Conditions: Acute GVHD
Keywords: Acute GVHD Standard-Risk Sirolimus Refined Minnesota Risk Criteria Ann Arbor Biomarker Steroid-Free
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 127
Healthy volunteers: no

Brief summary:
The study is a Phase II randomized, open label, multicenter trial designed to identify whether sirolimus is a potential alternative to prednisone as an up-front treatment for patients with standard-risk acute GVHD defined according to clinical and biomarker-based risk stratification. This trial incorporates both a novel up front GVHD therapy (sirolimus) as well as a novel BMT CTN developed acute GVHD biomarker test.

Detailed description:
The study is a Phase II randomized, open label, multicenter trial designed to identify whether sirolimus is a potential alternative to prednisone as an up-front treatment for patients with standard-risk acute GVHD defined according to clinical and biomarker-based risk stratification.

Patients with previously untreated, standard-risk acute GVHD, according to the refined Minnesota Criteria, who are in need of systemic therapy, will have a 5 mL blood sample collected prior to randomization to assess their biomarker Ann Arbor Risk status. Ann Arbor scoring results will be provided 48-72 hours after randomization. Patients will begin their study treatment assignments within 24 hours of randomization. Those with biomarker results of combined AA1/2 risk will continue on their randomized study treatment and will be included for primary endpoint analysis (Day 28 complete or partial response) and all planned study procedures and assessments. In contrast, patients with AA3 biomarker risk and those patients with missing biomarker results may continue on their randomized therapies or start another therapy at their physicians' discretion. In addition, AA3 risk patients and those with missing results will not be considered in primary endpoint analysis, but will be included in a subset analysis.

Arms:
arm 1: Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. arm 2: Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established.

Interventions: intervention 1: Sirolimus intervention 2: Prednisone
Intervention descriptions: intervention 1: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m\^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization. intervention 2: Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.

Protocol document:
Prot_000.pdf: 
 
 
A Randomized, Phase II, Multicenter, Open Label Study Evaluating 
Sirolimus and Prednisone in Patients with Refined Minnesota Standard Risk, 
Ann Arbor 1/2 Confirmed Acute Graft-Versus-Host Disease 
 
BMT CTN PROTOCOL 1501 
Version 2.0 
 
Study Chairpersons 
Joseph Pidala, MD, PhD1and Margaret MacMillan, MD3 
 
Protocol Team 
Amin Alousi, MD2 
Claudio Anasetti, MD1 
Joseph Antin, MD4 
Peter Dawson, PhD5 
Adam Mendizabal, PhD5 
James Ferrara, MD6 
Vincent Ho, MD4 
Mary Horowitz, MD7 
John Levine, MD8 
Madan Jagasia, MD10 
Eric Leifer, PhD9 
Marco Mielcarek, MD11 
Brent Logan, PhD7 
Shernan Holtan, MD3 
Javier Bolaños-Meade, MD12 
Mehdi Hamadani, MD7 
Alan Howard, PhD13 
Theresa Pritchard, MS5 
 
Lauren Kunz, PhD9 
 
Sponsored by the National Institutes of Health 
National Heart, Lung, and Blood Institute 
National Cancer Institute 
 
1 H. Lee Moffitt Cancer Center 
2 University of Texas, MD Anderson Cancer 
Center 
3 University of Minnesota 
4 Dana Farber Cancer Institute 
5 The Emmes Corporation 
6 Mount Sinai Medical Center 
7 Center for International Blood and Marrow 
Transplant Research, Medical College of 
Wisconsin 
8 University of Michigan 
9 National Heart, Lung, and Blood Institute  
10 Vanderbilt University Medical Center 
 
11 Fred Hutchinson Cancer Research Center 
12 Johns Hopkins University 
13 National Marrow Donor Program 
 
 
 
_______________________________ 
_______________________________ 
Approval Signature (Protocol Chair) 
Approval Signature (Protocol Officer) 


 
Core Study Participants: 
Affiliate Study Participants: 
BMT Program at Northside Hospital 
Baylor College of Medicine Consortium 
Case Western Reserve University Consortium  
City of Hope National 
Dana Farber Consortium 
Duke University Medical Center 
Fred Hutchinson Cancer Research Center 
H. Lee Moffitt Cancer Center 
Johns Hopkins University 
Memorial Sloan-Kettering Cancer Center 
Ohio State Consortium 
Pediatric BMT Consortium 
University of Florida Consortium 
University of Michigan Consortium 
University of Minnesota 
University of Nebraska Consortium 
University of Pennsylvania Cancer Center 
University of Texas, MD Anderson Cancer Center 
Virginia Commonwealth University MCV Hospitals 
Washington University, Barnes Jewish Hospital 
Medical College of Wisconsin 
 
 
 


Blood and Marrow Transplant Clinical Trials Network 
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PROTOCOL SYNOPSIS – BMT CTN PROTOCOL 1501 
 
A Randomized, Phase II, Multicenter, Open Label Study Evaluating Sirolimus and 
Prednisone in Patients with Refined Minnesota Standard Risk, Ann Arbor 1/2 Confirmed 
Acute Graft-Versus-Host Disease 
 
 
Co-Chairs: 
Joseph Pidala, MD, PhD and Margaret MacMillan, MD 
 
Study Design: 
The study is a Phase II randomized, open label, multicenter trial 
designed to identify whether sirolimus is a potential alternative to 
prednisone as an up-front treatment for patients with  standard-risk 
acute GVHD defined according to clinical and biomarker-based 
risk stratification.  
 
 
Patients with previously untreated, standard-risk acute GVHD, 
according to the refined Minnesota Criteria, who are in need of 
systemic therapy, will have a 5 mL blood sample collected prior to 
randomization to assess their biomarker Ann Arbor Risk status.  
Ann Arbor scoring results will be provided 48-72 hours after 
randomization. Patients will begin their study treatment 
assignments within 24 hours of randomization. Those with 
biomarker results of combined AA1/2 risk will continue on their 
randomized study treatment and will be included for primary 
endpoint analysis and all planned study procedures and 
assessments. In contrast, patients with AA3 biomarker risk and 
those patients with missing biomarker results may continue on 
their randomized therapies or start another therapy at their 
physicians’ discretions.  In addition, AA3 risk patients and those 
with missing results will not be considered in primary endpoint 
analysis, but will be included in a subset analysis. 
 
Primary Objective: 
The primary objective is to assess the rate of complete remission 
(CR)/partial remission (PR) on day 28 post-randomization in 
patients with standard-risk acute GVHD defined by both clinical 
and AA1/2 risk status. 
 
Secondary Objectives: 
Secondary objectives are to assess the following: 
1. The proportion of patients with an acute GVHD response on 
Day 28 (CR or PR) and who are on a prednisone (or prednisone 
dose-equivalent corticosteroid) dose of 0.25mg/kg/day or less.  
2. Proportions of CR, PR, mixed response, no response and 
progression among surviving patients at Day 14, 28 and 56.  
3. Treatment failure (treatment failure defined as: no response, 
progression, administration of additional therapy for GVHD 


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iv 
beyond primary therapy, or mortality) at Day 14, 28, and 
56.Incidence of chronic GVHD by 6 and 12 months post-
randomization. 
4. Incidence of systemic infections within 6 months of 
randomization. 
5. Freedom from acute GVHD progression, chronic GVHD, 
malignancy relapse and mortality at 6 months and 12 months 
post-randomization. 
6. Disease-free and overall survival at 6 and 12 months post 
randomization. 
7. GVHD-free survival at 6 and 12 months post-randomization.   
8. Non-relapse mortality at 6 and 12 months post-randomization. 
 
Exploratory Objectives: 
Exploratory objectives are to assess the following: 
1. Steroid-dose (measured in prednisone-equivalent) on Days 7, 
14, 21, 28, 35, 42 and 56. 
2. Use of topical (skin, GI) agents for acute GVHD therapy. 
3. Incidence of discontinuation of immune suppression, and 
immune suppression discontinuation without GVHD or disease 
progression/recurrence by Days 56, 180, and 365 post-therapy. 
4. Incidence of EBV-associated lymphoproliferative disorder or 
EBV reactivation requiring therapy 
5. Incidence of corticosteroid- and sirolimus-associated 
complications (collected in all patients): 
a. Incidence of hyperglycemia (defined as a random 
glucose >200mg/dL or fasting glucose >126mg/dL) and 
use of diabetes therapy (use of insulin and/or oral 
medications to control and/or maintain glucose levels)  
at baseline, Day 28 and Day 56. 
b. Change from baseline in functional myopathy score at 
Day 56 and 6-months post-randomization. 
i. Hip Flexor and Quadriceps Strength via 
handheld dynamometer 
ii. Two Minute Walk Test 
iii. 5-time Sit-to-Stand 
iv. Adult Myopathy Assessment Tool (AMAT)  
c. Incidence of hyperlipidemia as measured by fasting 
lipid panel at baseline, Days 28, 56 and 180 post-
randomization. 
d. Incidence of post-transplant thrombotic 
microangiopathy (TMA) by 6 months post-
randomization. 
6. Proportion of patients requiring therapy for CMV-reactivation 
by day 56 post-randomization. 


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7. Change in patient-reported outcomes from enrollment to Day 
56, 6 months and 12 months. 
a. MD Anderson Symptom Inventory (MDASI) 
b. FACT-BMT 
c. MOS Short Form 36 (SF-36)  
d. PedsQL (Pediatric patients) 
8. A secondary descriptive analysis will evaluate outcomes for 
AA3 patients. 
 
 
Eligibility: 
Patients of all ages with newly diagnosed standard-risk acute 
GVHD, diagnosed according to Refined Minnesota Criteria. All 
allogeneic donor sources and all conditioning regimens are 
allowed. Biopsy confirmation of GVHD is not required unless 
institutional practice mandates biopsy confirmation to make a 
GVHD treatment decision. Patients must have an absolute 
neutrophil count (ANC) greater than 500/µL.  Patients must be 
able to tolerate oral or enterically-administered medication. 
Patients must have 5 mL blood samples collected for Ann Arbor 
Scoring. No previous systemic immune suppressive therapy for 
acute GVHD is allowed except topical corticosteroid use.  Patients 
receiving sirolimus within 14 days of screening will be excluded.  
Patients with an active or recent (within 7 days) episode of 
transplant associated microangiopathy are not eligible.  Patients 
with acute GVHD after donor lymphocyte infusion are not eligible. 
Patients with clinical presentation resembling de novo chronic 
GVHD or overlap syndrome are not eligible. 
 
Treatment Description: 
Patients will be randomly assigned 1:1 to sirolimus vs. prednisone 
at 2mg/kg/day starting dose. Sirolimus will be loaded and then 
kept at maintenance dosing for target therapeutic levels for 
minimum duration through Day 56 post-randomization  Prednisone 
will be kept at 2mg/kg/day x 3 days, and then tapered according to 
individual treating clinician judgment. 
 
Accrual Objective: 
150 total patients will be enrolled and randomized 1:1 to sirolimus 
vs. prednisone. It is anticipated that ~20% of randomized patients 
will have AA3 status or missing biomarker results resulting in 120 
patients for the analysis of the primary endpoint. 
 
Accrual Period: 
The estimated accrual period is 2 years. 
 
Study Duration: 
Patients will be followed for 12 months following initiation of 
therapy. 
 


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Safety Monitoring: 
The rate of failure of sirolimus therapy by Day 42 post-
randomization, defined as the addition of a systemic immune 
suppressive therapy beyond prednisone among those patients 
originally treated with sirolimus, will be monitored using a 
sequential probability ratio test (SPRT) for binary data.  The SPRT 
will contrast a 25% and 50% 42-day rate of sirolimus failure. Day 
56 mortality will also be assessed for safety monitoring using a 
censored exponential SPRT contrasting a 10% and 25% rate of 
overall mortality. 
 
 


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 TABLE OF CONTENTS 
 
1. 
BACKGROUND AND RATIONALE ......................................................................... 1-1 
1.1. 
Introduction .................................................................................................................... 1-1 
1.2. 
Risk Stratification by Onset Organ Severity ............................................................... 1-2 
1.3. 
Risk Stratification by Blood Biomarkers ..................................................................... 1-2 
1.4. 
Results of Previous aGVHD Therapy Trials ............................................................... 1-3 
1.5. 
Sirolimus as Primary, Steroid-Free aGVHD Therapy ............................................... 1-4 
1.6. 
Study Rationale: ............................................................................................................. 1-5 
2. 
STUDY DESIGN ............................................................................................................ 2-1 
2.1. 
Study Overview .............................................................................................................. 2-1 
2.2. 
Hypothesis and Specific Objectives .............................................................................. 2-1 
2.2.1. 
Primary Hypothesis ..................................................................................................... 2-1 
2.3. 
Study Objectives............................................................................................................. 2-1 
2.3.1. 
Primary Objective: ...................................................................................................... 2-1 
2.3.2. 
Secondary Objectives are to assess the following: ..................................................... 2-1 
2.3.3. 
Exploratory Objectives are to assess the following: ................................................... 2-2 
2.4. 
Patient Eligibility ........................................................................................................... 2-2 
2.4.1. 
Inclusion Criteria ......................................................................................................... 2-2 
2.4.2. 
Exclusion Criteria........................................................................................................ 2-3 
2.5. 
Treatment Plan............................................................................................................... 2-4 
2.5.1. 
Randomization ............................................................................................................ 2-4 
2.5.2. 
Ann Arbor Scoring ...................................................................................................... 2-4 
2.5.3. 
Sirolimus (rapamycin, Rapamune®) .......................................................................... 2-5 
2.5.4. 
Prednisone ................................................................................................................. 2-16 
2.5.5. 
GVHD Prophylaxis Medications .............................................................................. 2-17 
2.5.6. 
Topical and Ancillary GVHD Therapies .................................................................. 2-17 
2.5.7. 
Management of study therapy after GVHD Progression or Non-response: ............. 2-17 
3. 
STUDY ENDPOINTS .................................................................................................... 3-1 
3.1. 
Primary Endpoint .......................................................................................................... 3-1 
3.1.1. 
Response Definitions .................................................................................................. 3-1 
3.2. 
Secondary Endpoints ..................................................................................................... 3-1 
3.2.1. 
Proportion of Patients with CR/PR and Steroid Dose 0.25 mg/kg or less .................. 3-1 
3.2.2. 
Proportion of response ................................................................................................ 3-2 
3.2.3. 
Treatment Failure ........................................................................................................ 3-2 
3.2.4. 
Incidence of Chronic GVHD ...................................................................................... 3-2 
3.2.5. 
Incidence of Systemic Infections ................................................................................ 3-2 
3.2.6. 
Event-Free Survival .................................................................................................... 3-2 
3.2.7. 
Disease-free and Overall Survival .............................................................................. 3-3 
3.2.8. 
GVHD-Free Survival .................................................................................................. 3-4 
3.2.9. 
Non-relapse Mortality ................................................................................................. 3-4 
3.3. 
Exploratory Endpoints .................................................................................................. 3-4 
3.3.1. 
Steroid Dose ................................................................................................................ 3-4 


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3.3.2. 
Topical Therapy .......................................................................................................... 3-4 
3.3.3. 
Discontinuation of Immune Suppression .................................................................... 3-4 
3.3.4. 
Incidence of EBV-associated lymphoproliferative disorder ....................................... 3-4 
3.3.5. 
Steroid- and sirolimus- associated complications (collected in all patients): ............. 3-4 
3.3.6. 
CMV-reactivation ....................................................................................................... 3-5 
3.3.7. 
Patient-reported Outcomes .......................................................................................... 3-5 
3.3.8. 
AA3 Biomarker Outcomes .......................................................................................... 3-6 
4. 
PATIENT ENROLLMENT AND EVALUATION .................................................... 4-1 
4.1. 
Approaching Patients, Eligibility Screening and Obtaining Consent ....................... 4-1 
4.2. 
Enrollment/Randomization ........................................................................................... 4-1 
4.2.1. 
Treatment .................................................................................................................... 4-1 
4.3. 
Study Monitoring ........................................................................................................... 4-2 
4.3.1. 
Follow-up Schedule .................................................................................................... 4-2 
4.4. 
Assessments .................................................................................................................... 4-4 
4.5. 
Weekly GVHD Monitoring ........................................................................................... 4-8 
4.6. 
Adverse Event Reporting .............................................................................................. 4-8 
4.6.1. 
Required Adverse Event Reporting ............................................................................ 4-9 
5. 
STATISTICAL CORRELATIONS ............................................................................. 5-1 
5.1. 
Study Design ................................................................................................................... 5-1 
5.1.1. 
Accrual ........................................................................................................................ 5-1 
5.1.2. 
Randomization ............................................................................................................ 5-1 
5.1.3. 
Primary Endpoint ........................................................................................................ 5-1 
5.1.4. 
Primary Hypothesis ..................................................................................................... 5-1 
5.1.5. 
Sample Size and Power Considerations ...................................................................... 5-2 
5.2. 
Interim Analysis and Stopping Guidelines .................................................................. 5-3 
5.2.1. 
Interim Analysis .......................................................................................................... 5-3 
5.2.2. 
Guidelines for Safety Monitoring ............................................................................... 5-3 
5.2.3. 
Demographic and Baseline Characteristics ................................................................. 5-5 
5.2.4. 
Analysis of Primary Endpoint ..................................................................................... 5-6 
5.2.5. 
Analysis of Secondary Endpoints ............................................................................... 5-6 
5.2.6. 
Analysis of Exploratory Endpoints ............................................................................. 5-7 
5.2.7. 
Secondary Analysis of AA3 Patients: ......................................................................... 5-9 
5.2.8. 
Exploratory Subgroup Analysis: ................................................................................. 5-9 
 
LIST OF APPENDICES 
 
APPENDIX A 
HUMAN SUBJECTS 
APPENDIX B 
LABORATORY PROCEDURES 
APPENDIX C 
DIAGNOSIS AND SCORING OF ACUTE AND CHRONIC GVHD 
APPENDIX D 
DERIVATION OF A SEQUENTIAL TEST STATISTIC FOR 
CENSORED EXPONENTIAL DATA 
APPENDIX E 
SUGGESTED PREDNISONE TAPER SCHEDULE 
APPENDIX F 
REFERENCES 


Blood and Marrow Transplant Clinical Trials Network 
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1-1 
CHAPTER 1 
 
 
1. 
BACKGROUND AND RATIONALE 
 
1.1. 
Introduction 
 
Acute graft-versus-host disease (aGVHD) is a frequent complication of allogeneic hematopoietic 
cell transplantation (HCT) involving activation of donor T-lymphocytes against host tissues.1 
Despite immune suppression prophylaxis, up to 50% of HCT recipients will experience aGVHD 
of varying severity.2  The syndrome of aGVHD involves multiple target organs, including the 
skin (presenting most frequently as a maculopapular rash), intestinal tract (presenting as 
nausea/vomiting and/or diarrhea), and liver (presenting as cholestatic liver injury with or without 
transaminase elevation).  The mainstay of treatment of aGVHD for over 3 decades has been 
high-dose corticosteroids, typically dosed at the prednisone equivalent of 1-2 mg/kg per day.3  
Corticosteroid therapy has several shortcomings, including both limited efficacy and toxicity 
including infection, hyperglycemia, hypertension, hyperlipidemia, and osteoporosis.   
 
One of the challenges that remains daunting in the clinical management of allogeneic HCT 
recipients is knowing which patients are likely to have mild aGVHD who would possibly be 
spared the side effects of prolonged high doses of corticosteroids.  Different approaches to risk 
stratify patients with aGVHD have been recently developed and refined.  These strategies 
include models built upon initial clinical staging of aGVHD target organs (e.g., skin, intestinal 
tract, and liver) and blood biomarker-based approaches.  Both of these strategies hold value in 
identifying patients who are likely to respond well (i.e., demonstrate a complete response [CR] 
or partial response [PR]) to corticosteroids and thus less likely to die due to complication of the 
transplant (i.e., experience transplant-related mortality [TRM]).4  
 
 
 


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1.2. 
Risk Stratification by Onset Organ Severity 
 
In 1990, Weisdorf et al. identified in multivariate analyses that overall stage score (sum of each 
aGVHD organ stage 0-4, plus 1 point for upper GI, for a maximum score of 13) was strongly 
associated with likelihood of CR.3  Based upon this initial observation that single organ 
involvement was more likely to achieve a CR than multi-organ involvement, the GVHD Risk 
Score was subsequently developed by the Minnesota group.5  Multivariate analysis of the 
outcomes of 864 consecutive patients from 1990-2007 yielded the following high-risk organ 
stages:  skin stage 4, lower gastrointestinal stage 3+, liver stage 3+, or skin stage 3 and lower 
gastrointestinal or liver stage 2+ GVHD.   
 
The GVHD Risk Score has recently been refined using 
data from multiple centers as well as Blood and 
Marrow Transplant Clinical Trials Network (BMT 
CTN) clinical trials 0302 and 0802 6 with a total of 
1,723 patients used in modeling – the largest aGVHD 
cohort analyzed for their characteristics and outcomes 
to date. Developed using clinical grouping and 
recursive 
partitioning, 
this 
new 
Risk 
Score 
(http://z.umn.edu/MNAcuteGVHDRiskScore) 
can 
classify patients into high-risk (HR) or standard risk at 
the onset of aGVHD symptoms.  In this model, 84% of 
patients are classified as standard risk, defined as 
single organ involvement (stage 1-3 skin or stage 1-2 
GI) or two organ involvement (stage 1-3 skin plus 
stage 1 GI; or stage 1-3 skin plus stage 1-4 liver), with 
a day 28 CR/PR rate of 69% (Figure 1).  All others are considered HR, with a day 28 CR/PR rate 
of 43%.  This model can be used in real time at the bedside, making it practical for stratification 
in clinical trials.   
 
1.3. 
Risk Stratification by Blood Biomarkers 
 
Serum proteomic patterns associated with aGVHD were first 
published approximately 10 years ago7,8.  The University of 
Michigan group has significantly expanded the proteomic 
profiling of patients with aGVHD in recent years by 
developing a 3-level risk stratification system, Ann Arbor 1 
(AA1) low-risk aGVHD, Ann Arbor 2 (AA2) intermediate-
risk aGVHD, and Ann Arbor 3 (AA3) high-risk aGVHD.  
The Ann Arbor score is based upon serum or plasma levels of 
tumor necrosis factor receptor-1 (TNFR1), regenerating islet-
derived 3-alpha (REG3α), and suppression of tumorigenicity 
2 (ST2) measured at diagnosis of GVHD, regardless of clinical 
severity (grades I-IV). Each Ann Arbor score corresponds to a 
distinct risk of six-month non-relapse mortality (NRM), such 
that Ann Arbor 1 GVHD has <10% NRM, Ann Arbor 2 
Figure 1.  Comparison of day 28 CR/PR in MN 
Standard vs. High Risk aGVHD patients. 
Figure 2.  Comparison of day 28 
CR/PR in AA1, AA2, and AA3 
biomarker-based risk stratified patients. 


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GVHD ~25% NRM, and Ann Arbor 3 GVHD has >40% NRM.  The scoring algorithm was 
validated in an independent test set of patients with aGVHD from the University of Michigan 
and the University of Regensberg, and in a separate validation set from multicenter Blood and 
Marrow Transplant Clinical Trials Network (BMT CTN) aGVHD treatment trials 0302 and 
0802.9  Relapse rates do not differ between Ann Arbor scores and thus the differences in non-
relapse mortality translate into significant differences in survival. Differences in response to 
treatment account for the vast majority of differences in NRM.  Patients with AA1 demonstrate 
81% CR/PR at day 28 and AA2 patients demonstrate 68% CR/PR at day 28 (Figure 2).  In 
contrast, high risk AA3 patients demonstrate 46% CR/PR at day 28. Furthermore, treatment 
responses for patients with AA3 GVHD are significantly less likely to be durable compared to 
AA1 and AA2 patients. Only 21% of AA3 patients remain in CR without flare at six months 
from diagnosis compared to 47% of AA1/2 patients (p<0.001). Importantly, similar proportions 
of patients are assigned to each Ann Arbor score in each of the three standard groupings of 
Glucksberg grades (I vs. II vs. III/IV). Thus, approximately 20% of all newly diagnosed GVHD 
cases have a high risk biomarker profile. These patients have poor responses to primary 
treatment, experience high NRM even when the clinical presentation is not severe, such as a 
<50% skin rash. Given their high likelihood of treatment failure, these patients are not good 
candidates for steroid sparing primary GVHD treatment trials. While compelling differences are 
observed in AA1/AA2 versus AA3 cohorts above, blood GVHD biomarkers have never 
previously been used to prospectively risk stratify patients.  
 
In February 2017, the same group that developed the Ann Arbor scoring system published that 
the concentrations of two biomarkers, ST2 and REG3α, measured on day 7 after HCT predicted 
lethal GVHD. This group, now located at Mount Sinai School of Medicine, developed and 
validated the MAGIC (Mount Sinai Acute GVHD International Consortium) algorithm from 
1287 patients who received  an allogeneic HCT at 11 
different centers in the United States, Europe, and Asia 
[Hartwell JCI Insight 2017]. The MAGIC two biomarker 
algorithm is able to predict GVHD outcomes at multiple 
timepoints after HCT, including day 7, day 14 (unpublished 
data), at GVHD onset [Hartwell, JCI Insight 2017], and after 
one week of GVHD treatment with systemic steroids 
[Major-Monfried, ASH 2016]. As shown in the figure, the 
MAGIC algorithm generates Ann Arbor scores with the 
same risk for NRM as the three biomarker algorithm, but 
more patients are assigned to the low risk group (Ann Arbor 
1) and the high risk group (Ann Arbor 3) than with the three biomarker algorithm. As of April 7, 
2017 no patient’s classification as AA1/2 or AA3 would have changed if the MAGIC algorithm 
had been used since the activation of BMT CTN 1501. Thus, given its advantages for design of 
future GVHD clinical trials incorporating biomarkers and the lack of impact on this study, the 
MAGIC algorithm will replace the three biomarker algorithm for determining Ann Arbor risk 
status. 
 
1.4. 
Results of Previous aGVHD Therapy Trials 
 


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To date, two multicenter aGVHD treatment trials have been conducted in the Blood and Marrow 
Transplant Clinical Trials Network (BMT CTN).  The first, BMT CTN 0302, was a multicenter, 
randomized, four-arm phase II trial that was designed to identify the agent most promising for 
use in addition to corticosteroids for the front-line therapy of aGVHD.  180 patients with a new 
diagnosis of aGVHD were randomized between the addition of etanercept, mycophenolate 
mofetil (MMF), denileukin diftitox, or pentostatin.  The proportion of day 28 CR/PR was highest 
in the MMF arm at 60%.10  Thus, MMF was selected for a randomized phase III trial of MMF 
versus placebo for first-line therapy of aGVHD in the subsequent study, BMT CTN 0802.  In 
CTN 0802, MMF did not meet the primary endpoint of extending GVHD-free survival at day 56 
at a planned interim analysis of 235, and the trial was terminated for futility.11  Day 28 CR/PR 
was approximately 50% in both arms of this study, with no statistically significant difference 
between the two.  Neither BMT CTN 0302 nor 0802 were risk-stratified according to clinical or 
biomarker-based strategies.  
 
1.5. 
Sirolimus as Primary, Steroid-Free aGVHD Therapy 
 
A retrospective analysis was conducted to examine activity of sirolimus as a sole, steroid-free, 
acute GVHD therapy.12 A total of 32 HCT recipients with new onset acute GVHD treated at the 
Moffitt Cancer Center were included. Median age was 60 (range 28-73), 72% were not in 
remission from their malignancy at time of HCT, and original GVHD prophylaxis consisted of 
tacrolimus/methotrexate (n=29), or tacrolimus/mycophenolate mofetil (n=3). Patients were 
treated with sirolimus as the primary therapy for acute GVHD at median of 30 (range 15 – 106) 
days after HCT. Acute GVHD was biopsy confirmed in 31/32 cases, and included a 
representative mix of target organ involvement (skin 17, 53%; GI 21, 66%, and liver 5, 16%). 
Overall grade was I (n=4, 13%), II (n=24, 75%), or III (n=4, 13%). None had overall grade IV. 
When evaluated according to Minnesota risk stratification, 27 (84%) were standard risk and 5 
(16%) were high risk. Sirolimus was administered orally as a median loading dose of 6mg (range 
2 to 9 mg), followed by maintenance dosing to sustain the desired target therapeutic levels (5-
14ng/mL). Tacrolimus was decreased to target a range between 3-7 ng/ml. This approach was 
safe, and thrombotic microangiopathy (TMA) was infrequent (n=3 cases total). Per BMT CTN 
consensus criteria, this was grade 1 in one case, and grade 2 in two cases. TMA resolved with 
dose reduction of tacrolimus in all cases. 
 
Sixteen (50%) patients achieved CR of acute GVHD (defined as sustained complete resolution 
GVHD for 4 weeks without addition of prednisone or other systemic immune suppressive 
agents) following primary therapy with sirolimus. Among these 16 patients who achieved 
complete resolution of acute GVHD with sirolimus alone, initial overall response (composite of 
partial and complete response) was achieved at median of 7 days (range 5 – 21 days) and 
complete response was achieved by a median of 14 days (range 5 – 28 days). In two of these 
cases, recurrent acute GVHD developed 7 – 12 weeks after initial CR; resolution of recurrent 
acute GVHD was achieved in both with the addition of 0.2 – 0.5 mg/kg body weight of 
prednisone.  
 
In the remaining 16 cases, systemic glucocorticoids were initiated at a median of 9 days (range 2 
– 28 days) after initiation of sirolimus with a prednisone-equivalent median dose of 0.5 (range 
0.2 – 1) mg/kg, and 12 achieved resolution of acute GVHD. Uniform criteria for initiation of 


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systemic steroids after first line sirolimus were not employed. Prednisone was started for 
persistent acute GVHD manifestations of unchanged severity in 6 cases (median 9 days from 
sirolimus initiation, range 2-19 days), grade progression in 6 cases (median 9 days from 
sirolimus initiation, range 2-16 days), in the setting of partial response in 2 cases (6-7 days after 
sirolimus initiation), and in 2 cases for recurrent acute GVHD within 4 weeks after initial 
complete response to sirolimus. Four (12%) had persistent acute GVHD that was treated with 
mycophenolate mofetil. Of these four patients, one died following primary disease relapse, two 
died from non-relapse causes (sepsis, and refractory acute GVHD with sepsis), and one survived.  
 
