A Prospective Study of Remestemcel-L, Ex-vivo Cultured Adult Human Mesenchymal Stromal Cells, for the Treatment of Pediatric Participants Who Have Failed to Respond to Steroid Treatment for Acute Graft-Versus-Host Disease (aGVHD)

• Sponsor: Mesoblast, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02336230
• Collaborator: Quintiles, Inc. (Industry)
• Enrollment: 55
• Locations: 20
• Arm: 1
• Actual Duration (Months): 34.2
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Grade B aGVHD; Grade C aGVHD; Grade D aGVHD	Drug: remestemcel-L	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Single-arm, Prospective Study of Remestemcel-L, Ex-vivo Culture-Expanded Adult Human Mesenchymal Stromal Cells, for the Treatment of Pediatric Patients Who Have Failed to Respond to Steroid Treatment for Acute GVHD
• Actual Study Start Date: Jun 4, 2015
• Actual Primary Completion Date: Apr 9, 2018
• Actual Study Completion Date: Apr 9, 2018

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Remestemcel-L 2×10^6 MSCs/kg 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.

Drug: remestemcel-L; 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.

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (ORR) at Day 28 Post Initiation of Therapy [Day 28]

   ORR was defined as the percentage of participants who had achieved overall response. Overall response was defined as complete response (CR) plus partial response (PR) as per aGVHD response criteria. CR was defined as resolution of aGVHD in all involved organs. PR was defined as organ improvement of at least 1 stage without worsening of any other organ.

Secondary Outcome Measures

1. Overall Survival (OS) Rate at Day 100 Post Initiation of Therapy [Day 100]

   Overall survival rate was defined as percentage of participants who survived. OS was defined as the time to death from the start of drug therapy.

2. OS Rate at Day 100 Post Initiation of Therapy, Stratified by Responder Status at Day 28 [Day 100]

   Overall survival rate was defined as percentage of participants who survived. OS was defined as the time to death from the start of drug therapy.

3. OS Rate at Day 100 Post Initiation of Therapy, Stratified by Baseline aGVHD Grade [Day 100]

   OS rate was defined as percentage of participants who survived. OS was defined as the time to death from the start of drug therapy. Maximum severity of acute GVHD was assessed by using International Bone Marrow Transplant Registry (IBMTR) index. The severity index was defined as: Grade A (skin Stage 1: extent of rash <25%); Grade B (skin Stage 2: extent of rash 25 to 50% or liver Stage 1 to 2: total bilirubin 34 to 102 micromoles per liter [mcmol/L] or intestinal tract Stage 1 to 2: volume of diarrhea 550 to 1500 milliliters per day [mL/day]); Grade C (skin Stage 3: extent of rash > 50% or liver Stage 3: total bilirubin 103 to 255 mcmol/L or intestinal tract Stage 3: volume of diarrhea >1500 mL/day); Grade D (skin Stage 4: extent of rash bullae or liver Stage 4: total bilirubin >255 or intestinal tract Stage 4: volume of diarrhea severe pain and ileus).

4. OS Rate at Day 100 Post Initiation of Therapy, Stratified by Organ Involvement [Day 100]

   OS rate was defined as percentage of participants who survived. OS was defined as the time to death from the start of drug therapy. The data was summarized for organ involvement: skin only, lower GI only, and multi-organ.

5. OR Rate at Day 56 and 100 Post Initiation of Therapy [Day 56 and Day 100]

   OR rate was defined as the percentage of participants who had achieved overall response. Overall response was defined as CR plus PR as per aGVHD response criteria. CR was defined as resolution of aGVHD in all involved organs. PR was defined as organ improvement of at least 1 stage without worsening of any other organ.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Months to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Participant is diagnosed with Grade B-D acute GVHD requiring corticosteroid systemic therapy. The participant may have Grade C or D aGVHD involving the skin, liver, and/or 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. Participant has failed to respond to steroid treatment, with failure to respond defined as any Grade B-D [International Bone Marrow Transplant Registry (IBMTR) grading] aGVHD that shows progression within 3 days, or no improvement within 7 days of consecutive treatment with 2 mg/kg/day methylprednisolone or equivalent.

