Conditions: Graft-versus-Host Disease Immune System Disorders
Keywords: GVHD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 236
Healthy volunteers: no

Brief summary:
The study is a Phase III, randomized double blind, placebo controlled, and trial evaluating the addition of Mycophenolate mofetil (MMF) vs. placebo to systemic corticosteroids as initial therapy for acute Graft Vs Host Disease (GVHD). The primary endpoint will be GVHD free survival at Day 56 post randomization.

Detailed description:
Corticosteroids have been used as primary therapy for acute GVHD for many years. Historical published and unpublished data from Johns Hopkins, M. D. Anderson, University of Michigan and others defined an expected 35%-53% complete response (CR) at Day +28 of corticosteroid therapy for previously untreated patients with acute GVHD.

BMT CTN study 0302 (NCT00224874)was a randomized Phase II study evaluating etanercept, mycophenolate mofetil, denileukin diftitox or pentostatin in addition to corticosteroids. The results of that study suggested that mycophenolate mofetil produced the highest rates of CR at Day 28 and overall survival, supporting its evaluation in a Phase III study. Day 56 GVHD-free survival for the four treatment arms (all combining corticosteroids with one of the four study drugs) ranged from 39-71% across the four study arms.

Arms:
arm 1: Corticosteroids with placebo arm 2: Corticosteroids with Mycophenolate Mofetil

Interventions: intervention 1: Mycophenolate Mofetil intervention 2: Placebo
Intervention descriptions: intervention 1: Oral dosing should be delivered in 250 mg units. For those \< 40 kg, IV dosing should be within ± 10% of the exact dose. Intravenous doses are infused over a two-hour period.

* Patients who weight \> 60 kg should receive MMF 1 gm PO/IV every 8 hours.
* Patients who weight between 40-60 kg should receive 750 mg PO/IV every 8 hours.
* Patients who weight \<40 kg should receive 20 mg/kg IV or PO every 8 hours. intervention 2: Oral dosing should be delivered in 250 mg units blinded placebo. For those \< 40 kg, IV dosing should be within ± 10% of the exact dose. Intravenous doses are infused over a two-hour period.

* Patients who weight \> 60 kg should receive placebo 1 gm PO/IV every 8 hours.
* Patients who weight between 40-60 kg should receive 750 mg PO/IV every 8 hours.
* Patients who weight \<40 kg should receive 20 mg/kg IV or PO every 8 hours.

Protocol document:
Prot_SAP_ICF_000.pdf: 
BMT CTN 0802 
A Multi-Center, Randomized, Double Blind, Phase 
III Trial Evaluating Corticosteroids with 
Mycophenolate Mofetil vs. Corticosteroids with 
Placebo as Initial Systemic Treatment of Acute 
GVHD 
NCT01002742 


-
 
 
A Multi-Center, Randomized, Double Blind, Phase III Trial 
Evaluating Corticosteroids with Mycophenolate Mofetil  
vs. Corticosteroids with Placebo as Initial Systemic  
Treatment of Acute GVHD 
 
BMT CTN PROTOCOL 0802 
Version 3.0 
 
Study Chair 
Javier Bolaños-Meade, MD1 
Study co-Chair 
Vincent T. Ho, MD2 
 
Protocol Team 
 
Amin Alousi, MD3 
Joseph Antin, MD2 
Kate Barowski4 
Shelly Carter, ScD4 
James Ferrara, MD5 
Mary Horowitz, MD6 
John Levine, MD5 
Margaret MacMillan, MD7 
Paul Martin, MD8 
Marco Mielcarek, MD8 
Brent Logan, PhD6 
Georgia Vogelsang, MD1 
Daniel Weisdorf, MD7 
 
 
Sponsored by the National Institutes of Health 
National Heart, Lung, and Blood Institute 
National Cancer Institute 
 
1 Johns Hopkins University 
2 Dana Farber Cancer Institute 
3 University of Texas, MD Anderson Cancer 
Center 
4 The EMMES Corporation  
5 University of Michigan 
6 Center for International Blood and Marrow Transplant 
Research, Medical College of Wisconsin 
7 University of Minnesota 
8 Fred Hutchinson Cancer Research Center 
 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
i 
Core Study Participants: 
 
Affiliate Study Participants: 
Case Western Reserve University Consortium 
   - Ohio State University  
   - Oregon Health & Science University 
   - University Hospitals of Cleveland 
   - Washington University, Barnes Jewish Hospital 
City of Hope National Medical Center 
Dana Farber Cancer Institute 
   - Brigham & Women’s Hospital 
   - Massachusetts General Hospital 
Duke University Medical Center 
Fred Hutchinson Cancer Research Center 
Johns Hopkins  
Memorial Sloan-Kettering Cancer Center 
Pediatric Bone and Marrow Transplant 
   - Children’s Healthcare of Atlanta 
   - Children’s Medical Center of Dallas 
   - Children’s Memorial - Northwestern 
   - Hackensack University Medical Center 
   - Levine Children’s Hospital 
   - Medical University of South Carolina 
   - Nationwide Children’s Hospital 
   - OHSU, Doernbecher Children’s Hospital 
   - Penn State College of Medicine 
   - Roswell Park Cancer Institute, Pediatric BMT 
   - UCLA, Mattel Children’s Hospital 
   - University of Alabama at Birmingham 
   - University of Mississippi Medical Center 
   - University of North Carolina at Chapel Hill 
   - University of Utah/ Primary Children’s Medical 
Center 
Stanford Hospital and Clinics 
University of California, San Diego Medical Center 
University of Florida College of Medicine 
University of Michigan Cancer Center 
University of Minnesota  
University of Pennsylvania 
University of Texas, MD Anderson Cancer Center 
 
 
Avera Hematology & Transplant Center 
Banner Research Institute 
Baylor University Medical Center 
Beth Israel Deaconess Medical Center 
Blood & Marrow Transplant Program at 
Northside Hospital 
Colorado Blood Cancer Institute 
Hackensack University Medical Center 
Indiana BMT at Beech Grove 
Loyola University Medical Center 
Mayo Clinic 
Medical College of Wisconsin 
Rush University Medical Center 
Texas Transplant Institute 
Tufts Medical Center 
University of Iowa Hospital & Clinics 
Utah BMT/ University of Utah Medical 
School 
Virginia Commonwealth University, 
MCV Hospital 
Weill Cornell Medical College 
 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
ii 
PROTOCOL SYNOPSIS – BMT CTN PROTOCOL 0802 
 
A Multi-Center, Randomized, Double Blind, Phase III Trial Evaluating Corticosteroids 
with Mycophenolate Mofetil vs. Corticosteroids with Placebo as Initial Systemic  
Treatment of Acute GVHD 
 
Principal Investigator: 
Javier Bolaños Meade, MD 
Co-Principal Investigator: Vincent T. Ho, MD 
 
Study Design: 
The study is a Phase III, randomized double blind, placebo 
controlled trial evaluating the addition of MMF vs. placebo to 
systemic corticosteroids as initial therapy for acute GVHD.  The 
primary endpoint will be GVHD free survival at Day 56 post 
randomization. 
 
Corticosteroids have been used as primary therapy for acute 
GVHD for many years.  Historical published and unpublished data 
from Johns Hopkins, M. D. Anderson, University of Michigan and 
others defined an expected 35%-53% complete response (CR) at 
Day +28 of corticosteroid therapy for previously untreated patients 
with acute GVHD. 
 
BMT-CTN 0302 was a randomized Phase II study evaluating 
etanercept, 
mycophenolate 
mofetil, 
denileukin 
diftitox 
or 
pentostatin in addition to corticosteroids.  The results of that study 
suggested that mycophenolate mofetil produced the highest rates of 
CR at Day 28 and overall survival, supporting its evaluation in a 
Phase III study.  Day 56 GVHD-free survival for the four treatment 
arms (all combining corticosteroids with one of the four study 
drugs) ranged from 39-71% across the four study arms. 
 
In this trial, patients with newly diagnosed acute GVHD will 
receive corticosteroids and will be randomized to also receive 
either placebo or mycophenolate mofetil.  Each arm will be 
assessed for safety (stopping rules defined) and efficacy. 
 
Primary Objective: 
The primary objective is to estimate graft-versus-host disease free 
survival (acute or chronic) at Day 56 after randomization without 
additional therapy. 
 
Secondary Objectives: 
Secondary objectives include: 
1. Proportions of complete, partial (PR), mixed response, no 
response and progression among surviving patients at Day 14, 
28 and 56.  
2. Treatment failure (treatment failure defined as: no response, 
progression, administration of additional therapy for GVHD, or 
mortality) at Day 14, 28, and 56. 


BMT CLINICAL TRIALS NETWORK 
 
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iii 
3. The incidence of acute GVHD flare after CR/PR requiring 
additional agent (including 2.5 mg/kg/day of prednisone [or 
methylprednisolone equivalent of 2 mg/kg/day]) for systemic 
therapy before Day 56 post-randomization.   
4. Incidence of discontinuation of immune suppression without 
acute GVHD flare and without disease progression/recurrence 
by Days 56, 180, and 360 post-therapy. 
5. Steroid dose at Day 28 and 56 post-randomization. 
6. Incidence of topical/non-absorbable therapy given by Day 56. 
7. Incidence of chronic GVHD by 6 and 12 months post-
randomization. 
8. Overall and GVHD-free survival at 6 and 12 months post-
randomization. 
9. Incidence of systemic infections within 6 months of initiation 
of therapy. 
10. Incidence of EBV-associated lymphoproliferative disorder or 
EBV reactivation requiring therapy. 
11. Disease-free survival at 6 and 12 months post randomization. 
12. Non-relapse mortality at 6 and 12 months. 
13. Change in patient-reported outcomes from enrollment to Day 
56. 
 
Eligibility: 
Patients must have acute GVHD (grade I-IV) requiring systemic 
therapy.  No previous systemic immune suppressive therapy for 
acute GVHD is allowed except for a maximum 72 hours of prior 
corticosteroid therapy.  Patients receiving MMF within 7 days of 
screening will be excluded.  Patients must have an absolute 
neutrophil count (ANC) greater than 500/μL.  Patients with acute 
GVHD after salvage donor lymphocytes are not eligible 
(preplanned DLI is allowed).  
 
Treatment Description: 
All patients will receive prednisone 2 mg/kg/day PO (or 
methylprednisolone at 1.6mg/kg/day IV) divided in 1-2 daily 
doses.  Prednisone may be tapered as tolerated according to 
institutional practice.  However, prednisone taper may not start 
sooner than 3 days after randomization, and the prednisone dose 
can 
not 
be 
less 
than 
0.25 mg/kg/day 
prednisone 
(methylprednisolone 
0.2 
mg/kg/day) 
at 
Day 
28 
post-
randomization.   
 
Patients will be randomized in a 1:1 fashion to receive either 
placebo or mycophenolate mofetil 1 gm PO or IV every 8 hours.  
Study drug (MMF/Placebo) should be discontinued by Day 56, or 
when prednisone taper is complete, whichever occurs first.  
 
Patients developing acute GVHD during GVHD prophylaxis (e.g. 
calcineurin inhibitor, sirolimus, etc.) should have their prophylaxis 


BMT CLINICAL TRIALS NETWORK 
 
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Version 3.0 dated January 31, 2011 
 
 
iv 
medication continued during the study period if possible.  
Concurrent or addition of topical steroid therapy (skin creams, oral 
beclomethasone, and other non-absorbable steroids) is allowed. 
 
In addition to prescribed study drug plus corticosteroids, all 
patients should receive transfusion support per institutional 
practice; anti-infective prophylaxis against herpes viruses, 
Pneumocystis jiroveci, bacterial and fungal infections should be 
followed according to institutional practices.  Pre-emptive 
monitoring and treatment strategy for CMV is strongly 
recommended. 
 
GVHD organ stage scores, overall clinical grade, biopsy 
information for GVHD, GVHD medications, presence of chronic 
GVHD, and steroid dose will be recorded weekly and reported to 
the BMT CTN Data Coordinating Center (DCC). 
 
Accrual Objective: 
186 patients will be accrued per study arm (a total of 372 patients). 
 
Accrual Period: 
The estimated accrual period is 3 years. 
 
Study Duration: 
Patients will be followed for 12 months following initiation of 
therapy. 
 
 


BMT CLINICAL TRIALS NETWORK 
 
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Version 3.0 dated January 31, 2011 
 
 
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STUDY SCHEMA 
 
Aim:  To determine if the addition of mycophenolate mofetil to corticosteroids as initial therapy for acute 
GVHD improves GVHD free survival and overall clinical outcome. 
 
Inclusion Criteria 
1. Acute GVHD diagnosed after allogeneic 
hematopoietic stem cell transplant using either bone 
marrow, PBSC or cord blood.  
2. Acute GVHD developing after pre-planned DLI is 
eligible. 
3. Grade I-IV acute GVHD requiring systemic 
therapy. 
4. Patients of all ages will be included. 
5. Biopsy confirmation of GVHD is recommended, 
but not required.  Enrollment should not be delayed 
awaiting biopsy or pathology results.   
6. The patient must have received no previous 
systemic immune suppressive therapy for 
treatment of acute GVHD, except for a maximum 
72 hours of prior corticosteroid therapy  
7. Clinical status at enrollment to allow tapering of  
prednisone to not less than 0.25 mg/kg/day 
prednisone (0.2 mg/kg/day methylprednisolone) at 
Day 28 of therapy 
8. ANC greater than 500/μL. 
9. Signed informed consent and/or assent. 
10. Assent and educational materials provided to, and 
reviewed with, patients under the age of 18. 
Exclusion Criteria 
1. Mycophenolate mofetil or mycophenolic acid 
(Myfortic) given within 7 days of enrollment. 
2. Active uncontrolled infection. 
3. Relapsed/persistent malignancy requiring rapid 
immune suppression withdrawal. 
4. Patients that have undergone an unscheduled (or not 
part of original transplant therapy plan) DLI. 
5. Patients unlikely to be available at the transplant 
center on Day 28 and 56 of therapy. 
6. A clinical syndrome resembling de novo chronic 
GVHD developing at any time after BMT. 
7. Other drugs for GVHD treatment 
8. If any prior steroid therapy (for indication other than 
GVHD), treatment at doses > 0.5 mg/kg/day 
methyl-prednisolone within 7 days prior to onset of 
GVHD. 
9. Patients who are pregnant, breast feeding, or if 
sexually active, unwilling to use effective birth 
control for the duration of the study. 
10. Adults unable to provide informed consent 
11. Patient on dialysis. 
12. Patients with severe veno-occlussive disease of the 
liver who in the judgment of the treating physician 
are not expected to have normalized bilirubin by 
Day 56. 
13. Patients with a history of intolerance/allergy to 
MMF.  
 
After 3 days of full dose corticosteroids + MMF/placebo: Taper steroids as tolerated according to institutional 
practices, but to no less than 0.25 mg/kg/day prednisone (or 0.2 mg/kg/day methylprednisolone) on Day 28.  Steroid 
taper may not start sooner than 3 days after randomization if GVHD is improving.  Improvement is defined as any 
clinically recognizable lessening of skin rash, redness, or extent; lessening of diarrhea or lowered bilirubin (though it 
does not have to be greater than or equal to one stage improvement in any involved organ), without worsening in 
any organ. 
 
If acute GVHD progresses within 5 days or no response within 14 days, then treat with alternative systemic 
secondary GVHD therapy at the physician’s discretion.  This patient would be considered a failure for the primary 
endpoint.  This patient will be considered “off study treatment”, but will remain on study to be followed for study 
endpoints.   
 
If acute GVHD flares during taper of prednisone, steroid dosing may be re-escalated or secondary therapy 
added at the discretion of the treating physician.  Re-escalation of steroid for GVHD flare alone will not be 
considered as treatment failure. 


BMT CLINICAL TRIALS NETWORK 
 
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vi 
STUDY SCHEMA (cont’d) 
 
Suggested prednisone taper for responders (round 
to nearest 5 mg of prednisone): 
2 mg/kg/day once or twice a day Days 1-5. 
1.5 mg/kg/day once daily Days 6-10. 
1 mg/kg/day Days 11-15. 
0.5 mg/kg/day Days 16-20 
0.25 mg/kg/day Days 21-28 (prednisone may be 
tapered as tolerated to no less than 0.25 mg/kg/day 
(methylprednisolone 0.2 mg/kg/day) at Day 28.  
Then taper according to institutional guidelines.  
The goal is to get to < 0.2 mg/per/kg per day of 
prednisone or < 0.16 mg/per/kg per day of 
methylprednisolone by Day 56. 
Primary endpoint: 
- Acute and chronic GVHD free survival at Day 56 
after randomization. 
Secondary endpoints: 
- Proportion of CR, PR, mixed response, no response 
and progression, among surviving patients at Days 
14, 28 and 56. 
- Treatment failure (defined as no response, 
progression, administration of additional therapy fro 
GVHD, or mortality) at Days 14, 28, and 56. 
- Incidence of acute GVHD flares after CR/PR 
requiring additional agents (including 2.5 mg/kg/day 
of prednisone [or methylprednisolone equivalent of 2 
mg/kg/day]) for systemic therapy before Day 56. 
- Incidence of discontinuation of immune suppression 
without acute GVHD flare and without disease 
progression/recurrence by Days 56, 180, and 360 
post-therapy. 
- Steroid dose at Day 28 and Day 56.  
- Incidence of topical/non absorbable therapy at Day 
56. 
- Incidence of Chronic GVHD by 6 and 12 months. 
- Overall and GVHD free survival at 6 and 12 months 
after randomization. 
- Incidence of systemic infections within 6 months of 
therapy. 
- Incidence of EBV PTLD or EBV reactivation 
requiring therapy. 
- Disease-free survival at 6 and 12 months post 
randomization. 
- Non-relapse mortality at 6 and 12 months post 
randomization. 
- Change in patient-reported outcomes from enrollment 
to Day 56. 
 