A matched cohort treated with standard (1mg/kg/day starting dose) prednisone for acute GVHD 
was assembled. These were matched to the primary sirolimus therapy cohort according to acute 
GVHD organ involvement and severity, as well as HLA matching, donor, graft source, and 
initial GVHD prophylaxis. Nineteen of these 32 subjects (59%) achieved complete remission, as 
compared to 16/32 (50%) of those treated with sirolimus primary therapy (p=0.47). In total, these 
data support safety and activity of sirolimus as a steroid-free primary therapy for acute GVHD.  
 
1.6. 
Study Rationale: 
 
Advances are needed in primary therapy of acute GVHD, as standard corticosteroid therapy is 
incompletely successful and associated with toxicity. Additionally, a growing body of evidence 
suggests that standard-risk GVHD patients can be identified using clinical and biomarker-based 
risk stratification tools. Lower-intensity therapy may be effective and spare toxicity in this 
setting. Existing data support safety and activity of sirolimus as a sole, steroid-free primary 
therapy in acute GVHD, however a prospective randomized trial is needed. Using a combined 
risk stratification approach, we will select a standard-risk (refined Minnesota standard risk, Ann 
Arbor 1/2 risk) acute GVHD population and conduct a randomized phase II trial examining acute 
GVHD response rates after primary therapy with either  sirolimus or standard prednisone 
(2mg/kg/day starting dose, followed by taper) therapy. 
 
 


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CHAPTER 2 
 
 
2. 
STUDY DESIGN 
 
2.1. 
Study Overview 
 
The study is a multicenter, Phase II, randomized trial assessing sirolimus as primary therapy for 
standard-risk (refined Minnesota standard risk, Ann Arbor (AA) 1/2 biomarker risk) acute 
GVHD. This trial incorporates both a novel up front GVHD therapy (sirolimus) as well as a 
novel BMT CTN developed acute GVHD biomarker. Given the two novel aspects of this trial, 
the purpose of the study is to estimate differences in response rates between for acute GVHD 
patients identified as standard risk by both clinical and biomarker risk assessment and 
randomized to sirolimus or prednisone. Secondary objectives will assess safety, measures of 
steroid burden and toxicity as well as quality of life.  
 
2.2. 
Hypothesis and Specific Objectives 
 
2.2.1. 
Primary Hypothesis 
The primary hypothesis is that sirolimus and prednisone will achieve comparable Day 28 CR/PR 
rates in the treatment of standard-risk acute GVHD (defined by both refined Minnesota clinical 
standard-risk criteria and AA1/2 biomarker risk group). 
 
2.3. 
Study Objectives 
 
2.3.1. 
Primary Objective: 
The primary objective is to assess the rate of complete remission (CR)/ partial remission (PR) on 
day 28 post-randomization in patients with standard-risk acute GVHD defined by both clinical 
and AA1/2 risk status.. 
 
2.3.2. 
Secondary Objectives are to assess the following: 
1. The proportion of patients with an acute GVHD response on Day 28 (CR or PR) and who 
are on a prednisone (or prednisone dose-equivalent corticosteroid) dose of 0.25mg/kg/day 
or less.  
2. Proportions of CR, PR, mixed response, no response and progression among surviving 
patients at Day 14, 28 and 56.  
3. Treatment failure (treatment failure defined as: no response, progression, administration 
of additional therapy for GVHD beyond primary therapy, or mortality) at Day 14, 28, and 
56. 
4. Incidence of chronic GVHD by 6 and 12 months post-randomization. 
5. Incidence of systemic infections within 6 months of randomization. 
6. Freedom from acute GVHD progression, chronic GVHD, malignancy relapse and 
mortality at 6 months and 12 months post-randomization. 
7. Disease-free and overall survival at 6 and 12 months post randomization. 


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8. GVHD-free survival at 6 and 12 months post-randomization.   
9. Non-relapse mortality at 6 and 12 months post-randomization. 
 
2.3.3. 
Exploratory Objectives are to assess the following: 
1. Steroid-dose (measured in prednisone-equivalent) on Days 7, 14, 21, 28, 35, 42 and 56. 
2. Use of topical (skin, GI) agents for acute GVHD therapy. 
3. Incidence of discontinuation of immune suppression, and immune suppression 
discontinuation without GVHD or disease progression/recurrence by Days 56, 180, and 
365 post-therapy. 
4. Incidence of EBV-associated lymphoproliferative disorder or EBV reactivation requiring 
therapy 
5. Incidence of corticosteroid- and sirolimus-associated complications (collected in all 
patients): 
a. Incidence of hyperglycemia (defined as a random glucose >200mg/dL or fasting 
glucose >126mg/dL) and use of diabetes therapy (use of insulin and/or oral 
medications to control and/or maintain glucose levels)  at baseline, Day 28 and 
Day 56. 
b. Change from baseline in functional myopathy score at Day 56 and 6-months post-
randomization. 
i. Hip Flexor and Quadriceps Strength via handheld dynamometer 
ii. Two Minute Walk Test 
iii. 5-time Sit-to-Stand 
iv. Adult Myopathy Assessment Tool (AMAT)  
c. Incidence of hyperlipidemia as measured by fasting lipid panel at baseline, Days 
28, 56 and 180 post-randomization. 
d. Incidence of post-transplant thrombotic microangiopathy (TMA) by 6 months 
post-randomization. 
6. Proportion of patients requiring therapy for CMV-reactivation by day 56 post-
randomization. 
7. Change in patient-reported outcomes from enrollment to Day 56, 6 months and 12 
months. 
a. MD Anderson Symptom Inventory (MDASI) 
b. FACT-BMT 
c. MOS Short Form 36 (SF-36)  
d. PedsQL (Pediatric patients) 
8. A secondary descriptive analysis will evaluate outcomes for AA3 patients. 
 
2.4. 
Patient Eligibility 
 
2.4.1. 
Inclusion Criteria 
Biopsy of involved organs with acute graft-versus-host disease (GVHD) is encouraged, but not 
required for study entry. Enrollment/randomization includes commitment to continue steroids or 
sirolimus as specified in the protocol, as well as the required follow-up observations.  If, 
according to institutional practice, the intention to treat a patient depends on histologic results, 


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the patient should not be enrolled on the BMT CTN 1501 study, until the biopsy results are 
available.  Patients can be enrolled with only a clinically established diagnosis. If an unexpected 
biopsy result is reported, the treating physician/center should contact the protocol chair(s) to 
discuss further course of action. 
1. Patients with their first presentation of standard-risk acute GVHD, according to refined 
Minnesota Criteria. Refined Minnesota Criteria are available at 
https://redcap.ahc.umn.edu/surveys/?s=bNmFhseJIf. Standard-risk acute GVHD 
according to the refined Minnesota Risk Criteria requires meeting one of the criteria 
below6: 
a. Single organ involvement 
i. Stage 1-3 skin 
ii. Stage 1 upper GI 
iii. Stage 1-2 lower GI 
b. Multiple organ involvement  
i. Stage 1-3 skin plus stage 1 upper GI 
ii. Stage 1-3 skin plus stage 1 lower GI 
iii. Stage 1-3 skin plus stage 1 lower GI plus stage 1 upper GI 
iv. Stage 1-3 skin plus stage 1-4 liver 
v. Stage 1 lower GI plus stage 1 upper GI. 
2. Acute Minnesota Standard Risk GVHD requiring systemic immune suppressive therapy.  
3. Acute GVHD developing after allogeneic hematopoietic cell transplantation using either 
bone marrow, peripheral blood, or umbilical cord blood.  Recipients of non-
myeloablative, reduced intensity conditioning and myeloablative transplants are eligible. 
All allogeneic donor sources are permitted, including siblings, unrelated donors, HLA-
haploidentical related donors and umbilical cord blood. 
4. Patients that have never received systemic immune suppressive therapy for treatment of 
active GVHD (topical skin and GI corticosteroids are allowed). 
5. Ability to tolerate oral or enterically-administered medications. 
6. Patients of all ages.   
7. Absolute neutrophil count (ANC) greater than 500/µL. 
8. Biopsy confirmation of GVHD is not required.  Enrollment should not be delayed for 
biopsy or pathology results unless local institutional practice mandates biopsy 
confirmation to make a GVHD treatment decision.  
9. Written informed consent and/or assent from patient, parent or guardian. 
10. Collection of a 5 ml blood sample (red top for serum) from the patient for Ann Arbor 
Scoring and ready to be shipped immediately after randomization. 
 
2.4.2. 
Exclusion Criteria 
1. Patients receiving sirolimus (for any indication including GVHD prophylaxis) within 14 
days of screening for enrollment. 
2. Relapsed, progressing or persistent malignancy requiring withdrawal of systemic immune 
suppression. 
3. Patients with acute GVHD developing after a donor lymphocyte infusion. 
4. Active or recent (within 7 days) episode of transplant associated microangiopathy. 


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5. Patients with uncontrolled infections will be excluded.  Infections are considered 
controlled if appropriate therapy has been instituted and, at the time of enrollment, no 
signs of progression are present.  Progression of infection is defined as hemodynamic 
instability attributable to sepsis, new symptoms, worsening physical signs or radiographic 
findings attributable to infection. Persisting fever without other signs or symptoms will 
not be interpreted as progressing infection. 
6. Patients unlikely to be available for evaluation at the transplant center on Day 28 and 56 
of therapy. 
7. A clinical presentation resembling de novo chronic GVHD or overlap syndrome (as 
defined in Appendix C) developing before or present at the time of enrollment. 
8. Patients receiving systemic corticosteroids for any indication within 7 days before the 
onset of acute GVHD, except the following:  Stable replacement doses of corticosteroids 
for adrenal insufficiency are permitted (e.g. hydrocortisone total dose of 10-12 
mg/m2/day or prednisone 5-7.5mg daily or equivalent). Corticosteroids administered as 
premedication before transfusion of blood products or before intravenous medications to 
prevent infusion reactions are allowed.  
9. Patients who are pregnant or breastfeeding. 
10. Females of childbearing potential (FCBP) or a man who has sexual contact with a FCBP 
and is unwilling to use effective birth control for the duration of the study.   
11. Patients on dialysis.  
12. Patients on mechanical ventilation.   
13. Patients with severe hepatic sinusoidal obstruction syndrome who in the judgment of the 
treating physician are not expected to have normalized bilirubin by Day 56 after 
enrollment. 
14. Patients with a history of hypersensitivity to sirolimus or any component of the 
formulation. 
 
2.5. 
Treatment Plan 
 
2.5.1. 
Randomization 
A 5 mL blood sample (red top tube) for Ann Arbor Scoring must be collected from the patient 
prior to enrollment/randomization in AdvantageEDC (see section 2.5.2).  Upon confirmation of 
eligibility in AdvantageEDC, the study participant will be randomized in a 1:1 fashion to receive 
either sirolimus or prednisone.  Study treatment (sirolimus/prednisone) should be initiated as 
soon as possible after randomization.  A maximum of 24 hours from randomization to first dose 
of study medication is allowable.   
 
2.5.2. 
Ann Arbor Scoring 
Immediately after randomization, the 5 ml of blood (red top for serum) will be shipped priority 
overnight for early morning arrival at the Biomarker Laboratory of the Icahn School of Medicine 
at Mount Sinai for biomarker analysis. Samples can be shipped Monday to Friday, and results 
can be delivered Tuesday through Saturday. Once received in the laboratory, the GVHD 
biomarkers used to assign the Ann Arbor GVHD score will be measured by ELISA using 
standard technical procedures in a CLIA certified laboratory. Processing the sample, measuring, 
and confirming the ELISA assay results take 4.5 hours (range 4-6 hours). Once the Ann Arbor 


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score is confirmed, the investigator at the participating center will be notified if the patient has 
AA1/2 biomarker risk, AA3 biomarker risk or missing biomarker results. Notification of the 
patient’s Ann Arbor results will occur within 72 hours of study enrollment/randomization 
(usually within 48 hours). 
 
Those with AA1/2 status will remain on their randomized therapy.  AA3 patients and patients 
with missing biomarker results can continue on their randomized therapy, or another therapy, per 
the discretion of the treating physician.  All patients, regardless of treatment received or 
biomarker status, must complete all planned study assessments. Patients with AA1/2 biomarker 
status and clinical standard risk will be included in the analysis for the primary endpoint. In 
contrast, patients with AA3 status or missing biomarker status will not be considered for the 
primary analysis, but will be included as a secondary descriptive analysis. GVHD response and 
therapy used in patients with AA3 status may be used in exploratory analyses to generate 
hypotheses for future high risk GVHD trials. 
 
2.5.3. 
Sirolimus (rapamycin, Rapamune®) 
Drug Information 
Description, Administration and Storage 
Sirolimus is a naturally occurring compound produced by Streptomyces hygroscopicus.  In 
addition to its immunosuppressive properties, sirolimus has antifungal, antiviral and 
antineoplastic properties.  
*Patients can be treated with either Rapamune (sirolimus) or generic sirolimus, however it is 
strongly recommended to use one of these agents consistently throughout the therapy period.  
 
1) 
Oral solution:  
Sirolimus oral solution is supplied in cartons of 2 oz (60 mL fill) amber glass bottles, or 
foil pouches.  The oral solution contains sirolimus at a concentration of 1 mg/mL and the 
following inactive ingredients: Phosal 50 PG (phosphatidylcholine, propylene glycol, 
monodiglycerides, ethanol, soy fatty acids, and ascorbyl palmitate) and polysorbate 80.  
The oral solution also contains 1.5% - 2.5% ethanol.  The appropriate dose of sirolimus 
oral solution should be measured using the provided amber colored oral syringe and is 
diluted in at least 2 oz (1/4 cup) of water or orange juice to improve palatability.  No 
other liquids, including grapefruit juice, should be used for dilution.  After vigorous 
mixing, the diluted dose should be taken immediately.  Refill the container with an 
additional volume (recommended minimum of 4 oz (1/2 cup) of water or orange juice), 
stir vigorously, and drink or administer at once to assure delivery of all of the medication.  
Small children may not be able to consume the recommended volumes of water or orange 
juice suggested for dilution and may need lesser volumes. 
 
Sirolimus oral solution provided in bottles may develop a slight haze when refrigerated.  
If such a haze occurs allow the product to stand at room temperature and shake gently 
until the haze disappears.  The presence of this haze does not affect the quality of the 
product. Rapamune® Oral Solution bottles and pouches should be stored protected from 


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light and refrigerated at 2C to 8C (36F to 46F).  The syringe should be discarded after 
one use.  After dilution, the preparation should be used immediately. 
 


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2) 
Tablets:  
Sirolimus tablets are available as white, tan or yellow-to-beige triangular-shaped tablets 
marked “RAPAMUNE 1 mg,” “RAPAMUNE 0.5 mg” or “RAPAMUNE 2 mg” 
respectively, in bottles containing 100 tablets or cartons containing 10 blister cards each 
with 10 tablets (0.5 mg and 1 mg formulations only).  Each tablet contains sirolimus and 
the following inactive ingredients: sucrose, lactose, polyethylene glycol 8000, calcium 
sulfate, microcrystalline cellulose, pharmaceutical glaze, talc, titanium dioxide, 
magnesium stearate, povidone, poloxamer 188, polyethylene glycol 20,000, glyceryl 
monooleate, carnauba wax, and other ingredients.  The 0.5 mg and 2 mg tablets also 
contain yellow iron (ferric) oxide and brown iron (ferric) oxide.  Sirolimus tablets should 
be stored at 20 to 25C (68 - 77F).  Cartons should be used to protect blister cards and 
strips from light.  Sirolimus tablets should be dispensed in a tight, light-resistant 
container.  Sirolimus tablets should not be split or crushed. 
 
3) 
Pharmacology: 
The absorption of sirolimus is rapid after administration of Rapamune Oral Solution, 
with a mean Tmax of 1-2 hours in different study populations. Oral bioavailability is only 
14% in stable renal transplant patients due to first pass metabolism in the liver and the 
intestinal wall, plus counter transport in the gut lumen by P-glycoprotein. Mean 
bioavailability of sirolimus after administration of the tablet is about 27% higher relative 
to the oral solution. However, clinical equivalence has been demonstrated for the 2-mg 
dose.  Co-administration with high fat meals leads to reduced Cmax, prolonged Tmax 
and increased AUC, meaning that sirolimus should be taken consistently with or without 
food. The distribution of sirolimus is notable for extensive partitioning into blood cells 
and approximately 92% is bound to human plasma proteins.  Sirolimus is a substrate for 
CYP3A4 and P-glycoprotein, and is extensively metabolized by O-demethylation and/or 
hydroxylation to at least 7 major metabolites.  The parent compound contributes to more 
than 90% of the immunosuppressive activity.  The excretion of Sirolimus is 91% fecal 
and only 2.2% via the urine. 
 
Whole blood sirolimus trough levels in renal transplant recipients who were administered 
daily doses of 2 mg or 5 mg at 4 hours after Neoral®) were 8.59 ± 4.01 ng/mL and 17.3 ± 
7.4 ng/mL, respectively, as measured by LC/MS/MS.  Whole blood trough levels 
significantly correlated with steady state AUC (r2=0.96).  Six days of multiple dosing 
were required to achieve steady state.  Alternatively, a loading dose of three times the 
maintenance dose will provide near steady state concentrations within one day in most 
patients.  
 
The mean  SD terminal elimination half life (T1/2) of sirolimus after multiple dosing in 
stable renal transplant patients was 62  16 hours.  The mean T1/2 increased from 79  
12 hours in subjects with normal hepatic function to 113  41 hours in patients with 
impaired hepatic function.  Dosage reduction is recommended for patients with mild to 
moderate hepatic impairment.  Limited pharmacokinetic data are available in pediatric 
patients with chronically impaired renal function but indicates similar Tmax (0.62-1.6 h) 
and T1/2 (31-111h).  Clearance is slower in males compared to females but dose 


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adjustments based on gender are not recommended.  There were no differences between 
African Americans and non-African Americans. 
 
Sirolimus administration 
Patients randomized to sirolimus will receive a loading dose after which a trough sirolimus level 
will be measured.  Based upon this sirolimus level, patients will either receive additional loading, 
or commence once daily maintenance sirolimus with levels checked routinely as described 
below.   
 
The initial loading dose of sirolimus is required per protocol. Subsequent management of 
sirolimus dosing and adherence to intended therapeutic levels is strongly encouraged, but – due 
to inter-individual variation in drug metabolism and other factors – it is expected that drug levels 
can’t be entirely kept within the desired range for all serial measures for all patients. In standard 
practice, frequent adjustment of sirolimus dosing is needed to achieve and maintain desired 
therapeutic levels. Thus, variation in actual dose of sirolimus and sirolimus drug levels over time 
will not be considered protocol deviations. The recommended dosing and drug levels serve as a 
practice guideline, not a protocol mandated procedure. These rules apply to dosing and 
monitoring of tacrolimus and cyclosporine on trial as well. 
 
Sirolimus Loading dose  
The loading dose of sirolimus is as follows: 
Patients >12 years of age: 6 mg PO once 
Patients ≤12 years of age:  5 mg/m2/dose PO once (max 6 mg PO once) 
 
Patients on voriconazole should reduce the loading dose by 50% - 90%, according to institutional 
practice. 
Patients on  posaconazole, isavuconazole and fluconazole should receive 50% of recommended 
loading dose. 
 
Sirolimus Level after Loading Dose 
A trough sirolimus level should be performed promptly after the loading dose (within 24-48 
hours).  Both initial and subsequent sirolimus level monitoring can be done both at centers 
participating in this protocol (if levels can be resulted within 48 hours) or through an external 
laboratory (also to result levels within 48 hours of receiving the sample). Study centers will work 
with the protocol team to ensure this is possible 7 days per week. The target serum sirolimus 
level after the loading dose is 10-14 ng/mL.  The following is a management guideline based 
upon the initial sirolimus level: 
Level 
Management 
< 5 ng/mL 
Re-load with same loading dose 
5- <10 
ng/mL 
Re-load with 50% of initial loading dose 
10-14 ng/mL Move to maintenance dosing 


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>14 ng/mL 
Hold sirolimus and recheck level daily. Start 
maintenance therapy when level is < 14ng/mL 
 
Initial planned maintenance dose (revised as needed based on observed sirolimus levels): 
Patients >12 years of age: 2mg PO once daily 
Patients ≤12 years of age: 2 mg/m2/dose PO once daily (max 2mg daily) 
 
Patients on voriconazole, posaconazole or isavuconazole should receive 10% of recommended 
maintenance dose (as an initial dose adjustment). Subsequent dose modification to maintain 
desired therapeutic levels will be tailored to each individual patient.  When calculating dosing, 
review medication list for potential drug interactions.  CYP-450 and p-glycoprotein drug 
interactions.  See other dose modifications in sections below.  
 
Maintenance Sirolimus Levels  
Adults: Sirolimus levels should be performed twice weekly until at steady state, then weekly for 
the sirolimus therapy duration.  For dose changes, recheck sirolimus level after 3 days of therapy 
at new dose. 
Pediatrics:  Due to variability in the half-life of sirolimus in children < 12 years old, levels 
should be checked Monday, Wednesday and Friday until 2 consistent levels, then weekly.   For 
dose changes, recheck sirolimus level after 3 days of therapy at new dose. 
 
Maintenance Sirolimus level goals: 
- Target sirolimus level from outset through resolution of acute GVHD is 10-14ng/mL.  
Level 
Management 
< 5 ng/mL 
Re-load with 50% loading dose and increase 
maintenance sirolimus dose by 10-25%  
5 - <10 ng/mL 
Increase sirolimus dose by 10-25% 
10-14 ng/mL 
Continue on current dose and repeat in 1 week 
>14 ng/mL 
Hold sirolimus and recheck level daily.  
Resume therapy when level is < 14 ng/mL.  
▪ Initial level >14-20 ng/mL:  Resume therapy at 10-25% lower dose 
▪ Initial level > 20 ng/mL:  Resume therapy at 25-50% lower dose 
- After acute GVHD is completely resolved, the target therapeutic range can be decreased 
to 5-10ng/mL 
Level 
Management 
< 5 ng/mL 
Re-load with 50% loading dose and increase 
maintenance sirolimus dose by 10-25%  
5-10 ng/mL 
Continue current dose and repeat in 1 week 
>10 - 14 
ng/mL 
Decrease current dose by 10-25% and repeat 
in 1 week 


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>14 ng/mL 
Hold sirolimus and recheck level daily.  
Resume therapy when level is < 10 ng/mL.    
▪ Initial level 11-14 ng/mL:  Resume therapy at 10-25% lower dose 
▪ Initial level > 14 ng/mL:  Resume therapy at 25-50% lower dose 
Duration of Sirolimus: 
All patients should receive therapeutic sirolimus until at least day 56 after initiation.  
Thereafter, the decision of when and how to taper is at the discretion of the treating physician. 
Suggested Sirolimus Taper: 
The following is a suggested sirolimus taper after completion of the required period of therapy: 
Reduce dose by 1/3 dose per month to complete taper off over 3 months.   
Sirolimus therapy guidance: 
• Sirolimus tablets should not be crushed, split or chewed. 
• It is recommended to not administer oral suspension via NG or NJ, as this can obstruct 
the tube. Administration by G or J tube is acceptable. 
• To minimize the variability of exposure to sirolimus, it should be taken at a consistent 
time of day and consistently with or without food.  
• Fatty foods increase overall absorption (AUC). 
• Sirolimus solution (1 mg/ml) may be mixed with ¼ cup of water or orange juice (no other 
liquids should be used). Cup should than be refilled with another 1/2 cup of water of 
orange juice, stirred vigorously, and then administered. 
• Sirolimus solution may also be inserted in a gelatin capsule using a tuberculin syringe. 
• Sirolimus should not be taken within 4 hours after administration of Neoral® (or 
Gengraf®) cyclosporine oral solution and/or cyclosporine gelatin capsules because 
premarketing studies in healthy volunteers demonstrated 116%-512% elevations of mean 
Cmax and 148%-230% elevations in AUC when sirolimus oral solution or tablets were 
simultaneously administered with Neoral but not when the doses were separated by 4 
hours. 
• Grapefruit juice reduces CYP3A4-mediated metabolism of sirolimus and must not be 
administered with sirolimus or used for dilution. 
• Extreme caution when subject is on voriconazole therapy (see section 2.5.3.4) 
• Emesis: The sirolimus dose may be repeated within 15 minutes of a vomited dose.  
• Impaired renal function does not mandate dosage adjustment.   
• Impaired hepatic function should prompt consideration for sirolimus maintenance doses 
to be reduced but no dose adjustment of the loading dose is necessary. Maintenance 
doses of sirolimus may be reduced by approximately one third in patients with hepatic 
impairment (Child-Pugh Score of ≥ 7/15 based on the sum of 1, 2 and 3 points 
respectively for each of: serum bilirubin in mg/dL (< 2, 2-3, > 3), serum albumin in 
mg/dL (> 3.5, 2.8-3.5, < 2.8), INR (< 1.7, 1.71-2.2, >2.2), hepatic encephalopathy (none, 
grade I-II, grade III-IV), or ascites (none, slight, moderate/refractory).  


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• Interchangeability of oral solution and tablets: Two-milligram Rapamune Oral 
Solution is clinically equivalent to 2-milligram Rapamune oral tablets; hence, are 
interchangeable on a milligram to milligram basis.  However, it is not known if higher 
doses of Rapamune Oral Solution are clinically equivalent to higher doses of tablets on a 
milligram to milligram basis  
 
Expected toxicity and management guidelines 
TABLE 1.  SIROLIMUS TOXICITIES 
 
Common 
>20% 
Occasional 
2-20% 
Rare 
<2% 
Immediate 
Within 1-2 days of 
receiving drug 
Headache (L), hypertension 
(L), nausea, diarrhea, 
immuno-suppression (L), 
fever, constipation 
Chest pain, insomnia, 
dyspepsia, vomiting, dyspnea 
Hypotension, asthma, increased 
cough, flu like syndrome, 
tachycardia, anorexia, 
hypersensitivity reactions 
(exfoliative dermatitis, 
angioedema) 
Prompt 
Within 2-3 weeks, 
prior to the next 
course 
Tremor (L), renal 
dysfunction, elevated 
creatinine/BUN, anemia, 
pain (abdominal, back, 
pain), hyperlipidemia, 
hypercholesteremia, 
hypertrigylceridemia, 
hyperglycemia, peripheral 
edema, weight gain, 
arthralgia 
Elevated LFTs (with elevated 
sirolimus levels), stomatitis, 
urinary tract infections, URIs, 
mild thrombocytopenia, 
leukopenia, 
hyper/hypokalemia (L), 
hypophosphatemia, rash, hives, 
pruritis, delayed wound 
healing or dehiscence (L), 
hypomagnesaemia (L), 
proteinuria 
Opportunistic infections, pleural 
and pericardial effusions, non-
infectious pneumonitis or 
bronchiolitis-obliterans 
organizing pneumonia and 
pulmonary fibrosis, thrombosis, 
myalgias, increased risk of CNI-
induced HUS/TTP/TMA (L) 
  
Delayed 
Any time later 
during therapy, 
excluding the above 
conditions 
Acne 
 
Chronic renal dysfunction, renal 
tubular necrosis, CHF, ascites, 
arthrosis, bone necrosis, 
osteoporosis 
Late 
Any time after 
completion of 
treatment 
 
 
Lymphoproliferative disorders, 
skin malignancies 
Unknown 
Frequency and 
Timing 
Sirolimus was embryo/fetotoxic in rats at dosages of approximately 0.2 to 0.5; clinical doses were 
adjusted for body surface area. It is not known whether sirolimus is excreted in human milk. 
(L) Toxicity may also occur later. 
Toxicities will be scored as per the NCI’s Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0, unless otherwise specified.  
 
• Hyperlipidemia: In the Phase III studies, treatment of new-onset hypercholesterolemia 
with lipid-lowering agents was required in 42-52% of patients enrolled in the sirolimus 
arms.  Concomitant administration of sirolimus and HMG-CoA reductase inhibitors 
(statins) and/or fibrates appeared to be well tolerated.  However, statins or fibrates should 
only be administered with caution to patients being treated with sirolimus and a CNI, at 
doses which are reduced according to label recommendations.  Treated patients should be 
monitored for the development of rhabdomyolysis.  Sirolimus should be continued during 


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therapy for hypercholesterolemia and hypertriglyceridemia unless the lipid levels are 
uncontrollable with standard therapy and are deemed to be at risk to the subject, per the 
treating physician. 
 
• Thrombotic Microangiopathy (TMA): Studies in adult transplant patients have shown an 
increase in TMA from 4.2% when patients were treated with tacrolimus or cyclosporine 
alone compared to 10.8% in patients treated with the tacrolimus/sirolimus combination.13  
TMA may occur both in the setting of sirolimus and/or CNI levels being above the 
therapeutic range or when levels are within desired ranges.  Although complete renal 
recovery occurred in 92% of these patients, the potential seriousness of this complication 
requires careful monitoring and management.  
 