3. Participant must be able to be treated with remestemcel-L within 4 days of signing of informed consent.

4. Participants who have had persistent GI GVHD manifested by diarrhea with stool volume < 500 mL/kg/day (for participants >50 kg) or <30 mL/kg/day (for participants ≤50 kg). See GVHD Organ Severity Criteria (Table 2) for values in mL/m^2. In the absence of nausea or vomiting, participants could have been considered to have Grade B GVHD if:

5. other causes of diarrhea had been ruled out (eg, Clostridium difficile, adenovirus or cytomegalovirus [CMV] infection, or oral magnesium administration), and if

6. the low stool volume reflected the effects of fasting, narcotics, or antidiarrheal medications.

7. Participant must have adequate renal function as defined by a calculated creatinine clearance of >30 mL/min per 1.73 m^2. For participants 1 to 18 years of age, creatinine clearance is calculated using the Bedside Schwartz equation:

Glomerular filtration rate (GFR, in mL/min per 1.73 m^2) = (0.413 * height [cm])/serum creatinine (mg/dL)

For participants younger than 1 year of age, renal function is determined using the

Schwartz equation adjusted for this age group:

Creatinine clearance (mL/min per 1.73 m^2= (height [cm] x 0.45)/ (serum creatinine [mg/dL]).

1. Participant has a minimum Karnofsky/Lansky Performance Level of at least 30 at the time of study entry.

2. Participant (or legal representative where appropriate) must be capable of providing written informed consent.

3. Female participants of childbearing potential (≥10 years of age) are required to use a medically accepted method of contraception and to agree to continue use of this method for the duration of the study and for the follow-up time period. Acceptable methods of contraception include abstinence, barrier method with spermicide, intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, implanted, and injected) in conjunction with a barrier method.

4. Male participants with partners of childbearing potential must agree to use adequate contraception (barrier method or abstinence) during the study, including the follow-up time period.

5. The participant must be willing and able to comply with study requirements, remain at the clinic, and return to the clinic for the follow-up evaluation during the study period, as specified in this protocol.

Exclusion Criteria:

1. Participant has Grade B aGvHD with skin-only involvement.

2. Participant has received any second line therapy to treat aGVHD prior to screening.

3. Participant has received systemic agents other than steroids and prophylactic agents for primary treatment of aGVHD.

4. Participant 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 fractional inspired oxygen concentration (FiO2) of 28% via other delivery methods in order to sustain an O2 saturation of 92%.

5. Participant has any underlying or current medical or psychiatric condition that, in the opinion of the Investigator, would interfere with the evaluation of the participant including but not limited to uncontrolled infection, heart failure, or pulmonary hypertension.

6. Participant has received any stem cell agents (other than hematopoietic graft) during study participation or within 30 days prior to study entry. Previous use of irradiated granulocytes within 30 days is permitted.

7. Participant has received an HSCT transplant for a solid tumor disease.

8. Participant has had prior treatment with mesenchymal stem cells (MSCs), including remestemcel-L.

9. Participant shows evidence of severe (required treatment) hepatic veno-occlusive disease (VOD) or sinusoidal obstruction at screening.

10. Participant 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. Participant shows evidence of encephalopathy, as defined by a change in mental status since the onset of aGVHD.

12. Participant is a female who is pregnant, lactating, or is planning a pregnancy during study participation, or in the follow-up period.

13. Participant currently being treated for a solid tumor malignancy.

14. Participant has participated in any interventional clinical trial for an aGVHD therapeutic agent. However, in exceptional cases, experimental agents may have been administered to enrolled participants at the Investigator's discretion.

15. Participant has participated or is currently participating in any autologous and allogeneic stem cell or gene therapy study for the treatment of aGVHD. Participants participating in investigative protocols aimed at modification of the transplant graft (such as T-cell depletion) or aimed at modification of the conditioning regimen are allowed in the study.

