Safety Follow-up Through 180 Days of Treatment With Remestemcel-L in Study MSB-GVHD001 in Pediatric Patients Who Have Failed to Respond to Steroid Treatment for Acute GVHD
Phase: PHASE3
Conditions: Grade B Acute Graft Versus Host Disease, Grade C Acute Graft Versus Host Disease, Grade D Acute Graft Versus Host Disease
Sponsor: Mesoblast, Inc.

Official Title: 
Safety Follow-up Through 180 Days of Treatment with Remestemcel-L in 
Study MSB-GVHD001 in Pediatric Patients who have Failed to Respond to 
Steroid Treatment for Acute GVHD 
NCT Number: 
NCT02652130 
Document Date: 
Protocol Version 4.0: 01 December 2016 
SAP Version 5.0: 10-July-2018 

EXTENSION STUDY PROTOCOL 
 
Protocol Title: Safety Follow-up Through 180 Days of Treatment with 
Remestemcel-L in Study MSB-GVHD001 in Pediatric Patients who have Failed to 
Respond to Steroid Treatment for Acute GVHD 
  
IND Number: 07939 
Protocol Number: MSB-GVHD002 
Clinical Development: Phase 3 
Version: 4.0 
Protocol Date:  01 December 2016 
 
 
 
Sponsor:  Mesoblast International Sàrl 
Route de Pre-Bois 20 
c/o Accounting & Management Service SA, 
1217 Meyrin 
Switzerland 
 
 
 
 
Sponsor Authorized Representatives: 
 
 
 
_______________________________ 
, MD 
 
Mesoblast, Inc. 
 
 
 
 
  
 
 
 
 
 
     
 
 
 
 
 
    
     
 
Confidentiality Statement 
 
The information in this document is confidential and is provided to you as an investigator, 
potential investigator, or consultant for review by you, your staff, and applicable Institutional 
Review Board/Ethics Committee members. This information shall not be disclosed to others 
without prior written authorization from Mesoblast, Inc. except to the extent necessary to obtain 
informed consent from those persons to whom the drug may be administered. 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 2 of 79 
Mesoblast 
 
INVESTIGATOR’S SIGNATURE 
Study Title:  Safety Follow-up Through 180 Days of Treatment with Remestemcel-L in 
Study MSB-GVHD001 in Pediatric Patients who have Failed to Respond to Steroid 
Treatment for Acute GVHD 
 
I have read and understood the contents of this protocol and the Investigator’s Brochure and 
agree to conduct this study in compliance with the protocol, Good Clinical Practice, and other 
applicable regulatory requirements.  I accept the oversight of the study monitor designated by 
Mesoblast and the control procedures, including verification by access to source documents, as 
required by the study monitoring and audit functions of Mesoblast or its designee and the audit 
functions of regulatory agencies in accordance with Good Clinical Practice. 
 
I understand that any changes to this protocol not associated with procedures necessary for the 
safety of subjects that are instituted by the Investigator without previous discussion with the 
Mesoblast Medical Director or designee would constitute a violation of the protocol. 
 
I agree that the investigational agents supplied by Mesoblast will be used solely for the purpose 
of conducting this investigation.  
 
I will personally conduct the investigation as described herein and in the Mesoblast Clinical 
Research Agreement. 
 
Agreement Signature: 
 
 
 
______________________  
_____________________ 
 
_______________ 
Principal Investigator  
 
Principal Investigator  
 
Date 
(Please print)  
 
 
(Signature) 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 3 of 79 
Mesoblast 
 
GENERAL INFORMATION 
 
Physician for trial-related questions: 
, MD 
 
Mesoblast 
505 Fifth Avenue 
Level 3 
New York, NY 10017 
USA 
Office:   +1 212 880 2060 
Email:  
 
 
 
Contact for trial-related safety issues: 
Medical Affairs Department  
Safety & Pharmacovigilance 
Mesoblast 
505 Fifth Avenue 
Level 3 
New York, NY 10017 
USA 
Mobile: 
 or 
 
Email: 
 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 4 of 79 
Mesoblast 
 
PROTOCOL SYNOPSIS 
Sponsor 
Mesoblast International Sàrl 
Study Phase  
Phase 3 
Protocol number 
MSB-GVHD002 
Investigational Product 
Remestemcel-L (ex-vivo cultured adult human mesenchymal stromal cells [MSCs]) 
cryopreserved in Plasma-Lyte® A supplemented with human serum albumin (5%) and 
dimethyl sulfoxide (10%). Remestemcel-L is stored and distributed in cryogenic bags  
(100 x 106  MSCs in 15mL (6.7 x 106 cells/mL)) and vials (25 x 106 MSCs in 3.8 mL  
(6.25 x 106 cells/mL)). 
Protocol Title 
Safety Follow-up Through 180 days of Treatment With Remestemcel-L in Study MSB-
GVHD001 in Pediatric Patients who Have Failed to Respond to Steroid Treatment for 
Acute GVHD 
Indication 
Ongoing safety assessment follow up to Protocol MSB-GVHD-001 of remestemcel-L 
treatment in pediatric subjects with acute Graft versus Host Disease (aGVHD), following 
allogeneic hematopoietic stem cell transplant (HSCT), that have failed to respond to 
treatment with systemic corticosteroid therapy .  
Objectives 
Primary Objective:   
To describe the safety through 180 days of remestemcel-L treatment in subjects who 
participated in Protocol MSB-GVHD001.  No additional investigational agent 
(remestemcel-L) will be administered in this safety follow-up protocol.  
 
Secondary Objectives:   
1. To assess survival at 180 days 
2. To obtain an assessment for GVHD activity to investigational medicinal product 
(IMP) administered in MSB-GVHD001. 
3. To assess the proportion of subjects able to taper steroids by 50% at each time point 
from Day 100 to Day 180.  
4. To assess the time to addition of any second-line GVHD treatment agent  
5. To assess the number of days to a GVHD flare 
6. To evaluate subjects for evidence of chronic GVHD. 
 
 
 
 
 
 
  
 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 5 of 79 
Mesoblast 
 
 
 
 
 
Study Design 
This is a safety follow-up study through 180 days of remestemcel-L treatment in subjects 
who participated in MSB-GVHD001. This study will also explore duration of response over 
time. Subjects who participated in MSB-GVHD001 and received at least one dose of 
remestemcel-L as outlined in that protocol will be evaluated at baseline (Day 100) and at 
Days 120, 140, 160 and 180 for safety endpoints. Subjects who participated in Protocol 
MSB-GVHD001and received the first 8 doses of remestemcel-L as outlined in that protocol 
will be evaluated at baseline (Day 100) and at Days 120, 140, 160 and 180 after initial 
remestemcel-L infusion for evidence of duration of response over time. 
Study Population 
Safety population: All subjects who participated in Protocol MSB-GVHD001 and received 
at least one remestemcel-L infusion in that protocol. 
 
Duration of response population: All subjects who participated in Protocol MSB-
GVHD001, received the first 8 doses of remestemcel-L as outlined in that protocol, and 
showed overall response (OR) or very good partial response (VGPR) to remestemcel-L at 
Day 28. 
Inclusion Criteria 
Patients are eligible for the study if all of the following criteria are met:  
1. Subjects must have participated in Protocol MSB-GVHD001 and have received at 
least one infusion of remestemcel-L. 
2. Subject or subject’s authorized representative must be capable of providing written 
informed consent.  Assent, if applicable, must also be collected when required by 
the IRB/EC. 
3. Female subjects of childbearing potential (≥ 10 years of age); (Appendix 7) must 
use a medically accepted method of contraception and must agree to continue use of 
this method for the duration of the study and for the follow-up time period. 
Acceptable methods of contraception include abstinence, barrier method with 
spermicide, intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, 
implanted, and injected) in conjunction with a barrier method.  
4. The subject must be willing and able to comply with study procedures, remain at the 
clinic as required during the study period, and return to the clinic for the follow-up 
evaluation as specified in this protocol. 
Exclusion Criteria 
1. The investigator believes it to be in the best interest of the subject not to participate 
in the safety follow up study. 
2. Subject has participated or is currently participating in any autologous or allogeneic 
stem cell or gene therapy study for the treatment of aGVHD. Patients participating 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 6 of 79 
Mesoblast 
 
in investigative protocols aimed at modification of the transplant graft (such as T 
cell depletion) or aimed at modification of the conditioning regimen will be allowed 
in the study. 
Assessments  
Primary Endpoints  
Safety through 180 days of remestemcel-L treatment in subjects who participated in 
Protocol MSB-GVHD001 and received at least one infusion of remestemcel-L.  
 
Safety 
1. Adverse events 
2. Serious adverse events 
3. Survival through Day 180 
4. Ectopic tissue formation 
 
Secondary Endpoints 
1. Survival at 180 days for subjects who received the initial therapy through 
28 days as outlined in Protocol MSB-GVHD001 
2. GVHD activity at time points evenly divided amongst the term, from Day 100 to 
Day 180 specifically at Days 120, 140, 160 and 180 relative to baseline 
assessment in MSB-GVHD001. 
3. Steroid doses at Days 120, 140, 160 and 180, including proportion of subjects 
able to taper steroids by 50% by each time point. Guideline for steroid taper is 
located in Appendix 6. 
4. Time to addition of any second-line GVHD treatment agent 
5. The number of days to GVHD flares 
6. Evidence of chronic GVHD at any time from Day 0 to Day 180. Guidelines for 
chronic GVHD assessment is located in Appendix 8. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Duration of Study 
Subjects who participated in Protocol MSB-GVHD001 will be followed-up for safety, and 
duration of response through 180 days post initiation of treatment. Total duration of study 
participation per subject for Protocol MSB-GVHD001 and Protocol MSB-GVHD002 is up 
to 180 days with the last 80 days being in Protocol MSB-GVHD002. 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 7 of 79 
Mesoblast 
 
Statistical Analysis 
General 
Categorical variables will be summarized using frequencies and percentages. Continuous 
variables will be summarized using descriptive statistics (n, mean, standard deviation [SD], 
median, minimum, and maximum). Confidence intervals, if presented, will be at the 95% 
confidence level. 
 
The baseline value for a variable is defined as the last non-missing observation prior to or 
equal to the first dose date of study treatment in MSB-GVHD001. Data collected at 
unscheduled time points will not be summarized at the unscheduled time points.  
 
Study day will be calculated from the first infusion date from MSB-GVHD001, unless 
otherwise specified. 
 
Analysis Populations 
The analysis population for the safety assessment in this study will include all subjects from 
Protocol MSB-GVHD001 who have signed the Informed Consent form and have received 
at least one dose of remestemcel-L. The analysis population for the duration of response 
assessments in this study will include Protocol MSB-GVHD001 subjects with overall 
response and VGPR to remestemcel-L at Day 28, who have signed the Informed Consent 
form and have completed treatment for the first 28 days, as prescribed in Protocol MSB-
GVHD001.  
 
Safety Analyses 
Safety assessments will be summarized with descriptive statistics for subjects in the 
analysis population. Listings will be provided for adverse events (AEs), serious adverse 
events (SAEs), 12-lead ECG and ectopic tissue formation. Vital signs will be provided as 
change from baseline tables by infusion number categories. 
Interim 
Analysis 
No interim analysis is planned for this study 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 8 of 79 
Mesoblast 
 
Figure 1:  Study Design of MSB-GVHD001 and MSB-GVHD002 
 
†Subjects who have a GVHD flare of Grade B-D after achieving a complete response (CR) at 
Day 28 (following Initial Therapy) or Day 56 (following continued therapy) and before Day 70 
may receive additional remestemcel-L treatment per the Initial Treatment plan. 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 9 of 79 
Mesoblast 
 
TABLE OF CONTENTS 
 
INVESTIGATOR’S SIGNATURE ..................................................................................2 
LIST OF TABLES ...........................................................................................................14 
LIST OF FIGURES .........................................................................................................14 
LIST OF APPENDICES .................................................................................................14 
GLOSSARY OF ABBREVIATIONS ............................................................................15 
1. 
BACKGROUND .......................................................................................................18 
1.1 
Acute Graft-versus Host Disease ....................................................................18 
1.2 
Current Treatment of aGVHD and Prognosis ................................................19 
1.3 
Grading of Acute GVHD ................................................................................20 
1.4 
Clinical Endpoints for Evaluation of aGVHD Treatment ..............................22 
1.5 
Mesenchymal Stromal Cells (MSCs) as Therapy for Acute GVHD ..............24 
 
 
 
 
1.8 
Clinical Safety of Remestemcel-L ..................................................................25 
1.9 
Potential Risks of MSCs .................................................................................25 
1.10 
Benefits ...........................................................................................................26 
2. 
CLINICAL RATIONALE .......................................................................................28 
2.1 
Rationale for the Study ...................................................................................28 
2.2 
Rationale for Study Design .............................................................................28 
2.3 
Rationale for Subject Population ....................................................................29 
2.4 
Rationale for Dosing Regimen and Treatment Period ....................................29 
3. 
STUDY OBJECTIVES ............................................................................................29 
3.1 
Objectives .......................................................................................................29 
3.2 
Primary Objective ...........................................................................................30 
3.3 
Secondary Objectives: ....................................................................................30 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 10 of 79 
Mesoblast 
 
4. 
STUDY DESIGN ......................................................................................................30 
4.1 
Overview of Study Design ..............................................................................30 
4.1.1 
Primary Endpoints ...........................................................................31 
4.1.2 
Secondary Endpoints .......................................................................31 
 