 


BMT CLINICAL TRIALS NETWORK 
 
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Version 3.0 dated January 31, 2011 
 
 
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STUDY DESIGN SCHEMATIC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary Endpoint: 
Proportion of patients surviving at Day 56 after enrollment without acute or chronic GVHD and 
without other systemic agents added for treatment of GVHD.  
Enroll within 72 hours  
of new onset acute GVHD meeting other eligibility 
criteria  
Randomize to MMF or placebo and corticosteroids 
at 2 mg/kg prednisone/day PO or IV equivalent in 
methylprednisolone (1.6 mg/kg) 
Continue to enroll until 372 patients have been 
recruited to 186 patients per arm 


BMT CLINICAL TRIALS NETWORK 
 
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TABLE OF CONTENTS 
 
1. 
BACKGROUND AND RATIONALE ......................................................................... 1-1 
1.1. 
Acute Graft-vs.-Host Disease ........................................................................................ 1-1 
1.2. 
Primary Therapy for Acute GVHD ............................................................................. 1-1 
1.2.1. 
Mycophenolate Mofetil/Placebo ................................................................................. 1-5 
2. 
STUDY DESIGN ............................................................................................................ 2-1 
2.1. 
Study Design ................................................................................................................... 2-1 
2.2. 
Primary Objective and Rationale for Study Design ................................................... 2-1 
2.3. 
Eligibility ......................................................................................................................... 2-1 
2.3.1. 
Inclusion Criteria ......................................................................................................... 2-1 
2.3.2. 
Exclusion Criteria........................................................................................................ 2-2 
2.3.3. 
Informed Consent ........................................................................................................ 2-3 
2.4. 
Treatment Plan............................................................................................................... 2-3 
2.4.1. 
Randomization ............................................................................................................ 2-3 
2.4.2. 
Corticosteroid Dosing and Taper ................................................................................ 2-3 
2.4.3. 
MMF/Placebo Formulation, Dosing, and Duration .................................................... 2-4 
2.5. 
Toxicities and Guidelines for Dose Reduction/Withholding Study Drug ................. 2-6 
2.6. 
Unblinding ...................................................................................................................... 2-7 
2.7. 
GVHD Progression or Non-response ........................................................................... 2-7 
2.8. 
Acute GVHD Flare ........................................................................................................ 2-7 
2.9. 
Supportive Care Guidelines .......................................................................................... 2-8 
2.10. GVHD Scoring ............................................................................................................... 2-8 
2.11. Chronic GVHD............................................................................................................. 2-10 
2.12. Studies of GVHD Biology ............................................................................................ 2-10 
3. 
STUDY ENDPOINTS .................................................................................................... 3-1 
3.1. 
Primary Endpoint .......................................................................................................... 3-1 
3.1.1. 
Staging and Grading of Acute GVHD ........................................................................ 3-1 
3.2. 
Secondary Endpoints ..................................................................................................... 3-1 
3.2.1. 
Proportion of CR, PR, MR, NR and Progression ........................................................ 3-2 
3.2.2. 
Proportion of Primary Treatment Failures .................................................................. 3-2 
3.2.3. 
GVHD Flares Requiring Additional Therapy ............................................................. 3-2 
3.2.4. 
Immunosuppression Discontinuation .......................................................................... 3-2 
3.2.5. 
Steroid Dose at Days 28 and 56 after Randomization ................................................ 3-2 
3.2.6. 
Incidence of Topical/Non-absorbable Therapy by Day 56 ......................................... 3-3 
3.2.7. 
Chronic GVHD ........................................................................................................... 3-3 
3.2.8. 
Overall and GVHD-free Survival ............................................................................... 3-3 
3.2.9. 
Systemic Infections though Day 180 .......................................................................... 3-3 
3.2.10. 
Incidence of EBV ........................................................................................................ 3-3 
3.2.11. 
Disease-free Survival at 6 and 12 Months Post-randomization .................................. 3-3 
3.2.12. 
Non-relapse Mortality at 6 and 12 Months Post-randomization ................................. 3-3 
3.2.13. 
Change in Patient-reported Outcomes from Enrollment to Day 56 ............................ 3-3 
4. 
PATIENT ENROLLMENT AND EVALUATION .................................................... 4-1 


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4.1. 
Enrollment and Randomization ................................................................................... 4-1 
4.1.1. 
Randomization ............................................................................................................ 4-1 
4.2. 
Study Monitoring ........................................................................................................... 4-1 
4.2.1. 
Follow-up Schedule .................................................................................................... 4-1 
4.2.2. 
Assessments ................................................................................................................ 4-3 
4.2.3. 
Weekly GVHD Monitoring......................................................................................... 4-5 
4.2.4. 
Serious Adverse Event (SAE) Reporting .................................................................... 4-5 
4.2.5. 
Study Drug Dose Reduction Monitoring .................................................................... 4-5 
4.3. 
Discontinuation Criteria ................................................................................................ 4-5 
5. 
Statistical Considerations .............................................................................................. 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 
5.2. 
Sample Size and Power Considerations ....................................................................... 5-1 
5.3. 
Interim Analysis and Stopping Guidelines .................................................................. 5-2 
5.3.1. 
Interim Analysis for Efficacy and Futility .................................................................. 5-2 
5.3.2. 
Operating Characteristics of the Design ..................................................................... 5-3 
5.3.3. 
Guidelines for Safety Monitoring ............................................................................... 5-4 
5.3.4. 
Safety Analysis ........................................................................................................... 5-5 
5.3.5. 
Monitoring Guidelines for Dose Reduction ................................................................ 5-5 
5.4. 
Demographic and Baseline Characteristics ................................................................. 5-6 
5.5. 
Analysis of Secondary Endpoints ................................................................................. 5-6 
5.5.1. 
Proportion of CR, PR, MR, NR and Progression ........................................................ 5-6 
5.5.2. 
Proportion of Primary Treatment Failures among Surviving Patients ........................ 5-6 
5.5.3. 
GVHD Flares Requiring Additional Therapy ............................................................. 5-7 
5.5.4. 
Immunosuppression Discontinuation .......................................................................... 5-7 
5.5.5. 
Steroid Dose at Days 28 and 56 after Randomization ................................................ 5-7 
5.5.6. 
Incidence of Topical/Non-absorbable Therapy by Day 56 ......................................... 5-7 
5.5.7. 
Chronic GVHD ........................................................................................................... 5-7 
5.5.8. 
Overall and GVHD-free Survival ............................................................................... 5-7 
5.5.9. 
Systemic Infections though Day 180 .......................................................................... 5-8 
5.5.10. 
Incidence of EBV ........................................................................................................ 5-8 
5.5.11. 
Disease-free Survival at 6 and 12 Months Post-randomization .................................. 5-8 
5.5.12. 
Non-relapse Mortality at 6 and 12 Months Post-randomization ................................. 5-8 
5.5.13. 
Change in Patient-Reported Outcomes from Enrollment to Day 56........................... 5-8 
 
 
 


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x 
LIST OF APPENDICES 
 
APPENDIX A 
HUMAN SUBJECTS 
APPENDIX B 
INFORMED CONSENTS 
APPENDIX C 
LABORATORY PROCEDURES 
APPENDIX D 
DERIVATION OF A SEQUENTIAL TEST STATISTIC FOR 
CENSORED EXPONENTIAL DATA 
APPENDIX E 
M.D. ANDERSON SYMPTOM INVENTORY (MDASI) CORE 
ITEMS 
APPENDIX F 
REFERENCES 
 
 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
1-1 
CHAPTER 1 
 
 
1. 
BACKGROUND AND RATIONALE 
 
1.1. Acute Graft-vs.-Host Disease 
 
Acute graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic 
stem cell (HSC) transplantation.1  Acute GVHD produces significant morbidity and complicates 
patient management, resulting in organ toxicity, frequent infections, malnutrition and substantial 
delay in recovery from transplantation.  
 
Acute GVHD usually occurs within the first 3-4 months of allogeneic HSCT and may involve 
the skin, liver and intestinal tract.  It is believed that T-lymphocytes contained in the donor graft 
respond in vivo to disparate major (HLA) or minor (non-HLA) histocompatibility antigens 
expressed by recipient tissues, initiating a cascade of events leading to the signs and symptoms 
of acute GVHD.1   
 
The syndrome of acute GVHD includes the following signs and symptoms.  Skin involvement 
(maculopapular exanthem) is usually the first sign.  Lesions may be pruritic or painful, red to 
violaceous in color, and often involve the palms and soles. Acute GVHD of the gut may involve 
the stomach, small bowel and colon producing persistent nausea and vomiting or profuse 
diarrhea, intestinal bleeding, cramping abdominal pain and ileus.  Liver GVHD produces 
cholestatic liver injury with hyperbilirubinemia and, in some cases, hepatocellular enzyme 
elevations.   
 
The use of cyclosporine (CSA) or tacrolimus (FK) plus short course methotrexate (MTX) has 
lowered the risk for acute GVHD compared to single agent or other combination therapy, but 
even with these regimens, 35-50% of patients develop Grade 2-4 acute GVHD.1, 2, 3  Older 
recipients or those with unrelated or partially HLA-matched donors may develop more frequent 
or possibly more therapy-resistant acute GVHD. 
 
1.2. Primary Therapy for Acute GVHD 
 
Corticosteroids have served as the primary therapy for acute GVHD for over three decades. 
There is some variability among investigators and transplant centers regarding the optimal 
starting dose of corticosteroids, particularly in early stage GVHD.  However, a recommended 
initial dose of corticosteroids for moderate to severe (Grade II-IV) acute GVHD accepted in most 
transplant centers is 2 mg/kg/day of methylprednisolone, or an equivalent steroid.1, 2, 3  The 
response rate to single-agent corticosteroid therapy, when analyzed in large retrospective reviews 
is approximately 50%. 4, 5  Doses higher than 2 mg/kg/day have not been associated with 
improvement in response rates.6  Despite an initial response, many patients will experience a 
flare of their GVHD upon steroid taper, and the durability of response is often substantially 
lower.  In acute GVHD developing after matched unrelated and related donor transplantation, 
durable remission of acute GVHD with steroid alone were reported in only 24% and 40% of 
patients, respectively.7, 8 


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Response to initial treatment is a key predictor of clinical outcome.  Mortality in patients with 
grade II-IV acute GVHD is greatest among those who fail to achieve a complete response to 
initial treatment.4, 5, 8, 9  A very early response, as evidenced by the ability to begin a steroid taper 
on Day 5 of therapy is also associated with a favorable prognosis.10  It is possible that early 
responders do better, at least in part, because the steroid taper begins sooner and reduces the risk 
of complicating opportunistic infections, a common cause of death.  In general, cutaneous 
disease responds promptly but lower gastro-intestinal and hepatic involvement responds less well 
to therapy.4  Other risks for failure of initial therapy include early onset of GVHD, increasing 
HLA disparity and older age.4, 5 
 
The suboptimal response and long-term survival associated with corticosteroids alone has 
prompted investigation of additional immunosuppressive agents in the initial therapy of acute 
GVHD.  Unfortunately, this strategy has to date not yielded superior outcomes compared to 
steroids alone.   In some cases, the benefit of better initial GVHD control with an additional 
agent is offset by a higher risk of infection or other side effects.  The most widely studied agent 
in this context is anti-thymocyte globulin (ATG).  Single arm Phase II studies of prednisone + 
ATG as initial therapy of acute GVHD have reported response rates from 67% to 80%.11, 12  
However, in a randomized trial of prednisolone r equine ATG, there was no difference in 
response rates or survival, but infectious morbidity, especially CMV disease and pneumonitis, 
was higher in the combined immunosuppression group.13   
 
Other biologic agents have also been studied as an adjunct to corticosteroids as initial therapy for 
acute GVHD.  Lee et al randomized 102 patients to receive the monoclonal anti-CD25 (the IL-2 
receptor alpha chain) antibody, daclizumab (1 mg/kg) on Days 1, 4 and weekly thereafter or 
placebo in conjunction with corticosteroids.  While response rates were similar in both groups 
(53 vs. 51%), survival at 100 days and 1 year was inferior in the steroid + daclizumab group.14  
A randomized study evaluating BT563 (an antibody against the IL-2 receptor) also did not 
demonstrate an advantage over placebo when combined with prednisone alone.15  A randomized 
trial adding a CD5-specific immunotoxin vs placebo to methylprednisolone also yielded similar 
clinical results. 16   Manifestations of acute GVHD responded more quickly in the 
immunoconjugate arm, but benefits were not durable.  Finally, Uberti et al reported a 75% 
response rate in 20 patients with biopsy proven acute GVHD when etanercept, a recombinant 
TNF-alpha receptor fusion protein capable of neutralizing TNF, was given in conjunction with 
corticosteroids with tacrolimus.17  
 
Recently, the Blood and Marrow Transplant Clinical Trials Network completed a multi-center 
randomized, four-arm, Phase II trial (BMT CTN 0302) designed to identify the most promising 
agent for combination with steroids as initial therapy for the treatment of GVHD.18  Between 
August 2005 and March 2008, 180 patients with newly diagnosed GVHD were randomized to 
receive steroids (2 mg/kg/day methylprednisolone) plus either etanercept, mycophenolate 
mofetil, denileukin diftitox or pentostatin.  The primary objective was to estimate the complete 
response rate at Day 28 for each of the four agents and evaluate secondary outcomes pertinent to 
the best agent for testing in a planned follow-up Phase III trial against steroids alone.  The 
median age of patients was 50 yrs (range, 7.5–69.9) with 96% >18 yrs; 39% had AML and 63% 
were male.  The graft was peripheral blood (PB) in 61%, bone marrow (BM) in 25% and cord 


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blood (CB) in 14%.  Myeloablative conditioning was used for 66% of patients, and 53% of 
patients had unrelated donors.  Forty-four patients (24%) received mycophenolate mofetil as 
GVHD prophylaxis and were randomized to 1 of the 3 non-mycophenolate mofetil arms.  
 
At enrollment, 68% of patients had grade I-II GVHD; 32% had grade III/IV GVHD.  Fifty-three 
percent of patients had visceral organ involvement at the time of enrollment.  The treatment arms 
were balanced except cord blood grafts were more common in the denileukin diftitox arm (26%, 
p=0.006); peripheral blood grafts were more common in the etanercept arm (78%, p=0.006); and 
the mycophenolate mofetil arm had more myeloablative transplants (82%, p=0.04).  The 
proportion of complete responses at Day 28 were: etanercept (26%), mycophenolate mofetil 
(60%), denileukin diftitox (53%) and pentostatin (38%).  Day 56 complete plus partial response 
rates were 59%, 78%, 68%, and 71%, respectively.  Six month chronic GVHD (cGVHD) 
incidence was: etanercept (21%), mycophenolate mofetil (25%), denileukin diftititox (29%), and 
pentostatin (24%).  Overall survival at 6 months was etanercept (59%), mycophenolate mofetil 
(71%), denileukin diftitox (63%), and pentostatin (55%), respectively.  After excluding patients 
who received mycophenolate mofetil prophylaxis, the mycophenolate mofetil arm still had the 
highest Day 28 complete response rate and overall survival.  Overall toxicities and post-
randomization infections were less frequent in patients randomized to mycophenolate mofetil 
and etanercept.  These efficacy and toxicity data, particularly response, survival, cGVHD, and 
infections, suggest that mycophenolate mofetil in conjunction with steroids to be the most 
promising regimen to compare against steroids alone in a randomized Phase III trial.  A summary 
of the results can be seen in Table 1.2.  With these data in mind, we have developed the current 
Phase III study to further test the addition of mycophenolate mofetil to steroids as initial therapy 
of GVHD. 
  