To meet the definition (BMT CTN Consensus Definition) for TMA, a patient must have 
all of the following: 
1. RBC fragmentation and ≥ 2 schistocytes per high-power field on peripheral smear 
2. Concurrent increased serum LDH above institutional baseline 
3. Concurrent renal* and/or neurologic dysfunction without other explanations 
4. Negative direct and indirect Coombs test results 
 
*Doubling of serum creatinine from baseline (baseline = creatinine before hydration 
and conditioning) or 50% decreased in creatinine clearance from baseline 
 
BMT CTN Consensus for TMA severity scoring: 
 
Grade I 
Evidence of RBC destruction (schistocytosis) without clinical 
consequences 
Grade II 
Evidence of RBC destruction with increased creatinine ≤ 3 x ULN  
Grade III 
Evidence of RBC destruction with creatinine > 3 x ULN not requiring 
dialysis 
Grade IV 
Evidence of RBC destruction with renal failure requiring dialysis, and/or 
encephalopathy 
 
• Hematological Toxicity: ANC, hematocrit and platelet counts will be monitored at each 
visit. A thorough investigation should be made to assess for possible causes of the 
cytopenia (recurrent disease, infection, drug effect other than sirolimus, TMA, 
autoimmune hemolytic anemia/thrombocytopenia, GVHD, late engraftment of platelets 
in cord blood transplant, etc.).  If other causes have been ruled out and cytopenias are 
significant (ANC<500, platelets <20K) sirolimus doses may be decreased by 50%.  If the 
cytopenia does not resolve after two weeks, sirolimus may be held.  If counts improve, 
restart sirolimus at 50% of dose and titer to full dose as tolerated. 
Sirolimus drug interactions, co-administration of calcineurin inhibitors, and dose-
modification for concurrent azole therapy 
 


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Drug interactions: 
Sirolimus is a substrate for cytochrome CYP 3A4 and a P-glycoprotein (P-gp).  
Drugs that may increase sirolimus blood concentrations include CYP 3A4, 5, or P-gp inhibitors:  
• Calcineurin inhibitors: Simultaneous administration of cyclosporine soft gelatin capsules 
(Neoral®) results substantial increases in the sirolimus Cmax and AUC.  This is avoided 
if sirolimus is taken 4 hours after administration of cyclosporine. 
• Calcium Channel Blockers: diltiazem, nicardipine, nifedipine, verapamil and amlodipine. 
Sirolimus should be monitored and a dose adjustment may be necessary.  
• Triazole antifungal agents: fluconazole, itraconazole, clotrimazole, posaconazole, 
isavuconazole voriconazole and ketoconazole. The magnitude of increases sirolimus 
Cmax, tmax, and AUC is such that sirolimus should be administered cautiously together 
with fluconazole, itraconazole, or posaconazole, and with extreme caution if 
administered together with voriconazole or isavuconazole.  If co-administration is 
unavoidable, then the dose of sirolimus should be greatly reduced at the time of initiation 
of the antifungal medication as recommended in Table 2 and that there should be very 
frequent monitoring of trough concentrations of sirolimus in whole blood.  Sirolimus 
concentrations should be measured upon initiation, during co-administration, and at 
discontinuation of antifungal treatment, with sirolimus doses adjusted accordingly. 
• Macrolide antibiotics: clarithromycin, erthyromycin, telithromycin, troleandomycin (but 
NOT azithromycin). 
• Gastrointestinal prokinetics: cisapride, metocloproramide. 
Drugs that may decrease sirolimus blood concentrations include CYP 3A4, 5, 7 or P-gp inducers:  
• Anticonvulsants: carbamazepine, Phenobarbital, phenytoin. 
• Antibiotics: Rifampin, rifanpentine. 
• Herbs: St. John’s Wort (Hypericum perforatum). 
Care should be taken when other drugs or substances that are metabolized by CYP3A4 or P-
glycoprotein are administered concomitantly with sirolimus.  Grapefruit juice reduced CYP3A4 
mediated metabolism of sirolimus and must not be used for dilution. 
 
Co-administration of calcineurin inhibitors:  
When co-administered with sirolimus, recommend target levels are as follows: 
 
The target serum level for tacrolimus is 3-7 ng/mL 
  
The target serum level for cyclosporine is 120-200 ng/mL 
 
Dose adjustments are based upon clinical judgment of the managing physician after considering 
clinical toxicity, serum levels, GVHD, concomitant drug use and the rate of rise or decline of the 
serum level. Following represent suggested dose adjustments in calcineurin inhibitors, when 
initiating sirolimus to achieve target levels specified above. 
 


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Calcineurin inhibitor actual 
serum level prior to 
initiating sirolimus 
Recommended target serum level 
for calcineurin inhibitors when co-
administered with sirolimus 
Recommended dose 
adjustment to 
achieve 
recommended target 
serum level 
tacrolimus > 10 ng/mL 
tacrolimus = 3-7 ng/mL 
50% dose reduction 
tacrolimus = 7.1-10 ng/mL 
tacrolimus = 3-7 ng/mL 
33% dose reduction 
tacrolimus ≤ 7.0 ng/mL 
tacrolimus = 3-7 ng/mL 
No change 
cyclosporine > 400 ng/mL 
cyclosporine = 120-200 ng/mL 
50% dose reduction 
cyclosporine = 201-399 
ng/mL 
cyclosporine = 120-200 ng/mL 
33% dose reduction 
cyclosporine ≤ 200 ng/mL 
cyclosporine = 120-200 ng/mL 
No change 
*When calcineurin inhibitors (cyclosporine, tacrolimus) are given with prednisone (i.e. 
among patients not randomized to the sirolimus arm of this trial), standard practices are 
recommended for dosing/monitoring of these agents. Suggested target levels for these agents 
in the absence of sirolimus are cyclosporine 200-400ng/mL and tacrolimus 5-15ng/mL. Again, 
these are recommendations (not protocol mandated), and management is directed by the treating 
physician. 
 
Dose-modification in setting of azole therapy: 
Antifungal prophylaxis: Triazole antifungal medications are expected to increase serum CNI and 
sirolimus levels, therefore, dosages of CNIs and sirolimus, should be adjusted accordingly using 
the guidelines recommended in Table 2 and 3. 
 
TABLE 2 - PRE-EMPTIVE DOSE REDUCTION OF SIROLIMUS OR CNIs WHEN 
AZOLES ARE INITIATED AT STEADY STATE LEVELS OF SIROLIMUS OR CNIs 
Antifungal 
Cyclosporine 
Tacrolimus 
Sirolimus 
 
Dose  
Dose  
Dose  
Voriconazole 
50% 
67% 
90% 
Posaconazole 
25% 
67% 
90% 
Isavuconazole 
50% 
67% 
90% 
Itraconazole 
50% 
50% 
ND 
Fluconazole 
25% 
25% 
50% 
*Notes: 
1. If voriconazole must be added to control fungal infection then following the 90% reduction in 
sirolimus dosing14 and/or 50%-67% reduction in CNI dosing SRL and/or CNI serum levels should 
be measured 24-48 hours later and then every 3-4 days until levels are stable and in the desired 
range.  If voriconazole is given intravenously or if voriconazole and sirolimus are not given 
together, these guidelines may not apply because the effect on bioavailability of sirolimus will be 
weaker. 


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2. Note that sirolimus tablets should not be split or crushed.  Fractional dose of sirolimus may be 
achieved by drawing an appropriate volume of the 1 mg/mL oral liquid formulation into a 1 mL 
syringe and swallowed directly (or mixed with water or orange juice; no other liquids, including 
grapefruit juice, should be used for dilution). 
3. If posaconazole or itraconazole or high-dose fluconazole are added then SRL and/or CNI serum 
levels should be followed 48-72 hours later and then every 3-5 days until levels are stable and in 
the desired range. 
 
TABLE 3 - ANTICIPATE DOSE INCREASE OF SIROLIMUS OR CNIs WHEN 
AZOLES ARE STOPPED DURING CONCOMITANT SIROLIMUS OR CNI THERAPY 
Antifungal 
Cyclosporine 
Tacrolimus 
Sirolimus 
 
Dose  
Comment 
Dose  
Comment 
Dose  
Comment 
Voriconazole 
2-fold 
Dose increase 
may not be 
necessary for    
5-10 days 
3-fold 
Dose increase 
may not be 
necessary for   
5-10 days 
10-fold 
Dose increase 
may not be 
necessary for    
5-10 days 
Posaconazole 
1.3-
fold 
3-fold 
ND 
Isavuconazole 
2-fold 
3-fold 
10-fold 
Itraconazole 
2-fold 
2-fold 
ND 
Fluconazole 
1.3-
fold 
1.3-fold 
2-fold 
Note:   Although sirolimus and CNI doses may need to be substantially increased when azole therapy is stopped, the 
azole mediated inhibition of cytochrome CYP 3A4 (and other) and P-glycoprotein may take 5-10 days to 
abate and therefore immediate dose increases are not advised.  Rather, sirolimus and CNI dose increases 
should be cautious and based on more frequent monitoring of the sirolimus and/or CNI levels as appropriate.   
 
Additional considerations for calcineurin inhibitor (CNI) therapy: 
• Children generally require a larger total daily dose of CNI by weight than adults. If aged 
< 6 years, every 8 hour administration may be required to maintain desirable serum 
trough levels. For those patients in whom adequate serum trough levels cannot be 
maintained using intermittent oral or IV dosing, continuous IV infusion may be 
warranted.  
• Review of concomitant medications for potential interactions that may significantly 
alter serum CNIs levels is essential because CNIs undergo extensive metabolism by the 
hepatic and intestinal cytochrome P-450 system which may impact toxicity and efficacy 
of CNIs.   
• Although elevated CNI blood levels are more frequently associated with toxicity 
(especially renal or hepatic), “therapeutic” CNI blood levels may also be associated with 
toxicity (e.g. significant tremors). Therefore, dose decreases are recommended for 
significant organ toxicities that manifest despite a “therapeutic” CNI level. 
• Emesis: A repeat dose of CNI may be given if emesis happens within 15 minutes of 
taking the planned dose.  
• CNIs should be administered at a consistent time each day and in relation to meals.  
Neoral oral solution should be administered in orange or apple juice at room temperature.   


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• Subjects should avoid beverages containing the enzyme bergamottin (grapefruit juice, 
Sunny Delight, Fresca, and Squirt) when taking CNIs.  
• Distal paraesthetic pain or burning during the infusion may be alleviated by extending 
the IV infusion time for Sandimmune from the standard of 1 hour to as long as 6 hours. 
Alternatively, cyclosporine may be administered as a continuous infusion over 24 hours 
for patients intolerant of intermittent administration.  
• Monitor closely for an acute allergic reaction for the first 30 minutes after starting 
tacrolimus IV infusion and at frequent intervals thereafter.   
• Intravenous route of administration is preferred for patients with progressive GVHD 
of the liver or gastro-intestinal tract until GVHD is clinically improved and the oral 
route reliable. 
• If the oral route becomes temporarily unfeasible and conversion to the intravenous 
formulation is required the following recommendations are made: 
Starting Oral 
Formulation 
Conversion to IV formulation 
Prograf® 
IV Prograf = 0.25 x total daily dose of oral Prograf but should be 
given as continuous daily infusion 
Neoral® 
IV Sandimmune = 0.4 x total daily dose of Neoral 
Gengraf® 
IV Sandimmune = 0.4 x total daily dose of Gengraf 
Sandimmune® 
IV Sandimmune = 0.25 x total daily dose of oral Sandimmune 
 
2.5.4. 
Prednisone 
Patients randomized to steroids will receive prednisone 2mg/kg/day PO (or methylprednisolone 
1.6 mg/kg/day IV).  Patients unable to take tablets can use oral prednisolone solution 2 
mg/kg/day.  For patients that weigh over 100kg, maximal starting dose of prednisone will be 
200mg (or 2mg/kg based on a modified starting weight of 100kg). For calculation of subsequent 
prednisone doses/kg on subsequent measures, the modified starting weight of 100kg will be 
used. 
 
Duration of Steroids and Taper 
All patients should receive prednisone 2mg/kg/day PO (or methylprednisolone 1.6 mg/kg/day 
IV) for at least 3 full days (72 hours).  This starting dose was carefully selected for the following 
reasons: (1) Both the clinical and biomarker-based risk stratification systems have been 
developed in the setting of patients treated with this starting prednisone dose; (2) The 
2mg/kg/day starting dose was used in both BMT CTN 0302 and CTN 0802 trials, and expected 
prednisone response rates and allied power calculations for this trial are derived from this 
preliminary data; (3) Variable starting doses would confound the analysis of prednisone taper in 
this trial; (4) Prior randomized clinical trial data supported greater requirement for secondary 
systemic immune suppressive therapy in those treated with 1mg/kg vs. 2mg/kg starting dose.15 
Thereafter (after 72 hours of 2mg/kg/day dose), the decision of when and how to taper is at the 
discretion of the treating physician. A potential prednisone taper is provided in Appendix E. 
 


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2.5.5. 
GVHD Prophylaxis Medications 
Medications such as cyclosporine and tacrolimus (if used as GVHD prophylaxis when acute 
GVHD developed) should be continued at therapeutic doses adjusted as necessary for renal, 
central nervous system (CNS) or other toxicity using conventional management guidelines.   
 
2.5.6. 
Topical and Ancillary GVHD Therapies 
Topical skin therapy for acute GVHD, including skin creams, as well as GI topical agents (e.g., 
beclomethasone or budesonide), are not encouraged on trial, however are not prohibited. Use of 
topical agents for management of acute GVHD will be recorded as a secondary endpoint 
assessment in this trial.  No rules or guideline for taper and discontinuation for topical agents is 
provided in this protocol. 
 
Ancillary/supportive care measures for acute GVHD such as the use of anti-motility agents for 
diarrhea, including octreotide, is allowed at the discretion of the treating physician.  Use of 
ursodiol to prevent/reduce gall bladder sludging, or prevent hepatic transplant complications is 
also allowed according to institutional guidelines. 
 
2.5.7. 
Management of study therapy after GVHD Progression or Non-response: 
The following guidelines describe intended management of initial randomized therapy and 
thresholds for starting secondary therapy: 
 
1. Initial randomized therapy should be given for at least 4 days before considering initiation of 
secondary therapy. As progressive manifestations of GVHD (new organ involvement or 
increased organ specific symptoms sufficient to increase the organ stage by one or more)  can be 
ultimately stabilized and controlled in this initial therapy timeframe, secondary therapy should 
only be considered if GVHD continues to progress after this period. 
 
2. If no response (no improvement in any affected organ) is observed after 7-10 days of initial 
randomized therapy, secondary therapy can be considered.  
 


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CHAPTER 3 
 
 
3. 
STUDY ENDPOINTS 
 
3.1. 
Primary Endpoint 
The primary endpoint is the rate of complete remission (CR)/partial remissions (PR) on Day 28 
post-randomization in patients with standard-risk acute GVHD (defined by both refined 
Minnesota clinical standard-risk criteria and AA1/2 biomarker risk group).  Scoring of CR/PR 
are in comparison to the participant’s acute GVHD status (score) on the day of randomization. 
 
3.1.1. 
Response Definitions 
Scoring of CR, PR, MR, NR and progression are in comparison to the participant’s acute GVHD 
status (score) on the day of randomization. 
 
CR is defined as a score of 0 for the GVHD grading in all evaluable organs.  For example, 
for a response to be scored as CR at Day 56 or later, the participant must still be in CR on that 
day and have had no intervening additional therapy for an earlier progression, PR or NR.  
 
Partial response (PR) is defined as improvement in one or more organs involved with 
GVHD symptoms without progression in others.  For example, for a response to be scored as 
PR at Day 28 or later, the participant must still be in PR on that day and have had no intervening 
additional therapy for an earlier progression, PR or no response (NR).  
 
Mixed response (MR) is defined as improvement in one or more organs with deterioration 
in another organ manifesting symptoms of GVHD or development of symptoms of GVHD 
in a new organ. 
 
Progression is defined as deterioration in at least one organ without any improvement in 
others. 
 
No response (NR) is defined as absence of any improvement or progression as defined. 
Patients receiving secondary therapy (including need to re-escalate steroid dose to ≥ 2.5 
mg/kg/day of prednisone [or methylprednisolone equivalent of 2 mg/kg/day]) will be classified 
as non-responders. Patients who are assigned to the sirolimus arm who require initiation of 
systemic corticosteroids for the treatment of acute GVHD will be considered as non-responders 
for purposes of primary endpoint assessment. 
 
3.2. 
Secondary Endpoints 
 
3.2.1. 
Proportion of Patients with CR/PR and Steroid Dose 0.25 mg/kg or less 
The proportion of patients with an acute GVHD response on Day 28 (CR or PR) and who are on 
a prednisone (or prednisone dose-equivalent corticosteroid) dose of 0.25mg/kg/day or less. Note 


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that use of prednisone below the threshold on the sirolimus arm will not be considered a failure 
for this endpoint. 
 
3.2.2. 
Proportion of response 
Proportions of CR, PR, mixed response, no response and progression among surviving patients at 
Day 14, 28 and 56.  
 
3.2.3. 
Treatment Failure 
Treatment failure is defined as: death, no response, progression, administration of additional 
therapy beyond primary therapy for GVHD ((or re-escalation of steroid dose to ≥ 2.5 mg/kg/day 
of prednisone (or methylprednisolone equivalent of 2 mg/kg/day) or initiation of corticosteroids 
for the treatment of acute GVHD for patients assigned to the sirolimus arm), at Day 14, 28, and 
56. 
3.2.4. 
Incidence of Chronic GVHD 
Chronic GVHD is defined per NIH Consensus Criteria (see Appendix C).  The incidence of 
chronic GVHD at 6 and 12 months post-randomization will be computed for each treatment arm, 
including organ involvement and severity, and overall global composite score 
(mild/moderate/severe). 
 
3.2.5. 
Incidence of Systemic Infections 
All microbiologically documented infections or significant infections requiring 
antibiotic/antifungal therapy occurring after initiation of therapy will be reported by site of 
disease, date of onset, and severity.  For definitions see the BMT CTN MOP.   
 
3.2.6. 
Event-Free Survival 
Event-free survival is defined here as freedom from acute GVHD progression, chronic GVHD, 
malignancy relapse and mortality at 6 months and 12 months post-randomization. 
 
Malignancy relapse is defined as follows:  
 
Relapse is defined by either morphological or cytogenetic evidence of acute leukemia or MDS 
consistent with pre-transplant features, or radiologic evidence of lymphoma, documented or not 
by biopsy.  Progression of disease applies to patients with lymphoproliferative diseases 
(lymphoma or chronic lymphocytic leukemia) not in remission prior to transplantation.  The 
event is defined as increase in size of prior sites of disease or evidence of new sites of disease, 
documented or not by biopsy.  
 
 


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Acute leukemia and MDS – Relapse will be diagnosed when there is: 
- 
Reappearance of leukemia blast cells in the peripheral blood; or, 
- 
>5% blasts in the bone marrow, not attributable to another cause (e.g. bone marrow 
regeneration) 
- 
The appearance of previous or new dysplastic changes (MDS specific) within the bone 
marrow with or without falling donor chimerism; or  
- 
The development of extramedullary leukemia or leukemic cells in the cerebral spinal 
fluid or 
- 
The reappearance of cytogenetic abnormalities present prior to transplantation 
 
Lymphoproliferative Diseases – Relapse or progression will be diagnosed when there is: 
- 
Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size.  Increased FDG uptake in a 
previously unaffected site will only be considered relapsed or progressive disease after 
confirmation with other modalities. In patients with no prior history of pulmonary 
lymphoma, new lung nodules identified by CT are mostly benign.  Thus, a therapeutic 
decision should not be made solely on the basis of the PET without histologic 
confirmation. 
- 
At least a 50% increase from nadir in the sum of the product diameters of any previously 
involved nodes, or in a single involved node, or the size of other lesions (e.g., splenic or 
hepatic nodules).  To be considered progressive disease, a lymph node with a diameter of 
the short axis of less than 1.0 cm must increase by  50% and to a size of 1.5 x 1.5 cm or 
more than 1.5 cm in the long axis.  
Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the 
lesion was PET positive before therapy unless the lesion is too small to be detected with 
current PET systems (<1.5 cm in its long axis by CT). 
- 
In addition to the criteria above, patients with CLL who present in complete remission 
prior to transplantation may fulfill the relapse definition if there is reappearance of 
circulating malignant cells that are phenotypically characteristic of CLL.  
 
*Institution of any therapy to treat persistent, progressive or relapsed malignancy, 
including the withdrawal of immunosuppressive therapy or donor lymphocyte infusion, 
will be considered evidence of relapse/progression regardless of whether the criteria 
described above were met.  
 
3.2.7. 
Disease-free and Overall Survival  
Disease-free survival at 6 and 12 months post randomization. The events for disease-free 
survival are death and relapse of the underlying malignancy (see above – section 3.2.6 - 
definition for relapse/progression). Overall survival will be estimated at 6 and 12 months post-
randomization. 
 


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3.2.8. 
GVHD-Free Survival 
GVHD-free survival will be estimated at 6 and 12 months post-randomization.  Both acute and 
chronic GVHD will be considered in this estimate. 
 
3.2.9. 
Non-relapse Mortality 
Non-relapse mortality at 6 and 12 months. The events for non-relapse mortality are death due to 
any cause other than relapse of the underlying malignancy. 
 
 
3.3. 
Exploratory Endpoints 
 
3.3.1. 
Steroid Dose 
Doses of methylprednisolone will be converted to prednisone equivalents by multiplying the 
methylprednisolone dose by 1.25.  The prednisone dose for each patient at Days 7, 14, 21, 28, 
35, 42, 49, and 56 will be recorded. Prednisone doses for each patient will be converted to 
mg/kg. For patients that weigh over 100kg, maximal starting dose of prednisone will be 200mg 
(or 2mg/kg based on a modified starting weight of 100kg). For calculation of subsequent 
prednisone doses/kg on subsequent measures, the modified starting weight of 100kg will be 
used. The cumulative prednisone dose for each patient at Day 56 will be calculated by adding the 
doses (end of each week’s dose) for each of the first eight weeks of treatment, divided by the 
number of days of survival during this interval.   
 
3.3.2. 
Topical Therapy 
The proportion of patients using either topical skin or topical GI steroids will be calculated as a 
secondary endpoint.  Use of topical agents does not constitute systemic therapy, and does not 
result in designation of treatment failure. 
 
3.3.3. 
Discontinuation of Immune Suppression 
The dates of discontinuation of corticosteroids and other systemic immune suppressive 
medications will be recorded. Incidence of discontinuation of immune suppression will be 
assessed at Days 56, 180, and 365 post-therapy. A composite endpoint of complete immune 
suppression discontinuation together with freedom from any GVHD or malignancy 
progression/recurrence will also be examined. 
 
 
3.3.4. 
Incidence of EBV-associated lymphoproliferative disorder 
Incidence of EBV-associated lymphoproliferative disorder and EBV reactivation requiring 
therapy, such as reduction or withdrawal of immunosuppression, Rituximab or chemotherapy. 
 
 
3.3.5. 
Steroid- and sirolimus- associated complications (collected in all patients): 
 


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Incidence of hyperglycemia 
Incidence of hyperglycemia (defined as a random glucose >200mg/dL or fasting glucose 
>126mg/dL) and use of diabetes therapy (use of insulin and/or oral medications to control and/or 
maintain glucose levels) at baseline, Day 28 and Day 56. 
 
 
Functional Myopathy 
Change from baseline in functional myopathy score at Day 56 and 6-months post-randomization. 
i. 
Hip Flexor and Quadriceps Strength via handheld dynamometer 
ii. 
Two Minute Walk Test 
iii. 
5-time Sit-to-Stand 
iv. 
Adult Myopathy Assessment Tool (AMAT)  
 
Hyperlipidemia 
Incidence of hyperlipidemia as measured by fasting lipid panel at baseline, Days 28, 56 and 180 
post-randomization.  The proportion of patients in each study arm with elevation outside of 
normal range for each of the measured components of the fasting lipid panel (e.g. total 
cholesterol, LDL, HDL, and triglycerides) will be compared.  Lipid parameters and use of lipid-
lowering medications will be collected.   
 
Post-transplant thrombotic microangiopathy 
Incidence of post-transplant thrombotic microangiopathy (TMA) by 6 months post-
randomization. TMA definition is provided in section 2.5.3.3. 
 
3.3.6. 
CMV-reactivation 
Proportion of patients requiring new systemic treatment for an increasing CMV PCR level per 
institutional practice (patients receiving only standard of care viral prophylaxis will not be 
included in this assessent) for CMV-reactivation by Day 56 post-randomization. 
 
3.3.7. 
Patient-reported Outcomes 
These instruments will be completed by patients at enrollment, Day 56, 6 months, and 12 
months. Only English speaking adult and pediatric patients, and Spanish speaking adult patients 
are eligible to participate in the Health Quality of Life (HQL) component of this trial.  Patients 
>18 years will complete the FACT-BMT, MOS SF-36 and MDASI instruments. Patients > 8 
years through 18 years will complete the PedsQL™ Stem Cell Transplant Module. Surveys are 
completed by participants using self-completed instruments as a first choice.  If this method of 
data collection is not possible, then surveys and response options may be read verbatim to 
participants, either in person or over the phone, to collect data.  The method of survey 
completion, the date, and the language will be recorded in the database.  Surveys may not be 
completed by surrogates. 
 
Change in patient-reported outcomes from enrollment to Day 56 and 6 months will be calculated. 
 


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a. 
MD Anderson Symptom Inventory (MDASI) 
 
The MDASI is a 19 item instrument that captures 13 symptoms (0=“not present” to 10=“as bad 
as you can imagine”) and 6 items measuring interference with life from 0 (“did not interfere”) to 
10 (“interfered completely”)16.    It provides two summary scales: symptoms and interference.  
The MDASI will be scored according to the recommendations of the developers.  We estimate it 
will take 5 minutes to complete the MDASI.  Surveys are completed by participants using self-
completed instruments as a first choice.  If this method of data collection is not possible, then 
surveys and response options may be read verbatim to participants, either in person or over the 
phone, to collect data.  Surveys may not be completed by surrogates. 
b. 
FACT-BMT 
 
The FACT-BMT, Version 4 is a self-administered instrument designed to assess multi- 
dimensional aspects of the QOL in BMT patients. It consists of the 27-item FACT-General 
(FACT-G) and the 23-item Bone Marrow Transplantation Subscale (BMTS).17 The FACT-G 
assesses four primary dimensions of QOL, including physical well-being (7 items), social/family 
well-being (7 items), emotional well-being (6 items), and functional well-being (7 items). A five 
point Likert-type response scale ranging from 0 to 4 is used (0 = 'not at all'; 1 = 'a little bit'; 2 = 
'somewhat'; 3 = 'quite a bit'; and 4 = 'very much').  The original FACT-BMT was developed in 
English using a standardized approach for item derivation, reduction and testing, and has been 
used extensively in various clinical trials. The FACT-BMT has since been translated into other 
languages. 
 
c. 
MOS Short Form 36 (SF-36)  
 
The MOS SF-36 Version 2 is a 36-item self-report questionnaire which assesses patient-reported 
health and functioning.18 The instrument examines the following domains of QOL: physical 
functioning (PF), role functioning-physical (RP), bodily pain (BP), general health (GH), vitality 
(VT), social functioning (SF), role functioning-emotional (RE), and mental health (MH). Two 
summary scales from the SF-36 include the physical component score (PCS) and the mental 
component score (MCS). 
 
d. 
PedsQL  
 
The PedsQL measurement model for pediatric quality of life inventory is a multi-dimensional 
tool for monitoring health-related quality of life (HRQOL) in children and adolescents (age 2-
18).19 Age-specific versions for younger and older children are available. Physical, emotional, 
social, and school functioning are assessed. The PedsQL™ Stem Cell Transplant Module is a 46 
item instrument that measures health-related quality of life in children and adolescents 
undergoing hematopoietic stem cell transplant, and is developmentally appropriate for self-report 
in ages 8 through 18 years.20 
 
3.3.8. 
AA3 Biomarker Outcomes 
A secondary descriptive analysis will evaluate outcomes for AA3 patients. Patients with a 
missing AA result will be excluded. 


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4-1 
CHAPTER 4 
 
 
4. 
PATIENT ENROLLMENT AND EVALUATION 
 
4.1. 
Approaching Patients, Eligibility Screening and Obtaining Consent 
 
Patients with previously untreated, standard-risk acute GVHD, according to the refined 
Minnesota Criteria, who are in need of systemic therapy, will be approached as soon as possible.  
Patients willing to participate in the trial will sign an Institutional Review Board approved 
consent form.   Physicians will further evaluate each patient’s eligibility for randomization onto 
this study (see Section 2.4).  
 
4.2. 
Enrollment/Randomization 
 
Patients will be enrolled/randomized onto the study using the BMT CTN Advantage Electronic 
Data Capture (EDC).  Patients will be randomized to Sirolimus versus Prednisone in a 1:1 ratio.  
The following procedures shall be followed: 
1. An authorized user at the clinical center completes the initial screening by entering 
patient demographics and Segment A information (consent date, inclusion/exclusion 
criteria and confirmation that 5 mL of blood has been collected for Ann Arbor Scoring) 
on the Eligibility Form. 
2. If the patient is eligible, a study number and random treatment assignment is generated. 
3. A visit schedule based on enrollment date is displayed for printing. 
4. Immediately after randomization, the 5 ml blood sample will be shipped priority 
overnight for early morning arrival at the Biomarker Laboratory of the Icahn School of 
Medicine at Mount Sinai for biomarker analysis. 
If a connection is interrupted during a randomization session, the process is completely canceled 
and logged.  A backup manual registration and randomization system will also be available to 
provide for short-term system failure or unavailability. 
 
4.2.1. 
Treatment  
Treatment should be initiated as soon as possible after randomization.  A maximum of 24 hours 
is allowable.  
 
As per section 2.5.2, the patient’s Ann Arbor results will be provided to the treating physician 
within 48-72 hours of study enrollment/randomization. Patients with AA1/2 status will continue 
on their randomized therapy. In contrast, patients with AA3 status and patients with missing 
biomarker results may continue on the randomized therapy, or another therapy per individual 
treating physician discretion. 
 
 


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4.3. 
Study Monitoring 
 
4.3.1. 
Follow-up Schedule 
The Follow-up Schedule for scheduled study visits is outlined in Table 4.3. A detailed 
description of each of the forms and the procedures required for forms completion and 
submission can be found in the Data Management Handbook and User’s Guide. 
 
Follow-up Assessments: The timing of follow-up visits is based on the date of randomization.  
Following randomization, the Transplant Center can print a Patient Visit Schedule listing target 
dates for assessments.  Weeks 1-8 visits are primarily for acute GVHD scoring.  The subsequent 
visits are for follow-up reports. 
 
 
 


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Table 4.3 
 FOLLOW-UP SCHEDULE 
 
Assessment Time 
Target Day1 
(Days Post-Enrollment) 
1 week 
7 days 
2 weeks 
14 days 
3 weeks 
21 days 
4 weeks 
28 days 
5 weeks 
35 days 
6 weeks 
42 days 
7 weeks 
49 days 
8 weeks 
56 days 
90 days 
90 days 
6 months 
180 days 
12 months 
365 days 
1Target day range = 3 days for Day 7 (subsequent 
visits through Day 56 must be scheduled weekly and 
within 3 days of target date). Target day range 14 
days for Day 90 and 6 months; and 28 days for 12 
months. 
Criteria for Forms Submission:  
All data for patients are recorded in the electronic Case Report Forms (eCRF) exclusively 
designed for the study.  The Principal Investigator at each of the participating centers is 
responsible for complete, accurate and timely reporting of data. 
 
Criteria for timeliness of submission for all study forms are detailed in the Data Management 
Handbook and User’s Guide.  Forms that are not entered into AdvantageEDC within the 
specified time will be considered delinquent.  A missing form will continue to be requested 
either until the form is entered into the AdvantageEDC and integrated into the Data and 
Coordinating Center’s (DCC) master database, or until an exception is granted and entered into 
the Missing Form Exception File, as detailed in the Data Management Handbook. 
 