 
4.2 
Study Duration ................................................................................................32 
4.3 
Study Sites ......................................................................................................35 
5. 
STUDY POPULATION ...........................................................................................35 
5.1 
Enrollment ......................................................................................................35 
5.2 
Eligibility Criteria ...........................................................................................35 
5.2.1 
Inclusion Criteria .............................................................................35 
5.2.2 
Exclusion Criteria ............................................................................36 
5.3 
Premature Subject Withdrawal .......................................................................36 
5.4 
Lost to Follow-Up...........................................................................................36 
5.5 
End of Study ...................................................................................................36 
6. 
STUDY PROCEDURE ............................................................................................37 
6.1 
Visit Schedule and Assessments .....................................................................37 
6.1.1 
Safety Assessments ..........................................................................38 
 
 
 
 
6.2 
Evaluation Period ............................................................................................43 
6.3 
Missing or Delayed Study Visits ....................................................................43 
6.4 
Background and Prior Second-Line Medication ............................................43 
6.5 
Concomitant Medication and Supportive Therapy .........................................44 
6.5.1 
Standard of Care for aGVHD ..........................................................44 
6.5.2 
Concomitant Medications ................................................................44 
6.5.3 
Steroid Taper ....................................................................................44 
6.5.4 
Escalating Therapy...........................................................................44 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 11 of 79 
Mesoblast 
 
6.5.5 
Supportive Care ...............................................................................45 
7. 
SAFETY GUIDANCE ..............................................................................................45 
7.1 
Definitions ......................................................................................................45 
7.1.1 
Adverse Event ..................................................................................45 
7.1.2 
Serious Adverse Event (SAE) -Immediately Reportable to the          
Sponsor ............................................................................................46 
7.1.3 
Severity ............................................................................................46 
7.2 
Relationship of Adverse Event to the IMP .....................................................47 
7.3 
Relationship to Study Procedure ....................................................................47 
8. 
REPORTING ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ......47 
8.1 
Procedures for Reporting Pregnancies ............................................................48 
8.2 
Laboratory Test Abnormalities .......................................................................48 
8.3 
Expedited Reporting to Health Authorities, Investigators, Institutional             
Review Boards, and Ethics Committees ........................................................49 
9. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN...................50 
9.1 
Statistical Analysis Plan .................................................................................50 
9.2 
Analysis Population ........................................................................................50 
9.3 
Demographic and Baseline Characteristics ....................................................51 
9.4 
Safety Data Analysis .......................................................................................51 
9.4.1 
Adverse Events and Serious Adverse Events ..................................51 
9.4.2 
Survival to Day 180 .........................................................................51 
9.4.3 
Ectopic Tissue Formation ................................................................52 
9.4.4 
Other ................................................................................................52 
9.5 
Secondary Endpoints Analysis .......................................................................52 
9.5.1 
Assessment of Survival at Day 180 .................................................52 
9.5.2 
GVHD Activity ................................................................................53 
9.5.3 
Steroid Dose .....................................................................................53 
9.5.4 
GVHD Flares ...................................................................................53 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 12 of 79 
Mesoblast 
 
9.5.5 
Second-line Treatment .....................................................................53 
9.5.6 
Chronic GVHD ................................................................................53 
 
 
 
 
 
 
 
               
    
 
 
 
9.8 
Interim Analysis ..............................................................................................54 
9.9 
Handling of Missing Values ...........................................................................54 
10. DATA COLLECTION, MANAGEMENT AND QUALITY ASSURANCE ......55 
10.1 
Assignment of Preferred Terms and Original Terminology ...........................55 
11. STUDY COMMITTEES .........................................................................................55 
11.1 
Independent Data and Safety Monitoring Board (DSMB) .............................55 
 
 
12. LAWS, REGULATIONS, AND ETHICS ..............................................................56 
12.1 
Local Regulations/Declaration of Helsinki ....................................................56 
12.2 
Informed Consent ...........................................................................................56 
12.3 
Institutional Review Board/ Ethics Committees (IRB/EC) ............................57 
12.4 
Protocol Adherence ........................................................................................58 
12.5 
Protocol Deviation ..........................................................................................58 
13. CONDITIONS FOR MODIFYING THE PROTOCOL ......................................58 
14. CONDITIONS FOR TERMINATING THE STUDY ..........................................58 
14.1 
Enrollment Hold and Stopping Rules .............................................................58 
15. STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING ....................59 
15.1 
Investigator's Files / Retention of Documents ................................................59 
15.2 
Source Documents and Background Data ......................................................60 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 13 of 79 
Mesoblast 
 
15.3 
Audits and Inspections ....................................................................................60 
15.4 
Electronic Case Report Forms ........................................................................60 
16. MONITORING OF STUDY ...................................................................................60 
17. CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT                
RECORDS ................................................................................................................61 
18. PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS.......61 
18.1 
Right to Publish ..............................................................................................61 
18.2 
Publication Steering Committee .....................................................................61 
18.3 
Procedure ........................................................................................................62 
19. STUDY COMPLETION ..........................................................................................63 
20. REFERENCES .........................................................................................................64 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 14 of 79 
Mesoblast 
 
LIST OF TABLES 
Table 1:  Worldwide Incidence of Steroid Refractory aGVHD ........................................18 
Table 2:  GVHD Organ Severity Criteria ..........................................................................21 
Table 3:  IBMTR and Glucksberg Grades from Organ Stage ...........................................22 
Table 4:  Acute GVHD Response Criteria .........................................................................23 
    
 
Table 6:  Schedule of Assessments and Procedures ..........................................................33 
Table 7:  Laboratory Tests .................................................................................................41 
Table 8:  NIH Common Criteria for Adverse Events (CTCAE) Scale † ...........................46 
 
 
LIST OF FIGURES 
Figure 1:  Study Design of MSB-GVHD001 and MSB-GVHD002....................................8 
Figure 2:  Probability of survival according to maximum GVHD grade for a sampling of 
607 aGVHD patients from the CIBMTR registry .............................................20 
 
 
 
LIST OF APPENDICES 
 
 
 
 
 
Appendix 6:  Recommended Steroid Taper .......................................................................74 
Appendix 7:  Childbearing Potential, Pregnancy Testing, and Contraception ..................75 
Appendix 8:  Chronic GVHD-Specific Measures .............................................................76 
 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 15 of 79 
Mesoblast 
 
GLOSSARY OF ABBREVIATIONS 
ACR 
Albumin-to-creatinine ratio 
ADA 
American Diabetes Association 
ADL 
AE 
Activities of Daily Living 
Adverse event 
AEI 
Adverse events of interest 
aGVHD 
Acute Graft versus Host Disease 
ALT [SGPT] 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ASBMT 
American Society for Blood and Marrow Transplant 
AST [SGOT] 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical Classification System 
AUC 
Area under the plasma concentration-time curve 
BMI 
BP 
Body mass index 
Blood pressure 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
cGVHD 
Chronic Graft versus Host Disease 
CI 
Confidence interval 
CK 
Creatine kinase 
CMV 
Cytomegalovirus 
CR 
Complete response 
CRF 
Case report form 
CRT 
Cardiac resynchronization therapy 
CSR 
Clinical study report 
CTCAE 
CV 
DAS28 
Common Terminology Criteria for Adverse  Events 
Cardiovascular 
Disease Activity Score in 28 Joints 
DBP 
Diastolic blood pressure 
DCS 
DLCO 
Data collection specification 
Diffusing capacity for carbon monoxide 
DMC 
Data monitoring committee 
DMSO 
DSMB 
Dimethyl sulfoxide 
Data safety monitoring board 
EAC 
Events adjudication committee 
EC 
Ethics committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form(s) 
EDC 
Electronic data capture 
EEA 
ELISA 
EOT 
European Economic Area 
Enzyme-linked immunosorbant assay 
End of treatment 
eGFR  
Estimated glomerular filtration rate 
eForm 
Electronic form (page) 
EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 16 of 79 
Mesoblast 
 
GLOSSARY OF ABBREVIATIONS 
FPG 
Fasting plasma glucose 
FiO2  
Fractional inspired oxygen concentration 
GI 
Gastrointestinal 
-GT 
Gamma-glutamyl transpeptidase 
GCP 
Good clinical practice 
GMP 
Good manufacturing practice 
GFR 
GVHD 
Glomerular filtration rate 
Graft versus Host Disease 
HbA1c 
Glycosylated hemoglobin  
Hct 
Hematocrit 
HDL 
 
High density lipoprotein 
 
HLA 
HLT 
Human leukocyte antigen 
High Level Term 
hMSC 
Human mesenchymal stem cells 
HR 
Heart Rate 
 
 
hsCRP 
High sensitivity C-reactive protein 
HSCT  
Hematopoietic stromal cell transplantation 
IB 
ICD 
ICF 
Investigator’s brochure 
Implantable cardioverter defibrillator 
Informed consent form 
IBMTR 
International Bone Marrow Transplant Registry 
ICH 
IEC 
International Conference on Harmonization 
Independent Ethics Committee 
IL 
 
Interleukin 
 
IMP 
Investigational medicinal product 
IND 
Investigational new drug  
INN 
International non-proprietary name 
IRB 
Institutional review board 
ITT 
Intent to treat  
IUD  
Intrauterine device 
IVRS 
Interactive voice response system 
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
LOCF 
Last observation carried forward 
MLR 
Mixed lymphocyte reaction 
MRI 
Magnetic resonance Imaging 
MDRD 
Modification of diet in renal disease 
mITT 
Modified intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSC 
Mesenchymal Stromal Cells  
MR 
Mixed Response 
NIH 
National Institutes of Health 
NR  
No response 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 17 of 79 
Mesoblast 
 
GLOSSARY OF ABBREVIATIONS 
O2 
Oxygen 
OR 
Overall response 
 
 
PFT 
Pulmonary function testing 
PP 
Per protocol population 
PR 
Partial Response 
PRA 
PT 
Panel reactive antibody 
Preferred Term 
PT/INR 
RANKL 
 
Prothrombin time/international normalized ratio 
Receptor Activator of Nuclear Factor Kappa-B Ligand 
 
RBC 
Red blood cell 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SaO2/SAT 
Oxygen (O2) saturation by pulse oximetry 
SAP 
Safety analysis population 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SEM 
 
Standard error of the mean 
 
SMBG 
Self-monitored blood glucose  
SMT 
SPC 
SOC 
 
Study management team 
Summary of product characteristics 
System organ class 
 
 
 
SUSAR 
T1DM 
TG 
Suspected unexpected serious adverse reaction 
Type 1 diabetes mellitus 
Triglycerides 
TNF-α 
Tumor necrosis factor-α 
ULN 
Upper limit of normal 
VGPR 
Very good partial response 
VOD 
Veno-occlusive disease 
v/v 
Volume/volume 
WBC 
White blood cell 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 18 of 79 
Mesoblast 
 
1. 
BACKGROUND  
1.1 
Acute Graft-versus Host Disease  
Graft versus host disease (GVHD) is a progressive and lethal complication of hematopoietic 
stromal cell transplantation (HSCT) and donor leukocyte infusion.  Two clinically distinct forms 
of GVHD have been described; acute GVHD, which typically occurs within 100 days of HSCT,1 
and chronic GVHD, which is characterized by later onset.2  However, this arbitrary temporal 
distinction between the acute and chronic forms of GVHD has been largely discarded with the 
recognition of these forms as discrete pathophysiologic conditions defined by separate clinical 
and diagnostic criteria.3,4 
 
Occurrence of acute GVHD (aGVHD) after allogeneic transplantation is fairly common, with 
Grades II to IV aGVHD reported in approximately 39% of cases involving sibling donors and 
59% of cases with unrelated donors.5  Overall, an estimated 20% to 80% of patients who receive 
allogeneic HSCT develop acute GVHD, even after prophylaxis with immunosuppressive agents.6  
 
While aGVHD is common among patients with allogeneic transplantation, overall, it is a rare 
disease, affecting about 10,000 individuals per year worldwide, with an estimated 2,000 cases 
found in children (Table 1).  Approximately 5,500 of worldwide aGVHD cases are refractory to 
steroid,1 of which 1,000-1,200 are pediatric cases. 
 
Table 1:  Worldwide Incidence of Steroid Refractory aGVHD 
 
All Patients 
Pediatric  
(<18 years) 
Allogeneic HSCT 
25,000 
5,000 
aGVHD Requiring systemic treatment  (Grades B-D) 
10,000 
2,000 
Refractory aGVHD 
5,000-6,000 
1,000-1,200 
Source: CIBMTR Research Analysis. 
 
In aGvHD, alloreactive T cells present in the donor cell transplant recognize the recipient’s 
tissues as foreign and mount an immunological attack, causing inflammation and tissue damage 
primarily affecting the gastrointestinal (GI) tract, skin, and liver.7  Human leukocyte antigen 
(HLA) disparity between HSC donor and recipient is the key driver of GVHD, causing donor 
T cells to recognize recipient tissue as foreign.7.  The severity of the disease is associated with 
the degree of HLA mismatch between the donor and the recipient, and a greater mismatch will 
result in more aggressive alloreactivity. 8  Damage to recipient tissue caused by the HSCT 
conditioning regimen (irradiation or chemo-ablation) creates a cellular and molecular 
environment that is conducive to GVHD. The tissue damage leads to the increased secretion of 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 19 of 79 
Mesoblast 
 
proinflammatory cytokines, which promote donor T cell proliferation and differentiation and 
interaction with recipient antigen presenting cells. Alloreactive donor T cells traffic to target 
tissues (skin, gut, liver) and release soluble mediators that mediate cytotoxicity and end organ 
damage. Other donor immune cells, including natural killer cells, neutrophils and monocytes, are 
also activated and recruited to target organs and contribute to host tissue destruction.9  This 
adverse immune reaction increases over time as the expanding tissue damage mediated by 
alloreactive immune cells leads to more cytokine production.  A vicious cycle ensues: 
amplification of cytokine expression supports further proliferation and activation of alloreactive 
immune cells, which in turn leads to further tissue damage.7. Consequently, aGVHD potentially 
involves multiple organ systems, with varying degrees of clinical severity. 
 
