Clinical trial NCT02336230
Conditions: Grade B aGVHD Grade C aGVHD Grade D aGVHD
Keywords: GVHD
Sponsor: Mesoblast, Inc.
Start date: 2015-06-04; Completion date: 2018-04-09
Enrollment: 55 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study plans to treat at least 60 pediatric participants, male and female, between the ages of 2 months and 17 years inclusive with aGVHD following allogeneic hematopoietic stem cell transplant (HSCT) that has failed to respond to treatment with systemic corticosteroid therapy. Participants may have Grades C and D aGVHD involving the skin, liver and/or gastrointestinal (GI) tract or Grade B aGVHD involving the liver and/or GI tract, with or without concomitant skin disease.

Detailed description:
Remestemcel-L will be evaluated in pediatric participants with aGVHD following allogeneic HSCT that has failed to respond to treatment with systemic corticosteroid therapy.

Arms: arm 1: Participants were treated with intravenous (IV) remestemcel-L at a dose of 2×10\^6 mesenchymal stromal cells (MSCs)/kilogram (kg) actual body weight at Screening, twice per week, for each of 4 consecutive weeks (initial therapy) given at least 3 days apart and no more than 5 days apart for any infusion. Eligible participants received an additional once per week infusion, for each of 4 consecutive weeks (continued therapy) of remestemcel-L and twice per week infusions, for each of 4 consecutive weeks (aGVHD flare therapy) of remestemcel-L at the same initial therapy dose of 2×10\^6 MSCs/kg actual body weight at Screening.
Interventions: intervention 1: remestemcel-L
Intervention descriptions: intervention 1: Participants were treated with IV remestemcel-L at a dose of 2 x 10\^6 MSC/kg (actual body weight at screening) twice per week for each of 4 consecutive weeks. Infusions were administered at least 3 days apart and no more than 5 days apart for any infusion.

Protocol documents:
Prot_SAP_000.pdf: 
Official Title: 
A Single-arm, Prospective Study of Remestemcel-L, Ex-vivo Cultured Adult 
Human Mesenchymal Stem Cells, for the Treatment of Pediatric Patients 
who Have Failed to Respond to Steroid Treatment for acute GVHD 
NCT Number: 
NCT02336230 
Document Date: 
Protocol Version 7.0: 18 December 2017 
SAP Version 5.0: 08 February 2018 




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INVESTIGATOR’S SIGNATURE 
 
Study Title: A Single-arm, Prospective Study of Remestemcel-L, Ex-vivo Cultured Adult 
Human Mesenchymal Stromal Cells for the Treatment of 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) 






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Study Population 
This study will evaluate the efficacy and safety of remestemcel-L in pediatric subjects with 
aGVHD that has failed to respond only to first-line systemic steroid treatment. The trial will 
exclude subjects who have received second-line treatment for aGVHD prior to study 
screening, in order to evaluate remestemcel-L’s effects in the absence of other second-line 
agents. The study plans to treat at least 48 pediatric subjects, male and female, between the 
ages of 2 months and 17 years inclusive, with acute Graft versus Host Disease (aGVHD) 
following allogeneic hematopoietic stem cell transplant (HSCT) that has failed to respond 
to treatment with systemic corticosteroid therapy. Subjects may have Grades C and D 
aGVHD involving the skin, liver and/or gastrointestinal (GI) tract or Grade B aGVHD 
involving the liver and/or GI tract, with or without concomitant skin disease. 
Acute GVHD Treatment Response Criteria 
Complete response (CR)- Resolution of aGVHD in all involved organs 
Partial response (PR)- Organ improvement by at least one stage without worsening of any 
other organ. 
Overall response (OR)- Includes both complete response and partial response 
Very good partial response (VGPR)- Subset of PR patients: Fulfillment of the CR criteria 
with the exception of one or more of the following: 
Skin: no rash, non-progressive stage 1 rash, or residual erythematous rash involving <25% 
of the body surface without bullae ( not including residual faint erythema or 
hyperpigmentation); 
Liver: resolving elevations of total serum bilirubin concentration or total serum bilirubin 
concentration of <2 mg/dl or <25% of baseline at enrollment 
Gut: minimal gastrointestinal symptoms as described below: 
Tolerating food or enteral feeding 
Predominantly formed stools 
No overt GI bleeding or abdominal cramping 
No more than occasional nausea or vomiting 
Mixed response (MR)- Improvement in at least one evaluable organ stage with worsening in 
another 
No response (NR)- No change in any organ stage in any organ system and no improvement 
in organ stage 
Progression- Deterioration in at least one organ system by one stage or more with no 
improvement in any other organ 
Responder- Subjects who achieve an overall response (OR) 
Non-responder- Subjects who do not achieve an OR. 
Efficacy Assessments 
Primary Endpoint 
The rate of overall response (OR) in the study population at Day 28 post initiation of 
therapy (Day 0) with remestemcel-L (MSC). 




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2. Subject is 2 months to 17 years of age, inclusive 
3. Subject has failed to respond to steroid treatment, with failure to respond defined as 
any Grade B-D (IBMTR grading) aGVHD that shows progression within 3 days or 
no improvement within 7 days of consecutive treatment with 2 mg/kg/day of 
methylprednisolone or equivalent. 
4. Subject must be able to be treated with remestemcel-L within 4 days of signing of 
informed consent. 
5. Subjects who have had persistent GI GVHD, as manifested by diarrhea with stool 
volume < 500 mL/ day (for subjects >50 kg), or < 30 mL/kg/day (for subjects ≤50 
kg). See Table 2: GVHD Organ Severity Criteria for values in ml/m2. In the 
absence of nausea or vomiting, subject may still be considered to have Grade B 
GVHD if 
a. other causes of diarrhea have been ruled out (e.g., C. difficile, adenovirus or 
cytomegalovirus (CMV) infection, oral magnesium administration) 
 
and if 
 
b. the low stool volume reflects the effects of fasting, narcotics, or anti- 
diarrheal medications. 
 
6. Subject must have adequate renal function, as defined by a calculated creatinine 
clearance of >30 mL/min per 1.73m2. For subjects 1 to 18 years of age, creatinine 
clearance should be calculated using the Bedside Schwartz equation: 
 
GFR (ml/min per 1.73 m2) = [0.413  height (cm)]/Serum creatinine (mg/dl) 
 
For subjects less than 1 year old, renal function should be determined using the 
Schwartz equation adjusted for this age group: 
 
Creatinine clearance (ml/min per1.73 m2)= (height [cm] x 0.45)/ (serum creatinine 
[mg/dL]) 
 
7. Subject has a minimum Karnofsky/Lansky Performance Level of 30 at the time of 
study entry 
8. Subject (or legal representative where appropriate) must be capable of providing 
written informed consent. 
9. Female subjects of childbearing potential (≥ 10 years of age) 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. Guidance on childbearing potential and 
pregnancy testing is located in Appendix 6. 


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10. Male subjects with partners of childbearing potential must agree to use adequate 
contraception (barrier method or abstinence) during the study, including the follow- 
up time period. 
11. The subject must be willing and able to comply with study requirements, remain at 
the clinic, and return to the clinic for the follow-up evaluation, as specified in this 
protocol during the study period. 
Exclusion Criteria 
Subjects will not be eligible for participation in the study if they meet ANY of the 
following criteria: 
1. Subject has Grade B aGVHD with skin-only involvement. 
2. Subject has received any second line therapy to treat aGVHD prior to screening. 
3. Subject has received systemic agents other than steroids and prophylactic agents for 
primary treatment of acute GVHD. 
4. Subject shows evidence of diffuse alveolar hemorrhage or other active pulmonary 
disease, which is likely to require more than 2L of oxygen via face mask or an 
estimated FiO2 of 28% via other delivery methods in order to sustain an O2 
saturation of 92%. 
5. Subject has any underlying or current medical or psychiatric condition that, in the 
opinion of the Investigator, would interfere with the evaluation of the subject, 
including but not limited to uncontrolled infection, heart failure, pulmonary 
hypertension, etc. 
6. Subject has received any stem cell agents (other than hematopoietic graft) during 
study participation or within 30 days prior to study entry. Donor Leukocyte 
Infusion (DLI) is excluded during study participation or within 30 days prior to 
study entry. Previous use of irradiated granulocytes within 30 days is permitted. 
7. Subject has received an HSCT transplant for a solid tumor disease. 
8. Subject has had prior treatment with mesenchymal stromal cells (MSCs), including 
remestemcel-L. 
9. Subject shows evidence of severe (require treatment) hepatic veno-occlusive disease 
(VOD) or sinusoidal obstruction at screening. 
10. Subject has had positive laboratory test results indicating infection with the human 
immunodeficiency virus (HIV) at any time and/or active hepatitis B or C virus 
infection within 3 months prior to screening. 
11. Subject shows evidence of encephalopathy as defined by a change in mental status 
since the onset of aGVHD. 
12. Subject is a female who is pregnant, lactating, or is planning a pregnancy during 
study participation, including the follow-up period. 
13. Subject is currently being treated for a solid tumor malignancy. 
14. Subject has participated in any interventional clinical trial for an aGVHD 
therapeutic agent. However, in exceptional cases (see Section 7.9.1), experimental 
agents may be administered to enrolled subjects at the Investigator’s discretion. 
15. 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 


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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. 
16. Subject has a known hypersensitivity to dimethyl sulfoxide (DMSO) or to porcine 
or bovine proteins. 
Treatment Groups 
This is a single-arm study; all enrolled subjects are to be treated with remestemcel-L. 
Treatment Plan 
The trial design, including treatment plan, is outlined schematically in Figure 1, which 
follows this synopsis. 
Initial Therapy 
Subjects will be treated with intravenous (IV) remestemcel-L at a dose of 2 x 106 MSC/kg 
(actual body weight at screening) twice per week for each of 4 consecutive weeks. 
Infusions will be administered at least 3 days apart and no more than 5 days apart for any 
infusion. All 8 infusions must be administered by Day 28 ± 2 days. 
Subjects may continue to be treated with a stable dose of systemic steroid therapy until they 
are eligible for steroid taper and may continue on an established regimen of baseline 
prophylactic therapy following initiation of remestemcel-L (Day 0). No other medications 
for the treatment of aGVHD are to be introduced to subjects during the initial 28 days post 
remestemcel-L administration unless disease progression, as defined below, has occurred. 
Addition of other secondary line agents prior to Day 28 would constitute failure to respond, 
in which case, the treated subject would remain on the study for safety follow up. 
Any changes in baseline prophylaxis regimen should be recorded in the eCRF and reason 
for change in regimen should be discussed with the Medical Monitor. Changes in dose or 
prophylactic agent due to administration route intolerance or toxicities are allowed at the 
discretion of the investigator with prior approval from the Medical Monitor as these 
changes could be confused as second-line therapies. 
Steroid taper 
If improvement in GVHD, as defined by OR, is observed for a period of 3-5 days and after 
at least two doses of remestemcel-L, the dosing of methylprednisolone or equivalent may 
be tapered. A steroid taper rate of at least 10% of the dose per week, not exceeding 25% of 
the dose per week, is recommended as described in Appendix 5, with the goal of 
discontinuing steroid by 10 weeks after initiating taper. 
Assessments 
GVHD assessments will be performed at screening and weekly, beginning on Day 14, until 
Day 100 (±7 days)/End of Study. Assessments must be after the 2nd dose of remestemcel-L 
is administered for each assessment week of the Initial Therapy period (or after the 1st dose 
of remestemcel-L during Continued Therapy). The weekly assessment visits should be 


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conducted at least 24 hours after the most recent remestemcel -L infusion. Weekly GVHD 
assessments will be used to determine whether the subject’s GVHD status has progressed 
from baseline assessment (through Day 28), according to the definition of progression of 
disease, below. From Day 28 to Day 100, weekly GVHD assessments will be compared to 
the most recent prior assessment to determine whether the subject’s GVHD status has 
progressed. Rescue therapy may be administered if necessary. If new GVHD medications 
are administered as rescue therapy based on these assessment(s), no further remestemcel-L 
infusions will be allowed. Subjects would remain in the study regardless of response and 
would continue to be evaluated per the assessment schedule. 
 
Progression of disease is defined as increase by one or more grade from screening/baseline 
assessment up to Day 28 and as increase by one or more grade from the most recent prior 
assessment from Day 28 to Day 100. Progression is not defined as ‘mixed response’ 
according to the definitions described above under Acute GVHD Treatment Response 
Criteria. 
 
