, besides 
the above planned subgroup analyses for this age group (12-<18 years), data of demographics 
and exposure will be presented.
Japanese patients
Subgroup analyses will also be performed for the patients treated in Japan. No selection will be 
done on the basis of ethnicity, the purpose being to evaluate the population of patients living in 
Japan, not a specific ethnic set of patients. The analysis will be done the same way as in region 
subgroup specified above.
2.3
Patient disposition, demographics and other baseline 
characteristics
The Full Analysis Set (FAS) will be used for all baseline and demographic summaries and 
listings unless otherwise specified. Summaries will be reported by treatment arm and for all 
patients and listings will be reported by treatment arm to assess baseline comparability.  No 
inferential statistics will be provided.
Basic demographic and background data
All demographic and baseline disease characteristics data will be summarized and listed by 
treatment arm. Categorical data (e.g. gender, age groups: 12- <18 vs. 18-65 vs. >65 years, race, 
ethnicity) will be summarized by frequency counts and percentages; the number and percentage 
of patients with missing data will be provided. Continuous data (e.g. age, weight, height, body 
mass index) will be summarized by descriptive statistics (N, mean, median, standard deviation,
Q1, Q3, minimum and maximum). 
Baseline stratification factors
The number (%) of patients in each stratum (Grades II, III, IV) based on data obtained from the 
IRT system will be summarized overall and by treatment arm for the FAS. Discordances 
between the stratum recorded in IRT at the time of randomization and the actual stratum 
recorded in the clinical database through the data collected on eCRF will be cross-tabulated and 
listed.
Diagnosis and extent of disease
Summary statistics will be tabulated for diagnosis and extend of disease in underlying disease, 
stem cell transplant and acute GvHD. 


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For underlying disease, the analysis will include the following: primary diagnosis category and 
subcategory, details of primary diagnosis, time since diagnosis of underlying disease, CIBMTR 
risk assessment.
For transplant related disease history, the analysis will include the following: conditioning 
regimen type, total HCT-specific comorbidity index score, time since transplant, time from 
diagnosis of underlying disease to transplant, stem cell type, cytomegalovirus status, donor 
information including age, gender, HLA typing method, HLA match score, source of grafts 
(related/unrelated),  CMV status, T-cell depleted (Y/N), total nucleated cell dose.
For aGvHD disease history, the analysis will include the following: time since diagnosis of 
aGvHD grade ≥2, aGvHD grade when diagnosis of grade ≥2, steroid refractory aGvHD criteria 
met (progression after at least 3 days, failure to achieve a response after 7 days, flare failure 
during taper), prior aGvHD therapy (steroid  +/- CNI, steroid +/- other systemic aGvHD 
treatment, steroid +/- CNI +/-other systemic aGvHD treatment,), time from diagnosis of aGvHD 
grade ≥2 to steroid refractory, time since steroid refractory aGvHD, aGvHD grade at 
randomization, aGvHD organ involvement, steroid dose at randomization.
Medical history
Medical history and ongoing conditions, including underlying disease conditions and symptoms 
entered on eCRF will be summarized and listed by treatment arm. The summaries will be 
presented by primary system organ class (SOC), preferred term (PT) and treatment arm. 
Medical history and current medical conditions will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology. The MedDRA version used for reporting will 
be specified in the CSR and as a footnote in the applicable tables/listings.
Other
Intended BAT strategy in case of SR aGvHD  prior to randomization will be summarized by 
treatment arm.
All data collected at baseline including child bearing potential will be listed.
2.3.1
Patient disposition
Enrollment by country and center will be summarized for all screened patients and also by 
treatment arm. The number (%) of randomized  patients will be presented overall and by 
treatment group. The number (%) of screened and not-randomized patients and the reasons for 
screening failure will also be displayed. The number (%) of patients in the FAS who are still on 
treatment, who discontinued the treatment phases (randomized treatment, crossover treatment) 
as well as the reason for discontinuation, and the survival follow-up will be presented overall 
and by treatment group.
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. All protocol deviations will be listed.


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Analysis sets
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarized  by 
treatment group and stratum.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Duration of exposure in days to ruxolitinib and BAT will be summarized by means of 
descriptive statistics. It will also be categorized into time intervals; frequency counts and 
percentages will be presented for the number (%) of patients in each interval. Duration of 
exposure to each BAT regimen (anti-thymocyte globulin (ATG), extracorporeal photopheresis 
(ECP), mesenchymal stromal cells (MSC), low-dose methotrexate (MTX), mycophenolate 
mofetil (MMF), mTOR inhibitors (everolimus or sirolimus), etanercept, or infliximab) will be 
summarized using the same approach.
Actual cumulative dose, dose intensity (DI) and relative dose intensity (RDI) will be 
summarized for the ruxolitinib arm. Patients randomized to Investigator’s choice of BAT will 
receive various different categories of therapy. 
The number (%) of patients who have dose changes or interruptions, and the reasons, will be 
summarized for ruxolitinib group.
Patient level listings of all doses administered on treatment along with dose change reasons will 
be produced. 
The Safety Set and Crossover Analysis Set will be used for all summaries on randomized 
treatment and crossover treatment, respectively. The Safety Set will be used for listings of study 
treatment.
Duration of exposure to study treatment
Duration of exposure to randomized treatment (days) = (last date of exposure to randomized
treatment) – (date of first administration of randomized treatment) + 1. 
Duration of exposure to crossover treatment (days) = (last date of exposure to crossover 
treatment) – (date of first administration of crossover treatment) + 1. 
The last date of exposure to study treatment is the latest of the last dates of exposure to study 
treatment (see Table 2-4).
Table 2-4
Definition of last date of exposure of study treatment
Scenario
Definition of last date of 
exposure of study treatment
Example
Scenario 1: Study 
treatment with a 
periodical administration
The planned end date of the last 
period in which the last non-zero 
dose of the study treatment was last 
administered.
Example 1: In a once-a-week 
administration, the last date of 
exposure is the date of last 
administration + 6 days.


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Note :  If the patient changed to 
another BAT, died or was lost to 
follow-up before the derived last 
date, the last date of exposure to 
study treatment is the date prior to 
the start of the next BAT, date of 
death or the date of last contact, 
respectively. 
If the derived last date of exposure 
goes beyond the data cutoff date, it 
should be truncated to the date of 
data cutoff.
Example 2: In a twice-a-week 
administration, the last date of 
exposure is the date of last
administration + 3 days.
Scenario 2: Study 
treatment with daily/IV 
administration 
Date of last administration of a non -
zero dose of the study treatment.
Example 3: A patient had a 
permanent discontinuation of the 
study treatment 06Jan2017 after 
being 
put 
on 
a 
temporary 
interruption since 01Jan2017. In 
this case the last date of exposure 
is- 31Dec2016. 
Scenario 3: Study 
treatment as an 
antibody 
Date of last administration of a non -
zero dose of the study drug + 
number of days antibody persists in 
vivo – 1 day.
Note :  If the patient changed to 
another BAT, died or was lost to 
follow-up before the derived last 
date, the last date of exposure to 
study treatment is the date prior to 
the start of the next BAT, date of 
death or the date of last contact, 
respectively.
If the derived last date of exposure 
goes beyond the data cutoff date, it 
should be truncated to the date of 
data cutoff.
Example 4: For a study treatment
which antibody persists in vivo for 
28 days, the last date of exposure 
is the date of last administration + 
28 days – 1 day.
Summary of duration of exposure of study treatment in days will include categorical summaries 
(based on clinically meaningful time intervals) and continuous summaries (i.e. mean, standard 
deviation etc.) using appropriate units of time.
Duration of exposure in patient-years
The duration of exposure in patient-years is a total of the duration of exposure in years from all 
the patients in a treatment group. It will be calculated for randomized treatment (by treatment 
group) and crossover treatment, respectively.
Duration of treatment period


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Duration of randomized treatment period (days) = end date of on-randomized-treatment 
period – date of first administration of randomized treatment + 1
Duration of crossover treatment period (days) = end date of on-crossover-treatment period 
– date of first administration of crossover treatment + 1
The on-randomized-treatment period and on-crossover-treatment period are defined in Section 
2.1.1. 
The duration of randomized treatment period in days for ruxolitinib and BAT will be 
summarized by means of descriptive statistics. It will also be categorized into time intervals; 
frequency counts and percentages will be presented for the number (%) of patients in each 
interval. The duration of crossover treatment period will be summarized similarly. As patients 
randomized to BAT may crossover between Day 28 and Week 24, the time from the 
randomization to the first dose of crossover treatment will also be summarized.
Duration of treatment period in patient-years 
The duration of treatment period (randomized and crossover) in patient-years is a total of the 
duration of treatment period in years from all the patients in a treatment group. It will be 
calculated for randomized treatment (ruxolitinib vs. BAT) and crossover treatment separately. 
Cumulative dose
The planned cumulative dose for ruxolitinib refers to the total planned dose as per the protocol 
(10 mg bid) up to the last dose date. 
The actual cumulative dose of randomized ruxolitinib refers to the total actual dose of 
randomized ruxolitinib as documented in the DAR eCRF. 
The actual cumulative dose of crossover ruxolitinib refers to the total actual dose 
administered, over the duration for which the patient is on the crossover ruxolitinib as 
documented in the DAR eCRF. 
For patients who did not take any drug the cumulative dose is by definition equal to zero.
Dose intensity and relative dose intensity of ruxolitinib
Dose intensity (DI) of randomized ruxolitinib for patients with non-zero duration of exposure 
is defined as follows: 
DI (mg / day) = Actual cumulative dose (mg) of randomized ruxolitinib / Duration of exposure 
to randomized ruxolitinib (days).
Dose intensity (DI) of crossover ruxolitinib for patients with non-zero duration of exposure 
is defined as follows: 
DI (mg / day) = Actual cumulative dose (mg) of crossover ruxolitinib / Duration of exposure to 
crossover ruxolitinib (days).
For patients who did not take any drug the DI is by definition equal to zero. 
Planned dose intensity (PDI) is defined as follows:
PDI (mg / day) = Planned Cumulative dose (mg) / Duration of exposure (days).


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The protocol planned starting dose for ruxolitinib is 10 mg BID.
Relative dose intensity (RDI) is defined as follows:
RDI = DI (mg / day)  / PDI (mg / day).  
DI and RDI will be summarized for randomized and crossover ruxolitinib treatment, separately.
The actual cumulative dose, DI and RDI up to Day 28 visit, Day 56 visit and last date of 
exposure to study treatment (randomized or crossover) will be summarized. 
The number (%) of patients at total daily dose 5 mg, 10 mg, 15 mg and 20 mg will be 
summarized at Day 28 visit, Day 56 visit and last date of exposure to study treatment.
Dose reductions, interruptions or permanent discontinuations
The number of patients who have dose changes, or interruptions, and the reasons, will be 
summarized for ruxolitinib (randomized and crossover treatment separately). The number of 
patients who have dose permanent discontinuations and the reasons, will be summarized by 
treatment group.
‘Dose changed’, ‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the 
Dosage Administration CRF pages (DAR) will be used to determine the dose changes, 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 
separate interruptions. However, if the reason is the same in this mentioned multiple entries on 
consecutive days, then it will be counted as one interruption. 
2.4.2
Prior, concomitant and post therapies
2.4.2.1
Prior aGvHD treatment
The number and percentage of patients who received any prior aGvHD treatment (medications 
and procedures) will be summarized by lowest ATC class, preferred term and treatment arm. 
Listings will be produced for prior aGvHD treatment. 
The above analyses will be performed using the FAS.
2.4.2.2
Prior prophylaxis
The number and percentage of patients who received any prophylaxis prior to randomization 
will be summarized by lowest ATC class, preferred term and treatment arm using FAS. 
The number and percentage of patients who received prior aGvHD therapy that started before 
aGvHD diagnosis date and continued after diagnosis will be summarized by lowest ATC class, 
preferred term and treatment arm using FAS.
Listings will be generated for prophylaxis.


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2.4.2.3
Systemic corticosteroid
Doses of methylprednisolone will be converted to prednisone equivalents by multiplying the 
methylprednisolone dose by 1.25.
The weight-adjusted doses will be calculated by dividng the baseline weight (last measurement 
on or before the randomization).
The duration of exposure and the peak dose will be summarized for pre-randomizatition period, 
between screening and randomization.
The duration of exposure will be summarized for on-randomized-treatment period and on-
crossover-treatment period separately. It will also be categorized into time intervals; frequency 
counts and percentages will be presented for the number (%) of patients in each interval. The 
actual cumulative dose, dose intensity and relative dose intensity (relative to the starting dose 
of corticosteroids) will be summarized up to Day 28 visit, Day 56 visit and end of on-treatment 
period. These analyses will be based on Safety Set. The data will be reported on the DAR eCRF 
through the end of randomized treatment per EOT Disposition eCRF, and on the Prior and 
Concomitant Medications eCRF after the end of randomized treatment. The list of systemic 
corticosteroid will be documented in Data Handling Plan.
2.4.2.4
Calcineurin inhibitors (CNIs) during study treatment
The duration of exposure will be summarized for CNIs (cyclosporine or tacrolimus) during on-
randomized-treatment period and on-crossover-treatment period, respectively. It will also be 
categorized into time intervals; frequency counts and percentages will be presented for the 
number (%) of patients in each interval. These analyses will be based on Safety Set. The data 
will be reported on the DAR eCRF through the end of randomized treatment per EOT 
Disposition eCRF, and on the Prior and Concomitant Medications eCRF after the end of 
randomized treatment. The list of CNIs will be documented in Data Handling Plan.
2.4.2.5
Additional systemic aGvHD therapy
New additional systemic aGvHD therapy (medications and procedures) since start of study 
treatment will be listed and summarized by lowest ATC class, preferred term, overall and by 
treatment group by means of frequency counts and percentages using FAS.
2.4.2.6
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 


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MedDRA and summarized by SOC and preferred term. The summaries for randomized 
treatment phase using Safety Set will include:

Medications starting on or after the start of randomized treatment but no later than end of 
on-randomized-treatment period; and

Medications starting prior to start of randomized treatment and continuing after the start of 
randomized treatment.
The summaries for crossover treatment phase using Crossover Analysis Set will include:

Medications starting on or after the start of crossover treatment but no later than end of 
on-crossover-treatment period; and

Medications starting prior to start of crossover treatment and continuing after the start of 
crossover treatment.
All concomitant therapies will be listed using Safety Set. Any concomitant therapies starting
and ending prior to the start of randomized treatment or starting beyond end of on-randomized-
treatment period if not crossed over, or starting beyond end of on-crossover-treatment period if 
crossed over, will be flagged in the listing. 
The prohibited concomitant medications will be summarized by lowest ATC class and preferred 
term up to the end of on-randomized-treatment and on-crossover-treatment periods, 
respectively. The list of prohibited medications will be provided and updated regularly by 
clinical team according to the clinical database review. The topical medications are excluded 
from the list.
In addition, a subset of concomitant medications i.e. transfusions (red blood cells and platelets) 
will be grouped and summarized by treatment group. 
The aGvHD prophylaxis on or after treatment start will be summarized by lowest ATC class, 
preferred term and treatment arm using FAS.
2.5
Analysis of the primary objective
The primary objective of the study is to compare the overall response rate (ORR) at Day 28
between the ruxolitinib arm and BAT arm  in steroid refractory aGvHD patients.
2.5.1
Primary endpoint
The primary endpoint was reported in the primary analysis, and will not be repeated in this final
analysis, except for the subgroup analyses.
ORR at Day 28 is defined as the proportion of patients with complete response (CR) or partial 
response (PR) at Day 28 according to standard criteria [Harris 2016].  Note that response is 
relative to the assessment of aGvHD at randomization.

Complete response is defined as a score of 0 for the aGvHD grading in all evaluable 
organs that indicates complete resolution of all signs and symptoms of aGvHD in all 
evaluable organs without administration of additional systemic therapies for any earlier 
progression, mixed response or non-response of aGvHD.  

Partial response is defined as improvement of 1 stage in 1 or more organs involved with 
aGvHD signs or symptoms without progression in other organs or sites without 


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administration of additional systemic therapies for an earlier progression, mixed response 
or non-response of aGvHD.  

Lack of response is defined as no response, mixed response, or progression.

No response is defined as absence of improvement in any organ involved by aGvHD, 
without worsening in any involved organ.  

Mixed response is defined as improvement of at least 1 stage in the severity of 
aGvHD in at least one organ accompanied by progression in another organ or 
development of signs or symptoms of aGvHD in a new organ.

Progression is defined as worsening in 1 or more organs by 1 or more stages without 
improvement in any involved organ
A flare in aGvHD is defined as any increase in signs or symptoms of  aGvHD after an initial 
response (CR or PR). However, a flare may not lead to progression or additional systemic 
therapy. Only flares in GvHD that require new additional systemic therapy, will be considered 
aGvHD flare failure. Patients who fail corticosteroid taper fulfilling either one of the following 
criteria should initiate additional systemic therapy:

Requirement for an increase in the corticosteroid dose to methylprednisolone ≥2 
mg/kg/day (or equivalent  prednisone dose ≥2.5 mg/kg/day), OR   

Failure to taper the methylprednisolone dose to <0.5 mg/kg/day (or equivalent prednisone
dose <0.6 mg/kg/day) for a minimum 7 days.
A patient will not be considered a responder at Day 28 if any of the following events occurs:

Missing aGvHD assessment at baseline or Day 28 

No CR or PR at Day 28 

Additional systemic therapy for aGvHD prior to Day 28
Compared to the protocol version 00, ‘discontinuation from randomized treatment’ has been 
dropped as reason.  Since some BATs have fixed duration which is less than 8 weeks, to avoid 
bias, discontinuation from randomized treatment will not be used to disqualify the response or 
durable response. Also duration of response will not be censored based on treatment 
discontinuation.
Acute GvHD will be assessed according to standard criteria [Harris 2016], as described in 
protocol Appendix 1. Grade will be calculated based on the staging of the organs and recorded 
on the eCRF by the Investigator. The Investigator reported grade will be used for randomization 
and reported grade and response for all analyses. Grade and response will be calculated by the 
sponsor for the purposes of data review only and sensitivity analysis. 
2.5.2
Statistical hypothesis, model, and method of analysis
The primary efficacy analysis is the comparison of ORR at Day 28 between the two treatment 
arms. The following statistical hypotheses will be tested to address the primary efficacy 
objective: 
H0: ORRrux ≤ ORRBAT  vs.   H1: ORRrux > ORRBAT
where ORRrux and ORRBAT are the overall response rates at Day 28 in the ruxolitinib and BAT 
groups, respectively. The Cochrane-Mantel-Haenszel chi-square test, stratified by the 






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2.5.5
ORR at Crossover Day 28 
ORR at Crossover Day 28 is defined as the proportion of crossover patients with complete 
response (CR) or partial response (PR) at Crossover Day 28 according to standard criteria 
[Harris 2016]. ORR will be summarized using descriptive statistics (N, %) along with two-sided 
exact binomial 95% CIs [Clopper and Pearson 1934] based on the CAS using local investigators’ 
review of aGvHD assessment data. Note that response is relative to the last assessment of 
aGvHD prior to or at the start date of crossover treatment (ruxolitinib).
A patient will not be considered a responder at Crossover Day 28 if any of the following events 
occurs:

Missing aGvHD assessment at Crossover baseline or Crossover Day 28 

No CR or PR at Crossover Day 28 

Additional systemic therapy for aGvHD prior to Crossover Day 28
In addition, shift tables of aGvHD stage by organ and treatment group will be produced to 
compare Crossover baseline to Crossover Day 28.
2.6
Analysis of the key secondary objective
The key secondary objective of the study is to determine whether treatment with ruxolitinib has 
better durable ORR at Day 56 compared with BAT.
2.6.1
Key secondary endpoint
The key secondary endpoint was reported in the primary analysis, and will not be repeated in 
this final analysis.
Durable ORR at Day 56 is defined as the proportion of all patients in each arm who achieve a 
complete response (CR) or partial response (PR) at Day 28 and maintain a CR or PR at Day 56. 
If a patient is a CR at Day 28 and a PR at Day 56, he/she will be considered as a durable 
responder. A patient will not be considered a durable responder at Day 56 if any of the following 
events occurs:

Not a  responder at Day 28

Missing aGvHD assessment at Day 56 

No CR or PR at Day 56. 

Additional systemic therapy for aGvHD prior to Day 56
Durable ORR will be calculated based on the FAS using local investigators review of aGvHD
assessment data. 
The patients randomized to BAT who meet cross-over criteria and cross-over to ruxolitinib 
are considered to have the additional systemic therarpy for aGvHD, and will not be 
considered as a responder afterwards.
In addition, shift tables of aGvHD stage by organ and treatment group will be produced to 
compare Day 28 to Day 56 value for the patients who achieved PRs at Day 28.




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In addition, shift tables of aGvHD stage by organ and treatment group will be produced to 
compare Crossover Day 28 to Crossover Day 56 value for the patients who achieved PRs at 
Crossover Day 28.
2.7
Analysis of secondary efficacy objective(s)
The other secondary efficacy objectives are to: 

Evaluate the two treatment arms with respect to ORR at other time points, e.g. Day 14

Evaluate the two treatment arms with respect to duration of response (DOR)

Evaluate the two treatment arms with respect to overall survival (OS)

Evaluate the two treatment arms with respect to event free survival (EFS)

Evaluate the two treatment arms with respect to failure free survival (FFS)

Evaluate the two treatment arms with respect to Non-relapse mortality (NRM)

Evaluate the two treatment arms with respect to incidence of malignancy 
relapse/progression (MR)

Describe cumulative steroid dosing until Day 56 and until EOT in each treatment arm

Evaluate the two treatment arms with respect to incidence of cGvHD

Evaluate the two treatment arms with respect to BOR at any time points up to Day 28
All the secondary efficacy endpoint analyses are non-comparative in nature and will be 
analyzed using the Full Analysis Set (FAS).
2.7.1
Secondary efficacy endpoints
Overall Response Rate at Day 14
Overall Response Rate at Day 14 is defined as the proportion of patients with complete response 
(CR) or partial response (PR) at Day 14 according to standard criteria [Harris 2016]. This 
endpoint was reported in the primary analysis, and will not be repeated in this final analysis.
Duration of response (DOR)
Duration of response is defined for patients whose overall response at Day 28 is complete 
response (CR) or partial response (PR) according to standard criteria [Harris 2016]. The start 
date is the date of first documented response of CR or PR (i.e., the start date of response), which 
could be prior to or at Day 28. If it’s prior to Day 28, there should not be progression or addition 
of systemic therapies for aGvHD between the start date of response and Day 28. The end date 
is defined as the date of progression or the date of addition of systemic therapies for aGvHD on 
or after Day 28.
Death without prior observation of aGvHD progression and onset of chronic GvHD are 
considered to be competing risks.
Duration of response will be censored at the last response assessment prior to or at the analysis 
cut-off date, if no events/competing risk occurred before or at the cut-off date.  
Overall survival (OS) 


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Overall survival 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 latest date the 
patient was known to be alive (on or before the cut-off date). 
Event Free Survival (EFS)
Event-free survival is defined as the time from the date of randomization to the date of 
hematologic disease relapse/progression, graft failure or death due to any cause. If a patient is 
not known to have any event, then EFS will be censored at the latest date the patient was known 
to be alive (on or before the cut-off date). 
Failure Free Survival (FFS)
Failure-free survival is defined as the time from the date of randomization to date of 
hematologic disease relapse/progression, non-relapse mortality or addition of new systemic 
aGvHD treatment. 
Non-relapse mortality (NRM) 
Non-relapse mortality is defined as the time from date of randomization to date of death not 
preceded by hematologic disease relapse/progression. Hematologic disease relapse/progression 
is considered a competing risk for NRM with the date of hematologic disease 
relapse/progression being the earlier of documented hematologic disease relapse/progression or 
institution of therapy to treat potential hematologic disease relapse/progression. If a patient is 
not known to have died or to have relapsed/progressed, then NRM will be censored at the latest 
date the patient was known to be alive (on or before the cut-off date). 
Incidence of Malignancy Relapse/Progression (MR)
Malignancy relapse/progression is defined as the time from date of randomization to 
hematologic malignancy relapse/progression. Deaths not preceded by hematologic malignancy 
relapse/progression are competing risks. If a patient is not known to have event or competing 
risks, then MR will be censored at the latest date the patient was known to be alive (on or before 
the cut-off date). 
Incidence of cGvHD
cGvHD is defined as the diagnosis of any cGvHD including mild, moderate, severe. Incidence 
of cGvHD is the time from date of randomization to onset of cGvHD. Deaths without prior 
onset of cGvHD and hematologic disease relapse/progression are competing risks. If a patient 
is not known to have event or competing risks, then the incidence of cGvHD will be censored 
at the latest date the patient was known to be alive (on or before the cut-off date).  
Best Overall Response
Best overall response (BOR) is defined as proportion of patients who achieved overall response 
(CR or PR) at any time point up to and including Day 28, and had no additional systemic 
therapy for aGvHD prior to the time point. This endpoint was reported in the primary analysis, 
and will not be repeated in this final analysis.   
2.7.2
Statistical hypothesis, model, and method of analysis
Overall Response Rate at Day 14 


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Overall response rate will be calculated based on the local investigators review of aGvHD
assessment data. It will be summarized using descriptive statistics (N, %) by treatment arm 
along with two-sided exact binomial 95% CIs [Clopper and Pearson 1934]. Odds ratio and 95% 
Wald confidence limits calculated from stratified Cochran-Mantel-Haenszel test will be also 
presented.
Duration of response (DOR)
The estimated cumulative incidence rates and 95% confidence intervals at 1, 2, 6, 12, 18 and 
24 months will be presented for each treatment group. The cumulative incidence curve will be 
plotted. DOR will be listed and summarized by treatment group for all patients in the FAS with 
overall response of CR or PR at Day 28.  
Overall survival (OS) 
OS will be analyzed according to the randomized treatment group and strata assigned at 
randomization (aGvHD grade: Grade II vs. III vs. IV). The OS distribution will be estimated 
using the Kaplan-Meier method, and the Kaplan-Meier curves, medians, 1, 2, 6, 12, 18 and 24 
month survival estimates and 95% confidence intervals [Brookmeyer and Crowley 1982] will 
be presented for each treatment group. The hazard ratio for OS will be calculated, along with 
its 95% confidence interval, using a stratified Cox model. 
OS follow-up time will be summarized by treatment group for all patients in FAS. It will also 
be categorized into time intervals; frequency counts and percentages will be presented for the 
number (%) of patients in each interval.
Event Free Survival (EFS)
EFS will be analyzed according to the randomized treatment group and strata assigned at 
randomization. The EFS distribution will be estimated using the Kaplan-Meier method, and the 
Kaplan-Meier curves, medians, 1, 2, 6, 12, 18 and 24 month survival estimates and 95% 
confidence intervals [Brookmeyer and Crowley 1982] will be presented for each treatment 
group. The hazard ratio for EFS will be calculated, along with its 95% confidence interval, 
using a stratified Cox model.
A sensitivity analysis including aGvHD progression as an event will be performed using the
same approach.
Failure Free Survival (FFS)
Cumulative incidence curve for FFS as well as estimates at 1, 2, 6, 12, 18 and 24 months with 
95% confidence intervals will be presented for each treatment group, accounting for onset of 
chronic GvHD as the competing risk. 
The FFS distribution will be estimated using the Kaplan-Meier method, and the Kaplan-Meier 
curveswill be presented for each treatment group. The hazard ratio for FFS will be calculated, 
along with its 95% confidence interval, using a stratified Cox model.
In addition, the cumulative incidence of each of the three components considering the other two 
components as a competing risks will be estimated. Onset of chronic GvHD is considered as a 
competing risk for all three types of failure. The cumulative incidence curves will be plotted for 
each treatment group. 