Corrections in the eCRF are to be conducted only by authorized personnel and may require 
authorization prior to implementation of corrections. However, all earlier entries are retrievable 
despite corrections.  All corrections are recorded automatically concerning date, time point and 
person. Plausibility and completeness of the eCRF are verified by personnel at the Data 
Coordinating Center.   
 
At all times, the Principal Investigators at the participating centers have full responsibility for 
ensuring accuracy and authenticity of all clinical and laboratory data entered on the eCRFs. 
 


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Reporting Patient Deaths: The Recipient Death Information must be entered into the web-
based data entry system within 24 hours of knowledge of a patient’s death.  If the cause of death 
is unknown at that time, it need not be recorded at that time.  However, once the cause of death is 
determined, the form must be updated. 
 
Center for International Blood and Marrow Transplant Research (CIBMTR) Data 
Reporting: Centers participating in BMT CTN trials must register pre and post-transplant 
outcomes on all consecutive hematopoietic stem cell transplants done at their institution during 
their time of participation to the Center for International Blood and Marrow Transplant Research 
(CIBMTR).  Registration is done using procedures and forms of the Stem Cell Transplant 
Outcomes Database (SCTOD).  (Note: Federal legislation requires submission of these forms for 
all US allotransplant recipients.)  Additionally, CIBMTR pre- and post- transplant Report Forms 
must also be submitted for all patients enrolled on this trial according to the randomization 
assigned to the patient at the time of initial registration with the CIBMTR.  Long-term follow-up 
of patients on this study will continue through routine CIBMTR mechanisms. 
 
4.4. 
Assessments 
 
All assessments are considered standard-of-care unless identified below by “*.” 
 
Prior to Enrollment/Randomization  
 The following pre-enrollment/randomization assessments must be completed within the 
designated timeframe listed below. 
 
1. Protocol-required 5 ml of blood (red top for serum) for the determination of biomarker 
risk status collected immediately prior to enrollment/randomization.   
2. Complete acute GVHD staging and grading information including assessments of rash, 
diarrhea, nausea/vomiting, weight and liver function tests; Biopsy (if done) of involved 
tissue (standard of care, not research) within 24 hours prior to enrollment. 
3. Recording of all systemic immune suppressive therapy (as appropriate: tacrolimus, 
cyclosporine, etc.), as well as topical agents within 24 hours prior to enrollment. 
4. History and physical exam including height and weight, patient/disease/transplantation 
baseline variables within 7 days prior to enrollment. 
5. CBC with differential, platelet count within 7 days prior to enrollment. 
6. Liver function tests (bilirubin, alkaline phosphatase, AST, ALT) plus creatinine within 7 
days prior to enrollment. 
7. Pregnancy test per institutional practice (if applicable) within 30 days prior to enrollment. 
The 5 ml blood sample for biomarker analysis must be shipped as soon as possible after 
randomization to the Biomarker Laboratory of the Icahn School of Medicine at Mount 
Sinai (see Appendix B). 
 
Prior to Initiation of Study Therapy  


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Baseline assessments must be completed within 48 hours prior to initiation of study therapy 
unless otherwise indicated. 
1. Karnofsky or Lansky Performance Status 
2. Toxicity assessment 
3. Baseline patient-reported outcome measures (M.D. Anderson Symptom Inventory, 
FACT-BMT, SF-36, or PedsQL (Pediatrics)*  Only English speaking adult and pediatric 
patients, and Spanish speaking adult patients are eligible to participate in the Health 
Quality of Life (HQL) component of this trial.  Patients >18 years will complete the 
FACT-BMT, MOS SF-36 and MDASI instruments. Patients > 8 years through 18 years 
will complete the PedsQL™ Stem Cell Transplant Module. 
4. OPTIONAL 40 mL blood sample for research laboratory studies (see Appendix B) * 
Patients with weight < 13 kg will have 3 mL/kg collected. 
 
Baseline assessments required to be done as close to enrollment (day 0) as possible 
1. Baseline myopathy assessments* (may be done up to 96 hours after enrollment) 
a. Hip Flexor and Quadriceps Strength via handheld dynamometer 
b. Two Minute Walk Test 
c. 5-time Sit-to-Stand 
d. Adult Myopathy Assessment Tool (AMAT)  
 
2. Fasting lipid profile (may be done up to 96 hours after enrollment) 
 
Post-Randomization  
The following post-randomization assessments are required of all patients, regardless of therapy 
received. 
1. Karnofsky or Lansky performance status at Days 56, 90, 180 and 365  
2. Complete acute GVHD staging and grading information including assessments of rash, 
diarrhea, nausea/vomiting, weight and liver function tests weekly through Day 56; Day 
90, 6 and 12 months 
3. Chronic GVHD evaluation (if present) Day 28, 56, 90, and 6 and 12 months 
4. CBC with differential, chemistry (including liver function tests) weekly through Day 56; 
Day 90, 6, and 12 months  
5. Fasting lipid profile at Day 28, 56, and 6 months 
6. Toxicity evaluation weekly through Day 56; Day 90, 6 months and 12 months 
7. Recording of all systemic immune suppression, including steroid dose and drug levels (as 
appropriate for sirolimus, cyclosporine, tacrolimus) weekly through Day 56, Day 90, 6, 
and 12 months. Second-line immune suppressive therapy (therapy beyond initial 


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randomized therapy of either sirolimus or prednisone) should be recorded at each of these 
time points. 
8. Use of topical (skin, GI) steroid agents weekly through Day 56; Day 90, 6 and 12 
months. 
9. Data on systemic infections, and EBV PTLD (or EBV requiring therapy), recorded as per 
the BMT CTN (Technical) MOP through 12 months. 
10. EBV & CMV monitoring as per institutional practice. 
11. Myopathy assessments at Day 56 and 6 months.* 
a. Hip Flexor and Quadriceps Strength via handheld dynamometer 
b. Two Minute Walk Test 
c. 5-time Sit-to-Stand 
d. Adult Myopathy Assessment Tool (AMAT)  
12. Patient reported outcomes (M.D. Anderson Symptom Inventory, FACT-BMT, SF-36, or 
PedsQL (Pediatrics)) at Day 56, 6 months and 1 year.* Only English speaking adult and 
pediatric patients, and Spanish speaking adult patients are eligible to participate in the 
Health Quality of Life (HQL) component of this trial.  Patients >18 years will complete 
the FACT-BMT, MOS SF-36 and MDASI instruments. Patients > 8 years through 18 
years will complete the PedsQL™ Stem Cell Transplant Module. 
13. OPTIONAL 30-40 mL blood samples for research laboratory studies at Day 7, 28, and 56 
(see Appendix B).* Patients with weight <13 kg will have ≤3 mL/kg collected at each 
individual time point. 
 


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4-7 
Table 4.4 – REQUIRED ASSESSMENTS 
 
Pre- 
Randomize 
Pre- 
Therapy 
Days Post Randomization 
 
Baseline  
7* 
14* 
21* 
28* 
35* 
42* 
49* 
56 *  
90** 
180*** 365*** 
History and physical exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (if applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky/Lansky performance status 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
Acute GVHD evaluation 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chronic GVHD evaluation 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
X 
CBC with differential, platelet count 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Basic chemistry (creatinine) 
X 
 
X 
X 
X 
X 
X 
X 
X- 
X 
X 
X 
X 
Liver function tests (alkaline phosphatase, bilirubin, AST, ALT) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting lipid profile 
 
X1 
 
 
 
X 
 
 
 
X 
 
X 
 
Toxicity and AE evaluation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Recording of all systemic immune suppression, including steroid dose 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug level monitoring (e.g. tacrolimus, cyclosporine) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Use of second-line immune suppressive therapy 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Use of topical agents 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Malignancy relapse, death 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Systemic infections 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EBV PTLD, or EBV requiring therapy 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMV reactivation requiring therapy 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Myopathy assessments 
 
X2 
 
 
 
 
 
 
 
X 
 
X 
 
Patient-reported outcomes: MDASI, FACT-BMT, MOS SF-36, PedsQL3 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
REQUIRED 5 mL blood sample for Ann Arbor Panel Scoring collection 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
OPTIONAL Research blood samples for ancillary studies (see Appendix 
B)5 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
*      +/- 3 days to allow for scheduling flexibility, holidays, etc.  Subsequent visits through Day 56 must be scheduled weekly. 
**    +/- 14 days to allow for scheduling flexibility 
***  +/- 28 days to allow for scheduling flexibility 
1   The fasting lipid panel may be done up to 96 hours after enrollment. 
2      Myopathy assessments may be done up to 96 hours after enrollment. 
3   Only English speaking adult and pediatric patients, and Spanish speaking adult patients are eligible to participate in the Health Quality of Life (HQL) component of this trial.  Patients >18 years 
will complete the FACT-BMT, MOS SF-36 and MDASI instruments. Patients > 8 years through 18 years will complete the PedsQL™ Stem Cell Transplant Module. 
4    Required blood sample for Ann Arbor Scoring must be collected prior to enrollment/randomization and shipped overnight immediately afterwards. 
5    Patients with weight < 13 kg will have ≤3 mL/kg collected 
 


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4.5. 
Weekly GVHD Monitoring 
 
GVHD scoring will be performed weekly for 8 weeks from study entry.  Days 0, 28 and 56 (+3 
days) scoring must be performed by direct observation at the Transplant Center.  Evaluations at 
other time points may be performed by competent clinicians other than at the Transplant Center 
but Transplant Center is responsible for collecting all required data. 
 
4.6. 
Adverse Event Reporting 
 
Adverse Event: An adverse event (AE) is any undesirable sign, symptom or medical condition 
or experience that develops or worsens in severity after starting the first dose of study treatment 
or any procedure specified in the protocol, even if the event is not considered to be related to the 
study.   
 
Expectedness: An adverse event can be Expected or Unexpected  
• Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is considered 
expected when it appears in the current adverse event list, the Investigator’s Brochure, 
the package insert or is included in the informed consent document as a potential risk. 
• Unexpected adverse events are those that vary in nature, intensity or frequency from 
information in the current adverse event list, the Investigator’s Brochure, the package 
insert, or when it is not included in the informed consent document as a potential risk. 
 
Serious Adverse Event: A serious adverse event (SAE), as defined by 21 CFR 312.32, is any 
adverse event that results in one of the following outcomes, regardless of causality and 
expectedness:  
• Results in death 
• Is life-threatening. Life-threatening means that the person was at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form. 
• Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-
hour hospitalization or prolonged a hospitalization beyond the expected length of stay). 
Hospitalization admissions and/or surgical operations scheduled to occur during the study 
period, but planned prior to study entry are not considered SAEs if the illness or disease 
existed before the person was enrolled in the trial, provided that it did not deteriorate in 
an unexpected manner during the trial (e.g., surgery performed earlier than planned). 
• Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
• Is a congenital anomaly or birth defect; or 
• Is an important medical event when, based upon appropriate medical judgment, it may 
jeopardize the participant and require medical or surgical intervention to prevent one of 


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the outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home; blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
Medical and scientific judgment should be exercised in deciding whether expected reporting is 
also appropriate in situations other than those listed above.  For example, important medical 
events may not be immediately life threatening or result in death or hospitalization but may 
jeopardize the subject or may require intervention to prevent one of the outcomes listed in the 
definition above (e.g., suspected transmission of an infectious agent by a medicinal product is 
considered a Serious Adverse Event). Any event is considered a Serious Adverse Event if it is 
associated with clinical signs or symptoms judged by the investigator to have a significant 
clinical impact. 
 
4.6.1. 
Required Adverse Event Reporting 
Adverse event reporting will be consistent with BMT CTN procedures (BMT CTN 
Administrative Manual of Procedures, Chapter 6). It is BMT CTN policy that AEs must be 
reported even if the investigator is unsure whether a relationship exists between the adverse 
event and the use of study treatment.  Unexpected, serious adverse events (SAEs) will be 
reported through an expedited AE reporting system via AdvantageEDC.  Unexpected, life-
threatening and fatal SAEs must be reported within 24 hours of knowledge of the event.  All 
other unexpected SAEs must be reported within three business days of knowledge of the event.  
Events entered in AdvantageEDC will be reported using NCI’s Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.0.  Expected AEs will be reported using NCI’s Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on 
the Form Submission Schedule. Any expected life-threatening SAE not collected on another 
study form must be reported through the expedited AE reporting system via AdvantageEDC. 
 
The Data and Safety Monitoring Board will receive summary reports of all unexpected SAEs on 
a semi-annual basis. 
 
 


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5-1 
CHAPTER 5 
 
 
5. 
STATISTICAL CORRELATIONS 
 
5.1. 
Study Design 
 
The study is designed as a Phase II randomized, open label, multicenter trial to identify whether 
sirolimus is a potential alternative to prednisone as an up-front treatment for patients with 
standard risk acute GVHD (defined by both refined Minnesota standard clinical risk and AA1/2 
biomarker risk group).  The hypothesis is that sirolimus will produce comparable response rates 
while also reducing steroid burden in this population. As this is the first trial prospectively 
assessing sirolimus in a multicenter setting, the trial is not designed to formally declare non-
inferiority but rather to estimate the difference in response rates between the sirolimus arm and 
the prednisone (or standard of care) arm. Estimation of this difference along with establishing 
more precise estimates for a key secondary endpoint with a response definition incorporating a 
measure of steroid burden (requirement a patient is on less than 0.25 mg/kg at Day 28) will allow 
assessment of sirolimus as a potential upfront treatment for GVHD response.  
 
Patients will be randomized to either sirolimus or prednisone.  The primary endpoint is complete 
or partial response (relative to their GVHD status on the day of randomization) on Day 28 post-
randomization with secondary endpoints assessing alternate definitions of efficacy, safety, 
steroid burden and quality of life. The target enrollment is 120 eligible, randomized AA1/2 
patients. One hundred and fifty patients are expected to be randomized as approximately 20% of 
randomized patients will have AA3 status results or missing biomarker results and be removed 
from the primary analysis (see the Primary Endpoint Section for details). 
 
5.1.1. 
Accrual 
It is estimated that accrual will take 2 years. 
 
5.1.2. 
Randomization 
Randomization will be performed in a 1:1 ratio using random block sizes for the two arms and 
stratified by transplant center.   
 
5.1.3. 
Primary Endpoint 
The primary endpoint of the study is defined in Chapter 3. Briefly, the primary endpoint is 
complete or partial response of acute GVHD (as compared to status at day of randomization) on 
Day 28 post-randomization. Note that patients classified as AA3 per the biomarker criteria and 
patients with missing biomarker results will be excluded from the primary analysis (i.e. primary 
and secondary endpoints) population and described in a secondary analysis. 
 
5.1.4. 
Primary Hypothesis 
The primary hypothesis is that up front treatment with sirolimus will result in comparable CR/PR 
rates as up front treatment with prednisone. No formal hypothesis testing will take place. Instead 


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5-2 
the difference in response rates between the two arms will be estimated with a 90% confidence 
interval.  
 
5.1.5. 
Sample Size and Power Considerations 
The primary endpoint is CR/PR at Day 28 post-randomization. Background data on treatment 
with sirolimus is available for 27 standard risk (Minnesota Criteria) patients. The overall CR/PR 
rate in the population was 88.9% (95% CI 77.0%, 100.0%). If patients receiving any level of 
prednisone are considered failures (per Chapter 3) then the observed CR/PR rate was 55.6% 
(95% CI 36.8%-74.3%). Considering background data from BMT CTN 0802, data were 
available for 95 placebo treated patients meeting the standard risk criteria at GVHD onset. The 
response rate in that population was 64.2% (95% CI 54.6%-73.9%). Note that PR was not 
formally adjudicated by the Endpoint Review Committee for BMT CTN 0802. Instead a 
response of Better Grade (compared to grade at diagnosis) was adjudicated and considered here 
as a surrogate for PR. While the point estimates differ slightly, the confidence intervals for the 
two populations are overlapping. Table 5.1 shows the lower bound of a 90% asymptotic 
confidence interval given two scenarios: 1) success rate of 60% in each arm and 2) success rate 
of 60% in the prednisone arm and 50% in the sirolimus arm (sirolimus response rate is 10% 
lower). 
Table 5.1: Lower Bound of Asymptotic 90% Confidence Interval For Difference in 
Response Rates Between Sirolimus and Prednisone Arms Assuming Equal Rates (60%) 
and a 10% Lower Response Rate in the Sirolimus Arm With a 20% Inflation Due To 
Biomarker Results 
Randomized Analyzed 
N Analyzed Per 
Arm 
Lower Bound of 
90% Confidence 
Interval Assuming 
No Difference 
Between 
Treatment Arms* 
Lower Bound of 
90% Confidence 
Interval Assuming 
Sirolimus 
Response Rate is 
10% Lower* 
125 
100 
50 
-16% 
-26% 
150 
120 
60 
-15% 
-25% 
175 
140 
70 
-14% 
-24% 
200 
160 
80 
-13% 
-23% 
225 
180 
90 
-12% 
-22% 
250 
200 
100 
-12% 
-22% 
* Difference calculated as Sirolimus response rate minus Prednisone response rate. 
 
The number randomized assumes that 20% of randomized patients will have biomarker results 
indicating high risk disease (AA3) or missing biomarker results. Note that 60 analyzable patients 
per arm (150 randomized) will result in a lower bound of 15% assuming that the success rates in 
the two populations are equivalent. If sirolimus is 10% worse than the prednisone arm, the lower 
bound of the confidence interval will exceed 15%. Difference in Day 28 CR/PR rate across the 
two arms will be reported with associated 90% confidence interval, however no pre-planned 
difference or width of confidence interval will be used to indicate failure of either arm or serve 


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as a requirement for consideration of secondary endpoints (i.e. formal non-inferiority will not be 
declared in this trial). A key secondary endpoint is the proportion of patients in CR/PR with a 
steroid dose of ≤0.25 mg/kg by Day 28. Of the 95 placebo patients, 22.1% (95% CI 13.8% - 
30.5%) achieved a CR/PR by Day 28 and were receiving ≤0.25 mg/kg. This estimate may not be 
reliable, however, as the taper for BMT CTN 0802 suggested a minimum of 0.25 mg/kg on Day 
28 as such this may be an underestimate of the true rate. Using the upper end of the confidence 
interval, sixty patients per arm would provide 80.6% power (two-sided 5% type 1 error rate) to 
test for a difference of 25% between the two groups (30% Prednisone vs. 55% Sirolimus). 
 
5.2. 
Interim Analysis and Stopping Guidelines 
 
5.2.1. 
Interim Analysis 
There will be no interim analyses for efficacy or futility as this is a small phase II study. 
 
5.2.2. 
Guidelines for Safety Monitoring 
Monitoring of two key safety endpoints will be conducted monthly, and if rates significantly 
exceed pre-set thresholds, the NHLBI will be notified in order that the DSMB can be advised.  
Policies and composition of the DSMB are described in the BMT CTN's Manual of Procedures.  
The stopping guidelines serve as trigger for consultation with the DSMB for additional review. 
The key safety endpoints for this study are: 1) failure of sirolimus therapy with a failure for the 
stopping rule defined as the addition of a systemic immune suppressive therapy beyond 
prednisone among those patients originally treated with sirolimus and 2) overall mortality. Both 
of these endpoints will be monitored among AA1/2 patients only; failure of sirolimus therapy 
will be monitored in the sirolimus arm only. 
 
5.2.2.1 Day 42 Failure of Sirolimus Therapy 
 
The rate of sirolimus failure will be monitored up to 42 days post-randomization.  At least three 
events must be observed in order to trigger review.  The expected probability of 42 day sirolimus 
failure is approximately 25-30% (estimate derived from primary sirolimus monotherapy data, as 
well as anticipated rate of secondary therapy use beyond prednisone in prior BMT CTN aGVHD 
therapy trials).11,12  Each month, the null hypothesis that the 42-day sirolimus failure rate is less 
than or equal to 25% is tested.  For this rule, a binomial sequential probability ratio test (SPRT) 
will be implemented.  
 
This sequential testing procedure conserves type I error at 5% across all of the monthly 
examinations for the sirolimus arm.  The SPRT can be represented graphically.  At each monthly 
interim analysis, the number of evaluable patients on study is plotted against the total number of 
treatment failures.  The continuation region of the SPRT is defined by two parallel lines.  Only 
the upper boundary will be used for monitoring to protect against excessive 42-day sirolimus 
failure.  If the graph crosses the upper boundary, the SPRT rejects the null hypothesis, and 
concludes that there are more events than predicted by the number of evaluable patients on study.  
Otherwise, the SPRT continues until enrollment is complete. Only failures that occur on or 
before the patient has been followed for 42 days are counted.   
 


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5-4 
The boundaries for the binary SPRT were constructed by setting the null rate of sirolimus failure 
to be 25% versus an alternative of 50% for 42-day sirolimus failure. To construct the boundary, 
the nominal type I and type II errors were set to be 10% and 5% respectively. The upper 
boundary is defined by a slope of 0.36907 and an upper intercept of 2.04921. Since the upper 
boundary alone is being used, the actual type I error of the binomial SPRT will be less than the 
nominal value without a substantial increase in type II error for the alternatives of interest (i.e. 
sirolimus therapy failure rates higher than expected). Table 5.2.1 illustrates the number of 
observed events required to cross the boundary for the binomial SPRT. 
TABLE 5.2.1:  Safety Monitoring Guidelines for Failure of Sirolimus Therapy 
Number Evaluable Patients Number of Events On or Prior to Day 42 
4-5 
4 
6-7 
5 
8-10 
6 
11-13 
7 
14-16 
8 
17-18 
9 
19-21 
10 
22-24 
11 
25-26 
12 
27-29 
13 
30-32 
14 
33-35 
15 
36-37 
16 
38-40 
17 
41-43 
18 
44-45 
19 
46-48 
20 
49-51 
21 
52-54 
22 
55-56 
23 
57-59 
24 
60 
25 


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5-5 
5.2.2.2 Day 56 Overall Mortality 
 
Day 56 overall mortality is the second key safety endpoint. This endpoint will be monitored 
within each treatment arm using an extension of the (SPRT) for censored exponential data, as 
described in greater detail below and in Appendix D. In brief, unlike the binary SPRT which 
assesses the event rate in the number of evaluable patients, the censored exponential SPRT 
considers the number of events relative to the total at risk time observed on study. The SPRT is 
represented graphically with the number of events on the y-axis and the total at risk time on the 
x-axis. The upper boundary of the SPRT will be used to guard against excess mortality. This 
procedure assumes a censored exponential distribution for overall mortality during the first 56 
days, and censors follow-up time after 56 days.  
 
Based on background data for standard risk acute GVHD patients, the expected Day 56 overall 
mortality is 13.1%. As this estimate includes AA3 patients in addition to AA1/2, to be 
conservative, the null for the monitoring bound will be set at 10%. An SPRT contrasting 10% vs 
25% Day 56 overall mortality results in decision boundaries with a common slope of 1.18 and an 
upper intercept of 2.29 based on nominal type 1 and type II errors of 9% and 10% respectively 
with the type I and II errors selected based on the simulation study and the actual operating 
characteristics of the SPRT shown in Table 5.2.2 that assumed uniform accrual of 60 individuals 
over a 24 month time period, and exponential time to failure after randomization.   
 
TABLE 5.2.2:  OPERATING CHARACTERISTICS OF SEQUENTIAL TESTING 
PROCEDURE FROM A SIMULATION STUDY WITH 10,000 REPLICATIONS 
Day 56 Overall Mortality 
True 56-Day Rate 
10% 
15% 
20% 
25% 
Probability Reject Null 
0.053 
0.281 
0.641 
0.888 
Mean Month Stopped 
25.2 
22.1 
16.8 
12.0 
Mean # Endpoints in 56 Days 
5.8 
7.6 
7.9 
7.0 
Mean # Patients Enrolled 
58.2 
51.6 
40.4 
29.6 
 
If the true Day 56 overall mortality rate is in line with the expected rate (i.e. 10%), then the 
stopping guideline has a 5% probability of being triggered. If the true overall mortality rate is 
higher than expected (i.e. 25% by Day 56), then the stopping guideline has an 89% probability of 
being triggered (on average 12 months after opening when 30 patients have been enrolled). 
 
No monitoring of secondary therapy delivered beyond prednisone will be performed in the 
prednisone arm, as this treatment is considered standard of care. We will prospectively monitor 
the rate of AA3 participants which is expected to be 20% of standard risk patients. This rate will 
be reported (with a 95% confidence interval) to the DSMB at each semiannual meeting to 
determine if the rate is higher than expected. 
5.2.3. 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for all patients.  Characteristics to 
be examined are: age, gender, race/ethnicity, performance status, primary disease, risk status, 
transplant conditioning therapy characteristics, donor type and HLA mismatch, graft source, 


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5-6 
initial GVHD prophylaxis delivered, donor and recipient CMV status, acute GVHD organ 
staging and overall grade at enrollment, topical steroid therapy use.  Between group comparisons 
will be performed for continuous variables via a t-test (or Wilcoxon Rank-Sum) and for 
categorical variables, via the chi-square test (or Fisher’s Exact as appropriate). 
 
5.2.4. 
Analysis of Primary Endpoint 
The difference in Day 28 CR/PR rates between arms will be estimated along with a 90% 
confidence interval. Note that patients classified as high risk per biomarker results and patients 
with missing biomarker results will be excluded from the primary analysis. In addition to the 
difference in rates, within arm CR/PR rates will be estimated with accompanying confidence 
intervals.   
 
5.2.5. 
Analysis of Secondary Endpoints 
Given the large number of secondary endpoints, a significance level of 5% will be used for all 
comparisons (and 95% confidence intervals). This provides some control of multiplicity without 
overly restricting the study’s ability to detect differences. 
 
1. Proportion of Patients with CR/PR and Steroid Dose 0.25 mg/kg or less 
This is a key secondary endpoint of the trial. The rates will be estimated within each arm and 
comparison between arms will occur using the Z test for binomial proportions (or Barnard’s 
Exact Unconditional as appropriate). 
 
2.  Proportion of response 
Proportions of complete, partial (PR), mixed response, no response and progression among 
surviving patients at Day 14, 28 and 56 will be compared between the treatment groups using the 
chi-square test (or Fisher’s Exact as appropriate).   
 
3.  Treatment Failure 
Proportion of primary treatment failures at Days 14, 28 and 56 will be compared using the Z test 
for comparing binomial proportions (or Barnard’s Exact Unconditional test as appropriate). 
4. Incidence of Chronic GVHD 
Cumulative incidence of chronic GVHD will be estimated (treating death and relapse as a 
competing risk) and curves will be compared using Gray’s test. Estimates and confidence 
intervals will be provided for 6 and 12 months post-randomization. 
 
5.  Incidence of Systemic Infections 
Frequencies of infections will be tabulated by site of disease, date of onset, and severity.  The 
time to first serious infection will be described using the cumulative incidence function with 
death as the competing risk, and compared between treatments using Gray’s test. 
 
6.  Event-Free Survival 
Event-free survival within each treatment group will be estimated using Kaplan-Meier 
methodology with event time being the earliest time a patient met one of the various criteria for 
failure or time of last follow-up for those patients not meeting the failure criteria. Pre-specified 


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5-7 
time points of interest are 6 and 12 months post-randomization. Estimates and confidence 
intervals will be calculated for these time points. 
 
7. Overall Survival  
Overall survival will be estimated using Kaplan-Meier methodology with event time being the 
earliest time of death or last follow-up. Pre-specified time points of interest are 6 and 12 months 
post-randomization. Estimates and  confidence intervals will be calculated for these timepoints. 
 
8.  Disease-Free Survival 
Disease-free survival will be estimated using Kaplan-Meier methodology with event time being 
the earliest time a patient experienced a relapse of underlying malignancy, death or last follow-
up. Pre-specified time points of interest are 6 and 12 months post-randomization. Estimates and  
confidence intervals will be calculated for these time points. 
 
9.  GVHD-Free Survival 
The proportion of patients alive and GVHD free at 6 and 12 months post-randomization will be 
estimated and compared between treatment groups using the Z test for comparing binomial 
proportions (or Barnard’s Exact Unconditional test as appropriate). 
 
10.  Non-relapse Mortality 
Cumulative incidence of non-relapse mortality will be estimated (treating relapse as a competing 
risk) and curves will be compared using Gray’s test. Estimates and confidence intervals will be 
provided for 6 and 12 months post-randomization. 
 
5.2.6. 
Analysis of Exploratory Endpoints 
The following endpoints and subgroup analyses are considered exploratory and will be analyzed 
at a significance level similar to the secondary endpoints. 
 
1. Steroid Dose 
Cumulative steroid dose will be described and compared between the treatment groups using a 
Wilcoxon Rank Sum test. 
 
2.  Topical Therapy 
The proportion of patients using either topical skin or topical GI steroids will be estimated within 
treatment group and by use at randomization. Among patients entering with no history of topical 
therapy, the proportion of patients initiating new topical treatment will be compared between 
treatment groups using the Z test for comparing binomial proportions (or Barnard’s Exact 
Unconditional test as appropriate). 
 
3. Discontinuation of Immune Suppression 
Cumulative incidence of immune suppression discontinuation will be estimated (treating death as 
a competing risk) and curves will be compared using Gray’s test. Estimates and confidence 
intervals will be provided for Day 56, 6 and 12 months post-randomization. 
 
4. Incidence of EBV-associated lymphoproliferative disorder 


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5-8 
The incidence of EBV-associated lymphoproliferative disorder or EBV reactivation therapy will 
be described using the cumulative incidence function, treating death as the competing risk.  
Cumulative incidence curves will be compared between treatments using Gray’s test. 
 
5. Incidence of hyperglycemia 
Incidence of hyperglycemia and use of diabetes therapy at baseline, Day 28 and Day 56 will be 
estimated and compared between arms using a Z-test (or Barnard’s Exact Unconditional as 
appropriate). 
 
6.  Functional Myopathy 
Change from baseline in functional myopathy score at Day 56 and 6-months post-randomization. 
i. 
Hip Flexor and Quadriceps Strength via handheld dynamometer 
ii. 
Two Minute Walk Test 
iii. 
5-time Sit-to-Stand 
iv. 
Adult Myopathy Assessment Tool (AMAT)  
These measures will first be assessed in patients with available data. Change from baseline 
within treatment group will be assessed using a Wilcoxon Signed Rank test at each timepoint. 
Change from baseline at each timepoint will be compared between treatment groups using a 
Wilcoxon Rank Sum test.  
 
7.  Hyperlipidemia 
Prevalence of hyperlipidemia as measured by fasting lipid panel and use of lipid-lowering agents 
at baseline, Days 28, 56 and 180 post-randomization will be compared between groups at each 
timepoint using a Z-test for binomial proportions (or Barnard’s Exact Unconditional test as 
appropriate). 
 