Acute GVHD primarily affects the skin, the liver, and the gastrointestinal (GI) tract, though the 
GVHD reaction targets a number of different host cells, including those of the skin epithelia and 
mucosa, hair follicles, intestinal crypts, liver bile ducts, bone marrow, and immune system.1,7  
Disease onset often manifests clinically as a pruritic maculopapular rash that first appears on the 
nape of the neck, shoulders, ears, palms of the hands, and soles of the feet.  The liver is the next 
most commonly affected organ after skin; symptoms of liver involvement include jaundice and 
increased alkaline phosphatase levels that indicate damage to the bile canaliculi and portend 
cholestasis.  The GI tract is the third organ among the tissues most commonly affected in acute 
GVHD, frequently presenting as nausea, vomiting, intestinal bleeding, cramping, and diarrhea. 
GI involvement is often the most severe of the organs affected and can be the most difficult to 
treat.  The large volumes of watery diarrhea common to intestinal involvement in acute GVHD 
often transitions into bloody diarrhea that prompt the need for frequent transfusions.7  
 
1.2 
Current Treatment of aGVHD and Prognosis 
Presently, there are no approved therapies for treatment of aGVHD.  Available treatment options 
to prevent aGVHD have historically involved front-line therapy with glucocorticoids along with 
different combinations of prophylaxis agents such as methotrexate and cyclosporine A.6,10-12  
While many patients who develop aGVHD respond well to first-line corticosteroid treatment, 
steroids achieve complete response rates in only approximately 50% of cases.13  Many aGVHD 
patients display inadequate response to corticosteroid, with approximately 10% to 30% of 
aGVHD patients progressing to the more severe Glucksberg Grades III or IV GVHD.5 
 
As shown by the survival curves in Figure 2, prognosis for patients with the most severe forms of 
aGVHD (IBMTR Grades C and D) is dismal, primarily because of greater risk for infectious 
complications, immunosuppression- mediated toxicity, and often incomplete GVHD remission.14  

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 20 of 79 
Mesoblast 
 
Patients that do not respond to steroid therapy have expected one-year survival rates of just 5% 
to 30%.6,8,15-19  A wide variety of second-line immunosuppressive agents are commonly used to 
treat steroid-refractory aGVHD (SR-aGVHD), though there is little evidence to support the 
efficacy of these drugs as secondary therapy for aGVHD.6   
 
Figure 2:  Probability of survival according to maximum GVHD grade for a sampling of 
607 aGVHD patients from the CIBMTR registry 
 
 
1.3 
Grading of Acute GVHD 
Acute GVHD is a heterogeneous set of disease processes that potentially involves multiple organ 
systems, with varying degrees of severity by organ system.  Disease onset typically manifests 
most commonly in the skin, with the GI tract and liver as the next most common sites involved.17  
Historically, classification systems of aGVHD have been established to segregate aGVHD 
according to severity.  The severity grade of aGVHD has been shown to correspond to overall 
survival, with increased transplant-related mortality correlating with higher aGVHD grade.20  

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 24 of 79 
Mesoblast 
 
1.5 
Mesenchymal Stromal Cells (MSCs) as Therapy for Acute GVHD 
 
 
 
 
 
   
 
 
 
 
 
   
 
MSCs have been shown to attenuate inflammatory and immunological processes relevant to 
GVHD. MSCs demonstrate immunosuppressive activity in T cell-driven immune responses in 
animal models of allogenic skin graft rejection and GVHD.33,34,35  In vitro, MSCs suppress T-cell 
proliferation in response to allo-antigenic and mitogenic stimulation, and stimulate an increase in 
the regulatory T cell (Treg) population. 36,37,38  Data suggest that Tregs play an important role in 
inhibiting allogeneic T cell response and aGVHD.6,7  In co-culture systems, MSCs alter the 
cytokine secretion profile of immune cells (dendritic cells, naïve and effector T cells, natural 
killer cells), decreasing expression of pro-inflammatory cytokines (e.g. IFNγ, TNFα) and 
increasing secretion of anti-inflammatory cytokines (e.g. IL-4, IL-10).33  The immunomodulatory 
effects of MSCs are attributable, at least in part, to secretion of soluble factors such as PGE2.33  
In addition, MSCs may mediate tissue protection and repair at sites of injury in GVHD by 
secretion of soluble factors that are known to mediate processes such as inhibition of apoptotic 
cell death, recruitment of endogenous stem cell populations and angiogenesis.39,40,41  
 
 
 
 
  
 
 
 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 25 of 79 
Mesoblast 
 
1.8 
Clinical Safety of Remestemcel-L 
Refer to the remestemcel-L clinical safety as summarized in the MSB-GVHD001 protocol. 
 
1.9 
Potential Risks of MSCs 
A list of adverse events (AEs) possibly or probably related to remestemcel-L use is found in the 
Investigator’s Brochure (IB) and in Protocol MSB-GVHD001 Section 1.7.8.  All AEs were 
events commonly expected in the treated population, independent of the infusions of hMSCs.  
The most common adverse events observed for remestemcel-L in clinical trials of pediatric 
GVHD were infections, gastrointestinal disorders, and respiratory, thoracic and mediastinal 
disorders. 
 
Due to the known immune modulating effects of hMSCs, there is a risk of immune suppression 
and increased infection risk.  Subjects undergoing treatment for GVHD are typically severely 
immunocompromised.  Treatment with remestemcel-L may lead to further immunosuppression.  
Therefore, the potential exists for an increased risk of infectious complications.  Careful subject 
monitoring and appropriate anti-infective prophylaxis is recommended. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
In theory, cells grown and expanded outside the body have the potential to be contaminated, and 
infection could be introduced to the subject at the time of infusion.  This risk is made negligible 
by processing cells in a Good Manufacturing Practice (GMP)-compliant production facility, 
utilizing a closed system, and then by reconstituting them in a cell processing facility 
immediately prior to administration.  The potential risks of introducing a donor-derived 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 26 of 79 
Mesoblast 
 
infectious agent are minimized by strict adherence to the 21CFR1271 Subpart C Donor 
Eligibility and multiple screenings/testing of remestemcel-L for adventitious agents prior to 
release.  The IB contains a full list of donor screening tests performed on all lots of remestemcel-
L during production. 
 
 
 
 
 
There has been no experience with pregnant women receiving infusions of remestemcel-L. The 
effects of remestemcel-L infusion on the developing fetus have not been established pre-
clinically or in clinical trials.  Thus, all females of childbearing potential (subjects ≥ 10 years of 
age) and post-pubescent males with female partners of childbearing potential are to consent to 
use an effective method of birth control during this treatment protocol in a manner that 
minimizes risk of failure.  Abstinence is an option.  Guidelines on childbearing potential and 
contraceptives are located in Appendix 7. 
 
1.10 
Benefits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 27 of 79 
Mesoblast 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 28 of 79 
Mesoblast 
 
 
 
 
 
      
 
2. 
CLINICAL RATIONALE 
2.1 
Rationale for the Study 
There are currently no approved therapies for aGVHD in the US.  Standard front-line treatment 
generally consists of corticosteroid, which produce a complete response in about half of all 
subjects.13  Even with the availability of corticosteroids, approximately 10% to 30% of aGVHD 
subjects develop more severe aGVHD of Glucksberg Grades III or IV.5  A variety of 
immunosuppressants are currently used as second-line therapy, though none of these have 
established efficacy against steroid-refractory aGVHD.6  The reported one-year survival rate for 
subjects that do not respond to steroid therapy ranges from 5% to 30%.6,8,15-19  There is thus a 
strong need for agents with demonstrated efficacy for treating steroid-refractory aGVHD.  
 
MSB-GVHD001 will provide a series of prescribed doses of remestemcel-L and a follow up 
period of 100 days.  There is a great interest in collecting data regarding treatment of aGVHD 
with respect to the duration of response, the ability to taper steroid and other secondary treatment 
and thereby mitigate potential side effects, the development of chronic GVHD after at least 
partial response to treatment, and any change in quality of life.  Accordingly, this study will 
assess the efficacy and safety of remestemcel-L in pediatric patients with aGVHD refractory to 
corticosteroid. 
 
2.2 
Rationale for Study Design 
Overall response, as defined by the response to treatment at Day 28, has been positively 
associated with non-relapse mortality at 6 months and 2 years.26,28  Response at Day 28 has been 
supported guidelines issued by the expert panel of the American Society for Blood and Marrow 
Transplant (ASBMT) in 200924 as well as by subsequent studies.25,27  Treatment of acute GVHD, 
which results in response by 28 days, has been shown to correlate well with survival rates at Day 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 29 of 79 
Mesoblast 
 
100.  Recovery after acute treatment as well as the period after treatment has been associated 
with an increased incidence of opportunistic infections and many other AEs, some due to the 
effects of the disease itself and many due to the treatment intervention, particularly with 
protracted high-dose steroid use.  This study will provide safety data through 180 days after 
treatment of aGVHD.  In addition, the present study will also provide information with regard to 
survival at Day 180, the ability to taper steroid doses and secondary medications and thereby 
mitigate potential risks, the development of chronic GVHD after at least partial response to 
treatment, quality of life (QoL), and duration of response.  Though validated tools for QoL are 
limited for pediatric subjects, this study will evaluate several tools and accommodate those 
subjects too young to answer for themselves.  
 
2.3 
Rationale for Subject Population 
This study will explore duration of response and evaluate the safety of remestemcel-L in 
pediatric subjects with aGVHD that has failed to respond to first-line systemic steroid treatment 
who participated in MSB-GVHD001.  The safety population will be comprised of any subject 
who received at least one infusion of remestemcel-L in MSB-GVHD001. Survival at Day 180 
will be evaluated.  Additionally, duration of response will be explored in subjects who completed 
initial therapy of remestemcel-L (first 8 doses) in MSB-GVHD001 and responded to therapy, in 
order to best assess the impact of a response to treatment of aGVHD.   
 
2.4 
Rationale for Dosing Regimen and Treatment Period 
There is no treatment intervention in this study; all remestemcel-L dosing will have occurred in 
the MSB-GVHD001 study. 
 
3. 
STUDY OBJECTIVES 
3.1 
Objectives 
In clinical studies, MSCs elicited improved clinical response over placebo in subjects with 
aGVHD, which will have been evaluated in the MSB-GVHD001 study.  Here in protocol MSB-
GVHD002, we will describe safety for the MSB-GVHD001 population through 180 days of 
remestemcel-L treatment and explore duration of response of treating aGvHD that has failed to 
respond to first-line steroid treatment in pediatric subjects. 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 30 of 79 
Mesoblast 
 
3.2 
Primary Objective 
Safety through 180 days of remestemcel-L treatment in subjects who participated in Protocol 
MSB-GVHD001.  No additional investigational agent (remestemcel-L) will be administered in 
this safety follow-up protocol. 
 
3.3 
Secondary Objectives:  
1. To assess survival at 180 days 
2. To obtain an assessment for GVHD activity to investigational medicinal product (IMP) 
administered in MSB-GVHD001. 
3. To assess proportion of subjects able to taper steroids by 50% at each time point from 
Day 100 to Day 180.  
4. To assess the time to addition of any second-line GVHD treatment agent 
5. To assess the number of days to a GVHD flare 
6. To evaluate subjects for evidence of chronic GVHD. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. 
STUDY DESIGN 
4.1 
Overview of Study Design  
This is a 180-day safety follow-up study of MSB-GVHD001, which will also explore duration of 
response over time.  Subjects who participated in MSB-GVHD001 and received at least one 
remestemcel-L infusion will be evaluated at baseline (Day 100) and at Days 120, 140, 160 and 
180 for safety endpoints.  Subjects who participated in Protocol MSB-GVHD001and received 
the first 8 doses of remestemcel-L, as outlined in that protocol, and showed overall response or 
VGPR at Day 28 will be evaluated at baseline (Day 100) and at Days 120, 140, 160 and 180 after 
initial remestemcel-L infusion for evidence of duration of response over time. 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 31 of 79 
Mesoblast 
 
4.1.1 
Primary Endpoints  
To describe the safety through 180 days of remestemcel-L treatment in subjects who participated 
in Protocol MSB-GVHD001 and received at least one infusion of remestemcel-L.  
 
Safety parameters to be assessed include:  
1. Adverse events 
2. Serious adverse events 
3. Survival through Day 180 
4. Ectopic tissue formation. 
 