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TABLE 1.2:  SUMMARY OF STUDY RESULTS FOR BMT CTN 0302 
Outcome 
Treatment Arm 
Etanercept (N=46) 
MMF (N=45) 
Denileukin Diftitox (N=47) 
Pentostatin (N=42) 
 
Day 28 CR 
 
12 
(26%) 
Skin: 12/36 
(33%) 
 
27 
(60%) 
Skin: 
21/35 
(60%) 
 
25 
(53%) 
Skin: 17/35 
(49%) 
 
16  
(38%) 
Skin: 14/34 
(41%) 
L.G.I.: 4/12 
(33%) 
L.G.I.: 
12/18 
(67%) 
L.G.I.: 5/14 
(36%) 
L.G.I.: 7/17 
(41%) 
U.G.I.: 5/10 
(50%) 
U.G.I.: 11/12 
(92%) 
U.G.I.:10/14 
(71%) 
U.G.I.: 8/13 
(62%) 
Liver: 2/6  
(33%) 
Liver: 
5/7 
(71%) 
Liver: 
3/7 
(43%) 
Liver: 
2/5 
(40%) 
Day 28 CR  
(excl. prior MMF ) 
9 (28%) 
27 (60%) 
15 (48%) 
11 (39%) 
Day 28 CR/PR 
22 (48%) 
35 (78%) 
28 (60%) 
26 (62%) 
Day 56 CR/PR 
27 (59%) 
35 (78%) 
32 (68%) 
30 (71%) 
Day 56 Trea 
tment Fail 
12 (26%) 
4 (9%) 
12 (26%) 
13 (31%) 
OS Post-Randomization 
at 6 months 
59% 
(95% CI: 43%- 72%) 
71% 
(95% CI: 54%- 82%) 
63% 
(95% CI: 47%- 76%) 
55% 
(95% CI: 38%- 69%) 
OS Post-Randomization 
at 6 months (excl. prior 
MMF) 
70% 
(95% CI: 51%-83%) 
71% 
(95% CI: 54%-82%) 
61% 
(95% CI: 40%-76%) 
54% 
(95% CI: 33%-71%) 
Cum Incidence of Initial 
D/C of steroids at 9 
months 
34% 
(95 % CI: 20%- 48%) 
31% 
(95% CI: 17%-45%) 
20%  
(95% CI: 8%-32%)  
20% 
(95% CI: 8%-33%) 
Cum Incidence Day 56 
Grade 3-5 Toxicity (%) 
76% 
(95% CI: 63%-88%) 
80%  
(95% CI: 67%-92%) 
76% 
(95% CI: 64%-89%) 
67%  
(95% CI: 52%-81%) 
Cum Incidence Severe/ 
Life Threatening/ Fatal 
Infections at Day 270 
47%  
(95% CI: 32%-62%) 
44%  
(95% CI: 29%-59%) 
58%  
(95% CI: 43%-72%) 
56%  
(95% CI: 40%-71%) 
Cum Incidence 
of acute GVHD Flare 
after CR at Day 90 
36% 
(95% CI: 21%- 50%) 
28% 
(95% CI: 14%- 41%) 
35% 
(95% CI: 21%- 49%) 
36% 
(95% CI: 21%- 51%) 
Cum Incidence of 
cGVHD at Day 180 
21% 
(95% CI: 9%- 33%) 
25% 
(95% CI: 11%- 39%) 
29% 
(95% CI: 15%- 43%) 
24% 
(95% CI: 10%- 38%) 
Cum Incidence 
of Relapse at Day 180 
14% 
(95% CI: 3%- 24%) 
10% 
(95% CI: 1%- 19%) 
9% 
(95% CI: 1%- 19%) 
13% 
(95% CI: 2%- 24%) 
 


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1.2.1. Mycophenolate Mofetil/Placebo 
 
Pharmacology and Mechanism of Action 
Mycophenolate mofetil (MMF) is a morpholinoethyl ester of mycophenolic acid (MPA). A 
product of several penicillium species, MPA possesses antibacterial, antifungal, antiviral, 
antitumor and immunosuppressive properties.  MMF is a pro-drug since the immunosuppressive 
activity is evident only after hydrolysis to MPA.  MMF was developed to enhance the 
bioavailability of MPA.  MPA mediates its effect by inhibiting inosine monophosphate 
dehydrogenase (IMPDH), an enzyme that catalyzes the oxidation of inosine monophosphate to 
xanthine monophosphate, an intermediate metabolite in the synthesis of guanosine triphosphate 
(GTP).  Lymphocytes rely on the de novo purine synthesis pathway for the nucleotides necessary 
for DNA synthesis; other cells can also rely on the salvage pathway.  The action of MPA results 
in the depletion of the nucleotide pool in cell synthesis.  An additional mode of action of MPA 
may be that, by depletion of GTP, it inhibits recruitment of leukocytes to sites of inflammation 
by inhibiting the glycosylation of lymphocyte glycoproteins involved in intercellular adhesion.  
 
MMF in acute GVHD  
Mycophenolate mofetil (MMF) is an agent already commonly used as GVHD prophylaxis, or 
treatment of steroid refractory GVHD after allogeneic SCT.  MMF suppresses T cell 
proliferation by reversibly inhibiting the synthesis of the purine guanosine triphosphate.  Basara 
et al initially reported a 65% response rate in 17 patients with steroid-refractory acute GVHD 
and updated the series to include 36 patients.19, 20  Similar response rates were noted in other 
small studies.21, 22  MMF is also used commonly in combination with a calcineurin inhibitor as a 
GVHD prophylaxis regimen for allogeneic SCT, especially in reduced intensity conditioning 
transplantation and umbilical cord blood transplantation.23, 24 ,25 
 
Pharmacokinetics of MMF and GVHD responses 
Pharmacokinetic studies in solid organ transplantation suggest that MMF therapeutic efficacy 
may be improved when MMF is administered as q8hrs dosing instead of q12 hours dosing.26, 27   
Furthermore, there is extensive experience with using MMF at TID dosing in the GVHD 
prophylaxis setting after allogeneic SCT, and this higher dosing schedule has been to be well 
tolerated.  Pharmacokinetic studies from the antecedent phase II trial (BMT CTN 0302), where 
the starting MMF dose was 1 gram BID, have further shown that an increase in MMF dosing to 
q8Hrs (TID) may be warranted, as described below. 
 
Among the 180 subjects enrolled in the BMT CTN 0302 Acute GVHD Trial from November 
2005 to March 2008, 45 subjects were randomized to MMF.  Blood samples for pharmacokinetic 
analyses of mycophenolic acid (MPA, the active metabolite of MMF) were available for 32 of 
the 45 subjects in the first 2 weeks of treatment.  Although the sample size was small, PK data 
from these patients showed that following dosing at 1 gm BID, 45-59% of the trough levels were 
low (defined as MPA trough <0.5 mcg/mL, or free MPA troughs <15 ng/mL), while < 5% had 
levels that were considered high.  These results confirm that a sizeable fraction of patients likely 
had under-dosing of MMF on the 1gm BID schedule.  Analysis of MPA levels with GVHD 
responses in this trial further demonstrated that trough MPA concentrations affect efficacy.  
Although MPA within the first 2 weeks of treatment did not appear to influence response at Day 


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28, MPA total (>0.5 mcg/mL) and free (>15 ng/mL) troughs were associated with higher CR/PR 
at Day 56.   
 
Based in part upon these results, the starting dose of MMF/placebo in the current proposed trial 
will be 1gm TID.  We believe that this schedule will insure that a greater proportion of patients 
will have therapeutically suitable drug exposure.  Treating physicians will be given discretion for 
reducing the MMF/Placebo dose from TID to BID base on potential toxicities (Section 2.5), and 
the rates of sustained dose reductions on both arms will be monitored in interim analyses to 
assure patient safety (see monitoring plan, Section 4.25 and Chapter 5). 
 


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CHAPTER 2 
 
 
2. 
STUDY DESIGN 
 
2.1. Study Design 
 
This trial is designed to evaluate the best therapy for acute GVHD in a prospective, multi-center, 
randomized, double blind Phase III trial.  Each study arm will include corticosteroids plus either 
mycophenolate mofetil or placebo.   
 
Accrual Objective: 
186 patients will be accrued per study arm (a total of 372 patients). 
 
Accrual Period: 
The estimated accrual period is 3 years. 
 
Study Duration: 
Patients will be followed for 12 months following initiation of 
therapy. 
 
2.2. Primary Objective and Rationale for Study Design 
 
The primary objective is to estimate graft-versus-host disease free survival (acute or chronic) at 
Day 56 after randomization to steroids plus mycophenolate mofetil or steroids plus placebo 
without additional therapy.  Data from BMT CTN 0302 identified mycophenolate mofetil as the 
most promising agent to be tested in this Phase III study and was the most effective and least 
toxic of the drugs tested (mycophenolate mofetil, etanercept, pentostatin and denileukin diftitox). 
 
2.3. Eligibility 
 
2.3.1. Inclusion Criteria 
 
Biopsy of involved tissue is strongly encouraged, but not required for study entry.  The clinical 
diagnosis of acute GVHD requiring systemic therapy with corticosteroids is necessary for 
enrollment on the trial.  Enrollment and randomization includes commitment to continue both 
steroids and study drug as indicated by the protocol as well as the required follow-up 
observations.  If the intention to treat a patient depends on histologic results, the patient should 
not be enrolled on the BMT CTN 0802 study until the results are known.  Patients can be 
enrolled only with a clinically established diagnosis.  Histologic confirmation of acute GVHD is 
not required, but can be used as supportive evidence for the diagnosis. If an unexpected biopsy 
result occurs, and the treating physician feels it is necessary to take the patient off study, the 
center should contact the protocol chair. 
1. Acute GVHD developing after allogeneic hematopoietic stem cell transplant using either 
bone marrow, peripheral blood stem cells or cord blood.  Recipients of non-
myeloablative and myeloablative transplants are eligible.   
2. Acute GVHD after planned donor lymphocyte infusion or planned T cell addback are 
eligible. 


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3. De novo acute GVHD requiring systemic therapy. GVHD is defined as the presence of 
skin rash and/or persistent nausea, vomiting, and/or diarrhea and/or cholestasis presenting 
in a context in which acute GVHD is likely to occur and where other etiologies such as 
drug rash, enteric infection, or hepatotoxic syndromes are unlikely or have been ruled 
out.  Note that patients with stage I and II skin only (overall grade I) or isolated upper 
gastrointestinal (GI) involvement are eligible if the treating physician deems that 
systemic high-dose corticosteroid treatment is indicated. 
4. The patient must have had no previous systemic immune suppressive therapy for 
treatment of acute GVHD except for a maximum 72 hours of prior corticosteroid therapy 
at >0.5mg/kg/day methylprednisolone or equivalent after the onset of acute GVHD. 
5. Clinical status at enrollment to allow tapering of steroids to not less than 0.25 mg/kg/day 
prednisone (0.2 mg/kg/day methylprednisolone) at Day 28 of therapy. 
6. Absolute neutrophil count (ANC) greater than 500/μL. 
7. Written informed consent and/or assent from patient, parent or guardian. 
8. Documentation that the assent document and education materials have been provided to, 
and reviewed with, patients between the ages of 7 and 17. 
9. Patients of all ages are eligible.  
10. Biopsy confirmation of GVHD is recommended, but not required.  Enrollment should not 
be delayed for biopsy or pathology results unless these are to be used to decide about 
whether to treat for GVHD.  
 
2.3.2. Exclusion Criteria 
1. Patients receiving mycophenolate mofetil or mycophenolic acid (Myfortic) within seven 
days of screening for enrollment. 
2. Patients with uncontrolled infections will be excluded.  If a bacterial or viral infection is 
present, patients must be receiving definitive therapy and have no signs of progressing 
infection for 72 hours prior to enrollment.  If a fungal infection is present, patients must 
be receiving definitive systemic anti-fungal therapy and have no signs of progressing 
infection for 1 week prior to enrollment. 
Progressing infection is defined as hemodynamic instability attributable to sepsis or 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. 
3. Relapsed/persistent malignancy requiring rapid immune suppression withdrawal. 
4. Patients with GVHD after an unplanned DLI, i.e., DLI that was not part of their original 
transplant therapy plan, or DLI given for treatment of persistent or recurrent malignancy 
after transplantation. 
5. Patients unlikely to be available at the transplantation center on Day 28 and 56 of 
therapy. 


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6. A clinical syndrome resembling de novo chronic GVHD developing at any time after 
allotransplantation. 
7. Patients receiving other drugs for the treatment of GVHD.   
8. Patients receiving methylprednisolone > 0.5 mg/kg/day (or 0.6 mg/kg/day prednisone) 
within 7 days before the onset of acute GVHD.  If steroid therapy has been administered 
for treatment of a non-*9+' UHODWHG FRQGLWLRQ DQG WDSHUHG WR   PJNJGD\
methylprednisolone (0.6 mg/kg/day prednisone) for seven or more days before the onset 
of acute GVHD, the patient is eligible.  
9. Patients who are pregnant, breast feeding, or, if sexually active, unwilling to use effective 
birth control for the duration of the study.  Available evidence and/or expert consensus is 
inconclusive or is inadequate for determining infant risk when used during breastfeeding, 
therefore breast feeding patients are not eligible. 
10. Adults unable to provide informed consent. 
11. Patients on dialysis.   
12. Patients with severe hepatic VOD or sinusoidal obstruction syndrome who in the 
judgment of the treating physician are not expected to have normalized bilirubin by Day 
56 after enrollment. 
13. Patients with a history of intolerance/allergy to MMF. 
 
2.3.3. Informed Consent 
 
The informed consent process will begin at recognition of subject eligibility and consent will be 
obtained per institutional practices before study therapy is initiated. 
 
2.4. Treatment Plan 
 
2.4.1. Randomization 
 
After registration and enrollment, the study participant will be randomized in a 1:1 fashion to 
receive either MMF or placebo as described in Chapter 5. 
 
2.4.2. Corticosteroid Dosing and Taper 
 
All patients enrolled on this trial will receive steroids at a dose of prednisone 2mg/kg/day PO (or 
methylprednisolone 1.6 mg/kg/day IV) as therapy of acute GVHD.  Pediatric patients unable to 
take tablets can use oral prednisolone solution 2 mg/kg/day.  Steroid taper may follow local 
institutional practice.  However, for those improving, steroid taper may not start sooner than 3 
days after randomization and the steroid dose must not be tapered to less than 0.25 mg/kg/day 
prednisone (or 0.2 mg/kg/day methylprednisolone) on Day 28.  
 


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The following is a suggested prednisone taper.  
 
Suggested taper for responders 
(2 mg/kg/day prednisone orally=1.6 methylprednisolone mg/kg/day I.V.)  
 
2 mg/kg/day of prednisone orally (or 1.6 mg/kg/day of methylprednisolone I.V) divided 
once or twice/day Days 1-5 
1.5 mg/kg/day once daily Days 6-10 
1 mg/kg/day once daily Days 11-15 
0.5 mg/kg/day of prednisone once daily Days 16-20 
0.25 mg/kg/day of prednisone once daily Days 21-28 
Patients should be tapered as tolerated to no less than 0.25 mg/kg/day (methylprednisolone 
0.2 mg/kg/day) by Day 28. 
Then taper according to institutional guidelines with a goal to reach < 0.2 mg/per/kg per 
day of prednisone or < 0.16 mg/per/kg per day of methylprednisolone by Day 56. 
 
2.4.3. MMF/Placebo Formulation, Dosing, and Duration 
 
Study treatment (MMF/placebo) should be initiated as soon as possible after randomization.  A 
maximum of 48 hours is allowable.   
 
Formulation and Drug Supply 
 
MMF/Placebo will be obtained by the BMT CTN/EMMES, and distributed through an 
independent contractor.  Questions regarding study drug orders and study drug distribution 
should be directed to the trial protocol coordinator at EMMES.  MMF/placebo will be provided 
by the BMT CTN for up to 8 weeks.  Oral MMF/placebo is available as 250 mg capsules in 
bottles of  70 each.  Capsules should be stored at room temperature.   
 
Intravenous: MMF/placebo for intravenous use will be supplied as a lyophilized powder.  The 
study drug will be reconstituted by injecting 5% Dextrose in Water (D5W) into each vial. 
Intravenous MMF/placebo does not contain an antibacterial preservative; therefore, the study 
drug should be prepared under aseptic conditions.  Reconstitute each vial with 14 mL D5W.  
Gently shake vial to dissolve the drug.  Further dilute into D5W for a final concentration of 
6 mg/mL.  Dilute 1-g doses in 140 mL D5W.  Intravenous mycophenolate is incompatible with 
normal saline and other saline containing diluents.  Only D5W solution should be used for 
reconstitution and infusion solution.  Infusion lines should be flushed only with D5W. 
 
The Pharmacist at each center should prepare each dose of drug to avoid errors.  Because of the 
potential teratogenic effects of MMF, pharmacists should follow institutional guidelines for the 
preparation of similar types of solutions.  At the completion of the study, unused MMF/Placebo 
study drug should be returned to the study team by the patient for destruction as per institutional 
practice of the Investigational Pharmacy. 
 


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The investigator (and/or hospital pharmacist) will ensure that all study drug is stored in a secured 
area under recommended storage conditions and is dispensed by qualified staff members.  All 
study drug will be accounted for on medication inventory sheets. 
 
The BMT CTN will be allowed at intervals, and upon request during the study, to check unused 
supplies.  Accounting for the use of supplies will be by reference to each center's record of 
supplies received, the dispensing records for the total number of patients enrolled at each center 
and the unused and returned supplies. 
 
The investigator is responsible for maintaining drug accountability records.  Drug accountability 
records will be reviewed during monitoring visits.  Each institution may use their own drug 
accountability log.  Study drug must be administered only to patients enrolled in this study as per 
the protocol. 
 
Dose and Administration 
 
For BMT CTN 0802, the dose of MMF will be different than the one used in 0302.  This is based 
on the pharmacologic analysis of patients receiving MMF enrolled on BMT CTN 0302.  This 
will insure a substantially greater proportion of patients will have therapeutically suitable drug 
exposure. 
 