Day 28 Therapy Assessment: 
A therapy assessment will be performed on Day 28 (±2 days) to determine treatment 
response and whether a subject will be provided continued therapy. The Day 28 therapy 
assessment must be at least 24 hours after the last dose of remestemcel-L is administered. 
Continued Therapy will be allowed for subjects according to their response to treatment, as 
described below. 
 
Day 56 Assessment of Response to Continued Therapy 
A therapy assessment will be performed on Day 56 (±2 days) from treatment initiation for 
subjects receiving Continued Therapy after Day 28, in order to determine treatment 
response to the Continued Therapy. The Day 56 therapy assessment must be at least 24 
hours after the last administration of remestemcel-L. 
 
Continued Therapy 
Eligible subjects may receive an additional 4 once-weekly infusions of remestemcel-L at 
the same initial dose of 2 x 106 MSC/kg actual body weight at screening, which would 
begin within one week after the Day 28 therapy assessment. Infusions will be given once 
weekly (± 2 days) and all infusions must be administered within 28 days (± 2 days) from 
the first infusion. No additional treatment with remestemcel-L is allowed at any other point 
in time unless the criterion for GVHD flare, as defined in this protocol, is met. 
 
Eligibility for Continued Therapy 
Eligibility to receive Continued Therapy after the initial 4-week treatment period is 
dependent upon the results of the subject’s response assessments at Day 28, as defined in 
Table 4, compared with baseline, as follows: 


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Complete Response (CR): If a subject displays CR, then no additional remestemcel-L will 
be administered. 
No Response (NR): If a subject displays NR, then no additional remestemcel-L will be 
administered. 
Partial Response (PR): If a subject displays PR, the subject will receive Continued 
Therapy. 
Mixed Response (MR): If a subject displays MR, the subject will receive Continued 
Therapy. 
GVHD flare: Subjects who have a GVHD flare of Grade B-D, after achieving a CR and 
before Day 70 post treatment initiation, may receive additional remestemcel-L treatment 
per the Initial Therapy plan, consisting of remestemcel-L, IV, at a dose of 2 x 106 MSC/kg 
actual body weight at screening, twice per week for each of 4 consecutive weeks. GVHD 
flare is defined as any increase in aGVHD symptoms (measured by GVHD grade B-D) 
beyond 28 days post first infusion, subsequent to achieving CR to Initial Therapy, or 
beyond Day 56 after achieving CR to Continued Therapy. If a subject has begun other 
second line GVHD therapy, they would not be eligible to receive additional remestemcel-L 
treatment. Subjects are eligible for a single treatment for flare. 
Other GVHD therapy 
If a subject begins other second-line GVHD therapy within the period of Initial and 
Continued Therapy (through Day 56, if applicable), he or she would be considered to have 
failed treatment and would be ineligible to receive any further remestemcel-L therapy upon 
receiving the other second-line GVHD therapy. 
Route of Administration and Dose 
Remestemcel-L (ex-vivo cultured adult human MSCs) will be administered intravenously at 
a dose of 2 x106 MSC /kg of actual body weight at screening. Remestemcel-L is stored and 
distributed in cryogenic bags and cryogenic vials. 
Duration of Treatment 
Enrolled subjects will receive Initial Therapy for 4 weeks; eligible subjects will receive 
Continued Therapy for an additional four weeks, beginning within one week after the end 
of Initial Therapy period. Subjects may receive Flare Therapy for an additional four weeks 
if flare criteria is met. 
Duration of Study 
Subjects may receive treatment for up to 8 weeks and will be followed out to 
100 ± 7 days. Total duration of study participation per subject is up to 111 days to account 
for the 4-day screening window and End of Study visit ±7 days. 


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An extension study under a separate protocol (MSB- GVHD002), subsequent to the present 
study, is being conducted in order to capture health outcomes and safety data out to Day 
180. 
Statistical Analysis 
Sample Size 
The primary objective of this trial is to confirm efficacy of remestemcel-L in improving 
Day 28 OR rate within the efficacy population. For assessment of efficacy, an effect size of 
20%, which has been deemed clinically meaningful based on discussions with clinical 
experts on aGVHD, was used to calculate the null hypothesis. The null hypothesis was 
calculated using 45% OR, a rate that is 20-points lower than the anticipated 65% OR rate to 
remestemcel-L. This estimated 45% response rate is supported by data showing comparable 
Day 28 OR rates for historical populations of aGVHD patients treated with standard of 
care, which varies across institutions, but generally consists of treatment with immune- 
suppressive agents used serially or in combination. Sample size was determined using a 
normal approximation to the binomial distribution under the assumption of a two-sided test 
of significance level 5% for a single proportion and a difference in proportion of 20%. This 
is equivalent to one-sided testing at 2.5% of the null hypothesis that the Day 28 OR rate is 
at most, 45%, versus the alternative hypothesis that the Day 28 OR rate is 65% or greater. 
The minimum sample size required to meet the primary objective with 80% power is 48 for 
the FAS population. At least 48 subjects will be enrolled. In order to account for 
dropouts/missing data and to ensure that this study has sufficient power, an additional 
increased enrollment of up to 10% of the minimum required enrollment (48) is planned. 
Statistical Methods 
Analysis Populations 
As this is a single arm study, the evaluable population for efficacy will be considered the 
full analysis set (FAS), which will include all subjects who provided informed consent, 
were screened and found eligible to enter the study. The modified full analysis set (mFAS) 
is the same as the FAS, but only for patients treated with IMP in cryogenic vials. The 
primary and secondary efficacy analyses will be performed on the FAS population. The 
per-protocol (PP) population will include all subjects from the FAS population who had no 
major protocol violations during the study. The primary and secondary efficacy analyses 
performed on the mFAS and PP populations will be considered supportive. The safety 
population will include all subjects who have signed the informed consent form and have 
received at least one dose of study drug. We may conduct sensitivity analyses comparing 
results from patients treated with product in vials to results for all patients for each of the 
analysis populations. 
General Statistical Considerations: 
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). Two-sided confidence intervals at the 95% level will 


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be presented for estimates of proportions. All statistical tests will be two-sided at the 
alpha<0.05 level of significance, unless otherwise noted. 
 
The primary and secondary analyses will be based on the FAS population. Primary and 
secondary analyses performed on the mFAS and PP populations will be considered 
supportive. Analyses of the PP populations will be used to assess sensitivity and thus will 
be considered supportive. 
 
Pre-treatment demographics and subject characteristics will be summarized. Time from 
HSCT to onset of aGVHD and from 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. 
 
Efficacy Analyses 
OR at Day 28 as response to remestemcel-L treatment is the primary efficacy endpoint. 
Missing data for the primary endpoint will be considered as non-responders. Details on 
imputation will be specified in the Statistical Analysis Plan (SAP) prior to database lock. A 
hypothesis test will be performed to assess whether the percentage of responders is 
statistically significantly different from the control percentage of 45% used to calculate the 
null hypothesis. 
 
Survival will be assessed from initial remestemcel-L treatment to the last date of 
assessment. The association between Day 28 OR and survival at Day 100, and between Day 
28 VGPR and survival at Day 100, 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 100 survival Kaplan-Meier curves will be plotted by Day 28 
responder and non-responder groups, and differences between these groups will be tested 
for a statistically significant difference using the log-rank test. The odds ratio for survival 
at Day 100 given responder status at Day 28 will be presented and tested for statistical 
significance (whether statistically significantly greater than 1). 
 
Additional secondary endpoints will be evaluated. The rate of VGPR will be described. 
The number and proportion of VGPR responders, non-responders, and missing values, at 
Day 28, Day 56, and at Day 100 will be summarized. The rates of OR and VGPR at Day 
28, Day 56, and at Day 100 will be reported by skin, gut (lower GI), or liver involvement at 
baseline. The rates of OR and VGPR will also be reported by the mutually exclusive Skin- 
only and “Not skin-only” categories. The number and percentage of responders at each 
time point and for each endpoint will be summarized by baseline GVHD grade. The 
number and percentage of survivors at Day 100 from first infusion date will be summarized 
by baseline grade and organ involvement. The incidence rate of GVHD progression 
requiring additional GVHD medications or therapy will be summarized by number and 
proportion of subjects. Side-by-side shift tables for response at Day 56 and response at 




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Figure 1: Schematic Diagram of the MSB-GVHD001 Trial Design 
 
 
 
†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 Therapy plan. 


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TABLE OF CONTENTS 
INVESTIGATOR’S SIGNATURE ..................................................................................2 
GENERAL INFORMATION ...........................................................................................3 
PROTOCOL SYNOPSIS ..................................................................................................4 
LIST OF TABLES ...........................................................................................................22 
LIST OF FIGURES .........................................................................................................22 
LIST OF APPENDICES .................................................................................................22 
GLOSSARY OF ABBREVIATIONS ............................................................................23 
1. 
BACKGROUND .......................................................................................................26 
1.1 
Acute Graft-versus Host Disease ....................................................................26 
1.2 
Current Treatment of aGVHD and Prognosis ................................................27 
1.3 
Grading of Acute GVHD ................................................................................29 
1.4 
Clinical Endpoints for Evaluation of aGVHD Treatment ..............................31 
1.5 
Mesenchymal Stromal Cells (MSCs) .............................................................33 
 
 
 
 
1.7 
Clinical Studies of MSCs ................................................................................39 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.7.8 
Potential Risks of MSCs ..................................................................49 
1.7.9 
Benefits ............................................................................................51 
2. 
CLINICAL RATIONALE .......................................................................................53 


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2.1 
Rationale for the Study ...................................................................................53 
2.1.1 
Rationale for Study Design ..............................................................53 
2.1.2 
Rationale for Subject Population .....................................................54 
2.1.3 
Rationale for Dosing Regimen and Treatment Period .....................55 
3. 
STUDY OBJECTIVES ............................................................................................56 
3.1 
Hypothesis ......................................................................................................56 
3.2 
Primary Objectives .........................................................................................56 
3.3 
Secondary Objectives .....................................................................................56 
 
 
4. 
STUDY DESIGN ......................................................................................................57 
4.1 
Overview of Study Design and Dosing Regimen ...........................................57 
4.1.1 
Primary Endpoint .............................................................................57 
4.1.2 
Secondary Endpoints .......................................................................57 
 
 
4.1.4 
Treatment Plan .................................................................................58 
4.2 
Study Duration ................................................................................................61 
4.3 
Extension Follow-up Study of Safety and Health Outcomes .........................61 
4.4 
Number of Subjects Assigned to Treatment Groups ......................................65 
4.5 
Study Sites ......................................................................................................65 
5. 
STUDY POPULATION ...........................................................................................65 
5.1 
Overview .........................................................................................................65 
5.2 
Eligibility Criteria ...........................................................................................65 
5.2.1 
Informed Consent .............................................................................65 
5.2.2 
Inclusion Criteria .............................................................................66 
5.2.3 
Exclusion Criteria ............................................................................67 
5.3 
Subject Discontinuation Criteria or Premature Subject Withdrawal ..............69 
5.3.1 
Lost to Follow-Up ............................................................................69 
5.4 
Rescreening of Screen-Failed Subjects...........................................................69 
5.5 
Rules for Discontinuing Investigational Medicinal Product (IMP) ................70 


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5.6 
Information to be Collected for Screen Failures .............................................70 
5.7 
End of Study ...................................................................................................71 
5.8 
Planned Follow-up Study of Safety and Health Outcomes ............................71 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT ................................................71 
 
 
 
 
6.3 
Handling and Accountability ..........................................................................72 
6.4 
Storage of Investigational Medicinal Product ................................................72 
6.5 
Destruction of the Investigational Medicinal Product ....................................72 
7. 
STUDY PROCEDURE ............................................................................................73 
7.1 
Visit Schedule and Assessments .....................................................................73 
7.1.1 
Screening Period ..............................................................................73 
7.1.2 
At Each Infusion Day.......................................................................74 
7.2 
Efficacy Assessments .....................................................................................76 
7.2.1 
GVHD Assessments .........................................................................76 
7.2.2 
Therapy Assessments .......................................................................77 
7.3 
Safety Assessments .........................................................................................78 
7.3.1 
Physical Examination.......................................................................78 
7.3.2 
Vital Signs ........................................................................................78 
7.3.3 
Height and Weight ...........................................................................79 
7.3.4 
Electrocardiogram (ECG) ................................................................79 
7.3.5 
Adverse Events ................................................................................79 
7.3.6 
Assessment of Infusional Toxicity ..................................................80 
7.3.7 
Pregnancy Tests ...............................................................................80 
7.3.8 
Clinical Laboratory Evaluations ......................................................80 
7.3.9 
Assessment of Ectopic Tissue Formation (optional per 
Investigator’s discretion) .................................................................82 
7.4 
Long-Term Safety and Efficacy Follow-Up ...................................................82 
7.5 
Missing or Delayed Study Visits ....................................................................82 