4.1.2 
Secondary Endpoints  
1. Survival at 180 days for subjects who received the complete initial therapy through 28 
days as outlined in Protocol MSB-GVHD001 
2. GVHD activity at time points evenly divided amongst the term from Day 100 to Day 180, 
specifically at Days 120, 140, 160 and 180, relative to baseline assessment in MSB-
GVHD001. 
3. Steroid doses at Days 120, 140, 160 and 180, including proportion of subjects able to 
taper steroids by 50% by each time point. Guideline for steroid taper is located in 
Appendix 6. 
4. Time to addition of any second-line GVHD treatment agent 
5. The number of days to GVHD flares 
6. Evidence of chronic GVHD at any time from Day 0 to Day 180. Guidelines for chronic 
GVHD assessment are located in Appendix 8. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 32 of 79 
Mesoblast 
 
4.2 
Study Duration 
In the present study, MSB-GVHD002, subjects who participated in Protocol MSB-GVHD001 
will be followed-up for safety and for duration of response from Day 100 through 180 days from 
MSB-GVHD001 Day 0.  Subjects will be assessed in the present study according to the schedule 
of planned assessments, as summarized in Table 6.  Thus, the total duration of study participation 
per subject for Protocol MSB-GVHD001 and Protocol MSB-GVHD002 will be up to 180 days 
(± 7 days), with the last 80 of the 180 days under Protocol MSB-GVHD002. 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 34 of 79 
Mesoblast 
 
 
 
 
 
 
  
j  Pregnancy test will be performed on all females of childbearing potential (subjects ≥10 years of age). Guidance on childbearing potential and pregnancy testing is located in Appendix 7. 
k  All AEs will be collected in this study. Adverse events with an onset date after the visit window of Day 100 (Day 107 – as allowed in protocol MSB-GVHD001) will be collected in MSB-GVHD002. 
Adverse events with an onset date before the visit window of Day 100 (Day 106 – as allowed in protocol MSB-GVHD001) will be collected in MSB-GVHD001 
l  CT scans and MRI are optional and may be omitted at the discretion of the Investigator. 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 35 of 79 
Mesoblast 
 
4.3 
Study Sites 
This study will be conducted in approximately 40 different sites. 
 
5. 
STUDY POPULATION 
5.1 
Enrollment  
The study plans to evaluate only those subjects who participated in Protocol MSB-GVHD001.  
All subjects who enrolled in Protocol MSB-GVHD001 and who meet the inclusion and 
exclusion criteria for MSB-GVHD002 will be enrolled in Protocol MSB-GVHD002, using the 
same subject number they received in MSB-GVHD001.  Subjects will be followed through 180 
days after initial therapy with remestemcel-L. 
 
5.2 
Eligibility Criteria 
5.2.1 
Inclusion Criteria 
Subjects are eligible for the study if all of the following criteria are met:  
1. Subjects must have participated in Protocol MSB-GVHD001 and have received at least 
one infusion of remestemcel-L. 
2. Subject or subject’s authorized representative must provide written informed consent.  
Assent, if applicable, must also be collected when required by the IRB/EC. 
3. Female subjects of childbearing potential (≥ 10 years of age) (Appendix 7) must use a 
medically accepted method of contraception and must agree to continue use of this 
method for the duration of the study and for the follow-up time period.  Acceptable 
methods of contraception include abstinence, barrier method with spermicide, 
intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, implanted, and 
injected) in conjunction with a barrier method.  
4. The subject must be willing and able to comply with study procedures, remain at the 
clinic as required during the study protocol, and return to the clinic for the follow-up 
evaluations as specified in this protocol. 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 36 of 79 
Mesoblast 
 
5.2.2 
Exclusion Criteria 
Subjects are eligible for the study as long as the following criteria are not met: 
1. The investigator believes it to be in the best interest of the subject not to participate in the 
safety follow up study. 
2. Subject has participated or is currently participating in any autologous or allogeneic stem 
cell or gene therapy study for the treatment of aGVHD. Patients participating in 
investigative protocols aimed at modification of the transplant graft (such as T cell 
depletion) or aimed at modification of the conditioning regimen will be allowed in the 
study.  
 
5.3 
Premature Subject Withdrawal 
Subjects may voluntarily withdraw from the study for any reason at any time.  Subjects may be 
also considered withdrawn if they state an intention to withdraw, fail to return for visits, or 
become lost to follow-up.   
At a minimum, the following should be collected when a subject withdraws: 
 The reason the subject discontinued 
 The date of the last assessment and/or contact   
 Adverse events (AEs) , including concomitant medications used to treat AEs 
 Final (end of study) assessments. 
 
5.4 
Lost to Follow-Up 
A subject is considered to have been lost to follow-up if he/she is unable to be contacted by the 
investigator post randomization after reasonable efforts have been made to contact the subject.  
The investigator should show “due diligence” by documenting in the source documents steps 
taken to contact the subject, e.g., dates of telephone calls or  registered letters.  The end of 
participation for a subject lost to follow-up is the date of the last known contact (e.g., visit or 
telephone contact).  
 
5.5 
End of Study 
The end of study is defined as any one of the following, whichever occurs first: 
 The date of the last scheduled visit for the last subject 
 The date of death of the last subject 
 The date of withdrawal of the last subject. 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 37 of 79 
Mesoblast 
 
Individual subjects will be deemed to have completed study when they have completed all 
required protocol procedures and assessments.  For subjects with ongoing adverse events at the 
last scheduled visit, the end of study date will be deemed to be the last scheduled visit date. 
 
6. 
STUDY PROCEDURE 
6.1 
Visit Schedule and Assessments 
Table 6 lists all planned assessments, which are marked with an “X” when the visits are 
performed.  Subjects should be seen for all visits on the designated day or at a time that is as 
close as possible to the designated day.  The study assessment schedule in Table 6 outlines all 
procedures to be performed on subjects at the scheduled visits.   
 
In order to minimize variability in evaluations, ideally, the same individuals should perform the 
same tests on all the subjects at a given trial site. 
The following assessments and procedures will be performed at study visits: 
 Informed consent.  Subject may be consented on MSB-GVHD002 simultaneously when 
being provided with the MSB-GVHD001 consent, or at any visit up through Day 180 (± 
7 days). If the IRB/EC has not yet approved the consent for MSB-GVHD002 at Day 100 
(MSB-GVHD001), the Investigator should make all efforts to have the IRB/EC approved 
consent for MSB-GVHD002 presented to the subject no later than Day 180 (± 7 days).  
See Section 6.3 for additional information about handling of visits from Day 100 through 
Day 160 when an IRB/EC approved consent is not available. 
 Review of inclusion / exclusion criteria 
 Physical examination 
 Height and weight 
 Vital signs (heart rate [HR], blood pressure [BP], temperature, and respiratory rate [RR]) 
 GVHD assessment (skin, lower GI, upper GI, liver) using the same method as that of 
MSB-GVHD001 
 O2 saturation by pulse oximetry (SaO2/SAT) 
 Adverse event (AE) assessment  
 Incidence of chronic GVHD (cGVHD) (Appendix 8) 
 Survival status  
 Information on hospitalization status (namely the date of hospitalization) 
 Steroid dose(s)  
 Prior and concomitant medications 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 38 of 79 
Mesoblast 
 
 Laboratory assessments 
o Hematology (including CMV, please see Table 6 for details) 
o Serum chemistry 
o Urinalysis 
 
 
 Optional CT scan or MRI of the chest, abdomen, and pelvis at the discretion of the 
investigator. Scans may contribute information with regard to baseline disease burden 
and may also provide baseline for evaluation of future possible ectopic tissue formation. 
For CT, use intravenous (IV) contrast; if IV is contraindicated for any reason, oral is 
acceptable even in the presence of GI GVHD. 
 12-Lead ECG 
 
 
  
 
 
 
 Serum pregnancy test for female subjects ≥10 years of age (see Appendix 7 for guidance 
on childbearing potential and pregnancy testing) 
 Transfusion (if applicable).  Type of transfusion and the number of units will be recorded 
in the eCRF. 
 
Measurement of all clinical parameters should be performed as described in Table 6. Standard 
instructions for determining these parameters are provided in the following sections. 
 
6.1.1 
Safety Assessments 
Many of the study assessments scheduled for Day 100 will be completed during the MSB-
GVHD001 protocol and, therefore, will not be completed at the Day 100 visit for this protocol. 
 
6.1.1.1 Physical Examination 
A physical examination, including but not limited to, examination for evidence of adverse 
events, will be performed at Day 120, Day 140, Day 160, the end of study/Day 180, and at 
unscheduled visits as needed.     
 
Information about physical examinations must be available in the source documentation at the 
study site.  Significant new findings made after the Day 100 visit that meet the definition of an 
AE or SAE must be recorded on the Adverse Event CRF.  

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 39 of 79 
Mesoblast 
 
6.1.1.2 Vital Signs 
Vital sign measurements should be performed at Days 120, 140, 160, End Of Study/Day 180, 
and at unscheduled visits as needed. 
 
Measurements of vital signs will include sitting systolic blood pressure (SBP), diastolic blood 
pressure (DBP), heart rate (HR), temperature, and respiratory rate (RR).   
 
Vital signs will be measured after approximately 5 minutes of quiet rest with the subject in a 
sitting position.  Ideally, the site should have a dedicated blood pressure machine and use the 
same machine and blood pressure measurement method for all subjects during the trial.  
 
6.1.1.3 Oxygen Saturation 
Concurrent with vital sign measurements, Oxygen saturation (SaO2/SAT) will be monitored by 
pulse oximetry.  Supplemental oxygen may be administered as needed but should be noted in the 
source documents 
 
6.1.1.4 Height and Weight 
Height and weight measurements should be performed at End of Study/Day 180 or at 
unscheduled visits as needed. 
 
Measurement of height from a standing position should be performed with the subject’s shoes 
removed, the knees straightened, and head held upright.  For infants, height should be measured 
lying down, and measurements should be recorded as recumbent length.  
 
Measurement of weight should be performed without shoes or extra layers of clothing (e.g., 
sweater or jacket) during the measurement.  Subjects should be weighed on the same scales at all 
visits. 
 
6.1.1.5 12-Lead Electrocardiogram (ECG) 
12-lead electrocardiogram (ECG) will be performed at End of Study/Day 180 or at unscheduled 
visits as needed, to assess any changes in cardiac physiology from prior measurements 
performed at Day 0 and Day 100 in MSB-GVHD001.  Subjects should be in a supine or semi-
supine position for at least 5 minutes prior to the recording.  The same recording position (supine 
or semi-supine) and the same equipment should be used for each subject throughout the study.   
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 40 of 79 
Mesoblast 
 
All ECG tracings must be (1) reviewed by a medically qualified member of the study team, (2) 
annotated to indicate any clinical finding, (3) signed and dated by the medically qualified 
member, and (4) filed with the notes for the subjects.  ECG parameters will be entered into the 
CRF, and if any ECG abnormality is associated with an (S)AE, it must be entered in the (S)AE 
CRF. 
 
Heart rate (HR), pulse rate (PR), QRS and QT durations should also be noted on the CRF along 
with the ECG parameters. 
 
6.1.1.6 (Serious) Adverse Events 
All (S)AEs, including those considered to have a causal relationship to the IMP, will be collected 
at each assessment time point.  (S)AEs collected will consist of both solicited and events 
voluntarily reported by the subjects. 
 
6.1.1.7 Pregnancy Tests 
A serum pregnancy test may be performed by the site personnel for all females of childbearing 
potential (subjects ≥10 years of age) Study/Day 180 and at unscheduled visits and at the 
Investigator’s discretion, as needed.  Details on pregnancy testing requirements are located in 
Appendix 7. 
 
6.1.1.8 Laboratory Evaluations  
A designated laboratory (or laboratories) will perform the analyses of all specimens collected. 
Collection, shipment of samples, and reporting of results by the central or local (if needed) 
laboratory (or laboratories) will be detailed in the laboratory manual provided to the 
Investigators. If age/weight of the patient does not allow for this additional blood volume, then 
values from local labs will serve as the Day 160 values used for the present study.  The 
laboratory tests to be performed for subjects in this study are listed in Table 7.  
 
If necessary, laboratory assessments may be performed by a laboratory other than the designated 
central laboratory.  In this case, normal ranges of test values for this laboratory should be 
provided to the sponsor. 
 
The Investigator at each site is required to review all clinically relevant laboratory results 
requested in the protocol and to record those results in the CRF.  The diagnosis associated with 
any clinically significant laboratory abnormalities should be recorded as an (S)AE on the CRF.  

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 42 of 79 
Mesoblast 
 
6.1.1.9 Assessment of Ectopic Tissue Formation 
To detect any ectopic tissue formation, a radiologist and an Investigator at each study site may 
compare the optional CT scan or MRI performed during screening for MSB-GVHD001with the 
optional CT scan or MRI performed at end of study/Day 180 or at an unscheduled visit to 
determine if there is ectopic tissue formation.  If applicable, the same method of radiologic scan 
should be used for both evaluations.  If the formation of ectopic tissue is suspected, further 
evaluation may include MRI or positron-emission tomography (PET) scanning, and possibly 
biopsy. 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 44 of 79 
Mesoblast 
 
6.5 
Concomitant Medication and Supportive Therapy 
6.5.1 
Standard of Care for aGVHD 
All enrolled subjects will continue to receive institutionally defined standard of care (i.e., 
maintenance of steroid treatment and other prophylactic treatment for aGVHD) as described in 
MSB-GVHD001. 
 
Investigators should provide standard of care treatment for viral infections as appropriate, 
including prophylaxis and treatment if there is evidence of viral reactivation and/or infection. 
 
6.5.2 
Concomitant Medications 
Subjects may continue to be treated with systemic steroid therapy and receive any second-line 
therapy as necessary at the discretion of the Investigator and per institutional guidelines. 
 
Information on all concomitant medications and therapy will be collected for this study.  All new 
pharmacologic and non-pharmacologic treatment used by study subjects from Day 100 to Day 
180 should be recorded in the corresponding CRF.  Concomitant medications will be coded 
using the most recent WHO Drug Dictionary (WHO-DD)52 and summarized by ATC code. 
 