16. Participant has a known hypersensitivity to dimethyl sulfoxide (DMSO) or to murine, porcine, or bovine proteins.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
2	Children's Hospital of Orange County	Orange	California	United States	92868
3	University of California at San Francisco	San Francisco	California	United States	94143
4	Children's Hospital Colorado Center for Cancer/Blood Disorders	Aurora	Colorado	United States	80045
5	Alfred I. DuPont Hospital for Children of the Nemours Foundation	Wilmington	Delaware	United States	19803
6	Miami Children's Research Institute	Miami	Florida	United States	33136
7	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
8	Children's Hospital of Michigan	Detroit	Michigan	United States	48201
9	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
10	Washington University	Saint Louis	Missouri	United States	63110
11	Columbia University Medical Center	New York	New York	United States	10032
12	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10174
13	Albert Einstein College of Medicine	New York	New York	United States	10467
14	Duke University Medical Center	Durham	North Carolina	United States	27705
15	Oregon University	Portland	Oregon	United States	97239
16	Medical University of South Carolina	Charleston	South Carolina	United States	29425
17	Texas Transplant Institute	San Antonio	Texas	United States	78229
18	Virginia Commonwealth University	Richmond	Virginia	United States	23284
19	Fred Hutchinson Cancer Research	Seattle	Washington	United States	98109
20	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Mesoblast, Inc.
• Quintiles, Inc.

Investigators

• Study Director: Christopher James, Mesoblast, Inc.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 8, 2018

More Information

Publications

None provided.

• Responsible Party: Mesoblast, Inc.
• ClinicalTrials.gov Identifier: NCT02336230
• Other Study ID Numbers: MSB-GVHD001
• First Posted: Jan 12, 2015
• Last Update Posted: Mar 17, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Mesoblast, Inc.: GVHD
• Additional relevant MeSH terms: Remestemcel-l

Study Results

Participant Flow

Arm/Group Title	Remestemcel-L 2×10^6 MSCs/kg
Arm/Group Description	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.
Period Title: Overall Study
STARTED	55
Full Analysis Set (FAS)	55
Safety Analysis Population	54
COMPLETED	42
NOT COMPLETED	13

Baseline Characteristics

Arm/Group Title	Remestemcel-L 2×10^6 MSCs/kg
Arm/Group Description	Participants were treated with IV remestemcel-L at a dose of 2×10^6 MSCs/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.
Overall Participants	55
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	7.3 (5.45)
Sex: Female, Male (Count of Participants)
Female	20 36.4%
Male	35 63.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	18 32.7%
Not Hispanic or Latino	36 65.5%
Unknown or Not Reported	1 1.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 5.5%
Asian	3 5.5%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	8 14.5%
White	31 56.4%
More than one race	10 18.2%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR) at Day 28 Post Initiation of Therapy
Description	ORR was defined as the percentage of participants who had achieved overall response. Overall response was defined as complete response (CR) plus partial response (PR) as per aGVHD response criteria. CR was defined as resolution of aGVHD in all involved organs. PR was defined as organ improvement of at least 1 stage without worsening of any other organ.
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

FAS included all participants who provided informed consent, were screened, and were found eligible to enter the study.

Arm/Group Title	Remestemcel-L 2×10^6 MSCs/kg
Arm/Group Description	Participants were treated with IV remestemcel-L at a dose of 2×10^6 MSCs/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.
Measure Participants	55
Number [percentage of participants]	69.1 125.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Remestemcel-L 2×10^6 MSCs/kg
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments	P-value was calculated from the binomial distribution under the assumption of a 0.45 success rate for the null hypothesis.
	Method	Binomial Distribution
	Comments

2. Secondary Outcome

Title	Overall Survival (OS) Rate at Day 100 Post Initiation of Therapy
Description	Overall survival rate was defined as percentage of participants who survived. OS was defined as the time to death from the start of drug therapy.
Time Frame	Day 100

Outcome Measure Data

Analysis Population Description

FAS included all participants who provided informed consent, were screened, and were found eligible to enter the study.

Arm/Group Title	Remestemcel-L 2×10^6 MSCs/kg
Arm/Group Description	Participants were treated with IV remestemcel-L at a dose of 2×10^6 MSCs/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.
Measure Participants	55
Number [percentage of participants]	74.5 135.5%

3. Secondary Outcome

Title	OS Rate at Day 100 Post Initiation of Therapy, Stratified by Responder Status at Day 28
Description	Overall survival rate was defined as percentage of participants who survived. OS was defined as the time to death from the start of drug therapy.
Time Frame	Day 100

Outcome Measure Data

Analysis Population Description

FAS included all participants who provided informed consent, were screened, and were found eligible to enter the study. Number analyzed is the number of participants with data available for given category.