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7.6 
Subject Demographics and Other Baseline Characteristics ............................82 
7.7 
Monitoring after Administration of IMP ........................................................83 
7.8 
Background, First-Line, Second-Line, and Concomitant Medication ............84 
7.9 
Concomitant Medication and Supportive Therapy .........................................84 
7.9.1 
Standard of Care for aGVHD...........................................................84 
7.9.2 
Concomitant Medications ................................................................84 
7.9.3 
Steroid Taper ....................................................................................85 
7.9.4 
Escalating of Steroid Therapy ..........................................................85 
7.9.5 
Supportive Care ...............................................................................85 
 
 
 
 
 
 
8. 
SAFETY GUIDANCE .............................................................................................86 
8.1 
Definitions ......................................................................................................86 
8.1.1 
Adverse Event ..................................................................................86 
8.1.2 
Serious Adverse Event (SAE) (Immediately Reportable to the 
Sponsor) ...........................................................................................87 
8.1.3 
Severity ............................................................................................87 
8.2 
Relationship of Adverse Event to the IMP .....................................................88 
8.3 
Relationship to Study Procedure .....................................................................88 
9. 
REPORTING ADVERSE EVENTS .......................................................................89 
9.1 
Procedures for Reporting Adverse Events and Serious Adverse Events ........89 
9.2 
24-Hour Urgent Medical Contact ...................................................................90 
9.3 
Procedures for Reporting Pregnancies ............................................................90 
9.4 
Laboratory Test Abnormalities .......................................................................90 
9.5 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Ethics Committees ........................................................91 
10. STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN ..................92 
10.1 
Study Design and Randomization ...................................................................92 


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10.1.1 
Sample Size and Power ....................................................................92 
10.1.2 
Sample Size for Interim Analysis of Futility ...................................93 
10.1.3 
Interim Analysis of Futility ..............................................................93 
10.2 
Statistical Analysis Plan .................................................................................94 
10.2.1 
General Statistical Considerations: ..................................................94 
10.3 
Analysis Populations ......................................................................................94 
10.3.1 
Full Analysis Set (FAS) ...................................................................94 
10.3.2 
Modified Full Analysis Set (mFAS) ................................................95 
10.3.3 
Safety Population .............................................................................95 
10.3.4 
Per-Protocol (PP) Population ...........................................................95 
10.4 
Demographic and Baseline Characteristics ....................................................95 
10.5 
Efficacy Analysis ............................................................................................96 
10.5.1 
Primary Efficacy Endpoint ...............................................................96 
10.5.2 
Secondary Efficacy Endpoints .........................................................96 
 
 
10.6 
Safety Data Analysis .....................................................................................100 
10.6.1 
Primary Safety Endpoints ..............................................................100 
10.6.2 
Adverse Events and Serious Adverse Events ................................100 
10.6.3 
Infusional Toxicity .........................................................................101 
10.6.4 
Other Safety Analyses ....................................................................101 
11. DATA COLLECTION, MANAGEMENT AND QUALITY ASSURANCE ....102 
11.1 
Assignment of Preferred Terms and Original Terminology .........................102 
12. STUDY COMMITTEES .......................................................................................102 
12.1 
Independent Data and Safety Monitoring Board (DSMB) ...........................102 
 
 
 
 
12.2.2 
Follow-up of Safety and Health Outcomes ....................................103 
13. LAWS, REGULATIONS, AND ETHICS ............................................................103 
13.1 
Local Regulations/Declaration of Helsinki ..................................................103 


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13.2 
Informed Consent .........................................................................................104 
13.3 
Institutional Review Board/ Ethics Committees (IRB/EC) ..........................104 
13.4 
Protocol Adherence ......................................................................................105 
13.5 
Protocol Deviation ........................................................................................105 
14. CONDITIONS FOR MODIFYING THE PROTOCOL ....................................105 
15. CONDITIONS FOR TERMINATING THE STUDY ........................................105 
15.1 
Enrollment Hold and Stopping Rules ...........................................................106 
16. STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING ..................106 
16.1 
Investigator's Files / Retention of Documents ..............................................106 
16.2 
Source Documents and Background Data ....................................................107 
16.3 
Audits and Inspections ..................................................................................107 
16.4 
Electronic Case Report Forms ......................................................................107 
17. MONITORING OF STUDY .................................................................................108 
18. CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT 
RECORDS ..............................................................................................................108 
19. PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS .....108 
19.1 
Right to Publish ............................................................................................108 
19.2 
Publication Steering Committee ...................................................................109 
19.3 
Procedure ......................................................................................................109 
19.4 
Multi-Center Study .......................................................................................110 
20. STUDY COMPLETION ........................................................................................110 
21. REFERENCES .......................................................................................................111 


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LIST OF TABLES 
Table 1: Worldwide Incidence of Steroid Refractory aGVHD .........................................26 
Table 2: GVHD Organ Severity Criteria¥ .........................................................................30 
Table 3:  IBMTR and Glucksberg Grades from Organ Stage ............................................31 
Table 4: Acute GVHD Response Criteria .........................................................................32 
 
 
 
 
 
 
 
 
 
Table 10:  Summary of Treatment Plan .............................................................................59 
Table 11: Schedule of Assessments and Procedures ........................................................62 
Table 12: Laboratory Tests† ..............................................................................................81 
Table 13: Monitoring Procedures During and After Administration of IMP ...................83 
Table 14: NIH Common Criteria for Adverse Events (CTCAE) Scale † ..........................88 
Table 15: Sample Size Consideration ...............................................................................93 
 
LIST OF FIGURES 
Figure 1: Schematic Diagram of the MSB-GVHD001 Trial Design ................................15 
Figure 2:  Probability of Survival According to Maximum GVHD Grade for a Sampling of 
607 aGVHD Patients from the CIBMTR Registry ............................................28 
 
 
 
LIST OF APPENDICES 
 
 
 
 
Appendix 5: Recommended Steroid Taper .....................................................................120 
Appendix 6: Childbearing Potential, Pregnancy Testing, and Contraception ................121 


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GLOSSARY OF ABBREVIATIONS 
ACI 
Acute Cardiac Infarct Study 
ACR 
Albumin-to-creatinine ratio 
ADA 
American Diabetes Association 
AE 
Adverse event 
aGVHD 
Acute Graft versus Host Disease 
ALT [SGPT] 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST [SGOT] 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
BMI 
BP 
Body mass index 
Blood pressure 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CK 
Creatine kinase 
CMV 
Cytomegalovirus 
CMH 
Cochran-Mantel-Haenszel 
CPK 
Creatine phosphokinase 
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 
DLI 
Donor Leukocyte Infusion 
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 
EOT 
European Economic Area 
End of Treatment 
eGFR 
Estimated glomerular filtration rate 
EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FPG 
Fasting plasma glucose 
FiO2 
Fractional inspired oxygen concentration 


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GLOSSARY OF ABBREVIATIONS 
GFP 
Green fluorescence protein 
GI 
Gastrointestinal 
γ-GT 
Gamma-glutamyl transpeptidase 
GCP 
Good clinical practice 
GMP 
Good Manufacturing Practice 
GFR 
GVHD 
Glomerular filtration rate 
Graft versus Host Disease 
GGT 
Gamma-glutamyl transpeptidase 
HbA1c 
Glycosylated hemoglobin 
HBsAg 
Hepatitis B surface antigen 
HBcAb 
Hepatitis B core antibody 
Hct 
Hematocrit 
HCV 
Hepatitis C virus 
HDL 
High density lipoprotein 
HIV 
Human immunodeficiency virus 
HLA 
HLT 
Human leukocyte antigen 
High Level Term 
hMSC 
Human mesenchymal stem cells 
HR 
Heart Rate 
hsCRP 
High sensitivity C-reactive protein 
HSCT 
Hematopoietic stem 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 
MA 
Medical advisor 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
mFAS 
Mean corpuscular volume 
Modified full analysis set 
MLR 
Mixed lymphocyte reaction 
MPC 
Mesenchymal precursor cells 
MPV 
Mean platelet volume 


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GLOSSARY OF ABBREVIATIONS 
MDRD 
Modification of Diet in Renal Disease 
mITT 
Modified intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
Mixed Response 
MSC 
MTX 
Mesenchymal stromal cells 
Methotrexate 
NR 
No Response 
NIH 
NSAID 
National Institutes of Health 
Non-Steroidal Anti-inflammatory Drugs 
NYHA 
New York Heart Association 
O2 
Oxygen 
OR 
Overall Response 
PedsQL™ 
Pediatric Quality of Life Inventory™ 
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 
QLS 
Quintiles Lifecycle Safety 
RBC 
Red blood cell 
RDW 
Red cell distribution width 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SEM 
Standard Error of Mean 
SMBG 
Self-monitored blood glucose 
SMT 
SPC 
SOC 
Study Management Team 
Summary of Product Characteristics 
System Organ Class 
SUSAR 
TG 
Suspected Unexpected Serious Adverse Reaction 
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 


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1. 
BACKGROUND 
1.1 
Acute Graft-versus Host Disease 
Graft versus host disease (GVHD) is a progressive and lethal complication of hematopoietic 
stem cell transplantation (HSCT) and donor leukocyte infusion. Two clinically distinct forms of 
GVHD have been described, consisting of 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 definable 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, 4 1,000-1,200 of which 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 


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environment that is conducive to GVHD. The tissue damage leads to the increased secretion of 
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 onset 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 FDA-approved therapies for treatment of steroid-refractory 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 


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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, the 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 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 


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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 One of the first grading systems, published by Glucksberg and colleagues in 1974, 21 
involves assigning a stage of 1 to 4 to each involved organ, as described in Table 2, and 
combining these stages to yield an overall grade ranging from I to IV (Table 3). 
 
Another grading system, which will be used in the present study, was devised by the 
International Bone Marrow Transplant Registry (IBMTR) and classifies aGVHD severity on a 
scale of A to D. While a modified Glucksberg grading system is recommended in the most 
current published consensus statement for diagnosis and management of aGVHD, 12 the current 
study will use the IBMTR classification system in order to maintain consistency with previous 
studies of remestemcel-L for aGVHD. Table 3 presents a summary of the IBMTR compared 
with the IBMTR grading systems for GVHD. 22 








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1.5 
Mesenchymal Stromal Cells (MSCs) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 32-34 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. 35-37 Data suggest that Tregs play an important role in 
inhibiting allogeneic T cell response and aGVHD. 6,38 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) 32   The 
immunomodulatory effects of MSCs are attributable, at least in part, to secretion of soluble 
factors such as PGE2. 32 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. 39-41 
 
 
 
 
 
 
 
 
 












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1.7 
Clinical Studies of MSCs 
MSCs have been used for immunologic, gastrointestinal, and cardiac indications in humans, as 
described below and summarized in Table 6 and Table 7. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.7.8 
Potential Risks of MSCs 
A list of adverse events (AEs) possibly or probably related to remestemcel-L use is found in the 
Investigators Brochure. All AEs were events commonly expected in the treated population, 
independent of the infusions of hMSCs. The most common AEs observed for remestemcel-L in 
clinical trials of pediatric GVHD were infections, gastrointestinal disorders, and respiratory, 
thoracic and mediastinal disorders. 
 
Infusion reaction though, uncommon (≥1/1,000 to ≤1/100), has been reported in subjects treated 
with remestemcel-L. An acute infusion reaction may include fever, chills, urticarial, hypotension, 
shortness of breath, difficulty breathing, hypoxia or other signs of acute respiratory distress. 


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Infusional toxicity was evaluated by continuously monitoring the subject’s vital signs and 
oxygen saturation via pulse oximetry from the time of investigational agent infusion until two 
hours after starting the infusion of study drug. To reduce the potential for infusion reaction, it is 
recommended that subjects receive premedication with hydrocortisone and diphenhydramine. 
Premedication should occur 30-60 minutes prior to infusion of remestemcel-L. 
 
Due to the known in vitro immune modulating effects of human MSCs, 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. 
 