Oral dosing should be delivered in either 250 mg units or identical blinded placebo.   
For those < 40 kg, IV dosing should be within ± 10% of the exact dose.  Intravenous doses are 
infused over a two-hour period.  The study drug capsule may not be opened to administer. 
x 
Patients who weigh > 60 kg should receive MMF 1 gm PO/IV every 8 hours. 
x 
Patients who weigh between 40-60 kg should receive 750 mg PO/IV every 8 hours. 
x 
Patients who weigh <40 kg should receive 20 mg/kg IV or PO (up to 750 mg/kg) every 8 
hours. 
x 
Patients with ANC < 1000 at the time of enrollment should receive study drug 
every 12 hours.  Once ANC  1000 q8 hour dosing should be instituted. 
 
If patients with GI GVHD cannot tolerate the pills, then MMF should be administered 
intravenously for the first 3-7 days of therapy and converted to oral MMF as soon as possible 
after the initial 3-7 days of therapy if oral medications and this limited fluid intake are tolerated. 
 
Duration of Study Therapy 
 
MMF/placebo should be discontinued at Day 56, or when the patient is tapered off steroids, 
whichever occurs earlier. 
 
GVHD Prophylaxis Medications 
 
Medications such as cyclosporine, tacrolimus, sirolimus (if used as GVHD prophylaxis when 
acute GVHD developed) should be continued at therapeutic doses adjusted as necessary for 


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renal, central nervous system (CNS) or other toxicity using conventional management 
guidelines.  The recommended therapeutic trough level of cyclosporine is 200-400 ng/mL 
measured by whole blood HPLC; institutional levels for other assays.  The recommended 
therapeutic trough level is 5-15 ng/mL for tacrolimus and 3-12 ng/mL for sirolimus.   
 
Topical and Ancillary GVHD Therapies: 
 
Topical therapy for acute GVHD, including skin creams or GI non-absorbable steroids are 
allowed and should be used according to institutional practices.  Use of topical agents for 
management of acute GVHD will be recorded as a secondary endpoint assessment in this trial. 
 
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. Toxicities and Guidelines for Dose Reduction/Withholding Study Drug 
 
Infection: 
Mycophenolate mofetil is potent immunosuppressive agent.  Its use has been associated with 
increased risks of opportunistic infections.  In the acute GVHD setting, where corticosteroids and 
the disease itself further compromise the immune system, particular caution must be paid to the 
risks of additional infections.  See Section 2.9 for supportive care guidelines to minimize 
infections.   
 
Patients with severe infections may have their study drug held at the attending physician's 
discretion.  Study drug can be reinstituted when the infection episode is controlled and 
hemodynamic stability restored.  Replacement doses must not be given, and administration of the 
study drug should not be extended.  Administration of the study drug will be discontinued 
permanently if administration is suspended for more than 14 days. 
 
GI toxicity: 
Administration of MMF may produce diarrhea, abdominal pain, and vomiting.  Gastrointestinal 
bleeding and bowel perforation have also been described infrequently.  If GI toxicity requires 
medication for control of persistent vomiting or diarrhea (not related to GVHD), a dose reduction 
to twice a day can be instituted or, if symptoms persist and are severe (Grade 3 or 4), the study 
drug (MMF/placebo) can be stopped for 48-72 hours.  IV MMF can be used in patients 
experiencing severe GI toxicity to avoid stopping study drug.  If GI toxicity does not resolve 
within 48-72 hours of stopping the study drug, then this toxicity is not likely related to the study 
medication and the drug should be restarted at the original dose.  Administration of the study 
drug will be discontinued permanently if administration is suspended for more than 14 days.  The 
Protocol Chair or co-Chair should be consulted before discontinuing MMF for GI toxicity.   
 
Myelosuppression:   
Use of MMF may be associated with myelosuppression.  If the ANC is less than 1000/PL, 
MMF/placebo dosing should be reduced to every 12 hour dosing.  2QFH$1&TKRXU


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dosing should be resumed.  If the ANC is less than 500/PL, the drug should be discontinued until 
neutrophil recovery occurs, and restarted at q12 hour dosing.  Use of filgrastim or perfilgrastim 
or sarmograstim or discontinuation of other myelosuppressive agents is allowed.  Administration 
of the study drug will be discontinued permanently if administration is suspended for more than 
14 days. 
 
Guidelines for Renal Insufficiency:  
As free MPA exposure has not been directly correlated with renal dysfunction, patients on renal 
replacement therapy are excluded from entry on this trial.  However, if renal insufficiency 
(estimated GFR <25) develops or dialysis is needed after study entry, the study drug dose should 
be reduced from every 8 to every 12 hours. 
 
Hepatic Dysfunction:  
No adjustments of MMF/placebo are required for liver dysfunction. 
 
Other Unexpected Toxicities: 
Study drug may be held for other  CTC v.3 Grade 3-4 toxicities that are considered probably 
related to MMF/study drug (such as severe apthous ulcers, hypogammaglobulinemia, red cell 
aplasia) at the discretion of the treating physician.  Administration of the study drug will be 
discontinued permanently if administration is suspended for more than 14 days. 
 
2.6. Unblinding 
 
There will be no unblinding or crossover as part of this trial.  Unblinding will be allowed only if 
a critical action is needed, the situation is life-threatening, and the unblinding is deemed to be 
necessary to the patient’s clinical care.  Permission for unblinding must be obtained from the 
medical monitor of the study. Given that there are no data supporting MMF as the preferred 
second line treatment in patients with inadequate responses to first line treatment, unblinding to 
allow patients to receive MMF as second line therapy off study will not be allowed. 
 
2.7. GVHD Progression or Non-response 
 
If acute GVHD progresses (new organ involvement or increased organ specific symptoms 
sufficient to increase the organ stage by one or more) after at least 5 days of study drug 
administration, or if there is no response (no reduction in any GVHD organ staging) after 14 
days of study drug administration, administration of the study drug may be discontinued, and the 
patient may be treated with alternative secondary GVHD therapy at the discretion of the treating 
physician.   
 
2.8. Acute GVHD Flare 
 
If acute GVHD flares during taper of prednisone, the dose of steroids may be increased at the 
discretion of the treating physician as long as this increase is to less than 2.5 mg/kg/day of 
prednisone (or methylprednisolone equivalent of 2 mg/kg/day), as in this case it will be 
considered adding a “new agent” and the patient will be scored as a failure.   
 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
2-8 
2.9. Supportive Care Guidelines 
 
In addition to prescribed study drug plus corticosteroids, all patients should receive the 
following: 
x Transfusion support per institutional practice 
x Anti-infective prophylaxis against herpes viruses, Pneumocystis jiroveci, bacterial and 
fungal infections should be followed according to standard institutional practices.   
x Routine CMV antigenemia/viral load testing by hybrid capture or PCR based methods 
per institutional guidelines (with preemptive ganciclovir or valganciclovir therapy in 
patients who develop a positive assay, as per institutional guidelines).  CMV testing is 
recommended weekly through at least Day +100 post transplant. 
 
2.10. GVHD Scoring 
 
As acute and chronic GVHD free survival at Day 56 is the primary endpoint evaluation for the 
trial, accurate and timely data collection with respect to both acute and chronic GVHD (if 
present) will be a crucial aspect of this trial.   
 
Weekly acute GVHD organ stage scores, overall clinical grade, biopsy information for GVHD 
and relevant differential diagnosis will be recorded and reported to the DCC.  Organ 
involvement, biopsy information, staging, differential diagnosis, and GVHD therapy should be 
documented in the medical record using the BMT CTN GVHD scoring stamp or equivalent (see 
below). 
 
Symptoms of chronic GVHD, if present, will be reported according to the BMT CTN MOP 
(Chapter 2) and reported on the GVHD symptom record. 
 
A sample acute GVHD data record suggested for use in this trial is shown below. 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
2-9 
 
Today’s BMT CTN 0802 Clinical Acute GVHD Assessment 
Today’s Date  ___________ 
    Patient ID/Name  ________________________________________________     Karnofsky/Lansky ____________________ 
 
    
 
 
Codes 
 
 
 
 
            Differential Diagnosis 
 
    0 
1 
2 
3 
4 
5 
 
 GVHD 
Drug 
 Rxn 
 Cond 
  Reg 
TPN 
Infect 
VOD 
Other 
Skin 
     
 
% body rash:________ 
      
 
  
 
 
Lower GI 
      
Vol: ______________ 
          
 
 
Upper GI 
   
 
 
 
 
          
 
 
Liver 
     
 
Current bili: _________ 
            
 
 
Systemic Agents:  
 CSA 
 Tacrolimus 
 Infliximab 
 Dacluzimab 
 
 
 Pentostatin 
 Prednisone 
 Sirolimus 
 Methylprednisolone 
 
 Etanercept 
 Study Drug 
 
 Open Label MMF 
 Ontak 
 
 Other 
____________________ 
Topical Agents:   Skin topical steroids   YES     NO;   Non-absorbed oral steroids (e.g., Budesonide, Entocort)    YES     NO 
Is the patient eating equivalent of one meal/day?     YES     NO     Is the patient having formed stools?     YES     NO 
Does the patient have evidence of chronic GVHD?    YES     NO 
Current study drug (MMF/Placebo) dose: __________g ;  Frequency:   TID,   BID, or   Other __________ ;  Formulation:     PO  or   IV 
 
Current steroid dose:   Prednisone ________ mg/day or ________ mg/kg/day;     Methylprednisolone ________ mg/day or ________mg/kg/day 
+DVWKHVWHURLGGRVHEHHQLQFUHDVHGWRPJNJGD\RISrednisone (or 2 mg/kg/day methylpred)?  YES     NO;  if yes, date dose increased ___________ 
  
If yes, reason for dose increase:  flare for GVHD;   Idiopathic Pneumonia Syndrome (IPS);   other (please specify) __________________________ 
 
Code Definitions: 
Skin: 
0  No rash 
1  Maculopapular rash, < 25% of body surface 
2  Maculopapular rash, 25-50% of body surface 
3  Generalized erythroderma 
4  Generalized erythroderma with bullous formation 
and desquamation 
Lower GI (Diarrhea): 
0  No diarrhea 
1  P/GD\RUP/NJGD\ 
2  501-1000 mL/day or 10-19.9 mL/kg/day 
3  1001-1500 mL/day or 20-30 mL/kg/day 
4  > 1500 mL/day or > 30 mL/kg/day 
5  Severe abdominal pain with or without ileus, or 
stool with frank blood or melena 
Upper GI: 
0 No protracted nausea and 
vomiting 
1 Persistent nausea, vomiting 
or anorexia 
Liver (Bilirubin): 
0  < 2.0 mg/dL 
1  2.1-3.0 mg/dL 
2  3.1-6.0 mg/dL 
3  6.1-1.0 mg/dL 
4  > 15.0 mg/dL 
 
Signature ________________________________________    Date ____________                                                                                                              Version 1.0 
 
 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
2-10 
2.11. Chronic GVHD  
 
Patients developing signs/symptoms of chronic GVHD (cGVHD) will have symptoms recorded 
on the cGVHD scoring form at the scheduled follow-up visits. 
 
Definite and Possible Manifestations of Chronic GVHD* 
Organ System 
Definite manifestations of chronic GVHD 
Possible manifestations of chronic GVHD 
Skin 
Scleroderma (superficial or fasciitis), lichen 
planus, vitiligo, scarring alopecia, 
hyperkeratosis pilaris, contractures from skin 
immobility, nail bed dysplasia 
Eczematoid rash, dry skin, maculopapular 
rash, hyperpigmentation, hair loss 
Mucous 
membranes 
Lichen planus, non-infectious ulcers, corneal 
erosions/non-infectious conjunctivitis 
Xerostomia, keratoconjunctivitis sicca  
GI tract 
Esophageal strictures, steatorrhea 
Anorexia, malabsorption, weight loss, 
diarrhea, abdominal pain 
Liver 
None 
Elevation of alkaline phosphatase, 
transaminitis, cholangitis, 
hyperbilirubinemia 
GU 
Vaginal stricture, lichen planus 
Non-infectious vaginitis, vaginal atrophy 
Musculoskeletal/ 
Serosa 
Non-septic arthritis, myositis, myasthenia, 
polyserositis, contractures from joint 
immobilization 
Arthralgia 
Hematologic 
None 
Thrombocytopenia, eosinophilia, 
autoimmune cytopenias 
Lung 
Bronchiolitis obliterans  
Bronchiolitis obliterans with organizing 
pneumonia, interstitial pneumonitis 
*From BMT CTN MOP Chapter 2 
 
2.12. Studies of GVHD Biology 
 
No validated biomarkers exist for acute GVHD. The BMT CTN Biomarkers Committee 
suggested four recently published biomarkers for validation.  Paczesny et al screened plasma 
with antibody microarrays for 120 proteins in a discovery set of 42 transplant patients that 
revealed eight potential biomarkers for diagnostic of GVHD.28  They then measured by ELISA 
the levels of these biomarkers in samples from 424 transplant patients randomly divided into 
training (n = 282) and validation (n = 142) sets.  Logistic regression analysis of these eight 
proteins determined a composite biomarker panel of four proteins (interleukin-2-receptor-alpha, 
tumor-necrosis-factor-receptor-1, interleukin-8, and hepatocyte growth factor) that optimally 
discriminated patients with and without GVHD.  In patients with GVHD, Cox regression 
analysis revealed that the biomarker panel predicted survival independently of GVHD severity.  
The authors suggested that the panel of four biomarkers can confirm the diagnosis of GVHD in 
patients at onset of clinical symptoms of GVHD and provide prognostic information independent 
of GVHD severity. 
 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
2-11 
If consent for optional future research samples was obtained, plasma will be collected on Day 0 
and Day 28 post-treatment and analyzed for the 4-protein biomarker panel.  Donor chimerism 
results recorded at the time nearest to each sample collection will be noted.  Remaining plasma 
sample aliquots will be stored along with an additional Day 56 plasma sample for future 
biomarker studies.  Additionally, whole blood collected from the recipient on Day 0 
(representing donor DNA) and buccal swabs for DNA from the recipient will be collected, 
frozen and stored for future GVHD related studies.  


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
3-1 
CHAPTER 3 
 
 
3. 
STUDY ENDPOINTS 
 
3.1. Primary Endpoint 
 
The primary endpoint is the proportion of GVHD-free survival; that is, the percent of patients 
surviving at Day 56 after enrollment without acute or chronic GVHD and without other systemic 
DJHQWV RU HVFDODWLRQ RI VWHURLGV WR  2.5 mg/kg/day of prednisone [or methylprednisolone 
equivalent of 2 mg/kg/day]) added for treatment of GVHD.  
 
3.1.1. Staging and Grading of Acute GVHD 
 
In this study we will classify patients by a modified Keystone grading schema.   
 
TABLE 3.1: STAGING 
 
Stage 0 
Stage 1 
Stage 2 
Stage 3 
Stage 4 
Skin 
No rash 
Rash < 25% 
BSA 
25-50% 
> 50% 
Generalized 
erythroderma 
Plus bullae and 
desquamation 
Gut 
Adult:  
< 500 ml/day  
Child: < 10 
ml/kg/day 
Adult:  
500–1000 ml/day  
Child: 10 -19.9 
ml/kg/day 
Adult: 1001-
1500 ml/day  
Child: 20 – 30 
ml/kg/day  
Adult: 
 >1500 ml/day  
Child: > 30 
ml/kg/day 
Severe 
abdominal pain 
+/- ileus, flank 
blood or melena 
UGI 
 
Severe 
nausea/vomiting 
 
 
 
Liver 
Bilirubin 
PJGO 
2.1-3 mg/dl 
3.1-6mg/dl 
6.1-15mg/dl 
>15mg/dl 
 
 
3.2. Secondary Endpoints 
 
Response Definitions: 
CR is defined as a CIBMTR score of 0 for the GVHD grading in all evaluable organs.  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 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.   


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
3-2 
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 steURLG GRVH WR  2.5 
mg/kg/day of prednisone [or methylprednisolone equivalent of 2 mg/kg/day]) will be classified 
as non-responders. 
 
3.2.1. Proportion of CR, PR, MR, NR and Progression 
 
Proportion of Complete Response (CR), Partial Response (PR), Mixed Response (MR), No 
Response (NR) and Progression among surviving patients at Days 14, 28 and 56:  Scoring of 
CR, PR, MR, NR and progression are in comparison to the participant’s acute GVHD status 
(score) on Day 0 of the study. 
 
3.2.2. Proportion of Primary Treatment Failures 
 
Proportion of primary treatment failures among surviving patients at Days 14, 28 and 56: No 
response, progression, administration of additional systemic therapy for GVHD (or re-escalation 
RI VWHURLG GRVH WR   PJNJGD\ RI SUHGQLVRQH or methylprednisolone equivalent of 2 
mg/kg/day), or mortality by Day 14, 28 or 56 post-initiation of treatment will be considered a 
primary treatment failure. 
 