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2.8.1
Adverse events (AEs)
For reporting of AEs the overall observation period will be divided into mutually exclusive 
categories, including pre-treatment, on-treatment (randomized or crossover), post-treatment  
periods as defined in Section 2.1.1.
AE summaries will include all AEs occurring (new or worsening) during on-treatment period. 
All AEs collected in the AE eCRF page will be listed along with the information collected on 
those AEs e.g. AE relationship to study drug, AE outcome etc. AEs with start date outside of 
on-treatment period will be flagged in the listings. 
AEs will be summarized by number and percentage of patients 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 patient with multiple occurrences of an AE will be counted only 
once in the respective AE category. A patient with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event.
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables.
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 the descending frequency in the ruxolitinib arm.
The following adverse event summaries will be produced by treatment arm; overview of 
adverse events and deaths, 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, and leading to fatal outcome. In 
addition, a summary of serious adverse events with 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
AEs adjusted for patient duration of treatment period 
In order to account for differences in exposure of the ruxolitinib arm relative to the BAT arm 
due to crossover from BAT to ruxolitinib after Day 28 visit, incidence rates of adverse events 
may be presented by adjusting for duration of treatment period in patient-years where relevant.
2.8.1.2
Adverse events of special interest / grouping of AEs
Data analysis of AESIs
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to compound ruxolitinib. These groupings are defined using MedDRA 
terms, SMQs (standardized MedDRA queries), HGLTs (high level group terms), HLT (high 
level terms) and/or PTs (preferred terms). Customized SMQs (Novartis MedDRA queries, 
NMQ) may also be used. A NMQ is a customized group of search terms which defines a medical 
concept for which there is no official SMQ available or the available SMQ does not completely 
fit the need. It may include a combination of single terms and/or an existing SMQ, narrow or 
broad. 


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For each AESI (selection from the Case Retrieval Sheet), number and percentage of patients 
with at least one event of the AESI occurring during on-treatment period will be summarized.
Summaries of AESIs will be provided by treatment arm, (specifying grade, SAE, relationship, 
leading to treatment discontinuation, leading to dose adjustment/interruption, hospitalization, 
death etc.).
A listing of all grouping levels down to the MedDRA preferred terms used to define each AESI 
will be generated. 
In addition to summarizing infections by CTCAE grade, they will also be summarized using 
infection severity (protocol Appendix 2) up to Day 31 (the upper bound of the Day 28 visit 
window), and cutoff date. Summary of infections by SOC, HLGT, HLT and PT up to Day 31, 
and cutoff date will be generated.
Proportion of patients developing second primary malignancies will be summarized for on-
treatment period, post-treatment period and both.
2.8.2
Deaths
Separate summaries for on-treatment and all deaths (including post-treatment death and 
crossover-period death) will be produced by treatment arm, system organ class and preferred 
term. 
All deaths will be listed and post-treatment deaths will be flagged. A separate listing of deaths 
prior to starting treatment will be provided for all screened patients.
2.8.3
Laboratory data
On analyzing laboratory, data from all sources (central and local laboratories) will be combined. 
The summaries will include all assessments available for the lab parameter collected no later 
than end of the on-treatment periods (randomized or crossover).
Grading of laboratory 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.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
The following summaries will be produced for hematology and biochemistry laboratory data 
(by laboratory parameter and treatment):

Shift tables using CTC grades to compare baseline to the worst on-treatment  value 

Shift tables using CTC grades to compare baseline to Day 28
The following listings will be produced for the laboratory data:

Listings of all laboratory data, with CTC grades and classification relative to the 
laboratory normal range. Lab data collected during the post-treatment period will be 
flagged.  

Listing of all CTC grade 3 or 4 laboratory toxicities


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In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots may be 
produced.
The categorical analysis of hepatic lab values will be summarized for both randomizd treatment 
period and crossover treatment period, displayed in a separate table. Please use the Novartis 
Hepatotoxicity Guideline ‘Update to Hepatic lab values TFLs_released 28Feb2020’ for 
reference. The table of categorical hepatic lab values should now flag ‘Combined elevations 
post-baseline’ where ‘combined elevations’ are ‘based on the peak values at any post-baseline 
time for a subject’. 
The following listings will be produced for the laboratory data:

Listings of hepatic laboratory data, with CTC grades and classification relative to the 
laboratory normal range. Lab data collected during the post-treatment period will be 
flagged. 
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
Not applicable.
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 mass index (kg/m2), body 
temperature (°C), pulse (beats per minute), systolic and diastolic blood pressure (mmHg). 
Data handling
Vital signs collected 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 clinically notable vital sign criteria are provided in Table 2-5
below.
Table 2-5
Clinically notable changes in vital signs
Vital sign 
(unit)
Clinically notable criteria
above normal value 
below normal value
Weight (kg)
increase > 10% from Baseline
decrease  > 10% from Baseline
Systolic blood 
pressure 
(mmHg)
>=180 with increase from baseline 
of >=20
<=90 with decrease from baseline 
of >=20
Diastolic blood 
pressure 
(mmHg)
>=105 with increase from baseline 
of >=15
<=50 with decrease from baseline 
of >=15


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Vital sign 
(unit)
Clinically notable criteria
above normal value 
below normal value
Pulse rate 
(bpm)
>=100 with increase from baseline 
of >25%
<=50 with decrease from baseline of 
> 25%
Body 
temperature
>= 39.1 
-
The number and percentage of patients with notable vital sign values (high/low) will be 
presented  by treatment arm.         
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. 
Additional Analyses
Time to first occurrence of grade 3 infection
Time to first occurrence of infection is defined as time from start of study treatment to the date 
of first occurrence of grade 3 infection severity per protocol Appendix 2, i.e. time in days is 
calculated as (start date of first occurrence of infection ) – (start of study treatment) +1. 
In the absence of an event during the on-treatment period, the censoring date applied will be 
the earliest of the following dates: 

death date

end date of on-treatment period  (randomized or crossover) 

data cut-off date

withdrawal of informed consent date
Failure curves (ascending Kaplan-Meier curves) will be constructed by treatment arm. Median 
together with 95% confidence interval as well as 25th percentile and 75th percentile will be 
presented for each treatment arm. 
A sensitivity analysis will be conducted considering deaths or end of treatment phase 
(randomized or crossover) without prior infection as competing risks. Cumulative incidence 
curve for time to grade 3 infection as well as estimates at 1, 2 and 6 months with 95% confidence 
intervals will be presented for each treatment group. 
In addition, the median time to occurrence for the subset of patients who experienced infection 
will be calculated. Simple descriptive statistics, median, min and max as well as 25th percentile 
and 75th percentile, will be presented.
2.9
Pharmacokinetic endpoints
The pharmacokinetic endpoints were reported in the primary analysis, and has not been reported 
in the second analysis. Further results will be presented in the full analysis. 


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Pharmacokinetic Analysis Set (PAS) will be used in all pharmacokinetic data analysis and PK 
summary statistics. 
Plasma samples for extensive PK will be taken at Day 1 (start of treatment), at Day 7 (week 1) 
for the first 25 adult patients and all adolescents to characterize the PK after first dose, and at 
steady state by non-compartmental analysis.  Additional PK samples will be taken at later visits 
for all patients to characterize exposure-efficacy, exposure-safety 
 
as data allows. Concentrations will be expressed in mass per volume units.
PK parameters
The PK parameters that will be determined are shown in Table 2-6. The PK parameters of 
ruxolitinib will be calculated from the extensive PK data based on the non-compartmental 
methods using Phoenix WinNonlin® (Pharsight, Mountain View, CA) software. Additional PK 
parameters may be estimated as needed.
Table 2-6
Non-compartmental PK parameters for ruxolitinib
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) (ng 
x hr/mL)
AUCinf 
The AUC from time zero to infinity (ng x hr/mL)
AUCtau 
The AUC calculated to the end of a dosing interval (12 hr) at steady-state (ng x hr/mL)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (ng/mL)
Ctrough
The observed plasma concentration obtained prior to administration of the next dose 
(pre-dose concentration) (mass x volume-1)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (thr)
Lambda_z
Smallest (slowest) disposition (hybrid) rate constant (hr-1) may also be used for 
terminal elimination rate constant (hr-1)
T1/2
The elimination half-life associated with the terminal slope (z) of a semi logarithmic 
concentration-time curve (hr). 
CL/F
The total body clearance of drug from the plasma (L/hr)
Vz/F
The apparent volume of distribution during terminal phase (associated with z) (L)
Racc
Accumulation ratio (AUC at steady state/AUC Day 1)
Descriptive statistics (n, arithmetic mean, CV% mean, standard deviation (SD), median, 
geometric mean, CV% geo-mean, minimum and maximum) will be presented for the ruxolitinib 
arm for Pharmacokinetic Analysis Set for all PK parameters defined in Table 2-6 except Tmax, 
where only n, median, minimum and maximum will be presented. 
All individual PK parameters will be listed for the ruxolitinib arm using the Full Analysis Set.
The potential impact of severity of GI GvHD on ruxolitinib pharmacokinetic parameters will 
be explored by summarizing PK parameters by baseline lower GI stage and producing box plots 
of AUCinf, AUCtau and Cmax by lower GI stage.




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Missing values for any PK data will not be imputed and will be treated as missing.
2.10
PD and PK/PD analyses
Analysis of relationship between ruxolitinib exposure and efficacy/safety
endpoints
This analysis will be described and reported separately to the CSR. The following are objectives 
for exposure-response analysis:

Characterize the exposure-efficacy relationship of ruxolitinib in terms of exposure and 
efficacy response, with efficacy response defined as( overall response rate at Day 28 and 
durable response at Day 56, duration of response, overall survival at 6 months and any 
other relevant endpoints, and exposure defined plasmaconcentration, PK parameter or 
dose, as appropriate) 

Characterize the exposure-safety relationship of ruxolitinib in terms of exposure and
safety response, where safety response is defined as various categorizations of AEs
(frequency of;severity of AEs, AEs of interest to be defined prior to analysis or laboratory 
parameters).

Average steady-state exposures and/or other PK parameters for the population will 
becomputed by the POP PK model accounting for dose modifications or dose 
interruptions up to the day prior to the day of assessments. Population PK derived 
parameters will be used for exposure-response analysis by appropriate methods
For duration of response and overall survival, if the primary endpoint is significant and 
sufficient events have accrued (i.e., at analysis time points after the primary analysis), a Cox 
regression model with appropriate patient demographic and prognostic factors as covariates and 
the log-trough level as a time dependent covariate will be fitted if appropriate. To account for 
dose adjustments between trough sampling time points the trough concentration will be adjusted 
by dividing by the actual dose prior to the trough in question and multiplying by the arithmetic 
mean dose since the last trough sample or start of dosing as applicable. The calculation of the 
arithmetic mean dose should count any dose interruptions as a zero dose for the days that no 
dose was given. Goodness of fit of the model will also be examined. The survival time should 
be calculated from the time of first dose rather than the time of randomization. The hazard ratio 
and 95% confidence interval for a two-fold increase in exposure will be displayed if appropriate. 
Kaplan-Meier curves may be used to summarize the data based on relevant quantiles of PK.
For incidence of specific AEs, Day 28 response (if the primary endpoint is significant) and Day 
56 durable response (if the primary and key secondary endpoints are significant), logistic 
regression models may be used including log-average trough concentration and other 
demographic and prognostic covariates in the model as appropriate. The trough concentration 
will be similarly adjusted to account for dose adjustments as described above. The average 
trough concentration included in the model for Day 28 response will be the arithmetic mean of 
the Day 7, Day 14, Day 21 and Day 28 adjusted trough concentration. A similar average trough 
concentration will be calculated for the Day 56 response except the Day 42 and Day 56 adjusted 
concentration will be double weighted compared to the others because they are representative 
of concentration over 2 weeks rather than 1. For analysis of adverse events the last trough 










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assuming that the ratio of aGvHD Grade II: III: IV is 0.2:0.4:0.4. It is expected that treatment 
with ruxolitinib will result in an 18% increase in the ORR, i.e., an expected odds ratio of 2.25 
(which corresponds to an increase in ORR to 75%). Power for the CMH test, stratifying on 
aGvHD grade, was calculated using software package East V6. In order to ensure 90% power
a total sample size of 308 patients are needed. 
With a sample size of 154 patients in each treatment arm, an observed odds ratio greater than 
or equal to 1.63 would achieve statistical significance for the primary endpoint. Assuming that 
the observed response rates in Grades II/III/IV in BAT arm are 69%/59%/50% (overall 57%), 
observed response rates ≥ 78%/70%/62% (overall 68%) in the ruxolitinib arm would achieve 
statistical significance.
3.2
Power for analysis of key secondary variables
Durable ORR at Day 56, as the key secondary variable, will be formally statistically tested, 
provided that the primary endpoint ORR at Day 28 is statistically significant. The hypotheses 
to be tested and details of the testing strategy are provided in Section 2.6.2. Based on [Van 
Groningen 2016], the durable ORR at Day 56 in the BAT arm is expected to be approximately 
35%. The stratum specific rates (Grade II 45%, Grade III 36%, Grade IV 30%) are obtained 
assuming that the ratio of aGvHD Grade II: III: IV is 0.2:0.4:0.4. It is expected that treatment 
with ruxolitinib will result in a 20% increase in the ORR, i.e., an expected odds ratio of 2.25 
(which corresponds to an increase in durable ORR to 55%). With these assumptions and sample 
size of 308 patients, the power for the key secondary endpoint is at least 90%.
With sample size 154 patients in each treatment arm, an observed odds ratio greater than or 
equal to 1.59 for durable ORR at Day 56 would achieve statistical significance. Assuming that 
the observed durable response rates in Grades II/III/IV in BAT arm are 45%/36%/30% (overall 
35%), observed durable response rates ≥ 57%/47%/41% (overall 47%) in the ruxolitinib arm 
would achieve statistical significance.
4
Change to protocol specified analyses
Compared to the protocol version 00, ‘discontinuation from randomized treatment’ has been 
dropped as reason.  Since some BATs have fixed duration which is less than 8 weeks, to avoid 
bias, discontinuation from randomized treatment will not be used to disqualify the response or 
durable response. Also duration of response will not be censored based on treatment 
discontinuation.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
The following rule should be used for the imputation of the dose end date for a given study 
treatment component:


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Scenario 1: If the dose end date is completely missing and there is no EOT page and no death 
date, the patient is considered as on-going: 
The patient should be treated as on-going and the cut-off date should be used as the dose end 
date.
Scenario 1 should not be applied for final CSR. All patients should have EOT page complete 
before the Database lock for Final CSR
Scenario 2: If the dose end date is completely or partially missing and the EOT page is available: 
Please note that date of assessment on EOT eCRF might be very different from last date of dose. 
Case 1: The dose end date is completely missing, and the EOT  completion date is complete, 
then this latter date should be used.  
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:  
Use Dec31yyyy
Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date: 
Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy  = the year 
of EOT date and mm < the month of  EOT date: 
Use last day of the Month (mm)
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study.
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:
Use the treatment start date
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed.
5.1.2
AE, ConMeds and safety assessment date imputation
Table 5-1
Imputation of start dates (AE, CM) and assessments (LB, EG, VS)
Missing 
Element
Rule
day, month, 
and year

No imputation will be done for completely missing dates
day, month

If available year = year of study treatment start date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY 
o
Else set start date = study treatment start date. 

If available year > year of study treatment start date then 01JanYYYY


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Missing 
Element
Rule

If available year < year of study treatment start date then 01JulYYYY
day

If available month and year = month and year of study treatment start 
date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY. 
o
Else set start date = study treatment start date.

If available month and year > month and year of study treatment start 
date then 01MONYYYY  

If available month and year < month year of study treatment start date 
then 15MONYYYY  
Table 5-2
Imputation of end dates (AE, CM) 
Missing 
Element
Rule 
(* if end date of the on-treatment period not > (death date, cut-off date, 
withdrawal of consent date))
day, month, 
and year

Completely missing end dates (incl. ongoing events) will be imputed 
by the end date of the on-treatment period* 
day, month

If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period * 
day

If partial end date contains month and year, set end date = earliest of 
last day of the month or end date of the on-treatment period*
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings.
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ 
rather than the end date provided. 
The above imputations are only used for analyses of time to and duration of AEs and 
concomitant medications. 
5.1.2.1
Other imputations
Incomplete date of initial diagnosis of aGvHD 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan. 
5.2
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
The latest available MedDRA version at the time of the analyses should be used. The MedDRA 
version used should be specified in the footnote of relevant tables.  


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AEs will be assessed 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). 
5.3
Laboratory parameters derivations
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. 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. 
CTCAE Grade 5 is not defined for laboratory values. 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.
Imputation Rules  
CTC grading for blood differentials is based on absolute values. However,  this data may not 
be reported as absolute counts but rather as percentage of WBC. 
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential
xxx count = (WBC count) * (xxx %value / 100)
Further derivation of laboratory parameters might be required for CTCAE grading. For instance, 
corrected calcium can be derived using the reported total calcium value and albumin at the same 
assessment using the following formula:
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4]
In order to apply the above formula, albumin values in g/L will be converted to g/dL by  
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium.
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above for grading.


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5.4
Statistical models
5.4.1
Primary analysis
The null hypothesis of equality of response rate in the two treatment arm will be tested against 
one-sided alternative.  The statistical hypotheses are:
H0: ORRrux ≤ ORRBAT  vs.   H1: ORRrux > ORRBAT
where ORRrux is the probability of response in ruxolitinib and ORRBAT is the probability  of 
response in BAT.
The Cochran-Mantel-Haenszel chi-square test X2
CMH (implemented again via SAS procedure
FREQ with CMH option in the TABLES statement) will be used to test the difference in
response rates between the treatment arms. The p-value corresponding to the CMH test for 
“general association” will be used which follows a Chi-square distribution with one degree of 
freedom.
If the sampling assumptions for chi-square test is not met, the exact Cochran-Mantel-Haenszel test
will be used (implemented via SAS procedure MULTTEST). The test is performed by running
a stratified version of the Cochran-Armitage permutation test [Armitage et al. 1969]. In studies 
with stratified randomization,  the  chi-square  approximation  is  considered  appropriate  for  
the  X2
CMH statistics if the rule of Mantel and Fleiss [Mantel and Fleiss 1980] is satisfied.
Logistic Regression 
Odds ratio will be used as a measure of association between treatment and response. The odds 
ratio will be derived from the logistic regression model (implemented using SAS procedure 
LOGISTIC, with treatment specified as an explanatory variable in the CLASS statement) 
which allows for including not only the stratification factor but also for adjustments for other 
covariates (both categorical and continuous). The odds ratio will be presented with 95% Wald 
confidence limits.
In cases where an exact test has been used to compare response rates, the odds ratio should be 
determined using exact logistic regression, and the odds ratio presented with exact 95% 
confidence limits. In these cases, SAS PROC LOGISTIC with EXACTONLY option will be 
used.
Confidence interval for response rate
Responses will be summarized in terms of percentage rates with 100(1 −α)% confidence 
interval using exact binomial confidence interval (implemented using SAS procedure FREQ
with EXACT statement for one-way table [Clopper and Pearson 1934].
Definition of new or additional systemic therapy for aGvHD
The data source to search for the new or additional systemic therapy would be from eCRFs of 
Prior and Concomitant Medication (CONMED) (with subcategory as treatment for aGvHD) 
and Dosage Administration Record (DAR).
Any of the following therapies represent new or additional systemic therapy for aGvHD: 


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1. Any new CNI therapy being initiated as ‘treatment for aGvHD’ after the baseline as 
recorded either on DAR or on CONMED, and never received prior to or at baseline
2. Any other systemic therapy (excluding CNI or systemic corticosteroid
(methylprednisolone, prednisone and prednisolone)) being started as ‘treatment for
aGvHD’ after the baseline and recorded on CONMED. Note: the therapy may have been 
taken prior to baseline but not at baseline.
3. Additional BAT at or after start of the initial BAT as recorded on DAR
4. Treatment with ruxolitinib after cross-over from BAT as recorded on DAR
5.4.2
Key secondary analysis
Same instructions as in Section 5.4.1.
5.4.3
Other secondary analysis
5.4.3.1
FACT-BMT
For FACT-BMT the subscale scores, the FACT-BMT total score and the FACT-BMT Trial 
Outcome Index (TOI) will be calculated. 
The subscales are physical well-being (PWB), social/family well-being (SWB), emotional well-
being (EWB), functional well-being (FWB) and bone marrow transplant subscale (BMTS).  For 
each subscale the corresponding score will be calculated based on the item response of the 
answered question according to the FACT-BMT Scoring Guide (Version 4). The scoring guide 
identifies those items that must be reversed before being added to obtain subscale totals.  
Negatively stated items are reversed by subtracting the response from “4”.  After reversing 
proper items, all subscale items are summed to a total, which is the subscale score.
If there are missing items, subscale scores can be prorated.  This is done by multiplying the sum 
of the subscale by the number of items in the subscale, then dividing by the number of items 
actually answered.  This can be done by using the formula below:
Prorated subscale score 
= [Sum of item scores] x [N of items in subscale]/[N of items answered]   
When there are missing data, prorating by subscale in this way is acceptable as long as more 
than 50% of the relevant items were answered. Note that not all items (questions) are used to 
calculate the scores (see Scoring Guide, version 4).  For all the scores the higher the score is the 
better the QOL is. 
The FACT-BMT Trial Outcome Index (TOI, score range: 0-96) is calculated as 
The FACT-BMT total score (score range: 0-148) is then calculated as the sum of all un-
weighted subscale scores:


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5.4.3.2
EQ-5D-5L
EQ-5D-5L consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression. Also the EQ-VAS is included. Each dimension has 5 levels (1-5).
The data were reported for all 5 dimensions. The proportion of reported problems for each level 
were reported. The changes from baseline were defined with a shift table. The below screenshot 
is from the Excel conversion document obtained from the EuroQol webpage on 5L Value Sets 
(http://www.euroqol.org/about-eq-5d/valuation-of-eq-5d/eq-5d-5l-value-sets.html). This UK 
value will be used to convert the “health state” to an “index value” for all patients in all countries. 
For example, if the health state is 11125, then the index value would be .316 and so on.


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6
Reference
1. Anderson JR, Cain KC and Gelber RD (1983). Analysis of survival by tumor response. 
Journal of Clinical Oncology, 1(11), 710-719.
2. Armitage P, McPherson CK and Rowe BC (1969). Repeated significance tests on 
accumulating data. J .R. Statist. Soc. A, 132, 232-244. 
3. Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival 
Time. Biometrics, 38, 29 - 41. 
4. Clopper CJ and Pearson ES (1934).  The use of confidence or fiducial limits illustrated in 
the case of the binomial.  Biometrical, 26, 404-413.
5. FDA briefing Document Oncologic Drugs Advisory Committee Meeting, July 24, 2012, 
Evaluation of radiologic review of progression-free survival in Non-hematologic 
malignancies. 
http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/on
cologicdrugsadvisorycommittee/ucm311141.pdf
6. Harris AC, Young R, Devine S, Hogan WJ, Ayuk F, Bunworasate U, Chanswangphuwana 
C, Efebera YA, Holler E, Litzow M, Ordemann R, Qayed M, Renteria AS, Reshef R, 
Wölfl M, Chen YB, Goldstein S, Jagasia M, Locatelli F, Mielke S, Porter D, Schechter T, 
Shekhovtsova Z, Ferrara JL, Levine JE. (2016) International, Multicenter Standardization 
of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount 
Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant; 22(1): 4-
10.
7. Korhonen P,  Laird NM and Palmgren J. Correcting for non-compliance in randomized 
trials: an application to the ATBC study (1999). Statistics in Medicine, 18, 2879-2897.
8. Mantel, N. and Joseph L Fleisś (1980). Minimum expected cell size requirements for the 
Mantel-Haenszel one degree-of-freedom Chi-Square Test and a related rapid procedure. 
American Journal of Epidemiology, 112, 129-134.
9. Martin PJ, Rizzo JD, Wingard JR, et al (2012) (2012) First- and second-line systemic 
treatment of acute graft-versus-host disease: recommendations of the American Society of 
Blood and Marrow Transplantation. Biol Blood Marrow Transplant; 18(8): 1150-63.
10. Robins JM and Tsiatis AA (1991). Correcting for non-compliance in randomized trials 
using rank preserving structural failure time models (RPSFTM). Commun. Statist.-Theory 
Meth., 20(8), 2609-31.
11. Van Groningen, LF, Liefferink AM, de Haan AF, Schaap NP, Donnelly JP, Blijlevens 
NM, van der Velden WJ. (2016) Combination Therapy with Inolimomab and Etanercept 
for Severe Steroid-Refractory Acute Graft-versus-Host Disease Biol Blood Marrow 
Transplant. 22(1):179-82.