Arm/Group Title	Remestemcel-L 2×10^6 MSCs/kg
Arm/Group Description	Participants were treated with IV remestemcel-L at a dose of 2×10^6 MSCs/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.
Measure Participants	55
Responders	86.8 157.8%
Non- Responders	47.1 85.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Remestemcel-L 2×10^6 MSCs/kg
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0032
	Comments	P-value was from a Cochran-Mantel-Haenszel (CMH) test stratified by baseline aGVHD grade.
	Method	CHM test
	Comments

4. Secondary Outcome

Title	OS Rate at Day 100 Post Initiation of Therapy, Stratified by Baseline aGVHD Grade
Description	OS rate was defined as percentage of participants who survived. OS was defined as the time to death from the start of drug therapy. Maximum severity of acute GVHD was assessed by using International Bone Marrow Transplant Registry (IBMTR) index. The severity index was defined as: Grade A (skin Stage 1: extent of rash <25%); Grade B (skin Stage 2: extent of rash 25 to 50% or liver Stage 1 to 2: total bilirubin 34 to 102 micromoles per liter [mcmol/L] or intestinal tract Stage 1 to 2: volume of diarrhea 550 to 1500 milliliters per day [mL/day]); Grade C (skin Stage 3: extent of rash > 50% or liver Stage 3: total bilirubin 103 to 255 mcmol/L or intestinal tract Stage 3: volume of diarrhea >1500 mL/day); Grade D (skin Stage 4: extent of rash bullae or liver Stage 4: total bilirubin >255 or intestinal tract Stage 4: volume of diarrhea severe pain and ileus).
Time Frame	Day 100

Outcome Measure Data

Analysis Population Description

FAS included all participants who provided informed consent, were screened, and were found eligible to enter the study. Number analyzed is the number of participants with data available for given category.

Arm/Group Title	Remestemcel-L 2×10^6 MSCs/kg
Arm/Group Description	Participants were treated with IV remestemcel-L at a dose of 2×10^6 MSCs/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.
Measure Participants	55
Grade B	50.0 90.9%
Grade C	82.6 150.2%
Grade D	73.1 132.9%

5. Secondary Outcome

Title	OS Rate at Day 100 Post Initiation of Therapy, Stratified by Organ Involvement
Description	OS rate was defined as percentage of participants who survived. OS was defined as the time to death from the start of drug therapy. The data was summarized for organ involvement: skin only, lower GI only, and multi-organ.
Time Frame	Day 100

Outcome Measure Data

Analysis Population Description

FAS included all participants who provided informed consent, were screened, and were found eligible to enter the study. Number analyzed is the number of participants with data available for given category.

Arm/Group Title	Remestemcel-L 2×10^6 MSCs/kg
Arm/Group Description	Participants were treated with IV remestemcel-L at a dose of 2×10^6 MSCs/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.
Measure Participants	55
Skin Only	78.6 142.9%
Lower GI Only	76.2 138.5%
Multi-organ (Any Combination)	70.0 127.3%

6. Secondary Outcome

Title	OR Rate at Day 56 and 100 Post Initiation of Therapy
Description	OR rate was defined as the percentage of participants who had achieved overall response. Overall response was defined as CR plus PR as per aGVHD response criteria. CR was defined as resolution of aGVHD in all involved organs. PR was defined as organ improvement of at least 1 stage without worsening of any other organ.
Time Frame	Day 56 and Day 100

Outcome Measure Data

Analysis Population Description

FAS included all participants who provided informed consent, were screened, and were found eligible to enter the study.