3.2.3. GVHD Flares Requiring Additional Therapy 
 
Flares are defined as any progression of acute GVHD after an initial response (i.e., earlier CR or 
PR) that requires re-escalation of steroid dosing, or initiation of additional topical or systemic 
therapy.  While all “flares” will be captured, only flares that require additional systemic therapy 
(that is additional drugs) or re-escalation of steroids to   PJNJGD\ RI SUHGQLVRQH >or 
methylprednisolone equivalent of 2 mg/kg/day] will be counted as failure for the primary 
endpoint.  The rate of all flares before Day 90 will be examined as a secondary endpoint 
 
3.2.4. Immunosuppression Discontinuation 
 
Discontinuation of immunosuppression will be assessed by Day 56, Day 180 and Day 360.  The 
date of discontinuation of corticosteroids will be recorded.  In addition, dates for discontinuation 
of all other systemic immunosuppressive medications (where applicable), including cyclosporine 
or tacrolimus, sirolimus, etc. for treatment or prevention of acute GVHD will be captured. 
 
3.2.5. Steroid Dose at Days 28 and 56 after Randomization 
 
Doses of methylprednisolone will be converted to prednisone equivalents by multiplying the 
methylprednisolone dose by 1.25.  Prednisone doses for each patient will be converted to mg/kg. 
The cumulative prednisone dose for each patient at Day 28 will be calculated by adding the 
doses (end of each week’s dose) for each of the first four weeks of treatment, divided by the 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
3-3 
number of days of survival during this interval.  The prednisone dose for each patient at Day 28 
and Day 56 will be recorded 
 
3.2.6. Incidence of Topical/Non-absorbable Therapy by Day 56 
 
The proportion of patients using either topical skin or topical GI steroids will be calculated. 
 
3.2.7. Chronic GVHD 
 
Chronic GVHD is defined per the BMT CTN Manual of Procedures (MOP) Chapter 2.  The 
incidence of chronic GVHD at 6 and 12 months will be computed for each treatment arm. 
 
3.2.8. Overall and GVHD-free Survival 
 
Overall survival and GVHD-free survival at Days 180 and 360 will be computed for each 
treatment arm. 
 
3.2.9. Systemic Infections though Day 180 
 
All 
microbiologically 
documented 
infections 
or 
significant 
infections 
requiring 
antibiotic/antifungal therapy occurring within six months of initiation of therapy will be reported 
by site of disease, date of onset, and severity.  For definitions see the BMT CTN MOP.   
 
3.2.10. Incidence of EBV 
 
Participating sites are to collect any incidence of EBV-associated lymphoproliferative disorder or 
EBV reactivation requiring therapy though Day 360. 
 
3.2.11. Disease-free Survival at 6 and 12 Months Post-randomization 
 
Disease-free survival at 6 and 12 months will be computed for each treatment arm.  The events 
for disease-free survival are death and relapse of the underlying malignancy. 
 
3.2.12. Non-relapse Mortality at 6 and 12 Months Post-randomization 
 
Non-relapse mortality at 6 and 12 months will be computed for each treatment arm.  The events 
for non-relapse mortality are death due to any cause other than relapse of the underlying 
malignancy. 
 
3.2.13. Change in Patient-reported Outcomes from Enrollment to Day 56 
 
Study participants who are able to communicate in English will self-complete the M.D. 
Anderson Symptom Inventory (MDASI) at enrollment prior to randomization and at Day 56 +/- 
7 days.  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”).  See the MDASI in Appendix E.  It provides two 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
3-4 
summary scales: symptoms and interference.29  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.  Although the 
MDASI has been psychometrically validated in 8 languages, including Spanish, given the 
exploratory nature of this endpoint we will only administer the MDASI to patients who are able 
to communicate in English.  Surveys may not be completed by surrogates. 
 
NOTE:  Long-term follow-up of patients on this study will continue through routine CIBMTR 
mechanisms. 
 
 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
4-1 
CHAPTER 4 
 
 
4. 
PATIENT ENROLLMENT AND EVALUATION 
 
4.1. Enrollment and Randomization 
 
Patients will be registered using the BMT CTN Advantage Electronic Data Capture (EDC).  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 (inclusion/exclusion criteria) of the 
Eligibility Form within 72 hours of need of systemic therapy for acute GVHD. 
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. 
 
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. 
 
4.1.1. Randomization  
 
Patients will be randomized within 72 hours of need of systemic therapy of acute GVHD.  
Patients will be randomized to MMF versus placebo in a 1:1 ratio.  Treatment should be initiated 
as soon as possible after randomization.  A maximum of 48 hours is allowable. 
 
4.2. Study Monitoring 
 
4.2.1. Follow-up Schedule 
 
The Follow-up Schedule for scheduled study visits is outlined in Table 4.2.1.  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. 
 
Criteria for Forms Submission: Criteria for timeliness of submission for all study forms are 
detailed in the Data Management Handbook and User’s Guide.  Forms that are not received at 
the DCC within the specified time will be considered delinquent.  Transplant Centers can view 
past due forms via the Web-based data entry system.  A missing form will continue to appear 
until the form is entered into the DCC’s master database, or until an exception is granted and 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
4-2 
entered into the Missing Form Exception File, as detailed in the Data Management Handbook 
and User’s Guide. 
 
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.   
 
Table 4.2.1 
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 
360 days 
 
1.Target day range = r3 days up for Day 7 (subsequent visits 
through Day 56 must be scheduled weekly). 
 
 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
4-3 
4.2.2. Assessments  
 
All assessments are considered standard-of-care unless identified below by “*.” 
 
Pre-Randomization    
1. Recommended biopsy of involved tissue (this is standard of care, not research) 
2. History and physical exam including height and weight 
3. Pregnancy test (if applicable) 
4. Complete acute GVHD staging and grading information including assessments of rash, 
diarrhea, nausea/vomiting, weight and liver function tests 
5. CBC with differential, platelet count 
6. Liver function tests (bilirubin, alkaline phosphatase, AST, ALT) plus creatinine 
7. Tacrolimus/cyclosporine level (if applicable) 
8. M.D. Anderson Symptom Inventory at Day 0 (see Appendix E) 
9. (OPTIONAL) Samples for laboratory studies at Day 0 (see Appendix C).*  Donor 
chimerism results to be recorded for the time nearest sample collection. 
Post-Randomization  
1. Karnofsky or Lansky performance status weekly until Day 56 and at Days 90, 180 and 
360  
2. Complete acute GVHD staging and grading information including assessments of rash, 
diarrhea, nausea/vomiting, weight and liver function tests weekly until Day 56, and 3, 6 
and 12 months, creatinine weekly until Day 28, and recommended creatinine on Days 35, 
42, 49, 56, and 3, 6, and 12 months. 
3. Chronic GVHD evaluation (if present) 3, 6 and 12 months 
4. CBC with differential, platelet count weekly until Day 56 
5. Toxicity evaluation weekly until Day 56 
6. Steroid dose weekly until Day 56, and at 3, 6 and 12 months 
7. Study drug (MMF/Placebo) dose and formulation weekly until Day 56 
8. Topical treatments for GVHD, weekly until Day 56 
9. (OPTIONAL) Samples for laboratory studies at Days 28 and 56 (see Appendix C).*  
Donor chimerism results to be recorded for the time nearest sample collection. 
10. Infections requiring therapy up to 6 months after randomization 
11. Occurrence of post-transplant lymphoproliferative disorder (PTLD) through Day 360 
12. M.D. Anderson Symptom Inventory at Day 56 (see Appendix E) 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
4-4 
Table 4.2.2  REQUIRED ASSESSMENTS 
 
 
 
(Day 0) 
Days Post Randomization 
 
Baseline  
7* 
14 
21 
28 
35 
42 
49 
56   
90** 180*** 360*** 
Suggested biopsy of involved tissue  
X 
 
 
 
 
 
 
 
 
 
 
 
History and physical exam 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (if applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky/Lansky performance status 
X 
X 
X 
X 
X 
X 
X 
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 
CBC with differential, platelet count 
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 
Toxicity evaluation 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Steroid dose 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dose 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Optional blood, and serum for ancillary laboratory 
studies (see Appendix C) 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Optional buccal Swab (see Appendix C) 
X 
 
 
 
 
 
 
 
 
 
 
 
M.D. Anderson Symptom Inventory (MDASI) 
X 
 
 
 
 
 
 
 
X 
 
 
 
Chimerism (% donor)1 
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 
 
1Donor chimerism results recorded at the time nearest to each sample collection will be noted. 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
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4-5 
4.2.3. 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. 
 
4.2.4. Serious Adverse Event (SAE) Reporting 
 
Unexpected, grade 3-5 adverse events (AE) will be reported through an expedited AE reporting system 
via AdvantageEDC.  Unexpected, grade 4-5 AEs must be reported within 24 hours of knowledge of the 
event.  Unexpected, grade 3 AEs must be reported within three business days of knowledge of the event.  
Unexpected, grade 3-5 AEs 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 3.0 at regular intervals as defined on the Form Submission 
Schedule. 
 
The Data and Safety Monitoring Board will receive summary reports of all Grade 3-5 
unexpected adverse experiences on an annual basis. 
 
4.2.5. Study Drug Dose Reduction Monitoring 
 
Because the dosing schedule of MMF in this trial will be more frequent (q8hrs) compared to the 
previous phase II trial, additional monitoring for potential toxicity will be implemented.  Patients 
who are felt to have potential toxicity related to the study drug (MMF/Placebo) may have their 
dosing reduced from TID to BID dosing at the discretion of the treating physician as outlined in 
Section 2.5.  The dose and schedule of MMF/placebo will be recorded weekly.  After 20 and 40 
patients have been enrolled, interim analyses will be performed to assess the incidence of 
sustained dose reduction from TID for reasons of toxicity in the MMF and placebo arms by Day 
28.  Sustained dose reduction will be defined as reduction from TID dosing for reasons of 
toxicity for the duration of at least 1 week without re-escalation of dose.  If the incidence of 
sustained dose reduction in the MMF arm is >30% higher than that observed in the placebo arm, 
the protocol team will consult with the Data and Safety Monitoring Board and consider 
amending the starting MMF/placebo dose to BID dosing for the entire study.  
 
4.3. Discontinuation Criteria 
 
Study drug therapy (MMF or placebo) shall be discontinued and not re-instituted if any one of 
the following criteria is met.  The patient will be taken off study drug therapy at that point, but 
still followed for primary and secondary study endpoints.  A response assessment will be made at 
the time of therapy discontinuation and at subsequent defined study endpoints.  The patient will 
not be replaced on study.  Note: though the study drug will be discontinued in the following 
circumstances, corticosteroid dosing will be managed as clinically indicated by the treating 
physician.  Follow-up data will be required unless consent for data collection is withdrawn: 
x Additional systemic GVHD therapy is added for disease progression or non-response 


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x Steroid dose is HVFDODWHG WR  2.5 mg/kg/day of prednisone (or methylprednisolone 
equivalent of 2 mg/kg/day) for disease progression or non-response 
x Development of toxicity that requires withholding of study medication for more then 14 
days (see Section 2.5 for details of dose modifications for toxicity) 
 
 
 


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5-1 
CHAPTER 5 
 
 
5. 
STATISTICAL CONSIDERATIONS 
 
5.1. Study Design 
 
The study is designed as a Phase III, randomized, double-blind, multicenter, prospective 
comparative study of steroids + MMF vs. steroids + placebo for treatment of acute GVHD.  The 
target enrollment is 372 patients. 
 
5.1.1.  Accrual 
 
It is estimated that three years of accrual will be necessary to enroll the targeted sample size.  
Both Core and non-Core Centers will enroll patients on this study.  Accrual will be reported by 
race, ethnicity, gender, and age (pediatric patients will be defined as < 18 years). 
 
5.1.2. Randomization 
 
Randomization will be performed in a 1:1 ratio using random block sizes for the two arms.  
Randomization will be stratified by transplant center and grade of GVHD (I-II vs. III-IV) at 
study entry. 
 
5.1.3. Primary Endpoint 
 
The primary endpoint is the GVHD-free survival proportion at Day 56 post randomization.  The 
primary analysis will be performed using the intent-to-treat principle so that all randomized 
patients will be included in the analysis.  Death, lack of CR at Day 56, initiation of additional 
therapy, or development of chronic GVHD will be considered failures for this endpoint.  Flares 
of acute GVHD after achieving CR will not result in a failure for the primary endpoint as long as 
the patient still achieves CR at Day 56 and does not need additional therapy. 
 
5.1.4. Primary Hypothesis 
 
The primary null hypothesis of the study is that there is no difference between the GVHD-free 
survival proportions for MMF compared to the placebo arm. 
 
Ho: 
pMMF = pPL 
Ha: 
pMMF z pPL 
 
5.2. Sample Size and Power Considerations 
 
GVHD-free survival at Day 56 post-randomization will be compared between the MMF and 
placebo using the Z test for comparing two binomial proportions.  The final analysis will be 
performed after all patients have been followed for a minimum of 56 days post-randomization.  


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Sample size and power considerations are based on estimates from BMT CTN Protocol 0302, the 
randomized Phase II study on which this Phase III study is based.  In BMT CTN 0302, the 
estimated Day 56 GVHD-free survival was 71% for the MMF arm (n=44) and 47% for the three 
combined non-MMF arms (n=134).  Although the observed difference in GVHD-free survival 
proportions was 24%, this was based on a small sample size for the MMF arm.  In this study, we 
target a more modest difference of 15%, which would still be considered clinically relevant.  The 
sample size of 186 patients per group, or 372 total, is sufficient to maintain type I error of 5% 
across all planned interim analyses (see below) while providing 80% statistical power for a two-
sided test to detect an increase in the GVHD-free survival proportion at Day 56 from 0.47 in the 
placebo arm to 0.62 in the MMF arm.   
 
5.3. Interim Analysis and Stopping Guidelines 
 
Interim analyses for efficacy and futility will be conducted at times coincident with regularly 
scheduled meetings of the NHLBI-appointed Data and Safety Monitoring Board (DSMB) at 
approximately six month intervals.  Monitoring of 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. 
 
5.3.1. Interim Analysis for Efficacy and Futility 
 
Analyses will be performed as described below for the primary endpoint.  Toxicity, adverse 
events, and other safety endpoints will be monitored regularly and reported to the DSMB at each 
interim analysis.  
 
At each interim analysis time point, a two-sided test to detect either an increase or decrease in the 
GVHD-free survival proportion at Day 56 will be performed.  The test statistic based on the Z 
test comparing binomial proportions will be compared to the critical values shown below.  All 
patients with at least 56 days of follow-up prior to the time of the interim analyses will be used to 
compute this statistic.  If the test statistic is outside the continuation range, the DSMB will 
discuss the continuation of the trial. 
 
In order to preserve the over-all type I error rate at 5%, efficacy and futility stopping rules will 
be constructed using error spending functions for both the type I error rate alpha and the type II 
error rate beta.  The error spending function defined by f(W PLQĮW3ĮZKLFKDSSUR[LPDWHVWKH
O’Brien-Fleming efficacy boundary, will be used for both error rates, except that stopping for 
futility will not be allowed until half of the patients are evaluable.  This error spending function 
approach permits necessary flexibility in the scheduling of interim analyses based on the rate of 
accrual and the timing of DSMB meetings.   
 
As an example, Table 5.3a shows the critical values and cumulative error rates for tests 
conducted every six months starting with the 8th month after the study opens to enrollment.  The 
column labeled “followed to 56 days” shows the expected number of individuals who have 
reached the 56-day post-randomization follow-up time point, assuming uniform accrual over a 
three-year period.  The fraction of patients followed to 56 days, as compared to a denominator 


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5-3 
comprised of the total sample of 372, quantifies the “statistical information” from which the 
critical values are computed.   
 
TABLE 5.3a – CRITICAL VALUES 
 
Calendar 
Time 
(Months) 
# of Patients 
Followed to  
56 Days 
Stop for 
Futility 
 if |Z|< 
Stop for 
Efficacy 
 if |Z|> 
Cumulative 
Type I  
Error 
Cumulative 
Type II  
Error 
8 
62 
- 
4.30 
.0002 
- 
14 
124 
- 
3.22 
.0018 
- 
20 
186 
0.28 
2.86 
.0062 
0.0250 
26 
248 
0.74 
2.58 
.0148 
0.0593 
32 
310 
1.38 
2.30 
.0289 
0.1157 
38 (Final) 
372 
2.05 
2.05 
.0500 
0.2000 
 
 
5.3.2. Operating Characteristics of the Design  
 
The statistical power to reject the null hypothesis of equal Day 56 GVHD-free survival is shown 
in Table 5.3b under a variety of scenarios, using the Z test comparing the Binomial proportions.  
These simulation results assume that the interim analyses are conducted at equally spaced 
information times.  Also shown are the stopping probabilities for efficacy or futility at each of 
the planned interim analyses.  This table shows that the target sample size of 372 patients has 
>80% power to detect a 15% improvement in GVHD-free survival. 
 