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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)


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Table of contents
Table of contents .................................................................................................................3
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints ...............................................................................9
2
Statistical methods.............................................................................................................13
2.1
Data analysis general information .........................................................................13
2.1.1
General definitions................................................................................13
2.2
Analysis sets ..........................................................................................................18
2.2.1
Subgroup of interest ..............................................................................19
2.3
Patient disposition, demographics and other baseline characteristics ...................21
2.3.1
Patient disposition.................................................................................22
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................23
2.4.1
Study treatment / compliance................................................................23
2.4.2
Prior, concomitant and post therapies...................................................26
2.5
Analysis of the primary objective..........................................................................28
2.5.1
Primary endpoint...................................................................................28
2.5.2
Statistical hypothesis, model, and method of analysis..........................29
2.5.3
Handling of missing values/censoring/discontinuations.......................30
2.5.4
Supportive analyses for ORR at Day 28 ...............................................30
2.5.5
ORR at Crossover Day 28.....................................................................31
2.6
Analysis of the key secondary objective ...............................................................32
2.6.1
Key secondary endpoint........................................................................32
2.6.2
Statistical hypothesis, model, and method of analysis..........................32
2.6.3
Handling of missing values/censoring/discontinuations.......................33
2.6.4
Durable ORR at Crossover Day 56.......................................................33
2.7
Analysis of secondary efficacy objective(s)..........................................................33
2.7.1
Secondary efficacy endpoints ...............................................................34
2.7.2
Statistical hypothesis, model, and method of analysis..........................35
2.7.3
Handling of missing values/censoring/discontinuations.......................37
2.8
Safety analyses.......................................................................................................37
2.8.1
Adverse events (AEs)............................................................................38
2.8.2
Deaths....................................................................................................39
2.8.3
Laboratory data .....................................................................................39
2.8.4
Other safety data ...................................................................................40


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2.9
Pharmacokinetic endpoints....................................................................................41
2.10
PD and PK/PD analyses.........................................................................................43
2.11
Patient-reported outcomes .....................................................................................44
45
47
2.14
Interim analysis......................................................................................................48
3
Sample size calculation .....................................................................................................48
3.1
Primary analysis.....................................................................................................48
3.2
Power for analysis of key secondary variables......................................................48
4
Change to protocol specified analyses ..............................................................................49
5
Appendix ...........................................................................................................................49
5.1
Imputation rules.....................................................................................................49
5.1.1
Study drug.............................................................................................49
5.1.2
AE, ConMeds and safety assessment date imputation..........................50
5.2
AEs coding/grading ...............................................................................................51
5.3
Laboratory parameters derivations ........................................................................52
5.4
Statistical models...................................................................................................53
5.4.1
Primary analysis....................................................................................53
5.4.2
Key secondary analysis.........................................................................54
5.4.3
Other secondary analysis.......................................................................54
6
Reference...........................................................................................................................56


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List of abbreviations
AE
Adverse event
AESI
Adverse Event of Special Interest
aGvHD
Acute Graft vs. Host Disease
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
BAT
Best Available Therapy
bid
bis in diem/twice a day
BMI
BOR
Body Mass Index
Best Overall Response
BSA
Body Surface Area
cGvHD
chronic Graft vs. Host Disease
CIBMTR
Center for International Blood and Marrow Transplant Research
CMH
Cochran–Mantel–Haenszel
CMV
Cytomegalovirus
CR
Complete Response
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DAR
Dose Administration Record
DMC
Data Monitoring Committee 
eCRF
Electronic Case Report Form
EFS
Event-Free Survival
FACT-BMT
Functional Assessment of Cancer Therapy - Bone Marrow Transplantation
FAS
Full Analysis Set
FFS
Failure-Free Survival
GvHD
Graft vs. Host Disease
HCT
Hematopoietic Cell Transplantation
IRT
Interactive Response Technology that includes Interactive Voice Response
System and Interactive Web Response System
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
NRM
Non Relapse Mortality
ORR
Overall Response Rate
OS
Overall Survival
PAS
Pharmacokinetic analysis set
PD
Pharmacodynamics
PK
Pharmacokinetics
PPS
Per-Protocol Set
PR
Partial response 
PRO
Patient-reported Outcomes
QoL
Quality of Life
RAP
Report and Analysis Process


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RPSFT
Rank-Preserving Structure Failure Time
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
WBC
White Blood Cells
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the Clinical Study Report 
(CSR) of study CINC424C2301, a phase III, randomized, open-label, multi-center study of 
ruxolitinib versus best available therapy in patients with corticosteroid-refractory acute graft vs. 
host disease (aGvHD Grade II-IV) after allogeneic stem cell transplantation.
The content of this SAP is based on protocol CINC424C2301 version 02. All decisions 
regarding final analysis, as defined in the SAP document, have been made prior to database 
lock of the study data.
1.1
Study design
This is a phase III, randomized, open-label, multi-center study of ruxolitinib versus best 
available therapy in patients with corticosteroid-refractory acute graft vs. host disease after 
allogeneic stem cell transplantation. Approximately 308 patients will be  randomized to one of 
the following treatment arms in 1:1  ratio:

Ruxolitinib

BAT
Randomization will be stratified by the aGvHD grade (Grade II vs. Grade III vs. Grade IV).
Overall response rate (ORR) at Day 28, as assessed by local investigators’ review of aGvHD
response and using standard criteria [Harris 2016], is the primary endpoint in this study. Durable 
overall response rate at Day 56 is the key secondary endpoint. 
The primary analysis including the analysis on primary and key secondary endpoints was
performed with the cut-off date as 25-Jul-2019 after all patients have completed their Day 56 
visit or have discontinued study. The primary analysis data were summarized in the primary 
clinical study report (CSR). 
Further analyses on secondary endpoints will be performed when all patients have completed 6 
months treatment or discontinued from study participation earlier.
The final analysis will occur once all patients have completed the study (up to 24 months from 
randomization). All available data from all patients up to end of study, inclusive of OS, will be 
reported in a final CSR.
No formal interim efficacy analysis is planned in this study. 




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1.2
Study objectives and endpoints
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 2.5
To compare the efficacy of ruxolitinib vs. 
Investigator’s choice Best Available Therapy 
(BAT) in patients with Grade II-IV SR-aGvHD 
assessed by Overall Response Rate (ORR) at 
Day 28
Overall response rate (ORR) at Day 28 after 
randomization, defined as the proportion of 
patients in each arm demonstrating a complete 
response (CR) or partial response (PR) without 
requirement for additional systemic therapies for 
an earlier progression, mixed response or non-
response. Scoring of response will be relative to 
the organ stage at the time of randomization.
CMH analyses, stratified by aGvHD grade
Key secondary endpoint
Refer to Section 2.6
To compare the rate of durable ORR at Day 56 
between ruxolitinib and BAT
Proportion of all patients in each arm who achieve 
a complete response (CR) or partial response 
(PR) at Day 28 and maintain a CR or PR at Day 
56.
CMH analyses, stratified by aGvHD grade
Other secondary endpoints
Refer to Sections 2.7, 2.8, 2.9, 2.10, 2.11
To estimate ORR at Day 14
Proportion of patients who achieved ORR 
(CR+PR) at Day 14. 
To assess Duration of response
Duration of response (DOR) is assessed for 
responders only and is defined as the time from 
first response until aGvHD progression or the date 
of additional systemic therapies for aGvHD. Onset 
of chronic GvHD, or death without prior 
observation 
of 
aGvHD 
progression 
are 
considered as competing risks.


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Objective
Endpoint
Analysis
To assess the cumulative steroid dose until Day 
56
Weekly cumulative steroid dose for each patient 
up to Day 56 or end of treatment will be calculated. 
To assess Overall Survival (OS)
Overall survival, defined as the time from the date 
of randomization to the date of death due to any 
cause. 
Probability of overall survival at Months 1, 2, 6, 12, 
18 & 24 will be estimated from the Kaplan-Meier 
curves for each arm.
To assess Event-Free Survival (EFS)
Event-free survival, defined as the time from the 
date of randomization to the date of hematologic 
disease relapse/progression, graft failure, or 
death due to any cause. 
Probability of EFS at Months 1, 2, 6, 12, 18 & 24 
will be estimated from the Kaplan-Meier curves for 
each arm.
To assess Failure-Free Survival (FFS)
Failure-free survival, defined as the time from the 
date of randomization to date of hematologic 
disease 
relapse/progression, 
non-relapse 
mortality, or addition of new systemic aGvHD 
treatment.  
Cumulative incidence of FFS at Months 1, 2, 6, 
12, 18 & 24 will be estimated, considering each 
event as a competing risk for the other two.  Onset 
of chronic GvHD is considered as a competing 
risk. 
To assess Non Relapse Mortality (NRM)
Non-relapse mortality (NRM), defined as the time 
from date of randomization to date of death not 
preceded 
by 
hematologic 
disease 
relapse/progression. 
Cumulative incidence of NRM at Months 1, 2, 6, 
12, 18 & 24 will be estimated, considering
hematologic disease relapse/progression as 
competing events.
To
assess 
incidence 
of 
Malignancy 
Relapse/Progression (MR) 
Malignancy Relapse/Progression (MR) (refer to 
protocol Appendix 4), defined as the time from 
date of randomization to hematologic malignancy 
relapse/progression. Calculated for patients with 
underlying hematologic malignant disease.
Cumulative incidence of MR at Months 1, 2, 6, 12, 
18 & 24 will be estimated, considering deaths not 
preceded 
by 
hematologic 
malignancy 
relapse/progression as competing events.
To measure the incidence of cGvHD 
cGvHD, defined as the diagnosis of any cGvHD 
including mild, moderate, severe.  
Cumulative incidence of cGvHD at Months 1, 2, 6, 
12, 18 & 24 will be estimated, considering 
hematologic disease relapse/progression and 
death without prior cGvHD as competing events.
To estimate the rate of Best Overall Response 
(BOR)
Proportion of patients who achieve OR (CR+PR) 
at any time point up to and including Day 28 and 






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2
Statistical methods
2.1
Data analysis general information
The final analysis will be performed by Novartis. SAS version 9.4 or later and/or R version 
3.0.2 or later will be used to perform all data analyses and to generate tables, figures and listings.
Data included in the analysis
The analysis cut-off date for the second analysis of study data will be established after all 
randomized patients have completed approximately 6 months treatment or have discontinued 
treatment period or have discontinued study. All statistical analyses will be performed using all 
data collected in the database up to the data cutoff date. All data with an assessment date or
event start date (e.g. vital sign assessment date or start date of an adverse event) prior to or on
the cut-off date will be included in the analysis. Any data collected beyond the cut-off date will
not be included in the analysis and will not be used for any derivations.All events with start 
date before or on the cut-off date and end date after the cut-off date will be reported as ‘ongoing’. 
The same rule will be applied to events starting 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.
The analysis cutoff date for the final analysis of study data will be established when all patients 
have completed the study.
General analysis conventions
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of patients enrolled at centers, no center effect 
will be assessed. 
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables
by treatment group; a missing category will be included as applicable. Percentages will be
calculated using the number of patients in the relevant population or subgroup as the
denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate
descriptive statistics (i.e. mean, standard deviation, median, minimum, and maximum) by 
treatment group.
2.1.1
General definitions
Investigational drug and study treatment
Investigational drug, will refer to the ruxolitinib only. Whereas, study treatment will refer to 
ruxolitinib and BAT. 
Randomized treatment will refer to the study treatment received during the randomized 
treatment period. Up to Day 28 visit, more than one BAT regimen may be initiated as study 


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treatment. These regimens reported on the Dosage Administration Record (DAR) eCRF are 
considered randomized treatment. Crossover treatment will refer to the study treatment 
received during the crossover treatment period.
Date of first administration of randomized treatment
The date of first administration of randomized treatment is derived as the first date when a 
nonzero dose of randomized treatment was administered as per the DAR eCRF. The date of 
first administration of randomized treatment will also be referred as start of randomized
treatment.
Date of first administration of crossover treatment 
The date of first administration of crossover treatment is derived as the first date when a nonzero 
dose of crossover treatment was administered as per the DAR eCRF. The date of first 
administration of crossover treatment (ruxolitinib) will also be referred as start of crossover
treatment.
Date of last administration of randomized treatment 
The date of last administration of randomized treatment is defined as the last date when a 
nonzero dose of randomized treatment was administered as per DAR eCRF. 
Date of last administration of crossover treatment 
The date of last administration of crossover treatment is defined as the last date when a nonzero 
dose of crossover treatment (ruxolitinib) was administered as per DAR eCRF. 
Study day
The study day, describes the day of the event or assessment date, relative to the reference start 
date. 
The study day is defined as:
The date of the event (visit date, onset date of an event, assessment date etc.) −reference 
start date + 1 if event is on or after the reference start date;

The date of the event (visit date, onset date of an event, assessment date etc.) − reference 
start date if event precedes the reference start date.
The reference start date for safety assessments (e.g. adverse event onset, laboratory abnormality
occurrence, vital sign measurement, dose interruption, PK, etc.), 
 and PRO is the
start of randomized treatment.
The reference start date for all other, non-safety assessments (i.e., aGvHD assessment, survival, 
aGvHD progression, aGvHD response, underlying hematologic disease relapse/progression, 
etc.) is the date of randomization.
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative.


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Crossover study day
The crossover study day, describes the day of the event or assessment date, relative to the start 
of crossover treatment.
Crossover study day = date of event – start of crossover treatment + 1, if event is on or after the 
start of crossover treatment
Crossover study day = date of event – start of crossover treatment, if event precedes the start of 
crossover treatment
The crossover study day will be displayed in the data listings if an event starts on or after the 
start of crossover treatment.
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.
Baseline
Baseline for safety endpoints (except adverse events), 
 and patient reported 
outcomes is defined as the last assessment prior to or on the treatment start date. 
For evaluations after cross over, the baseline is defined as the last assessment prior to or on the 
start date of crossover treatment.
Baseline for efficacy endpoints is defined as the last assessment or procedure conducted prior 
to or on the date of randomization date + 3 days, but no later than the treatment start date.
If patients have no value as defined above, the baseline result will be missing.
On-treatment assessment/event and observation periods
For adverse event reporting the overall observation period will be divided into four mutually 
exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent at screening to the day 
before first administration of study treatment
2. on-randomized-treatment period: from date of first administration of randomized
treatment to 30 days after date of last actual administration of randomized treatment
(including start and stop date) or end of randomized treatment per End of Randomized 
Treatment Disposition eCRF, whichever is later; for those patients who cross over from 
BAT to ruxolitinib, the period is from date of first administration of randomized 
treatment to earlier of (i) 30 days after date of last actual administration of randomized 
treatment or end of randomized treatment per End of Randomized Treatment 
Disposition eCRF, whichever is later, (ii) the day before the date of first administration 
of crossover treatment. Up to Day 28 visit, more than one BAT regimen may be initiated
as study treatment. In this case, the last actual administration of randomized treatment
refers to the last actual administration of the last BAT regimen reported on the DAR 
eCRF.  


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3. on-crossover-treatment period: from date of first administration of crossover treatment 
to 30 days after date of last administration of crossover treatment (including start and 
stop date) or end of crossover treatment per End of Crossover Treatment Disposition 
eCRF, whichever is later.
4. post-treatment period: starting at Day 31 after last administration of study treatment or 
the day after end of study treatment per end of treatment disposition eCRFs, whichever 
is later.
If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period cannot 
be made, then the respective data will be assigned to the on-randomized-treatment period.  
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). The data on-randomized-treatment period and on-crossover-treatment 
period will be summarized separately. In addition, a separate summary for death including on-
treatment and post-treatment deaths will be provided.  In particular, summary tables for adverse 
events (AEs) will summarize only on-treatment events, with a start date during the on-treatment 
period (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 post-treatment period will be flagged.
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 two assessments within a time window are 
equidistant from the target date, then the later of the two  assessments will be used. If multiple 
assessments on the same date then the worst case will be used.  Data from all assessments 
(scheduled and unscheduled), including multiple assessments, will be listed.
The following time windows are defined for descriptive summary on aGvHD assessment, 
 PROs and safety (Table 2-1) by visit. The end of treatment assessment will be 
mapped into the time points if collected within 7 days of the last dose intake.  
Table 2-1
Time windows for aGvHD assessment, 
 PROs and safety 
assessment (lab, vital sign, etc.)
Time Window
Planned Visit Timing 
Time Window Definition
On treatment
Baseline1
Study Day 11
≤Study Days 1+3, no later 
than treatment start date
Baseline2
On or before Study Day 12
≤ Study Day 1 
Week 1
Study Day 7
Study Days 4 – 10
Week 2
Study Day 14
Study Days 11 – 17
Week 3  
Study Day 21
Study Days 18 – 24
Week 4
Study Day 28
Study Days 25 – 31
Week 5 
Study Day 35
Study Days 32 – 38


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Week 6  
Study Day 42
Study Days 39 – 45
Week 7
Study Day 49
Study Days 46 – 52
Week 8 
Study Day 56
Study Days 53 – 59
Week 12
Study Day 84
Study Days 71 – 98 
Week 16
Study Day 112
Study Days 99 – 126 
Week 20
Study Day 140
Study Days 127 – 154 
Week 24
Study Day 168
Study Days 155 – 182 
Safety follow-up
30 days after last dose
Last dose date + 30
Baseline1 for aGvHD assessment (efficacy); 
Baseline2 for PROs, safety assessments 
(safety);
Study Day 11 = randomization date;
Study Day 12 = start date of randomized treatment;
Crossover Study Day 1 = start date of crossover treatment
EOT (randomized treatment or crossover treatment) assessments are mapped to the time 
points.
Safety follow-up is a separate time point for PROs and safety assessments.
Last contact date 
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the last complete date among the following:
Table 2-2
Last contact date data sources
Source data
Conditions
Date of Randomization 
No Condition
Last date patient was known to be alive from 
Survival Follow-up page 
Patient status is reported to be alive, lost to 
follow-up or unknown.
Start/End dates from further aGvHD therapy
Non-missing medication/procedure term.
Start/End* dates from drug administration record 
Non-missing dose. Doses of 0 are allowed.
End of treatment date from end of treatment page
No condition.
- aGvHD assessment date
- any specific efficacy assessment date if 
available (e.g., cGvHD assessment, graft failure 
assessment, hematologic disease 
relapse/progression assessment)
Evaluation is marked as ‘done’.
Laboratory/PK collection dates/
 
Sample collection marked as ‘done’. 
Vital signs date
At least one non-missing parameter value
Start/End dates of AE 
Non-missing verbatim term


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The last contact date is defined as the latest complete date from the above list on or before the 
data 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. Completely imputed
dates (e.g. the analysis cut-off date programmatically imputed to replace the missing end date
of a dose administration record) will not be used to derive the last contact date. Partial date 
imputation is allowed for event (death)/censoring coming from ‘Survival information’ eCRF. 
The last contact date will be used for censoring of patients in the analysis of overall survival.
2.2
Analysis sets
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 and strata, they have been assigned to during the randomization procedure.
Per-Protocol Set 
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with requirements of the clinical study protocol.
The following list of protocol deviations will lead to exclusion of the patient from the Per-
Protocol Set:

Not steroid refractory aGvHD (PDID: INCL09 per SSD v22.0)

More than one prior systemic therapy for the treatment of aGvHD other than corticosteroids 
+/- CNI (prophylaxis or treatment) (PDID: EXCL01 per SSD v22.0)

Missing or incorrect aGvHD grade at randomization (PDID: OTH02, INCL07 per SSD 
v22.0)

Taking any prohibited medication as specified in this protocol after start of study treatment 
and before end of study treatment (PDID: COMD01, COMD02 per SSD v22.0)

Study treatment received different from treatment arm assigned by randomization (PDID: 
TRT02 per SSD v22.0)
Safety Set
The Safety Set includes all patients who received at least one dose of study treatment. 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 if the randomized treatment was never received during the randomized 
treatment period.
Crossover Analysis Set
The Crossover Analysis Set (CAS) comprises all patients randomized to and received BAT who 
then crossed over and received at least one dose of ruxolitinib.  This analysis set will be used 
for all analyses for crossover patients.




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The primary efficacy endpoint will be summarized by the following subgroups to examine the 
homogeneity of treatment effect provided that the primary efficacy analysis based on the FAS 
is statistically significant : 

Age group (12- <18, 18-65, >65 years)

Gender

Race

Region (Europe, Australia and Canada), Japan, Asia excluding Japan)

Acute GvHD grade (Grade II, III, IV) 

Source of grafts (related, not related)

Criteria for SR-aGvHD (progression after at least 3 days, failure to achieve a response 
after 7 days, flare failure during taper)

Prior aGvHD therapy (steroid  +/- CNI, steroid +/- other systemic aGvHD treatment, 
steroid +/- CNI +/- other systemic aGvHD treatment, )

Conditioning regimen type (myeloablative, non-myeloablative, reduced intensity)

Stem cell type (bone marrow, peripheral blood, single cord blood)

Donor HLA status (match, mismatch)

Note: HLA status Match score means that 1:1 match, e.g. 10/10, 8/8, 6/6, 12/12. 
Mismatch will be all the other scores.  

Donor gender match (F/F, M/M, F/M, M/F)

Donor CMV status (negative, positive)

Donor source/HLA match status (related and matched, related and mismatched, not related 
and matched, not related and mismatched)

aGvHD organ involvement at randomization (skin, liver, upper GI, lower GI)
No formal statistical test of hypotheses will be performed for the subgroups, only point estimate 
of the treatment effect and 95% confidence intervals will be provided (see Section 2.5 for further 
analysis details). The objective of the efficacy subgroup analysis is to demonstrate homogeneity 
of treatment effect in the above subgroups. 
Safety
Key safety analyses will be repeated on the Safety Set in the following subgroups:

Age group (12- <18, 18-65, >65 years)

Gender

Race

Region (Europe, Australia and Canada), Asia excluding Japan, Japan)

aGvHD organ involvement at randomization (skin, liver, upper GI, lower GI)    
The objective for carrying out these subgroup analyses is to identify potential safety issues 
that may be limited to or more commonly observed in a subgroup of patients.  The following 
summaries will be presented by subgroup:


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
AEs, irrespective of causality, by primary system organ class and preferred term

AEs with suspected relationship to study treatment, by primary system organ class and 
preferred term

Serious AEs, irrespective of causality, by primary system organ class and preferred term

Serious AEs with suspected relationship to study treatment, by primary system organ class 
and preferred term

On-treatment deaths, by primary system organ class and preferred term
Adolescent patients
In order to be able to make a separate risk/benefit assessment for the adolescent patients, besides 
the above planned subgroup analyses for this age group (12-<18 years), data of demographics 
and exposure will be presented.
Japanese patients
Subgroup analyses will also be performed for the patients treated in Japan. No selection will be 
done on the basis of ethnicity, the purpose being to evaluate the population of patients living in 
Japan, not a specific ethnic set of patients. The analysis will be done the same way as in region 
subgroup specified above.
2.3
Patient disposition, demographics and other baseline 
characteristics
The Full Analysis Set (FAS) will be used for all baseline and demographic summaries and 
listings unless otherwise specified. Summaries will be reported by treatment arm and for all 
patients and listings will be reported by treatment arm to assess baseline comparability.  No 
inferential statistics will be provided.
Basic demographic and background data
All demographic and baseline disease characteristics data will be summarized and listed by 
treatment arm. Categorical data (e.g. gender, age groups: 12- <18 vs. 18-65 vs. >65 years, race, 
ethnicity) will be summarized by frequency counts and percentages; the number and percentage 
of patients with missing data will be provided. Continuous data (e.g. age, weight, height, body 
mass index) will be summarized by descriptive statistics (N, mean, median, standard deviation,
Q1, Q3, minimum and maximum). 
Baseline stratification factors
The number (%) of patients in each stratum (Grades II, III, IV) based on data obtained from the 
IRT system will be summarized overall and by treatment arm for the FAS. Discordances 
between the stratum recorded in IRT at the time of randomization and the actual stratum 
recorded in the clinical database through the data collected on eCRF will be cross-tabulated and 
listed.
Diagnosis and extent of disease
Summary statistics will be tabulated for diagnosis and extend of disease in underlying disease, 
stem cell transplant and acute GvHD. 


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For underlying disease, the analysis will include the following: primary diagnosis category and 
subcategory, details of primary diagnosis, time since diagnosis of underlying disease, CIBMTR 
risk assessment.
For transplant related disease history, the analysis will include the following: conditioning 
regimen type, total HCT-specific comorbidity index score, time since transplant, time from 
diagnosis of underlying disease to transplant, stem cell type, cytomegalovirus status, donor 
information including age, gender, HLA typing method, HLA match score, source of grafts 
(related/unrelated),  CMV status, T-cell depleted (Y/N), total nucleated cell dose.
For aGvHD disease history, the analysis will include the following: time since diagnosis of 
aGvHD grade ≥2, aGvHD grade when diagnosis of grade ≥2, steroid refractory aGvHD criteria 
met (progression after at least 3 days, failure to achieve a response after 7 days, flare failure 
during taper), prior aGvHD therapy (steroid  +/- CNI, steroid +/- other systemic aGvHD 
treatment, steroid +/- CNI +/-other systemic aGvHD treatment,), time from diagnosis of aGvHD 
grade ≥2 to steroid refractory, time since steroid refractory aGvHD, aGvHD grade at 
randomization, aGvHD organ involvement, steroid dose at randomization.
Medical history
Medical history and ongoing conditions, including underlying disease conditions and symptoms
entered on eCRF will be summarized and listed by treatment arm. The summaries will be 
presented by primary system organ class (SOC), preferred term (PT) and treatment arm. 
Medical history and current medical conditions will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology. The MedDRA version used for reporting will 
be specified in the CSR and as a footnote in the applicable tables/listings.
Other
Intended BAT strategy in case of SR aGvHD  prior to randomization will be summarized by 
treatment arm.
All data collected at baseline including child bearing potential will be listed.
2.3.1
Patient disposition
Enrollment by country and center will be summarized for all screened patients and also by 
treatment arm. The number (%) of randomized  patients will be presented overall and by 
treatment group. The number (%) of screened and not-randomized patients and the reasons for 
screening failure will also be displayed. The number (%) of patients in the FAS who are still on 
treatment, who discontinued the treatment phases (randomized treatment, crossover treatment) 
as well as the reason for discontinuation, and the survival follow-up will be presented overall 
and by treatment group.
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. All protocol deviations will be listed.