6.5.3 
Steroid Taper 
If continued steroid therapy is required, the dosing of methylprednisolone or equivalent may be 
tapered at the discretion of the Investigator.  A steroid taper rate of at least 10% of the dose per 
week but not to exceed 25% of the dose per week is recommended as described in Appendix 6, 
with the goal of discontinuing steroid by 10 weeks after initiating taper. 
 
6.5.4 
Escalating Therapy 
Protocol guidelines for escalating therapy of aGVHD for worsening disease include: 
1. Worsening of symptoms for at least 3 days, or  
2. Grades C-D aGVHD persisting for at least 1 week despite treatment, or  
3. Grade B aGVHD persisting for at least 2 weeks despite treatment. 
 
Escalation of therapy does not constitute withdrawal of a subject from the study. If escalation of 
therapy occurs, the subject is to continue on study and receive all assessments per protocol. 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 45 of 79 
Mesoblast 
 
6.5.5 
Supportive Care 
In addition to prescribed investigational agent plus corticosteroids and prophylactic 
therapies, all subjects may receive the following: 
 Transfusion support per institutional practice. Type of transfusion and the number of units 
will be recorded in the eCRF. 
 Anti-infective prophylaxis directed towards: CMV, gram positive (encapsulated) bacteria, 
pneumocystis carinii and fungal infections per institutional practice. 
 
7. 
SAFETY GUIDANCE 
7.1 
Definitions  
7.1.1 
Adverse Event 
An AE is defined by the International Conference of Harmonization (ICH) guideline for Good 
Clinical Practice as any untoward medical occurrence in a subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with the treatment.  
 
An AE can therefore be any of the following: 
 Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product 
 Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition)  
 Recurrence of an intermittent medical condition (e.g., headache) not present at baseline  
 Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug. 
 
Adverse events that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (e.g., screening procedures such as biopsies etc.) are to be 
reported.  
 
Collection of all AEs will begin upon signing of the informed consent form (ICF).  Pre-existing 
conditions that worsen during a study are to be reported as AEs. 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 47 of 79 
Mesoblast 
 
7.2 
Relationship of Adverse Event to the IMP 
A determination will be made of the relationship between an adverse event and the IMP.  A 
causal relationship is present if a determination is made that there is a reasonable possibility that 
the adverse event may have been caused by the IMP.  In general, a causal relationship will be 
assigned when evidence exists to support the causal relationship.  As there is no prescribed 
treatment intervention in this study, relationship would be extrapolated backwards to dosing in 
protocol MSB-GVHD001. 
 
When assessing a potential relationship between the IMP and an AE, the following parameters 
should be considered: 
 Temporal relationship between IMP and/or protocol-specified procedures and the AE. 
 The biological plausibility that the IMP caused the event 
 Any underlying/concurrent illness in the subject 
 Concomitant medications the subject may have received  
 How commonly the event occurs in the study population, independent of treatment. 
 
7.3 
Relationship to Study Procedure  
For each adverse event, the relationship to the IMP delivery procedure must be recorded as either 
related (there is reasonable possibility of a causal relationship between the event and the study 
procedure) or not related (there is no reasonable possibility of a causal relationship between the 
event and the study procedure). 
 
8. 
REPORTING ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Any adverse event (AE) occurring after a subject has signed the informed consent (or 
randomization, as appropriate) should be recorded on the appropriate CRF page. 
 
Any SAE (as described in Section 7.1.2) occurring after a subject has signed the informed 
consent should be immediately reported to the sponsor or designee within 24 hours of the 
investigator’s knowledge of the event.  All subjects with an SAE must be followed up and the 
outcomes reported until the event is resolved or has stabilized.  
 
Upon occurrence of an SAE, the investigator must:  
 Immediately notify the sponsor’s designee, Quintiles Lifecycle Safety. SAE reporting 
will originate in the electronic data capture (EDC) system and an email will be sent to 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 48 of 79 
Mesoblast 
 
individuals with designated responsibility for safety.  The paper SAE form is in place as a 
back-up in the rare event that EDC is not accessible to the reporter of the SAE:  
o 
 
 Provide copy of all relevant source documents, including concomitant medications, as 
appropriate.     
 
All SAEs that are considered unexpected and related to the study product will be reported by the 
Sponsor or its designee as a 15-day report to the Regulatory Authorities as applicable and to all 
participating investigators. 
 
SAEs that are considered unexpected, related to the study and are life threatening, or result in 
death will be reported by the Sponsor or its designee to the appropriate Regulatory Authorities 
and to all participating investigators as a 7-day report. 
 
Each investigator must notify the IRB/EC responsible for reviewing the study at their site of all 
15-day or 7-day safety reports required by local regulations or IRB/EC requirements and shall 
provide the Sponsor or its designee with written confirmation of said IRB/EC notification. 
 
8.1 
Procedures for Reporting Pregnancies  
All pregnancies that occur during the study are to be reported immediately to the individual 
identified in the General Information page of this protocol, and the investigator must provide 
Sponsor or designee, by facsimile, a Pregnancy Tracking Form.  Pregnancies in female partners 
of male subjects are not required to be followed up.  All subjects who become pregnant will be 
monitored to the completion or termination of the pregnancy, including perinatal and neonatal 
outcome.  Monitoring of the subject should continue until conclusion of the pregnancy.  If the 
pregnancy is associated with an SAE (e.g. hemorrhage, spontaneous abortion), then in addition 
to the Pregnancy Form, a separate SAE form must be provided as described in Section 8. 
 
8.2 
Laboratory Test Abnormalities 
Laboratory test results will appear on laboratory reports that are submitted directly from the 
central laboratory.  Local laboratory results, if applicable, should be recorded on the CRF.  
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 49 of 79 
Mesoblast 
 
Any abnormal laboratory result that is clinically significant should be recorded as a single 
diagnosis in the CRF.  An abnormal laboratory result is considered to be clinically significant if 
it meets one or more of the following conditions: 
 Is accompanied by clinical symptoms. 
 Requires change in concomitant therapy (e.g. addition of, interruption of, discontinuation 
of, or any other change in a concomitant medication, therapy or treatment). 
 
These conditions will apply to any protocol- and non-protocol- specified safety laboratory results 
from tests performed after ICF signature that fall outside the laboratory reference range and are 
considered clinically significant.  These conditions will not apply to any abnormal laboratory 
results that are outside the laboratory reference range, yet does not meet the criteria for clinical 
significance; these latter results will be analyzed and reported as laboratory abnormalities. 
In the event of clinically significant abnormal laboratory test values, the tests should be repeated 
and followed up until they have returned to the normal range and/or the abnormality is 
adequately explained or accounted for.  If an acceptable explanation is established, it should be 
recorded on the CRF.  
 
8.3 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Ethics Committees 
The Sponsor will promptly evaluate all adverse events against cumulative product experience to 
quickly identify and communicate possible new safety findings to investigators, IRBs, IECs, and 
applicable health authorities based on applicable legislation. 
 
To determine reporting requirements for single adverse event cases, the Sponsor will assess the 
expectedness of these events using the following reference documents: 
 IMP IB 
 IMP Development Core Safety Information (DCSI) Document, if applicable. 
 
The Sponsor will compare the severity of each event and the cumulative event frequency 
reported for the study with the severity and frequency reported in the applicable reference 
document. 
 
Reporting requirements will also be based on the Investigator's assessment of causality and 
seriousness, with a provision for upgrading by the Sponsor as needed. 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 50 of 79 
Mesoblast 
 
9. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
9.1 
Statistical Analysis Plan 
Since this is an extension trial of MSB-GVHD001, data presented for MSB-GVHD002 will be 
presented in two ways:  
1. For the extension period only. This will include assessments beyond Day 100. 
2. For the entire period spanning both MSB-GVHD001 and MSB-GVHD002 trials. 
In particular, this includes time-to-event data (flares and therapy escalation), survival 
data, incidence of cGVHD, and frequency of flares. 
 
Categorical variables will be summarized using frequencies and percentages. Continuous 
variables will be summarized using descriptive statistics (n, mean, standard deviation [SD], 
median, minimum, and maximum). Confidence intervals, if presented, will have a two-sided 
95% confidence level. For time-to-event variables, Kaplan-Meier curves will be presented as 
appropriate.   
 
In general, the baseline value for a variable is defined as the last non-missing observation prior to 
or equal to the first dose date of study treatment in MSB-GVHD001.  Baseline for analyses of 
the entire period of MSB-GVHD001 and MSB-GVHD002 will be the same as baseline defined 
for Protocol MSB-GVHD001.  The baseline for the extension period beyond Day 100 will be the 
same values at the end of study/Day 100 for MSB-GVHD001.  Data collected at unscheduled 
time points will not be summarized at the unscheduled time points.  
 
The actual day relative to start of treatment will be determined from the first dose date in 
Protocol MSB-GVHD001, which will be considered ‘Study Day 0’.  Study day will be calculated 
from the first infusion date in Protocol MSB-GVHD001.  A detailed statistical analysis plan 
(SAP) will be finalized prior to the database lock.  
 
9.2 
Analysis Population 
The analysis population for safety in this study, the Safety Population, will include all subjects 
who received at least one dose of the study treatment in study MSB-GVHD001 and entered into 
study MSB-GVHD002. The population to be evaluated for duration of response will include all 
subjects who participated in Protocol MSB-GVHD001, received the first 8 doses of 
remestemcel-L as outlined in that protocol, and showed overall response (OR) or very good 
partial response (VGPR) to remestemcel-L at Day 28.  
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 51 of 79 
Mesoblast 
 
9.3 
Demographic and Baseline Characteristics 
Pre-treatment demographics and subject characteristics will be summarized.  Descriptive 
statistics [e.g., number of subjects, mean, standard deviation (SD), median, minimum, and 
maximum] will be calculated for continuous variables [e.g. age and weight] and frequency 
counts will be tabulated for categorical demographic variables [e.g. gender, ethnicity, race, 
underlying malignancy or leukemic disease at transplant, donor type, donor compatibility, HSCT 
source, grade of aGVHD at onset, grade of aGVHD at baseline].  Time from HSCT to onset of 
aGVHD and onset of aGVHD to initiation of study drug will be summarized. Involvement of the 
skin, lower gastrointestinal (GI) tract, and liver will be summarized by the number of subjects 
with one organ, two organs, or all three organs involved at baseline.  
 
9.4 
Safety Data Analysis 
9.4.1 
Adverse Events and Serious Adverse Events 
All (serious) adverse events in this study will be collected from the time the subject signs the 
ICF.  All (S)AEs will be collected in this study and summarized by treatment, dose, and severity.  
Numbers and rates of TEAEs and other safety variables will be tabulated by organ system and 
preferred term. 
 
At each time point, vital signs and safety laboratory parameters will be tabulated.  The 
continuous variables will be summarized by the descriptive statistics – mean, standard deviation, 
median, minimum and maximum.  Additionally, vital signs and laboratory parameters will be 
assessed for clinically significant abnormalities as well as shifts from baseline. 
 
9.4.2 
Survival to Day 180 
The number of subjects alive, deceased, lost to follow-up, or withdrawn from Day 0 (Protocol 
MSB-GVHD001) to Day 180 (Protocol MSB-GVHD002) will be summarized in a Subject 
Disposition table.  For subjects who died, the time to event will be calculated from date of 
transplant, date of aGVHD onset, and date of treatment initiation.  All other subjects will be 
censored and survival time will be calculated from the date of transplant, date of aGVHD onset, 
or date of treatment initiation to the date of last contact.   
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 52 of 79 
Mesoblast 
 
9.4.3 
Ectopic Tissue Formation 
To detect potential ectopic tissue formation, a radiologist and an Investigator at each study site 
may compare the CT scan or MRI performed during screening with the CT scan or MRI those 
performed at study end, if available, to determine if there is ectopic tissue formation.  The same 
method of radiologic scan should be used for both evaluations. If formation of ectopic tissue is 
suspected, further evaluation may include MRI or positron-emission tomography (PET) 
scanning, and possibly biopsy. 
 
As noted above, (S)AEs which represent ectopic tissue foci will be summarized by numbers and 
percentages. 
 
9.4.4 
Other  
For each applicable time point, key laboratory data, vital signs and safety laboratory parameters 
will be tabulated.  Vital signs and laboratory parameters will be assessed for clinically significant 
abnormalities and shifts from baseline (baseline as obtained in protocol MSB-GVHD001) will be 
presented. 
 
9.5 
Secondary Endpoints Analysis 
9.5.1 
Assessment of Survival at Day 180 
Survival will be assessed from initial remestemcel-L treatment to the end of study/Day 180. The 
numbers with percentages for survival, non-survival, or missing, including lost to follow-up, will 
be summarized at Day 180.  For tabulating responders at Day 28 from the MSB-GVHD001 study 
versus survivors at Day 180 the present study, percentages of survivors and deaths will be based 
on all subjects, including those with missing survival information for the lost to follow-up or 
withdrawn subjects.  The association between Day 28 OR and survival at Day 180, and between 
Day 28 VGPR and survival at Day 180, will be tested for statistical significance.  First, the 
associations will be tested using a Cochran–Mantel–Haenszel (CMH) test, stratifying by baseline 
aGVHD grade. Day 180 survival Kaplan-Meier curves will be plotted by Day 28 responder and 
non-responder groups, and differences between these groups will be tested for any statistically 
significant difference using the log-rank test. The odds ratio for survival at Day 180, given 
responder status at Day 28, will be presented and tested for statistical significance (whether 
statistically significantly greater than 1). 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 53 of 79 
Mesoblast 
 
9.5.2 
GVHD Activity  
GVHD activity will be assessed and summarized at time points evenly divided amongst the term 
from Day 100 to Day 180, specifically at Days 120, 140, 160 and 180, relative to baseline 
assessment in MSB-GVHD001. 
 