 
 
 
 
 
 
 
 
 
 
 
With consideration of the low incidence of ectopic tissue formation from the safety data, the risk 
of high radiation exposure from computed tomography (CT) scans, the required administration 
of contrast agents, and the potential need for anesthetics in an ailing pediatric subject population, 
Investigators may choose to omit CT/MRI scans at their own discretion, provided the 
rationale for omission is documented in the source documents. 
 
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 the cells in a processing facility immediately 
prior to administration. The potential risks of introducing a donor-derived infectious agent are 
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screenings 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. 
 
 
 
 
 
 
 
 
 
 
Remestemcel-L contains dimethyl sulfoxide (DMSO) 
 
 
 In non-clinical 
studies, DMSO has been reported to have potential adverse effects on the heart through negative 
inotropic or chronotropic actions on myocardium and decreased heart rates. In addition, DMSO 
has been associated with histamine release following degranulation of mast cells. Subjects that 
have a known allergy to sulfa drugs should be closely monitored for development of possible 
immune sensitivity reaction. In order to minimize potential reactions to DMSO, the subject is 
premedicated with diphenhydramine and hydrocortisone prior to infusion of remestemcel-L. 
 
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. All females of childbearing potential 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 such that risk of failure is minimized. 
 
1.7.9 
Benefits 
 
 
 
 
 
 
 






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randomized to a placebo group. With this anticipated limitation, this study will be single-arm, 
open-label, with a planned enrollment of at least 60 subjects aged 2 months to 17 years inclusive 
diagnosed with Grades B-D aGVHD who fail to respond to first-line corticosteroid treatment. 
 
The primary endpoint in this study will be OR, defined as complete response (CR) or partial 
response (PR), as described in Table 4, at 28 days after treatment initiation with remestemcel-L. 
Response to treatment at a fixed time point after initiating treatment have been shown in several 
studies to be associated with improvement in mortality up to 2 years post-transplant. 28-31 In 
particular, OR, as defined in Table 4, to treatment at Day 28 was associated with significantly 
lower rate of non-relapse mortality at 6 months and 2 years. 28-30 Response at Day 28 has been 
supported in a guideline issued by an expert panel of the American Society for Blood and 
Marrow Transplant (ASBMT) in 2009 as well as by subsequent studies 28,30,31; therefore OR at 
Day 28 is considered an appropriate primary endpoint for efficacy evaluation of treatment for 
aGVHD. 
 
2.1.2 
Rationale for Subject Population 
Analysis of remestemcel-L’s treatment effects in the absence of other prior or concomitant 
second-line therapy for aGVHD presents an opportunity to discern remestemcel-L’s efficacy 
without the potentially confounding effects of other treatment agents. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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To confirm the results of this pooled analysis, this study will evaluate the efficacy and safety of 
remestemcel-L in pediatric subjects with aGVHD that has failed to respond only to first-line 
systemic steroid treatment. The trial will exclude subjects who have received second-line 
treatment for aGVHD prior to study screening, in order to evaluate remestemcel-L’s effects in 
the absence of other second-line agents. 
 
Based on results from previous clinical studies, which demonstrated that remestemcel-L 
conferred clinical benefit primarily to subjects with aGVHD involving the liver and/or GI, 
subjects with Grade B skin-only involvement will be excluded. Accordingly, subjects in this 
study may have Grade C or D aGVHD involving the skin, liver, and/or gastrointestinal (GI) tract 
or may have Grade B aGVHD involving the liver and/or GI tract, with or without concomitant 
skin disease. 
 
 
 
 
 
2.1.3 
Rationale for Dosing Regimen and Treatment Period 
In early studies, subjects infused with hMSCs for the treatment of steroid refractory, severe acute 
GVHD have experienced improvement in their GVHD, as manifested by complete resolution of 
GVHD symptom by 6 of 14 subjects after one to three infusions of hMSCs with a median dose 
of 1 x 106 MSCs per kilogram. 42,43 This dosing regimen of hMSC was also well-tolerated. 42,43,50 
Based upon this experience, 1 – 2 x 106 MSCs per kilogram was deemed sufficient therapeutic 
benefit to aGVHD patients. 
 
  
 
 
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planned infusional dose for this study is 2 x 106 hMSCs/kg actual body weight at screening, 
twice per week for each of 4 consecutive weeks, with at least 3 days between infusions, for the 
first 4weeks. 
 
3. 
STUDY OBJECTIVES 
3.1 
Hypothesis 
Mesenchymal stromal cells (MSCs), the primary component of remestemcel-L, are non- 
hematopoietic cells isolated from adult bone marrow and expanded in culture. In vitro studies 
show that MSCs can inhibit alloantigen- and mitogen-stimulated T cell proliferation and promote 
an increase in the proportion of regulatory T cells, (Treg), which play an important role in 
inhibiting allogeneic T cell response in aGVHD. 54,55 In clinical studies, MSCs elicited improved 
clinical response over placebo in subjects with aGVHD. We hypothesize that remestemcel-L 
will display efficacy for treating aGVHD that has failed to respond to first-line steroid treatment 
in pediatric subjects. 
 
3.2 
Primary Objectives 
1. To evaluate the efficacy of remestemcel-L in pediatric subjects with Grades B-D aGVHD 
who have failed to respond to steroid treatment post allogeneic HSCT. 
2. To gather additional information on the safety of remestemcel-L in pediatric subjects 
with Grades B-D aGVHD that has failed to respond to steroid treatment post allogeneic 
HSCT. 
 
3.3 
Secondary Objectives 
1. To determine the correlation between response to remestemcel-L at Day 28 and survival 
at Day 100. 
2. To obtain quality of life data on remestemcel-L-treated subjects via the Pediatric Quality 
of Life Inventory™ (PedsQL™; Appendix 1 and Appendix 2) and the pediatric global 
health-related quality of life (HRQOL) Parent Proxy Report (Appendix 3). 
3. To measure the functional status of remestemcel-L-treated subjects using the 
Karnofsky/Lansky scale (Appendix 4). 
 
 
 
 


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4. 
STUDY DESIGN 
4.1 
Overview of Study Design and Dosing Regimen 
This trial is a prospective, single-arm study involving multiple study centers, to evaluate the 
efficacy and safety of remestemcel-L in pediatric subjects with acute GVHD who have failed to 
respond to systemic steroid treatment. The study plans to treat at least 48 pediatric subjects, 
male and female, between the ages of 2 months and 17 years inclusive with aGVHD following 
allogeneic hematopoietic stem cell transplant (HSCT) that has failed to respond to treatment with 
systemic corticosteroid therapy. Subjects may have Grades C and D aGVHD involving the skin, 
liver and/or gastrointestinal (GI) tract or Grade B aGVHD involving the liver and/or GI tract, 
with or without concomitant skin disease. 
 
Subjects will be treated with intravenous (IV) remestemcel-L at a dose of 2 x 106 MSC/kg actual 
body weight at screening, twice per week for each of 4 consecutive weeks. Eligible subjects will 
receive Continued Therapy, an additional 4 once weekly infusions of remestemcel-L at the same 
initial dose of 2 x 106 MSC/kg actual body weight at screening. Eligible subjects may also 
receive GVHD flare therapy, which consists of an additional 4 twice-weekly infusions of 
remestemcel-L at the same initial dose of 2 x 106 MSC/kg actual body weight at screening. 
 
4.1.1 
Primary Endpoint 
The primary endpoint will be overall response (OR), defined as complete response (CR) or 
partial response (PR; see Table 4), of the study population at 28 days post initiation of therapy 
(Day 0) with remestemcel-L. 
 
4.1.2 
Secondary Endpoints 
The secondary endpoints in this study will be the following: 
1. Overall survival at Day 100 post initiation of remestemcel-L therapy 
2. Rate of very good partial response (VGPR) at Day 28 post initiation of remestemcel-L 
therapy 
3. Rates of OR and VGPR at Day 100 post initiation of remestemcel-L therapy 
4. Rates of OR and VGPR at Days 28 and 100 post initiation of remestemcel-L therapy, 
stratified by organ involvement 
5. Rates of OR and VGPR at Days 28 and 100 post initiation of remestemcel-L therapy, 
stratified by individual subject organ involvement 
6. Rates of OR and VGPR at Days 28 and 100 post initiation of remestemcel-L therapy, 
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7. Overall survival at Day 100 post initiation of remestemcel-L therapy, stratified by 
baseline aGVHD grade and organ involvement 
8. Rate of aGVHD progression requiring additional GVHD medications/ therapy through 
Day 100 post initiation of remestemcel-L therapy 
9. Effect of additional remestemcel-L therapy after Day 28 on rate of OR and VGPR at 
Days 56 and 100 post initiation of remestemcel-L therapy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.1.4 
Treatment Plan 
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Any changes in baseline prophylaxis regimen should be recorded in the eCRF and reason for 
change in regimen should be discussed with the Medical Monitor. Changes in dose or 
prophylactic agent due to administration route intolerance or toxicities are allowed at the 
discretion of the investigator with prior approval from the Medical Monitor as these changes 
could be confused as second-line therapies. 
 
4.1.4.2 Continued Therapy 
Eligible subjects will receive an additional 4 once weekly infusions of remestemcel-L at the 
same initial dose of 2 x 106 MSC/kg actual body weight at screening, which will begin within 
one week after the Day 28 assessment (Table 10). Infusions will be given once weekly 
(± 2 days) and all 4 infusions must be administered within 28 days (±2 days). No additional 
treatment with remestemcel-L is allowed at any other point in time unless the criteria for GVHD 
flare, as defined in this protocol, is met. 
 
4.1.4.3 Eligibility for Continued Therapy 
Eligibility to receive additional therapy after the initial 4-week treatment period is dependent 
upon the results of the subjects’ response assessments, as defined in Table 4, at Day 28, as 
follows (Table 10): 
 
Complete response (CR): If a subject displays CR, then no additional remestemcel-L will be 
administered. 
 
No Response (NR): If a subject displays NR, then no additional remestemcel-L infusion will be 
administered. 
 
Partial Response (PR): If a subject displays PR, the subject will receive Continued Therapy. 
 
Mixed Response (MR): If a subject displays MR, the subjects will receive Continued Therapy. 
 
4.1.4.4 GVHD Flare 
Subjects who have a GVHD flare of Grade B-D after achieving a CR (after Initial or Continued 
Therapy) and before Day 70 may receive additional remestemcel-L treatment per the Initial 
Therapy plan (Table 10). GVHD flare is defined as any increase in aGVHD symptoms 
(measured by GVHD grade B-D) beyond 28 days post first infusion, subsequent to achieving CR 
to Initial Therapy, or beyond Day 56 after achieving CR to Continued Therapy. If a subject has 
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remestemcel-L therapy upon receiving the other second-line GVHD therapy. Subjects are 
eligible for a single treatment for flare. 
 
4.1.4.5 Other GVHD therapy 
If a subject begins other second-line GVHD therapy within the period of Initial and Continued 
Therapy (through Day 56, if applicable), he or she would be considered to have failed treatment 
and would be ineligible to receive any further remestemcel-L therapy upon receiving the other 
second-line GVHD therapy. 
 
Changes in prophylaxis regimen (change in dose or prophylactic agent) due to administration 
route intolerance or toxicities are allowed at the discretion of the investigator with prior approval 
from the Medical Monitor and are not considered second-line therapies. 
 
4.2 
Study Duration 
Enrolled subjects will receive Initial Therapy for 4 weeks; eligible subjects will receive therapy 
for an additional 4 (Continued Therapy) to 8 (Flare Therapy) weeks. Subjects will be assessed 
according to a schedule of planned assessments, as summarized in Table 11, and will be 
followed for up to 100 days. The total duration of study participation per subject will be up to 
111 days to account for the 4-day screening window and end of study visit ±7 days. 
 
4.3 
Extension Follow-up Study of Safety and Health Outcomes 
An extension study under a separate protocol (MSB-GVHD002), subsequent to the present 
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4.4 
Number of Subjects Assigned to Treatment Groups 
This is a single-arm study in which at least 48 enrolled subjects will be treated with 
remestemcel-L. 
 
4.5 
Study Sites 
This study will be conducted in approximately 35 different sites. 
 
5. 
STUDY POPULATION 
5.1 
Overview 
The study plans to treat at least 48 pediatric subjects, male and female, between the ages of 
2 months and 17 years inclusive. Subjects may have Grades C and D aGVHD involving the skin, 
liver and/or gastrointestinal (GI) tract or Grade B aGVHD involving the liver and/or GI tract, 
with or without concomitant skin disease. 
 