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Analysis sets
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarized  by 
treatment group and stratum.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Duration of exposure in days to ruxolitinib and BAT will be summarized by means of 
descriptive statistics. It will also be categorized into time intervals; frequency counts and 
percentages will be presented for the number (%) of patients in each interval. Duration of 
exposure to each BAT regimen (anti-thymocyte globulin (ATG), extracorporeal photopheresis 
(ECP), mesenchymal stromal cells (MSC), low-dose methotrexate (MTX), mycophenolate 
mofetil (MMF), mTOR inhibitors (everolimus or sirolimus), etanercept, or infliximab) will be 
summarized using the same approach.
Actual cumulative dose, dose intensity (DI) and relative dose intensity (RDI) will be 
summarized for the ruxolitinib arm. Patients randomized to Investigator’s choice of BAT will 
receive various different categories of therapy. 
The number (%) of patients who have dose changes or interruptions, and the reasons, will be 
summarized for ruxolitinib group.
Patient level listings of all doses administered on treatment along with dose change reasons will 
be produced. 
The Safety Set and Crossover Analysis Set will be used for all summaries on randomized 
treatment and crossover treatment, respectively. The Safety Set will be used for listings of study 
treatment.
Duration of exposure to study treatment
Duration of exposure to randomized treatment (days) = (last date of exposure to randomized
treatment) – (date of first administration of randomized treatment) + 1. 
Duration of exposure to crossover treatment (days) = (last date of exposure to crossover 
treatment) – (date of first administration of crossover treatment) + 1. 
The last date of exposure to study treatment is the latest of the last dates of exposure to study 
treatment (see Table 2-4).
Table 2-4
Definition of last date of exposure of study treatment
Scenario
Definition of last date of 
exposure of study treatment
Example
Scenario 1: Study 
treatment with a 
periodical administration
The planned end date of the last 
period in which the last non-zero 
dose of the study treatment was last 
administered.
Example 1: In a once-a-week 
administration, the last date of 
exposure is the date of last 
administration + 6 days.


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Note :  If the patient changed to 
another BAT, died or was lost to 
follow-up before the derived last 
date, the last date of exposure to 
study treatment is the date prior to 
the start of the next BAT, date of 
death or the date of last contact, 
respectively. 
If the derived last date of exposure 
goes beyond the data cutoff date, it 
should be truncated to the date of 
data cutoff.
Example 2: In a twice-a-week 
administration, the last date of 
exposure is the date of last
administration + 3 days.
Scenario 2: Study 
treatment with daily/IV 
administration 
Date of last administration of a non -
zero dose of the study treatment.
Example 3: A patient had a 
permanent discontinuation of the 
study treatment 06Jan2017 after 
being 
put 
on 
a 
temporary 
interruption since 01Jan2017. In 
this case the last date of exposure 
is- 31Dec2016. 
Scenario 3: Study 
treatment as an 
antibody 
Date of last administration of a non -
zero dose of the study drug + 
number of days antibody persists in 
vivo – 1 day.
Note :  If the patient changed to 
another BAT, died or was lost to 
follow-up before the derived last 
date, the last date of exposure to 
study treatment is the date prior to 
the start of the next BAT, date of 
death or the date of last contact, 
respectively. 
If the derived last date of exposure 
goes beyond the data cutoff date, it 
should be truncated to the date of 
data cutoff.
Example 4: For a study treatment
which antibody persists in vivo for 
28 days, the last date of exposure 
is the date of last administration + 
28 days – 1 day.
Summary of duration of exposure of study treatment in days will include categorical summaries 
(based on clinically meaningful time intervals) and continuous summaries (i.e. mean, standard 
deviation etc.) using appropriate units of time.
Duration of exposure in patient-years
The duration of exposure in patient-years is a total of the duration of exposure in years from all 
the patients in a treatment group. It will be calculated for randomized treatment (by treatment 
group) and crossover treatment, respectively.
Duration of treatment period


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Duration of randomized treatment period (days) = end date of on-randomized-treatment 
period – date of first administration of randomized treatment + 1
Duration of crossover treatment period (days) = end date of on-crossover-treatment period 
– date of first administration of crossover treatment + 1
The on-randomized-treatment period and on-crossover-treatment period are defined in Section 
2.1.1. 
The duration of randomized treatment period in days for ruxolitinib and BAT will be 
summarized by means of descriptive statistics. It will also be categorized into time intervals; 
frequency counts and percentages will be presented for the number (%) of patients in each 
interval. The duration of crossover treatment period will be summarized similarly. As patients 
randomized to BAT may crossover between Day 28 and Week 24, the time from the 
randomization to the first dose of crossover treatment will also be summarized.
Duration of treatment period in patient-years 
The duration of treatment period (randomized and crossover) in patient-years is a total of the 
duration of treatment period in years from all the patients in a treatment group. It will be 
calculated for randomized treatment (ruxolitinib vs. BAT) and crossover treatment separately. 
Cumulative dose
The planned cumulative dose for ruxolitinib refers to the total planned dose as per the protocol 
(10 mg bid) up to the last dose date. 
The actual cumulative dose of randomized ruxolitinib refers to the total actual dose of 
randomized ruxolitinib as documented in the DAR eCRF. 
The actual cumulative dose of crossover ruxolitinib refers to the total actual dose 
administered, over the duration for which the patient is on the crossover ruxolitinib as 
documented in the DAR eCRF. 
For patients who did not take any drug the cumulative dose is by definition equal to zero.
Dose intensity and relative dose intensity of ruxolitinib
Dose intensity (DI) of randomized ruxolitinib for patients with non-zero duration of exposure 
is defined as follows: 
DI (mg / day) = Actual cumulative dose (mg) of randomized ruxolitinib / Duration of exposure 
to randomized ruxolitinib (days).
Dose intensity (DI) of crossover ruxolitinib for patients with non-zero duration of exposure 
is defined as follows: 
DI (mg / day) = Actual cumulative dose (mg) of crossover ruxolitinib / Duration of exposure to 
crossover ruxolitinib (days).
For patients who did not take any drug the DI is by definition equal to zero. 
Planned dose intensity (PDI) is defined as follows:
PDI (mg / day) = Planned Cumulative dose (mg) / Duration of exposure (days).


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The protocol planned starting dose for ruxolitinib is 10 mg BID.
Relative dose intensity (RDI) is defined as follows:
RDI = DI (mg / day)  / PDI (mg / day).  
DI and RDI will be summarized for randomized and crossover ruxolitinib treatment, separately.
The actual cumulative dose, DI and RDI up to Day 28 visit, Day 56 visit and last date of 
exposure to study treatment (randomized or crossover) will be summarized. 
The number (%) of patients at total daily dose 5 mg, 10 mg, 15 mg and 20 mg will be 
summarized at Day 28 visit, Day 56 visit and last date of exposure to study treatment.
Dose reductions, interruptions or permanent discontinuations
The number of patients who have dose changes, or interruptions, and the reasons, will be 
summarized for ruxolitinib (randomized and crossover treatment separately). The number of 
patients who have dose permanent discontinuations and the reasons, will be summarized by 
treatment group.
‘Dose changed’, ‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the 
Dosage Administration CRF pages (DAR) will be used to determine the dose changes, 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 
separate interruptions. However, if the reason is the same in this mentioned multiple entries on 
consecutive days, then it will be counted as one interruption. 
2.4.2
Prior, concomitant and post therapies
2.4.2.1
Prior aGvHD treatment
The number and percentage of patients who received any prior aGvHD treatment (medications 
and procedures) will be summarized by lowest ATC class, preferred term and treatment arm. 
Listings will be produced for prior aGvHD treatment. 
The above analyses will be performed using the FAS.
2.4.2.2
Prior prophylaxis
The number and percentage of patients who received any prophylaxis prior to randomization 
will be summarized by lowest ATC class, preferred term and treatment arm using FAS. 
Listings will be generated for prophylaxis.


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2.4.2.3
Systemic corticosteroid
The duration of exposure and the peak dose will be summarized for pre-randomizatition period, 
between screening and randomization.
The duration of exposure will be summarized for on-randomized-treatment period and on-
crossover-treatment period separately. It will also be categorized into time intervals; frequency 
counts and percentages will be presented for the number (%) of patients in each interval. The 
actual cumulative dose, dose intensity and relative dose intensity (relative to the starting dose 
of corticosteroids) will be summarized up to Day 28 visit, Day 56 visit and end of on-treatment
period. These analyses will be based on Safety Set. The data will be reported on the DAR eCRF 
through the end of randomized treatment per EOT Disposition eCRF, and on the Prior and 
Concomitant Medications eCRF after the end of randomized treatment. The list of systemic 
corticosteroid will be documented in Data Handling Plan.
2.4.2.4
Calcineurin inhibitors (CNIs) during study treatment
The duration of exposure will be summarized for CNIs (cyclosporine or tacrolimus) during on-
randomized-treatment period and on-crossover-treatment period, respectively. It will also be 
categorized into time intervals; frequency counts and percentages will be presented for the 
number (%) of patients in each interval. These analyses will be based on Safety Set. The data 
will be reported on the DAR eCRF through the end of randomized treatment per EOT 
Disposition eCRF, and on the Prior and Concomitant Medications eCRF after the end of 
randomized treatment. The list of CNIs will be documented in Data Handling Plan.
2.4.2.5
Additional systemic aGvHD therapy
New additional systemic aGvHD therapy (medications and procedures) since start of study 
treatment will be listed and summarized by lowest ATC class, preferred term, overall and by 
treatment group by means of frequency counts and percentages using FAS.
2.4.2.6
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. The summaries for randomized 
treatment phase using Safety Set will include:

Medications starting on or after the start of randomized treatment but no later than end of 
on-randomized-treatment period; and

Medications starting prior to start of randomized treatment and continuing after the start of 
randomized treatment.


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The summaries for crossover treatment phase using Crossover Analysis Set will include:

Medications starting on or after the start of crossover treatment but no later than end of 
on-crossover-treatment period; and

Medications starting prior to start of crossover treatment and continuing after the start of 
crossover treatment.
All concomitant therapies will be listed using Safety Set. Any concomitant therapies starting
and ending prior to the start of randomized treatment or starting beyond end of on-randomized-
treatment period if not crossed over, or starting beyond end of on-crossover-treatment period if 
crossed over, will be flagged in the listing. 
The prohibited concomitant medications will be summarized by lowest ATC class and preferred 
term up to the end of on-randomized-treatment and on-crossover-treatment periods, 
respectively. The list of prohibited medications will be provided and updated regularly by 
clinical team according to the clinical database review. The topical medications are excluded 
from the list.
In addition, a subset of concomitant medications i.e. transfusions (red blood cells and platelets) 
will be grouped and summarized by treatment group. 
2.5
Analysis of the primary objective
The primary objective of the study is to compare the overall response rate (ORR) at Day 28
between the ruxolitinib arm and BAT arm  in steroid refractory aGvHD patients.
2.5.1
Primary endpoint
The primary endpoint was reported in the primary analysis, and will not be repeated in this 
second analysis, except for the subgroup analyses.
ORR at Day 28 is defined as the proportion of patients with complete response (CR) or partial 
response (PR) at Day 28 according to standard criteria [Harris 2016].  Note that response is 
relative to the assessment of aGvHD at randomization.

Complete response is defined as a score of 0 for the aGvHD grading in all evaluable 
organs that indicates complete resolution of all signs and symptoms of aGvHD in all 
evaluable organs without administration of additional systemic therapies for any earlier
progression, mixed response or non-response of aGvHD.  

Partial response is defined as improvement of 1 stage in 1 or more organs involved with 
aGvHD signs or symptoms without progression in other organs or sites without 
administration of additional systemic therapies for an earlier progression, mixed response 
or non-response of aGvHD.  

Lack of response is defined as no response, mixed response, or progression.

No response is defined as absence of improvement in any organ involved by aGvHD, 
without worsening in any involved organ.  

Mixed response is defined as improvement of at least 1 stage in the severity of 
aGvHD in at least one organ accompanied by progression in another organ or 
development of signs or symptoms of aGvHD in a new organ.


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
Progression is defined as worsening in 1 or more organs by 1 or more stages without 
improvement in any involved organ
A flare in aGvHD is defined as any increase in signs or symptoms of  aGvHD after an initial 
response (CR or PR). However, a flare may not lead to progression or additional systemic 
therapy. Only flares in GvHD that require new additional systemic therapy, will be considered 
aGvHD flare failure. Patients who fail corticosteroid taper fulfilling either one of the following 
criteria should initiate additional systemic therapy:

Requirement for an increase in the corticosteroid dose to methylprednisolone ≥2 
mg/kg/day (or equivalent  prednisone dose ≥2.5 mg/kg/day), OR   

Failure to taper the methylprednisolone dose to <0.5 mg/kg/day (or equivalent prednisone 
dose <0.6 mg/kg/day) for a minimum 7 days.
A patient will not be considered a responder at Day 28 if any of the following events occurs:

Missing aGvHD assessment at baseline or Day 28 

No CR or PR at Day 28 

Additional systemic therapy for aGvHD prior to Day 28
Compared to the protocol version 00, ‘discontinuation from randomized treatment’ has been 
dropped as reason.  Since some BATs have fixed duration which is less than 8 weeks, to avoid 
bias, discontinuation from randomized treatment will not be used to disqualify the response or 
durable response. Also duration of response will not be censored based on treatment 
discontinuation.
Acute GvHD will be assessed according to standard criteria [Harris 2016], as described in 
protocol Appendix 1. Grade will be calculated based on the staging of the organs and recorded 
on the eCRF by the Investigator. The Investigator reported grade will be used for randomization 
and reported grade and response for all analyses. Grade and response will be calculated by the 
sponsor for the purposes of data review only and sensitivity analysis. 
2.5.2
Statistical hypothesis, model, and method of analysis
The primary efficacy analysis is the comparison of ORR at Day 28 between the two treatment 
arms. The following statistical hypotheses will be tested to address the primary efficacy 
objective: 
H0: ORRrux ≤ ORRBAT  vs.   H1: ORRrux > ORRBAT
where ORRrux and ORRBAT are the overall response rates at Day 28 in the ruxolitinib and BAT 
groups, respectively. The Cochrane-Mantel-Haenszel chi-square test, stratified by the 
randomization stratification factor (i.e., aGvHD Grade II vs III vs. IV), will be used to compare 
ORR between the two treatment groups, at the one-sided 2.5% level of significance. 
The primary efficacy variable, ORR at Day 28, will be analyzed at the time when all patients 
have completed their Day 56 visit or discontinued earlier. The primary analysis will be 
performed on FAS according to ITT principle. ORR will be summarized using descriptive 
statistics (N, %) by treatment arm along with two-sided exact binomial 95% CIs [Clopper and 
Pearson 1934]. One-sided p-value, odds ratio and 95% Wald confidence limits calculated from 
stratified Cochran-Mantel-Haenszel test will be also presented.






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2.6
Analysis of the key secondary objective
The key secondary objective of the study is to determine whether treatment with ruxolitinib has 
better durable ORR at Day 56 compared with BAT.
2.6.1
Key secondary endpoint
The key secondary endpoint was reported in the primary analysis, and will not be repeated in 
this second analysis.
Durable ORR at Day 56 is defined as the proportion of all patients in each arm who achieve a 
complete response (CR) or partial response (PR) at Day 28 and maintain a CR or PR at Day 56. 
If a patient is a CR at Day 28 and a PR at Day 56, he/she will be considered as a durable 
responder. A patient will not be considered a durable responder at Day 56 if any of the following 
events occurs:

Not a  responder at Day 28

Missing aGvHD assessment at Day 56 

No CR or PR at Day 56. 

Additional systemic therapy for aGvHD prior to Day 56
Durable ORR will be calculated based on the FAS using local investigators review of aGvHD 
assessment data. 
The patients randomized to BAT who meet cross-over criteria and cross-over to ruxolitinib 
are considered to have the additional systemic therarpy for aGvHD, and will not be 
considered as a responder afterwards.
In addition, shift tables of aGvHD stage by organ and treatment group will be produced to 
compare Day 28 to Day 56 value for the patients who achieved PRs at Day 28.
2.6.2
Statistical hypothesis, model, and method of analysis
The following statistical hypotheses will be tested to address the key secondary efficacy 
objective: 
H0: DORRrux ≤ DORRBAT  vs.   H1: DORRrux > DORRBAT
where DORRrux and DORRBAT are the durable overall response rates at Day 56 in the ruxolitinib 
and BAT groups, respectively. The Cochrane-Mantel-Haenszel chi-square test, stratified by the 
randomization stratification factor (i.e., aGvHD Grade II vs III vs. IV), will be used to compare 
the durable ORR between the two treatment groups, at the one-sided 2.5% level of significance, 
if the primary endpoint is significant. 
The key secondary efficacy variable, durable ORR at Day 56, will be analyzed at the time when 
all patients have completed their Day 56 visit or discontinued earlier. The analysis will be based 
on FAS according to ITT principle. Durable ORR will be summarized using descriptive 
statistics (N, %) by treatment arm along with two-sided exact binomial 95% CIs [Clopper and 
Pearson 1934]. P-value, odds ratio and 95% Wald confidence limits calculated from stratified 
Cochran-Mantel-Haenszel test will be also presented. 


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The durable ORR at Day 56 will be tested hierarchically. That is, if the ORR at Day 28 is 
statistically significant, the durable ORR at Day 56 will be tested. If the ORR at Day 28 is not 
statistically significant, the durable ORR at Day 56 will not be tested.
2.6.3
Handling of missing values/censoring/discontinuations
Refer to Section 2.5.3
2.6.4
Durable ORR at Crossover Day 56
Durable ORR at Crossover Day 56 is defined as the proportion of all crossover patients who 
achieve a complete response (CR) or partial response (PR) at Crossover Day 28 and maintain a 
CR or PR at Crossover Day 56. Durable ORR at Crossover Day 56 will be summarized using 
descriptive statistics (N, %) along with two-sided exact binomial 95% CIs [Clopper and Pearson 
1934] based on the CAS using local investigators’ review of aGvHD assessment data. Note that 
response is relative to the last assessment of aGvHD prior to or at the start date of crossover 
treatment (ruxolitinib).
A patient will not be considered a durable responder at Crossover Day 56 if any of the following 
events occurs:

Not a responder at Crossover Day 28

Missing aGvHD assessment at Crossover Day 56 

No CR or PR at Crossover Day 56. 

Additional systemic therapy for aGvHD prior to Crossover Day 56
In addition, shift tables of aGvHD stage by organ and treatment group will be produced to 
compare Crossover Day 28 to Crossover Day 56 value for the patients who achieved PRs at 
Crossover Day 28.
2.7
Analysis of secondary efficacy objective(s)
The other secondary efficacy objectives are to: 

Evaluate the two treatment arms with respect to ORR at other time points, e.g. Day 14

Evaluate the two treatment arms with respect to duration of response (DOR)

Evaluate the two treatment arms with respect to overall survival (OS)

Evaluate the two treatment arms with respect to event free survival (EFS)

Evaluate the two treatment arms with respect to failure free survival (FFS)

Evaluate the two treatment arms with respect to Non-relapse mortality (NRM)

Evaluate the two treatment arms with respect to incidence of malignancy 
relapse/progression (MR)

Describe cumulative steroid dosing until Day 56 in each treatment arm

Evaluate the two treatment arms with respect to incidence of cGvHD

Evaluate the two treatment arms with respect to BOR at any time points up to Day 28
All the secondary efficacy endpoint analyses are non-comparative in nature and will be 
analyzed using the Full Analysis Set (FAS).


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2.7.1
Secondary efficacy endpoints
Overall Response Rate at Day 14
Overall Response Rate at Day 14 is defined as the proportion of patients with complete response 
(CR) or partial response (PR) at Day 14 according to standard criteria [Harris 2016]. This 
endpoint was reported in the primary analysis, and will not be repeated in this second analysis.
Duration of response (DOR)
Duration of response is defined for patients whose overall response at Day 28 is complete 
response (CR) or partial response (PR) according to standard criteria [Harris 2016]. The start 
date is the date of first documented response of CR or PR (i.e., the start date of response), which 
could be prior to or at Day 28. If it’s prior to Day 28, there should not be progression or addition 
of systemic therapies for aGvHD between the start date of response and Day 28. The end date 
is defined as the date of progression or the date of addition of systemic therapies for aGvHD on 
or after Day 28.
Death without prior observation of aGvHD progression and onset of chronic GvHD are 
considered to be competing risks.
Duration of response will be censored at the last response assessment prior to or at the analysis 
cut-off date, if no events/competing risk occurred before or at the cut-off date.  
Overall survival (OS) 
Overall survival 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 latest date the 
patient was known to be alive (on or before the cut-off date). 
Event Free Survival (EFS)
Event-free survival is defined as the time from the date of randomization to the date of 
hematologic disease relapse/progression, graft failure or death due to any cause. If a patient is 
not known to have any event, then EFS will be censored at the latest date the patient was known 
to be alive (on or before the cut-off date). 
Failure Free Survival (FFS)
Failure-free survival is defined as the time from the date of randomization to date of 
hematologic disease relapse/progression, non-relapse mortality or addition of new systemic 
aGvHD treatment. 
Non-relapse mortality (NRM) 
Non-relapse mortality is defined as the time from date of randomization to date of death not 
preceded by hematologic disease relapse/progression. Hematologic disease relapse/progression 
is considered a competing risk for NRM with the date of hematologic disease 
relapse/progression being the earlier of documented hematologic disease relapse/progression or 
institution of therapy to treat potential hematologic disease relapse/progression. If a patient is 
not known to have died or to have relapsed/progressed, then NRM will be censored at the latest 
date the patient was known to be alive (on or before the cut-off date). 
Incidence of Malignancy Relapse/Progression (MR)


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Malignancy relapse/progression is defined as the time from date of randomization to 
hematologic malignancy relapse/progression. Deaths not preceded by hematologic malignancy 
relapse/progression are competing risks. If a patient is not known to have event or competing 
risks, then MR will be censored at the latest date the patient was known to be alive (on or before 
the cut-off date). 
Incidence of cGvHD
cGvHD is defined as the diagnosis of any cGvHD including mild, moderate, severe. Incidence 
of cGvHD is the time from date of randomization to onset of cGvHD. Deaths without prior 
onset of cGvHD and hematologic disease relapse/progression are competing risks. If a patient 
is not known to have event or competing risks, then the incidence of cGvHD will be censored 
at the latest date the patient was known to be alive (on or before the cut-off date).  
Best Overall Response
Best overall response (BOR) is defined as proportion of patients who achieved overall response 
(CR or PR) at any time point up to and including Day 28, and had no additional systemic 
therapy for aGvHD prior to the time point. This endpoint was reported in the primary analysis, 
and will not be repeated in this second analysis.   
2.7.2
Statistical hypothesis, model, and method of analysis
Overall Response Rate at Day 14 
Overall response rate will be calculated based on the local investigators review of aGvHD 
assessment data. It will be summarized using descriptive statistics (N, %) by treatment arm 
along with two-sided exact binomial 95% CIs [Clopper and Pearson 1934]. Odds ratio and 95% 
Wald confidence limits calculated from stratified Cochran-Mantel-Haenszel test will be also 
presented.
Duration of response (DOR)
The estimated cumulative incidence rates and 95% confidence intervals at 1, 2, 6, 12, 18 and 
24 months will be presented for each treatment group. The cumulative incidence curve will be 
plotted. DOR will be listed and summarized by treatment group for all patients in the FAS with 
overall response of CR or PR at Day 28.  
Overall survival (OS) 
OS will be analyzed according to the randomized treatment group and strata assigned at 
randomization (aGvHD grade: Grade II vs. III vs. IV). The OS distribution will be estimated 
using the Kaplan-Meier method, and the Kaplan-Meier curves, medians, 1, 2, 6, 12, 18 and 24 
month survival estimates and 95% confidence intervals [Brookmeyer and Crowley 1982] will 
be presented for each treatment group. The hazard ratio for OS will be calculated, along with 
its 95% confidence interval, using a stratified Cox model. 
OS follow-up time will be summarized by treatment group for all patients in FAS. It will also 
be categorized into time intervals; frequency counts and percentages will be presented for the 
number (%) of patients in each interval.
Event Free Survival (EFS)


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EFS will be analyzed according to the randomized treatment group and strata assigned at 
randomization. The EFS distribution will be estimated using the Kaplan-Meier method, and the 
Kaplan-Meier curves, medians, 1, 2, 6, 12, 18 and 24 month survival estimates and 95% 
confidence intervals [Brookmeyer and Crowley 1982] will be presented for each treatment 
group. The hazard ratio for EFS will be calculated, along with its 95% confidence interval, 
using a stratified Cox model.
A sensitivity analysis including aGvHD progression as an event will be performed using the
same approach.
Failure Free Survival (FFS)
Cumulative incidence curve for FFS as well as estimates at 1, 2, 6, 12, 18 and 24 months with 
95% confidence intervals will be presented for each treatment group, accounting for onset of 
chronic GvHD as the competing risk. 
The FFS distribution will be estimated using the Kaplan-Meier method, and the Kaplan-Meier 
curveswill be presented for each treatment group. The hazard ratio for FFS will be calculated, 
along with its 95% confidence interval, using a stratified Cox model.
In addition, the cumulative incidence of each of the three components considering the other two 
components as a competing risks will be estimated. Onset of chronic GvHD is considered as a 
competing risk for all three types of failure. The cumulative incidence curves will be plotted for 
each treatment group. 
A sensitivity analysis including aGvHD progression as an event will be performed using the 
same approach.
Non-relapse mortality (NRM) 
NRM will be analyzed in the FAS population according to the randomized treatment group 
and strata assigned at randomization (aGvHD grade: Grade II vs. III vs. IV).  The cumulative 
incidence curve for NRM as well as estimates at 1, 2, 6, 12, 18 and 24 months with 95% 
confidence intervals will be presented for each treatment group.  
As a sensitivity analysis, the cumulative incidence curve for NRM as well as estimates at 1, 2, 
6, 12, 18 and 24 months with 95% confidence intervals will be presented for patients with 
underlying hematologic malignant disease in each treatment group.
Incidence of Malignancy Relapse/Progression (MR)
The cumulative incidence curve for MR and estimates at 1, 2, 6, 12, 18 and 24 months with 95% 
confidence intervals will be presented for patients with underlying hematologic malignant 
disease, accounting for NRM as the competing risk.
In addition, the proportion of patients who had hematologic malignancy relapse/progression 
and its 95% confidence interval at 1, 2, 6, 12, 18 and 24 months will be presented by treatment 
group for patients with underlying hematologic malignant disease. Odds ratio and 95% Wald 
confidence limits calculated from stratified Cochran-Mantel-Haenszel test will be also 
presented.
Cumulative steroid dosing until Day 56


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Overall and weekly cumulative steroid dose for each patient up to Day 56 or discontinuation of 
randomized treatment will be tabulated.  In addition, the relative dose intensity (RDI), by week, 
will be calculated relative to the starting dose of corticosteroids and categorized as (1) complete 
reduction where patients are tapered off corticosteroids by D56, (2) ≤50% RDI  and (3) >50% 
RDI. The proportion of patients in each category and corresponding 95% confidence intervals 
will be presented by treatment group. Odds ratio and 95% confidence limits calculated from 
Fisher’s exact test will be also presented for the proportion of patients who are completely 
tapered off corticosteroids by D56. Average corticosteroid dose during the week ending on Days 
14, 28, 56, 84, and 168 will also be tabulated and plotted.
Incidence of cGvHD
The cumulative incidence of cGvHD and estimates at 1, 2, 6, 12, 18 and 24 months with 95% 
confidence intervals will be presented, accounting for competing risks. The cumulative 
incidence curve will be plotted for each treatment group.
The listing of cGvHD will be provided. Onset of cGvHD (first event) will summarized. The 
proportion of subjects with different overall severity of cGvHD will be presented, as well as the 
proportion of patients with required systemic treatment for cGvHD.
Best Overall Response
Best overall response will be calculated based on the local investigators review of aGvHD 
assessment data. It will be summarized using descriptive statistics (N, %) by treatment arm 
along with two-sided exact binomial 95% CIs [Clopper and Pearson 1934]. Odds ratio and 95% 
Wald confidence limits calculated from stratified Cochran-Mantel-Haenszel test will be also 
presented.
2.7.3
Handling of missing values/censoring/discontinuations
Refer to Section 2.5.3
2.8
Safety analyses
All safety analyses will be based on Safety Set, except that the summary of safety data during 
the crossover treatment phase will be based on Crossover Analysis Set. All listings and tables 
will be presented by treatment group. For safety evaluations (except for AE) during randomized 
treatment phase, the last available assessment on or before the date of start of randomized
treatment is taken as the “baseline” assessment. For safety evaluations (except for AE) during 
crossover treatment phase, the last available assessment on or before the date of start of 
crossover treatment is taken as the “baseline” assessment.  
Due to possible crossover from BAT to ruxolitinib arm after Day 28, imbalance in exposure 
between the two arms is expected. Therefore, safety summaries for the randomized treatment 
will be performed for the following periods, unless specified:

Up to Day 31 (the upper bound of the Day 28 visit window);

Up to the earlier of i) cutoff date, ii) end date of on-randomized-treatment period;
The on-randomized-treatment period is defined in Section 2.1.1. 