9.5.3 
Steroid Dose 
Steroid doses at Days 120, 140, 160 and 180, including proportion of subjects able to taper 
steroids by 50% by each time point will be summarized.  Guideline for steroid taper is located in 
Appendix 6. 
 
9.5.4 
GVHD Flares 
The numbers with the percentages of GVHD flares will be summarized and presented.  The time 
to a GVHD flare from the Day 0 and Day 100 will be determined and summarized with a 
Kaplan-Meier curve. 
 
9.5.5 
Second-line Treatment 
The number of days to addition of any second-line GVHD treatment agent, from Day 100 in the 
present study, will be determined and summarized by the mean, standard deviation, median, 
minimum and maximum.  The number of second-line treatments used will also be determined 
and descriptively summarized.  
 
9.5.6 
Chronic GVHD 
Subjects will be evaluated for evidence of chronic GVHD at any time from Day 0 to Day 180.  
The time to first sign of chronic GVHD will be summarized.  The number and percentage of 
subjects developing cGVHD will be tabulated for the overall safety population as well as for the 
population stratified by baseline GVHD grade, number of infusions received, and Day 28 
responder/non-responder categories. 
 
 
 
 
 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 54 of 79 
Mesoblast 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
9.8 
Interim Analysis 
No interim analysis is planned for this study. 
 
9.9 
Handling of Missing Values 
In general, for safety analyses, observed values will be used, and no imputation will be made for 
missing values.  For specific endpoints and special instances, details for handling missing values 
will be described in the statistical analysis plan (SAP). 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 55 of 79 
Mesoblast 
 
10. 
DATA COLLECTION, MANAGEMENT AND QUALITY ASSURANCE 
The overall procedures for quality assurance of clinical study data are described in the Sponsor’s 
(or designee’s) Standard Operational Procedures (SOPs). 
 
Data for this study will be recorded using electronic Case Report Forms (eCRFs).     
 
The site is expected to respond to all SAE queries within 24 hours and to all other queries within 
5 business days.  A Mesoblast representative or a designee will perform final data review and 
external data reconciliations prior to all major milestones, including database close and lock. 
 
10.1 
Assignment of Preferred Terms and Original Terminology 
For classification purposes, preferred terms will be assigned by the Sponsor to the original terms 
entered on the CRF (CTCAE terms), using the most up-to-date version of the Medical Dictionary 
for Regulatory Activities (MedDRA)54 terminology for adverse events and diseases and for 
treatments and surgical and medical procedures. 
 
11. 
STUDY COMMITTEES 
11.1 
Independent Data and Safety Monitoring Board (DSMB) 
The Data and Safety Monitoring Board (DSMB) is a multidisciplinary group that is independent 
of both the sponsor and CRO, which consists of one biostatistician and physicians with expertise 
in relevant disciplines, who collectively have experience in the management of clinical trial 
subject.  The DSMB is also knowledgeable in the conduct and monitoring of randomized clinical 
trials.   
 
The DSMB will meet at regular intervals to review enrollment status, baseline characteristics of 
the study population, all treatment-emergent safety reports, and status of therapeutic benefit.  The 
chairperson of the DSMB will be notified of all SAEs.  
 
The DSMB will recommend one of the following at each of their meetings: 
 Continue the trial 
 Modify the trial (amend the protocol) 
 Stop enrollment in the trial. 
 
Additional details regarding the specifics of the DSMB operations may be found in the DSMB 
Charter. 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 56 of 79 
Mesoblast 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12. 
LAWS, REGULATIONS, AND ETHICS 
12.1 
Local Regulations/Declaration of Helsinki 
This clinical study shall be conducted in full compliance with current material and relevant laws 
and regulations and investigators will use best efforts to ensure such compliance.  This clinical 
study will also be conducted in compliance with principles outlined in the “Guideline for Good 
Clinical Practices” ICH tripartite Guideline55 and with the ethical principles of the “Declaration 
of Helsinki”56  or with the laws and regulations of the country in which the research is 
conducted, including but not limited to the EU Clinical Trial Directive.57   
 
12.2 
Informed Consent  
It is the responsibility of the investigator, or a person designated by the investigator, if local 
regulations permit, to obtain signed informed consent from each subject prior to the subject’s 
participation in this study after adequate explanation of the aims, methods, anticipated benefits, 
and potential hazards of the study.  For subjects who are not qualified to or are incapable of 
giving legal consent, written consent must be obtained from a legally acceptable representative.  
In cases where both the subject and his/her legal representative are unable to read, an impartial 
witness must be present during the entire informed consent discussion.  After the subject and 
representative have orally consented to participation in the trial, the witness’ signature on the 
form would attest that the information in the consent form was accurately explained and 
understood.  The investigator or designee must also explain that the subjects are free to refuse to 
enter or withdraw from the study at any time and for any reason that a copy of the consent would 
be provided to the subject, and that the process by which consent is obtained is described in the 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 57 of 79 
Mesoblast 
 
source documentation.  The CRFs for this study would contain a section for documenting subject 
informed consent, which must be completed appropriately.  If new safety information results in 
significant changes in the benefit/risk assessment, the consent form should be reviewed and 
updated if necessary.  All subjects, including those already being treated, should be informed of 
the new information, provided with a copy of the revised form, and give their consent to continue 
in the study in accordance with the IRB/EC requirements. 
 
Subjects will authorize the use of their protected health information during the informed consent 
process in accordance with the applicable privacy requirements (e.g., HIPAA, local Regulatory 
Agency).  Subjects who deny permission to use and disclose protected health information will 
not be eligible to participate in the study.  The Investigator will ensure that study documents 
forwarded to Mesoblast and any other documents contain no mention of subject names. 
 
12.3 
Institutional Review Board/ Ethics Committees (IRB/EC) 
This protocol and any modifications, appropriate consent procedures, or accompanying material 
provided to the subject, such as subject information sheets or descriptions of the study used to 
obtain informed consent and advertisements or compensation given to the subject, will be 
reviewed and approved by appropriate Competent Authority and IRBs/ECs. 
 
Before initiation of the trial at each investigational site, approval from the appropriate IRB/EC 
must be obtained.  Written approval must be obtained before a trial site is initiated or the 
investigational product is released to the investigator.  
 
Any extensions or renewals of IRB/EC approval must be obtained during the course of the study.  
If required, approvals must also be obtained for any changes to the protocol, the informed 
consent form, the written information provided to subjects and/or other procedures. 
 
Any new information that may adversely affect the safety of the subjects or the conduct of the 
study will be reported promptly to the IRB/EC by the Investigator and/or the Sponsor, in 
accordance with applicable local requirements.  Written summaries of the study status will be 
submitted to the IRB/EC annually, or more frequently if required by the EC/IRB. On completion 
of the study, the IRB/EC will be notified that the study has ended. 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 58 of 79 
Mesoblast 
 
12.4 
Protocol Adherence 
Investigators will ensure that due diligence is applied in order to avoid protocol deviations. All 
significant protocol deviations will be reported to the IRB/EC in accordance with IRB/EC 
requirements.  All significant protocol deviations will be recorded and reported in the CSR. 
 
12.5 
Protocol Deviation   
A protocol deviation is defined as an intentional or unintentional change or non-compliance with 
a research protocol. 
 
13. 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Requests from investigators to modify the protocol for ongoing studies will be considered only 
with consultation between an appropriate representative of the Sponsor and the Investigator.  
Protocol modifications must be prepared by a representative of the Sponsor and initially 
reviewed and approved by the Sponsor. 
 
All protocol modifications must be submitted to the appropriate IRB/EC for information and 
approval in accordance with local requirements, and to Regulatory Agencies if required.  Approval 
must be obtained before any changes can be implemented, with the exception of changes necessary 
to eliminate an immediate hazard to trial subjects, or change(s) involving only logistical or 
administrative aspects of the trial (e.g. change in monitor[s], change of telephone number[s]). 
 
14. 
CONDITIONS FOR TERMINATING THE STUDY 
Mesoblast reserves the right to terminate the study at any time under the conditions specified in 
the Clinical Trial Agreement.  In the event the trial is terminated before the planned completion 
date, action will be taken to assure the protection of the subjects’ interests. 
 
14.1 
Enrollment Hold and Stopping Rules 
Subject safety will be continuously monitored.  The investigator site will report all SAEs, 
including all deaths immediately as outlined in Section 8. 
 
Additionally, all AEs including all deaths will be periodically reported to the DSMB as per the 
DSMB charter.  The DSMB will investigate these complications through a complete safety 
review.  The DSMB will then determine whether enrollment should be continued, suspended, or 
terminated and their decision will be communicated to the Sponsor.  

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 59 of 79 
Mesoblast 
 
Further details regarding the role, responsibilities and procedures of the DSMB are provided in 
the DSMB Charter. 
 
15. 
STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING 
15.1 
Investigator's Files / Retention of Documents 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents should 
be classified into two different separate categories, consisting of: 1) An Investigator's Study File 
and 2) subject clinical source documents. 
 
The Investigator's Study File will contain the protocol/amendments and schedule of assessments, 
IRB/EC and governmental approval with correspondence, sample informed consent, drug 
records, staff curriculum vitae, authorization forms, and other appropriate 
documents/correspondence.  In addition, at the end of the study the Investigator will receive the 
subject data, including an audit trail containing a complete record of all changes to data, query 
resolution correspondence, and reasons for changes, in a readable format on CD that must be 
kept with the Investigator’s Study File. 
 
Subject clinical source documents may include subject hospital/clinic records, physician's and 
nurse's notes, appointment book, original laboratory reports, ECG, special assessment reports, 
signed informed consent forms, and consultant letters.  The Investigator must keep the 
Investigator’s Study File and subject clinical source documents (including the archival CD) on 
file for at least 15 years after completion or discontinuation of the study, or in accordance with 
ICH guidelines and local regulations, whichever is of greater duration.  After this specified time 
period, the documents may be destroyed.  Study sites must notify the sponsor prior to destroying 
any trial-related documents. 
 
Should the Investigator wish to assign the study records to another party or move them to another 
location, the Sponsor must be notified in advance. 
 
If the Investigator cannot guarantee compliance with this archiving requirement at the 
investigational site for any or all of the documents, special arrangements must be made between 
the Investigator and the Sponsor to store these documents in a sealed container(s) outside of the 
site in order to ensure that they can be returned sealed to the Investigator in the event of a 
regulatory audit.  Where source documents are required for continued care of subjects, 
appropriate copies should be made for storing outside of the site. 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 60 of 79 
Mesoblast 
 
15.2 
Source Documents and Background Data 
The Investigator shall provide to the Sponsor, upon request, any required background data from 
the study documentation or clinic records.  This is particularly important in cases where errors in 
data transcription are suspected.  In cases of special problems and/or governmental queries or 
requests for audit inspections, it is also necessary for the Sponsor to have direct access to the 
complete study records, provided that subject confidentiality is protected. 
 
15.3 
Audits and Inspections 
Source documents for this trial must be made available by the Investigator to appropriately 
qualified personnel from the Sponsor’s (or designee's) Quality Assurance Unit or its designees or 
to health authority inspectors, upon appropriate notification.  Verification of the CRF data must 
be by direct inspection of source documents. 
 
15.4 
Electronic Case Report Forms  
Data for this study will be captured via an Electronic Data Capture (EDC) system using eCRFs.  
The data will be entered into the EDC system by trained site personnel per the eCRF Completion 
Guidelines.  An audit trail will maintain a record of initial entries and changes made; reasons for 
change; time and date of entry; and user name of person authorizing entry or change.   
 
An eCRF must be completed for each subject. For each screen-failed subject, the reason for 
screen failure will be collected in the termination eCRF along with the corresponding screen 
failure reason.  The entire subject casebook of data must be reviewed and electronically signed 
by the PI or by an authorized delegate from the study staff.  This also applies to records for those 
randomized subjects who fail to complete the study.  If a subject withdraws early from the study, 
the reason must be noted in the termination eCRF.  If a subject is withdrawn from the study 
because of a treatment-limiting AE, attempts should be made to clearly document the outcome. 
 
The Investigator should ensure the accuracy, completeness, and timeliness of the data reported to 
the sponsor in the eCRFs and in all required reports.  
 
16. 
MONITORING OF STUDY 
The Sponsor’s responsible monitor (or designee) will contact and visit the Investigator regularly 
and will be permitted, upon request, to inspect the trial records, including CRFs and other 
pertinent data, provided that subject confidentiality is maintained in accordance with local 
requirements. 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 61 of 79 
Mesoblast 
 
It will be the monitor's responsibility to inspect the CRFs at regular intervals throughout the 
study to ensure protocol adherence and that the data entered on the CRFs are complete, 
consistent, and accurate.  The monitor must verify that the subject received the study drug 
assigned by the randomization center (by controlling the written confirmation of the 
randomization by central randomization system).  The monitor will also have access to 
laboratory test reports and other subject records as applicable needed to verify entries on the 
CRFs.  The Investigator (or deputy) must agree to cooperate with the monitor to ensure that any 
problems detected in the course of these monitoring visits are resolved. 
 
17. 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS 
The Investigator must ensure that subject anonymity is maintained and that subject identity is 
protected from unauthorized parties.  On CRFs or other documents submitted to the sponsor, 
subjects should be referenced by an identification code rather than by their names.  The 
Investigator should keep a subject enrollment log showing codes, names and addresses.  The 
Investigator should maintain documents that will not be submitted to the Sponsor (e.g., subjects’ 
written consent forms) in strict confidence. 
 