5.2 
Eligibility Criteria 
5.2.1 
Informed Consent 
The informed consent document will be used to explain the risks and benefits of participation to 
the patient and/or the patient’s guardian in simple terms prior to treatment. Written authorization 
for use and disclosure of personal health information (PHI) as per the requirements under the 
Health Insurance Portability and Accountability Act (HIPAA) (45 CFR 164) or per local privacy 
regulation must be obtained as part of the informed consent process. Authorization can be 
included in the informed consent form or can be issued as a separate document. The treating 
physician is responsible for ensuring that written informed consent, including written 
authorization for use and disclosure of PHI and appropriate signatures and dates, is obtained 
from each patient before any protocol-related procedures including any pre-treatment procedures 
are performed. As subjects treated with remestemcel-L under this protocol will be under 18 at 
the time of informed consent, a signature from a parent or legal guardian indicating informed 
consent will be required. 
 
The informed consent document must include the elements required by Food & Drug 
Administration (FDA) regulations in the Code of Federal Regulations (21 CFR Part 50), written 
authorization for use and disclosure of PHI (45 CFR 164) and International Conference on 
Harmonization (ICH) guidelines, as applicable. The treating physician agrees to obtain approval 
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for use and disclosure of PHI authorization document used in the execution of the protocol, prior 
to submission to the Institutional Review Board (IRB) or Ethics Committee (EC). In the event 
the subject is re-screened for participation, a new and written authorization for use and disclosure 
of PHI document must be signed. 
 
An extension study under a separate protocol (MSB-GVHD002), subsequent to the present 
study, is being conducted in order to capture health outcomes and safety data out to Day 180. 
Subjects may be presented with the IRB/EC approved consents for MSB-GVHD001 and MSB- 
GVHD002 simultaneously at the time of consent onto this protocol. 
 
5.2.2 
Inclusion Criteria 
Subjects are eligible for the study if all of the following criteria are met: 
1. Subject was diagnosed with Grade B-D acute GVHD requiring corticosteroid systemic 
therapy. The subject may have Grade C or D aGVHD involving the skin, liver, and/or 
gastrointestinal (GI) tract or may have Grade B aGVHD involving the liver and/or GI 
tract, with or without concomitant skin disease. Acute GVHD is defined as the presence 
of skin rash and/or persistent nausea, vomiting, and/or diarrhea and/or cholestasis 
presenting in a context in which aGVHD is likely to occur and where other etiologies 
such as drug rash, enteric infection, or hepatotoxic syndromes are unlikely or have been 
ruled out. 
2. Subject is 2 months to 17 years of age, inclusive. 
3. Subject has failed to respond to steroid treatment, with failure to respond defined as any 
Grade B-D (IBMTR grading) aGVHD that shows progression within3 days 
or no improvement within 7 days of consecutive treatment with 2 mg/kg/day of 
methylprednisolone or equivalent. 
4. Subject must be able to be treated with remestemcel-L within 4 days of signing of 
informed consent. 
5. Subjects who have had persistent GI GVHD manifested by diarrhea with stool volume 
less than 500 mL/day (for subjects >50 kg) or less than 30 mL/kg/day(for subjects 
≤50 kg). See Table 2: GVHD Organ Severity Criteria for values in ml/m2. In the absence 
of nausea or vomiting, subject may still be considered to have Grade B GVHD if: 
a. other causes of diarrhea have been ruled out (e.g., C. difficile, adenovirus or 
cytomegalovirus (CMV) infection, oral magnesium administration) and if 
b. the low stool volume reflects the effects of fasting, narcotics, or anti-diarrheal 
medications. 


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6. Subject must have adequate renal function as defined by a calculated creatinine clearance 
of >30 mL/min per 1.73 m2. For subjects 1 to 18 years of age creatinine clearance should 
be calculated using the Bedside Schwartz equation:56,57 
 
GFR (ml/min per 1.73 m2) = [0.413  height (cm)]/Serum creatinine (mg/dl) 
 
For subjects less than 1 year old, renal function should be determined using the Schwartz 
equation adjusted for this age group: 
 
Creatinine clearance (ml/min per1.73 m2)= (height [cm] x 0.45)/ (serum creatinine 
[mg/dL]) 
 
7. Subject has a minimum Karnofsky/Lansky Performance Level of 30 at the time of study 
entry. 
8. Subject (or legal representative where appropriate) must be capable of providing written 
informed consent. 
9. Female subjects of childbearing potential (≥ 10 years of age) 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. Guidance on childbearing potential and pregnancy 
tests are located in Appendix 6. 
10. Male subjects with partners of childbearing potential must agree to use adequate 
contraception (barrier method or abstinence) during the study, including the follow-up 
time period. 
11. The subject must be willing and able to comply with study requirements, remain at the 
clinic, and be willing and able to return to the clinic for the follow-up evaluation, as 
specified in this protocol during the study period. 
 
5.2.3 
Exclusion Criteria 
Subjects will not be eligible for participation in the study if they meet ANY of the following 
criteria: 
1. Subject has Grade B aGVHD with skin-only involvement. 
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3. Subject has received systemic agents other than steroids and prophylactic agents for 
primary treatment of acute GVHD. 
4. Subject shows evidence of diffuse alveolar hemorrhage or other active pulmonary 
disease, which is likely to require more than 2L of oxygen via face mask or an estimated 
FiO2 of 28% via other delivery methods in order to sustain an O2 saturation of 92%. 
5. Subject has any underlying or current medical or psychiatric condition that, in the opinion 
of the Investigator, would interfere with the evaluation of the subject including but not 
limited to uncontrolled infection, heart failure, pulmonary hypertension, etc. 
6. Subject has received any stem cell agents (other than hematopoietic graft) during study 
participation or within 30 days prior to study entry. Donor Leukocyte Infusion (DLI) is 
excluded during study participation or within 30 days prior to study entry. Previous use 
of irradiated granulocytes within 30 days is permitted. 
7. Subject has received an HSCT transplant for a solid tumor disease. 
8. Subject has had prior treatment with mesenchymal stromal cells (MSCs), including 
remestemcel-L. 
9. Subject shows evidence of severe (require treatment) hepatic veno-occlusive disease 
(VOD) or sinusoidal obstruction at screening. 
10. Subject has had positive laboratory test results indicating infection with the human 
immunodeficiency virus (HIV) at any time and/or active hepatitis B or C virus infection 
within 3 months prior to screening. 
11. Subject shows evidence of encephalopathy as defined by a change in mental status since 
the onset of aGVHD. 
12. Subject is a female who is pregnant, lactating, or is planning a pregnancy during study 
participation, or in the follow-up period. 
13. Subject is currently being treated for a solid tumor malignancy. 
14. Subject has participated in any interventional clinical trial for an aGVHD therapeutic 
agent. However, in exceptional cases (see Section 7.9.1), experimental agents may be 
administered to enrolled subjects at the Investigator’s discretion. 
15. 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. 
16. Subject has a known hypersensitivity to dimethyl sulfoxide (DMSO) or to murine, 
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5.3 
Subject Discontinuation Criteria or 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. 
 
The Investigator may discontinue any subject for any reason that may interfere significantly with 
the trial procedures and/or the interpretation of results. In addition, a subject may be withdrawn 
from the study if the Investigator determines that continued participation in this trial would pose 
a significant safety risk for the subject. 
 
At a minimum, the following should be collected when a subject discontinues: 
• The reason the subject discontinued 
• The date of last treatment 
• The date of the last assessment and/or contact 
• Adverse events (AEs), including concomitant medications used to treat AEs 
• Final (end of study) Assessments. 
 
5.3.1 
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-enrollment, 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). 
 
5.4 
Rescreening of Screen-Failed Subjects 
Screen-failed subjects may be re-screened once at the Investigator’s discretion. If the 
rescreening takes place within one week of the screen failure, only the tests the subject has failed 
at screening should be repeated at the rescreening. If the rescreening occurs one week or more 
after the initial screening, all screening tests should be repeated. 


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5.5 
Rules for Discontinuing Investigational Medicinal Product (IMP) 
Subjects may discontinue IMP under the following circumstances: 
• Subject voluntarily withdraws from the study 
• Subject is withdrawn from the study at the Investigator’s discretion 
• Subject completes study requirements 
• Death. 
 
Every effort should be made to complete the ‘End of Study’ assessments for all subject 
withdrawals / terminations. 
 
If the subject discontinues from the treatment protocol and has an ongoing adverse experience at 
the time of discontinuation, the subject must receive follow-up for at least 2 weeks to clarify the 
nature of the AE. If clinical visit(s) are necessary, the procedures performed during the follow-up 
visit(s) will be recorded on unscheduled visit pages of the CRF. If the AE has not resolved after 
a 2-week period, a plan for further follow-up of the subject will be created by the treating 
physician in consultation with the Medical Monitor. 
 
5.6 
Information to be Collected for Screen Failures 
Subjects who are consented and are screened for eligibility into the trial, but do not meet the 
inclusion/exclusion criteria for trial entry, will be considered screen failures. Subjects who 
provide consent but discontinue the trial prior to being given IMP will also be considered screen 
failures. 
 
The following information must be recorded on the respective case report forms (CRFs) for all 
screen failures: 
• Demography 
• Inclusion/exclusion criteria 
• Adverse events 
• End of screening disposition. 


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5.7 
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. 
 
Individual subjects will be considered to have completed the study when they have completed all 
required protocol procedures and assessments. For subjects with ongoing AEs at the last 
scheduled visit, the end of study date will be deemed the last scheduled visit date. The study site 
staff will perform the appropriate closeout/last visit assessments. 
 
5.8 
Planned Follow-up Study of Safety and Health Outcomes 
An extension study under a separate protocol (MSB-GVHD002), subsequent to the present 
study, is being conducted in order to capture health outcomes and safety data out to Day 180. 
Subjects may be presented with the IRB/EC approved consents for MSB-GVHD001 and MSB- 
GVHD002 simultaneously at the time of consent onto this protocol. 
 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.3 
Handling and Accountability 
Remestemcel-L will be provided to the study sites by the Sponsor or designee. Only the 
Investigator(s) or their designee(s) will be permitted to administer the IMP to subjects 
participating in this protocol. 
 
The IMP must be received by a person designated by the Investigator at the study site, handled 
and stored safely and properly, and kept in a secured location that is accessible only by the 
designated person(s). Upon receipt, the designee must update the IMP accountability records, 
including records of IMP order, and maintain and store the records in a secure location. The 
CRA will review the records at the monitoring visits. 
 
Details regarding the accountability records are provided in the study Investigational Medicinal 
Product (IMP) Manual. 
 
6.4 
Storage of Investigational Medicinal Product 
The IMP will be shipped directly either from Mesoblast or a designated central distributor to the 
cell processing technologist in the Cell Processing Laboratory at the study site. The IMP will be 
shipped to the site in the vapor phase of a liquid nitrogen cryoshipper. The IMP will be stored in 
the vapor phase of a secured liquid nitrogen freezer where access to the area is strictly limited to 
the Cell Processing Laboratory personnel. The IMP will be appropriately identified and 
segregated from other products. Details regarding the storage, handling, and preparation of the 
IMP are provided in the study IMP manual. 
 
6.5 
Destruction of the Investigational Medicinal Product 
Partially used IMP will be discarded according to the study site’s destruction policy, and the 
discarding will be recorded in the accountability log. 
 
Local or institutional regulations may require immediate destruction of any unused IMP for 
safety reasons. In these cases, it may be acceptable for the investigational site staff to destroy 
unused IMP before a monitoring inspection, provided that source document verification is 
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of IMP that was shipped, dispensed, returned and destroyed. Written authorization must be 
obtained from the Sponsor at study start up before destruction of the IMP. 
 
The unused IMP provided by the Sponsor may be returned to the Sponsor. Where local or 
institutional regulations permit, destruction of IMP will occur at a location designated by the 
Sponsor. Written authorization must be obtained from the Sponsor prior to the return or 
destruction of the IMP. 
 
7. 
STUDY PROCEDURE 
Table 11 Schedule of Assessments and Procedures, 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 11 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. 
 
7.1 
Visit Schedule and Assessments 
7.1.1 
Screening Period 
Subjects will enter the screening period once the written informed consent has been signed. 
The following assessments and procedures will be performed at the screening visit: 
• Written informed consent and written authorization for use and disclosure of personal 
health information 
• Physical examination 
• Height and weight 
• Vital Signs (heart rate [HR], blood pressure [BP], temperature, and respiratory rate [RR]) 
• O2 saturation by pulse oximetry (SaO2/SAT) monitored by pulse oximetry. 
 