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For the summaries up to cutoff date, some may be presented by adjusting for the duration of 
randomized treatment period in patient-years where relevant.
2.8.1
Adverse events (AEs)
For reporting of AEs the overall observation period will be divided into mutually exclusive 
categories, including pre-treatment, on-treatment (randomized or crossover), post-treatment  
periods as defined in Section 2.1.1.
AE summaries will include all AEs occurring (new or worsening) during on-treatment period. 
All AEs collected in the AE eCRF page will be listed along with the information collected on 
those AEs e.g. AE relationship to study drug, AE outcome etc. AEs with start date outside of 
on-treatment period will be flagged in the listings. 
AEs will be summarized by number and percentage of patients 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 patient with multiple occurrences of an AE will be counted only 
once in the respective AE category. A patient with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event.
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables.
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 the descending frequency in the ruxolitinib arm.
The following adverse event summaries will be produced by treatment arm; overview of 
adverse events and deaths, 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, and leading to fatal outcome. In 
addition, a summary of serious adverse events with 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
AEs adjusted for patient duration of treatment period 
In order to account for differences in exposure of the ruxolitinib arm relative to the BAT arm 
due to crossover from BAT to ruxolitinib after Day 28 visit, incidence rates of adverse events 
may be presented by adjusting for duration of treatment period in patient-years where relevant.
2.8.1.2
Adverse events of special interest / grouping of AEs
Data analysis of AESIs
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to compound ruxolitinib. These groupings are defined using MedDRA 
terms, SMQs (standardized MedDRA queries), HGLTs (high level group terms), HLT (high 
level terms) and/or PTs (preferred terms). Customized SMQs (Novartis MedDRA queries, 
NMQ) may also be used. A NMQ is a customized group of search terms which defines a medical 
concept for which there is no official SMQ available or the available SMQ does not completely 


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fit the need. It may include a combination of single terms and/or an existing SMQ, narrow or 
broad. 
For each AESI (selection from the Case Retrieval Sheet), number and percentage of patients 
with at least one event of the AESI occurring during on-treatment period will be summarized.
Summaries of AESIs will be provided by treatment arm, (specifying grade, SAE, relationship, 
leading to treatment discontinuation, leading to dose adjustment/interruption, hospitalization, 
death etc.).
A listing of all grouping levels down to the MedDRA preferred terms used to define each AESI 
will be generated. 
In addition to summarizing infections by CTCAE grade, they will also be summarized using 
infection severity (protocol Appendix 2) up to Day 31 (the upper bound of the Day 28 visit 
window), and cutoff date. Summary of infections by SOC, HLGT, HLT and PT up to Day 31, 
and cutoff date will be generated.
Proportion of patients developing second primary malignancies will be summarized for on-
treatment period, post-treatment period and both.
2.8.2
Deaths
Separate summaries for on-treatment and all deaths (including post-treatment death) will be 
produced by treatment arm, system organ class and preferred term. 
All deaths will be listed and post-treatment deaths will be flagged. A separate listing of deaths 
prior to starting treatment will be provided for all screened patients.
2.8.3
Laboratory data
On analyzing laboratory, data from all sources (central and local laboratories) will be combined. 
The summaries will include all assessments available for the lab parameter collected no later 
than end of the on-treatment periods (randomized or crossover).
Grading of laboratory 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.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
The following summaries will be produced for hematology and biochemistry laboratory data 
(by laboratory parameter and treatment):

Shift tables using CTC grades to compare baseline to the worst on-treatment  value 
The following listings will be produced for the laboratory data:

Listings of all laboratory data, with CTC grades and classification relative to the 
laboratory normal range. Lab data collected during the post-treatment period will be 
flagged.  

Listing of all CTC grade 3 or 4 laboratory toxicities


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In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots may be 
produced.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
Not applicable.
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 mass index (kg/m2), body 
temperature (°C), pulse (beats per minute), systolic and diastolic blood pressure (mmHg). 
Data handling
Vital signs collected 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 clinically notable vital sign criteria are provided in Table 2-5
below.
Table 2-5
Clinically notable changes in vital signs
Vital sign 
(unit)
Clinically notable criteria
above normal value 
below normal value
Weight (kg)
increase > 10% from Baseline
decrease  > 10% from Baseline
Systolic blood 
pressure 
(mmHg)
>=180 with increase from baseline 
of >=20
<=90 with decrease from baseline 
of >=20
Diastolic blood 
pressure 
(mmHg)
>=105 with increase from baseline 
of >=15
<=50 with decrease from baseline 
of >=15
Pulse rate 
(bpm)
>=100 with increase from baseline 
of >25%
<=50 with decrease from baseline of 
> 25%
Body 
temperature
>= 39.1 
-
The number and percentage of patients with notable vital sign values (high/low) will be 
presented  by treatment arm.         
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. 


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Additional Analyses
Time to first occurrence of grade 3 infection
Time to first occurrence of infection is defined as time from start of study treatment to the date 
of first occurrence of grade 3 infection severity per protocol Appendix 2, i.e. time in days is 
calculated as (start date of first occurrence of infection ) – (start of study treatment) +1. 
In the absence of an event during the on-treatment period, the censoring date applied will be 
the earliest of the following dates: 

death date

end date of on-treatment period  (randomized or crossover) 

data cut-off date

withdrawal of informed consent date
Failure curves (ascending Kaplan-Meier curves) will be constructed by treatment arm. Median 
together with 95% confidence interval as well as 25th percentile and 75th percentile will be 
presented for each treatment arm. 
A sensitivity analysis will be conducted considering deaths or end of treatment phase 
(randomized or crossover) without prior infection as competing risks. Cumulative incidence 
curve for time to grade 3 infection as well as estimates at 1, 2 and 6 months with 95% confidence 
intervals will be presented for each treatment group. 
In addition, the median time to occurrence for the subset of patients who experienced infection 
will be calculated. Simple descriptive statistics, median, min and max as well as 25th percentile 
and 75th percentile, will be presented.
2.9
Pharmacokinetic endpoints
The pharmacokinetic endpoints were reported in the primary analysis, and will not be reported 
in this second analysis. Further results will be presented in the full analysis. 
Pharmacokinetic Analysis Set (PAS) will be used in all pharmacokinetic data analysis and PK 
summary statistics. 
Plasma samples for extensive PK will be taken at Day 1 (start of treatment), at Day 7 (week 1) 
for the first 25 adult patients and all adolescents to characterize the PK after first dose, and at 
steady state by non-compartmental analysis.  Additional PK samples will be taken at later visits 
for all patients to characterize exposure-efficacy, exposure-safety 
as data allows. Concentrations will be expressed in mass per volume units.
PK parameters
The PK parameters that will be determined are shown in Table 2-6. The PK parameters of 
ruxolitinib will be calculated from the extensive PK data based on the non-compartmental 
methods using Phoenix WinNonlin® (Pharsight, Mountain View, CA) software. Additional PK 
parameters may be estimated as needed.






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
Characterize the exposure-safety relationship of ruxolitinib in terms of exposure and
safety response, where safety response is defined as various categorizations of AEs
(frequency of;severity of AEs, AEs of interest to be defined prior to analysis or laboratory 
parameters).

Average steady-state exposures and/or other PK parameters for the population will 
becomputed by the POP PK model accounting for dose modifications or dose 
interruptions up to the day prior to the day of assessments. Population PK derived 
parameters will be used for exposure-response analysis by appropriate methods
For duration of response and overall survival, if the primary endpoint is significant and 
sufficient events have accrued (i.e., at analysis time points after the primary analysis), a Cox 
regression model with appropriate patient demographic and prognostic factors as covariates and 
the log-trough level as a time dependent covariate will be fitted if appropriate. To account for 
dose adjustments between trough sampling time points the trough concentration will be adjusted 
by dividing by the actual dose prior to the trough in question and multiplying by the arithmetic 
mean dose since the last trough sample or start of dosing as applicable. The calculation of the 
arithmetic mean dose should count any dose interruptions as a zero dose for the days that no 
dose was given. Goodness of fit of the model will also be examined. The survival time should 
be calculated from the time of first dose rather than the time of randomization. The hazard ratio 
and 95% confidence interval for a two-fold increase in exposure will be displayed if appropriate. 
Kaplan-Meier curves may be used to summarize the data based on relevant quantiles of PK.
For incidence of specific AEs, Day 28 response (if the primary endpoint is significant) and Day 
56 durable response (if the primary and key secondary endpoints are significant), logistic 
regression models may be used including log-average trough concentration and other 
demographic and prognostic covariates in the model as appropriate. The trough concentration 
will be similarly adjusted to account for dose adjustments as described above. The average 
trough concentration included in the model for Day 28 response will be the arithmetic mean of 
the Day 7, Day 14, Day 21 and Day 28 adjusted trough concentration. A similar average trough 
concentration will be calculated for the Day 56 response except the Day 42 and Day 56 adjusted 
concentration will be double weighted compared to the others because they are representative 
of concentration over 2 weeks rather than 1. For analysis of adverse events the last trough 
concentration prior to the AE will be included in the model. Other exposure measures may be 
considered if appropriate. The odds ratio and its 95% confidence interval for a two-fold increase 
in exposure will be displayed as appropriate.
2.11
Patient-reported outcomes
The FACT-BMT along with the EQ-5D-5L will be used to collect data on the patient’s disease-
related symptoms and health-related quality of life. Responses to the FACT-BMT and EQ-5D-
5L will be generated in accordance with the respective scoring manual. Further details on the 
scoring of FACT-BMT and EQ-5D are given in Appendix 5.4.3.1 and Appendix 5.4.3.2.
These PRO instruments are planned to be administered on randomization day and every week 
during the first 2 months, and every 4 weeks thereafter until the end of treatment. 
The baseline is defined as the last PRO assessment prior to or on the treatment start date .
FACT-BMT will not be used in patients under age 18 years.








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2.14
Interim analysis
No formal interim analysis is planned for this trial. 
Early PK analysis
To compare the exposure of 10 mg BID in the SR aGvHD population to the known exposure in 
MPN patients, the early extensive ruxolitinib PK data on the first 25 adult patients (including 
any adolescent patients randomized at that time) will be explored once available, also in the 
context of concomitant medications. However, there will be no comparison between the two 
treatment arms because PK data are not collected in BAT patients.
DMC safety data analysis
DMC will be instituted in this study and will review the safety data as outlined according the 
DMC charter. A separated set of SAP and TFL shells will be provided to detail the analysis.
3
Sample size calculation
The study with a total of 308 patients and 1:1 randomization (ruxolitinib vs. BAT) stratified on 
aGvHD grade (Grade II vs. Grade III vs. Grade IV) has 90% power to test for the primary 
endpoint (ORR at Day 28) and approximately 90% power to test for the key secondary endpoint 
(durable ORR at Day 56). The family wise α-level will be controlled at 0.025 overall for the 
two comparisons. Specifically, this study will claim to have achieved the efficacy objective 
when the primary endpoint ORR at Day 28 shows a significant treatment effect at one-sided α 
= 0.025. Conditional on significance of the primary endpoint, the key secondary endpoint 
durable ORR at Day 56 will be tested at one-sided α = 0.025. 
3.1
Primary analysis
The sample size calculation is based on the primary variable ORR at Day 28. The hypotheses 
to be tested and details of the testing strategy are described in Section 2.5.2 and Section 3. 
Based on Martin P. et al BBMT 2013, the ORR at Day 28 in the BAT arm is expected to be 
58%. The stratum specific rates (Grade II 69%, Grade III 59%, Grade IV 50%) are obtained 
assuming that the ratio of aGvHD Grade II: III: IV is 0.2:0.4:0.4. It is expected that treatment 
with ruxolitinib will result in an 18% increase in the ORR, i.e., an expected odds ratio of 2.25 
(which corresponds to an increase in ORR to 75%). Power for the CMH test, stratifying on 
aGvHD grade, was calculated using software package East V6. In order to ensure 90% power 
a total sample size of 308 patients are needed. 
With a sample size of 154 patients in each treatment arm, an observed odds ratio greater than 
or equal to 1.63 would achieve statistical significance for the primary endpoint. Assuming that 
the observed response rates in Grades II/III/IV in BAT arm are 69%/59%/50% (overall 57%), 
observed response rates ≥ 78%/70%/62% (overall 68%) in the ruxolitinib arm would achieve 
statistical significance.
3.2
Power for analysis of key secondary variables
Durable ORR at Day 56, as the key secondary variable, will be formally statistically tested, 
provided that the primary endpoint ORR at Day 28 is statistically significant. The hypotheses 


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to be tested and details of the testing strategy are provided in Section 2.6.2. Based on [Van 
Groningen 2016], the durable ORR at Day 56 in the BAT arm is expected to be approximately 
35%. The stratum specific rates (Grade II 45%, Grade III 36%, Grade IV 30%) are obtained 
assuming that the ratio of aGvHD Grade II: III: IV is 0.2:0.4:0.4. It is expected that treatment 
with ruxolitinib will result in a 20% increase in the ORR, i.e., an expected odds ratio of 2.25 
(which corresponds to an increase in durable ORR to 55%). With these assumptions and sample 
size of 308 patients, the power for the key secondary endpoint is at least 90%.
With sample size 154 patients in each treatment arm, an observed odds ratio greater than or 
equal to 1.59 for durable ORR at Day 56 would achieve statistical significance. Assuming that 
the observed durable response rates in Grades II/III/IV in BAT arm are 45%/36%/30% (overall 
35%), observed durable response rates ≥ 57%/47%/41% (overall 47%) in the ruxolitinib arm 
would achieve statistical significance.
4
Change to protocol specified analyses
Compared to the protocol version 00, ‘discontinuation from randomized treatment’ has been 
dropped as reason.  Since some BATs have fixed duration which is less than 8 weeks, to avoid 
bias, discontinuation from randomized treatment will not be used to disqualify the response or 
durable response. Also duration of response will not be censored based on treatment 
discontinuation.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
The following rule should be used for the imputation of the dose end date for a given study 
treatment component:
Scenario 1: If the dose end date is completely missing and there is no EOT page and no death 
date, the patient is considered as on-going: 
The patient should be treated as on-going and the cut-off date should be used as the dose end 
date.
Scenario 1 should not be applied for final CSR. All patients should have EOT page complete 
before the Database lock for Final CSR
Scenario 2: If the dose end date is completely or partially missing and the EOT page is available: 
Please note that date of assessment on EOT eCRF might be very different from last date of dose. 
Case 1: The dose end date is completely missing, and the EOT  completion date is complete, 
then this latter date should be used.  
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:  
Use Dec31yyyy


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Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date: 
Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy  = the year 
of EOT date and mm < the month of  EOT date: 
Use last day of the Month (mm)
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study.
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:
Use the treatment start date
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed.
5.1.2
AE, ConMeds and safety assessment date imputation
Table 5-1
Imputation of start dates (AE, CM) and assessments (LB, EG, VS)
Missing 
Element
Rule
day, month, 
and year

No imputation will be done for completely missing dates
day, month

If available year = year of study treatment start date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY 
o
Else set start date = study treatment start date. 

If available year > year of study treatment start date then 01JanYYYY

If available year < year of study treatment start date then 01JulYYYY


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Missing 
Element
Rule
day

If available month and year = month and year of study treatment start 
date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY. 
o
Else set start date = study treatment start date.

If available month and year > month and year of study treatment start 
date then 01MONYYYY  

If available month and year < month year of study treatment start date 
then 15MONYYYY  
Table 5-2
Imputation of end dates (AE, CM) 
Missing 
Element
Rule 
(* if end date of the on-treatment period not > (death date, cut-off date, 
withdrawal of consent date))
day, month, 
and year

Completely missing end dates (incl. ongoing events) will be imputed 
by the end date of the on-treatment period* 
day, month

If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period * 
day

If partial end date contains month and year, set end date = earliest of 
last day of the month or end date of the on-treatment period*
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings.
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ 
rather than the end date provided. 
The above imputations are only used for analyses of time to and duration of AEs and 
concomitant medications. 
5.1.2.1
Other imputations
Incomplete date of initial diagnosis of aGvHD 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan. 
5.2
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
The latest available MedDRA version at the time of the analyses should be used. The MedDRA 
version used should be specified in the footnote of relevant tables.  
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03. 


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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). 
5.3
Laboratory parameters derivations
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. 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. 
CTCAE Grade 5 is not defined for laboratory values. 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.
Imputation Rules  
CTC grading for blood differentials is based on absolute values. However,  this data may not 
be reported as absolute counts but rather as percentage of WBC. 
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential
xxx count = (WBC count) * (xxx %value / 100)
Further derivation of laboratory parameters might be required for CTCAE grading. For instance, 
corrected calcium can be derived using the reported total calcium value and albumin at the same 
assessment using the following formula:
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4]
In order to apply the above formula, albumin values in g/L will be converted to g/dL by  
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium.
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above for grading.


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5.4
Statistical models
5.4.1
Primary analysis
The null hypothesis of equality of response rate in the two treatment arm will be tested against 
one-sided alternative.  The statistical hypotheses are:
H0: ORRrux ≤ ORRBAT  vs.   H1: ORRrux > ORRBAT
where ORRrux is the probability of response in ruxolitinib and ORRBAT is the probability  of 
response in BAT.
The Cochran-Mantel-Haenszel chi-square test X2
CMH (implemented again via SAS procedure
FREQ with CMH option in the TABLES statement) will be used to test the difference in
response rates between the treatment arms. The p-value corresponding to the CMH test for 
“general association” will be used which follows a Chi-square distribution with one degree of 
freedom.
If the sampling assumptions for chi-square test is not met, the exact Cochran-Mantel-Haenszel test
will be used (implemented via SAS procedure MULTTEST). The test is performed by running
a stratified version of the Cochran-Armitage permutation test [Armitage et al. 1969]. In studies 
with stratified randomization,  the  chi-square  approximation  is  considered  appropriate  for  
the  X2
CMH statistics if the rule of Mantel and Fleiss [Mantel and Fleiss 1980] is satisfied.
Logistic Regression 
Odds ratio will be used as a measure of association between treatment and response. The odds 
ratio will be derived from the logistic regression model (implemented using SAS procedure 
LOGISTIC, with treatment specified as an explanatory variable in the CLASS statement) 
which allows for including not only the stratification factor but also for adjustments for other 
covariates (both categorical and continuous). The odds ratio will be presented with 95% Wald 
confidence limits.
In cases where an exact test has been used to compare response rates, the odds ratio should be 
determined using exact logistic regression, and the odds ratio presented with exact 95% 
confidence limits. In these cases, SAS PROC LOGISTIC with EXACTONLY option will be 
used.
Confidence interval for response rate
Responses will be summarized in terms of percentage rates with 100(1 −α)% confidence 
interval using exact binomial confidence interval (implemented using SAS procedure FREQ
with EXACT statement for one-way table [Clopper and Pearson 1934].
Definition of new or additional systemic therapy for aGvHD
The data source to search for the new or additional systemic therapy would be from eCRFs of 
Prior and Concomitant Medication (CONMED) (with subcategory as treatment for aGvHD) 
and Dosage Administration Record (DAR).
Any of the following therapies represent new or additional systemic therapy for aGvHD: 


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1. Any new CNI therapy being initiated as ‘treatment for aGvHD’ after the baseline as 
recorded either on DAR or on CONMED, and never received prior to or at baseline
2. Any other systemic therapy (excluding CNI or systemic corticosteroid
(methylprednisolone, prednisone and prednisolone)) being started as ‘treatment for
aGvHD’ after the baseline and recorded on CONMED. Note: the therapy may have been 
taken prior to baseline but not at baseline.
3. Additional BAT at or after start of the initial BAT as recorded on DAR
4. Treatment with ruxolitinib after cross-over from BAT as recorded on DAR
5.4.2
Key secondary analysis
Same instructions as in Section 5.4.1.
5.4.3
Other secondary analysis
5.4.3.1
FACT-BMT
For FACT-BMT the subscale scores, the FACT-BMT total score and the FACT-BMT Trial 
Outcome Index (TOI) will be calculated. 
The subscales are physical well-being (PWB), social/family well-being (SWB), emotional well-
being (EWB), functional well-being (FWB) and bone marrow transplant subscale (BMTS).  For 
each subscale the corresponding score will be calculated based on the item response of the 
answered question according to the FACT-BMT Scoring Guide (Version 4). The scoring guide 
identifies those items that must be reversed before being added to obtain subscale totals.  
Negatively stated items are reversed by subtracting the response from “4”.  After reversing 
proper items, all subscale items are summed to a total, which is the subscale score.
If there are missing items, subscale scores can be prorated.  This is done by multiplying the sum 
of the subscale by the number of items in the subscale, then dividing by the number of items 
actually answered.  This can be done by using the formula below:
Prorated subscale score 
= [Sum of item scores] x [N of items in subscale]/[N of items answered]   
When there are missing data, prorating by subscale in this way is acceptable as long as more 
than 50% of the relevant items were answered. Note that not all items (questions) are used to 
calculate the scores (see Scoring Guide, version 4).  For all the scores the higher the score is the 
better the QOL is. 
The FACT-BMT Trial Outcome Index (TOI, score range: 0-96) is calculated as 
The FACT-BMT total score (score range: 0-148) is then calculated as the sum of all un-
weighted subscale scores:


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5.4.3.2
EQ-5D-5L
EQ-5D-5L consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression. Also the EQ-VAS is included. Each dimension has 5 levels (1-5).
The data were reported for all 5 dimensions. The proportion of reported problems for each level 
were reported. The changes from baseline were defined with a shift table. The below screenshot 
is from the Excel conversion document obtained from the EuroQol webpage on 5L Value Sets 
(http://www.euroqol.org/about-eq-5d/valuation-of-eq-5d/eq-5d-5l-value-sets.html). This UK 
value will be used to convert the “health state” to an “index value” for all patients in all countries. 
For example, if the health state is 11125, then the index value would be .316 and so on.