8.  Post-transplant thrombotic microangiopathy 
Cumulative incidence of post-transplant thrombotic microangiopathy will be estimated (treating 
death as a competing risk) and curves will be compared using Gray’s test. Estimates and 
confidence intervals will be provided for 6 months post-randomization. 
 
9.  CMV-reactivation 
Proportion of patients requiring therapy for CMV-reactivation by Day 56 post-randomization 
will be compared between treatment groups using a Z-test (or Barnard’s Exact unconditional as 
appropriate). 
 
10.  Change in Patient-Reported Outcomes from Enrollment to Day 56, 6 months and 1 year. 
Participant self-reported measures will be assessed using the MDASI, FACT-BMT, and MOS 
SF-36 (or PedsQL for Pediatric patients) at enrollment, day 56, 6 months and 1 year.  These will 
be scored according to the recommendations of the developers.  Patient reported outcomes at 
each time point will be summarized using simple descriptive statistics (mean, SD).  PRO among 
survivors at each time point will be compared between treatment arms in an initial analysis using 
two sample t-statistics.  The missing data pattern of the PRO measurements will be examined 
using graphical techniques and logistic regression models conditional on survival.  At each time 
point, estimates of the difference in PRO between the treatments conditional on survival at that 


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5-9 
time point will be obtained using inverse probability of censoring weighting with independent 
estimating equations to account for missing data.  
 
5.2.7. 
Secondary Analysis of AA3 Patients: 
A secondary analysis will consider study outcomes for AA3 patients (note patients with missing 
biomarker results will be excluded). Roughly 30 AA3 patients are expected to be enrolled with 
15 receiving sirolimus while awaiting results and 15 receiving prednisone. Outcomes for these 
patients will be described by initial treatment to assess whether up front sirolimus vs. prednisone 
impacted outcome. Due to small numbers, the analysis will be primarily descriptive as we are not 
likely to have power to detect differences between the groups. 
 
5.2.8. 
Exploratory Subgroup Analysis: 
Rates of Day 28 CR/PR (and 95% confidence intervals) will be estimated for each treatment 
group by donor type, graft source, and HLA mismatch (matched vs. mismatched). As the 
numbers for these subgroup analyses will be small, the intent is not to formally declare 
differences between subgroups, but rather to identify the potential for differences that may need 
to be accounted for in future trials. 


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A-1 
APPENDIX A 
 
HUMAN SUBJECTS 
 


Blood and Marrow Transplant Clinical Trials Network 
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A-2 
APPENDIX A 
 
HUMAN SUBJECTS 
 
 
Subject consent: The Network will provide templates of the consent and assent forms to each 
center.  Each center will customize the templates according to their local requirements and 
submit for review by the DCC for adequacy prior to submitting to the local Internal Review 
Board (IRB) or the NMDP IRB of Record.  Each center must provide evidence of IRB approval 
of the protocol and consent/assent forms.  
 
Candidates for the study will be identified as described in Chapter 4 of the protocol.  The 
Principal Investigator or his/her designee at each transplant center will contact the candidates, 
provide the patient with information about the purpose of the study and obtain consent. A trained 
person will enroll/randomize the patient in the AdvantageEDC system. 
 
Confidentiality: Confidentiality will be maintained by individual names being masked and 
assigned a patient identifier code.  The code relaying the patient’s identity with the ID code will 
be kept separately at the center.  The ID code will be transmitted to the network.   
 
Participation of women, children, minorities and other populations: Women, children and 
ethnic minorities will be included in this study. 
 
Accrual will be monitored within each center with the expectation that the enrolled patient 
population is representative of the transplanted patient population at each center.  Representation 
will be examined by comparing gender, race, ethnicity and age distributions.  Accrual of 
minority patients will be expected to be in proportion to the number of minority patients 
transplanted at each center.  The DCC and NHLBI will discuss enrollment anomalies with the 
centers. 
 
 


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Information & Informed Consent Form 
 
Initials 
 
B-3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX B 
 
LABORATORY PROCEDURES 
 
 
 


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Information & Informed Consent Form 
 
Initials 
 
B-4 
APPENDIX B 
 
LABORATORY PROCEDURES 
 
 
A. Blood Samples for Protocol-required GVHD Risk Assessment – Ann Arbor Biomarker 
Panel Scoring 
 
Once consented, a 5 mL of blood sample (red top for serum) will be collected from the patient 
prior to randomization. The blood sample will be shipped on the day of collection after 
randomization by priority overnight FedEx for early morning arrival at the Biomarker 
Laboratory of the Icahn School of Medicine at Mount Sinai for biomarker panel analysis. 
Samples can be shipped Monday to Friday each week, and results can be delivered back to 
submitting clinical centers Tuesday through Saturday of each week. 
 
Once received in the laboratory, the GVHD biomarkers used to assign the Ann Arbor GVHD 
score will be measured by ELISA using standard technical procedures in a CLIA certified 
laboratory. Processing the sample, measuring, and confirming the ELISA assay results takes 4.5 
hours (range 4-6 hours). Once the Ann Arbor score is confirmed, the investigator at the 
participating center will be notified if the patient has Ann Arbor 1/2, Ann Arbor 3 or missing 
biomarker risk status by telephone with email confirmation. Treating physicians will be notified 
of the patient’s Ann Arbor GVHD score within 72 hours of study enrollment and randomization 
(usually within 48 hours), and will receive a written laboratory report for the patient’s chart 
detailing the final Ann Arbor score assignment based upon the expert review of testing results 
and algorithm output. 
 
GVHD therapy for Ann Arbor 3 patients, which will be at the treating physician’s discretion, 
may be used in exploratory analyses to generate hypotheses for future high risk GVHD trials. 
 
B. Optional Research Samples Supporting Future Biomarker Studies 
 
Optional research blood samples will be drawn at baseline (pre-treatment), and then at the serial 
time points outlined in the table below. 
 
B.1 Rationale for type and schedule of planned optional research samples 
 
1. Optional Baseline samples 
 
Optional Baseline samples will be drawn prior to initiation of randomized therapy. While 
samples for subsequent RNA studies will be collected in PAXgene tubes (to stabilize RNA), 
other samples will be shipped to the BMT CTN Repository for processing, and aliquot storage.  
 
The major planned use of these optional research samples will be for discovery of new RNA and 
protein biomarkers of therapeutic response and subsequent mortality among standard risk acute 
GVHD patients. Both single time point baseline values and change from baseline to Day 7 values 
will be considered. Studies will be performed separately among sirolimus-treated or prednisone-
treated patients, and commonality of predictive markers will be explored. While protein markers 


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Information & Informed Consent Form 
 
Initials 
 
B-5 
of GVHD response and subsequent mortality have been well established in the setting of 
standard prednisone primary therapy, this has not been addressed in sirolimus primary therapy 
before. Thus, this trial offers a completely new opportunity for discovery. The concurrent 
collection of research blood samples from AA3 patients permits comparisons across the AA1/2 
vs. AA3 patients, both in the setting of sirolimus monotherapy and standard prednisone therapy. 
 
Additional PBMC isolated for immune reconstitution research will at minimum be used for 
establishing baseline pre-treatment levels of regulatory T cells (Treg). Change from this baseline 
value to subsequent measures (including Days 7, 28, and 56) will be compared across the 
sirolimus- and prednisone-treated patients. We hypothesize that sirolimus therapy will support 
greater percentage and absolute number of Treg, as well as Treg/Tconv ratio, over the therapy 
period in comparison to the prednisone-treated group. As well, correlation between Treg and 
Treg/Tconv ratio and GVHD response and subsequent outcomes will be examined.  
 
In addition to these studies, stored samples will be available for use by additional investigators. 
Submitted proposals for use of stored samples will be first reviewed by the protocol team and 
further adjudicated according to the procedures detailed in the BMT CTN MOP.  
 
2. Optional Serial samples following initiation of randomized therapy 
 
Sample types and procedures for optional serial follow up samples mirror those outlined for 
baseline samples.  
 
Change from baseline to subsequent samples (e.g. Day 7) will be examined in the predictive 
biomarker analyses outlined above. In particular, change in serum protein biomarkers from 
baseline to Day 7 will be prioritized. 
 
Single time point samples at Day 28 and 56 will also be utilized for studies examining 
association between RNA and protein biomarkers and Day 28 or 56 GVHD response categories 
outlined in the protocol. These interval time point samples (e.g. Day 28, Day 56) can also be 
used for prediction of later outcomes, including development of chronic GVHD, as well as 
development of immune tolerance as measured by freedom from GVHD and complete 
discontinuation of immune suppression. We anticipate that – with an anticipated median onset 
time of acute GVHD of approximately 20-30 days post-transplant – that the Day 56 sample 
(post-acute GVHD onset) will largely occur around 90 days post-transplant. This sample will be 
ideal for chronic GVHD predictive analyses, as this should precede median onset time for 
chronic GVHD (expected around 4-6 months post-HCT). Finally, these later sample time points 
will permit an extended view of Treg reconstitution from therapy initiation onward over a several 
month period. We will compare Treg reconstitution across study arms at both single time points, 
as well as the trajectory from baseline onward. 
 
B.2 Optional Research Sample procedures 
All optional research sample aliquots will be given unique bar code designations that cannot be 
linked back to the participant’s name or other identifying information. Laboratory test results, 
clinical information, etc., associated with the coded samples may be provided to the Investigators 
to associate biological findings with clinical outcomes.  Investigators will be able to link results 


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Version 2.0 dated July 7, 2017 
 
 
Information & Informed Consent Form 
 
Initials 
 
B-6 
from serial serum sample aliquots (for example: Pre-treatment, Day 7, Day 28 post-treatment 
initiation samples).  Similarly, investigators will be able to link data from different sample types.  
All optional research samples will be collected and shipped same-day (Monday-Friday) to the 
BMT CTN Biorepository for next-day processing (Tuesday-Saturday) and sample aliquot 
storage. Sample collection and shipping procedures are detailed in the BMT CTN 1501 Research 
Sample Information Guide. 
 
OPTIONAL Research Sample Collection Schedule, Processing and Aliquot Storage Summary  
Optional Research Samples (collected from all patients that provided consent for research samples) 
Time Points 
Sample 
Quantity1 
Stored 
Material 
Sample 
Processing 
& Storage 
Site 
Aliquots Stored 
Purpose 
Pre-Treatment 
&  
Post- Initiation of 
Treatment  
Day 28 ± 3 
Day 56 ± 3 
10 mL 
PAXgene 
Whole 
Blood 
Lysate 
BMT CTN 
Biorepository 
Maximum 
4 aliquots 
2.5 mL-fill PAXgene tubes; 
stored at -80º C 
Gene Expression 
Profile Research 
Pre-Treatment 
&  
Post- Initiation of 
Treatment  
Day 7 ± 3 
Day  28 ± 3 
Day 56 ± 3 
20 mL 
Heparin 
Viable 
PBMC 
BMT CTN 
Biorepository 
Maximum 
6 aliquots 
1.0 mL aliquots containing ~ 
2.5-5.0 x 106 PBMC; controlled-
rate frozen and stored in LN2 
Immune 
Reconstitution 
Research 
10 mL 
Serum 
Clot Tube 
Serum 
BMT CTN 
Biorepository 
Maximum 
10 aliquots 
~ 0.5 mL aliquots; 
stored at -80º C 
Proteomic and 
miRNA Biomarker 
Research 
1  Sample Quantity Patients with weight < 13 kg will have ≤ 3 mL/kg collected at each individual time point Research samples 
should be drawn in the following descending order of priority to total permissible volume: (1) 20mL heparin tube for PBMC, (2) 
10mL serum clot tube for serum, and (3) 10mL PAXgene tube for whole blood lysate 


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C-1 
APPENDIX C 
 
DIAGNOSIS AND SEVERITY SCORING FOR ACUTE  
AND CHRONIC GVHD 
 


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C-2 
APPENDIX C 
 
DIAGNOSIS AND SEVERITY SCORING FOR ACUTE AND CHRONIC GVHD 
 
 
1. GVHD organ staging21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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C-3 
 
2. Grading of Chronic GVHD (NIH Criteria)22 
 
 
Organ scoring of chronic GVHD. ECOG indicates Eastern Cooperative Oncology Group; KPS, Karnofsky Performance Status; LPS, Lansky 
Performance Status; BSA, body surface area; ADL, activities of daily living; LFTs, liver function tests; AP, alkaline phosphatase; ALT, alanine 
aminotransferase; ULN, normal upper limit. *Weight loss within 3 months. Skin scoring should use both percentage of BSA involved by disease 
signs and the cutaneous features scales. When a discrepancy exists between the percentage of total body surface (BSA) score and the skin feature 
score, OR if superficial sclerotic features are present (Score 2), but there is impaired mobility or ulceration (Score 3), the higher level should be 
used for the final skin scoring. To be completed by specialist or trained medical providers. **Lung scoring should be performed using both the 
symptoms and FEV1 scores whenever possible. FEV1 should be used in the final lung scoring where there is discrepancy between symptoms and 
FEV1 scores. 


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C-4 
 
 


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C-6 
3. Categories of Acute and Chronic GVHD 
 
 
Categories of Acute and Chronic GVHD 
Category 
Time of 
Symptoms 
after HCT  
Presence 
of Acute 
GVHD 
Features 
Presence of 
Chronic 
GVHD 
Features* 
Acute GVHD 
Classic acute GVHD 
≤100 d 
Yes 
No 
Late-onset acute GVHD 
>100 d 
Yes 
No 
Chronic GVHD 
Classic chronic GVHD 
No time 
limit 
No 
Yes 
Overlap syndrome 
No time 
limit 
Yes 
Yes 
*As defined in section 4 (below) 


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C-7 
4. Signs and Symptoms of Chronic GVHD22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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D-1 
APPENDIX D 
 
DERIVATION OF A SEQUENTIAL TEST STATISTIC  
FOR CENSORED EXPONENTIAL DATA 


Blood and Marrow Transplant Clinical Trials Network 
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Version 2.0 dated July 7, 2017 
 
 
 
APPENDIX D 
 
DERIVATION OF A SEQUENTIAL TEST STATISTIC FOR CENSORED 
EXPONENTIAL DATA 
 
 
Background – The Sequential Probability Ratio Test 
 
Let 
)
(.,
f
be the density function for random variable X.  According to Neyman and Pearson, 
the most powerful test of 
o
H


:
0
 versus
1
1 :


H
 decides in favor of 
1
H  or 
0
H if 

c
Ln 
 or 

c
Ln 
, respectively, where 


n
i
i
i
n
x
f
x
f
L
)
;
(
/)
;
(
0
1


is the likelihood ratio, and 
c is 
determined to have the size .  When the sample size is not fixed in advance, further 
improvement is possible by using Wald’s Sequential Probability Ratio Test (SPRT).  The SPRT 
continues to sample as long as 
A
L
B
n 

 for some constant 
A
B

1
, stops sampling and 
decides in favor of 
1
H as soon as 
A
Ln 
, and stops sampling and decides in favor of 
0
H as soon 
as 
B
Ln 
. 
 
The usual measures of performance of such a procedure are the error probabilities 

and of 
rejecting 
0
H when 
0


, and of accepting 
0
H when 
1


, respectively, and the expected 
sample size 
)
(
)
|
(
N
E
N
E
j
j 

.  Wald and Wolfowitz showed that among all tests, sequential or 
not, for which 


)
reject 
(
Pr
0
0
H
 and 


)
reject 
(
Pr
0
1
H
, and for which 
)
(N
E j
 are finite, j=0,1, 
the SPRT with error probabilities 

 and minimizes 
)
(
0 N
E
 and 
)
(
1 N
E
.  If, in addition, the 
,...
2
,1 x
x
 are independent and identically distributed (i.i.d.) with density function 
)
,
( 
x
f
, with 
monotone likelihood ratio in 
)
(x

, then any SPRT for testing 
0
against 
)
(
0
1


 has non-
decreasing power function. 
 
For the SPRT with error probabilities 

and , the SPRT boundaries are given approximately by 

/)
1( 

A
 and 
)
1
/(




B
.  The operating characteristics of the SPRT are given by 
)
/(
)1
(
)
,
,
,
,
(
)
(
)
(
)
(
1
0








h
h
h
B
A
A
O



 where 
)
(
h
is the non-trivial solution to the equation 

1
)
;
(
))
,
(
/)
;
(
(
)
(
2
1
dx
x
f
x
f
x
f
h




.   
 
The formula 
)
;
(
/]
log
)
(
log
)]
(
1
[[(
)
;
(




z
E
B
O
A
O
N
E



provides the average sample number 
for an arbitrary .  The sample size distribution is very highly skewed, 
2
)]
(
[
)
(
N
E
N
Var

.  Thus 
we will consider a truncated test with maximum sample size of 
0
N  and simulate to obtain the 
operating characteristics of the test. 
 
 


Blood and Marrow Transplant Clinical Trials Network 
Sirolimus vs. Prednisone – Protocol 1501 
Version 2.0 dated July 7, 2017 
 
 
 
Derivation of the SPRT for Uncensored Exponential Survival Times 
 
For example, we wish to construct a sequential test for the composite null hypothesis that the rate 
of treatment-related mortality (TRM) at 100 days is less than or equal to 30% versus the 
alternative hypothesis that it is greater than or equal to 50%.  For the derivation of the 
uncensored SPRT, we will require that the type I error of the test be less than 5%, and that the 
test provide 80% power to reject the null hypothesis under a specified alternative that the true 
rate is 50%.  A maximum sample size of 50 patients will be permitted. 
 
Let us assume that the survival times, 
nT
T
T
,...,
,
2
1
, are completely observed (uncensored) and are 
i.i.d. with exponential density function 
T
e
T
f





)
,
(
.  These assumptions will be relaxed to 
incompletely observed data subsequently.  In the exponential parameterization, a 100-day 
survival rate of 70% translates into a mean survival of 0.768 years (

0

1.303), and 50% 
translates into a mean survival of 0.395 years (

1

2.532). 
 
The SPRT is derived with reference to a simple null and alternative hypothesis, in this case, 


o
H


:
0
 1.303 versus
1
1 :


H
 = 2.532.  However, since the log-likelihood ratio for the 
exponential, 








n
i
n
i
n
i
i
i
i
T
n
x
f
x
f
)
(
))
log(
)
(log(
)
,
(
log
)
;
(
log
0
1
0
1
0
1






, is a 
monotone function of 
n
i
iT , the power of the test is non-decreasing in .  Thus the SPRT is a 
one-sided level .05 test of a composite null (
303
.1
:
0


o
H


) versus a composite alternative (
303
.1
:
1


o
H


), with power of 
80
.
1


 at the selected alternative 


1


2.532. 
 
The SPRT can be represented graphically.  The continuation region is bounded by two parallel 
lines with common slope 



)
/(
)
log
(log
1
0
1
0




0.541, and intercepts 


)
/(
log
1
0


A
-2.256 
and 


)
/(
log
1
0


B
1.270, for the lower and upper bounds, respectively.  As each individual unit 
is put on trial and observed to fail, the cumulative sum of failure times,
n
i
iT , is recomputed, and 
plotted against the current sample size, n.  When this graph crosses the lower boundary, the null 
hypothesis is rejected. 
 
The maximum sample size of 50 patients requires that the SPRT be truncated.  We choose to 
truncate the SPRT by declaring that if the test has failed to terminate after 50 patients, that the 
null hypothesis will be accepted.  Since the probability that the untruncated SPRT would reject 
the null at a sample size of 50 is negligible, it makes little difference how the final boundary 
value is selected, and this rule is chosen for simplicity.   
 
Derivation of a Modified SPRT for Censored Exponential Data 
 
The assumption of uncensored exponential survival times is flawed.  However, we consider it 
reasonable to assume the hazard for TRM is constant over the first 100 days post-transplant, and 


Blood and Marrow Transplant Clinical Trials Network 
Sirolimus vs. Prednisone – Protocol 1501 
Version 2.0 dated July 7, 2017 
 
 
 
we will restrict our attention to this time interval.  Furthermore, it is not practical to conduct a 
clinical study by putting each individual on trial, and waiting until that individual is observed to 
fail.  We relax our assumptions as follows.  Firstly, each individual’s time on study will be 
computed as time from transplant to failure, or to the 100 day time point, whichever comes first.  
Secondly, we will put individuals on trial as soon as they become available, without waiting for 
the previous individual to fail. 
 
Let us consider the impact of relaxing these assumptions one at a time.  In a fixed sample size 
trial with uncensored exponential failure times, mean survival time is estimated by the sample 
mean of the failure times, or total time on study divided by the number of individuals enrolled.  
When censoring is introduced, the estimate becomes the total time on study divided by the 
number of observed (non-censored) failures.  This suggests that in an exponential SPRT test 
modified to incorporate censoring, we replace the observed failure times, 
nT
T
T
,...,
,
2
1
, with 
censored failures times, 
nx
x
x
,...,
,
2
1
, and the current sample size, n, with the number of observed 
failures, d .   
 
Now we relax the second assumption, and put individuals on trial as soon as they become 
available, without waiting for the previous individual to fail.  Assume that three years are 
required for accrual of 50 patients to the study, and that the final analysis takes place 100 days 
after the last patient is entered.  Putting all of this together, we propose a modified truncated 
SPRT, where at any interim time point, s , ranging from 0 to 3 years 100 days, the sum of 
observed time on study, 
n
i
i s
X
)
(
is plotted against the number of observed failures, 
)
(s
d
.  In 
practice, monitoring will be scheduled monthly after the start of enrollment to the study.  A 
further modification to the SPRT was to only use the lower boundary for stopping since the 
primary focus of the monitoring is to protect against unacceptable 100-day TRM rates. 
 
Operating Characteristics of the Modified SPRT Test for Censored Exponential Data 
 
Recall that the uncensored SPRT targeted a drop in survival at Day 100 from 70% to 50%, with 
type I and II errors of 5% and 20%.  Since only the lower boundary is used for monitoring, the 
continuation region of the test was bounded below by a line with a slope of 0.541 and intercept 
of –2.256.  The effect of truncation is to reduce the power of the test.  In order to compensate for 
this, we raise the lower boundary to make it easier to cross.  Under the further assumption of 
uniform accrual over a three year period, and monthly interim analyses over the course of the 
study, the operating characteristics of the modified SPRT were obtained from a simulation study.  
These simulation show that an intercept of –1.741, corresponding to setting parameters  and 
to 10% and 15%, result in empirical type I and II error rates of  about 5% and 20%.   
 
 
 


Blood and Marrow Transplant Clinical Trials Network 
Sirolimus vs. Prednisone – Protocol 1501 
Version 2.0 dated July 7, 2017 
 
 
 
Table E-1   Operating Characteristics of Sequential Testing Procedures from a Simulation 
Study with 100,000 Replications 
 
Treatment-Related Mortality (TRM) 
True 100-Day Rate 
30% 
35% 
40% 
45% 
50% 
Probability Reject Null 
0.07 
0.20 
0.41 
0.66 
0.86 
Mean Month Stopped 
34.5 
32.3 
28.5 
23.5 
18.5 
Mean # Endpoints in 100 Days 
13.8 
15.0 
15.1 
14.0 
12.1 
Mean # Patients Enrolled 
48 
45 
40 
33 
26 
While the motivation for this testing procedure is largely heuristic rather than theoretical, the 
simulation results validate the approach.  When the true rate of TRM on or before Day 100 was 
30%, the test crossed the lower boundary in 7119 of 100,000 replications, for an estimated type I 
error rate of 7%.  When the true rate of TRM on or before Day 100 was 50%, the test failed to 
cross the boundary in 14226 of 100,000 replications, for an estimated type II error rate of 14%.  
And on average, the boundary will be crossed at 18.5 months, when 26 patients will be enrolled 
to the study. 
 
It is interesting to note that the SPRT derived above for exponential failure times with censoring 
at 100 days, has operating characteristics which are similar to those of a more traditional SPRT, 
derived for binomial variates with success probability equal to the 100 day failure rate.  Using 
time to failure rather than a simple binary indicator of failure, leads to little improvement in 
power when failure times are censored relatively soon after entry on study.  We speculate that if 
the constant hazard rate over the first 100 days were high, the exponential test would reject faster 
than the binomial test, but have not conducted simulation studies to demonstrate this. 


Blood and Marrow Transplant Clinical Trials Network 
Sirolimus vs. Prednisone – Protocol 1501 
Version 2.0 dated July 7, 2017 
 
 
E-1 
APPENDIX E 
 
SUGGESTED PREDNISONE TAPER FOR  
RESPONDING PATIENTS 


Blood and Marrow Transplant Clinical Trials Network 
Sirolimus vs. Prednisone – Protocol 1501 
Version 2.0 dated July 7, 2017 
 
 
 
 
APPENDIX E 
 
SUGGESTED PREDNISONE TAPER FOR RESPONDING PATIENTS 
 
 
Days 
Dose 
Minimum of 3 days 
 
2mg/kg/day  
Minimum of 7 days 
 
1mg/kg/day 
Taper weekly 
thereafter at the 
following intervals 
Week 2 
0.5 mg/kg/day once daily 
 
Week 3 
0.25 mg/kg/day once daily 
 
Week 4 
0.2 mg/kg/day once daily 
 
Week 5 
0.1 mg/kg/day once daily 
 
Week 6 
0.1 mg/kg/day every other day 
 
Week 7 
Discontinue 
 
 


Blood and Marrow Transplant Clinical Trials Network 
Sirolimus vs. Prednisone – Protocol 1501 
Version 2.0 dated July 7, 2017 
 
 
F-1 
APPENDIX F 
 
REFERENCES 


Blood and Marrow Transplant Clinical Trials Network 
Sirolimus vs. Prednisone – Protocol 1501 
Version 1.3 dated April 19, 2017 
 
 
 
 
APPENDIX F 
 
REFERENCES 
 
 
 
1. 
Holtan SG, Pasquini M, Weisdorf DJ. Acute graft-versus-host disease: a bench-to-
bedside update. Blood 2014;124:363-73. 
2. 
Ziakas PD, Zervou FN, Zacharioudakis IM, Mylonakis E. Graft-versus-host disease 
prophylaxis after transplantation: a network meta-analysis. PloS one 2014;9:e114735. 
3. 
Weisdorf D, Haake R, Blazar B, et al. Treatment of moderate/severe acute graft-versus-
host disease after allogeneic bone marrow transplantation: an analysis of clinical risk features 
and outcome. Blood 1990;75:1024-30. 
4. 
MacMillan ML, DeFor TE, Weisdorf DJ. The best endpoint for acute GVHD treatment 
trials. Blood 2010;115:5412-7. 
5. 
MacMillan ML, DeFor TE, Weisdorf DJ. What predicts high risk acute graft-versus-host 
disease (GVHD) at onset?: identification of those at highest risk by a novel acute GVHD risk 
score. British journal of haematology 2012;157:732-41. 
6. 
MacMillan ML, Robin M, Harris AC, et al. A Refined Risk Score for Acute Graft-versus-
Host Disease that Predicts Response to Initial Therapy, Survival, and Transplant-Related 
Mortality. Biology of blood and marrow transplantation : journal of the American Society for 
Blood and Marrow Transplantation 2015. 
7. 
Srinivasan R, Daniels J, Fusaro V, et al. Accurate diagnosis of acute graft-versus-host 
disease using serum proteomic pattern analysis. Experimental hematology 2006;34:796-801. 
8. 
Wang H, Clouthier SG, Galchev V, et al. Intact-protein-based high-resolution three-
dimensional quantitative analysis system for proteome profiling of biological fluids. Mol Cell 
Proteomics 2005;4:618-25. 
9. 
Levine JE, Braun TM, Harris AC, et al. A prognostic score for acute graft-versus-host 
disease based on biomarkers: a multicentre study. Lancet Haematology 2015;2:e21–e9. 
10. 
Alousi AM, Weisdorf DJ, Logan BR, et al. Etanercept, mycophenolate, denileukin, or 
pentostatin plus corticosteroids for acute graft-versus-host disease: a randomized phase 2 trial 
from the Blood and Marrow Transplant Clinical Trials Network. Blood 2009;114:511-7. 
11. 
Bolanos-Meade J, Logan BR, Alousi AM, et al. Phase 3 clinical trial of 
steroids/mycophenolate mofetil vs steroids/placebo as therapy for acute GVHD: BMT CTN 
0802. Blood 2014;124:3221-7; quiz 335. 
12. 
Pidala J, Tomblyn M, Nishihori T, et al. Sirolimus demonstrates activity in the primary 
therapy of acute graft-versus-host disease without systemic glucocorticoids. Haematologica 
2011;96:1351-6. 
13. 
Ho VT, Cutler C, Carter S, et al. Blood and marrow transplant clinical trials network 
toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem 
cell transplantation. Biology of blood and marrow transplantation : journal of the American 
Society for Blood and Marrow Transplantation 2005;11:571-5. 
14. 
Marty FM, Lowry CM, Cutler CS, et al. Voriconazole and sirolimus coadministration 
after allogeneic hematopoietic stem cell transplantation. Biology of blood and marrow 
transplantation : journal of the American Society for Blood and Marrow Transplantation 
2006;12:552-9. 


Blood and Marrow Transplant Clinical Trials Network 
Sirolimus vs. Prednisone – Protocol 1501 
Version 1.3 dated April 19, 2017 
 
 
 
 
15. 
Mielcarek M, Furlong T, Storer BE, et al. Effectiveness and safety of lower dose 
prednisone for initial treatment of acute graft-versus-host disease: a randomized controlled trial. 
Haematologica 2015;100:842-8. 
16. 
Cleeland CS, Mendoza TR, Wang XS, et al. Assessing symptom distress in cancer 
patients: the M.D. Anderson Symptom Inventory. Cancer 2000;89:1634-46. 
17. 
McQuellon RP, Russell GB, Cella DF, et al. Quality of life measurement in bone marrow 
transplantation: development of the Functional Assessment of Cancer Therapy-Bone Marrow 
Transplant (FACT-BMT) scale. Bone Marrow Transplant 1997;19:357-68. 
18. 
McHorney CA, Ware JE, Jr., Raczek AE. The MOS 36-Item Short-Form Health Survey 
(SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health 
constructs. Med Care 1993;31:247-63. 
19. 
Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality 
of Life Inventory version 4.0 generic core scales in healthy and patient populations. Med Care 
2001;39:800-12. 
20. 
Lawitschka A, Guclu ED, Varni JW, et al. Health-related quality of life in pediatric 
patients after allogeneic SCT: development of the PedsQL Stem Cell Transplant module and 
results of a pilot study. Bone Marrow Transplant 2014;49:1093-7. 
21. 
Harris AC, Young R, Devine S, et al. International, Multicenter Standardization of Acute 
Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute 
GVHD International Consortium. Biology of Blood and Marrow Transplantation 2016;22:4 - 10. 
22. 
Jagasia MH, Hildegard TG, Arora M, et al. National Institutes of Health Consensus 
Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 
2014 Diagnosis and Staging Working Group Report. Biology of blood and marrow 
transplantation : journal of the American Society for Blood and Marrow Transplantation 
2015;21:389-401 
 
 Hartwell MJ, Özbek U, Holler E, et al. An early biomarker algorithm predicts lethal graft-
versus-host disease and survival. JCI Insight. 2017 Feb 9;2(3):e89798. doi: 
10.1172/jci.insight.89798. 
 