18. 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
18.1 
Right to Publish 
Subject to the restrictions in this Article 18 and processes described in this Section 19, 
Investigator may individually communicate, orally present or publish in scientific journals or 
other scholarly media the Study results.  Sponsor retains all right and title to, as well as interest 
in, the Study data and case report forms.  Authorship will be determined by mutual agreement 
according to guidelines published by the International Committee of Medical Journal Editors 
(ICMJE).58  
 
18.2 
Publication Steering Committee 
A Publication Steering Committee (the “Committee”), comprised of lead investigators who are 
appointed by the Sponsor will be responsible for the creation, review, and submission of 
publications and presentations relating to the Study (e.g., primary manuscript on design, baseline 
data, mortality, efficacy, and safety data), sub-study, and ancillary analyses after completion of 
the Study.  The Committee will encourage and support other manuscript(s) for 
publication, content for speaking engagements, abstracts of papers, poster presentations and 
similar material by the Study Center and/or Investigator as deemed appropriate by the 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 62 of 79 
Mesoblast 
 
Committee.  Committee review and approval must be obtained prior to submission of any 
publication or public display of the Study results, alone or in aggregate.   
 
18.3 
Procedure   
Investigator shall provide Sponsor with a written copy of any proposed publication or other 
disclosure of the Study results, including disclosures at research seminars, lectures and 
professional meetings and submission of papers for publication, at least sixty (60) days prior to 
submission for publication or disclosure so that Sponsor may have a reasonable opportunity 
to:  (i) review and comment on the contents of the proposed publication or disclosure; 
(ii) identify any trade secrets, proprietary information or Confidential Information (other than the 
Study results themselves) of Sponsor to be deleted from the proposed publication or disclosure; 
and (iii) protect proprietary rights to Inventions or products developed or investigated under the 
Study.  Sponsor shall provide, in writing, any comments to Investigator and/or identify any of the 
Sponsor’s trade secrets, proprietary information or Confidential Information (other than the 
Study results themselves) to be edited from the proposed publication or disclosure within the 
sixty (60) day period.  Upon Sponsor’s reasonable request, Investigator shall delay publishing or 
disclosure for a period not to exceed one hundred twenty (120) days from the date of receipt of 
such materials by Sponsor to permit the Sponsor to file patent applications or otherwise seek 
proprietary protection of subject matter disclosed in any proposed publication or other 
disclosure.  In addition, Investigator shall give due regard to Sponsor’s legitimate interests, such 
as manuscript authorship, coordinating and maintaining the proprietary nature of submissions to 
Regulatory Authorities, and coordinating with other ongoing studies in the same field, and agree 
to accept Sponsor’s reasonable comments and suggestions with respect to such publications or 
disclosures. 
 
Investigator and Study Center acknowledge that the Study is part of a multicenter study.  
Accordingly and notwithstanding anything to the contrary herein, Study Center and/or 
Investigator shall not publish or present the Study results until after the first publication, primary 
manuscript, or presentation regarding the overall study is completed, the results of the Study 
from all the sites have been published in a single publication or eighteen (18) months after 
acceptance of the manuscript or the conclusion of the Study at all Study sites whichever occurs 
earliest, the.  Thereafter, Study Center and/or Investigator may publish or disclose Study results 
in accordance with the provisions of this Section 18. 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 63 of 79 
Mesoblast 
 
19. 
STUDY COMPLETION 
Mesoblast reserves the right to terminate this protocol prematurely for reasonable cause provided 
that written notices are submitted a reasonable time in advance of the intended termination. The 
Investigator may also terminate the protocol at his or her site for reasonable cause, after 
providing written notice to Mesoblast a reasonable time in advance of the intended termination. 
Advance notice is not required by either party if the protocol is stopped due to safety concerns. If 
Mesoblast terminates the protocol for safety reasons, it will immediately notify the Investigator 
by telephone and subsequently provide written instructions for termination. If the Investigator 
elects to terminate the study at his or her site, the Investigator will be responsible for returning all 
investigational products and study-related documents to Mesoblast in a timely manner. Source 
documents supporting study-related data must be retained by the Investigator as previously 
described. 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 64 of 79 
Mesoblast 
 
20. 
REFERENCES 
1. Jacobsohn DA, Vogelsang GB. Acute graft versus host disease. Orphanet journal of rare 
diseases. 2007;2:35. 
2. Pidala J. Graft-vs-host disease following allogeneic hematopoietic cell transplantation. 
Cancer control : journal of the Moffitt Cancer Center. Oct 2011;18(4):268-276. 
3. Rezvani AR, Storb RF. Prevention of graft-vs.-host disease. Expert opinion on 
pharmacotherapy. Aug 2012;13(12):1737-1750. 
4. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus 
development project on criteria for clinical trials in chronic graft-versus-host disease: I. 
Diagnosis and staging working group report. Biology of blood and marrow 
transplantation : journal of the American Society for Blood and Marrow Transplantation. 
Dec 2005;11(12):945-956. 
5. Jagasia M, Arora M, Flowers ME, et al. Risk factors for acute GVHD and survival after 
hematopoietic cell transplantation. Blood. Jan 5 2012;119(1):296-307. 
6. Martin PJ, Rizzo JD, Wingard JR, et al. First- and second-line systemic treatment of 
acute graft-versus-host disease: recommendations of the American Society of Blood and 
Marrow Transplantation. Biology of blood and marrow transplantation : journal of the 
American Society for Blood and Marrow Transplantation. Aug 2012;18(8):1150-1163. 
7. Goker H, Haznedaroglu IC, Chao NJ. Acute graft-vs-host disease: pathobiology and 
management. Experimental hematology. Mar 2001;29(3):259-277. 
8. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD 
Grading. Bone marrow transplantation. Jun 1995;15(6):825-828. 
9. van den Brink, M. R. and S. J. Burakoff (2002). "Cytolytic pathways in haematopoietic 
stem-cell transplantation." Nat Rev Immunol 2(4): 273-281. 
10. Michallet M, Perrin MC, Belhabri A, et al. Impact of cyclosporine and 
methylprednisolone dose used for prophylaxis and therapy of graft-versus-host disease on 
survival and relapse after allogeneic bone marrow transplantation. Bone marrow 
transplantation. Jan 1999;23(2):145-150. 
11. Dignan FL, Amrolia P, Clark A, et al. Diagnosis and management of chronic graft-
versus-host disease. British journal of haematology. Jul 2012;158(1):46-61. 
12. Dignan FL, Clark A, Amrolia P, et al. Diagnosis and management of acute graft-versus-
host disease. British journal of haematology. Jul 2012;158(1):30-45. 
13. Bacigalupo A. Management of acute graft-versus-host disease. British journal of 
haematology. Apr 2007;137(2):87-98. 
14. Perez L, Anasetti C, Pidala J. Have we improved in preventing and treating acute graft-
versus-host disease? Current opinion in hematology. Nov 2011;18(6):408-413. 
15. Deeg HJ. How I treat refractory acute GVHD. Blood. May 15 2007;109(10):4119-4126. 
16. MacMillan ML, Weisdorf DJ, Wagner JE, et al. Response of 443 patients to steroids as 
primary therapy for acute graft-versus-host disease: comparison of grading systems. 
Biology of blood and marrow transplantation : journal of the American Society for Blood 
and Marrow Transplantation. 2002;8(7):387-394. 
17. Martin PJ, Schoch G, Fisher L, et al. A retrospective analysis of therapy for acute graft-
versus-host disease: initial treatment. Blood. Oct 15 1990;76(8):1464-1472. 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 65 of 79 
Mesoblast 
 
18. Weisdorf D, Haake R, Blazar B, et al. Treatment of moderate/severe acute graft-versus-
host disease after allogeneic bone marrow transplantation: an analysis of clinical risk 
features and outcome. Blood. Feb 15 1990;75(4):1024-1030. 
19. Davies SM, Wang D, Wang T, et al. Recent decrease in acute graft-versus-host disease in 
children with leukemia receiving unrelated donor bone marrow transplants. Biology of 
blood and marrow transplantation : journal of the American Society for Blood and 
Marrow Transplantation. Mar 2009;15(3):360-366. 
20. Gratwohl A, Hermans J, Apperley J, et al. Acute graft-versus-host disease: grade and 
outcome in patients with chronic myelogenous leukemia. Working Party Chronic 
Leukemia of the European Group for Blood and Marrow Transplantation. Blood. Jul 15 
1995;86(2):813-818. 
21. Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft-versus-host disease 
in human recipients of marrow from HL-A-matched sibling donors. Transplantation. Oct 
1974;18(4):295-304. 
22. Cahn JY, Klein JP, Lee SJ, et al. Prospective evaluation of 2 acute graft-versus-host 
(GVHD) grading systems: a joint Societe Francaise de Greffe de Moelle et Therapie 
Cellulaire (SFGM-TC), Dana Farber Cancer Institute (DFCI), and International Bone 
Marrow Transplant Registry (IBMTR) prospective study. Blood. Aug 15 
2005;106(4):1495-1500. 
23. Rowlings PA, Przepiorka D, Klein JP, et al. IBMTR Severity Index for grading acute 
graft-versus-host disease: retrospective comparison with Glucksberg grade. British 
journal of haematology. Jun 1997;97(4):855-864. 
24. Martin PJ, Bachier CR, Klingemann HG, et al. Endpoints for clinical trials testing 
treatment of acute graft-versus-host disease: a joint statement. Biology of blood and 
marrow transplantation : journal of the American Society for Blood and Marrow 
Transplantation. Jul 2009;15(7):777-784. 
25. MacMillan ML, DeFor TE, Weisdorf DJ. The best endpoint for acute GVHD treatment 
trials. Blood. Jul 1 2010;115(26):5412-5417. 
26. Saliba RM, Couriel DR, Giralt S, et al. Prognostic value of response after upfront therapy 
for acute GVHD. Bone marrow transplantation. Jan 2012;47(1):125-131. 
27. Levine JE, Logan B, Wu J, et al. Graft-versus-host disease treatment: predictors of 
survival. Biology of blood and marrow transplantation : journal of the American Society 
for Blood and Marrow Transplantation. Dec 2010;16(12):1693-1699. 
28. Pavletic SZ. Response as an end point in treatment trials for acute GVHD. Bone marrow 
transplantation. Feb 2012;47(2):161-163. 
 
 
 
 
30. Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD. Human mesenchymal stem 
cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation. 
Jan 1 2002;105(1):93-98. 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 66 of 79 
Mesoblast 
 
31. Deans RJ, Moseley AB. Mesenchymal stem cells: biology and potential clinical uses. 
Experimental hematology. Aug 2000;28(8):875-884. 
32. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human 
mesenchymal stem cells. Science. Apr 2 1999;284(5411):143-147. 
33. Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal stem cells suppress 
lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Experimental 
hematology. Jan 2002;30(1):42-48. 
34. Tobin, L.M., M.E. Healy, et al. (2012). “Human mesenchymal stem cells suppress donor 
CD4+ T cell proliferation and reduce pathology in a humanized mouse model of acute 
graft-versus-host disease.” Clin Exp Immunol 172: 333-348. 
35. Auletta, J.J., S.K. Eid, et al. (2015). “Human mesenchymal stromal cells attenuate graft-
versus-host disease and maintain graft-versus-leukemia activity following experimental 
allogeneic bone marrow transplantation.” Stem Cells 33: 601-614. 
36. Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress 
T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 
May 15 2002;99(10):3838-3843. 
37. Klyushnenkova E1, Mosca JD, Zernetkina V, Majumdar MK, Beggs KJ, Simonetti DW, 
Deans RJ, McIntosh KR. T cell responses to allogeneic human mesenchymal stem cells: 
immunogenicity, toleranceand suppression. J Biomed Sci. 2005;12(1):47-57 . 
38. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune 
cell responses. Blood. Feb 15 2005;105(4):1815-1822. 
39. Kinnaird, T., E. Stabile, et al. (2004). "Marrow-derived stromal cells express genes 
encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo 
arteriogenesis through paracrine mechanisms." Circ Res 94(5): 678-685. 
40. Semont, A., C. Demarquay, et al. (2013). "Mesenchymal stem cell therapy stimulates 
endogenous host progenitor cells to improve colonic epithelial regeneration." PLoS One 
8(7): e70170. 
41. Semont, A., S. Francois, et al. (2006). "Mesenchymal stem cells increase self-renewal of 
small intestinal epithelium and accelerate structural recovery after radiation injury." Adv 
Exp Med Biol 585: 19-30. 
42. Rasmusson I, Ringden O, Sundberg B, Le Blanc K. Mesenchymal stem cells inhibit the 
formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or 
natural killer cells. Transplantation. Oct 27 2003;76(8):1208-1213. 
43. Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O. Mesenchymal stem 
cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses 
independently of the major histocompatibility complex. Scandinavian journal of 
immunology. Jan 2003;57(1):11-20. 
44. Maitra B, Szekely E, Gjini K, et al. Human mesenchymal stem cells support unrelated 
donor hematopoietic stem cells and suppress T-cell activation. Bone marrow 
transplantation. Mar 2004;33(6):597-604. 
45. Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S. Donor-type 
CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 67 of 79 
Mesoblast 
 
allogeneic bone marrow transplantation. The Journal of experimental medicine. Aug 5 
2002;196(3):389-399. 
46. Joffre O, Santolaria T, Calise D, et al. Prevention of acute and chronic allograft rejection 
with CD4+CD25+Foxp3+ regulatory T lymphocytes. Nature medicine. Jan 
2008;14(1):88-92. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
52. WHO Drug Dictionary. Available at http://www.umc-
products.com/DynPage.aspx?id=73480&mn1=1629. The Uppsala Monitoring Center. 
53. Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Available at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. 
2010. 
54. Brown E. Medical Dictionary for Regulatory Activities (MedDRA®). In: Mann RD, 
Andrews EB, eds. Pharmacovigilance, Second Edition Chichester, UK and 
http://onlinelibrary.wiley.com/doi/10.1002/9780470059210.ch13/summary: John Wiley 
& Sons, Ltd; 2007. 
55. International Conference on Harmonisation of technical requirements for registration of 
pharmaceuticals for human u. ICH harmonized tripartite guideline: Guideline for Good 
Clinical Practice. Journal of postgraduate medicine. Jan-Mar 2001;47(1):45-50. 
56. World Medical A. World Medical Association Declaration of Helsinki: ethical principles 
for medical research involving human subjects. JAMA : the journal of the American 
Medical Association. Nov 27 2013;310(20):2191-2194. 
57. Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on 
the approximation of the laws, regulations and administrative provisions of the Member 
states relating to the implementation of good clinical practice in the conduct of clinical 
trials on medicinal products for human use. In: Union TEPatCotE, ed. L 121/31. 
Available at: http://eur-
lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2001:121:0034:0044:en:PDF.  
Accessed December 20, 2013: Official Journal of the European Communities; 2001. 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 68 of 79 
Mesoblast 
 