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6
Reference
1. Anderson JR, Cain KC and Gelber RD (1983). Analysis of survival by tumor response. 
Journal of Clinical Oncology, 1(11), 710-719.
2. Armitage P, McPherson CK and Rowe BC (1969). Repeated significance tests on 
accumulating data. J .R. Statist. Soc. A, 132, 232-244. 
3. Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival 
Time. Biometrics, 38, 29 - 41. 
4. Clopper CJ and Pearson ES (1934).  The use of confidence or fiducial limits illustrated in 
the case of the binomial.  Biometrical, 26, 404-413.
5. FDA briefing Document Oncologic Drugs Advisory Committee Meeting, July 24, 2012, 
Evaluation of radiologic review of progression-free survival in Non-hematologic 
malignancies. 
http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/on
cologicdrugsadvisorycommittee/ucm311141.pdf
6. Harris AC, Young R, Devine S, Hogan WJ, Ayuk F, Bunworasate U, Chanswangphuwana 
C, Efebera YA, Holler E, Litzow M, Ordemann R, Qayed M, Renteria AS, Reshef R, 
Wölfl M, Chen YB, Goldstein S, Jagasia M, Locatelli F, Mielke S, Porter D, Schechter T, 
Shekhovtsova Z, Ferrara JL, Levine JE. (2016) International, Multicenter Standardization 
of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount 
Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant; 22(1): 4-
10.
7. Korhonen P,  Laird NM and Palmgren J. Correcting for non-compliance in randomized 
trials: an application to the ATBC study (1999). Statistics in Medicine, 18, 2879-2897.
8. Mantel, N. and Joseph L Fleisś (1980). Minimum expected cell size requirements for the 
Mantel-Haenszel one degree-of-freedom Chi-Square Test and a related rapid procedure. 
American Journal of Epidemiology, 112, 129-134.
9. Robins JM and Tsiatis AA (1991). Correcting for non-compliance in randomized trials 
using rank preserving structural failure time models (RPSFTM). Commun. Statist.-Theory 
Meth., 20(8), 2609-31.
10. Van Groningen, LF, Liefferink AM, de Haan AF, Schaap NP, Donnelly JP, Blijlevens 
NM, van der Velden WJ. (2016) Combination Therapy with Inolimomab and Etanercept 
for Severe Steroid-Refractory Acute Graft-versus-Host Disease Biol Blood Marrow 
Transplant. 22(1):179-82.




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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
12JUL2019 
8:00
Clarification 
of definition
Modified the definition of non-
responder to be aligned within the 
compound 
Sec 2.5, 2.6, 
2.7
12JUL2019 
8:00
Addition of 
definition
Added the definition of additional 
systemic therapy 
Sec 5.4
12JUL2019 
8:00
Clarification 
of definition
Updated the list of PDs for PPS 
patient classification 
Sec 2.2
26AUG019 
8:00
Clarification 
of definition
Added  the scoring calculation rules 
for PRO
Sec 5.4


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Table of contents
Table of contents .................................................................................................................3
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints ...............................................................................9
2
Statistical methods.............................................................................................................13
2.1
Data analysis general information .........................................................................13
2.1.1
General definitions................................................................................13
2.2
Analysis sets ..........................................................................................................18
2.2.1
Subgroup of interest ..............................................................................19
2.3
Patient disposition, demographics and other baseline characteristics ...................21
2.3.1
Patient disposition.................................................................................22
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................22
2.4.1
Study treatment / compliance................................................................22
2.4.2
Prior, concomitant and post therapies...................................................26
2.5
Analysis of the primary objective..........................................................................27
2.5.1
Primary endpoint...................................................................................28
2.5.2
Statistical hypothesis, model, and method of analysis..........................29
2.5.3
Handling of missing values/censoring/discontinuations.......................29
2.5.4
Supportive analyses for ORR at Day 28 ...............................................29
2.5.5
ORR at Crossover Day 28.....................................................................30
2.6
Analysis of the key secondary objective ...............................................................31
2.6.1
Key secondary endpoint........................................................................31
2.6.2
Statistical hypothesis, model, and method of analysis..........................31
2.6.3
Handling of missing values/censoring/discontinuations.......................32
2.6.4
Durable ORR at Crossover Day 56.......................................................32
2.7
Analysis of secondary efficacy objective(s)..........................................................32
2.7.1
Secondary efficacy endpoints ...............................................................33
2.7.2
Statistical hypothesis, model, and method of analysis..........................34
2.7.3
Handling of missing values/censoring/discontinuations.......................36
2.8
Safety analyses.......................................................................................................36
2.8.1
Adverse events (AEs)............................................................................37
2.8.2
Deaths....................................................................................................38
2.8.3
Laboratory data .....................................................................................38
2.8.4
Other safety data ...................................................................................39


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2.9
Pharmacokinetic endpoints....................................................................................40
2.10
PD and PK/PD analyses.........................................................................................42
2.11
Patient-reported outcomes .....................................................................................43
44
46
2.14
Interim analysis......................................................................................................47
3
Sample size calculation .....................................................................................................47
3.1
Primary analysis.....................................................................................................47
3.2
Power for analysis of key secondary variables......................................................47
4
Change to protocol specified analyses ..............................................................................48
5
Appendix ...........................................................................................................................48
5.1
Imputation rules.....................................................................................................48
5.1.1
Study drug.............................................................................................48
5.1.2
AE, ConMeds and safety assessment date imputation..........................49
5.2
AEs coding/grading ...............................................................................................50
5.3
Laboratory parameters derivations ........................................................................51
5.4
Statistical models...................................................................................................52
5.4.1
Primary analysis....................................................................................52
5.4.2
Key secondary analysis.........................................................................53
6
Reference...........................................................................................................................55


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List of abbreviations
AE
Adverse event
AESI
Adverse Event of Special Interest
aGvHD
Acute Graft vs. Host Disease
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
BAT
Best Available Therapy
bid
bis in diem/twice a day
BMI
BOR
Body Mass Index
Best Overall Response
BSA
Body Surface Area
cGvHD
chronic Graft vs. Host Disease
CIBMTR
Center for International Blood and Marrow Transplant Research
CMH
Cochran–Mantel–Haenszel
CMV
Cytomegalovirus
CR
Complete Response
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DAR
Dose Administration Record
DMC
Data Monitoring Committee 
eCRF
Electronic Case Report Form
EFS
Event-Free Survival
FACT-BMT
Functional Assessment of Cancer Therapy - Bone Marrow Transplantation
FAS
Full Analysis Set
FFS
Failure-Free Survival
GvHD
Graft vs. Host Disease
HCT
Hematopoietic Cell Transplantation
IRT
Interactive Response Technology that includes Interactive Voice Response
System and Interactive Web Response System
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
NRM
Non Relapse Mortality
ORR
Overall Response Rate
OS
Overall Survival
PAS
Pharmacokinetic analysis set
PD
Pharmacodynamics
PK
Pharmacokinetics
PPS
Per-Protocol Set
PR
Partial response 
PRO
Patient-reported Outcomes
QoL
Quality of Life
RAP
Report and Analysis Process


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RPSFT
Rank-Preserving Structure Failure Time
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
WBC
White Blood Cells
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the Clinical Study Report 
(CSR) of study CINC424C2301, a phase III, randomized, open-label, multi-center study of 
ruxolitinib versus best available therapy in patients with corticosteroid-refractory acute graft vs. 
host disease (aGvHD Grade II-IV) after allogeneic stem cell transplantation.
The content of this SAP is based on protocol CINC424C2301 version 02. All decisions 
regarding final analysis, as defined in the SAP document, have been made prior to database 
lock of the study data.
1.1
Study design
This is a phase III, randomized, open-label, multi-center study of ruxolitinib versus best 
available therapy in patients with corticosteroid-refractory acute graft vs. host disease after 
allogeneic stem cell transplantation. Approximately 308 patients will be  randomized to one of 
the following treatment arms in 1:1  ratio:

Ruxolitinib

BAT
Randomization will be stratified by the aGvHD grade (Grade II vs. Grade III vs. Grade IV).
Overall response rate (ORR) at Day 28, as assessed by local investigators’ review of aGvHD
response and using standard criteria [Harris 2016], is the primary endpoint in this study. Durable 
overall response rate at Day 56 is the key secondary endpoint. 
The primary analysis including the analysis on primary and key secondary endpoints will be 
performed after all patients have completed their Day 56 visit or have discontinued study. The 
primary analysis data will be summarized in the primary clinical study report (CSR). 
Further analyses on secondary endpoints will be performed when all patients have completed 6 
months treatment or discontinued from study participation earlier.
The final analysis will occur once all patients have completed the study (up to 24 months from 
randomization). All available data from all patients up to end of study, inclusive of OS, will be 
reported in a final CSR.
No formal interim efficacy analysis is planned in this study. 




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1.2
Study objectives and endpoints
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 2.5
To compare the efficacy of ruxolitinib vs. 
Investigator’s choice Best Available Therapy 
(BAT) in patients with Grade II-IV SR-aGvHD 
assessed by Overall Response Rate (ORR) at 
Day 28
Overall response rate (ORR) at Day 28 after 
randomization, defined as the proportion of 
patients in each arm demonstrating a complete 
response (CR) or partial response (PR) without 
requirement for additional systemic therapies for 
an earlier progression, mixed response or non-
response. Scoring of response will be relative to 
the organ stage at the time of randomization.
CMH analyses, stratified by aGvHD grade
Key secondary endpoint
Refer to Section 2.6
To compare the rate of durable ORR at Day 56 
between ruxolitinib and BAT
Proportion of all patients in each arm who achieve 
a complete response (CR) or partial response 
(PR) at Day 28 and maintain a CR or PR at Day 
56.
CMH analyses, stratified by aGvHD grade
Other secondary endpoints
Refer to Sections 2.7, 2.8, 2.9, 2.10, 2.11
To estimate ORR at Day 14
Proportion of patients who achieved ORR 
(CR+PR) at Day 14. 
To assess Duration of response
Duration of response (DOR) is assessed for 
responders only and is defined as the time from 
first response until aGvHD progression or the date 
of additional systemic therapies for aGvHD. Onset 
of chronic GvHD, or death without prior 
observation 
of 
aGvHD 
progression 
are 
considered as competing risks.


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Objective
Endpoint
Analysis
To assess the cumulative steroid dose until Day 
56
Weekly cumulative steroid dose for each patient 
up to Day 56 or end of treatment will be calculated. 
To assess Overall Survival (OS)
Overall survival, defined as the time from the date 
of randomization to the date of death due to any 
cause. 
Probability of overall survival at Months 1, 2, 6, 12, 
18 & 24 will be estimated from the Kaplan-Meier 
curves for each arm.
To assess Event-Free Survival (EFS)
Event-free survival, defined as the time from the 
date of randomization to the date of hematologic 
disease
relapse/progression, graft failure, or 
death due to any cause. 
Probability of EFS at Months 1, 2, 6, 12, 18 & 24 
will be estimated from the Kaplan-Meier curves for 
each arm.
To assess Failure-Free Survival (FFS)
Failure-free survival, defined as the time from the 
date of randomization to date of hematologic 
disease 
relapse/progression, 
non-relapse 
mortality, or addition of new systemic aGvHD 
treatment.  
Cumulative incidence of FFS at Months 1, 2, 6, 
12, 18 & 24 will be estimated, considering each 
event as a competing risk for the other two.  Onset 
of chronic GvHD is considered as a competing 
risk. 
To assess Non Relapse Mortality (NRM)
Non-relapse mortality (NRM), defined as the time 
from date of randomization to date of death not 
preceded 
by 
hematologic 
disease 
relapse/progression. 
Cumulative incidence of NRM at Months 1, 2, 6, 
12, 18 & 24 will be estimated, considering 
hematologic disease relapse/progression as 
competing events.
To
assess 
incidence 
of 
Malignancy 
Relapse/Progression (MR) 
Malignancy Relapse/Progression (MR) (refer to 
protocol Appendix 4), defined as the time from 
date of randomization to hematologic malignancy 
relapse/progression. Calculated for patients with 
underlying hematologic malignant disease.
Cumulative incidence of MR at Months 1, 2, 6, 12, 
18 & 24 will be estimated, considering deaths not 
preceded 
by 
hematologic 
malignancy 
relapse/progression as competing events.
To measure the incidence of cGvHD 
cGvHD, defined as the diagnosis of any cGvHD 
including mild, moderate, severe.  
Cumulative incidence of cGvHD at Months 1, 2, 6, 
12, 18 & 24 will be estimated, considering 
hematologic disease relapse/progression and
death without prior cGvHD as competing events.
To estimate the rate of Best Overall Response 
(BOR)
Proportion of patients who achieve OR (CR+PR) 
at any time point up to and including Day 28 and 






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2
Statistical methods
2.1
Data analysis general information
The final analysis will be performed by Novartis. SAS version 9.4 or later and/or R version 
3.0.2 or later will be used to perform all data analyses and to generate tables, figures and listings.
Data included in the analysis
The analysis cut-off date for the primary analysis of study data will be established after all 
randomized patients have completed Day 56 visit or have discontinued treatment period or have 
discontinued study. All statistical analyses will be performed using all data collected in the 
database up to the data cutoff date. All data with an assessment date or event start date (e.g. 
vital sign assessment date or start date of an adverse event) prior to or on the cut-off date will 
be included in the analysis. Any data collected beyond the cut-off date will not be included in 
the analysis and will not be used for any derivations.
All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘ongoing’. The same rule will be applied to events starting 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.
The analysis cutoff date for the final analysis of study data will be established when all patients 
have completed the study.
General analysis conventions
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of patients enrolled at centers, no center effect 
will be assessed. 
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables
by treatment group; a missing category will be included as applicable. Percentages will be
calculated using the number of patients in the relevant population or subgroup as the
denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate
descriptive statistics (i.e. mean, standard deviation, median, minimum, and maximum) by 
treatment group.
2.1.1
General definitions
Investigational drug and study treatment
Investigational drug, will refer to the ruxolitinib only. Whereas, study treatment will refer to 
ruxolitinib and BAT. 
Randomized treatment will refer to the study treatment received during the randomized 
treatment period. Up to Day 28 visit, more than one BAT regimen may be initiated as study 


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treatment. These regimens reported on the Dosage Administration Record (DAR) eCRF are 
considered randomized treatment. Crossover treatment will refer to the study treatment 
received during the crossover treatment period.
Date of first administration of randomized treatment
The date of first administration of randomized treatment is derived as the first date when a 
nonzero dose of randomized treatment was administered as per the DAR eCRF. The date of 
first administration of randomized treatment will also be referred as start of randomized
treatment.
Date of first administration of crossover treatment 
The date of first administration of crossover treatment is derived as the first date when a nonzero 
dose of crossover treatment was administered as per the DAR eCRF. The date of first 
administration of crossover treatment (ruxolitinib) will also be referred as start of crossover
treatment.
Date of last administration of randomized treatment 
The date of last administration of randomized treatment is defined as the last date when a 
nonzero dose of randomized treatment was administered as per DAR eCRF. 
Date of last administration of crossover treatment 
The date of last administration of crossover treatment is defined as the last date when a nonzero 
dose of crossover treatment (ruxolitinib) was administered as per DAR eCRF. 
Study day
The study day, describes the day of the event or assessment date, relative to the reference start 
date. 
The study day is defined as:
The date of the event (visit date, onset date of an event, assessment date etc.) −reference 
start date + 1 if event is on or after the reference start date;

The date of the event (visit date, onset date of an event, assessment date etc.) − reference 
start date if event precedes the reference start date.
The reference start date for safety assessments (e.g. adverse event onset, laboratory abnormality
occurrence, vital sign measurement, dose interruption, PK, etc.), 
 and PRO is the
start of randomized treatment.
The reference start date for all other, non-safety assessments (i.e., aGvHD assessment, survival, 
aGvHD progression, aGvHD response, underlying hematologic disease relapse/progression, 
etc.) is the date of randomization.
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative.


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Crossover study day
The crossover study day, describes the day of the event or assessment date, relative to the start 
of crossover treatment.
Crossover study day = date of event – start of crossover treatment + 1, if event is on or after the 
start of crossover treatment
Crossover study day = date of event – start of crossover treatment, if event precedes the start of 
crossover treatment
The crossover study day will be displayed in the data listings if an event starts on or after the 
start of crossover treatment.
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.
Baseline
Baseline for safety endpoints (except adverse events), 
 and patient reported 
outcomes is defined as the last assessment prior to or on the treatment start date. 
For evaluations after cross over, the baseline is defined as the last assessment prior to or on the 
start date of crossover treatment.
Baseline for efficacy endpoints is defined as the last assessment or procedure conducted prior 
to or on the date of randomization date + 3 days, but no later than the treatment start date.
If patients have no value as defined above, the baseline result will be missing.
On-treatment assessment/event and observation periods
For adverse event reporting the overall observation period will be divided into four mutually 
exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent at screening to the day 
before first administration of study treatment
2. on-randomized-treatment period: from date of first administration of randomized
treatment to 30 days after date of last actual administration of randomized treatment
(including start and stop date) or end of randomized treatment per End of Randomized 
Treatment Disposition eCRF, whichever is later; for those patients who cross over from 
BAT to ruxolitinib, the period is from date of first administration of randomized 
treatment to earlier of (i) 30 days after date of last actual administration of randomized 
treatment or end of randomized treatment per End of Randomized Treatment 
Disposition eCRF, whichever is later, (ii) the day before the date of first administration 
of crossover treatment. Up to Day 28 visit, more than one BAT regimen may be initiated
as study treatment. In this case, the last actual administration of randomized treatment
refers to the last actual administration of the last BAT regimen reported on the DAR 
eCRF.  


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3. on-crossover-treatment period: from date of first administration of crossover treatment 
to 30 days after date of last administration of crossover treatment (including start and 
stop date) or end of crossover treatment per End of Crossover Treatment Disposition 
eCRF, whichever is later.
4. post-treatment period: starting at Day 31 after last administration of study treatment or 
the day after end of study treatment per end of treatment disposition eCRFs, whichever 
is later.
If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period cannot 
be made, then the respective data will be assigned to the on-randomized-treatment period.  
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). The data on-randomized-treatment period and on-crossover-treatment 
period will be summarized separately. In addition, a separate summary for death including on-
treatment and post-treatment deaths will be provided.  In particular, summary tables for adverse 
events (AEs) will summarize only on-treatment events, with a start date during the on-treatment 
period (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 post-treatment period will be flagged.
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 two assessments within a time window are 
equidistant from the target date, then the later of the two  assessments will be used. If multiple 
assessments on the same date then the worst case will be used.  Data from all assessments 
(scheduled and unscheduled), including multiple assessments, will be listed.
The following time windows are defined for descriptive summary on aGvHD assessment, 
 PROs and safety (Table 2-1) by visit. The end of treatment assessment will be 
mapped into the time points if collected within 7 days of the last dose intake.  
Table 2-1
Time windows for aGvHD assessment, 
 PROs and safety 
assessment (lab, vital sign, etc.)
Time Window
Planned Visit Timing 
Time Window Definition
On treatment
Baseline1
Study Day 11
≤Study Days 1+3, no later 
than treatment start date
Baseline2
On or before Study Day 12
≤ Study Day 1 
Week 1
Study Day 7
Study Days 4 – 10
Week 2
Study Day 14
Study Days 11 – 17
Week 3  
Study Day 21
Study Days 18 – 24
Week 4
Study Day 28
Study Days 25 – 31
Week 5 
Study Day 35
Study Days 32 – 38


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Week 6  
Study Day 42
Study Days 39 – 45
Week 7
Study Day 49
Study Days 46 – 52
Week 8 
Study Day 56
Study Days 53 – 59
Week 12
Study Day 84
Study Days 71 – 98 
Week 16
Study Day 112
Study Days 99 – 126 
Week 20
Study Day 140
Study Days 127 – 154 
Week 24
Study Day 168
Study Days 155 – 182 
Safety follow-up
30 days after last dose
Last dose date + 30
Baseline1 for aGvHD assessment (efficacy); 
Baseline2 for safety assessments 
(safety);
Study Day 11 = randomization date;
Study Day 12 = start date of randomized treatment;
Crossover Study Day 1 = start date of crossover treatment
EOT (randomized treatment or crossover treatment) assessments are mapped to the time 
points.
Safety follow-up is a separate time point for PROs and safety assessments.
Last contact date 
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the last complete date among the following:
Table 2-2
Last contact date data sources
Source data
Conditions
Date of Randomization 
No Condition
Last date patient was known to be alive from 
Survival Follow-up page 
Patient status is reported to be alive, lost to 
follow-up or unknown.
Start/End dates from further aGvHD therapy
Non-missing medication/procedure term.
Start/End* dates from drug administration record 
Non-missing dose. Doses of 0 are allowed.
End of treatment date from end of treatment page
No condition.
- aGvHD assessment date
- any specific efficacy assessment date if 
available (e.g., cGvHD assessment, graft failure 
assessment, hematologic disease 
relapse/progression assessment)
Evaluation is marked as ‘done’.
Laboratory/PK collection dates/
 
Sample collection marked as ‘done’. 
Vital signs date
At least one non-missing parameter value
Start/End dates of AE 
Non-missing verbatim term


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The last contact date is defined as the latest complete date from the above list on or before the 
data 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. Completely imputed
dates (e.g. the analysis cut-off date programmatically imputed to replace the missing end date
of a dose administration record) will not be used to derive the last contact date. Partial date 
imputation is allowed for event (death)/censoring coming from ‘Survival information’ eCRF. 
The last contact date will be used for censoring of patients in the analysis of overall survival.
2.2
Analysis sets
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 and strata, they have been assigned to during the randomization procedure.
Per-Protocol Set 
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with requirements of the clinical study protocol.
The following list of protocol deviations will lead to exclusion of the patient from the Per-
Protocol Set:

Not steroid refractory aGvHD (PDID: INCL09 per SSD v22.0)

More than one prior systemic therapy for the treatment of aGvHD other than corticosteroids 
+/- CNI (prophylaxis or treatment) (PDID: EXCL01 per SSD v22.0)

Missing or incorrect aGvHD grade at randomization (PDID: OTH02, INCL07 per SSD 
v22.0)

Taking any prohibited medication as specified in this protocol after start of study treatment 
and before end of study treatment (PDID: COMD01, COMD02 per SSD v22.0)

Study treatment received different from treatment arm assigned by randomization (PDID: 
TRT02 per SSD v22.0)
Safety Set
The Safety Set includes all patients who received at least one dose of study treatment. 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 if the randomized treatment was never received during the randomized 
treatment period.
Crossover Analysis Set
The Crossover Analysis Set (CAS) comprises all patients randomized to and received BAT who 
then crossed over and received at least one dose of ruxolitinib.  This analysis set will be used 
for all analyses for crossover patients.




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The primary efficacy endpoint will be summarized by the following subgroups to examine the 
homogeneity of treatment effect provided that the primary efficacy analysis based on the FAS 
is statistically significant : 

Age group (12- <18, 18-65, >65 years)

Gender

Race

Region (Europe (including Australia and Canada), Asia excluding Japan, Japan)

Acute GvHD grade (Grade II, III, IV) 

Source of grafts (related, not related)

Criteria for SR-aGvHD (progression after at least 3 days, failure to achieve a response 
after 7 days, flare failure during taper)

Prior aGvHD therapy (steroid  +/- CNI, steroid +/- other systemic aGvHD treatment, 
steroid +/- CNI +/- other systemic aGvHD treatment, )    
No formal statistical test of hypotheses will be performed for the subgroups, only point estimate 
of the treatment effect and 95% confidence intervals will be provided (see Section 2.5 for further 
analysis details). The objective of the efficacy subgroup analysis is to demonstrate homogeneity 
of treatment effect in the above subgroups. 
Safety
Key safety analyses will be repeated on the Safety Set in the following subgroups:

Age group (12- <18, 18-65, >65 years)

Gender

Race
The objective for carrying out these subgroup analyses is to identify potential safety issues 
that may be limited to or more commonly observed in a subgroup of patients.  The following 
summaries will be presented by subgroup:

AEs, irrespective of causality, by primary system organ class and preferred term

AEs with suspected relationship to study treatment, by primary system organ class and 
preferred term

Serious AEs, irrespective of causality, by primary system organ class and preferred term

Serious AEs with suspected relationship to study treatment, by primary system organ class 
and preferred term

On-treatment deaths, by primary system organ class and preferred term
Adolescent patients
In order to be able to make a separate risk/benefit assessment for the adolescent patients, besides 
the above planned subgroup analyses for this age group (12-<18 years), data of demographics 
and exposure will be presented.
Japanese patients
Subgroup analyses will also be performed for the patients treated in Japan. No selection will be 
done on the basis of ethnicity, the purpose being to evaluate the population of patients living in 


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Japan, not a specific ethnic set of patients. The analysis will be done the same way as in region 
subgroup specified above.
2.3
Patient disposition, demographics and other baseline 
characteristics
The Full Analysis Set (FAS) will be used for all baseline and demographic summaries and 
listings unless otherwise specified. Summaries will be reported by treatment arm and for all 
patients and listings will be reported by treatment arm to assess baseline comparability.  No 
inferential statistics will be provided.
Basic demographic and background data
All demographic and baseline disease characteristics data will be summarized and listed by 
treatment arm. Categorical data (e.g. gender, age groups: 12- <18 vs. 18-65 vs. >65 years, race, 
ethnicity) will be summarized by frequency counts and percentages; the number and percentage 
of patients with missing data will be provided. Continuous data (e.g. age, weight, height, body 
mass index) will be summarized by descriptive statistics (N, mean, median, standard deviation,
Q1, Q3, minimum and maximum). 
Baseline stratification factors
The number (%) of patients in each stratum (Grades II, III, IV) based on data obtained from the 
IRT system will be summarized overall and by treatment arm for the FAS. Discordances 
between the stratum recorded in IRT at the time of randomization and the actual stratum 
recorded in the clinical database through the data collected on eCRF will be cross-tabulated and 
listed.
Diagnosis and extent of disease
Summary statistics will be tabulated for diagnosis and extend of disease in underlying disease, 
stem cell transplant and acute GvHD. 
For underlying disease, the analysis will include the following: primary diagnosis category and 
subcategory, details of primary diagnosis, time since diagnosis of underlying disease, CIBMTR 
risk assessment.
For transplant related disease history, the analysis will include the following: conditioning 
regimen type, total HCT-specific comorbidity index score, time since transplant, time from 
diagnosis of underlying disease to transplant, stem cell type, cytomegalovirus status, donor 
information including age, gender, HLA typing method, HLA match score, source of grafts 
(related/unrelated),  CMV status, T-cell depleted (Y/N), total nucleated cell dose.
For aGvHD disease history, the analysis will include the following: time since diagnosis of 
aGvHD grade ≥2, aGvHD grade when diagnosis of grade ≥2, steroid refractory aGvHD criteria 
met (progression after at least 3 days, failure to achieve a response after 7 days, flare failure 
during taper), prior aGvHD therapy (steroid  +/- CNI, steroid +/- other systemic aGvHD 
treatment, steroid +/- CNI +/-other systemic aGvHD treatment,), time from diagnosis of aGvHD 
grade ≥2 to steroid refractory, time since steroid refractory aGvHD, aGvHD grade at 
randomization, aGvHD organ involvement, steroid dose at randomization.