Major-Monfried H, Özbek U, Renteria AS. Biomarkers predict graft-vs-host disease outcomes 
better than clinical response after one week of treatment. Blood 2016 128:510 (abstract). 
 
 
 
 

SAP_001.pdf: 


Version 1.0 
1 
June 7, 2018 
 
BMT CTN Protocol 1501 Statistical Analysis Plan (SAP) 
Version 1.0     Date: 6/7/2018 
 
Prepared by: Michael Martens   Date: 1/4/2018 
Reviewed by: Raphael Fraser    Date: 01/15/2018 
Approved by: Joseph Pidala   Date:  6/7/18 
 
 
 


Version 1.0 
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June 7, 2018 
 
Table of Contents 
 
1. 
General Review of Study Design and Process ................................................................... 5 
 
Study Objectives ......................................................................................................................... 5 
 
Primary Objective ................................................................................................................... 5 
 
Secondary Objectives............................................................................................................ 5 
 
Exploratory Objectives .......................................................................................................... 5 
 
Study Design and Procedures .................................................................................................. 7 
 
Primary Hypothesis and Primary Endpoint ........................................................................ 7 
 
Accrual Plan and Randomization ......................................................................................... 7 
 
Duration of Follow-up ............................................................................................................ 7 
 
Study Population ........................................................................................................................ 7 
 
Treatment Description ............................................................................................................... 7 
 
Response Variables and Data Collection Time Points ......................................................... 8 
2. 
General Statistical Considerations ...................................................................................... 9 
 
Sample Size and Power Calculations ..................................................................................... 9 
 
Handling Missing Data ............................................................................................................. 10 
 
Multiple Comparisons .............................................................................................................. 10 
 
Interim Analyses ....................................................................................................................... 11 
 
Safety Monitoring Guidelines .................................................................................................. 11 
 
Timing of Analysis .................................................................................................................... 13 
 
Software ..................................................................................................................................... 13 
 
Analysis Populations ................................................................................................................ 13 
 
Primary Analysis Population ............................................................................................... 13 
 
Safety Analysis Population ................................................................................................. 14 
 
General Analysis Guidelines ................................................................................................... 14 
3. 
Participant Characteristics and Compliance ..................................................................... 14 
 
Demographics and Baseline Characteristics ....................................................................... 14 
 
Participant Compliance ............................................................................................................ 15 
4. 
Analysis Plan ........................................................................................................................ 15 
 
Analysis of the Primary Endpoint ........................................................................................... 15 
 
Analysis of the Secondary Endpoints .................................................................................... 16 
 
Proportion of Participants with CR/PR and Steroid Dose 0.25 mg/kg/day or Less .... 16 
 
Disease Response ............................................................................................................... 16 
 
Treatment Failure ................................................................................................................. 16 
 
Chronic GVHD ...................................................................................................................... 17 
 
Systemic Infections .............................................................................................................. 17 
 
Event-Free Survival ............................................................................................................. 17 
 
Overall Survival (OS) ........................................................................................................... 18 
 
Disease-free Survival (DFS) ............................................................................................... 18 
 
GVHD-free Survival ............................................................................................................. 18 
 
Non-relapse Mortality (NRM) ......................................................................................... 19 
 
Analysis of the Exploratory Endpoints ................................................................................... 19 


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June 7, 2018 
 
 
Steroid Dose ......................................................................................................................... 19 
 
Topical Therapy .................................................................................................................... 19 
 
Discontinuation of Immune Suppression .......................................................................... 19 
 
EBV-associated lymphoproliferative disorder .................................................................. 20 
 
Hyperglycemia ...................................................................................................................... 20 
 
Functional Myopathy............................................................................................................ 20 
 
Hyperlipidemia ...................................................................................................................... 20 
 
Thrombotic microangiopathy .............................................................................................. 21 
 
CMV reactivation .................................................................................................................. 21 
 
Patient-Reported Outcomes ........................................................................................... 21 
 
Secondary Analysis of AA3 Participants ...................................................................... 21 
5. 
Template of Proposed Table/Figure/Listing (TFL) Shells ................................................ 21 
6. 
References ............................................................................................................................ 22 
Appendix ....................................................................................................................................... 23 
Exhibit 1501-1:  Participant Disposition and Follow-Up ............................................................... 23 
Exhibit 1501-2:  Participant Demographics and Baseline Characteristics ................................ 23 
Exhibit 1501-3:  Complete Response / Partial Response at Day 28 ......................................... 28 
Exhibit 1501-4:  Complete Response / Partial Response and Steroid Dose 0.25/mg/kg/day 
or Less at Day 28 .............................................................................................................................. 29 
Exhibit 1501-5:  Disease Response ............................................................................................... 30 
Exhibit 1501-6:  Treatment Failure ................................................................................................. 31 
Exhibit 1501-7:  Chronic GVHD ...................................................................................................... 32 
Exhibit 1501-8:  Systemic Infections .............................................................................................. 34 
Exhibit 1501-9:  Event-Free Survival .............................................................................................. 36 
Exhibit 1501-10:  Overall Survival ................................................................................................... 38 
Exhibit 1501-11:  Disease-Free Survival ....................................................................................... 39 
Exhibit 1501-12: GVHD-free Survival ............................................................................................. 41 
Exhibit 1501-13:  Non-relapse Mortality ......................................................................................... 42 
Exhibit 1501-14: Steroid Dose......................................................................................................... 43 
Exhibit 1501-15: Topical Therapy ................................................................................................... 44 
Exhibit 1501-16:  Discontinuation of Immune Suppression ........................................................ 45 
Exhibit 1501-16:  EBV-associated Lymphoproliferative Disorder .............................................. 47 
Exhibit 1501-17: Hyperglycemia ..................................................................................................... 48 
Exhibit 1501-18:  Functional Myopathy .......................................................................................... 49 
Exhibit 1501-19:  Hyperlipidemia .................................................................................................... 51 
Exhibit 1501-20:  Thrombotic Microangiopathy ............................................................................ 54 
Exhibit 1501-21: CMV Reactivation ................................................................................................ 55 
Exhibit 1501-22:  Patient-Reported Outcomes ............................................................................. 56 
Exhibit 1501-23: Incidence of Toxicities of Grade 3-5 ................................................................. 60 
Supplemental Exhibit 1501-1:  Enrollment .................................................................................... 61 
Supplemental Exhibit 1501-2:  Significant Protocol Deviations .................................................. 61 
Supplemental Exhibit 1501-3:  Primary Cause of Death ............................................................. 61 
Supplemental Exhibit 1501-4:  Adverse Events ........................................................................... 61 


Version 1.0 
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Supplemental Exhibit 1501-5:  Serious or Grades 3-5 Adverse Events ................................... 61 
Supplemental Exhibit 1501-6:  Safety Monitoring (Safety Endpoints) ....................................... 62 
 
 


Version 1.0 
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Protocol  
BMT CTN #1501 is titled “A Randomized, Phase II, Multicenter, Open Label, Study 
Evaluating Sirolimus and Prednisone in Participants with Refined Minnesota Standard 
Risk, Ann Arbor 1/2 Confirmed Acute Graft-Versus-Host Disease”.  
1. General Review of Study Design and Process 
 Study Objectives  
BMT CTN protocol #1501 is a Phase II randomized, open label, multicenter trial 
designed to identify whether sirolimus is a potential alternative to prednisone (standard 
of care) as an up-front treatment for participants with standard-risk acute GVHD defined 
per clinical and biomarker-based risk stratification. 
 
Primary Objective 
The primary objective is to assess the rate of complete response (CR)/partial response 
(PR) on day 28 post-randomization in participants with standard-risk acute GVHD 
defined by both clinical and Ann Arbor (AA) 1/2 risk status. 
 
Secondary Objectives 
The secondary objectives of the study are to assess:   
 
The proportion of participants with an acute GVHD response on Day 28 (CR or 
PR) and who are on a prednisone (or prednisone dose-equivalent corticosteroid) 
dose of 0.25mg/kg/day or less.  
 
Proportions of participants with CR, PR, mixed response, no response, and 
progression among surviving participants at Day 14, 28 and 56.  
 
Treatment failure (treatment failure defined as: no response, progression, 
administration of additional therapy for GVHD beyond primary therapy, or 
mortality) at Day 14, 28, and 56 
 
Incidence of chronic GVHD by 6 and 12 months post-randomization. 
 
Incidence of systemic infections within 6 months of randomization. 
 
Freedom from acute GVHD progression, chronic GVHD, malignancy relapse, 
and mortality at 6 months and 12 months post-randomization. 
 
Disease-free and overall survival at 6 and 12 months post randomization. 
 
GVHD-free survival at 6 and 12 months post-randomization.   
 
Non-relapse mortality at 6 and 12 months post-randomization. 
 
Exploratory Objectives 
The exploratory objectives of the study are to assess:   
 
Cumulative steroid dose (prednisone-equivalent) through Day 56 post 
randomization. 


Version 1.0 
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June 7, 2018 
 
 
Use of topical (skin, GI) agents for acute GVHD therapy at baseline and during 
the study’s duration. 
 
Incidence of discontinuation of immune suppression, and immune suppression 
discontinuation without GVHD or disease progression/recurrence by Days 56, 
180, and 365 post-therapy. 
 
Incidence of EBV-associated lymphoproliferative disorder or EBV reactivation 
requiring therapy 
 
Incidence of corticosteroid- and sirolimus-associated complications (collected in 
all participants): 
 
Incidence of hyperglycemia (defined as a random glucose >200mg/dL or fasting 
glucose >126mg/dL) and use of diabetes therapy (use of insulin and/or oral 
medications to control and/or maintain glucose levels) at baseline, Day 28 and 
Day 56.  
 
Hip Flexor and Quadriceps Strength score via handheld dynamometer at 
baseline, Day 56, and 6 months post-randomization 
 
Two Minute Walk Test score at baseline, Day 56, and 6 months post-
randomization 
 
5-time Sit-to-Stand Test score at baseline, Day 56, and 6 months post-
randomization 
 
Adult Myopathy Assessment Tool (AMAT) score at baseline, Day 56, and 6 
months post-randomization  
 
Incidence of hyperlipidemia as measured by fasting lipid panel at baseline, Days 
28, 56 and 180 post-randomization. 
 
Incidence of post-transplant thrombotic microangiopathy (TMA) by 6 months 
post-randomization. 
 
Proportion of participants requiring therapy for CMV-reactivation by day 56 post-
randomization. 
 
Change in patient-reported outcomes from enrollment to Day 56, 6 months and 
12 months. 
 
MD Anderson Symptom Inventory (MDASI) score at baseline, Day 56, 6 months, 
and 12 months post-randomization 
 
FACT-BMT score at baseline, Day 56, 6 months, and 12 months post-
randomization 
 
MOS Short Form 36 (SF-36) score at baseline, Day 56, 6 months, and 12 
months post-randomization  
 
PedsQL (Pediatric participants) score at baseline, Day 56, 6 months, and 12 
months post-randomization 
 
A secondary descriptive analysis will evaluate all study outcomes in AA3 
participants. 


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 Study Design and Procedures  
 
Primary Hypothesis and Primary Endpoint 
The primary hypothesis of the study is that sirolimus treatment will achieve a comparable 
or superior rate of complete response (CR)/partial response (PR) in the treatment of 
standard-risk acute GVHD compared to prednisone treatment. 
The primary endpoint is the rate of CR/PR of acute GVHD on Day 28 post-randomization 
in participants with standard-risk acute GVHD defined by clinical and AA1/2 risk status. 
 
Accrual Plan and Randomization  
The target sample size of the study is 120 participants with AA1/2 biomarker status. It is 
expected that 80% of all randomized participants will have AA1/2 status. This requires 
150 total participants to be randomized in order to obtain the targeted number of AA1/2 
participants. 
The estimated accrual period is 2 years. 
Participants will be randomized to sirolimus or prednisone treatment in a 1:1 ratio. 
Randomization is stratified by treatment center using permuted blocks of randomly 
chosen sizes of 2 or 4. 
 
Duration of Follow-up 
Participants will be followed for 28 days from the time of randomization for the primary 
endpoint. Participants will be followed for 1 year from the time of randomization for other 
endpoints. 
The final analysis report will include the actual accrual and follow up status of the study 
with the actual timeline upon the study closure. 
 Study Population 
This study will consist of participants with newly diagnosed standard-risk acute GVHD, 
per refined Minnesota Risk Criteria1, following allogeneic hematopoietic cell 
transplantation. All donor sources and conditioning regimens are allowed. Participants 
must be able to tolerate oral or enterically-administered medication. No previous 
systemic immune suppressive therapy for treatment of acute GVHD is allowed except 
topical corticosteroid use.  Detailed inclusion and exclusion criteria for study participants 
can be found in the protocol. 
 Treatment Description 
Treatment will be initiated as soon as possible within the 24 hours following 
randomization. Sirolimus is administered as either tablets or an oral solution, beginning 
with a loading dose followed by maintenance doses determined by routinely measured 
trough sirolimus levels. Sirolimus therapy is continued at maintenance levels until Day 
56 post randomization, after which the decision to taper dosage is at the discretion of the 


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treating physician. Prednisone is administered as either tablets or an oral solution at a 
starting dose of 2 mg/kg/day or 200mg, whichever is lower, for a minimum of 72 hours, 
after which the choice to taper dosage is at the discretion of the treating physician. 
 Response Variables and Data Collection Time Points 
The response variables for this study include the primary, secondary, and safety 
endpoints. The primary endpoint is CR/PR at Day 28. Secondary endpoints include: 
 
CR/PR at Day 28 with steroid dose of 0.25mg/kg/day or less 
 
Disease response 
 
Treatment failure 
 
Chronic GVHD 
 
Systemic infection 
 
Event-free survival 
 
Overall survival 
 
Disease-free survival 
 
GVHD-free survival 
 
Non-relapse mortality 
 
Steroid dose  
 
Topical steroid therapy 
 
Discontinuation of immune suppression 
 
EBV-associated lymphoproliferative disorder 
 
Hyperglycemia 
 
Functional myopathy 
 
Hyperlipidemia 
 
Thrombotic microangiopathy 
 
CMV reactivation 
 
Patient-reported outcomes 
Safety endpoints included mortality, toxicity, and adverse events. Safety monitoring will 
be conducted per protocol schedule as described in Section 2.4 of this SAP. Adverse 
events will be reported per the BMT CTN (Manual of Procedures) MOP. 
Definitions for each endpoint are described in detail in the protocol and in section 4 of 
this SAP. 
Participants are required to complete both pre-randomization and post-randomization 
assessments. Pre-randomization assessments must be performed prior to and as close 
as possible to the participant’s enrollment / randomization on the trial. Post-
randomization assessments occur weekly up to Day 56 and then occur at Day 90, 180, 


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and 365 post-randomization. Data from these evaluations are collected on calendar-
driven clinical forms. Deaths, infections, hospitalizations, and adverse events are 
reported on event-driven clinical forms. 
2. General Statistical Considerations 
 Sample Size and Power Calculations 
The primary hypothesis is that sirolimus treatment will result in a comparable or superior 
CR/PR rate at Day 28 compared to prednisone treatment. As this is the first trial 
prospectively assessing sirolimus treatment in a multicenter setting, the trial is not 
designed to declare non-inferiority formally but rather to estimate the difference in 
response rates between the sirolimus arm and the prednisone (or standard of care) arm. 
In lieu of a formal hypothesis test, the difference in response rates between the two arms 
will be estimated with a 90% confidence interval. 
Background data on treatment with sirolimus is available for 27 standard risk (Minnesota 
Criteria) participants. The overall CR/PR rate in the population was 88.9% (95% CI 
77.0%, 100.0%). If patients receiving any level of prednisone are considered failures, the 
observed CR/PR rate was 55.6% (95% CI 36.8%-74.3%). Considering background data 
from BMT CTN 08022, a phase III acute GVHD treatment trial, data were available for 95 
placebo treated participants meeting the standard risk criteria at GVHD onset. The 
response rate in that population was 64.2% (95% CI 54.6%-73.9%). Note that PR was 
not formally adjudicated by the Endpoint Review Committee for BMT CTN 0802. Instead, 
a response of Better Grade (compared to grade at diagnosis) was adjudicated and is 
considered here as a surrogate for PR. While the point estimates differ slightly, the 
confidence intervals for the two populations are overlapping. Table 2.1 shows the lower 
bound of a 90% asymptotic confidence interval given two scenarios: 1) success rate of 
60% in each arm and 2) success rate of 60% in the prednisone arm and 50% in the 
sirolimus arm (sirolimus response rate is 10% lower). 
Table 2.1: Lower Bound of Asymptotic 90% Confidence Interval for Difference in 
Response Rates Between Sirolimus and Prednisone Arms, Assuming Equal Rates 
(60%) and a 10% Lower Response Rate in the Sirolimus Arm with a 25% Inflation 
Due to Biomarker Results 
Randomized Analyzed 
(AA1/2) 
N Analyzed 
Per Arm 
Lower Bound of 90% CI 
Assuming Equal Rates* 
Lower Bound of 90% CI 
Assuming Sirolimus Rate is 
10% Lower* 
125 
100 
50 
-16% 
-26% 
150 
120 
60 
-15% 
-25% 
175 
140 
70 
-14% 
-24% 
200 
160 
80 
-13% 
-23% 
225 
180 
90 
-12% 
-22% 
250 
200 
100 
-12% 
-22% 
* Difference calculated as Sirolimus response rate minus Prednisone response rate. 


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The number randomized is determined under the assumption that 80% of randomized 
participants will have biomarker results indicating standard risk disease (AA1 or 2). Note 
that 60 analyzable participants per arm (150 randomized) will result in a lower bound of 
15% if the success rates in the two populations are equivalent. If sirolimus is 10% worse 
than the prednisone arm, the lower bound of the confidence interval will exceed 15%. 
The difference in Day 28 CR/PR rates across the two arms will be reported with its 
associated 90% confidence interval, however no pre-planned difference or width of 
confidence interval will be used to indicate failure of either arm or serve as a requirement 
for consideration of secondary endpoints (i.e. formal non-inferiority will not be declared in 
this trial). A key secondary endpoint is the proportion of participants in CR/PR with a 
steroid dose of ≤0.25 mg/kg by Day 28. Of the 95 placebo participants, 22.1% (95% CI 
13.8% - 30.5%) achieved a CR/PR by Day 28 and were receiving ≤0.25 mg/kg. This 
estimate may not be reliable, however, as the taper for BMT CTN 0802 suggested a 
minimum of 0.25 mg/kg on Day 28; as such, this may be an underestimate of the true 
rate. Using the upper end of the confidence interval, sixty participants per arm would 
provide 80.6% power (two-sided 5% type 1 error rate) to test for a difference of 25% 
between the two groups (30% Prednisone vs. 55% Sirolimus). 
 Handling Missing Data 
Because the primary endpoint, aGVHD response at Day 28 post-randomization, is 
evaluable after a short time, we expect very little to no impact of missing data on its 
analysis. Furthermore, since all endpoints will be evaluable within 1 year of 
randomization, we do not expect missingness to affect their analyses appreciably. An 
Endpoint Review Committee will adjudicate data on the primary endpoint to resolve this 
endpoint for participants with missing data. Any remaining missing values which are not 
able to be adjudicated will be excluded from the analyses. If any participants have 
missing data on the primary endpoint, a sensitivity analysis that treats missing 
responses as failures for aGVHD response will be conducted to examine the robustness 
of analysis results. 
Based on previous BMT CTN studies and other clinical research, it is expected that the 
data collected on patient reported outcomes will not be complete. Logistic models will be 
constructed to investigate whether specific patient, clinical, or other variables are 
predictive of this missingness. If this is the case, inverse probability weighting will be 
employed to adjust for covariate-dependent missingness in comparing patient reported 
outcomes between treatment groups. 
 Multiple Comparisons 
The treatment groups are not being compared on the primary endpoint using a formal 
hypothesis test, so there is no need to specify a significance level for the primary 
analysis. Since this is a phase II trial with many secondary and exploratory endpoints, no 
explicit control for multiplicity will be incorporated; rather a significance level of 5% will 
be used for all comparisons on these outcomes.   


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 Interim Analyses 
There will be no interim analyses for efficacy or futility as this is a small phase II study. 
 Safety Monitoring Guidelines 
Monitoring of two key safety endpoints will be conducted monthly, and if rates 
significantly exceed pre-set thresholds, the NHLBI will be notified in order that the DSMB 
can be advised. The stopping guidelines serve as trigger for consultation with the DSMB 
for additional review. The key safety endpoints for this study are: 1) failure of sirolimus 
therapy and 2) overall mortality. Both endpoints will be monitored among AA 1/2 
participants only; failure of sirolimus therapy will be monitored in the sirolimus arm only. 
Failure of sirolimus therapy is defined as the addition of a systemic immune suppressive 
therapy beyond prednisone among those participants originally treated with sirolimus. 
The rate of sirolimus failure will be monitored up to 42 days post-randomization.  At least 
three events must be observed in order to trigger review.  The expected probability of 42 
day sirolimus failure is approximately 25-30% (derived from primary sirolimus 
monotherapy data, as well as anticipated rate of secondary therapy use beyond 
prednisone in prior BMT CTN aGVHD therapy trials)2,3. 
Each month, the null hypothesis that the 42-day sirolimus failure rate is less than or 
equal to 25% is tested using a binomial sequential probability ratio test (SPRT). This 
sequential testing procedure conserves type I error at 5% across all monthly 
examinations for the sirolimus arm. The SPRT can be represented graphically.  At each 
monthly interim analysis, the number of evaluable participants on study is plotted against 
the total number of treatment failures.  The continuation region of the SPRT is defined by 
two parallel lines.  Only the upper boundary will be used for monitoring in order to protect 
against excessive 42 day sirolimus failure.  If the graph crosses the upper boundary, the 
SPRT rejects the null hypothesis, and concludes that there are more events than 
predicted by the number of evaluable participants on study.  Otherwise, the SPRT 
continues until enrollment is complete. Only failures that occur on or before the patient 
has been followed for 42 days are counted. 
The boundaries for the binary SPRT were constructed by setting the null rate of 
sirolimus failure to be 25% versus an alternative of 50% for 42 day sirolimus failure. To 
construct the boundary, the nominal type I and type II errors were set to be 10% and 5% 
respectively. The upper boundary is defined by a slope of 0.37 and an upper intercept of 
2.05. Since the upper boundary alone is being used, the actual type I error of the 
binomial SPRT will be less than the nominal value without a substantial increase in type 
II error for the alternatives of interest (i.e. sirolimus therapy failure rates higher than 
expected). Table 2.2 illustrates the number of observed events required to cross the 
boundary for the binomial SPRT. 
 
 


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Table 2.2:  Safety Monitoring Guidelines for Failure of Sirolimus Therapy 
Number of Evaluable Participants Number of Events on or Prior to Day 42 
4-5 
4 
6-7 
5 
8-10 
6 
11-13 
7 
14-16 
8 
17-18 
9 
19-21 
10 
22-24 
11 
25-26 
12 
27-29 
13 
30-32 
14 
33-35 
15 
36-37 
16 
38-40 
17 
41-43 
18 
44-45 
19 
46-48 
20 
49-51 
21 
52-54 
22 
55-56 
23 
57-59 
24 
60 
25 
 
No monitoring of secondary therapy delivered beyond prednisone will be performed in 
the prednisone arm, as this treatment is considered standard care. 
Day 56 overall mortality is the second key safety endpoint. This endpoint will be 
monitored within each treatment arm using an extension of the (SPRT) for censored 
exponential data4. Unlike the binary SPRT which assesses the event rate in the number 
of evaluable participants, the censored exponential SPRT considers the number of 
events relative to the total time at risk on the study. The SPRT is represented graphically 
with the number of events on the y-axis and the total time at risk on the x-axis. The 
upper boundary of the SPRT will be used to guard against excess mortality. This 
procedure assumes an exponential distribution for overall mortality during the first 56 
days, with follow-up time censored at 56 days. 
Based on background data for standard risk acute GVHD participants, the expected Day 
56 overall mortality is 13.1%. As this estimate includes AA3 participants in addition to 
AA1/2, to be conservative, the null for the monitoring bound will be set at 10%. An SPRT 
contrasting 10% vs 25% Day 56 overall mortality results in decision boundaries with a 
common slope of 1.18 and an upper intercept of 2.29 based on nominal type 1 and type 
II errors of 9% and 10%, respectively, with the type I and II errors selected based on the 
simulation study and the actual operating characteristics of the SPRT shown in Table 2.3 


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that assumed uniform accrual of 60 individuals over a 24 month time period, and 
exponential time to failure after randomization. 
TABLE 2.3:  Operating Characteristics of Censored Exponential SPRT of Day 56 
Overall Mortality from a Simulation Study with 10,000 Replications 
True 56-Day Rate 
10% 
15% 
20% 
25% 
Probability Reject Null 
0.053 
0.281 
0.641 
0.888 
Mean Month Stopped 
25.2 
22.1 
16.8 
12.0 
Mean # Endpoints in 56 Days 
5.8 
7.6 
7.9 
7.0 
Mean # Participants Enrolled 
58.2 
51.6 
40.4 
29.6 
 
If the true Day 56 overall mortality rate is in line with the expected rate (i.e. 10%), then 
the stopping guideline has a 5% probability of being triggered. If the true overall mortality 
rate is higher than expected (i.e. 25% by Day 56), then the stopping guideline has an 
89% probability of being triggered (on average 12 months after opening when 30 
participants have been enrolled). 
 Timing of Analysis 
A data lock will be used for the primary analysis. The data lock will occur upon the 
completion of ERC adjudication on the study data and completion of related data quality 
assurance. An ERC Charter will define the scope of ERC review as well as the timeline 
for the data adjudication. The data lock will include the mature data on the primary and 
key secondary endpoints for the study participants. If the first lock occurs prior to the 
completion of 1 year of follow-up on all study participants, a second data lock will be 
performed in order to permit analysis of secondary endpoints requiring extended follow-
up. 
 Software 
All analyses will be conducted using SAS 9.4 or higher software and R version 3.1.0 or 
higher.  
 Analysis Populations  
 
Primary Analysis Population 
Participants will be analyzed according to the intent to treat (ITT) principle for this study, 
i.e. according to the treatment groups to which they were randomized, regardless of 
whether the assigned treatment was administered. Any participant who receives a 
treatment randomization number will be considered to have been randomized. Since the 
primary interest of this study is treatment in participants with standard risk acute GVHD, 
the primary analysis population will consist of all randomized AA1/2 participants with 
treatment classified per the ITT principle. 
The primary analysis for the primary, secondary, and exploratory endpoints will use the 
primary analysis population. A secondary analysis of the primary endpoint will be 


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performed, classifying participants by the initial treatment actually given. Another 
secondary analysis will consider primary and key secondary outcomes for all 
randomized AA3 participants classified per the ITT principle. An analysis of safety 
endpoints will also be conducted using the safety analysis population as described 
below. Analyses of each endpoint and population used will follow the analysis plan as 
described below in section 4 of this SAP. 
If a participant is deemed not eligible for the study after study registration or 
randomization occurs, he will be excluded from all analysis populations.  
 
Safety Analysis Population 
The reporting of serious adverse events will be consistent with standard BMT CTN 
procedures with the addition of any anticipated SAE related to sirolimus or prednisone 
therapy. All reported serious adverse events potentially associated with a study drug will 
be carefully examined with respect to the severity and relationship to the study drug. The 
type and severity of adverse events will be described. Safety data will be summarized 
using Medical Dictionary for Regulatory Activities (MeDRA) Coding Version 20.0 or 
above. 
The safety analysis population will be the same as the primary analysis population: all 
randomized AA1/2 participants categorized according to ITT. 
 General Analysis Guidelines 
Continuous variables will be described using the mean, standard deviation, median, and 
range. Categorical variables will be described using frequencies and proportions. All 
statistical tests will be two-sided at a 0.05 significance level unless otherwise specified. 
Any changes to the planned analyses and addition of any ad-hoc analyses will be 
documented in the final analysis report with justification given for the changes. If it is a 
change to analysis of an existing endpoint, the change should be clearly stated in the 
exhibit. If a new endpoint or analysis is performed, it should be included as a 
supplemental exhibit. 
3. Participant Characteristics and Compliance  
 Demographics and Baseline Characteristics  
Descriptive statistics for demographics and baseline characteristics of participants and 
donors will be presented by treatment group. Characteristics to be examined are: age, 
gender, race/ethnicity, performance status, primary disease, risk status, transplant 
conditioning regimen characteristics, donor type, HLA matching, graft source, initial 
GVHD prophylaxis delivered, donor and recipient CMV status, acute GVHD organ 
staging and overall grade at enrollment, and topical steroid therapy use. 
Data on performance status, primary disease, risk status, conditioning regimen 
characteristics, donor type, HLA matching, graft source, initial GVHD prophylaxis, and 


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donor and recipient CMV status will be retrieved from the CIBMTR database. All other 
variables will be collected on clinical forms.  
 Participant Compliance 
A table listing significant protocol deviations/violations will be provided with treatment 
assignments indicated. Compliance with protocol interventions will be evaluated as 
appropriate. Premature withdrawals will be described for each case. 
A consort diagram will be provided to illustrate study accrual, participant disposition, and 
follow up.   
The number of participants evaluated will be described in the tables and figures for each 
analysis. 
4. Analysis Plan  
 Analysis of the Primary Endpoint 
The primary endpoint for this study is complete response/partial response (CR/PR) of 
acute GVHD to therapy at Day 28 post-randomization. No formal hypothesis test will be 
performed. Instead, the difference in response rates between the two arms will be 
estimated with a 90% confidence interval. 
Acute GVHD response is categorized as complete response (CR), partial response 
(PR), mixed response (MR), no response (NR), and progression and is scored relative to 
the participant’s acute GVHD status (organ staging) entered on the day of 
randomization. Response categories are defined as follows: 
 
Complete response (CR): A stage of 0 for the GVHD grading in all evaluable 
organs.  For example, for a response to be scored as CR at Day 28, the 
participant must still be in CR on that day and have had no intervening additional 
therapy for an earlier progression, PR or NR. 
 