 
 
 
• Medical history, including any history of malignancies, and current condition 
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• Acute GVHD assessment (skin, lower GI, upper GI, liver) 
• Chronic GVHD assessment 
• CT or MRI scan of the chest, abdomen, and pelvis. Scans will contribute information 
with regard to baseline disease burden and will 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 contrast is acceptable even in the presence of GI 
GVHD. A previous CT scan or MRI may be used if performed up to 90 days prior to 
first IMP infusion or 24 hours after IMP infusion. 
NOTE: CT/MRI scans are optional and Investigators may choose to omit CT/MRI scans 
at their own discretion, provided the rationale for omission is documented in the source 
documents. 
• 12-lead electrocardiogram 
• Urinalysis 
• Laboratory assessments 
o Hematology (including viral screening, please see Table 12 for details) 
o Serum chemistry (including hsCRP, please see Table 12 for details) 
o ESR (local lab) 
 
 
• Karnofsky/Lansky performance assessment (see Appendix 4) 
• Serum pregnancy test for female subjects of childbearing potential ( ≥10 years of age) 
(see Appendix 6 for guidance on childbearing potential and pregnancy testing) 
• Pediatric Quality of Life Inventory™ (PedsQL™; Appendix 1 and Appendix 2) and the 
pediatric global health-related quality of life (HRQOL) Parent Proxy Report 
(Appendix 3) 
• Adverse event (AE) assessment. 
 
7.1.2 
At Each Infusion Day 
IMP infusions will be given to subjects who have signed the informed consent form, completed 
screening, and been deemed eligible for inclusion in the study. Initial Treatment infusion of IMP 
must be given within 4 days after signing of informed consent. Infusions of IMP must be given 
at least 3 days apart and no more than 5 days apart for any infusion. All 8 infusions must be 
administered by Day 28 (± 2 days). Continued Therapy infusions, when applicable, will be given 
once weekly (± 2 days). Flare therapy infusions, when applicable, will follow the same infusion 
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On the day of infusion, the following procedures/assessments will be performed: 
• Vital Signs (heart rate [HR], blood pressure [BP], temperature, and respiratory rate [RR]; 
please see Table 13 for time points) 
• Oxygen Saturation Monitoring: 
 
 
 
 
 
 
• Physical Examination 
• Pre-medication, consisting of hydrocortisone and diphenhydramine will be administered 
at least 30 minutes prior to the investigational agent 
 
 
 
 
 
 
 
 
• AE assessment 
• Concomitant medication assessment 
• Infusional toxicity assessment 
• IMP administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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o Detailed instructions on IMP preparation, handling, and administration may be found 
in the IMP Manual. 
 
7.1.2.1 Special Guidance for Investigators During IMP Infusion 
During IMP administration, infusion should be stopped if: 
1. The subject shows signs of respiratory compromise such as tachypnea, cyanosis, 
complains of shortness of breath, etc. regardless of the oximetry reading. 
2. SaO2/SAT decreases 
 
 
 
 
3. IMP infusion may be stopped at the discretion of the Investigator if there is an AE that 
the Investigator believes is related to the IMP, if there is an issue with IMP infusion, or 
the subject withdraws consent. 
 
If the toxicity evaluation during an infusion resulted in a worsening of a subject’s respiratory 
functioning by one or more grades (per the Common Toxicity Criteria for Adverse Events 
[CTCAE] assessment criteria, Table 14, Section 8.1.3) in comparison to the pre-infusion status, 
and the respiratory status did not return to baseline levels after symptomatic treatment, the 
Investigator must contact the Medical Monitor in order to discuss each specific case and 
determine whether the subject will be precluded from additional IMP infusions. 
 
No other medications should be given during the investigational agent infusion unless 
determined medically necessary by the Investigator. 
 
7.2 
Efficacy Assessments 
7.2.1 
GVHD Assessments 
GVHD assessments will be performed weekly, from Day 14 (±2 days) until Day 100 
(±7 days). During assessment weeks in the Initial Therapy period, the assessments must be 
performed after infusion of the 2nd dose of remestemcel-L for that week (or after the 1st dose of 
remestemcel-L during Continued Therapy). The weekly assessment visits should be conducted 
at least 24 hours after the most recent remestemcel-L infusion. These weekly GVHD 
assessments will be used to assess the GVHD status according to the definitions which are 
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Rescue therapy may be administered if necessary. If new GVHD medication(s) are administered 
as rescue therapy based on the assessment(s), no further remestemcel-L infusions will be 
allowed. Subjects will otherwise remain in the study regardless of response and will continue to 
be evaluated per the assessment schedule. 
 
Progression of disease is defined as deterioration of GVHD by at least one organ system by one 
organ stage or more from screening/baseline assessment up to Day 28 and from the most recent 
prior assessment from Day 28 to Day 100. Progression is not defined as ‘mixed response’ 
according to the definitions described above in Table 4. 
 
7.2.2 
Therapy Assessments 
Therapy assessments will be performed at each study visit after Day 0. Assessments must be 
after the 2nd dose of remestemcel-L is administered for each assessment week of the Initial 
Therapy period (or after the 1st dose of remestemcel-L during Continued Therapy). A schedule 
of the planned assessments is detailed in Table 11. 
 
Day 28 Therapy Assessment: 
A therapy assessment will be performed on Day 28 (±2 days) to determine treatment response 
and whether a subject will be provided Continued Therapy. The Day 28 therapy assessment 
must be at least 24 hours after the last dose of remestemcel-L is administered. Continued 
Therapy will be allowed for subjects according to their response to treatment, as described in 
Section 4.1.4.3. 
 
Day 56 Assessment of Response to Continued Therapy 
A therapy assessment will be performed on Day 56 (±2 days) for all subjects. The Day 56 
therapy assessment must be at least 24 hours after the last dose of remestemcel-L is administered 
for subjects receiving Continued Therapy, in order to determine treatment response to the 
Continued Therapy. 
 
Ongoing GVHD assessments will be performed to assess the subjects’ eligibility for flare 
treatment in accordance with Section 4.1.4.4. 


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7.3 
Safety Assessments 
All AEs, including those considered to have a causal relationship to the IMP, will be collected 
weekly at each assessment time point. AEs collected will consist of both solicited and events 
voluntarily reported by the subjects. 
 
Infusional toxicity will be evaluated at each remestemcel-L administration from the start of 
infusion to two hours after the start of IMP administration 
 
Measurement of all clinical parameters should be performed as described in Table 12. Standard 
instructions for determining these parameters are provided in the following sections. 
 
7.3.1 
Physical Examination 
A physical examination, including but not limited to a targeted examination for evidence of AEs, 
will be performed at Screening, Day 0, and at each weekly visits from Day 14 (±2 days) until 
Day 100 (±7 days). 
 
Information about physical examinations must be available in the source documentation at the 
study site. Significant findings that are present prior to the start of the study drug must be 
included in the relevant CRF on medical history/current medical conditions. Significant new 
findings made after the start of the study drug that meet the definition of an AE or SAE must be 
recorded on the Adverse Event CRF. 
 
7.3.2 
Vital Signs 
Measurements of vital signs (BP, HR, respiratory rate, temperature, and oxygen saturation) 
should be assessed at Screening, Day 0, and at each weekly assessment from Day 14 
(±2 days) through Day 100 (±7 days). Manual or automated procedures for obtaining BP are 
acceptable as long as the same method and same arm are used throughout the study. 
Measurements of vital signs will include sitting systolic blood pressure (SBP), diastolic blood 
pressure (DBP), heart rate (HR), oxygen saturation (SpO2, pulse oximetry), 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 
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Any clinically significant findings in vital sign measurements compared with baseline 
measurements should be recorded as an AE. 
 
7.3.3 
Height and Weight 
At the screening and end of study visits, height and weight should be measured. The weight 
measurement at Screening will be used to determine the dose of IMP to be used throughout the 
subject’s treatment period. 
 
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 
with the child 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. 
 
7.3.4 
Electrocardiogram (ECG) 
Electrocardiogram (ECG) will be performed at screening and at the End of Study/Day 100 
(±7 days) to assess any changes in cardiac physiology. 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. 
 
All ECG tracings must be (1) reviewed by a medically qualified member of the study team, 
(2) annotated to indicate any clinical finding, and (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 AE, it must be entered in the AE CRF. 
 
Heart rate, PR, QRS and QT durations should also be noted on the CRF along with the ECG 
parameters. 
 
7.3.5 
Adverse Events 
All AEs, including those considered to have a causal relationship to the IMP, will be collected 
weekly at each assessment time point. AEs collected will consist of both solicited and events 
voluntarily reported by the subjects. 


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7.3.6 
Assessment of Infusional Toxicity 
A theoretical risk of decreased respiratory function during the infusion exists, though to date, no 
infusional toxicities have been reported. Infusional toxicity will be evaluated by continuously 
monitoring the subject’s vital signs and SaO2/SAT via pulse oximetry from investigational agent 
administration through two hours after starting infusion. 
 
7.3.7 
Pregnancy Tests 
A serum pregnancy test will be performed by the site personnel for all female subjects of 
childbearing potential (≥10 years of age) at screening. At post-screening visits, a urine dipstick 
test will be performed for all female subjects of childbearing potential (≥10 years of age) as per 
Table 10. A positive dipstick test would require a serum sample to be sent to the central 
laboratory for confirmation. Pregnancy test dipsticks will be provided to the sites before study 
initiation. Details on pregnancy testing requirements are located in Appendix 6. 
 
7.3.8 
Clinical 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. Collection for local labs should be performed for all subjects at screening. If the 
age/weight of the subject permits, collection for central labs should also be performed at 
screening, in addition, in order to facilitate comparison of later samples sent to the central lab. If 
age/weight of the subject does not allow for this additional blood volume, then local labs at 
screening will serve as baseline labs. The laboratory tests to be performed for subjects in this 
study are listed in Table 12. 
 
If necessary, laboratory assessments may be performed by a laboratory other than the designated 
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 AE on the CRF. The 
reported AE should indicate the underlying abnormality or diagnosis (e.g., renal insufficiency) as 
opposed to the observed deviation in laboratory results (e.g., elevated creatinine) if in fact the 
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7.3.9 
Assessment of Ectopic Tissue Formation (optional per Investigator’s discretion) 
To detect any ectopic tissue formation, a radiologist and an Investigator at each study site will 
compare the CT/MRI scan, if collected at screening, with the CT/MRI scan performed at study 
end to determine if there is ectopic tissue formation. The same method of radiologic scan should 
be used for both evaluations. If the formation of ectopic tissue is suspected, further evaluation 
may be indicated, which could include positron-emission tomography (PET) scanning and 
possibly biopsy. 
 
With consideration of the low incidence of ectopic tissue formation from the safety data, the risk 
of high radiation exposure from computed tomography (CT) scans, the required administration 
of contrast agents, and the potential need for anesthetics in an ailing pediatric subject population, 
Investigators may choose to omit CT/MRI scans at their own discretion, provided the 
rationale for omission is documented in the source documents. 
 
7.4 
Long-Term Safety and Efficacy Follow-Up 
Long-term efficacy and safety assessments will be performed at Days 56 and 100. At Day 56 
(±2 days), a GVHD and remestemcel-L therapy assessment will be performed to determine 
whether subjects show response to Continued and/or Flare Therapy, when applicable. At 
Day 100 (±7 days), assessments of GVHD grade and survival will be determined. 
 
In addition, an extension study under a separate protocol (MSB-GVH002), subsequent to the 
present study, is also planned in order to capture health outcomes and safety data out to Day 180. 
 
7.5 
Missing or Delayed Study Visits 
Every effort should be made to ensure compliance with prescribed study visits. Missing of study 
visits is generally not permitted. However, in exceptional situations and with the Sponsor’s 
approval, visits may be postponed. 
 
7.6 
Subject Demographics and Other Baseline Characteristics 
Demographic data will include: 
• Gender 
• Age 
• Race and ethnicity 
• Smoking Status (Never Smoked, Current Smoker, Previous Smoker) 
• Weight 




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7.8 
Background, First-Line, Second-Line, and Concomitant Medication 
If an agent used for prophylaxis of aGVHD is discontinued and restarted prior to initiation of 
corticosteroids to treat aGVHD, it is considered a prophylactic agent. If the agent is restarted 
after initiation of corticosteroids to treat aGVHD, it would be considered a second-line agent. 
 