TABLE 5.3b – POWER TO REJECT THE NULL HYPOTHESIS  
UNDER VARIOUS SCENARIOS 
 
Proportion Alive and 
  
Probability of Stopping at Interim and Final Analyses 
Overall 
(Cumulative) 
GVHD-Free at Day 56 Reason for 
stopping 
By number of patients evaluable at time of Scheduled Analysis 
Placebo 
MMF 
62 
124 
186 
248 
310 
372 
Power 
0.47 
0.47 
Efficacy 
0 
0.002 
0.004 
0.008 
0.014 
0.021 
0.049 
  
  
Futility 
0 
0 
0.175 
0.372 
0.304 
0.1 
  
0.47 
0.52 
Efficacy 
0 
0.005 
0.013 
0.025 
0.043 
0.065 
0.151 
  
  
Futility 
0 
0 
0.14 
0.284 
0.28 
0.145 
  
0.47 
0.57 
Efficacy 
0.001 
0.02 
0.054 
0.098 
0.138 
0.153 
0.464 
  
  
Futility 
0 
0 
0.068 
0.13 
0.18 
0.157 
  
0.47 
0.62 
Efficacy 
0.005 
0.07 
0.161 
0.216 
0.213 
0.145 
0.809 
  
  
Futility 
0 
0 
0.021 
0.033 
0.058 
0.078 
  
0.47 
0.67 
Efficacy 
0.014 
0.18 
0.306 
0.263 
0.151 
0.056 
0.969 
  
  
Futility 
0 
0 
0.004 
0.004 
0.008 
0.015 
  
* from simulation with 100,000 replications 
 
 


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5.3.3. Guidelines for Safety Monitoring 
 
Monitoring of a key safety endpoint 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 guideline serves as trigger for consultation with the DSMB for additional review. 
 
The key safety endpoint for this study is mortality.  The rate of mortality will be monitored up to 
28 days post-randomization.  Monitoring will be performed monthly beginning after the third 
month of enrollment until enrollment is closed.  At least three events must be observed in order 
to trigger review.  Each month, the null hypothesis that the 28-day mortality rate is less than or 
equal to 7.5% is tested.  An extension of the sequential probability ratio test (SPRT) for censored 
exponential data will be used for monitoring, as described in greater detail below and in 
Appendix D. 
 
This sequential testing procedure conserves type I error at 5% across all of the monthly 
examinations.  The SPRT can be represented graphically.  At each monthly interim analysis, the 
total time on study is plotted against the total number of endpoints (e.g., patients experiencing 
death).  The continuation region of the SPRT is defined by two parallel lines.  Only the lower 
boundary will be used for monitoring to protect against excessive 28-day mortality.  If the graph 
falls below the lower boundary, the SPRT rejects the null hypothesis, and concludes that there 
are more events than predicted by the observed time on study.  Otherwise, the SPRT continues 
until enrollment reaches the maximum of 186 patients. 
 
This procedure assumes a censored exponential distribution for the time until death during the 
first 28 days, and censors follow-up time after 28 days.  Only deaths that occur on or before the 
patient has been followed for 28 days are counted.  Total time on study is computed as time from 
registration to death, or to 28 days, whichever comes first, summed for all patients on study. 
 
The usual measures of performance of an SPRT are the error probabilities D and E of rejecting 
H0 when T = T0 and of accepting H1 when T = T1, respectively, and the expected sample size 
E(N|Ti).  The tests to be used in this protocol were developed from the following SPRTs:   
x A SPRT contrasting 7.5% versus 22.5% 28-day rate of mortality results in decision 
boundaries with a common slope of 6.695 and a lower intercept of –12.691, with nominal 
type I and II errors of 9% and 15%, respectively. 
 
The actual operating characteristics of the truncated test, shown in Table 5.3c, were determined 
in a simulation study that assumed uniform accrual of 186 individuals over a three-year time 
period, and exponential time to failure after randomization.   
 


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5-5 
TABLE 5.3c:  OPERATING CHARACTERISTICS OF SEQUENTIAL TESTING 
PROCEDURE FROM A SIMULATION STUDY WITH 10,000 REPLICATIONS 
  
Day 28 MORTALITY 
 
True 28-Day Rate 
7.5% 
12.5% 
17.5% 
Probability Reject Null 
0.052 
0.449 
0.929 
Mean Month Stopped 
35.4 
25.5 
11.9 
Mean # Endpoints in 100 Days 
13.3 
16.0 
10.3 
Mean # Patients Enrolled 
178.0 
129.0 
61.2 
 
For example, the testing procedure rejects the null hypothesis in favor of the alternative 5% of 
the time when the true 28-day mortality rate is 7.5%, and 93% of the time when the rate is 
17.5%.  This corresponds to a type I error rate of D = 0.05 and a type II error rate of E = 0.07.  
When the true 28-day mortality rate is 17.5%, on average, the DSMB will be consulted 12 
months after opening, when 10 events have been observed in 61 patients. 
 
5.3.4. Safety Analysis 
 
The reporting of serious adverse events will be consistent with standard BMT CTN procedures.  
All reported serious adverse events potentially associated with study drug will be carefully 
examined with respect to the severity and relationship to study drug.  The type and severity of 
adverse events will be described. 
 
5.3.5. Monitoring Guidelines for Dose Reduction 
 
Rates of dose reduction will be compared between the blinded study arms early in accrual to 
determine whether there is evidence of a differential rate.  Such a difference would indicate that 
the starting dose should be decreased from 3 times daily to 2 times daily.  Dose reduction is 
defined as one week of sustained dose reduction from TID dosing through Day 28.  It is 
anticipated that rates of dose reduction will be low in the placebo arm, approximately 10-20%, 
and the monitoring rule is designed to identify a 30% absolute difference in dose reduction rates 
between the two study arms with 80% power.  If the monitoring rule is triggered, the DSMB will 
be notified and asked to review unblinded toxicity data in the two arms to assess whether the 
starting dose of MMF should be decreased. 
 
The dose reduction stopping rule is based on an O’Brien-Fleming boundary for the Z statistic 
comparing the probabilities of dose reduction by Day 28 between the two groups, with two looks 
at the data.  Death without dose reduction will be treated as the competing risk, and the 
cumulative incidence estimator will be applied to all randomized patients to estimate the 
probability of dose reduction in each group.  Dose reduction rates will be compared after 20 and 
40 patients are randomized and followed for 28 days in each arm.  Such early assessment will 
allow for at least 75% of the patients to be treated in the same way and with the same starting 
dose.  Enrollment will not be put on hold after the 20th and 40th patients are enrolled unless the 


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test statistic is close enough to the boundary that the additional follow up could potentially 
trigger the stopping rule.   
 
Details of the stopping rule are given in Table 5.3d.  Also contained in the table are the 
cumulative probabilities of triggering DSMB review as a function of the increase in dose 
reduction rates, assuming a 20% baseline dose reduction rate in the placebo arm.  These stopping 
probabilities are computed by simulating simple binomial proportions for the dose reduction rate 
in each group; in practice, the stopping rule would be based on the cumulative incidence 
estimator using all patients, including those with less than 28 days of follow-up.  The binomial 
calculation provides a conservative estimate of the power for this stopping rule.  The stopping 
rule controls the type I error rate at 5% if there is no increase in the dose reduction rates, and has 
more than 80% power to identify a 30% increase in the dose reduction rates within 40 patients.  
The type I error rate is still controlled and the power is higher if the baseline dose reduction rate 
is 10% (results not shown). 
 
 
TABLE 5.3d: MONITORING RULE AND OPERATING CHARACTERISTICS FOR 
DOSE REDUCTION RATES IN THE FIRST 40 PATIENTS PER ARM 
 
 
 
Cumulative stopping probability for absolute difference in 
dose reduction rates of 
# of patients 
per arm 
Stop if 
0% 
20% 
25% 
30% 
20 
|Z|>2.80 
0.006 
0.114 
0.200 
0.298 
40 
|Z|>2.05 
0.050 
0.512 
0.677 
0.822 
 
5.4. 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, 
acute GVHD grade at enrollment, donor age, donor gender, and donor ethnicity.  Between group 
comparisons will be performed for continuous variables via a t-test and for categorical variables, 
via the chi-square test. 
 
5.5. Analysis of Secondary Endpoints 
 
5.5.1. Proportion of CR, PR, MR, NR and Progression  
 
Proportions of Complete Response (CR), Partial Response (PR), Mixed Response (MR), No 
Response (NR) and Progression at Days 14, 28 and 56 will be compared between the treatment 
groups using the chi-square test.   
 
5.5.2. Proportion of Primary Treatment Failures among Surviving Patients 
 
Proportion of primary treatment failures among surviving patients at Days 14, 28 and 56 will be 
compared using the Z test for comparing binomial proportions. 


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5-7 
 
5.5.3. GVHD Flares Requiring Additional Therapy 
 
The proportion of patients experiencing a flare after an initial response will be evaluated at Day 
90 and compared between treatment groups using the Z test for comparing binomial proportions.  
This will be done both for all flares as well as flares that require additional systemic therapy.   
 
5.5.4. Immunosuppression Discontinuation 
 
The incidence of discontinuation of immunosuppression will be computed separately in each 
treatment group using the cumulative incidence curve, with death prior to discontinuation as the 
competing risk.  Pointwise 95% confidence intervals will be provided at Day 56, Day 180, and 
Day 360.  Comparison of the cumulative incidence curves between treatment will be done using 
Gray’s test.   
 
5.5.5. Steroid Dose at Days 28 and 56 after Randomization 
 
The median and range of steroid doses at each time point will be provided separately for each 
treatment group.  The median steroid dose will be compared between treatment groups using the 
Wilcoxon rank sum test.   
 
5.5.6. Incidence of Topical/Non-absorbable Therapy by Day 56 
 
The proportion of patients using topical/non-absorbable therapy by Day 56 will be compared 
between the treatment groups using the Z test for binomial proportions. 
 
5.5.7. Chronic GVHD 
 
The incidence of chronic GVHD will be computed using the cumulative incidence estimator, 
treating death prior to chronic GVHD as a competing risk.  Pointwise confidence intervals will 
be provided at 6 and 12 months, and the cumulative incidence curves will be compared using 
Gray’s test.   
 
5.5.8. Overall and GVHD-free Survival 
 
Overall survival will be computed using the Kaplan-Meier estimator.  Pointwise confidence 
intervals will be provided at Days 180 and 360.  Survival curves will be compared between 
treatment groups using the log-rank test.  GVHD-free survival will be estimated using simple 
proportions of patients alive and without GVHD if there is no censoring prior to 180 or 360 days.  
If there is censoring, the proportion of patients alive and without GVHD will be estimated in 
each treatment using multi-state model techniques.30   
 


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5-8 
5.5.9. Systemic Infections though Day 180 
 
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. 
 
5.5.10. Incidence of EBV 
 
The incidence of EBV-associated lymphoproliferative disorder or EBV reactivation therapy 
through Day 360 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. 
 
5.5.11. Disease-free Survival at 6 and 12 Months Post-randomization 
 
Disease-free survival will be estimated using the Kaplan-Meier method, treating death or relapse 
of malignancy as events in patients with malignancies.  This outcome will be compared between 
the two treatment groups using the log-rank test. 
 
5.5.12. Non-relapse Mortality at 6 and 12 Months Post-randomization 
 
Non-relapse mortality will be estimated using the cumulative incidence method, treating relapse 
as the competing risk.  The cumulative incidence curves for non-relapse mortality will be 
compared between the treatments using Gray’s test. 
 
5.5.13. Change in Patient-Reported Outcomes from Enrollment to Day 56 
 
Participant self-reported measures will be assessed at two time points using the MDASI at 
enrollment and at Day 56.  The MDASI will be scored according to the recommendations of the 
developers.  We will explore the range of scores to assess the medians, means and standard 
deviations observed.  Using repeated measures longitudinal models, we will use PROC MIXED 
to explore changes over time and major domains that differ between patients on the two trial 
arms.  In exploratory analyses, we will also investigate the clinical relevance of particular items 
in the MDASI, including the items which correlate with different organ manifestations of acute 
GVHD and the items most sensitive to change when acute GVHD improves objectively.  
 
 
 


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APPENDIX A 
 
HUMAN SUBJECTS 
 
 
 
 


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A-1 
APPENDIX A 
 
HUMAN SUBJECTS 
 
 
Subject consent: 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 and enroll them onto the study.  The study coordinator at each center will provide the 
patient with information about the purpose of the study and obtain consent.  The Network will 
provide a template of the consent form to each center.  Each center will customize the template 
according to their local requirements and submit it for review by the local Internal Review Board 
(IRB).  The DCC will verify the adequacy of the consent forms.  Each center must provide 
evidence of IRB approval.  
 
 
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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APPENDIX B 
 
INFORMED CONSENTS 
AND 
EDUCATIONAL MATERIAL 
 
 
 
INFORMED CONSENT TO PARTICIPATE IN RESEARCH 
 
ASSENT TO PARTICIPATE IN RESEARCH 
 
 
 


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Information & Informed Consent Form 
 
Initials _____________ 
B-1 
Informed Consent to Participate in Research 
 
 
 
 
 
 
 
 
 
 
Your Name:  
 
 
 
 
 
 
 
 
 
 
 
 
Study Title: 
A Multi-Center, Randomized, Double Blind, Phase III Trial Evaluating 
Corticosteroids with Mycophenolate Mofetil vs. Corticosteroids with Placebo 
as Initial Systemic Treatment of Acute GVHD. 
 
Protocol: 
0802 
 
Investigator: 
Javier Bolaños Meade, M.D.  
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins  
1650 Orleans Street 
Baltimore MD 21231  
Phone: 410-614-6398. 
 
Co-Investigator: Vincent T. Ho, M.D. 
Dana Farber Cancer Institute 
44 Binney Street  
Boston MA 02115 
Phone: 617-632-5938 
 
Transplant Center 
Investigator:  
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor: 
The National Institutes of Health (NIH) gave financial support for this 
research study through the Blood and Marrow Transplant Clinical Trials 
Network (BMT CTN).  
 
Introduction 
You are invited to join a research study.  This study will evaluate a GVHD treatment that 
includes the use of prednisone (a corticosteroid) and either: a placebo (sugar pill) or the study 
drug, mycophenolate mofetil (MMF).  The placebo is not a treatment and will have no effect on 
your condition.  The placebo or MMF will be randomly assigned to you. 
 
If you decide to join the study, you will receive either steroids and MMF, or steroids and a 
placebo.  If you choose not to join the study, you will receive standard treatment. 


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Information & Informed Consent Form 
 
Initials _____________ 
B-2 
 
This Consent Form will tell you about the purpose of the research, its possible risks and benefits, 
other options available to you, and your rights as a participant in the study.  Please take your time 
to make your decision.  
 
Everyone who takes part in research at [insert facility name] should know that: 
 Being in any research study is voluntary. 
 You may or may not benefit from being in the study.  Knowledge we gain from this study 
may benefit others. 
 If you join the study, you can quit the study at any time.   
 If you decide to quit the study, it will not affect your care at [insert name of facility or 
institution]. 
 Please ask the study staff questions about anything that you do not understand, or if you 
would like to have more information. 
 You can ask questions now or any time during the study. 
 Please take the time you need to talk about the study with your doctor, study staff, and 
your family and friends.  It is your decision to be in the study.  If you decide to join, 
please sign and date the end of the Consent Form. 
 
You and your doctor will discuss other treatment choices if you do not want to participate 
in this study. 
 
 
1. 
Background 
 
This research study is sponsored by The National Institutes of Health (NIH) through the Blood 
and Marrow Transplant Clinical Trials Network (BMT CTN).  The goal of this study is to find a 
better treatment for acute GVHD in people who have had an allogeneic blood stem cell 
transplant.  
 
Acute GVHD is a medical condition that can become very serious.  Acute GVHD is a common 
development after allogeneic stem cell transplant. It happens when the donor cells attack and 
damage your tissues after transplant.  Acute GVHD often causes:  
 Skin rashes 
 Nausea (feeling sick to your stomach) 
 Vomiting (throwing up) 
 Abdominal pain 
 Diarrhea  
 Liver damage that can cause inflammation in the liver or jaundice (yellowing of the skin 
or eyes)   


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Information & Informed Consent Form 
 
Initials _____________ 
B-3 
Patients with acute GVHD are at risk to develop chronic GVHD.  Chronic GVHD may also 
cause damage to other organs.  Acute and chronic GVHD may be bad enough to cause death. 
 
Corticosteroid (or steroid) medications, such as prednisone, are the standard of care for early 
treatment of GVHD.  However, less than half of patients will become free of acute GVHD when 
steroid treatment is used alone. Information from a BMT CTN study suggests that 
Mycophenolate mofetil or “MMF” in combination with standard steroid therapy may lower the 
risk of developing GVHD.  
 
MMF is a drug that blocks the growth of the immune cells (T lymphocytes), which are believed 
to cause GVHD.  MMF is approved by the U.S. Food and Drug Administration (FDA) to prevent 
rejection after organ transplant.  MMF has been used for years as a treatment for GVHD that 
does not respond to standard corticosteroid therapy, or to prevent GVHD after allogeneic stem 
cell transplant.  
 
 
2. 
Purpose 
 
You are invited to join this research study because you have developed acute graft-versus-host 
disease (GVHD) and your doctor feels that treatment for the GVHD is necessary.   
 
We will measure how the addition of MMF compares long-term to the standard treatment of 
steroids for acute GVHD.  Specifically, we also want to know if MMF will: 
 Reduce the symptoms and signs of acute GVHD, or  
 Eliminate acute GVHD completely.  
 
MMF will be compared to a placebo (sugar pill) to learn if it will reduce or eliminate your acute 
GVHD when added to the standard treatment of steroids.  
 