Partial response (PR): Improvement in one or more organs involved with GVHD 
symptoms without progression in others. 
 
Mixed response (MR): Improvement in one or more organs with either 
deterioration in another organ manifesting symptoms of GVHD or development of 
symptoms of GVHD in a new organ. 
 
Progression: Deterioration in at least one organ without any improvement in 
others. 
 
No response (NR): Absence of any improvement or progression 
Patients receiving secondary therapy (including need to re-escalate steroid dose to ≥ 2.5 
mg/kg/day of prednisone [or methylprednisolone equivalent of 2 mg/kg/day]) will be 
classified as non-responders. Patients who are assigned to the sirolimus arm who 
require initiation of systemic corticosteroids for the treatment of acute GVHD will be 
considered as non-responders for purposes of the primary endpoint assessment. 


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Participants that have died prior to Day 28 will be treated as nonresponders in the 
analysis. 
The reference for response evaluation is the GVHD organ staging reported at 
enrollment. The response rate (CR/PR) at Day 28 will be estimated using frequencies in 
each treatment group. A 90% Wald confidence interval for the difference in rates of the 
treatment groups will be computed.  
In a secondary analysis, rates of Day 28 CR/PR and their 95% confidence intervals will 
be estimated for each treatment group by donor type, graft source, and HLA mismatch 
(matched vs. mismatched). As the numbers for these subgroup analyses will be small, 
the intent is not to declare differences between subgroups formally, but rather to identify 
potential differences that may need to be considered in future trials. 
 Analysis of the Secondary Endpoints 
Since this is a phase II trial with many secondary and exploratory endpoints, no explicit 
control for multiplicity will be incorporated; rather a significance level of 5% will be used 
for all comparisons on these outcomes. 
 
Proportion of Participants with CR/PR and Steroid Dose 0.25 mg/kg/day 
or Less 
This is a refined endpoint of CR/PR and the use of a prednisone equivalent steroid dose 
of 0.25 mg/kg/day or less. The rates of CR/PR and steroid dose 0.25 mg/kg/day or less 
will be estimated within each arm and compared between arms using the Z test for 
binomial proportions (or Barnard’s Exact Unconditional Test5 as appropriate).  
Methylprednisone is considered to be 1.25 times as potent as prednisone, while 
prednisolone is dose-equivalent to prednisone. Note that use of prednisone below the 
threshold on the sirolimus arm will not be considered a failure for this endpoint. 
Participants that have died prior to Day 28 will be treated as nonreponders in the 
analysis. 
 
Disease Response 
The rates of complete response, partial response, mixed response, no response, and 
progression among surviving participants at Day 14, 28, and 56 will be estimated for 
each treatment group and compared between groups using Pearson’s chi-square test 
(or Fisher’s Exact Test as appropriate). 
 
Treatment Failure 
Treatment failure is a composite endpoint comprised of death, no response, progression, 
administration of additional therapy beyond primary therapy for GVHD [(or re-escalation 
of steroid dose to ≥ 2.5 mg/kg/day of prednisone (or methylprednisolone equivalent of 2 
mg/kg/day) or initiation of corticosteroids for the treatment of acute GVHD for 
participants assigned to the sirolimus arm] at Days 14, 28, and 56. Proportions of 
treatment failures for the treatment arms will be estimated and compared at Days 14, 28 


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and 56 using the Z test for comparing binomial proportions (or Barnard’s Exact 
Unconditional Test as appropriate). 
 
Chronic GVHD 
Chronic GVHD is defined by NIH Consensus Criteria. Cumulative incidence of chronic 
GVHD per this Criteria will be estimated for each treatment arm using the Aalen-
Johansen estimator6 and compared between arms using Gray’s test7, treating death and 
relapse as competing risks. Estimates and confidence intervals will be provided at 6 and 
12 months post-randomization. 
 
Systemic Infections 
Frequencies of infections will be tabulated by site of disease, date of onset, and severity.  
The time to first serious infection (Grade 2 or 3 per BMTCTN MOP) will be estimated for 
each treatment arm using the Aalen-Johansen estimator and compared between arms 
using Gray’s test, treating death as the competing risk. For the definition of infection 
severity, see the BMT CTN Manual of Procedures. 
 
Event-Free Survival 
Event-free survival is a composite endpoint of acute GVHD progression, chronic GVHD, 
malignancy relapse, and mortality. 
Malignancy relapse is defined as follows: 
Relapse is defined by either morphological or cytogenetic evidence of acute leukemia or 
MDS consistent with pre-transplant features, or radiologic evidence of lymphoma, 
documented or not by biopsy.  Progression of disease applies to participants with 
lymphoproliferative diseases (lymphoma or chronic lymphocytic leukemia) not in 
remission prior to transplantation.  The event is defined as increase in size of prior sites 
of disease or evidence of new sites of disease, documented or not by biopsy. 
Acute leukemia and MDS – Relapse will be diagnosed when there is: 
 
Reappearance of leukemia blast cells in the peripheral blood; or, 
 
>5% blasts in the bone marrow, not attributable to another cause (e.g. bone marrow 
regeneration). 
 
The appearance of previous or new dysplastic changes (MDS specific) within the 
bone marrow with or without falling donor chimerism; or  
 
The development of extramedullary leukemia or leukemic cells in the cerebral spinal 
fluid; or 
 
The reappearance of cytogenetic abnormalities present prior to transplantation. 
Lymphoproliferative Diseases – Relapse or progression will be diagnosed when there 
is: 


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June 7, 2018 
 
 
Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size.  Increased FDG uptake in a 
previously unaffected site will only be considered relapsed or progressive disease 
after confirmation with other modalities. In participants with no prior history of 
pulmonary lymphoma, new lung nodules identified by CT are mostly benign.  Thus, a 
therapeutic decision should not be made solely based on the PET without histologic 
confirmation. 
 
At least a 50% increase from nadir in the sum of the product diameters of any 
previously involved nodes, or in a single involved node, or the size of other lesions 
(e.g., splenic or hepatic nodules).  To be considered progressive disease, a lymph 
node with a diameter of the short axis of less than 1.0 cm must increase by 50% and 
to a size of 1.5 x 1.5 cm or more than 1.5 cm in the long axis.  
Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the 
lesion was PET positive before therapy unless the lesion is too small to be detected 
with current PET systems (<1.5 cm in its long axis by CT). 
 
In addition to the criteria above, participants with CLL who present in complete 
remission prior to transplantation may fulfill the relapse definition if there is 
reappearance of circulating malignant cells that are phenotypically characteristic of 
CLL.  
* Institution of any therapy to treat persistent, progressive or relapsed 
malignancy, including the withdrawal of immunosuppressive therapy or donor 
lymphocyte infusion, will be considered evidence of relapse/progression 
regardless7 of whether the criteria described above were met. 
Event-free survival within each treatment group will be described using the Kaplan-Meier 
estimator, with event time being the earliest time a patient met one of the various criteria 
for failure. Participants not meeting a failure criterion will be censored at time of last 
follow-up. Estimates and confidence intervals will be calculated at 6 and 12 months post-
randomization. 
 
Overall Survival (OS) 
Death from any cause will be considered an event for this endpoint. A participant’s event 
time will be censored if lost to follow up. OS at 6 and 12 months will be described using 
the Kaplan-Meier estimator and 95% confidence intervals will be computed. 
 
Disease-free Survival (DFS) 
Disease-free survival is a composite endpoint of the events death and relapse of the 
underlying malignancy. A participant’s event time will be censored if lost to follow up. 
DFS at 6 and 12 months will be described using the Kaplan-Meier estimator and 95% 
confidence intervals will be computed. 
 
GVHD-free Survival 
GVHD-free survival is a composite endpoint of the events death, acute GVHD, and 
chronic GVHD. The proportion of participants alive and GVHD free at 6 and 12 months 


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June 7, 2018 
 
post-randomization will be estimated and compared between treatment groups using the 
Z test for comparing binomial proportions (or Barnard’s Exact Unconditional Test as 
appropriate). 
 
Non-relapse Mortality (NRM) 
Non-relapse mortality (NRM) consists of deaths due to any cause other than relapse of 
the underlying malignancy. The cumulative incidence of non-relapse mortality will be 
estimated for each treatment group using the Aalen-Johansen estimator and groups will 
be compared using Gray’s test, treating relapse as a competing risk. Estimates and 
confidence intervals will be provided at 6 and 12 months post-randomization. 
 Analysis of the Exploratory Endpoints 
Since this is a phase II trial with many secondary and exploratory endpoints, no explicit 
control for multiplicity will be incorporated; rather a significance level of 5% will be used 
for all comparisons on these outcomes.   
 
Steroid Dose 
Doses of methylprednisolone will be converted to prednisone equivalents by multiplying 
the methylprednisolone dose by 1.25, while doses of prednisolone are considered 
equivalent to prednisone. The prednisone dose for each patient at Days 7, 14, 21, 28, 
35, 42, 49, and 56 will be recorded. Prednisone doses for each patient will be converted 
to mg/kg. For participants that weigh over 100kg, maximal starting dose of prednisone 
will be 200mg (or 2mg/kg based on a modified starting weight of 100kg). For calculation 
of subsequent prednisone doses/kg on subsequent measures, the modified starting 
weight of 100kg will be used. The cumulative prednisone dose for each patient at Day 56 
will be calculated by adding the doses (end of each week’s dose) for each of the first 
eight weeks of treatment, divided by the number of days of survival during this interval. 
This mean steroid dose will be described for each treatment group by median and range 
and will be compared between groups using the Wilcoxon Rank Sum test. 
 
Topical Therapy 
The proportion of participants using either topical skin or topical GI steroids at 
randomization will be estimated for each treatment group. Among participants entering 
with no topical therapy usage at baseline, the proportion of participants initiating new 
topical treatment will be described for each treatment group and compared between 
groups using the Z test for comparing binomial proportions (or Barnard’s Exact 
Unconditional Test as appropriate). 
 
Discontinuation of Immune Suppression 
The dates of discontinuation of corticosteroids and other systemic immune suppressive 
medications will be recorded. Cumulative incidence of immune suppression 
discontinuation will be described using the Aalen-Johansen estimator and curves will be 
compared using Gray’s test, treating death as the competing risk. Estimates and 


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confidence intervals will be provided at Day 56 and at 6 and 12 months post-
randomization. A refined endpoint of complete immune suppression discontinuation 
together with freedom from any GVHD or malignancy progression/recurrence will also be 
examined, treating death, GVHD, and malignancy progression/recurrence as competing 
risks. Its cumulative incidence for each treatment arm will be described using the Aalen-
Johansen estimator; curves will be compared using Gray’s test, treating death as the 
competing risk; and estimates and confidence intervals will be provided at Day 56 and at 
6 and 12 months post-randomization. 
 
EBV-associated lymphoproliferative disorder 
The cumulative incidence of EBV-associated lymphoproliferative disorder or EBV 
reactivation therapy will be described using the Aalen-Johansen estimator, treating 
death as the competing risk. Cumulative incidence curves will be compared between 
treatments using Gray’s test. 
 
Hyperglycemia 
Hyperglycemia is defined as a random glucose >200mg/dL or fasting glucose 
>126mg/dL and use of diabetes therapy, i.e. use of insulin and/or oral medications to 
control and/or maintain glucose level. The incidence of hyperglycemia and use of 
diabetes therapy at baseline, Day 28, and Day 56 will be estimated and compared 
between arms using a Z-test for comparing binomial proportions (or Barnard’s Exact 
Unconditional Test as appropriate). 
 
Functional Myopathy 
The change from baseline in functional myopathy score at Day 56 and 6 months post-
randomization will be evaluated. 
Functional Myopathy measures considered are: 
 
Hip Flexor and Quadriceps Strength via handheld dynamometer 
 
Two Minute Walk Test 
 
5-time Sit-to-Stand 
 
Adult Myopathy Assessment Tool (AMAT)  
These measures will be described for each treatment group at baseline, Day 56, and 6 
months using medians and ranges. Change from baseline within treatment group will be 
assessed using a Wilcoxon Signed Rank test at each timepoint. Change from baseline 
at each timepoint will be compared between treatment groups using a Wilcoxon Rank 
Sum test. 
 
Hyperlipidemia 
Prevalence of hyperlipidemia as measured by fasting lipid panel and/or use of lipid-
lowering agents at baseline, Days 28, 56 and 180 post-randomization will be compared 
between groups at each timepoint using a Z-test for binomial proportions (or Barnard’s 


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June 7, 2018 
 
Exact Unconditional Test as appropriate). For each of the measured components of the 
fasting lipid panel (e.g. total cholesterol, LDL, HDL, and triglycerides), the proportion of 
patients in each study arm with measurements outside of normal range (abnormally high 
for total cholesterol, LDL, and triglycerides; abnormally low for HDL) will also be 
compared in this manner. 
 
Thrombotic microangiopathy 
The proportion of participants experiencing thrombotic microangiopathy by 6 months 
post-randomization will be estimated and compared between treatment groups using the 
Z test for comparing binomial proportions (or Barnard’s Exact Unconditional Test as 
appropriate). 
 
CMV reactivation 
The proportion of participants with previous CMV exposure (either donor or recipient was 
previously CMV+) requiring new systemic treatment for an increasing CMV PCR level 
per institutional practice (participants receiving only standard of care viral prophylaxis will 
not be included in this assessment) by Day 56 post-randomization will be compared 
between treatment groups using a Z-test for comparing binomial proportions (or 
Barnard’s Exact Unconditional Test as appropriate). 
 
Patient-Reported Outcomes 
Patient-Reported Outcomes (PROs) assessed include the MDASI (MD Anderson 
Symptom Inventory), FACT-BMT, and MOS Short Form-36 (or PedsQL for pediatric 
participants) at enrollment and at Day 56, 6 months, and 12 months post-randomization.  
These will be scored per the recommendations of the developers. PROs at each time 
point will be summarized using simple descriptive statistics (mean, standard deviation, 
median, and range). PROs among survivors at each time point will be compared 
between treatment arms in an initial analysis using two sample t tests. The missing data 
pattern of the PRO measurements may be examined using graphical techniques and 
logistic regression models conditional on survival where, at each time point, estimates of 
the difference in PROs between the treatment groups conditional on survival would be 
obtained using inverse probability of censoring weighting with independent estimating 
equations to account for missing data. 
 
Secondary Analysis of AA3 Participants 
A secondary analysis will assess study outcomes for AA3 participants by treatment 
group (note that participants with missing biomarker results will be excluded). Due to the 
small number of AA3 participants expected, this analysis will be descriptive only as we 
are unlikely to have power to detect differences between the groups. 
5. Template of Proposed Table/Figure/Listing (TFL) Shells  
Table/Figure/Listing titles and layout are for illustration purposes only, and may not be 
the final layout or wording chosen for publications or presentations.  Actual format of the 


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June 7, 2018 
 
tables and figures may differ and will be subject to change in the final analysis report 
and/or publication. See the Appendix of this SAP for the exhibit titles and shells. 
 
6. References 
1 MacMillan ML, Robin M, Harris AC, et al. A refined risk score for acute graft-versus-
host disease that predicts response to initial therapy, survival, and transplant-related 
mortality. Biology of Blood and Marrow Transplantation. 2015, 21(4):761-767. 
2 Bolanos-Meade J, Logan BR, Alousi AM, et al. Phase 3 clinical trial of 
steroids/mycophenolate mofetil vs steroids/placebo as therapy for acute GVHD: BMT 
CTN 0802. Blood. 2014, 124:3221-3227. 
3 Pidala J, Tomblyn M, Nishihori T, et al. Sirolimus demonstrates activity in the primary 
therapy of acute graft-versus-host disease without systemic glucocorticoids. 
Haematologica. 2011, 96:1351-1356. 
4 Haggstrom G. Sequential Tests for Exponential Population and Poisson Processes. 
Rand Corporation. 1979. 
5 Barnard GA. A New Test for 2× 2 Tables. Nature. 1945, 156:177. 
6 Aalen OO and Johansen S. An empirical transition matrix for non-homogeneous 
Markov chains based on censored observations. Scandinavian Journal of Statistics. 
1978, 141-150. 
7 Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a 
competing risk. The Annals of Statistics. 1988, 1141-1154. 
 
 
 
 


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Appendix 
 
Exhibit 1501-1:  Participant Disposition and Follow-Up 
A consort diagram will be provided showing the number of participants, study 
assignment, and compliance with each phase of the protocol as applicable.  A table will 
be provided with descriptive statistics on length of follow-up by assigned treatment arm. 
Exhibit 1501-2:  Participant Demographics and Baseline Characteristics 
Baseline characteristics and demographics will be described by frequencies and 
percentages for categorical covariates, and mean, standard deviation, median, and 
range for continuous covariates. The following covariates will be included:  
 
Treatment group assignment 
 
Gender 
 
Ethnicity 
 
Race  
 
Patient age 
 
Karnofsky performance score  
 
Primary Disease 
 
Disease Status 
 
Conditioning regimen 
 
Conditioning regimen intensity 
 
Donor type 
 
Graft source 
 
HLA match score 
 
GVHD Prophylaxis at Transplant 
 
Donor/Recipient CMV Status 
 
Acute GVHD grade at enrollment 
 
Acute GVHD organ staging at enrollment 
 
Topical steroid use at enrollment 
 
Ann Arbor biomarker status 
Other baseline covariates will be summarized at the request of the investigators. 
 
 
Treatment Arm 
 
 
Sirolimus 
(N=) 
N (%) 
Prednisone 
(N=) 
N (%) 
Total 
(N=) 
N (%) 
Gender 
 
 
 
  Female 
 
 
 
  Male 
 
 
 
Ethnicity 
 
 
 
  Hispanic or Latino 
 
 
 
  Not Hispanic or Latino 
 
 
 
  Unknown 
 
 
 


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June 7, 2018 
 
 
Treatment Arm 
 
 
Sirolimus 
(N=) 
N (%) 
Prednisone 
(N=) 
N (%) 
Total 
(N=) 
N (%) 
  Not Answered 
 
 
 
Race 
 
 
 
  American Indian/Alaskan Native 
 
 
 
  Asian 
 
 
 
  Hawaiian/Pacific Islander 
 
 
 
  Black or African American 
 
 
 
  White 
 
 
 
  More than One Race 
 
 
 
  Other, Specify 
 
 
 
  Unknown 
 
 
 
  Not Answered 
 
 
 
Age, years 
 
 
 
  Mean (Std Dev) 
 
 
 
  Median (Range) 
 
 
 
Ann Arbor Biomarker Status 
 
 
 
   1 
 
 
 
   2 
 
 
 
   3 
 
 
 
   Missing 
 
 
 
Karnofsky Performance Score 
 
 
 
   90 - 100 
 
 
 
   Less than 90 
 
 
 
Primary Disease 
 
 
 
  Acute Lymphoblastic Leukemia (ALL) 
 
 
 
  Acute Myelogenous Leukemia (AML) 
 
 
 
  Chronic Myelogenous Leukemia (CML) 
 
 
 
  Other Leukemia 
 
 
 
  Myelodysplastic/Myeloprolifterative Disorders (MDS/MPN) 
 
 
 
  Non-Hodgkin Lymphoma (NHL) 
 
 
 
  Hodgkin Lymphoma 
 
 
 
  Plasma Cell Disorder/Multiple Myeloma 
 
 
 
  Inherited Abnormalities Erythrocyte Differention or Function  
 
 
Disease Status 
 
 
 
  Complete remission (CR) 
 
 
 


Version 1.0 
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June 7, 2018 
 
 
Treatment Arm 
 
 
Sirolimus 
(N=) 
N (%) 
Prednisone 
(N=) 
N (%) 
Total 
(N=) 
N (%) 
  Partial remission (PR) 
 
 
 
  Stable disease (SD) 
 
 
 
Conditioning Regimen1 
 
 
 
  ATG + FLUD + MEL  
 
 
 
  BU + ATG + clofarabine 
 
 
 
  BU + ATG + FLUD 
 
 
 
  BU + ATG + FLUD + vorinostat 
 
 
 
  BU + FLUD 
 
 
 
  BU + FLUD + THIO 
 
 
 
  CY + BU 
 
 
 
  CY + BU + FLUD 
 
 
 
  FLUD + MEL  
 
 
 
  TBI +CY 
 
 
 
  TBI + CY + FLUD 
 
 
 
  TBI + FLUD 
 
 
 
Conditioning Regimen Intensity 
 
 
 
  Myeloablative 
 
 
 
  Non-myeloablative or Reduced Intensity 
 
 
 
Donor Type 
 
 
 
  Related Donor 
 
 
 
  Unrelated Donor 
 
 
 
Graft Source 
 
 
 
  Bone Marrow 
 
 
 
  Peripheral Blood 
 
 
 
  Cord Blood 
 
 
 
HLA Match Score 
 
 
 
  Bone marrow or peripheral blood 8/8 
 
 
 
  Bone marrow or peripheral blood 7/8 
 
 
 
  Bone marrow or peripheral blood <= 6/8 
 
 
 
  Cord blood 6/6 
 
 
 
  Cord blood 5/6 
 
 
 
  Cord blood <= 4/6 
 
 
 
  Missing 
 
 
 
GVHD Prophylaxis at Transplant 
 
 
 


Version 1.0 
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June 7, 2018 
 
 
Treatment Arm 
 
 
Sirolimus 
(N=) 
N (%) 
Prednisone 
(N=) 
N (%) 
Total 
(N=) 
N (%) 
  Post-CY + Other(s) 
 
 
 
  TAC + MMF +- Other(s) (except post-CY) 
 
 
 
  TAC + MTX +- Other(s) (except MMF, post-CY) 
 
 
 
  CSA + MMF +- Other(s) (except post-CY) 
 
 
 
  CSA + MTX +- Other(s) (except MMF, post-CY) 
 
 
 
Donor/Recipient CMV Status 
 
 
 
  Pos/Pos 
 
 
 
  Pos/Neg 
 
 
 
  Neg/Pos 
 
 
 
  Neg/Neg 
 
 
 
Acute GVHD Grade at Enrollment 
 
 
 
  0 
 
 
 
  I 
 
 
 
  II 
 
 
 
  III 
 
 
 
  IV 
 
 
 
Acute GVHD Skin Organ Stage at Enrollment 
 
 
 
  0 
 
 
 
  1 
 
 
 
  2 
 
 
 
  3 
 
 
 
  4 
 
 
 
Acute GVHD Upper GI Organ Involvement at Enrollment  
 
 
  Yes 
 
 
 
  No 
 
 
 
Acute GVHD Lower GI Organ Stage at Enrollment 
 
 
 
  0 
 
 
 
  1 
 
 
 
  2 
 
 
 
  3 
 
 
 
  4 
 
 
 
Acute GVHD Liver Organ Stage at Enrollment 
 
 
 
  0 
 
 
 


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June 7, 2018 
 
 
Treatment Arm 
 
 
Sirolimus 
(N=) 
N (%) 
Prednisone 
(N=) 
N (%) 
Total 
(N=) 
N (%) 
  1 
 
 
 
  2 
 
 
 
  3 
 
 
 
  4 
 
 
 
Topical Steroid Use at Enrollment 
 
 
 
  Yes 
 
 
 
  No 
 
 
 
1 ATG =  antithymocyte globulin, BU = Busulfan, FLUD  =  Fludarabine,  CY  = Cyclophosphamide, MEL = 
Melphalan, TBI  = Total body irradiation,  THIO  =  Intrathecal thiotepa 
 
 


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Exhibit 1501-3:  Complete Response / Partial Response at Day 28 
The primary endpoint is complete response/partial response (CR/PR) of acute GVHD to 
therapy at Day 28 post-randomization. Participants that have died prior to Day 28 or 
receive secondary therapy are treated as nonresponders in the analysis. 
Acute GVHD Response at Day 28 by Treatment Group 
 
Sirolimus 
(N=) 
N (%) 
Prednisone 
(N=) 
N (%) 
Complete Response (CR) 
XX (XX.X%) 
XX (XX.X%) 
Partial Response (PR) 
XX (XX.X%) 
XX (XX.X%) 
Mixed Response (MR) 
XX (XX.X%) 
XX (XX.X%) 
No Response (NR) 
XX (XX.X%) 
XX (XX.X%) 
Progression 
XX (XX.X%) 
XX (XX.X%) 
Dead 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
 
Day 28 CR/PR Rates 
 
N 
Evaluable 
Estimate 
Standard Error 
90% CI 
Sirolimus 
XX 
XX.X% 
XX.X% 
(XX.X%, XX.X%) 
Prednisone 
XX 
XX.X% 
XX.X% 
(XX.X%, XX.X%) 
Difference (Sirolimus – 
Prednisone) 
XX 
XX.X% 
XX.X% 
(XX.X%, XX.X%) 
 
Clarify the population for the endpoint (n=?).  If n is not the same as the primary 
endpoint, explain why (e.g. patient not evaluable, missing data, etc.) Give details of not 
evaluable if the definition is not pre-specified in the protocol. 
 
 


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Exhibit 1501-4:  Complete Response / Partial Response and Steroid Dose 
0.25/mg/kg/day or Less at Day 28 
This is a refined endpoint of CR/PR and the use of a prednisone equivalent steroid dose 
of 0.25 mg/kg/day or less. Methylprednisone is considered to be 1.25 times as potent as 
prednisone, while prednisolone is dose-equivalent to prednisone. Note that use of 
prednisone below the threshold on the sirolimus arm is not considered a failure for this 
endpoint. Participants that have died or received secondary therapy prior to Day 28 are 
treated as nonreponders in the analysis. 
Day 28 CR/PR and Steroid Dose 0.25/mg/kg/day or Less by Treatment Group 
 
Sirolimus 
(N=) 
N (%) 
Prednisone 
(N=) 
N (%) 
P-value* 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
* Clarify test used (Z test of binomial proportions or Barnard’s Exact) 
 
Rates of Day 28 CR/PR with Steroid Dose 0.25/mg/kg/day or Less  
 
N Evaluable 
Estimate 
Standard Error 
95% CI 
Sirolimus 
XX 
XX.X% 
XX.X% 
(XX.X%, XX.X%) 
Prednisone 
XX 
XX.X% 
XX.X% 
(XX.X%, XX.X%) 
 
Clarify the population for the endpoint (n=?).  If n is not the same as the primary 
endpoint, explain why (e.g. patient not evaluable, missing data, etc.) Give details of not 
evaluable if the definition is not pre-specified in the protocol. 
 
 


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Exhibit 1501-5:  Disease Response 
Acute GVHD Response Among Surviving Patients by Treatment Group 
Assessment 
Time Point 
 
Sirolimus 
(N=) 
N (%) 
Prednisone 
(N=) 
N (%) 
P-value* 
Day 14 
Complete Response (CR) 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
Partial Response (PR) 
XX (XX.X%) 
XX (XX.X%) 
Mixed Response (MR) 
XX (XX.X%) 
XX (XX.X%) 
No Response (NR) 
XX (XX.X%) 
XX (XX.X%) 
Progression 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
Day 28 
Complete Response (CR) 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
Partial Response (PR) 
XX (XX.X%) 
XX (XX.X%) 
Mixed Response (MR) 
XX (XX.X%) 
XX (XX.X%) 
No Response (NR) 
XX (XX.X%) 
XX (XX.X%) 
Progression 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
Day 56 
Complete Response (CR) 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
Partial Response (PR) 
XX (XX.X%) 
XX (XX.X%) 
Mixed Response (MR) 
XX (XX.X%) 
XX (XX.X%) 
No Response (NR) 
XX (XX.X%) 
XX (XX.X%) 
Progression 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
* Clarify tests used (Chi square with 4 d.f. or Fisher’s Exact) 
Clarify the population for the endpoint (n=?).  If n is not the same as the primary 
endpoint, explain why (e.g. patient not evaluable, missing data, etc.) Give details of not 
evaluable if the definition is not pre-specified in the protocol. 
 
 


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Exhibit 1501-6:  Treatment Failure 
Treatment failure is defined as death, no response, progression, administration of 
additional therapy beyond primary therapy for GVHD [(or re-escalation of steroid dose to 
≥ 2.5 mg/kg/day of prednisone (or methylprednisolone equivalent of 2 mg/kg/day) or 
initiation of corticosteroids for the treatment of acute GVHD for participants assigned to 
the sirolimus arm]. 
Treatment Failure by Treatment Group 
Assessment 
Time Point 
 
Sirolimus 
(N=) 
N (%) 
Prednisone 
(N=) 
N (%) 
P-value* 
Day 14 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
Day 28 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
Day 56 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
* Clarify tests used (Z test of binomial proportions or Barnard’s Exact) 
Clarify the population for the endpoint (n=?).  If n is not the same as the primary 
endpoint, explain why (e.g. patient not evaluable, missing data, etc.) Give details of not 
evaluable if the definition is not pre-specified in the protocol. 
 
 


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Exhibit 1501-7:  Chronic GVHD 
Cumulative Incidence of Chronic GVHD by Treatment Arm 
 
* P-value from Gray’s test. Death and relapse are treated as competing risks. 
 
Maximum Severity of Chronic GVHD at 1 Year Post-Randomization by Treatment Group 
Severity 
Sirolimus 
(N=) 
N (%) 
Prednisone 
(N=) 
N (%) 
No cGVHD 
XX (XX.X%) 
XX (XX.X%) 
Mild 
XX (XX.X%) 
XX (XX.X%) 
Moderate 
XX (XX.X%) 
XX (XX.X%) 
Severe 
XX (XX.X%) 
XX (XX.X%) 
 
Cumulative Incidence Estimates and 95% Confidence Intervals for Chronic GVHD 
Time post-randomization 
Sirolimus 
Prednisone 
6 months 
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
12 months 
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
 
1
2
3
4
5
6
7
8
9
10
11
12
Months Post Randomization
0.0
0.2
0.4
0.6
0.8
1.0
Cumulative Incidence
p = 0.##
Prednisone
Sirolimus
60
56
52
50
47
43
41
40
39
37
35
34
60
56
51
47
45
44
42
41
38
36
35
33
Prednisone
Sirolimus
N at Risk


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Clarify the population for the endpoint (n=?).  If n is not the same as the primary 
endpoint, explain why (e.g. patient not evaluable, missing data, etc.) 
 