Arm/Group Title	Remestemcel-L 2×10^6 MSCs/kg
Arm/Group Description	Participants were treated with IV remestemcel-L at a dose of 2×10^6 MSCs/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.
Measure Participants	55
Day 56	58.2 105.8%
Day 100	69.1 125.6%

Adverse Events

Time Frame	From Baseline through 100 days of follow up
Adverse Event Reporting Description	All-cause Mortality: FAS included all participants who provided informed consent, were screened, and were found eligible to enter the study. Serious and Other (Non-serious) AEs: Safety Analysis Population included all participants who signed the informed consent form and received at least 1 dose of remestemcel-L.
Arm/Group Title	Remestemcel-L 2×10^6 MSCs/kg
Arm/Group Description	Participants were treated with IV remestemcel-L at a dose of 2×10^6 MSCs/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.
All Cause Mortality
	Remestemcel-L 2×10^6 MSCs/kg
	Affected / at Risk (%)	# Events
Total	13/55 (23.6%)
Serious Adverse Events
	Remestemcel-L 2×10^6 MSCs/kg
	Affected / at Risk (%)	# Events
Total	35/54 (64.8%)
Blood and lymphatic system disorders
Haemolytic uraemic syndrome	2/54 (3.7%)
Febrile neutropenia	1/54 (1.9%)
Haemolysis	1/54 (1.9%)
Pancytopenia	1/54 (1.9%)
Thrombotic microangiopathy	1/54 (1.9%)
Cardiac disorders
Cardiac arrest	1/54 (1.9%)
Cardiac failure	1/54 (1.9%)
Pericardial effusion	1/54 (1.9%)
Gastrointestinal disorders
Pneumatosis intestinalis	4/54 (7.4%)
Abdominal pain	1/54 (1.9%)
Diarrhoea	1/54 (1.9%)
Jejunal perforation	1/54 (1.9%)
Lower gastrointestinal haemorrhage	1/54 (1.9%)
Nausea	1/54 (1.9%)
Vomiting	1/54 (1.9%)
General disorders
Pyrexia	5/54 (9.3%)
Multiple organ dysfunction syndrome	5/54 (9.3%)
Asthenia	1/54 (1.9%)
Immune system disorders
Acute graft versus host disease	3/54 (5.6%)
Graft versus host disease in skin	2/54 (3.7%)
Graft versus host disease	1/54 (1.9%)
Infections and infestations
Staphylococcal infection	3/54 (5.6%)
BK virus infection	2/54 (3.7%)
Escherichia urinary tract infection	2/54 (3.7%)
Human herpesvirus 6 infection	2/54 (3.7%)
Pneumonia	2/54 (3.7%)
Sepsis	2/54 (3.7%)
Staphylococcal bacteraemia	2/54 (3.7%)
Adenovirus infection	1/54 (1.9%)
Cellulitis	1/54 (1.9%)
Clostridium difficile infection	1/54 (1.9%)
Enterococcal infection	1/54 (1.9%)
Epstein-Barr viraemia	1/54 (1.9%)
Fungaemia	1/54 (1.9%)
Fungal infection	1/54 (1.9%)
Gastroenteritis	1/54 (1.9%)
Lactobacillus infection	1/54 (1.9%)
Rotavirus infection	1/54 (1.9%)
Staphylococcal sepsis	1/54 (1.9%)
Investigations
Platelet count decreased	1/54 (1.9%)
White blood cell count decreased	1/54 (1.9%)
Metabolism and nutrition disorders
Dehydration	2/54 (3.7%)
Hyperglycaemia	1/54 (1.9%)
Hypermetabolism	1/54 (1.9%)
Metabolic acidosis	1/54 (1.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia recurrent	2/54 (3.7%)
Acute megakaryocytic leukaemia	1/54 (1.9%)
Nervous system disorders
Posterior reversible encephalopathy syndrome	2/54 (3.7%)
Somnolence	1/54 (1.9%)
Renal and urinary disorders
Acute kidney injury	1/54 (1.9%)
Cystitis haemorrhagic	1/54 (1.9%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure	5/54 (9.3%)
Acute respiratory distress syndrome	2/54 (3.7%)
Acute respiratory failure	2/54 (3.7%)
Respiratory distress	2/54 (3.7%)
Hypoxia	1/54 (1.9%)
Pleural effusion	1/54 (1.9%)
Pulmonary mass	1/54 (1.9%)