7.9 
Concomitant Medication and Supportive Therapy 
Information on all concomitant medications will be collected for this study, including 
information on all concomitant therapy to treat aGVHD. 
 
7.9.1 
Standard of Care for aGVHD 
All enrolled subjects will receive institutionally defined standard of care (i.e., maintenance of 
steroid treatment and other prophylactic treatment for aGVHD). In addition, investigators should 
provide standard of care for prevention and treatment of viral infections, particularly if there is 
evidence of viral reactivation. In some cases, such as those involving adenoviral treatment or 
where no other approved treatment is available, patients may be treated with experimental agents 
at the Investigator’s discretion. However, if a subject begins other second-line therapy for 
GVHD (e.g., anti-TNF or anti-IL-6 agents) within the period of Initial and Continued Therapy 
(through Day 56, if applicable), he or she would be considered to have failed treatment and 
would be ineligible to receive any further remestemcel-L therapy upon receiving the other 
second-line GVHD therapy. 
 
7.9.2 
Concomitant Medications 
Information on all concomitant medications will be collected for this study, including 
information on all concomitant therapy to treat aGVHD. 
 
Subjects may continue to be treated with a stable dose of systemic steroid therapy until subject is 
able to be tapered following initiation of remestemcel-L (Day 0). Subjects may also continue 
any prior therapy used for prophylaxis at a stable regimen from baseline. No other GVHD 
medications are to be introduced to subjects during the initial 28 days post remestemcel-L 
administration unless disease has progressed. 
 
If a subject begins other second-line GVHD therapy within the period of Initial and Continued 
Therapy (through Day 56, if applicable), he or she would be considered to have failed treatment 
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second-line GVHD therapy. However these subjects would remain on the study for safety 
follow up. 
 
Second line agents to treat GVHD will be coded using the World Health Organization dictionary 
(latest available version) and presented by preferred term for GVHD second line agents based on 
reported drugs for GVHD treatment. 
 
7.9.3 
Steroid Taper 
If improvement in GVHD (CR or PR) is observed for a period of 3-5 days and after at least two 
doses of remestemcel-L, the dosing of methylprednisolone or equivalent may be tapered. 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 5, with the goal of discontinuing steroid by 
10 weeks after initiating taper. 
 
7.9.4 
Escalating of Steroid Therapy 
Protocol guidelines for escalating steroid 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 steroid therapy prior to Day 28 does not constitute withdrawal of a subject from the 
study. If escalation of steroid therapy occurs, the subject is to continue on the study and receive 
all treatments and assessments per protocol. If second line agents are added, the subject would 
remain on study for safety follow up and would not receive any further remestemcel-L treatment. 
 
7.9.5 
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. 


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8. 
SAFETY GUIDANCE 
8.1 
Definitions 
8.1.1 
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 


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• 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. 
 
Recording of 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. 
 
8.1.2 
Serious Adverse Event (SAE) (Immediately Reportable to the Sponsor) 
An SAE is any AE that meets any of the following criteria: 
• Fatal (i.e., the AE actually causes or leads to death) 
• Life threatening (i.e., the AE, in the view of the Investigator, places the subject at 
immediate risk of death) 
o This does not include any AE that, had it occurred in a more severe form or was 
allowed to continue, might have caused death. 
• Requires or prolongs inpatient hospitalization 
• Results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions) 
• Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study 
drug 
• Significant medical event in the Investigator's judgment (e.g., may jeopardize the subject 
or may require medical/surgical intervention to prevent one of the outcomes listed 
above). 
 
8.1.3 
Severity 
A clinical determination will be made of the severity of an AE. The terms “severe” and 
“serious” are not synonymous. Severity is a description of the intensity of the manifestation of 
the AE and is distinct from seriousness, which implies a subject outcome. Severity will be 
assessed according to the US National Cancer Institute (NCI) Common Terminology Criteria for 
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9. 
REPORTING ADVERSE EVENTS 
9.1 
Procedures for Reporting Adverse Events and Serious Adverse Events 
Any AE occurring after a subject has signed the informed consent should be recorded on the 
appropriate CRF page. 
 
Any SAE (as described in Section 8.1.2) 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 (QLS). SAE 
reporting will originate in the electronic data capture (EDC) system and an email will be 
sent to individuals with designated responsibility for safety. Primary and secondary 
cause(s) of death will be recorded on the eCRFs for SAEs that are fatal. 
• 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 If the EDC is not available, email the SAE form to the QLS safety mailbox: 
 
• Provide copy of all relevant source documents, including medical history, and 
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 
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9.2 
24-Hour Urgent Medical Contact 
A Quintiles Medical Advisor is available for 24/7 urgent contact in this study.  If the Quintiles 
Medical Advisor is not able to provide 24/7 services for a period longer than 2 hours (e.g. for 
international business travel) or during vacations, adequate medical back-up with documented 
training on the protocol and experience with the therapeutic area will be arranged and 
communicated. The system of 24/7 coverage ensures that a qualified medical advisor is 
available for advice within a safe and reasonable time frame. 
 
The following additional numbers are also available for 24/7 urgent contact: 
 or 
 
 
9.3 
Procedures for Reporting Pregnancies 
All pregnancies that occur during the study are to be reported immediately to the individual 
identified in the clinical study personnel contact information section 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), in addition to the Pregnancy Form, a separate SAE form must be 
provided as described in Section 9. 
 
9.4 
Laboratory Test Abnormalities 
Laboratory test results will appear on laboratory reports that are submitted directly from the 
central laboratory. Local laboratory results should be recorded on the CRF, if applicable. 
 
Any laboratory result that fulfills the criteria for an SAE should be reported as both an SAE and 
as an AE in the CRF. 
 
Any treatment-emergent abnormal laboratory result that is clinically significant should be 
recorded as a single diagnosis in the CRF. A treatment-emergent 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). 


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These conditions will apply to any protocol- and non-protocol- specified safety and efficacy 
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. 
 
9.5 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Ethics Committees 
The Sponsor will promptly evaluate all AEs against cumulative product experience to identify 
and expeditiously communicate possible new safety findings to investigators, IRBs, IECs, and 
applicable health authorities based on applicable legislation. 
 
To determine reporting requirements for single AE 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 allowance for upgrading by the Sponsor as needed. 


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10. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
10.1 
Study Design and Randomization 
This is an open-label single-arm study. No randomization will take place. All enrolled subjects 
will be treated with remestemcel-L. 
 
10.1.1 
Sample Size and Power 
The primary objective of this trial is to confirm efficacy of remestemcel-L in improving Day 28 
OR rate within the full analysis set (FAS) population. 6 
 
For assessment of efficacy, an effect size of 20%, which has been deemed clinically meaningful 
based on discussions with clinical experts on aGVHD, was used to calculate the null hypothesis. 
The null hypothesis was calculated using 45% OR, a rate that is 20-points lower than the 
anticipated 65% OR rate to remestemcel-L. This estimated 45% response rate as the null 
hypothesis is further supported by data showing comparable Day 28 OR rates for historical 
populations of aGVHD patients treated with standard of care. 6,16 
 
 
 
 
 
 
 
 
 
In this study, a 28-day OR rate for a subject population treated only with steroids was 
conservatively anticipated to be 65%, 
 
 Hence, p=0.65 was chosen as the alternative 
hypothesis. 
 
Accordingly, the null and alternative hypotheses are as follows: 
H0: p = 0.45 
vs. 
Ha: p ≠ 0.45 
 
Sample size was determined using the East 6.0 software. The hypothesis test uses a normal 
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10.2 
Statistical Analysis Plan 
A Statistical Analysis Plan (SAP) will be prepared prior to Database Lock (DBL) containing 
details of the statistical analyses and data-handling rules planned for this trial. Post-DBL 
changes to the SAP will be documented in the Clinical Study Report. An overview of main 
methods is given below. 
 
10.2.1 
General Statistical Considerations: 
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 95% 
confidence level. 
 
The baseline value for a variable is defined as the last non-missing observation taken prior to or 
on the first dose date of study treatment. By this definition of baseline, post-baseline is defined 
as data collected after first infusion (complete or partial) of study treatment. Data collected at 
unscheduled time points will not be summarized at the unscheduled time points, but will be 
considered as for baseline. 
 
The first dose date will be considered the ‘Study Day 0’. The study day, the actual day relative to 
start of treatment, will be calculated from Study Day 0. 
 
The primary efficacy analysis will be based on the FAS population. Analyses of the mFAS and 
PP populations will be used to assess sensitivity and thus will be considered supportive. 
 
All statistical tests will be two-sided at the alpha=0.05 level of significance. Confidence 
Intervals will be two sided at the 95% level. 
 
10.3 
Analysis Populations 
10.3.1 
Full Analysis Set (FAS) 
This is a single-arm study with no randomization after screening. All subjects who provided 
informed consent, were screened and found eligible to enter the study will belong to the FAS 
population. The FAS will be used for the primary efficacy analysis. Secondary efficacy analyses 
will also be performed on the FAS population. 


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10.3.2 
Modified Full Analysis Set (mFAS) 
The mFAS is all subjects who provided informed consent, were screened and found eligible to 
enter the study, however, were treated with IMP stored in cryogenic vials. Primary and 
secondary efficacy analyses will also be performed on the mFAS population. 
 
10.3.3 
Safety Population 
The safety population will include all FAS subjects who receive at least one dose of study 
treatment (complete or partial). 
 
10.3.4 
Per-Protocol (PP) Population 
The per-protocol (PP) population will include all subjects who had no major protocol violations 
during the study. In general, not meeting inclusion criteria or meeting any exclusion criteria 
would be assessed as major protocol violations. 
 
The primary efficacy analysis will be repeated as a sensitivity analysis on the mFAS and PP 
populations. The key secondary efficacy analyses will be repeated for the mFAS and PP 
populations for Overall Survival at Day 100 post initiation of remestemcel-L therapy. The 
primary and secondary efficacy analyses performed on the mFAS and PP populations will be 
considered supportive. 
 
10.4 
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. 


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10.5 
Efficacy Analysis 
10.5.1 
Primary Efficacy Endpoint 
Overall Response (OR) at Day 28 
OR at Day 28 to remestemcel-L treatment is the primary efficacy endpoint. If a subject dies 
before Day 28 or if additional second-line treatment was required before Day 28, then the 
Day 28 response will considered “No Response” regardless of the actual response reported on 
the Day 28 assessment form or the end-of-trial form. For subjects enrolled but not treated, the 
Day 28 response will also be considered “No Response”. If a subject needs to withdraw from the 
study because of an SAE or because of need for palliative care due to a lack of GVHD response 
and has completed a 28 day end point assessment, the data from the 28-day assessment will be 
used. 
 
Missing data for the primary endpoint will be imputed non-responders. No other imputation is 
planned, as specified in the SAP. 
 
A hypothesis test will be performed to assess whether the percentage of responders is statistically 
significantly different from the historical control percentage of 45%. 
 
10.5.2 
Secondary Efficacy Endpoints 
10.5.2.1 Overall Survival at Day 100 post initiation of remestemcel-L therapy 
Survival will be assessed from initial remestemcel-L treatment to the last date of assessment. 
Since the trial period is 100 days, survival information will be censored at the 100 day time 
point. 
 
Data-handling rules taking account of visit windows for ascertaining survivor/non-survivor status 
at Day 100 will be detailed in the Statistical Analysis Plan (SAP). 
 
Percentages of survivors and deaths will be based on all subjects, including those with missing 
survival information for the lost to follow-up or withdrawal. 
 
The association between Day 28 OR and survival at Day 100, and between Day 28 VGPR and 
survival at Day 100, 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 100 survival Kaplan-Meier curves will be plotted by Day 28 responder and non-responder 
groups, and differences between these groups will be tested for a statistically significant 


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difference using the log-rank test. The odds ratio for survival at Day 100 given responder status 
at Day 28 will be presented and tested for statistical significance (whether statistically 
significantly greater than 1). 
 
10.5.2.2 Rate of Very Good Partial Response (VGPR) at Day 28 post initiation of 
remestemcel-L therapy 
The rate of VGPR, defined in Table 4, will be described.  The number and proportion of VGPR 
responders, non-responders, and missing values, will be summarized. The two sided 95% 
confidence intervals will be presented for these estimates. 
 
10.5.2.3 Rates of OR and VGPR at Day 100 post initiation of remestemcel-L therapy 
The number and percentage of responders at Day 100 and for each endpoint will be summarized. 
Confidence Intervals at the 95% level (two sided) will be presented for estimates of proportions. 
 