 


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Exhibit 1501-8:  Systemic Infections 
Number of Infections Reported by Treatment Group 
 
 
Sirolimus 
(N=) 
N (%) 
Prednisone 
(N=) 
N (%) 
Site 
Blood/Buffy Coat  
XX (XX.X%) 
XX (XX.X%) 
 
Disseminated - Generalized, 
Isolated at 2 or More Distinct 
Sites  
XX (XX.X%) 
XX (XX.X%) 
 
Brain  
XX (XX.X%) 
XX (XX.X%) 
 
Spinal Cord  
XX (XX.X%) 
XX (XX.X%) 
 
Meninges and CSF  
XX (XX.X%) 
XX (XX.X%) 
 
… 
XX (XX.X%) 
XX (XX.X%) 
 
[omitted 37 categories] 
XX (XX.X%) 
XX (XX.X%) 
 
… 
XX (XX.X%) 
XX (XX.X%) 
 
Spleen 
XX (XX.X%) 
XX (XX.X%) 
 
Other Unspecified 
XX (XX.X%) 
XX (XX.X%) 
Time of Onset Post-
Randomization 
Median days (range) 
XX (XX.X-XX.X) 
XX (XX.X-XX.X) 
 
0-90 days 
XX (XX.X%) 
XX (XX.X%) 
 
91-180 days 
XX (XX.X%) 
XX (XX.X%) 
 
181-270 days 
XX (XX.X%) 
XX (XX.X%) 
 
271-365 days 
XX (XX.X%) 
XX (XX.X%) 
Severity 
Grade 2 (Moderate) 
XX (XX.X%) 
XX (XX.X%) 
 
Grade 3 (Severe / Life 
Threatening) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 


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June 7, 2018 
 
Cumulative Incidence of Severe Infection by Treatment Arm 
* P-value from Gray’s test. Death is treated as the competing risk. 
 
Cumulative Incidence Estimates and 95% Confidence Intervals for Severe Infection 
Time post-randomization 
Sirolimus 
Prednisone 
6 months 
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
12 months 
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
 
Clarify the population for the endpoint (n=?).  If n is not the same as the primary 
endpoint, explain why (e.g. patient not evaluable, missing data, etc.) 
 
 
1
2
3
4
5
6
7
8
9
10
11
12
Months Post Randomization
0.0
0.2
0.4
0.6
0.8
1.0
Cumulative Incidence
p = 0.##
Prednisone
Sirolimus
60
56
52
50
47
43
41
40
39
37
35
34
60
56
51
47
45
44
42
41
38
36
35
33
Prednisone
Sirolimus
N at Risk


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Exhibit 1501-9:  Event-Free Survival 
Event-free survival is a composite endpoint of acute GVHD progression, chronic GVHD, 
malignancy relapse, and mortality. 
Event-Free Survival by Treatment Arm 
* P-value from log rank test. 
 
Kaplan Meier Estimates of Event-Free Survival 
 
Sirolimus 
Prednisone 
6 months 
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
12 months  
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
 
Follow-up time for Event-Free Survival 
 
Sirolimus 
Prednisone 
Median days (range) 
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
Details need to be added if any lost to follow-up. 
 
1
2
3
4
5
6
7
8
9
10
11
12
Months Post Transplant
0.0
0.2
0.4
0.6
0.8
1.0
Survival Probability
p = 0.##
Prednisone
Sirolimus
60
58
56
54
52
49
47
44
41
39
36
34
60
57
55
51
47
44
41
39
37
35
33
30
Prednisone
Sirolimus
N at Risk


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Clarify the population for the endpoint (n=?).  If n is not the same as the primary 
endpoint, explain why (e.g. patient not evaluable, missing data, etc.) 
 


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June 7, 2018 
 
Exhibit 1501-10:  Overall Survival 
Overall Survival by Treatment Arm 
* P-value from log rank test. 
 
Kaplan Meier Estimates of Overall Survival 
 
Sirolimus 
Prednisone 
6 months 
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
12 months  
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
 
Follow-up time for Overall Survival 
 
Sirolimus 
Prednisone 
Median days (range) 
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
Details need to be added if any lost to follow-up. 
 
Clarify the population for the endpoint (n=?).  If n is not the same as the primary 
endpoint, explain why (e.g. patient not evaluable, missing data, etc.) 
 
 
1
2
3
4
5
6
7
8
9
10
11
12
Months Post Transplant
0.0
0.2
0.4
0.6
0.8
1.0
Survival Probability
p = 0.##
Prednisone
Sirolimus
60
58
56
54
52
49
47
44
41
39
36
34
60
57
55
51
47
44
41
39
37
35
33
30
Prednisone
Sirolimus
N at Risk


Version 1.0 
39 
June 7, 2018 
 
Exhibit 1501-11:  Disease-Free Survival 
Disease-free survival is a composite endpoint of the events death and relapse of the 
underlying malignancy. 
Disease-Free Survival by Treatment Arm 
* P-value from log rank test. 
 
Kaplan Meier Estimates of Disease-Free Survival 
 
Sirolimus 
Prednisone 
6 months 
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
12 months  
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
 
Follow-up time for Disease -Free Survival 
 
Sirolimus 
Prednisone 
Median days (range) 
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
Details need to be added if any lost to follow-up. 
 
1
2
3
4
5
6
7
8
9
10
11
12
Months Post Transplant
0.0
0.2
0.4
0.6
0.8
1.0
Survival Probability
p = 0.##
Prednisone
Sirolimus
60
58
56
54
52
49
47
44
41
39
36
34
60
57
55
51
47
44
41
39
37
35
33
30
Prednisone
Sirolimus
N at Risk


Version 1.0 
40 
June 7, 2018 
 
Clarify the population for the endpoint (n=?).  If n is not the same as the primary 
endpoint, explain why (e.g. patient not evaluable, missing data, etc.) 
 


Version 1.0 
41 
June 7, 2018 
 
Exhibit 1501-12: GVHD-free Survival 
GVHD-free survival is a composite endpoint of the events death, acute GVHD, and 
chronic GVHD.  
GVHD-free Survival by Treatment Group 
Assessment 
Time Point 
 
Sirolimus 
(N=) 
N (%) 
Prednisone 
(N=) 
N (%) 
P-value* 
6 months 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
12 months 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
* Clarify test used (Z test of binomial proportions or Barnard’s Exact) 
 
Clarify the population for the endpoint (n=?).  If n is not the same as the primary 
endpoint, explain why (e.g. patient not evaluable, missing data, etc.) 
 
 
 
 


Version 1.0 
42 
June 7, 2018 
 
Exhibit 1501-13:  Non-relapse Mortality 
Non-relapse mortality (NRM) consists of deaths due to any cause other than relapse of 
the underlying malignancy. 
Cumulative Incidence of Non-Relapse Mortality by Treatment Arm 
* P-value from Gray’s test. Relapse is treated as the competing risk. 
 
Cumulative Incidence Estimates and 95% Confidence Intervals for Non-relapse Mortality 
Time post-randomization 
Sirolimus 
Prednisone 
6 months 
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
12 months 
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
 
Clarify the population for the endpoint (n=?).  If n is not the same as the primary 
endpoint, explain why (e.g. patient not evaluable, missing data, etc.) 
 
 
1
2
3
4
5
6
7
8
9
10
11
12
Months Post Randomization
0.0
0.2
0.4
0.6
0.8
1.0
Cumulative Incidence
p = 0.##
Prednisone
Sirolimus
60
56
52
50
47
43
41
40
39
37
35
34
60
56
51
47
45
44
42
41
38
36
35
33
Prednisone
Sirolimus
N at Risk


Version 1.0 
43 
June 7, 2018 
 
Exhibit 1501-14: Steroid Dose 
The cumulative prednisone-equivalent dose of steroids through Day 56 is described 
here. Doses of methylprednisolone will be converted to prednisone equivalents by 
multiplying the methylprednisolone dose by 1.25, while doses of prednisolone are 
considered equivalent to prednisone. Prednisone doses for each patient will be 
converted to mg/kg. For participants that weigh over 100kg, maximal starting dose of 
prednisone will be 200mg (or 2mg/kg based on a modified starting weight of 100kg). For 
calculation of subsequent prednisone doses/kg on subsequent measures, the modified 
starting weight of 100kg will be used. Cumulative prednisone dose for each patient at 
Day 56 is calculated by adding the doses (end of each week’s dose) for each of the first 
eight weeks of treatment, divided by the number of days of survival during this interval. 
Cumulative Steroid Dose at Day 56 by Treatment Group 
 
Sirolimus 
(N=) 
Prednisone 
(N=) 
P-value* 
Median (range) 
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
X.XXX 
* Wilcoxon Rank Sum test 
Clarify the population for the endpoint (n=?).  If n is not the same as the primary 
endpoint, explain why (e.g. patient not evaluable, missing data, etc.) Give details of not 
evaluable if the definition is not pre-specified in the protocol. 
 
 


Version 1.0 
44 
June 7, 2018 
 
Exhibit 1501-15: Topical Therapy 
Topical therapy consists of the use of either topical skin or topical GI steroids. 
Topical Therapy Use at Baseline by Treatment Group 
 
Sirolimus 
(N=) 
N (%) 
Prednisone 
(N=) 
N (%) 
Yes 
XX (XX.X%) 
XX (XX.X%) 
No 
XX (XX.X%) 
XX (XX.X%) 
 
Topical Therapy Use Post-Randomization Among Participants Free of Topical Therapy at Baseline 
by Treatment Group 
 
Sirolimus 
(N=) 
N (%) 
Prednisone 
(N=) 
N (%) 
P-value* 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
* Clarify test used (Z test of binomial proportions or Barnard’s Exact) 
 
Clarify the population for the endpoint (n=?).  If n is not the same as the primary 
endpoint, explain why (e.g. patient not evaluable, missing data, etc.) Give details of not 
evaluable if the definition is not pre-specified in the protocol. 
 
 
 


Version 1.0 
45 
June 7, 2018 
 
Exhibit 1501-16:  Discontinuation of Immune Suppression 
Discontinuation of immune suppression consists of discontinuation of corticosteroids and 
other systemic immune suppressive medications. 
Cumulative Incidence of Discontinuation of Immune Suppression by Treatment Arm 
* P-value from Gray’s test. Death is treated as the competing risk. 
 
Cumulative Incidence Estimates and 95% Confidence Intervals for Discontinuation of 
Immune Suppression 
Time post-randomization 
Sirolimus 
Prednisone 
Day 56 
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
6 months 
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
12 months 
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
 
 
 
 
1
2
3
4
5
6
7
8
9
10
11
12
Months Post Randomization
0.0
0.2
0.4
0.6
0.8
1.0
Cumulative Incidence
p = 0.##
Prednisone
Sirolimus
60
56
52
50
47
43
41
40
39
37
35
34
60
56
51
47
45
44
42
41
38
36
35
33
Prednisone
Sirolimus
N at Risk


Version 1.0 
46 
June 7, 2018 
 
GVHD- and relapse-free discontinuation of immune suppression is a refined endpoint 
consisting of complete immune suppression discontinuation together with freedom from 
any GVHD or malignancy progression/recurrence. 
Cumulative Incidence of GVHD- and Relapse-free Discontinuation of Immune 
Suppression by Treatment Arm 
* P-value from Gray’s test. Death is treated as the competing risk. 
 
Cumulative Incidence Estimates and 95% Confidence Intervals for GVHD- and Relapse-
free Discontinuation of Immune Suppression 
Time post-randomization 
Sirolimus 
Prednisone 
Day 56 
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
6 months 
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
12 months 
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
 
Clarify the population for the endpoint (n=?).  If n is not the same as the primary 
endpoint, explain why (e.g. patient not evaluable, missing data, etc.) 
 
 
1
2
3
4
5
6
7
8
9
10
11
12
Months Post Randomization
0.0
0.2
0.4
0.6
0.8
1.0
Cumulative Incidence
p = 0.##
Prednisone
Sirolimus
60
56
52
50
47
43
41
40
39
37
35
34
60
56
51
47
45
44
42
41
38
36
35
33
Prednisone
Sirolimus
N at Risk


Version 1.0 
47 
June 7, 2018 
 
Exhibit 1501-16:  EBV-associated Lymphoproliferative Disorder 
Cumulative Incidence of EBV-associated Lymphoproliferative Disorder 
 by Treatment Arm 
* P-value from Gray’s test. Death is treated as the competing risk. 
 
Cumulative Incidence Estimates and 95% Confidence Intervals for EBV-associated 
Lymphoproliferative Disorder 
Time post-randomization 
Sirolimus 
Prednisone 
6 months 
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
12 months 
XX.X (XX.X, XX.X) 
XX.X (XX.X, XX.X) 
 
Clarify the population for the endpoint (n=?).  If n is not the same as the primary 
endpoint, explain why (e.g. patient not evaluable, missing data, etc.) 
1
2
3
4
5
6
7
8
9
10
11
12
Months Post Randomization
0.0
0.2
0.4
0.6
0.8
1.0
Cumulative Incidence
p = 0.##
Prednisone
Sirolimus
60
56
52
50
47
43
41
40
39
37
35
34
60
56
51
47
45
44
42
41
38
36
35
33
Prednisone
Sirolimus
N at Risk


Version 1.0 
48 
June 7, 2018 
 
Exhibit 1501-17: Hyperglycemia 
Hyperglycemia is defined as a random glucose >200mg/dL or fasting glucose 
>126mg/dL and use of diabetes therapy, i.e. use of insulin and/or oral medications to 
control and/or maintain glucose level. 
Hyperglycemia by Treatment Group 
Assessment 
Time Point 
 
Sirolimus 
(N=) 
N (%) 
Prednisone 
(N=) 
N (%) 
P-value* 
Baseline 
Yes 
XX (XX.X%) 
XX (XX.X%) 
--- 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
Day 28 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
Day 56 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
* Clarify test used (Z test of binomial proportions or Barnard’s Exact) 
 
 


Version 1.0 
49 
June 7, 2018 
 
Exhibit 1501-18:  Functional Myopathy 
Functional myopathy measures considered are: 
 
Hip Flexor and Quadriceps Strength via handheld dynamometer 
 
Two Minute Walk Test 
 
5-time Sit-to-Stand 
 
Adult Myopathy Assessment Tool (AMAT)  
Functional Myopathy Scores by Treatment Group 
Measure 
Assessment 
Time 
Sirolimus 
(N=) 
Prednisone 
(N=) 
Treatment 
Comparison 
p-value2 
N 
Median 
(Range) 
p-
value1 
N 
Median 
(Range) 
p-
value1 
Hip Flexor 
and 
Quadriceps 
Strength 
Baseline 
XX 
XX.X 
(XX.X, 
XX.X) 
- 
XX 
XX.X 
(XX.X, 
XX.X) 
- 
- 
Day 56 
XX 
XX.X 
(XX.X, 
XX.X) 
X.XXX 
XX 
XX.X 
(XX.X, 
XX.X) 
X.XXX 
X.XXX 
6 months 
XX 
XX.X 
(XX.X, 
XX.X) 
X.XXX 
XX 
XX.X 
(XX.X, 
XX.X) 
X.XXX 
X.XXX 
Two Minute 
Walk Test 
Baseline 
XX 
XX.X 
(XX.X, 
XX.X) 
- 
XX 
XX.X 
(XX.X, 
XX.X) 
- 
- 
Day 56 
XX 
XX.X 
(XX.X, 
XX.X) 
X.XXX 
XX 
XX.X 
(XX.X, 
XX.X) 
X.XXX 
X.XXX 
6 months 
XX 
XX.X 
(XX.X, 
XX.X) 
X.XXX 
XX 
XX.X 
(XX.X, 
XX.X) 
X.XXX 
X.XXX 
5-time Sit-
to-Stand 
Baseline 
XX 
XX.X 
(XX.X, 
XX.X) 
- 
XX 
XX.X 
(XX.X, 
XX.X) 
- 
- 
Day 56 
XX 
XX.X 
(XX.X, 
XX.X) 
X.XXX 
XX 
XX.X 
(XX.X, 
XX.X) 
X.XXX 
X.XXX 
6 months 
XX 
XX.X 
(XX.X, 
XX.X) 
X.XXX 
XX 
XX.X 
(XX.X, 
XX.X) 
X.XXX 
X.XXX 
Adult 
Myopathy 
Assessment 
Tool 
Baseline 
XX 
XX.X 
(XX.X, 
XX.X) 
- 
XX 
XX.X 
(XX.X, 
XX.X) 
- 
- 
Day 56 
XX 
XX.X 
(XX.X, 
XX.X) 
X.XXX 
XX 
XX.X 
(XX.X, 
XX.X) 
X.XXX 
X.XXX 


Version 1.0 
50 
June 7, 2018 
 
6 months 
XX 
XX.X 
(XX.X, 
XX.X) 
X.XXX 
XX 
XX.X 
(XX.X, 
XX.X) 
X.XXX 
X.XXX 
1 Wilcoxon Signed Rank test comparing score change from baseline within treatment 
2 Wilcoxon Rank Sum test comparing score changes from baseline between treatments 
Clarify the population for the endpoint (n=?).  If n is not the same as the primary 
endpoint, explain why (e.g. patient not evaluable, missing data, etc.) 
 
 


Version 1.0 
51 
June 7, 2018 
 
Exhibit 1501-19:  Hyperlipidemia 
Hyperlipidemia Status at Randomization by Treatment Group 
Condition 
 
Sirolimus 
(N=) 
N (%) 
Prednisone 
(N=) 
N (%) 
P-value* 
Hyperlipidemia 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
High Total Cholesterol 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
High LDL 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
Low HDL 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
High Triglycerides 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
 
Hyperlipidemia Status at Day 28 by Treatment Group 
Condition 
 
Sirolimus 
(N=) 
N (%) 
Prednisone 
(N=) 
N (%) 
P-value* 
Hyperlipidemia 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
High Total Cholesterol 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
High LDL 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
Low HDL 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 


Version 1.0 
52 
June 7, 2018 
 
Not Evaluable 
XX 
XX 
High Triglycerides 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
 
Hyperlipidemia Status at Day 56 by Treatment Group 
Condition 
 
Sirolimus 
(N=) 
N (%) 
Prednisone 
(N=) 
N (%) 
P-value* 
Hyperlipidemia 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
High Total Cholesterol 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
High LDL 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
Low HDL 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
High Triglycerides 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
 
Hyperlipidemia Status at Day 180 by Treatment Group 
Condition 
 
Sirolimus 
(N=) 
N (%) 
Prednisone 
(N=) 
N (%) 
P-value* 
Hyperlipidemia 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
High Total Cholesterol 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
High LDL 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 


Version 1.0 
53 
June 7, 2018 
 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
Low HDL 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
High Triglycerides 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
* Clarify tests used (Z test of binomial proportions or Barnard’s Exact) 
 
Clarify the population for the endpoint (n=?).  If n is not the same as the primary 
endpoint, explain why (e.g. patient not evaluable, missing data, etc.) Give details of not 
evaluable if the definition is not pre-specified in the protocol. 
 
 
 


Version 1.0 
54 
June 7, 2018 
 
Exhibit 1501-20:  Thrombotic Microangiopathy 
Thrombotic Microangiopathy at 6 Months Post-randomization by Treatment Group 
 
Sirolimus 
(N=) 
N (%) 
Prednisone 
(N=) 
N (%) 
P-value* 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
Not Evaluable 
XX 
XX 
* Clarify test used (Z test of binomial proportions or Barnard’s Exact) 
 
Clarify the population for the endpoint (n=?).  If n is not the same as the primary 
endpoint, explain why (e.g. patient not evaluable, missing data, etc.) 
 
 
 


Version 1.0 
55 
June 7, 2018 
 
Exhibit 1501-21: CMV Reactivation 
CMV reactivation is evidenced by the requirement of new systemic treatment for an 
increasing CMV PCR level per institutional practice. 
 
CMV Reactivation by Day 56 by Treatment Group 
 
Sirolimus 
(N=) 
N (%) 
Prednisone 
(N=) 
N (%) 
P-value* 
Yes 
XX (XX.X%) 
XX (XX.X%) 
X.XXX 
No 
XX (XX.X%) 
XX (XX.X%) 
* Clarify test used (Z test of binomial proportions or Barnard’s Exact) 
 
Clarify the population for the endpoint (n=?).  If n is not the same as the primary 
endpoint, explain why (e.g. patient not evaluable, missing data, etc.) Give details of not 
evaluable if the definition is not pre-specified in the protocol. 
 
 
 


Version 1.0 
56 
June 7, 2018 
 
Exhibit 1501-22:  Patient-Reported Outcomes 
Patient-Reported Outcomes (PROs) assessed include the MDASI (MD Anderson 
Symptom Inventory), FACT-BMT, and MOS Short Form-36 (or PedsQL for pediatric 
participants) and are scored per the recommendations of the developers. 
MDASI Score by Treatment Group 
Assessment 
Time 
Sirolimus 
(N=) 
Prednisone 
(N=) 
P-
value* 
 
N 
Mean 
(SD) 
Median (Range) 
N 
Mean 
(SD) 
Median (Range) 
Baseline 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
X.XXX 
Day 56 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
X.XXX 
6 months 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
X.XXX 
12 months 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
X.XXX 
 
FACT-BMT Score by Treatment Group 
Assessment 
Time 
Sirolimus 
(N=) 
Prednisone 
(N=) 
P-
value* 
 
N 
Mean 
(SD) 
Median (Range) 
N 
Mean 
(SD) 
Median (Range) 
Baseline 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
X.XXX 
Day 56 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
X.XXX 
6 months 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
X.XXX 
12 months 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
X.XXX 
 
 
 
 
 
 
 
 


Version 1.0 
57 
June 7, 2018 
 
 
MOS-SF36 Score by Treatment Group 
Assessment 
Time 
Sirolimus 
(N=) 
Prednisone 
(N=) 
P-
value* 
 
N 
Mean 
(SD) 
Median (Range) 
N 
Mean 
(SD) 
Median (Range) 
Baseline 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
X.XXX 
Day 56 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
X.XXX 
6 months 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
X.XXX 
12 months 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
X.XXX 
 
PedsQL Score by Treatment Group 
Assessment 
Time 
Sirolimus 
(N=) 
Prednisone 
(N=) 
P-
value* 
 
N 
Mean 
(SD) 
Median (Range) 
N 
Mean 
(SD) 
Median (Range) 
Baseline 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
X.XXX 
Day 56 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
X.XXX 
6 months 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
X.XXX 
12 months 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
XX 
XX.X 
(XX.X) 
XX.X 
(XX.X, XX.X) 
X.XXX 
* Independent sample t-test 
 
 
The missing data pattern of the PRO measurements will be examined using graphical 
techniques and logistic regression models conditional on survival. At each time point, 
estimates of the difference in PROs between the treatment groups conditional on 
survival will be obtained using inverse probability of censoring weighting with 
independent estimating equations to account for missing data. 
 
 
 
 
 
 
 


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Logistic Models of Probability of Missing [PRO score] 
Assessment Time 
Effect 
N 
Odds ratio 
95% CI 
p-value 
Baseline 
Treatment 
 
 
 
 
    Prednisone 
XX 
1.000 
- 
- 
    Sirolimus 
XX 
X.XXX 
(X.XXX, X.XXX) 
X.XXX 
Covariate 1 
 
 
 
 
    Level 1 
XX 
1.000 
- 
- 
    … 
XX 
X.XXX 
(X.XXX, X.XXX) 
X.XXX 
    Level K 
XX 
X.XXX 
(X.XXX, X.XXX) 
X.XXX 
Covariate 2 
 
 
 
 
    Level 1 
XX 
1.000 
- 
- 
    … 
XX 
X.XXX 
(X.XXX, X.XXX) 
X.XXX 
    Level K 
XX 
X.XXX 
(X.XXX, X.XXX) 
X.XXX 
… 
 
 
 
 
Day 56 
Treatment 
 
 
 
 
    Prednisone 
XX 
1.000 
- 
- 
    Sirolimus 
XX 
X.XXX 
(X.XXX, X.XXX) 
X.XXX 
Covariate 1 
 
 
 
 
    Level 1 
XX 
1.000 
- 
- 
    … 
XX 
X.XXX 
(X.XXX, X.XXX) 
X.XXX 
    Level K 
XX 
X.XXX 
(X.XXX, X.XXX) 
X.XXX 
Covariate 2 
 
 
 
 
    Level 1 
XX 
1.000 
- 
- 
    … 
XX 
X.XXX 
(X.XXX, X.XXX) 
X.XXX 
    Level K 
XX 
X.XXX 
(X.XXX, X.XXX) 
X.XXX 
… 
 
 
 
 
6 months 
Treatment 
 
 
 
 
    Prednisone 
XX 
1.000 
- 
- 
    Sirolimus 
XX 
X.XXX 
(X.XXX, X.XXX) 
X.XXX 
Covariate 1 
 
 
 
 
    Level 1 
XX 
1.000 
- 
- 
    … 
XX 
X.XXX 
(X.XXX, X.XXX) 
X.XXX 
    Level K 
XX 
X.XXX 
(X.XXX, X.XXX) 
X.XXX 
Covariate 2 
 
 
 
 
    Level 1 
XX 
1.000 
- 
- 
    … 
XX 
X.XXX 
(X.XXX, X.XXX) 
X.XXX 
    Level K 
XX 
X.XXX 
(X.XXX, X.XXX) 
X.XXX 
… 
 
 
 
 
12 months 
Treatment 
 
 
 
 
    Prednisone 
XX 
1.000 
- 
- 
    Sirolimus 
XX 
X.XXX 
(X.XXX, X.XXX) 
X.XXX 
Covariate 1 
 
 
 
 
    Level 1 
XX 
1.000 
- 
- 
    … 
XX 
X.XXX 
(X.XXX, X.XXX) 
X.XXX 
    Level K 
XX 
X.XXX 
(X.XXX, X.XXX) 
X.XXX 
Covariate 2 
 
 
 
 


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    Level 1 
XX 
1.000 
- 
- 
    … 
XX 
X.XXX 
(X.XXX, X.XXX) 
X.XXX 
    Level K 
XX 
X.XXX 
(X.XXX, X.XXX) 
X.XXX 
… 
 
 
 
 
 
Inverse Probability of Missingness Weighting-adjusted [PRO score] by Treatment 
Group 
Assessment Time 
Sirolimus 
(N=) 
Prednisone 
(N=) 
P-value 
 
Mean 
95% CI 
Mean 
95% CI 
Baseline 
XX.X 
(XX.X, 
XX.X) 
XX.X 
(XX.X, 
XX.X) 
X.XXX 
Day 56 
XX.X 
(XX.X, 
XX.X) 
XX.X 
(XX.X, 
XX.X) 
X.XXX 
6 months 
XX.X 
(XX.X, 
XX.X) 
XX.X 
(XX.X, 
XX.X) 
X.XXX 
12 months 
XX.X 
(XX.X, 
XX.X) 
XX.X 
(XX.X, 
XX.X) 
X.XXX 
* Estimates were obtained by fitting GEE using an identity working correlation matrix, with robust standard 
errors used to compute 95% confidence intervals and obtain p-values from Wald tests of mean 
comparisons. 
 
 
Clarify the population for the endpoint (n=?).  If n is not the same as the primary 
endpoint, explain why (e.g. patient not evaluable, missing data, etc.) 
 
 
 
 


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Exhibit 1501-23: Incidence of Toxicities of Grade 3-5 
 
Toxicities by System Organ Class 
Toxicity 
Sirolimus 
(N=) 
N (%) 
Prednisone 
(N=) 
N (%) 
Grade 3-5 Oral Mucositis  
XX (XX.X%) 
XX (XX.X%) 
Grade 3-5 Cystitis noninfective 
XX (XX.X%) 
XX (XX.X%) 
Grade 3-5 Acute kidney injury 
XX (XX.X%) 
XX (XX.X%) 
Grade 3-5 Chronic kidney disease 
XX (XX.X%) 
XX (XX.X%) 
Grade 3-5 Hemorrhage 
XX (XX.X%) 
XX (XX.X%) 
Grade 3-5 Hypotension 
XX (XX.X%) 
XX (XX.X%) 
Grade 3-5 Hypertension 
XX (XX.X%) 
XX (XX.X%) 
Grade 3-5 Cardiac arrhythmia 
XX (XX.X%) 
XX (XX.X%) 
Grade 3-5 Left ventricular systolic dysfunction 
XX (XX.X%) 
XX (XX.X%) 
Grade 3-5 Somnolence 
XX (XX.X%) 
XX (XX.X%) 
Grade 3-5 Seizure 
XX (XX.X%) 
XX (XX.X%) 
Grade 3-5 Thrombotic thrombocytopenic purpura 
XX (XX.X%) 
XX (XX.X%) 
Grade 3-5 Capillary leak syndrome 
XX (XX.X%) 
XX (XX.X%) 
Grade 3-5 Hypoxia 
XX (XX.X%) 
XX (XX.X%) 
Grade 3-5 Dyspnea 
XX (XX.X%) 
XX (XX.X%) 
Grade 3-4 ALT 
XX (XX.X%) 
XX (XX.X%) 
Grade 3-4 AST 
XX (XX.X%) 
XX (XX.X%) 
Grade 3-4 Bilirubin 
XX (XX.X%) 
XX (XX.X%) 
Grade 3-4 Alkaline Phosphatase 
XX (XX.X%) 
XX (XX.X%) 
Received Dialysis? – Yes 
XX (XX.X%) 
XX (XX.X%) 
Abnormal Liver Function? – Yes 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
 


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Supplemental Exhibit 1501-1:  Enrollment  
A table will be provided showing actual monthly accrual for each participating center 
from study initiation to accrual closure.  
A figure will be provided showing projected and actual accrual from study initiation to 
accrual closure.  
 
Accrual to Protocol 1501 
Number of Participants 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Months Post Study Initiation 
 
Supplemental Exhibit 1501-2:  Significant Protocol Deviations 
A listing of significant protocol deviations will be provided to describe each deviation.   
Supplemental Exhibit 1501-3:  Primary Cause of Death 
A table summarizing the primary cause of death by treatment group will be provided.   
Supplemental Exhibit 1501-4:  Adverse Events 
A table summarizing the MedDRA-coded System Organ Class (SOC) of the adverse 
events reported will be provided by treatment group.   
Supplemental Exhibit 1501-5:  Serious or Grades 3-5 Adverse Events 
A table summarizing the SOC of the serious or Grades 3-5 adverse events will be 
provided by treatment group. 
 


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Supplemental Exhibit 1501-6:  Safety Monitoring (Safety Endpoints) 
Figure of SPRT to illustrate safety monitoring / stopping guidelines.