Vascular disorders
Capillary leak syndrome	1/54 (1.9%)
Hypertensive crisis	1/54 (1.9%)
Hypovolaemic shock	1/54 (1.9%)
Peripheral ischaemia	1/54 (1.9%)
Shock haemorrhagic	1/54 (1.9%)
Venoocclusive disease	1/54 (1.9%)
Other (Not Including Serious) Adverse Events
	Remestemcel-L 2×10^6 MSCs/kg
	Affected / at Risk (%)	# Events
Total	52/54 (96.3%)
Blood and lymphatic system disorders
Anaemia	4/54 (7.4%)
Neutropenia	3/54 (5.6%)
Cardiac disorders
Sinus tachycardia	5/54 (9.3%)
Pericardial effusion	3/54 (5.6%)
Tachycardia	3/54 (5.6%)
Endocrine disorders
Adrenal insufficiency	5/54 (9.3%)
Cushingoid	5/54 (9.3%)
Gastrointestinal disorders
Abdominal pain	10/54 (18.5%)
Vomiting	9/54 (16.7%)
Diarrhoea	6/54 (11.1%)
Abdominal distension	4/54 (7.4%)
Gastrointestinal haemorrhage	4/54 (7.4%)
Haematochezia	4/54 (7.4%)
Constipation	3/54 (5.6%)
Flatulence	3/54 (5.6%)
Nausea	3/54 (5.6%)
General disorders
Pyrexia	13/54 (24.1%)
Oedema peripheral	7/54 (13%)
Generalised oedema	3/54 (5.6%)
Hepatobiliary disorders
Hyperbilirubinaemia	3/54 (5.6%)
Immune system disorders
Chronic graft versus host disease	6/54 (11.1%)
Hypogammaglobulinaemia	6/54 (11.1%)
Graft versus host disease in skin	3/54 (5.6%)
Infections and infestations
Adenovirus infection	10/54 (18.5%)
Epstein-Barr viraemia	7/54 (13%)
BK virus infection	5/54 (9.3%)
Epstein-Barr virus infection	4/54 (7.4%)
Urinary tract infection	4/54 (7.4%)
Cytomegalovirus infection	3/54 (5.6%)
Oral candidiasis	3/54 (5.6%)
Pneumonia fungal	3/54 (5.6%)
Injury, poisoning and procedural complications
Allergic transfusion reaction	3/54 (5.6%)
Investigations
Transaminases increased	5/54 (9.3%)
Alanine aminotransferase increased	4/54 (7.4%)
Blood creatinine increased	3/54 (5.6%)
Electrocardiogram QT prolonged	3/54 (5.6%)
Metabolism and nutrition disorders
Hyperglycaemia	7/54 (13%)
Hypokalaemia	7/54 (13%)
Hypomagnesaemia	6/54 (11.1%)
Hyponatraemia	5/54 (9.3%)
Hypophosphataemia	4/54 (7.4%)
Hyperkalaemia	3/54 (5.6%)
Hypernatraemia	3/54 (5.6%)
Hypertriglyceridaemia	3/54 (5.6%)
Hypoalbuminaemia	3/54 (5.6%)
Malnutrition	3/54 (5.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	8/54 (14.8%)
Pain in extremity	4/54 (7.4%)
Joint swelling	3/54 (5.6%)
Nervous system disorders
Headache	4/54 (7.4%)
Tremor	3/54 (5.6%)
Psychiatric disorders
Agitation	4/54 (7.4%)
Anxiety	3/54 (5.6%)
Insomnia	3/54 (5.6%)
Renal and urinary disorders
Cystitis haemorrhagic	5/54 (9.3%)
Acute kidney injury	4/54 (7.4%)
Dysuria	4/54 (7.4%)
Respiratory, thoracic and mediastinal disorders
Cough	7/54 (13%)
Epistaxis	4/54 (7.4%)
Hypoxia	3/54 (5.6%)
Skin and subcutaneous tissue disorders
Dry skin	3/54 (5.6%)
Rash papular	3/54 (5.6%)
Skin hyperpigmentation	3/54 (5.6%)
Skin ulcer	3/54 (5.6%)
Vascular disorders
Hypertension	10/54 (18.5%)
Hypotension	8/54 (14.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Publications (abstracts, posters or presentations) must be presented to the Publication Steering Committee for review prior to submission or public display and are not allowed prior to the publication of the primary manuscript, or eighteen (18) months from the conclusion of the Study. PI shall provide Sponsor a copy of any proposed public disclosure at least 30 days prior to submission. Sponsor may ask PI to delay the disclosure for a maximum of 60 days to file proprietary protection.