We also want to collect extra blood samples and mouth swabs for future research on GVHD.  
You may take part in this additional study if you want to.  You can still be part of the main study 
even if you do not want to donate extra blood samples. 
 
 
3. 
Right to Ask Questions and/or Withdraw 
 
You have the right to ask questions about the study at any time.  If you have questions about 
your rights as a participant or you want to leave the study, please contact:  
[insert contact info] 
 
Being in this study is voluntary.  You can choose to not be in this study, or leave this study at 
any time.  If you choose to not take part or to leave this study, your regular medical care will not 
be affected in any way.  This includes standard care for your acute GVHD. 
 


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If you decide to leave this study after taking the study treatment, or are asked to leave by your 
doctor for medical reasons, you will need to come back to the doctor’s office for tests for your 
safety.  Even if you withdraw from the study, the information collected from your participation will 
be included in the study evaluation, unless you specifically ask that it not be included. 
 
Your study doctor and study staff will be available to answer any questions that you may have about 
your participation in, or your withdrawal from this study. 
 
 
4. 
Procedures 
 
Before you join the study, we will ask you about your medical history, and any medications you 
may be taking.  It is important that you do not participate in the study if you suffer from an 
allergy to mycophenolate mofetil (MMF); or if you are pregnant, breastfeeding or are likely to 
become pregnant during the study.  
 
Your doctor will do a number of tests to determine if you are able to join this study.  These tests 
include: 
 A physical exam that also measures the stage of your GVHD. 
 Your ability to do regular daily activities (performance status). 
 Routine blood tests to check your blood counts, how well your liver and kidneys work, 
and levels of GVHD prevention medications in your blood (if it applies to you). 
 Pregnancy test (if it applies to you). 
 
If you decide to join, we will ask you to sign this Consent Form, and you will get a copy of the 
signed form to keep. 
 
There will be two study groups.  One group will receive MMF and the other group will receive 
the placebo.  Both groups will receive the standard treatment of steroids.  About 372 patients will 
participate at several centers around the country.  Your study participation will last about 12 
months and you will be required to attend the clinic at least 8 times during the first 8 weeks of 
the study. 
 
You may take the assigned placebo or MMF for up to 8 weeks.  Once you stop taking the 
placebo or MMF, the study team will follow your health for up to 12 months after you first join 
the study. 
 
Another part of the study will ask questions about your symptoms. This information will be 
collected at two times: enrollment on the study and approximately 56 days later.  The survey has 
19 questions and should take less than 5 minutes to complete.  You may skip any questions you 
wish. 
 


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Randomization 
We will randomly assign you to one of two study groups using a computer.  This means that you 
will be put into a group by chance. It is like the flip of a coin or drawing names out of a hat.  You 
will have an equal chance of being placed in either group. 
 
You will not be told to which group you are assigned.  Study staff at your visits will not know 
your group assignment either.  We can find out which group you are assigned to if we ever need 
to know to protect your safety. 
 
Additional Study Visits and Procedures 
We will give you a placebo or MMF along with prednisone or methylprednisolone (steroids), 
which are standard treatment for acute GVHD.  The placebo and MMF come in the form of pills. 
If you cannot take pills, the placebo or MMF can be given to you through your vein (IV 
infusion).   
 
You will take your assigned drug three times each day for up to 8 weeks.  We will watch you 
closely for: 
 Signs of GVHD 
 Changes in your blood counts, liver and kidney function 
 Any side effects 
 Signs of infection 
 
Weekly Health Evaluations 
We will evaluate your health every week for 8 weeks once you start taking your study drug.  At 
your week 4 evaluation we will collect extra blood samples if you agreed to participate in the 
optional research sample portion of this study.  Each health evaluation will include tests to 
evaluate your: 
 GVHD stage 
 Ability to do daily activities (performance status) 
 Blood counts, liver and kidney function, and levels of GVHD prevention medications in 
your blood (if it applies to you) 
 Development of any side effects or signs of infection 
 
These tests and how often they are scheduled are standard care for patients with acute GVHD 
and would be done even if you were not part of this study. 
 
Monthly Health Evaluations 
Once you finish the 8 weeks of study treatment, we will evaluate you at approximately 3, 6 and 
12 months after you first joined the study.   During these visits, we will evaluate your: 
 
GVHD stage 
 
Ability to do daily activities (performance status) 


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 
Routine blood tests including your blood counts, how well your liver and kidneys work, 
and levels of GVHD prevention medications in your blood (if it applies to you) 
 
The evaluations at week 4 and week 8 must be done at the transplant center.  Other exams and 
tests may be done at the transplant center or at a local doctor’s office if your condition improves 
and it is closer to where you live, at the discretion of your transplant doctor.  
 
These tests and how often they are scheduled are standard care for patients with acute GVHD 
and would be done even if you were not part of this study. 
 
 
5. 
Alternative Treatments 
 
Current available treatments which may be used to treat acute GVHD include: 
 Corticosteroids without the study drug (standard treatment for GVHD) 
 Participation in another clinical trial (if available, check with your doctor) 
 
Every treatment option has benefits and risks.  Your study doctor will discuss these options with 
you.  If you decide not to participate in this research study, your medical care will not be affected 
in any way. 
 
 
6. 
Risks and Discomforts 
 
a.) Side Effects of Study Drugs 
All drugs can have side effects, including the standard therapy for GVHD (steroids) and 
MMF being tested in this study.  Your doctor will watch you carefully and will change 
your treatment if side effects develop.  MMF used in addition to steroids for GVHD is an 
experimental treatment, but information has already been collected on its effects in 
people.  We have a limited amount of information about children (pediatric patients) 
treated with MMF for GVHD.   
 
Placebo:   
The placebo will look and taste like MMF (mycophenolate mofetil) but it is not a drug.  
The placebo is not expected to have any side effects and it will have no effect on your 
condition. 
 
Mycophenolate Mofetil (MMF):   
MMF is a potent immunosuppressive drug that blocks the growth of the immune cells 
that can cause GVHD.  
 
Risks and side effects related to MMF include those that are: 
 
Common (more than 20% of patients) 
 Infection 
 Upset stomach, including nausea 
 


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Less common (less than 20% of patients) 
 Low blood counts  
 Vomiting  
 Diarrhea 
Rare but serious (less than 2-3% of patients) 
 Serious injury to your gut (digestive tract), including bloody stools and vomit 
 Secondary cancers, such as lymphoproliferative disease or lymphoma  
 Serious infections of the brain 
 Risk to a baby in pregnancy  
 Progressive Multifocal Leukoencephalopathy (PML) 
 
b.) Infections 
Because GVHD is caused by an immune attack on your tissues from the transplanted 
donor cells, all treatments for GVHD include drugs to control (suppress) that immune 
attack. There is a higher risk of infection in patients with GVHD and any treatment for 
GVHD may also increase your risk of infection.  Infections may be bad enough to cause 
death. 
 
You will need to take several antibiotics to prevent infection.  You will also be watched 
carefully for any infections while you are being treated for GVHD.  Tell your doctors 
promptly if you get a fever, chills, cough or any other symptoms that might be a sign of 
an infection. 
 
c.) Risks of Other Procedures Including Blood Draws   
There are no major risks associated with drawing blood.  Having your blood drawn can 
be uncomfortable and can sometimes cause a bruise.  In rare cases, a blood draw can 
cause fainting.  Only trained people will draw your blood. 
 
d.) Reproductive Risks 
MMF may cause injury or birth defects if it is taken during pregnancy.  Because of this, it 
is important that you are not pregnant or breast-feeding and do not become pregnant 
during the course of the study. 
 
If you are a woman and pregnancy is a possibility, you will need to take a pregnancy test 
before you start the study.  You should discuss ways to not become pregnant while you 
are participating on the study.  Unless you have been in menopause for at least 12 months 
in a row, pregnancy is a possibility. 
 
MMF can make birth control pills less effective.  You must either use abstinence or two 
non-hormone forms of birth control (such as a condom, diaphragm, or spermicide).  You 
must continue to prevent pregnancy before and during your treatment with MMF, and for 
at least 6 weeks after your treatment ends.  
 
Ask your doctor about abstinence or the most effective non-hormonal forms of birth 
control and which options are best for you.  If you do become pregnant while you are in 
the study, you should tell your doctor right away.  You will be removed from the study 


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Initials _____________ 
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drug and you will receive information on medical care, if you need it.  You must not 
continue to take the study drug if you are pregnant. 
 
e.) Unforeseen Risks 
New risks might appear at any time during the study that are different from the risks 
listed in this Consent Form.  We will promptly tell you of any new information that may 
affect your decision to participate. 
 
f.) Other Treatments or Medications  
Some medicines react with each other, and it is important that you tell the study doctor or 
staff about any other drugs, treatments, or medicines you are taking.   
 
This includes non-prescription medications, vitamins and herbal treatments.  It is also 
important that you tell the study staff about any changes to these medications during your 
participation in the study. 
 
g.) Risks of completing the survey 
Completion of the survey about your symptoms will not cause you any physical 
discomfort, although it is possible that you will find some of the questions or topics 
upsetting.  If you do, there will be someone available to speak with you.  They will be 
able to refer you to appropriate counselors or other support people. 
 
 
7. 
Possible Benefits 
 
Taking part in this study may or may not make your health better.  While doctors hope that MMF 
in combination with steroids will be more useful against acute GVHD compared to the usual 
treatment, there is no proof of this yet.  We do know that the information from this study will 
help doctors learn more about MMF in the treatment of acute GVHD.  This information could 
help future allogeneic transplant patients 
 
 
8. 
New Information Available During the Study 
 
During this research study, new information about the study drug or the risks and benefits of the 
study may become known to the study doctors.  If this happens, they will tell you about the new 
information. 
 
The new information may mean that you can no longer participate in the study, or that you may not 
want to continue in the study.  If this happens, the study doctor will stop your participation in the 
study and you will be offered all available care to suit your needs and medical conditions. 
 
 


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9. 
Privacy, Confidentiality and Use of Information 
 
Your confidentiality is one of our main concerns.  We will do our best to make sure that the 
personal information in your medical record will be kept private.  However, we cannot guarantee 
total privacy.   
 
Your personal information may be given out if required by law.  If information from this study is 
published or presented at scientific meetings, your name and other personal information will not be 
used.  Your study number is not related to your name, social security number or medical record 
number at [insert facility name]. 
 
Information about your transplant from your original medical records may be seen or sent to 
national and international transplant registries, including:  
 The Center for International Blood and Marrow Transplant Research (CIBMTR) 
 The National Marrow Donor Program (NMDP) 
 The Food and Drug Administration (FDA) 
 The National Institutes of Health (NIH), which include the National Heart, Lung, and Blood 
Institute (NHLBI) and the National Cancer Institute (NCI) 
 Data and Coordinating Center of the Blood and Marrow Transplant Clinical Trials Network 
(BMT CTN), and  
 Other authorized study organizations.   
 
We will not identify you by name in any publications or reports coming from these organizations or 
groups.   
 
 
10. 
Ending Your Participation 
 
The study doctor or the study sponsor may stop the study at any time.  We may ask you to leave 
the study if you do not follow directions or if you suffer from side-effects of the treatment.  If 
you are asked to leave the study, the reasons will be discussed with you.  
 
Possible reasons to end your participation in this study include: 
 You do not meet the study requirements.   
 You need a medical treatment not allowed in this study. 
 The study doctor decides that it would be harmful to you to stay in the study. 
 You are having serious side effects. 
 You become pregnant. 
 You cannot keep appointments or take study drugs as directed. 
 The company making the study drug/placebo is no longer able to supply it. 
 The study is stopped for any reason. 


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11. 
Physical Injury as a Result of Participation 
 
It is important that you tell your study doctor or study staff if you feel that you have been hurt or 
injured because of taking part in this study.  You will get medical treatment if you are injured as a 
result of taking part in this study.  You and/or your health plan will be charged for this treatment.  
This study will not pay for medical treatment.  In case of injury resulting from this study, you do not 
lose any of your legal rights to seek payment by signing this form. 
 
 
12. 
Compensation or Payment 
 
You will not be paid for your participation in the research study.  You will not get compensation or 
reimbursement for any extra expenses (travel, meals, etc.) you may have through your participation 
on this trial. 
 
 
13. 
Costs & Reimbursements 
 
Most of the visits for this research study are standard medical care for patients with GVHD and will 
be billed to your insurance company.  You and/or your health plan/insurance company will need to 
pay for some or all of the costs of standard treatment in this study.   
 
You or your insurance will not be charged for the study medication (MMF or placebo) or for the 
optional blood and DNA samples for research on this study.  The study drug will be provided free 
of charge while you are participating in the study. 
 
 
14. 
Ethical Review 
 
The ethical aspects of this research study have been reviewed and approved by [name of IRB]. 
 
 
15. 
Further Information 
 
If you need any information about this study, or if you have any problems while you are 
participating in this study you can contact the study doctor or his/her staff.  They may be contacted 
at the telephone numbers listed here: 
 
[Insert name and contact details]. 
 
 


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16. 
Independent Contact 
 
If you wish to speak to someone not directly involved in the study, or if you have any complaints 
about any aspect of the project, the way it is being conducted or any questions about your rights as a 
research participant, then you may contact:  
 
[Insert appropriate contact details] 
 
 
Please note: This section of the informed Consent Form is about an additional research 
study that will be done with people who are taking part in the main study.  You may take 
part in this additional study if you want to.  You can still be a part of the main study even if 
you say ‘no’ to take part in this additional study. 
 
 
Blood and DNA Samples for Research 
We are asking your permission to collect and store extra blood and a DNA sample.  These 
samples will be used for future research on GVHD tests and treatment.  DNA is a molecule that 
contains a person’s genetic information.  We would collect a sample of your DNA by using a 
mouth swab. 
 
DNA from your stored blood and DNA samples and your health information might be used in 
genome-wide association (GWA) studies for a future project either done or supported by the 
National Institutes of Health (NIH).  Genome-wide association studies are a way for scientists to 
identify genes involved in human disease.  This method searches the genome for small genetic 
changes that are more common in people with a particular disease than in people without the 
disease.  Each study can look at hundreds of thousands of genetic changes at the same time.  
Researchers use data from this type of study to find genes that may add to a person’s risk of 
developing a certain disease.  If your coded genetic and clinical information is used in such a 
study, the researcher is required to add the DNA test results and non-identifying information into 
a public research database.  This public database is called the NIH Genotype and Phenotype 
Database and it is managed by the National Center for Biotechnology Information (NCBI).  The 
NCBI will never have any information that would identify you, or link you to your information 
or research samples. 
 
A new federal law (2009), called the Genetic Information Nondiscrimination Act (GINA) 
generally makes it illegal for health insurance companies, group health plans, and employers of 
15 or more persons to discriminate against you based on your genetic information.  Health 
insurance companies and group health plans may not request your genetic information that we 
get from this research.  This means that they must not use your genetic information when making 
decisions regarding insurability.  Be aware that this new federal law will not protect you against 
genetic discrimination by companies that sell life insurance, disability insurance, or long-term 
care insurance. 
 
 


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Procedures 
 We will collect a sample of your DNA by using 4 mouth swabs on Day 0. 
 We will collect blood samples at three different dates in the study: Pre-treatment baseline 
at Day 0, and then on Day 28 and Day 56 after treatment begins.   
 The amount of blood collected from you is small – about 2 teaspoons (10-12mL) each 
time. 
 These samples will be used for protocol-defined studies and may also be stored 
indefinitely for future research.  
 
Withdrawal 
If you agree to allow your blood and DNA samples to be used for research, you can change your 
mind at any time.  If you change your mind, please contact [the Principal Investigator at your 
transplant center] in writing to state that you are withdrawing permission for your blood to be 
used for research.  His/her mailing address is on the first page of this Consent Form.  Any unused 
tissue will be destroyed if you withdraw your permission.  If you choose not to participate in 
this additional research there will be no change in your care. 
 
Benefits 
You will not benefit directly from providing blood and DNA samples for this study. 
 
Risks 
There are no major risks associated with drawing blood.  Having your blood drawn can be 
uncomfortable and can sometimes cause a bruise.  In rare cases, it can cause fainting.  Only 
trained people will draw your blood. 
 
Confidentiality and Your Medical Information 
The results of GVHD research done with your blood and DNA will not be part of your medical 
record and will not be shared with you. 
 
If you agree to allow your blood and DNA samples to be used for research, they will be collected 
confidentially and your name will not be on the tubes.  Only the study doctors or staff working 
with them will study the results from your blood and DNA samples. 
 
Information gained from research on your blood and DNA may be used to develop of diagnostic 
procedures or new treatments for GVHD in the future.  Your blood will not be sold to any 
person, institution, or company for financial gain or profit. 
 
Making Your Choice 
Please read each sentence below and think about your choice.  After reading each sentence, make 
your selection by checking one of the boxes.  If you have any questions, please talk to your 
doctor or nurse, or call our research review board at [IRB's phone number]. 
 


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No matter what you decide to do, it will not affect your care. 
 
 
I agree to allow my blood and DNA to be used for future research. 
 
 
I do not agree to allow my blood and DNA to be used for future research. 
 