10.5.2.4 Rates of OR and VGPR at Days 28 and 100 post initiation of remestemcel-L 
therapy stratified by organ involvement 
The rates of OR and VGPR at Day 28 and at Day 100 will be reported by skin, gut (lower GI), or 
liver involvement at baseline. Confidence Intervals at the 95% level (two sided) will be 
presented for estimates of proportions. 
 
10.5.2.5 Rates of OR and VGPR at Days 28 and 100 post initiation of remestemcel-L 
therapy stratified by individual subject organ involvement 
The rates of OR and VGPR at Day 28 and Day 100 will be reported by the mutually exclusive 
Skin-only and “Not skin-only” categories. Confidence intervals at the 95% level (two sided) will 
be presented for estimates of proportions. 
 
10.5.2.6 Rates of OR and VGPR at Days 28 and 100 post initiation of remestemcel-L 
therapy stratified by baseline aGVHD grade 
The number and percentage of responders at each time point and for each endpoint will be 
summarized by baseline GVHD grade. Two-sided confidence intervals at the 95% level will be 
presented for estimates of proportions. 


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10.5.2.7 Overall survival at Day 100 post initiation of remestemcel-L therapy stratified by 
baseline aGVHD grade and organ involvement 
The number and percentage of survivors at Day 100 from first infusion date will be summarized 
by baseline grade and organ involvement. Confidence Intervals at the 95% level (two sided) will 
be presented for estimates of proportions. 
 
10.5.2.8 Rate of aGVHD progression requiring additional GVHD medications/ therapy 
through Day 100 post initiation of remestemcel-L therapy 
The incidence rate of GVHD progression requiring additional GVHD medications or therapy 
will be summarized by number and proportion of subjects. Two-sided confidence intervals at the 
95% level will be presented for estimates of proportions. 
 
10.5.2.9 Effect of additional remestemcel-L therapy after Day 28 on rate of OR and VGPR 
at Days 56 and 100 post initiation of remestemcel-L therapy 
Side-by-side shift tables, for response at Day 56 and response at Day 100 versus response at Day 
28, summarizing the effect of additional IMP therapy, will be presented. 
 
Efficacy analyses will include a summary of aGVHD grade at baseline, Day 28, Day 56 and Day 
100. Shift tables in aGVHD organ stages from baseline to Day 28 will be presented. Shift tables 
for organ stages will also be presented by organ involvement. Shift tables will also be presented 
for skin-only stages and separately for “All Others” (that is, excluding skin-only). Response by 
organ for each of these groups (by individual organ involvement, skin-only and all-others) will 
also be summarized as improving, stable or progressing, together with the number of deaths in 
each case. 
 
As sensitivity analyses, survival will also be calculated from the day of transplant and from the 
day of diagnosis of aGVHD to the last date of contact. For all survival data, Kaplan-Meier 
survival curves will be generated and relevant subgroups will be compared using the log-rank 
test. Kaplan-Meier curves will also be generated by number of organs involved, and by number 
of infusions (categorized). 


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10.6 
Safety Data Analysis 
10.6.1 
Primary Safety Endpoints 
The primary safety parameters to be assessed include: 
1. Adverse events 
2. Serious adverse events 
3. Infusional toxicity 
4. Formation of ectopic tissue foci. 
 
Safety analyses will be performed in a descriptive fashion using the Safety population. 
 
10.6.2 
Adverse Events and Serious Adverse Events 
All 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. 
 
Serious adverse events, grouped by organ system and preferred term, will be summarized. 
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10.6.3 
Infusional Toxicity 
The number and percent of subjects with infusional toxicity will be summarized by System 
Organ Class (SOC), High Level Term (HLT), and Preferred Term (PT) based on the SAE report 
form with PT of infusion related reaction as designated by the Investigator. AEs which are 
infusional toxicity events will be summarized. 
 
10.6.4 
Other Safety Analyses 
10.6.4.1 Study Drug Exposure 
The total number of study drug infusions that subjects received and the extent of exposure will 
be summarized with descriptive statistics (n, mean, standard deviation [SD], median, minimum, 
and maximum). The number of subjects receiving fewer or greater than 8 study drug infusions 
will be summarized. 
 
10.6.4.2 Survival 
The number of subjects alive, dead, and lost to follow-up or withdrawal 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. 
 
10.6.4.3 Handling of Missing Values 
Missing data for the primary endpoint will be treated as non-responders. Details regarding the 
handling of missing values for all other endpoints will be detailed in the MSB-GVHD001 
Statistical Analysis Plan (SAP). 
 
10.6.4.4 Subgroups 
 


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11. 
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 the Medidata Rave System and eCRF. 
 
The site is expected to respond to all SAE queries within 24 hours and all others 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. 
 
11.1 
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 eCRF, using the most up-to-date version of the Medical Dictionary for Regulatory 
Activities (MedDRA) 64 terminology for AEs and diseases and for treatments and surgical and 
medical procedures. 
 
12. 
STUDY COMMITTEES 
12.1 
Independent Data and Safety Monitoring Board (DSMB) 
A data and safety monitoring board (DSMB) will be set up for the trial to oversee the 
management of the trial, review the overall safety data, and propose appropriate actions if 
necessary. The independent DSMB will consist of physicians with expertise in oncology, stem 
cell transplantation, and conduct of clinical trials and an independent biostatistician. The 
composition of the DSMB and its specific working procedures will be described in a separate 
charter. This charter will clearly specify attendees, rules and responsibilities, procedures, review 
meeting schedule and the data to be analyzed. 
 
The DSMB will follow the DSMB charter and data analyses will be done according to the 
DSMB charter. 
 
In addition to the regular monitoring of safety, one interim analysis is planned for this study as 
described in Section 10.1.3. The DSMB will review the data for futility and may make a 
recommendation on whether to stop the trial for futility, as a result of this interim analysis. 


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12.2.2 
Follow-up of Safety and Health Outcomes 
An extension study (MSB-GVHD002), subsequent to the present study, under a separate 
protocol is being conducted in order to capture health outcomes and safety data out to Day 180. 
Subjects may be presented with the IRB/EC approved consents for MSB-GVHD001 and MSB- 
GVHD002 simultaneously at the time of consent onto this protocol. 
 
13. 
LAWS, REGULATIONS, AND ETHICS 
13.1 
Local Regulations/Declaration of Helsinki 
This clinical study shall be conducted in full compliance with current material and relevant laws 
and regulations and the Investigator 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 Guideline 70 and with the ethical principles of the “Declaration 
of Helsinki” 71 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. 72 


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13.2 
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 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 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. 
 
13.3 
Institutional Review Board/ Ethics Committees (IRB/EC) 
This protocol and any modifications as well as appropriate consent procedures, any 
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 an 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. 


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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. 
 
13.4 
Protocol Adherence 
Investigators will ensure that due diligence is applied in order to avoid protocol deviations or 
violations as defined below. All significant protocol deviations and violations will be reported to 
the IRB/EC in accordance with IRB/EC requirements. All significant protocol deviations and 
violations will be recorded and reported in the CSR. 
 
13.5 
Protocol Deviation 
A protocol deviation is defined as an intentional or unintentional change or non-compliance with 
a research protocol. 
 
14. 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Requests from investigators to modify the protocol for ongoing studies will be considered only 
by consultation between an appropriate representative of the Sponsor and the Investigator. 
Protocol modifications must be prepared by a representative of the Sponsor 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, except for changes necessary to 
eliminate an immediate hazard to trial subjects, or when the change(s) involves only logistical or 
administrative aspects of the trial (e.g. change in monitor[s], change of telephone number[s]). 
 
15. 
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. 


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15.1 
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 9. 
 
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 investigate futility data during interim analysis review. The DSMB 
will then determine whether enrollment should be continued, continued with modification, 
suspended, or terminated, and their decision will be communicated to the Sponsor. Please refer 
to Section 10.1.3 and the SAP. 
 
16. 
STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING 
16.1 
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 
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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. 
 
16.2 
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. 
 
16.3 
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. 
 
16.4 
Electronic Case Report Forms 
Data for this study will be captured via an Electronic Data Capture (EDC) system by 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 enrolled subject. For each screen-failed subject, the 
reason for screen failure will be collected in the Completion eCRF along with the corresponding 
screen failure reason. The entire subject casebook of data must be reviewed and electronically 
signed by the Investigator or by an authorized delegate from the study staff. This also applies to 
records for those enrolled subjects who fail to complete the study. If a subject withdraws early 
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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. 
 
17. 
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. 
 
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. 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. 
 
18. 
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. 
 
19. 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
19.1 
Right to Publish 
Subject to the restrictions in this Article 18 and processes described in this Section 19, an 
Investigator may individually communicate, orally present, or publish in scientific journals or 
other scholarly media, the study results. The Sponsor retains the title and all rights to, as well as 
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agreement according to guidelines published by the International Committee of Medical Journal 
Editors (ICMJE). 73 
 
19.2 
Publication Steering Committee 
A Publication Steering Committee (the “Committee”) appointed by Sponsor will be responsible 
for the creation, review and submission of publications and presentations relating to the study 
(i.e. primary manuscript on design, baseline data, mortality, efficacy and safety data) and sub- 
study, 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 Committee. Prior approval by the Committee must be obtained 
before any publication or public display of the Study results, alone or in aggregate. 
 
19.3 
Procedure 
The 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 the 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. The Sponsor shall provide, in writing, any comments to the Investigator 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 
such 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 
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19.4 
Multi-Center Study 
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 19. 
 
20. 
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 the Sponsor in a timely 
manner. Source documents supporting study-related data must be retained by the Investigator as 
previously described. 


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21. 
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4. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus 
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5. Jagasia M, Arora M, Flowers ME, et al. Risk factors for acute GVHD and survival after 
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11. Dignan FL, Clark A, Amrolia P, et al. Diagnosis and management of acute graft-versus- 
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12. Dignan FL, Amrolia P, Clark A, et al. Diagnosis and management of chronic graft- 
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13. Bacigalupo A. Management of acute graft-versus-host disease. British journal of 
haematology. 2007;137(2):87-98. 
14. Perez L, Anasetti C, Pidala J. Have we improved in preventing and treating acute graft- 
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15. Deeg HJ. How I treat refractory acute GVHD. Blood. 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. 
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17. Martin PJ, Schoch G, Fisher L, et al. A retrospective analysis of therapy for acute graft- 
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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 
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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 
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Marrow Transplantation. 2009;15(3):360-366. 
20. Gratwohl A, Hermans J, Apperley J, et al. Acute graft-versus-host disease: grade and 
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21. Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft-versus-host disease 
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22. Cahn JY, Klein JP, Lee SJ, et al. Prospective evaluation of 2 acute graft-versus-host 
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23. Rowlings PA, Przepiorka D, Klein JP, et al. IBMTR Severity Index for grading acute 
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24. Carpenter PA, Macmillan ML. Management of acute graft-versus-host disease in 
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4. 
26. Martin PJ, Bachier CR, Klingemann HG, et al. Endpoints for clinical trials testing 
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marrow transplantation : journal of the American Society for Blood and Marrow 
Transplantation. 2009;15(7):777-784. 
27. Inamoto Y, Martin PJ, Storer BE, Mielcarek M, Storb RF, Carpenter PA. Response 
endpoints and failure-free survival after initial treatment for acute graft-versus-host 
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28. Saliba RM, Couriel DR, Giralt S, et al. Prognostic value of response after upfront therapy 
for acute GVHD. Bone marrow transplantation. 2012;47(1):125-131. 
29. Pavletic SZ. Response as an end point in treatment trials for acute GVHD. Bone marrow 
transplantation. 2012;47(2):161-163. 
30. MacMillan ML, DeFor TE, Weisdorf DJ. The best endpoint for acute GVHD treatment 
trials. Blood. 2010;115(26):5412-5417. 
31. Levine JE, Logan B, Wu J, et al. Graft-versus-host disease treatment: predictors of 
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for Blood and Marrow Transplantation. 2010;16(12):1693-1699. 








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Appendix 5: Recommended Steroid Taper 
 
Below schemes for steroid tapering is for guidance only. A steroid taper rate of at least 10% of 
the dose per week, not exceeding 25% reduction of the dose per week is suggested. 
 
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-GVHD001 
Clinical Study Protocol 
Version 7.0 
CONFIDENTIAL 
Page 121 of 121 
Mesoblast 
 
 
 
Appendix 6: 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.