58. International Committee of Medical Journal Editors (ICMJE). Recommendations for the 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals. 
2013. 
 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 69 of 79 
Mesoblast 
 
 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 70 of 79 
Mesoblast 
 
 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 71 of 79 
Mesoblast 
 
 
                 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 72 of 79 
Mesoblast 
 
  
 
 
   
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 73 of 79 
Mesoblast 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 74 of 79 
Mesoblast 
 
Appendix 6:  Recommended Steroid Taper 
 
Prednisone orally 
2.5 mg/kg/day divided in 2-3 doses 
Days 0-6 
2.5 mg/kg/day once daily 
Days 7-13 
2 mg/kg/day 
Days 14-21 
1.4 mg/kg/day 
Days 21-28 
0.75 mg/kg/day 
Days 29-35 
0.6 mg/kg/day 
Days 36-42 
0.4 mg/kg/day 
Days 43-49 
0.25 mg/kg/day 
Days 50-56 
0.1 mg/kg/day 
Days 57-63 
0.1 mg/kg/every other day 
Days 63-69 
Discontinue 
Day 70 
 
 
Methylprednisolone IV 
2 mg/kg/day divided in 2-3 doses 
Days 0-6 
2 mg/kg/day once daily 
Days 7-13 
1.5 mg/kg/day 
Days 14-21 
1.0 mg/kg/day 
Days 21-28 
0.5 mg/kg/day 
Days 29-35 
0.4 mg/kg/day 
Days 36-42 
0.3 mg/kg/day 
Days 43-49 
0.2 mg/kg/day 
Days 50-56 
0.1 mg/kg/day 
Days 57-63 
0.1 mg/kg/every other day 
Days 63-69 
Discontinue 
Day 70 
 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 75 of 79 
Mesoblast 
 
Appendix 7:  Childbearing Potential, Pregnancy Testing, and Contraception 
All women of childbearing potential (including those who have had a tubal ligation) will have a 
serum pregnancy test at Screening.  Post-screening, a urine pregnancy test will be performed at 
Day 56, Day 100, and at any unscheduled visits under protocol MSB-GVHD001.  On protocol 
MSB-GVHD002, a urine pregnancy test will be performed at End of Study/Day 180 and at any 
unscheduled visit. If the urine pregnancy test is positive, the result must be confirmed by a serum 
pregnancy test (conducted by the central laboratory).1 
 
All female patients are considered to be of childbearing potential unless they meet one of the 
following criteria: 
 The patient has been post-menopausal (amenorrheic) for at least 1 year 
 The patient had a surgical bilateral oophorectomy (with or without hysterectomy) more 
than 6 weeks prior to enrollment 
 The patient had a hysterectomy. 
 
Female patients of reproductive or childbearing potential who are unwilling to use a 
highly effective method of contraception for the duration of the study will be excluded from 
study participation.2 
 
Examples of highly effective contraception include the following: 
 Abstinence 
 Contraceptive pill or transdermal patch 
 Single barrier plus spermicide 
 Intrauterine device 
 Implants for contraception 
 Injections for contraception (with prolonged release) 
 Hormonal vaginal device 
 Sterilization, surgical tubal ligation 
 Sole sexual partner consisting of surgically sterilized male partner with appropriate post- 
surgical verification of the absence of spermatozoa in the ejaculate. 
Patients may provide verbal confirmation that the partner completed appropriate follow-up after 
vasectomy. Sites are not required to obtain partner medical records. 
 
1. Study or protocol-specific. 
2. IMP-specific and study-specific. 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 76 of 79 
Mesoblast 
 
Appendix 8:  Chronic GVHD-Specific Measures 
Chronic Graft-Versus-Host Disease Scoring Table  
Organ Scoring of Chronic Graft-Versus-Host Disease 
 
Score 0 
Score 1 
Score 2 
Score 3 
Performance Score: 
 
KPS   ECOG   LPS 
Asymptomatic 
and fully active 
(ECOG 0; KPS or 
LPS 100%)  
 Symptomatic, 
fully ambulatory, 
restricted only in 
physically strenuous 
activity (ECOG 1, 
KPS or LPS 80- 90%) 
 Symptomatic, 
ambulatory, capable of 
self-care, >50% of 
waking hours out of 
bed (ECOG 2, KPS or 
LPS 60- 70%) 
  Symptomatic, 
limited self-care, 
>50% of waking 
hours in bed (ECOG 
3-4, KPS or LPS 
<60%) 
Skin 
Clinical features: 
  Maculopapular rash 
  Lichen planus-like 
features 
  Papulosquamous 
lesions or ichthyosis 
  Hyperpigmentation 
  Hypopigmentation 
  Keratosis pilaris 
  Erythema 
  Erythroderma 
  Poikiloderma 
  Sclerotic features 
  Pruritus 
  Hair involvement 
  Nail involvement 
% BSA 
involved 
 
  No Symptoms 
  <18% BSA with 
disease signs but NO 
sclerotic features  
0  19-50% BSA OR 
involvement with 
superficial sclerotic 
features “not 
hidebound” (able to 
pinch)  
  >50% BSA OR 
deep sclerotic 
features “hidebound” 
(unable to pinch) OR 
impaired mobility, 
ulceration or severe 
pruritus  
Mouth 
  No symptoms 
  Mild symptoms 
with disease signs but 
not limiting oral 
intake significantly  
  Moderate 
symptoms with 
disease signs with 
partial limitation of 
oral intake  
  Severe symptoms 
with disease signs on 
examination with 
major limitation of 
oral intake  
Footnotes and abbreviations are provided at the end of the table.   
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 77 of 79 
Mesoblast 
 
Organ Scoring of Chronic Graft-Versus-Host Disease (Continued)  
 
Score 0 
Score 1 
Score 2 
Score 3 
Eyes 
Mean tear test (mm): 
>10 
6-10 
≤5 
Not done 
 
  No 
symptoms 
  Mild dry eye 
symptoms not affecting 
ADL (requiring eye 
drops <3xper day) OR 
asymptomatic signs of 
keratoconjunctivitis 
sicca  
  Moderate dry eye 
symptoms partially 
affecting ADL 
(requiring drops 
>3xper day or 
punctal plugs), 
without vision 
impairment  
  Severe dry eye 
symptoms significantly 
affecting ADL (special 
eyewear to relieve pain) 
OR unable to work 
because of ocular 
symptoms OR loss of 
vision caused by 
keratoconjunctivitis 
sicca  
Gastrointestinal tract 
  No 
symptoms 
  Symptoms such as 
dysphagia, anorexia, 
nausea, vomiting, 
abdominal pain or 
diarrhea without 
significant weight loss 
(<5%)  
  Symptoms 
associated with mild 
to moderate weight 
loss (5- 15%)  
  Symptoms 
associated with 
significant weight loss 
>15%, requires 
nutritional supplement 
for most calorie needs 
OR esophageal dilation  
Liver 
  Normal LFT 
  Elevated bilirubin, 
APa, AST or ALT 
<2xULN  
  Bilirubin >3 
mg/dL or bilirubin, 
enzymes 2-5xULN  
  Bilirubin or 
enzymes >5xULN  
Lungsb 
FEV1 
DLCO 
 
  No 
symptoms FEV1 
>80% OR 
LFS=2  
  Mild symptoms 
(shortness of breath after 
climbing one flight of 
steps) FEV1 60-79% OR 
LFS 3-5  
  Moderate 
symptoms (shortness 
of breath after 
walking on flat 
ground) FEV1 40-
59% OR LFS 6-9  
  Severe symptoms 
(shortness of breath at 
rest; requiring 02) FEV1 
<39% OR LFS 10-12  
Joints and fascia 
 
  No 
symptoms 
  Mild tightness of 
arms or legs, normal or 
mild decreased range of 
motion (ROM) and not 
affecting ADL  
  Tightness of 
arms or legs OR joint 
contractures, 
erythema thought due 
to fasciitis, moderate 
decrease ROM AND 
mild to moderate 
limitation of ADL  
  Contractures WITH 
significant decrease of 
ROM AND significant 
limitation of ADL 
(unable to tie shoes, 
button shirts, dress self 
etc.)  
Footnotes and abbreviations are provided at the end of the table.   

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 78 of 79 
Mesoblast 
 
Organ Scoring of Chronic Graft-Versus-Host Disease (Continued) 
 
Score 0 
Score 1 
Score 2 
Score 3 
Genital tract 
  No 
symptoms 
  Symptomatic with 
mild signs on exam 
and no effect on 
coitus and minimal 
discomfort with 
gynecologic exam  
  Symptomatic with 
moderate signs on exam 
and with mild 
dyspareunia or 
discomfort with 
gynecologic exam  
  Symptomatic 
with advanced signs 
(stricture, labial 
agglutination or 
severe ulceration) and 
severe pain with 
coitus or inability to 
insert vaginal 
speculum  
a AP may be elevated in growing children, and not reflective of liver dysfunction.   
b Pulmonary scoring should be performed using both the symptom and pulmonary function testing (PFT) scale 
whenever possible.  When discrepancy exists between pulmonary symptom or PFT scores, the higher value should 
be used for final scoring.  Scoring using the lung function score (LFS) is preferred, but if DLCO is not available, 
grading using FEV1 should be used.  The LFS is a global assessment of lung function after the diagnosis of 
bronchiolitis obliterans has already been established.  The percent predicted FEV1 and DLCO (adjusted for 
hematocrit but not alveolar volume) should be converted to a numeric score as follows: ≥80%=1; 70-79%=2; 60-
69%=3; 50-59%=4; 40-49%=5; <40%=6.  The LFS= FEV1 score+DLCO score, with a possible range of 2-12.   
 
ADL=activities of daily living; ALT=alanine aminotransferase; AP=alkaline phosphatase; AST=aspartate 
aminotransferase; BSA=body surface area; DLCO=diffusing capacity of the lung for carbon monoxide; 
ECOG=Eastern Cooperative Oncology Group; FEV1=forced expiratory volume in 1 second; KPS=Karnofsky 
Performance Scale; LFS =lung function score; LFTs=liver function  tests; LPS=Lansky Performance Scale; 
ROM=range of motion; ULN=upper limit of the normal range.   
 
Other indicators, clinical manifestations or complications related to chronic GVHD (check all 
that apply and assign a score to its severity (0-3) based on its functional impact where applicable 
(none=0, mild=1, moderate=2, severe=3) 
 
Esophageal stricture or web___ 
Pericardial effusion___ 
Pleural effusion(s)___ 
Ascites (serositis)___  
Nephrotic syndrome___ 
Peripheral neuropathy___ 
Myasthenia gravis___  
Cardiomyopathy___ 
Eosinophilia ≥0.5 x 109/L ___ 
Polymyositis___  
Cardiac conduction defects___ 
Coronary artery involvement___ 
Platelets ≥100 x 109/L ___   
Progressive onset____  
 
Others: 
Specify:_________________________________________________________________ 
 
 

MSB-GVHD002 
Version 4.0 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
Page 79 of 79 
Mesoblast 
 
Based on observations checked in the above table, select the severity of chronic GVHD for this 
assessment.   
 
 None 
 
 Mild chronic GVHD involves only 1 or 2 organs or sites (except the lung: see Note), with no 
clinically significant functional impairment (maximum of score 1 in all affected organs or sites).   
 
 Moderate chronic GVHD involves (1) at least 1 organ or site with clinically significant but no 
major disability (maximum score of 2 in any affected organ or site) or (2) 3 or more organs or 
sites with no clinically significant functional impairment (maximum score of 1 in all affected 
organs or sites).  A lung score of 1 will also be considered moderate chronic GVHD.   
 
 Severe chronic GVHD indicates major disability caused by chronic GVHD (score of 3 in any 
organ or site).  A lung score of 2 or greater will also be considered severe chronic GVHD.   
 
Note: A lung score of 1 will also be considered moderate chronic GVHD.  Severe chronic 
GVHD indicates major disability caused by chronic GVHD (score of 3 in any organ or site).  A 
lung score of 2 or greater will also be considered severe chronic GVHD.