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Medical history
Medical history and ongoing conditions, including underlying disease conditions and symptoms 
entered on eCRF will be summarized and listed by treatment arm. The summaries will be 
presented by primary system organ class (SOC), preferred term (PT) and treatment arm. 
Medical history and current medical conditions will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology. The MedDRA version used for reporting will 
be specified in the CSR and as a footnote in the applicable tables/listings.
Other
Intended BAT strategy in case of SR aGvHD  prior to randomization will be summarized by 
treatment arm.
All data collected at baseline including child bearing potential will be listed.
2.3.1
Patient disposition
Enrollment by country and center will be summarized for all screened patients and also by 
treatment arm. The number (%) of randomized  patients will be presented overall and by 
treatment group. The number (%) of screened and not-randomized patients and the reasons for 
screening failure will also be displayed. The number (%) of patients in the FAS who are still on 
treatment, who discontinued the treatment phases (randomized treatment, crossover treatment) 
as well as the reason for discontinuation, and the survival follow-up will be presented overall 
and by treatment group.
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. All protocol deviations will be listed.
Analysis sets
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarized  by 
treatment group and stratum.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Duration of exposure in days to ruxolitinib and BAT will be summarized by means of 
descriptive statistics. It will also be categorized into time intervals; frequency counts and 
percentages will be presented for the number (%) of patients in each interval. Duration of 
exposure to each BAT regimen (anti-thymocyte globulin (ATG), extracorporeal photopheresis 
(ECP), mesenchymal stromal cells (MSC), low-dose methotrexate (MTX), mycophenolate 
mofetil (MMF), mTOR inhibitors (everolimus or sirolimus), etanercept, or infliximab) will be 
summarized using the same approach.


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Actual cumulative dose, dose intensity (DI) and relative dose intensity (RDI) will be 
summarized for the ruxolitinib arm. Patients randomized to Investigator’s choice of BAT will 
receive various different categories of therapy. 
The number (%) of patients who have dose changes or interruptions, and the reasons, will be 
summarized for ruxolitinib group.
Patient level listings of all doses administered on treatment along with dose change reasons will 
be produced. 
The Safety Set and Crossover Analysis Set will be used for all summaries on randomized 
treatment and crossover treatment, respectively. The Safety Set will be used for listings of study 
treatment.
Duration of exposure to study treatment
Duration of exposure to randomized treatment (days) = (last date of exposure to randomized
treatment) – (date of first administration of randomized treatment) + 1. 
Duration of exposure to crossover treatment (days) = (last date of exposure to crossover 
treatment) – (date of first administration of crossover treatment) + 1. 
The last date of exposure to study treatment is the latest of the last dates of exposure to study 
treatment (see Table 2-4).
Table 2-4
Definition of last date of exposure of study treatment
Scenario
Definition of last date of 
exposure of study treatment
Example
Scenario 1: Study 
treatment with a 
periodical administration
The planned end date of the last 
period in which the last non-zero 
dose of the study treatment was last 
administered.
Note :  If the patient changed to 
another BAT, died or was lost to 
follow-up before the derived last 
date, the last date of exposure to 
study treatment is the date prior to 
the start of the next BAT, date of 
death or the date of last contact, 
respectively. 
If the derived last date of exposure 
goes beyond the data cutoff date, it 
should be truncated to the date of 
data cutoff.
Example 1: In a once-a-week 
administration, the last date of 
exposure is the date of last 
administration + 6 days.
Example 2: In a twice-a-week 
administration, the last date of 
exposure is the date of last
administration + 3 days.
Scenario 2: Study 
treatment with daily/IV 
administration 
Date of last administration of a non -
zero dose of the study treatment.
Example 3: A patient had a 
permanent discontinuation of the 
study treatment 06Jan2017 after 
being 
put 
on 
a 
temporary 
interruption since 01Jan2017. In 


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this case the last date of exposure 
is- 31Dec2016. 
Scenario 3: Study 
treatment as an 
antibody 
Date of last administration of a non -
zero dose of the study drug + 
number of days antibody persists in 
vivo – 1 day.
Note :  If the patient changed to 
another BAT, died or was lost to 
follow-up before the derived last 
date, the last date of exposure to 
study treatment is the date prior to 
the start of the next BAT, date of 
death or the date of last contact, 
respectively.
If the derived last date of exposure 
goes beyond the data cutoff date, it 
should be truncated to the date of 
data cutoff.
Example 4: For a study treatment
which antibody persists in vivo for 
28 days, the last date of exposure 
is the date of last administration + 
28 days – 1 day.
Summary of duration of exposure of study treatment in days will include categorical summaries 
(based on clinically meaningful time intervals) and continuous summaries (i.e. mean, standard 
deviation etc.) using appropriate units of time.
Duration of exposure in patient-years
The duration of exposure in patient-years is a total of the duration of exposure in years from all 
the patients in a treatment group. It will be calculated for randomized treatment (by treatment 
group) and crossover treatment, respectively.
Duration of treatment period
Duration of randomized treatment period (days) = end date of on-randomized-treatment 
period – date of first administration of randomized treatment + 1
Duration of crossover treatment period (days) = end date of on-crossover-treatment period 
– date of first administration of crossover treatment + 1
The on-randomized-treatment period and on-crossover-treatment period are defined in Section 
2.1.1. 
The duration of randomized treatment period in days for ruxolitinib and BAT will be 
summarized by means of descriptive statistics. It will also be categorized into time intervals; 
frequency counts and percentages will be presented for the number (%) of patients in each 
interval. The duration of crossover treatment period will be summarized similarly.
Duration of treatment period in patient-years 
The duration of treatment period (randomized and crossover) in patient-years is a total of the 
duration of treatment period in years from all the patients in a treatment group. It will be 
calculated for randomized treatment (ruxolitinib vs. BAT) and crossover treatment separately. 


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Cumulative dose
The planned cumulative dose for ruxolitinib refers to the total planned dose as per the protocol 
(10 mg bid) up to the last dose date. 
The actual cumulative dose of randomized ruxolitinib refers to the total actual dose of 
randomized ruxolitinib as documented in the DAR eCRF. 
The actual cumulative dose of crossover ruxolitinib refers to the total actual dose 
administered, over the duration for which the patient is on the crossover ruxolitinib as 
documented in the DAR eCRF. 
For patients who did not take any drug the cumulative dose is by definition equal to zero.
Dose intensity and relative dose intensity of ruxolitinib
Dose intensity (DI) of randomized ruxolitinib for patients with non-zero duration of exposure 
is defined as follows: 
DI (mg / day) = Actual cumulative dose (mg) of randomized ruxolitinib / Duration of exposure 
to randomized ruxolitinib (days).
Dose intensity (DI) of crossover ruxolitinib for patients with non-zero duration of exposure 
is defined as follows: 
DI (mg / day) = Actual cumulative dose (mg) of crossover ruxolitinib / Duration of exposure to 
crossover ruxolitinib (days).
For patients who did not take any drug the DI is by definition equal to zero. 
Planned dose intensity (PDI) is defined as follows:
PDI (mg / day) = Planned Cumulative dose (mg) / Duration of exposure (days).
The protocol planned starting dose for ruxolitinib is 10 mg BID.
Relative dose intensity (RDI) is defined as follows:
RDI = DI (mg / day)  / PDI (mg / day).  
DI and RDI will be summarized for randomized and crossover ruxolitinib treatment, separately.
The actual cumulative dose, DI and RDI up to Day 28 visit, Day 56 visit and last date of 
exposure to study treatment (randomized or crossover) will be summarized. 
The number (%) of patients at total daily dose 5 mg, 10 mg, 15 mg and 20 mg will be 
summarized at Day 28 visit, Day 56 visit and last date of exposure to study treatment.
Dose reductions, interruptions or permanent discontinuations
The number of patients who have dose changes, or interruptions, and the reasons, will be 
summarized for ruxolitinib (randomized and crossover treatment separately). The number of 
patients who have dose permanent discontinuations and the reasons, will be summarized by 
treatment group.


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‘Dose changed’, ‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the 
Dosage Administration CRF pages (DAR) will be used to determine the dose changes, 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 
separate interruptions. However, if the reason is the same in this mentioned multiple entries on 
consecutive days, then it will be counted as one interruption. 
2.4.2
Prior, concomitant and post therapies
2.4.2.1
Prior aGvHD treatment
The number and percentage of patients who received any prior aGvHD treatment (medications 
and procedures) will be summarized by lowest ATC class, preferred term and treatment arm. 
Listings will be produced for prior aGvHD treatment. 
The above analyses will be performed using the FAS.
2.4.2.2
Prior prophylaxis
The number and percentage of patients who received any prophylaxis prior to randomization 
will be summarized by lowest ATC class, preferred term and treatment arm using FAS. 
Listings will be generated for prophylaxis.
2.4.2.3
Systemic corticosteroid
The duration of exposure will be summarized for on-randomized-treatment period and on-
crossover-treatment period separately. It will also be categorized into time intervals; frequency 
counts and percentages will be presented for the number (%) of patients in each interval. The 
actual cumulative dose, dose intensity and relative dose intensity (relative to the starting dose 
of corticosteroids) will be summarized up to Day 28 visit, Day 56 visit and end of on-treatment
period. These analyses will be based on Safety Set. The data will be reported on the DAR eCRF 
through the end of randomized treatment per EOT Disposition eCRF, and on the Prior and 
Concomitant Medications eCRF after the end of randomized treatment. The list of systemic 
corticosteroid will be documented in Data Handling Plan.
2.4.2.4
Calcineurin inhibitors (CNIs) during study treatment
The duration of exposure will be summarized for CNIs (cyclosporine or tacrolimus) during on-
randomized-treatment period and on-crossover-treatment period, respectively. It will also be 
categorized into time intervals; frequency counts and percentages will be presented for the 
number (%) of patients in each interval. These analyses will be based on Safety Set. The data 
will be reported on the DAR eCRF through the end of randomized treatment per EOT 
Disposition eCRF, and on the Prior and Concomitant Medications eCRF after the end of 
randomized treatment. The list of CNIs will be documented in Data Handling Plan.


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2.4.2.5
Additional systemic aGvHD therapy
New additional systemic aGvHD therapy (medications and procedures) since start of study 
treatment will be listed and summarized by lowest ATC class, preferred term, overall and by 
treatment group by means of frequency counts and percentages using FAS.
2.4.2.6
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. The summaries for randomized 
treatment phase using Safety Set will include:

Medications starting on or after the start of randomized treatment but no later than end of 
on-randomized-treatment period; and

Medications starting prior to start of randomized treatment and continuing after the start of 
randomized treatment.
The summaries for crossover treatment phase using Crossover Analysis Set will include:

Medications starting on or after the start of crossover treatment but no later than end of 
on-crossover-treatment period; and

Medications starting prior to start of crossover treatment and continuing after the start of 
crossover treatment.
All concomitant therapies will be listed using Safety Set. Any concomitant therapies starting
and ending prior to the start of randomized treatment or starting beyond end of on-randomized-
treatment period if not crossed over, or starting beyond end of on-crossover-treatment period if 
crossed over, will be flagged in the listing. 
The prohibited concomitant medications will be summarized by lowest ATC class and preferred 
term up to the end of on-randomized-treatment and on-crossover-treatment periods, 
respectively. The list of prohibited medications will be provided and updated regularly by 
clinical team according to the clinical database review. 
In addition, a subset of concomitant medications i.e. transfusions (red blood cells and platelets) 
will be grouped and summarized by treatment group. 
2.5
Analysis of the primary objective
The primary objective of the study is to compare the overall response rate (ORR) at Day 28
between the ruxolitinib arm and BAT arm  in steroid refractory aGvHD patients.


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2.5.1
Primary endpoint
ORR at Day 28 is defined as the proportion of patients with complete response (CR) or partial 
response (PR) at Day 28 according to standard criteria [Harris 2016].  Note that response is 
relative to the assessment of aGvHD at randomization.

Complete response is defined as a score of 0 for the aGvHD grading in all evaluable 
organs that indicates complete resolution of all signs and symptoms of aGvHD in all 
evaluable organs without administration of additional systemic therapies for any earlier 
progression, mixed response or non-response of aGvHD.  

Partial response is defined as improvement of 1 stage in 1 or more organs involved with 
aGvHD signs or symptoms without progression in other organs or sites without 
administration of additional systemic therapies for an earlier progression, mixed response 
or non-response of aGvHD.  

Lack of response is defined as no response, mixed response, or progression.

No response is defined as absence of improvement in any organ involved by aGvHD, 
without worsening in any involved organ.  

Mixed response is defined as improvement of at least 1 stage in the severity of 
aGvHD in at least one organ accompanied by progression in another organ or 
development of signs or symptoms of aGvHD in a new organ.

Progression is defined as worsening in 1 or more organs by 1 or more stages without 
improvement in any involved organ
A flare in aGvHD is defined as any increase in signs or symptoms of  aGvHD after an initial 
response (CR or PR). However, a flare may not lead to progression or additional systemic 
therapy. Only flares in GvHD that require new additional systemic therapy, will be considered 
aGvHD flare failure. Patients who fail corticosteroid taper fulfilling either one of the following 
criteria should initiate additional systemic therapy:

Requirement for an increase in the corticosteroid dose to methylprednisolone ≥2 
mg/kg/day (or equivalent  prednisone dose ≥2.5 mg/kg/day), OR   

Failure to taper the methylprednisolone dose to <0.5 mg/kg/day (or equivalent prednisone 
dose <0.6 mg/kg/day) for a minimum 7 days.
A patient will not be considered a responder at Day 28 if any of the following events occurs:

Missing aGvHD assessment at baseline or Day 28 

No CR or PR at Day 28 

Additional systemic therapy for aGvHD prior to Day 28
Compared to the protocol version 00, ‘discontinuation from randomized treatment’ has been 
dropped as reason.  Since some BATs have fixed duration which is less than 8 weeks, to avoid 
bias, discontinuation from randomized treatment will not be used to disqualify the response or 
durable response. Also duration of response will not be censored based on treatment 
discontinuation.
Acute GvHD will be assessed according to standard criteria [Harris 2016], as described in 
protocol Appendix 1. Grade will be calculated based on the staging of the organs and recorded 
on the eCRF by the Investigator. The Investigator reported grade will be used for randomization 


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and reported grade and response for all analyses. Grade and response will be calculated by the 
sponsor for the purposes of data review only and sensitivity analysis. 
2.5.2
Statistical hypothesis, model, and method of analysis
The primary efficacy analysis is the comparison of ORR at Day 28 between the two treatment 
arms. The following statistical hypotheses will be tested to address the primary efficacy 
objective: 
H0: ORRrux ≤ ORRBAT  vs.   H1: ORRrux > ORRBAT
where ORRrux and ORRBAT are the overall response rates at Day 28 in the ruxolitinib and BAT 
groups, respectively. The Cochrane-Mantel-Haenszel chi-square test, stratified by the 
randomization stratification factor (i.e., aGvHD Grade II vs III vs. IV), will be used to compare 
ORR between the two treatment groups, at the one-sided 2.5% level of significance. 
The primary efficacy variable, ORR at Day 28, will be analyzed at the time when all patients 
have completed their Day 56 visit or discontinued earlier. The primary analysis will be 
performed on FAS according to ITT principle. ORR will be summarized using descriptive 
statistics (N, %) by treatment arm along with two-sided exact binomial 95% CIs [Clopper and 
Pearson 1934]. One-sided p-value, odds ratio and 95% Wald confidence limits calculated from 
stratified Cochran-Mantel-Haenszel test will be also presented.
2.5.3
Handling of missing values/censoring/discontinuations
Patients with missing assessments that prevent the evaluation of the primary endpoint will be 
considered non-responders on that treatment arm. This includes missing aGvHD response 
assessments at baseline and Days 28, 56.  
The following analysis windows (also in Table 2-1) will be applied to the target day for 
assessments on overall response, where target day for Week X is X*7.
Baseline assessment is the last aGvHD assessment prior to or on the date of randomization (Day 
1). A tolerance of up to 3 days from randomization will be considered in the analysis, but the 
baseline assessment will not be later than the date of treatment start.
Weeks 1, 2, 3, 4, 5, 6, 7, 8: -3 days/+3 days
Weeks 12 to 24: -13 days/+14 days
The analysis windows for assessments after crossover is similar, except that the baseline is the 
last aGvHD assessment prior to or on Crossover Day 1 (date of first administration of crossover 
treatment). 
No data imputation will be applied.
2.5.4
Supportive analyses for ORR at Day 28
To evaluate the treatment effect on each organ, shift tables of aGvHD stage by organ and 
treatment group will be produced to compare baseline to the Day 28 value.




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review of aGvHD assessment data. Note that response is relative to the last assessment of 
aGvHD prior to or at the start date of crossover treatment (ruxolitinib).
A patient will not be considered a responder at Crossover Day 28 if any of the following events 
occurs:

Missing aGvHD assessment at Crossover baseline or Crossover Day 28 

No CR or PR at Crossover Day 28 

Additional systemic therapy for aGvHD prior to Crossover Day 28
In addition, shift tables of aGvHD stage by organ and treatment group will be produced to 
compare Crossover baseline to Crossover Day 28.
2.6
Analysis of the key secondary objective
The key secondary objective of the study is to determine whether treatment with ruxolitinib has 
better durable ORR at Day 56 compared with BAT.
2.6.1
Key secondary endpoint
Durable ORR at Day 56 is defined as the proportion of all patients in each arm who achieve a 
complete response (CR) or partial response (PR) at Day 28 and maintain a CR or PR at Day 56. 
If a patient is a CR at Day 28 and a PR at Day 56, he/she will be considered as a durable 
responder. A patient will not be considered a durable responder at Day 56 if any of the following 
events occurs:

Not a  responder at Day 28

Missing aGvHD assessment at Day 56 

No CR or PR at Day 56. 

Additional systemic therapy for aGvHD prior to Day 56
Durable ORR will be calculated based on the FAS using local investigators review of aGvHD 
assessment data. 
The patients randomized to BAT who meet cross-over criteria and cross-over to ruxolitinib 
are considered to have the additional systemic therarpy for aGvHD, and will not be 
considered as a responder afterwards.
In addition, shift tables of aGvHD stage by organ and treatment group will be produced to 
compare Day 28 to Day 56 value for the patients who achieved PRs at Day 28.
2.6.2
Statistical hypothesis, model, and method of analysis
The following statistical hypotheses will be tested to address the key secondary efficacy 
objective: 
H0: DORRrux ≤ DORRBAT  vs.   H1: DORRrux > DORRBAT
where DORRrux and DORRBAT are the durable overall response rates at Day 56 in the ruxolitinib 
and BAT groups, respectively. The Cochrane-Mantel-Haenszel chi-square test, stratified by the 
randomization stratification factor (i.e., aGvHD Grade II vs III vs. IV), will be used to compare 


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the durable ORR between the two treatment groups, at the one-sided 2.5% level of significance, 
if the primary endpoint is significant. 
The key secondary efficacy variable, durable ORR at Day 56, will be analyzed at the time when 
all patients have completed their Day 56 visit or discontinued earlier. The analysis will be based 
on FAS according to ITT principle. Durable ORR will be summarized using descriptive 
statistics (N, %) by treatment arm along with two-sided exact binomial 95% CIs [Clopper and 
Pearson 1934]. P-value, odds ratio and 95% Wald confidence limits calculated from stratified 
Cochran-Mantel-Haenszel test will be also presented. 
The durable ORR at Day 56 will be tested hierarchically. That is, if the ORR at Day 28 is 
statistically significant, the durable ORR at Day 56 will be tested. If the ORR at Day 28 is not 
statistically significant, the durable ORR at Day 56 will not be tested.
2.6.3
Handling of missing values/censoring/discontinuations
Refer to Section 2.5.3
2.6.4
Durable ORR at Crossover Day 56
Durable ORR at Crossover Day 56 is defined as the proportion of all crossover patients who 
achieve a complete response (CR) or partial response (PR) at Crossover Day 28 and maintain a 
CR or PR at Crossover Day 56. Durable ORR at Crossover Day 56 will be summarized using 
descriptive statistics (N, %) along with two-sided exact binomial 95% CIs [Clopper and Pearson 
1934] based on the CAS using local investigators’ review of aGvHD assessment data. Note that 
response is relative to the last assessment of aGvHD prior to or at the start date of crossover 
treatment (ruxolitinib).
A patient will not be considered a durable responder at Crossover Day 56 if any of the following 
events occurs:

Not a responder at Crossover Day 28

Missing aGvHD assessment at Crossover Day 56 

No CR or PR at Crossover Day 56. 

Additional systemic therapy for aGvHD prior to Crossover Day 56
In addition, shift tables of aGvHD stage by organ and treatment group will be produced to 
compare Crossover Day 28 to Crossover Day 56 value for the patients who achieved PRs at 
Crossover Day 28.
2.7
Analysis of secondary efficacy objective(s)
The other secondary efficacy objectives are to: 

Evaluate the two treatment arms with respect to ORR at other time points, e.g. Day 14

Evaluate the two treatment arms with respect to duration of response (DOR)

Evaluate the two treatment arms with respect to overall survival (OS)

Evaluate the two treatment arms with respect to event free survival (EFS)

Evaluate the two treatment arms with respect to failure free survival (FFS)

Evaluate the two treatment arms with respect to Non-relapse mortality (NRM)


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
Evaluate the two treatment arms with respect to incidence of malignancy 
relapse/progression (MR)

Describe cumulative steroid dosing until Day 56 in each treatment arm

Evaluate the two treatment arms with respect to incidence of cGvHD

Evaluate the two treatment arms with respect to BOR at any time points up to Day 28
All the secondary efficacy endpoint analyses are non-comparative in nature and will be 
analyzed using the Full Analysis Set (FAS).
2.7.1
Secondary efficacy endpoints
Overall Response Rate at Day 14
Overall Response Rate at Day 14 is defined as the proportion of patients with complete response 
(CR) or partial response (PR) at Day 14 according to standard criteria [Harris 2016].  
Duration of response (DOR)
Duration of response is defined for patients whose overall response at Day 28 is complete 
response (CR) or partial response (PR) according to standard criteria [Harris 2016]. The start 
date is the date of first documented response of CR or PR (i.e., the start date of response), which 
could be prior to or at Day 28. If it’s prior to Day 28, there should not be progression or addition 
of systemic therapies for aGvHD between the start date of response and Day 28. The end date 
is defined as the date of progression or the date of addition of systemic therapies for aGvHD on 
or after Day 28.
Death without prior observation of aGvHD progression and onset of chronic GvHD are 
considered to be competing risks.
Duration of response will be censored at the last response assessment prior to or at the analysis 
cut-off date, if no events/competing risk occurred before or at the cut-off date.  
Overall survival (OS) 
Overall survival 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 latest date the 
patient was known to be alive (on or before the cut-off date). 
Event Free Survival (EFS)
Event-free survival is defined as the time from the date of randomization to the date of 
hematologic disease relapse/progression, graft failure or death due to any cause. If a patient is 
not known to have any event, then EFS will be censored at the latest date the patient was known 
to be alive (on or before the cut-off date). 
Failure Free Survival (FFS)
Failure-free survival is defined as the time from the date of randomization to date of 
hematologic disease relapse/progression, non-relapse mortality or addition of new systemic 
aGvHD treatment. 
Non-relapse mortality (NRM) 


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Non-relapse mortality is defined as the time from date of randomization to date of death not 
preceded by hematologic disease relapse/progression. Hematologic disease relapse/progression 
is considered a competing risk for NRM with the date of hematologic disease 
relapse/progression being the earlier of documented hematologic disease relapse/progression or 
institution of therapy to treat potential hematologic disease relapse/progression. If a patient is 
not known to have died or to have relapsed/progressed, then NRM will be censored at the latest 
date the patient was known to be alive (on or before the cut-off date). 
Incidence of Malignancy Relapse/Progression (MR)
Malignancy relapse/progression is defined as the time from date of randomization to 
hematologic malignancy relapse/progression. Deaths not preceded by hematologic malignancy 
relapse/progression are competing risks. If a patient is not known to have event or competing 
risks, then MR will be censored at the latest date the patient was known to be alive (on or before 
the cut-off date). 
Incidence of cGvHD
cGvHD is defined as the diagnosis of any cGvHD including mild, moderate, severe. Incidence 
of cGvHD is the time from date of randomization to onset of cGvHD. Deaths without prior 
onset of cGvHD and hematologic disease relapse/progression are competing risks. If a patient 
is not known to have event or competing risks, then the incidence of cGvHD will be censored 
at the latest date the patient was known to be alive (on or before the cut-off date).  
Best Overall Response
Best overall response (BOR) is defined as proportion of patients who achieved overall response 
(CR or PR) at any time point up to and including Day 28, and had no additional systemic 
therapy for aGvHD prior to the time point.  
2.7.2
Statistical hypothesis, model, and method of analysis
Overall Response Rate at Day 14 
Overall response rate will be calculated based on the local investigators review of aGvHD 
assessment data. It will be summarized using descriptive statistics (N, %) by treatment arm
along with two-sided exact binomial 95% CIs [Clopper and Pearson 1934]. Odds ratio and 95% 
Wald confidence limits calculated from stratified Cochran-Mantel-Haenszel test will be also 
presented.
Duration of response (DOR)
The estimated cumulative incidence rates and 95% confidence intervals at 1, 2, 6, 12, 18 and 
24 months will be presented for each treatment group. The cumulative incidence curve will be 
plotted. DOR will be listed and summarized by treatment group for all patients in the FAS with 
overall response of CR or PR at Day 28.  
Overall survival (OS) 
OS will be analyzed according to the randomized treatment group and strata assigned at 
randomization (aGvHD grade: Grade II vs. III vs. IV). The OS distribution will be estimated 
using the Kaplan-Meier method, and the Kaplan-Meier curves, medians, 1, 2, 6, 12, 18 and 24 


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month survival estimates and 95% confidence intervals [Brookmeyer and Crowley 1982] will 
be presented for each treatment group. The hazard ratio for OS will be calculated, along with 
its 95% confidence interval, using a stratified Cox model. 
Event Free Survival (EFS)
EFS will be analyzed according to the randomized treatment group and strata assigned at 
randomization. The EFS distribution will be estimated using the Kaplan-Meier method, and the 
Kaplan-Meier curves, medians, 1, 2, 6, 12, 18 and 24 month survival estimates and 95% 
confidence intervals [Brookmeyer and Crowley 1982] will be presented for each treatment 
group. The hazard ratio for EFS will be calculated, along with its 95% confidence interval, 
using a stratified Cox model.
A sensitivity analysis including aGvHD progression as an event will be performed using the
same approach.
Failure Free Survival (FFS)
Cumulative incidence curve for FFS as well as estimates at 1, 2, 6, 12, 18 and 24 months with 
95% confidence intervals will be presented for each treatment group, accounting for onset of 
chronic GvHD as the competing risk. 
In addition, the cumulative incidence of each of the three components considering the other two 
components as a competing risks will be estimated. Onset of chronic GvHD is considered as a 
competing risk for all three types of failure. The cumulative incidence curves will be plotted for 
each treatment group. 
A sensitivity analysis including aGvHD progression as an event will be performed using the 
same approach.
Non-relapse mortality (NRM) 

NRM will be analyzed in the FAS population according to the randomized treatment 
group and strata assigned at randomization (aGvHD grade: Grade II vs. III vs. IV).  The 
cumulative incidence curve for NRM as well as estimates at 1, 2, 6, 12, 18 and 24 months 
with 95% confidence intervals will be presented for each treatment group.  

As a sensitivity analysis, the cumulative incidence curve for NRM as well as estimates at 
1, 2, 6, 12, 18 and 24 months with 95% confidence intervals will be presented for patients 
with underlying hematologic malignant disease in each treatment group.
Incidence of Malignancy Relapse/Progression (MR)
The cumulative incidence curve for MR and estimates at 1, 2, 6, 12, 18 and 24 months with 95% 
confidence intervals will be presented for patients with underlying hematologic malignant 
disease, accounting for NRM as the competing risk.
In addition, the proportion of patients who had hematologic malignancy relapse/progression 
and its 95% confidence interval at 1, 2, 6, 12, 18 and 24 months will be presented by treatment 
group for patients with underlying hematologic malignant disease. Odds ratio and 95% Wald 
confidence limits calculated from stratified Cochran-Mantel-Haenszel test will be also 
presented.
Cumulative steroid dosing until Day 56


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Overall and weekly cumulative steroid dose for each patient up to Day 56 or discontinuation of 
randomized treatment will be tabulated.  In addition, the relative dose intensity (RDI), by week, 
will be calculated relative to the starting dose of corticosteroids and categorized as (1) complete 
reduction where patients are tapered off corticosteroids by D56, (2) ≤50% RDI  and (3) >50% 
RDI. The proportion of patients in each category and corresponding 95% confidence intervals 
will be presented by treatment group. Average corticosteroid dose during the week ending on 
Days 14, 28, 56, 84, and 168 will also be tabulated and plotted.
Incidence of cGvHD
The cumulative incidence of cGvHD and estimates at 1, 2, 6, 12, 18 and 24 months with 95% 
confidence intervals will be presented, accounting for competing risks. The cumulative 
incidence curve will be plotted for each treatment group.
Best Overall Response
Best overall response will be calculated based on the local investigators review of aGvHD 
assessment data. It will be summarized using descriptive statistics (N, %) by treatment arm 
along with two-sided exact binomial 95% CIs [Clopper and Pearson 1934]. Odds ratio and 95% 
Wald confidence limits calculated from stratified Cochran-Mantel-Haenszel test will be also 
presented.
2.7.3
Handling of missing values/censoring/discontinuations
Refer to Section 2.5.3
2.8
Safety analyses
All safety analyses will be based on Safety Set, except that the summary of safety data during 
the crossover treatment phase will be based on Crossover Analysis Set. All listings and tables 
will be presented by treatment group. For safety evaluations (except for AE) during randomized 
treatment phase, the last available assessment on or before the date of start of randomized
treatment is taken as the “baseline” assessment. For safety evaluations (except for AE) during 
crossover treatment phase, the last available assessment on or before the date of start of 
crossover treatment is taken as the “baseline” assessment.  
Due to possible crossover from BAT to ruxolitinib arm after Day 28, imbalance in exposure 
between the two arms is expected. Therefore, safety summaries for the randomized treatment 
will be performed for the following periods, unless specified:

Up to Day 31 (the upper bound of the Day 28 visit window);

Up to the earlier of i) cutoff date, ii) end date of on-randomized-treatment period;
The on-randomized-treatment period is defined in Section 2.1.1. 
For the summaries up to cutoff date, some may be presented by adjusting for the duration of 
randomized treatment period in patient-years where relevant.


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2.8.1
Adverse events (AEs)
For reporting of AEs the overall observation period will be divided into mutually exclusive 
categories, including pre-treatment, on-treatment (randomized or crossover), post-treatment  
periods as defined in Section 2.1.1.
AE summaries will include all AEs occurring (new or worsening) during on-treatment period. 
All AEs collected in the AE eCRF page will be listed along with the information collected on 
those AEs e.g. AE relationship to study drug, AE outcome etc. AEs with start date outside of 
on-treatment period will be flagged in the listings. 
AEs will be summarized by number and percentage of patients 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 patient with multiple occurrences of an AE will be counted only 
once in the respective AE category. A patient with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event.
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables.
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 the descending frequency in the ruxolitinib arm.
The following adverse event summaries will be produced by treatment arm; overview of 
adverse events and deaths, 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, and leading to fatal outcome. In 
addition, a summary of serious adverse events with 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
AEs adjusted for patient duration of treatment period 
In order to account for differences in exposure of the ruxolitinib arm relative to the BAT arm 
due to crossover from BAT to ruxolitinib after Day 28 visit, incidence rates of adverse events 
may be presented by adjusting for duration of treatment period in patient-years where relevant.
2.8.1.2
Adverse events of special interest / grouping of AEs
Data analysis of AESIs
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to compound ruxolitinib. These groupings are defined using MedDRA 
terms, SMQs (standardized MedDRA queries), HGLTs (high level group terms), HLT (high 
level terms) and/or PTs (preferred terms). Customized SMQs (Novartis MedDRA queries, 
NMQ) may also be used. A NMQ is a customized group of search terms which defines a medical 
concept for which there is no official SMQ available or the available SMQ does not completely 
fit the need. It may include a combination of single terms and/or an existing SMQ, narrow or 
broad. 


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For each AESI (selection from the Case Retrieval Sheet), number and percentage of patients 
with at least one event of the AESI occurring during on-treatment period will be summarized.
Summaries of AESIs will be provided by treatment arm, (specifying grade, SAE, relationship, 
leading to treatment discontinuation, leading to dose adjustment/interruption, hospitalization, 
death etc.).
A listing of all grouping levels down to the MedDRA preferred terms used to define each AESI 
will be generated. 
In addition to summarizing infections by CTCAE grade, they will also be summarized using 
infection severity (protocol Appendix 2) up to Day 31 (the upper bound of the Day 28 visit 
window), and cutoff date. 
Proportion of patients developing second primary malignancies will be summarized for on-
treatment period, post-treatment period and both.
2.8.2
Deaths
Separate summaries for on-treatment and all deaths (including post-treatment death) will be 
produced by treatment arm, system organ class and preferred term. 
All deaths will be listed and post-treatment deaths will be flagged. A separate listing of deaths 
prior to starting treatment will be provided for all screened patients.
2.8.3
Laboratory data
On analyzing laboratory, data from all sources (central and local laboratories) will be combined. 
The summaries will include all assessments available for the lab parameter collected no later 
than end of the on-treatment periods (randomized or crossover).
Grading of laboratory 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.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
The following summaries will be produced for hematology and biochemistry laboratory data 
(by laboratory parameter and treatment):

Shift tables using CTC grades to compare baseline to the worst on-treatment  value 
The following listings will be produced for the laboratory data:

Listings of all laboratory data, with CTC grades and classification relative to the 
laboratory normal range. Lab data collected during the post-treatment period will be 
flagged.  

Listing of all CTC grade 3 or 4 laboratory toxicities
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots may be 
produced.


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2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
Not applicable.
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 mass index (kg/m2), body 
temperature (°C), pulse (beats per minute), systolic and diastolic blood pressure (mmHg). 
Data handling
Vital signs collected 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 clinically notable vital sign criteria are provided in Table 2-5
below.
Table 2-5
Clinically notable changes in vital signs
Vital sign 
(unit)
Clinically notable criteria
above normal value 
below normal value
Weight (kg)
increase > 10% from Baseline
decrease  > 10% from Baseline
Systolic blood 
pressure 
(mmHg)
>=180 with increase from baseline 
of >=20
<=90 with decrease from baseline 
of >=20
Diastolic blood 
pressure 
(mmHg)
>=105 with increase from baseline 
of >=15
<=50 with decrease from baseline 
of >=15
Pulse rate 
(bpm)
>=100 with increase from baseline 
of >25%
<=50 with decrease from baseline of 
> 25%
Body 
temperature
>= 39.1 
-
The number and percentage of patients with notable vital sign values (high/low) will be 
presented  by treatment arm.         
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. 


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Additional Analyses
Time to first occurrence of grade 3 infection
Time to first occurrence of infection is defined as time from start of study treatment to the date 
of first occurrence of grade 3 infection severity per protocol Appendix 2, i.e. time in days is 
calculated as (start date of first occurrence of infection ) – (start of study treatment) +1. 
In the absence of an event during the on-treatment period, the censoring date applied will be 
the earliest of the following dates: 

death date

end date of on-treatment period  (randomized or crossover) 

data cut-off date

withdrawal of informed consent date
Failure curves (ascending Kaplan-Meier curves) will be constructed by treatment arm. Median 
together with 95% confidence interval as well as 25th percentile and 75th percentile will be 
presented for each treatment arm. 
A sensitivity analysis will be conducted considering deaths or end of treatment phase 
(randomized or crossover) without prior infection as competing risks. Cumulative incidence 
curve for time to grade 3 infection as well as estimates at 1, 2 and 6 months with 95% confidence 
intervals will be presented for each treatment group. 
In addition, the median time to occurrence for the subset of patients who experienced infection 
will be calculated. Simple descriptive statistics, median, min and max as well as 25th percentile 
and 75th percentile, will be presented.
2.9
Pharmacokinetic endpoints
Pharmacokinetic Analysis Set (PAS) will be used in all pharmacokinetic data analysis and PK 
summary statistics. 
Plasma samples for extensive PK will be taken at Day 1 (start of treatment), at Day 7 (week 1) 
for the first 25 adult patients and all adolescents to characterize the PK after first dose, and at 
steady state by non-compartmental analysis.  Additional PK samples will be taken at later visits 
for all patients to characterize exposure-efficacy, exposure-safety 
 
as data allows. Concentrations will be expressed in mass per volume units.
PK parameters
The PK parameters that will be determined are shown in Table 2-6. The PK parameters of 
ruxolitinib will be calculated from the extensive PK data based on the non-compartmental 
methods using Phoenix WinNonlin® (Pharsight, Mountain View, CA) software. Additional PK 
parameters may be estimated as needed.
Table 2-6
Non-compartmental PK parameters for ruxolitinib
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) (ng 
x hr/mL)






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(frequency of;severity of AEs, AEs of interest to be defined prior to analysis or laboratory 
parameters).

Average steady-state exposures and/or other PK parameters for the population will 
becomputed by the POP PK model accounting for dose modifications or dose 
interruptions up to the day prior to the day of assessments. Population PK derived 
parameters will be used for exposure-response analysis by appropriate methods
For duration of response and overall survival, if the primary endpoint is significant and 
sufficient events have accrued (i.e., at analysis time points after the primary analysis), a Cox 
regression model with appropriate patient demographic and prognostic factors as covariates and 
the log-trough level as a time dependent covariate will be fitted if appropriate. To account for 
dose adjustments between trough sampling time points the trough concentration will be adjusted 
by dividing by the actual dose prior to the trough in question and multiplying by the arithmetic 
mean dose since the last trough sample or start of dosing as applicable. The calculation of the 
arithmetic mean dose should count any dose interruptions as a zero dose for the days that no 
dose was given. Goodness of fit of the model will also be examined. The survival time should 
be calculated from the time of first dose rather than the time of randomization. The hazard ratio 
and 95% confidence interval for a two-fold increase in exposure will be displayed if appropriate. 
Kaplan-Meier curves may be used to summarize the data based on relevant quantiles of PK.
For incidence of specific AEs, Day 28 response (if the primary endpoint is significant) and Day 
56 durable response (if the primary and key secondary endpoints are significant), logistic 
regression models may be used including log-average trough concentration and other 
demographic and prognostic covariates in the model as appropriate. The trough concentration 
will be similarly adjusted to account for dose adjustments as described above. The average 
trough concentration included in the model for Day 28 response will be the arithmetic mean of 
the Day 7, Day 14, Day 21 and Day 28 adjusted trough concentration. A similar average trough 
concentration will be calculated for the Day 56 response except the Day 42 and Day 56 adjusted 
concentration will be double weighted compared to the others because they are representative 
of concentration over 2 weeks rather than 1. For analysis of adverse events the last trough 
concentration prior to the AE will be included in the model. Other exposure measures may be 
considered if appropriate. The odds ratio and its 95% confidence interval for a two-fold increase 
in exposure will be displayed as appropriate.
2.11
Patient-reported outcomes
The FACT-BMT along with the EQ-5D-5L will be used to collect data on the patient’s disease-
related symptoms and health-related quality of life. Responses to the FACT-BMT and EQ-5D-
5L will be generated in accordance with the respective scoring manual. Further details on the 
scoring of FACT-BMT and EQ-5D are given in Appendix 5.4.3.1 and Appendix 5.4.3.2.
These PRO instruments are planned to be administered on randomization day and every week 
during the first 2 months, and every 4 weeks thereafter until the end of treatment. 
The baseline is defined as the last PRO assessment prior to or on the date of randomization date
+ 3 days, but no later than the treatment start date..
FACT-BMT will not be used in patients under age 18 years.








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2.14
Interim analysis
No formal interim analysis is planned for this trial. 
Early PK analysis
To compare the exposure of 10 mg BID in the SR aGvHD population to the known exposure in 
MPN patients, the early extensive ruxolitinib PK data on the first 25 adult patients (including 
any adolescent patients randomized at that time) will be explored once available, also in the 
context of concomitant medications. However, there will be no comparison between the two 
treatment arms because PK data are not collected in BAT patients.
DMC safety data analysis
DMC will be instituted in this study and will review the safety data as outlined according the 
DMC charter. A separated set of SAP and TFL shells will be provided to detail the analysis.
3
Sample size calculation
The study with a total of 308 patients and 1:1 randomization (ruxolitinib vs. BAT) stratified on 
aGvHD grade (Grade II vs. Grade III vs. Grade IV) has 90% power to test for the primary 
endpoint (ORR at Day 28) and approximately 90% power to test for the key secondary endpoint 
(durable ORR at Day 56). The family wise α-level will be controlled at 0.025 overall for the 
two comparisons. Specifically, this study will claim to have achieved the efficacy objective 
when the primary endpoint ORR at Day 28 shows a significant treatment effect at one-sided α 
= 0.025. Conditional on significance of the primary endpoint, the key secondary endpoint 
durable ORR at Day 56 will be tested at one-sided α = 0.025. 
3.1
Primary analysis
The sample size calculation is based on the primary variable ORR at Day 28. The hypotheses 
to be tested and details of the testing strategy are described in Section 2.5.2 and Section 3. 
Based on Martin P. et al BBMT 2013, the ORR at Day 28 in the BAT arm is expected to be 
58%. The stratum specific rates (Grade II 69%, Grade III 59%, Grade IV 50%) are obtained 
assuming that the ratio of aGvHD Grade II: III: IV is 0.2:0.4:0.4. It is expected that treatment 
with ruxolitinib will result in an 18% increase in the ORR, i.e., an expected odds ratio of 2.25 
(which corresponds to an increase in ORR to 75%). Power for the CMH test, stratifying on 
aGvHD grade, was calculated using software package East V6. In order to ensure 90% power 
a total sample size of 308 patients are needed. 
With a sample size of 154 patients in each treatment arm, an observed odds ratio greater than 
or equal to 1.63 would achieve statistical significance for the primary endpoint. Assuming that 
the observed response rates in Grades II/III/IV in BAT arm are 69%/59%/50% (overall 57%), 
observed response rates ≥ 78%/70%/62% (overall 68%) in the ruxolitinib arm would achieve 
statistical significance.
3.2
Power for analysis of key secondary variables
Durable ORR at Day 56, as the key secondary variable, will be formally statistically tested, 
provided that the primary endpoint ORR at Day 28 is statistically significant. The hypotheses 


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to be tested and details of the testing strategy are provided in Section 2.6.2. Based on [Van 
Groningen 2016], the durable ORR at Day 56 in the BAT arm is expected to be approximately 
35%. The stratum specific rates (Grade II 45%, Grade III 36%, Grade IV 30%) are obtained 
assuming that the ratio of aGvHD Grade II: III: IV is 0.2:0.4:0.4. It is expected that treatment 
with ruxolitinib will result in a 20% increase in the ORR, i.e., an expected odds ratio of 2.25 
(which corresponds to an increase in durable ORR to 55%). With these assumptions and sample 
size of 308 patients, the power for the key secondary endpoint is at least 90%.
With sample size 154 patients in each treatment arm, an observed odds ratio greater than or 
equal to 1.59 for durable ORR at Day 56 would achieve statistical significance. Assuming that 
the observed durable response rates in Grades II/III/IV in BAT arm are 45%/36%/30% (overall 
35%), observed durable response rates ≥ 57%/47%/41% (overall 47%) in the ruxolitinib arm 
would achieve statistical significance.
4
Change to protocol specified analyses
Compared to the protocol version 00, ‘discontinuation from randomized treatment’ has been 
dropped as reason.  Since some BATs have fixed duration which is less than 8 weeks, to avoid 
bias, discontinuation from randomized treatment will not be used to disqualify the response or 
durable response. Also duration of response will not be censored based on treatment 
discontinuation.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
The following rule should be used for the imputation of the dose end date for a given study 
treatment component:
Scenario 1: If the dose end date is completely missing and there is no EOT page and no death 
date, the patient is considered as on-going: 
The patient should be treated as on-going and the cut-off date should be used as the dose end 
date.
Scenario 1 should not be applied for final CSR. All patients should have EOT page complete 
before the Database lock for Final CSR
Scenario 2: If the dose end date is completely or partially missing and the EOT page is available: 
Please note that date of assessment on EOT eCRF might be very different from last date of dose. 
Case 1: The dose end date is completely missing, and the EOT  completion date is complete, 
then this latter date should be used.  
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:  
Use Dec31yyyy


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Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date: 
Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy  = the year 
of EOT date and mm < the month of  EOT date: 
Use last day of the Month (mm)
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study.
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:
Use the treatment start date
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed.
5.1.2
AE, ConMeds and safety assessment date imputation
Table 5-1
Imputation of start dates (AE, CM) and assessments (LB, EG, VS)
Missing 
Element
Rule
day, month, 
and year

No imputation will be done for completely missing dates
day, month

If available year = year of study treatment start date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY 
o
Else set start date = study treatment start date. 

If available year > year of study treatment start date then 01JanYYYY

If available year < year of study treatment start date then 01JulYYYY


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Missing 
Element
Rule
day

If available month and year = month and year of study treatment start 
date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY. 
o
Else set start date = study treatment start date.

If available month and year > month and year of study treatment start 
date then 01MONYYYY  

If available month and year < month year of study treatment start date 
then 15MONYYYY  
Table 5-2
Imputation of end dates (AE, CM) 
Missing 
Element
Rule 
(* if end date of the on-treatment period not > (death date, cut-off date, 
withdrawal of consent date))
day, month, 
and year

Completely missing end dates (incl. ongoing events) will be imputed 
by the end date of the on-treatment period* 
day, month

If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period * 
day

If partial end date contains month and year, set end date = earliest of 
last day of the month or end date of the on-treatment period*
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings.
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ 
rather than the end date provided. 
The above imputations are only used for analyses of time to and duration of AEs and 
concomitant medications. 
5.1.2.1
Other imputations
Incomplete date of initial diagnosis of aGvHD 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan. 
5.2
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
The latest available MedDRA version at the time of the analyses should be used. The MedDRA 
version used should be specified in the footnote of relevant tables.  
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03. 


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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). 
5.3
Laboratory parameters derivations
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. 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. 
CTCAE Grade 5 is not defined for laboratory values. 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.
Imputation Rules  
CTC grading for blood differentials is based on absolute values. However,  this data may not 
be reported as absolute counts but rather as percentage of WBC. 
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential
xxx count = (WBC count) * (xxx %value / 100)
Further derivation of laboratory parameters might be required for CTCAE grading. For instance, 
corrected calcium can be derived using the reported total calcium value and albumin at the same 
assessment using the following formula:
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4]
In order to apply the above formula, albumin values in g/L will be converted to g/dL by  
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium.
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above for grading.


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5.4
Statistical models
5.4.1
Primary analysis
The null hypothesis of equality of response rate in the two treatment arm will be tested against 
one-sided alternative.  The statistical hypotheses are:
H0: ORRrux ≤ ORRBAT  vs.   H1: ORRrux > ORRBAT
where ORRrux is the probability of response in ruxolitinib and ORRBAT is the probability  of 
response in BAT.
The Cochran-Mantel-Haenszel chi-square test X2
CMH (implemented again via SAS procedure
FREQ with CMH option in the TABLES statement) will be used to test the difference in
response rates between the treatment arms. The p-value corresponding to the CMH test for 
“general association” will be used which follows a Chi-square distribution with one degree of 
freedom.
If the sampling assumptions for chi-square test is not met, the exact Cochran-Mantel-Haenszel test
will be used (implemented via SAS procedure MULTTEST). The test is performed by running
a stratified version of the Cochran-Armitage permutation test [Armitage et al. 1969]. In studies 
with stratified randomization,  the  chi-square  approximation  is  considered  appropriate  for  
the  X2
CMH statistics if the rule of Mantel and Fleiss [Mantel and Fleiss 1980] is satisfied.
Logistic Regression 
Odds ratio will be used as a measure of association between treatment and response. The odds 
ratio will be derived from the logistic regression model (implemented using SAS procedure 
LOGISTIC, with treatment specified as an explanatory variable in the CLASS statement) 
which allows for including not only the stratification factor but also for adjustments for other 
covariates (both categorical and continuous). The odds ratio will be presented with 95% Wald 
confidence limits.
In cases where an exact test has been used to compare response rates, the odds ratio should be 
determined using exact logistic regression, and the odds ratio presented with exact 95% 
confidence limits. In these cases, SAS PROC LOGISTIC with EXACTONLY option will be 
used.
Confidence interval for response rate
Responses will be summarized in terms of percentage rates with 100(1 −α)% confidence 
interval using exact binomial confidence interval (implemented using SAS procedure FREQ
with EXACT statement for one-way table [Clopper and Pearson 1934].
Definition of new or additional systemic therapy for aGvHD
The data source to search for the new or additional systemic therapy would be from eCRFs of 
Prior and Concomitant Medication (CONMED) (with subcategory as treatment for aGvHD) 
and Dosage Administration Record (DAR).
Any of the following therapies represent new or additional systemic therapy for aGvHD: 


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1. Any new CNI therapy being initiated as ‘treatment for aGvHD’ after the baseline as 
recorded either on DAR or on CONMED, and never received prior to or at baseline
2. Any other systemic therapy (excluding CNI or systemic corticosteroid
(methylprednisolone, prednisone and prednisolone)) being started as ‘treatment for
aGvHD’ after the baseline and recorded on CONMED. Note: the therapy may have been 
taken prior to baseline but not at baseline.
3. Additional BAT at or after start of the initial BAT as recorded on DAR
4. Treatment with ruxolitinib after cross-over from BAT as recorded on DAR
5.4.2
Key secondary analysis
Same instructions as in Section 5.4.1.
5.4.3
Other secondary analysis
5.4.3.1
FACT-BMT
For FACT-BMT the subscale scores, the FACT-BMT total score and the FACT-BMT Trial 
Outcome Index (TOI) will be calculated. 
The subscales are physical well-being (PWB), social/family well-being (SWB), emotional well-
being (EWB), functional well-being (FWB) and bone marrow transplant subscale (BMTS).  For 
each subscale the corresponding score will be calculated based on the item response of the 
answered question according to the FACT-BMT Scoring Guide (Version 4). The scoring guide 
identifies those items that must be reversed before being added to obtain subscale totals.  
Negatively stated items are reversed by subtracting the response from “4”.  After reversing 
proper items, all subscale items are summed to a total, which is the subscale score.
If there are missing items, subscale scores can be prorated.  This is done by multiplying the sum 
of the subscale by the number of items in the subscale, then dividing by the number of items 
actually answered.  This can be done by using the formula below:
Prorated subscale score 
= [Sum of item scores] x [N of items in subscale]/[N of items answered]   
When there are missing data, prorating by subscale in this way is acceptable as long as more 
than 50% of the relevant items were answered. Note that not all items (questions) are used to 
calculate the scores (see Scoring Guide, version 4).  For all the scores the higher the score is the 
better the QOL is. 
The FACT-BMT Trial Outcome Index (TOI, score range: 0-96) is calculated as 
The FACT-BMT total score (score range: 0-148) is then calculated as the sum of all un-
weighted subscale scores:


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5.4.3.2
EQ-5D-5L
EQ-5D-5L consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression. Also the EQ-VAS is included. Each dimension has 5 levels (1-5).
The data were reported for all 5 dimensions. The proportion of reported problems for each level 
were reported. The changes from baseline were defined with a shift table. The below screenshot 
is from the Excel conversion document obtained from the EuroQol webpage on 5L Value Sets 
(http://www.euroqol.org/about-eq-5d/valuation-of-eq-5d/eq-5d-5l-value-sets.html). This UK 
value will be used to convert the “health state” to an “index value” for all patients in all countries. 
For example, if the health state is 11125, then the index value would be .316 and so on.


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6
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