 
 
 
 
 
 
Signature 
Date 
 


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Health Insurance Portability and Accountability Act 1 (HIPAA1) Authorization to use and 
disclose individual health information for research purposes 
 
A. Purpose:   
As a research participant, I authorize the Principal Investigators and the researcher’s staff to 
use and disclose my individual health information for the purpose of conducting the research 
study:  
A Multi-Center, Randomized, Double Blind, Phase III Trial Evaluating Corticosteroids with 
Mycophenolate Mofetil vs. Corticosteroids with Placebo as Initial Systemic Treatment of 
Acute GVHD. 
 
B. Individual Health Information to be Used or Disclosed 
My individual health information that may be used or disclosed to do this research includes:  
 Demographic information (for example: date of birth, sex, weight)  
 Medical history (for example: diagnosis, complications with prior treatment) 
 Findings from physical exams 
 Laboratory test results obtained at the time of work up and after treatment (for example: 
blood tests, biopsy results)  
 
C. Parties Who May Disclose My Individual Health Information  
The researcher and the researcher’s staff may collect my individual health information from: 
(List hospitals, clinics or providers from which health care information can be requested). 
 
D. Parties Who May Receive or Use My Individual Health Information 
The individual health information disclosed by parties listed in item c and information 
disclosed by me during the course of the research may be received and used by the following 
parties: 
 
 Principal Investigator and the researcher’s staff 
Dr. Javier Bolaños Meade, Principal Investigator  
Dr. Vincent T. Ho, Co-Principal Investigator  
 National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute 
(NCI), both of the National Institutes of Health (NIH)  
 Study sponsors  
Blood and Marrow Transplant Clinical Trials Network (BMT CTN), data and 
coordinating center 
 
 U.S. government agencies that are responsible for overseeing research such as the Food 
and Drug Administration (FDA) and the Office of Human Research Protections (OHRP) 
 
 
1 HIPAA is the Health Insurance Portability and Accountability Act of 1996, a federal law related to privacy of health 
information 


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 U.S. government agencies that are responsible for overseeing public health concerns such 
as the Centers for Disease Control (CDC) and federal, state and local health departments. 
E. Right to Refuse to Sign this Authorization  
I do not have to sign this Authorization.  If I decide not to sign the Authorization, I will not 
be allowed to participate in this study or receive any treatment related to research that is 
provided through the study.  My decision not to sign this authorization will not affect any 
other treatment, payment, or enrollment in health plans or eligibility for benefits.   
F. Right to Revoke   
I can change my mind and withdraw this authorization at any time by sending a written 
notice to the Principal Investigator to inform the researcher of my decision. If I withdraw this 
authorization, the researcher may only use and disclose the protected health information 
already collected for this research study.  No further health information about me will be 
collected by or disclosed to the researcher for this study. 
 
G. Potential for Re-disclosure  
My individual health information disclosed under this authorization may be subject to re-
disclosure outside the research study and no longer protected. Examples include potential 
disclosures for law enforcement purposes, mandated reporting or abuse or neglect, judicial 
proceedings, health oversight activities and public health measures. 
 


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H. This authorization does not have an expiration date. 
 
 
TITLE: 
A Multi-Center, Randomized, Double Blind, Phase III Trial Evaluating 
Corticosteroids with Mycophenolate Mofetil vs. Corticosteroids with Placebo as 
Initial Systemic Treatment of Acute GVHD 
 
I have read and understood this Consent Form.  The nature and purpose of the research study has 
been explained to me.  I understand that I will be given a copy of this signed Consent Form 
 
 
 
 
 
 
 
 
Participant Name 
Date 
 
 
 
 
 
 
 
 
Participant Signature 
Date 
 
 
 
I certify that I have provided a verbal explanation of the details of the research study, including 
the procedures and risks.  I believe the participant has understood the information provided. 
 
 
 
 
 
 
 
 
Counseling Physician 
Date 
 
 
 
 
 
 
 
 
Signature of Counseling Physician 
Date 
 


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Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
Information & Assent Form 
 
Initials _____________ 
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Assent to Participate in Research 
 
 
 
 
 
 
 
 
 
Study Title: A Multi-Center, Randomized, Double Blind, Phase III Trial Evaluating 
Corticosteroids with Mycophenolate Mofetil vs. Corticosteroids with Placebo as 
Initial Systemic Treatment of Acute GVHD 
 
Protocol: 
0802 
 
 
A. Why am I here? 
We are inviting you to join our study because you have acute graft-versus-host disease 
(GVHD).  We want to learn if a new drug works better than the current drug we use to treat 
GHVD. 
 
GVHD happens when your donor cells from your transplant attack parts of the body like 
your skin, stomach or liver.  Both kids and adults can get GVHD.  It can be a very serious 
problem for some people. 
 
 
B. Why are you doing this study? 
We are doing this study because we want to learn if a single drug or a combination of drugs 
work better to get rid of graft-versus-host disease (GVHD). 
 Prednisone with a sugar pill (placebo) or 
 Prednisone with MMF (mycophenate mofetil). 
 
 
C. What will happen to me? 
If you say you want to be in the study, we will ask you for several things: 
 Permission to let us read your medical records and x-rays.  
 Check-ups with the study doctors.  
 Some blood from you (about 12 teaspoons).  A very small needle will be used to get 
blood.  
 We may also need a small piece (biopsy) of your skin, so we can study changes in 
your skin.  If you agree to this, we will use numbing medicine before we take a small 
piece of skin with a special tool called a “punch.” 


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Everyone in the study will take prednisone. 
 
You will also take MMF or sugar pills (placebos).  The doctors use a computer to choose 
which one. You will not know which drug you will take.  The computer will keep it a secret 
from everyone, including the study doctors.  If you get very sick, your study doctors can find 
out from the computer which drugs you take. 
 
You will take the MMF or sugar pills 3 times a day for up to 8 weeks.  If it is hard to 
swallow, the doctors can use a small needle to give it through your vein (IV) or your central 
line. 
 
Once you finish taking the drugs, you will have about 4 more check-ups with either the study 
doctors or your regular doctor over the next 12 months.   
 
We will watch you carefully for fevers, any sign of infection or other problems. 
 
 
D. Will it hurt? 
When you have your blood taken with a needle, it may feel like a pinch.  It will hurt for a 
minute and sometimes the place where the needle went might be red and sore. You might get 
a little bruise where the blood was taken but it goes away in a few days. 
 
If you have a skin biopsy, the numbing medicine burns when it goes in, but only for a few 
seconds.  When the numbing medicine wears off, there may be some mild pain.  It will leave 
a small scar. 
 
 
E. Will the study help me? 
We don’t know if the study will help you or not.  Your GVHD may stay the same, it may get 
better, or it may get worse. 
 
 
F. What if I have questions? 
You can ask any questions that you have about the study.  If you forget to ask a question and 
think of it later, you can call me [insert office number].  You can also ask your question the 
next time you see me. 
 
You can call the study office at any time to ask questions about the study. 
 
 
G. Do I have to be in this study? 
If you don’t want to be in the study, you need to tell us and your parent or guardian.  Your 
doctor will not be angry or upset if you don’t want to join.   
 
Whether you are in the study or not, you will still need to have treatment for your GVHD. 
 


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Version 3.0 dated January 31, 2011 
 
 
Information & Assent Form 
 
Initials _____________ 
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You can say yes now and change your mind at any time.   
 
Please talk this over with your parent or guardian before you decide if you want to be in the 
study.  We will also ask your parents to give their permission for you to join this study.  
 
Use of Blood and DNA Samples 
Some of your blood will be used to test for GVHD.  Some of your blood and a sample of cells 
from inside your cheek (DNA) will be saved for future studies.  To be in the study, you must 
agree to have your blood used for GVHD and other regular tests but you do not have to agree to 
have your blood or cheek cells (DNA) used in future studies. 
 
Please check one of the boxes below to show how you want your blood and cheek cells (DNA) 
to be used. 
 
 Yes, you may use my blood and cheek cell (DNA) samples for this study and future 
studies of GVHD. 
 No, you may not use my blood and cheek cell (DNA) samples. 
 
Writing your name on this page means that you agree to be in the study, and know what will 
happen to you.  If you decide to quit the study, all you have to do is tell the person in charge. 
 
You and your parent or guardian will get a copy of this form after you sign it. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Child 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Researcher 
 
 
 
 
 
Date 
 
 
 
 
 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
 
APPENDIX C 
 
LABORATORY PROCEDURES 
 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
C-1 
APPENDIX C 
 
LABORATORY PROCEDURES 
 
 
Research Specimens 
BMT CTN research samples collected in this protocol will be used for both protocol-defined 
testing as well as future, undefined research supporting the protocol.  All research sample 
aliquots will be given unique bar code designations that cannot be linked back to the recipient. 
Laboratory test results, clinical information, etc., associated with the coded samples are provided 
to the Investigator only after completion of the protocol.  Samples sent to researchers cannot be 
linked with any remaining samples at the repository. 
 
Patient samples will be collected both prior to the initiation of treatment and at two post-
treatment time points as specified below. 
¾ Peripheral Blood Sample (Pre-treatment: Day 0) – Whole Blood, Plasma 
¾ Buccal Swab Samples (Pre-treatment: Day 0) – Patient DNA  
¾ Peripheral Blood Samples (Post-treatment:  Day 28, and 56) –Plasma 
 
Samples processed into frozen cryovial aliquots will be shipped to the BMT CTN Repository on 
an annual basis in compliance with the shipping procedures specified in the BMT CTN MOP and 
the 0802 Laboratory Sample Guide. 
 
Biomarker Panel Testing 
For these studies, plasma samples collected on Day 0 and Day 28 post-treatment will be shipped 
from the BMT CTN Repository to the project laboratory and analyzed for a 4-protein biomarker 
panel.  The results from previous discovery and validation studies suggested that the panel of 
four biomarkers can confirm the diagnosis of aGVHD in patients at onset of clinical symptoms 
of aGVHD and provide prognostic information independent of aGVHD severity.  The plasma 
protein biomarker panel will include at minimum: interleukin-2-receptor-alpha, tumor-necrosis-
factor-receptor-1, interleukin-8, and hepatocyte growth factor (recent data would support the 
addition of elafin/trappin-2 to this panel).  Test panel and project laboratory to be finalized by the 
Protocol Team as additional on-going study reviews are completed and results discussed with 
principal investigators.  Donor chimerism results recorded at the time nearest to each sample 
collection will be noted. 
 
Future GVHD Studies 
Remaining Day 0 and Day 28 plasma sample aliquots will be stored along with additional Day 
56 plasma sample aliquots for future GVHD-related biomarker studies.  Additionally, whole 
blood collected from the patient on Day 0 (representing essentially donor DNA) and buccal 
swabs for DNA from the patient will be collected, frozen and stored for future GVHD-related 
biomarker studies. 
 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
C-2 
TABLE C-1: COLLECTION AND SHIPPING PROCEDURES AND COLLECTION 
SCHEDULE FOR PATIENT BLOOD SAMPLES FOR PROTOCOL-DEFINED 
BIOMARKER TESTING AND FOR FUTURE, UNDEFINED RESEARCH 
 
 
TIME 
POINTS 
COLLECTION 
OF SAMPLE 
TYPE OF PROCESSING 
AND STORAGE 
SPECIMEN 
TO BE 
SHIPPED 
PURPOSE 
OF 
SAMPLE 
SHIPPING 
SPECIFICATIONS 
Day 0 
6 mL peripheral 
blood (one 6 mL 
fill EDTA 
lavender-top tube) 
Source of Donor 
DNA 
Gently mix one of the 6 ml pre-
treatment blood tubes by gently 
inverting the tube for 60 seconds.  
Pipette a 1.0 mL aliquot of the 
whole blood into each of 6 cryovials 
and freeze at -70ºC in a scientific 
grade freezer. 
Whole 
Blood 
 
Future 
GVHD 
Studies 
Batch ship yearly, frozen on 
dry ice in a provided shipping 
container, FedEx priority 
overnight to the BMT CTN 
Repository. 
6 mL peripheral 
blood (one 6 mL 
fill EDTA 
lavender-top tube) 
 
Centrifuge the EDTA containing 
whole blood samples at 1000-1300 
x g or 2100 rpm for 10 minutes 
within 60 minutes of collection.  
Remove the separated plasma.  
Transfer ȝ/ aliquots to 4-6 
cryovials and freeze at -70ºC in a 
scientific grade freezer. 
Plasma 
 
Future 
GVHD 
Studies/4-
protein 
biomarker 
panel 
Batch ship yearly, frozen on 
dry ice in a provided shipping 
container, FedEx priority 
overnight to the BMT CTN 
Repository. 
4 buccal swabs 
Source of Patient 
DNA 
Brush swab against the inside of 
your cheek for approximately 10 
seconds.  Use the same force used 
to brush your teeth. Use one swab 
per section (quadrant) of your 
cheek. The 4 swabs should be dried 
for a minimum of 2 hours before 
they are processed for long-term 
frozen storage. 
 
Each dried swab is placed into a 
separate cryovial. Cut the stick so 
that the cotton swab tip fits well 
within the cryovial. Secure the 
cryovial cap and freeze at -70ºC in a 
scientific grade freezer. 
 
Cheek Swab 
Future 
GVHD 
Studies 
Batch ship yearly, frozen on 
dry ice in a provided shipping 
container, FedEx priority 
overnight to the BMT CTN 
Repository. 
Day 28 
 
10 mL peripheral 
blood (one 10 mL 
fill EDTA 
lavender-top tube) 
 
Centrifuge the EDTA containing 
whole blood samples at 1000-1300 
x g or 2100 rpm for 10 minutes 
within 60 minutes of collection.  
Remove the separated plasma.  
Transfer ȝ/ aliquots to 6-10 
cryovials and freeze at -70ºC in a 
scientific grade freezer. 
Plasma 
Future 
GVHD 
Studies/4-
protein 
biomarker 
Batch ship yearly, frozen on 
dry ice in a provided 
shipping container, FedEx 
priority overnight to the 
BMT CTN Repository. 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
C-3 
TIME 
POINTS 
COLLECTION 
OF SAMPLE 
TYPE OF PROCESSING 
AND STORAGE 
SPECIMEN 
TO BE 
SHIPPED 
PURPOSE 
OF 
SAMPLE 
SHIPPING 
SPECIFICATIONS 
Day 56 
10 mL peripheral 
blood (one 10 mL 
fill EDTA 
lavender-top tube) 
 
Centrifuge the EDTA containing 
whole blood samples at 1000-1300 
x g or 2100 rpm for 10 minutes 
within 60 minutes of collection.  
Remove the separated plasma.  
Transfer ȝ/ aliquots to 6-10 
cryovials and freeze at -70ºC in a 
scientific grade freezer. 
Plasma 
Future 
GVHD 
Studies 
Batch ship yearly, frozen on 
dry ice in a provided shipping 
container, FedEx priority 
overnight to the BMT CTN 
Repository. 
 
 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
 
APPENDIX D 
 
DERIVATION OF A SEQUENTIAL TEST STATISTIC FOR 
CENSORED EXPONENTIAL DATA 
 
 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
D-1 
APPENDIX D 
 
DERIVATION OF A SEQUENTIAL TEST STATISTIC FOR CENSORED 
EXPONENTIAL DATA 
 
 
Background – The Sequential Probability Ratio Test 
 
Let 
)
(.,T
f
be the density function for random variable X.  According to Neyman and Pearson, 
the most powerful test of 
o
H
T
T  
:
0
 versus
1
1 :
T
T  
H
 decides in favor of 
1
H  or 
0
H if 
D
c
Ln !
 or 
D
c
Ln 
, respectively, where 

 
n
i
i
i
n
x
f
x
f
L
)
;
(
/)
;
(
0
1
T
T
is the likelihood ratio, and 
D
c is 
determined to have the size D .  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 
D
and E of 
rejecting 
0
H when 
0
T
T  
, and of accepting 
0
H when 
1
T
T  
, respectively, and the expected 
sample size 
)
(
)
|
(
N
E
N
E
j
j {
T
.  Wald and Wolfowitz showed that among all tests, sequential or 
not, for which 
D
d
)
reject 
(
Pr
0
0
H
 and 
E
d
)
reject 
(
Pr
0
1
H
, and for which 
)
(N
E j
 are finite, j=0,1, 
the SPRT with error probabilities 
D
 and E 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 
)
,
(
T
x
f
, with 
monotone likelihood ratio in 
)
(x
W
, then any SPRT for testing 
0
T against 
)
(
0
1
T
T
!
 has non-
decreasing power function. 
 
For the SPRT with error probabilities 
D
and E , the SPRT boundaries are given approximately by 
D
E /)
1( 
 
A
 and 
)
1
/(
D
E

 
B
.  The operating characteristics of the SPRT are given by 
)
/(
)1
(
)
,
,
,
,
(
)
(
)
(
)
(
1
0
T
T
T
T
T
E
D
T
h
h
h
B
A
A
O


 
 where 
)
(T
h
is the non-trivial solution to the equation 
³
 1
)
;
(
))
,
(
/)
;
(
(
)
(
2
1
dx
x
f
x
f
x
f
h
T
T
T
T
.   
 
The formula 
)
;
(
/]
log
)
(
log
)]
(
1
[[(
)
;
(
T
T
T
T
z
E
B
O
A
O
N
E


 
provides the average sample number 
for an arbitrary T .  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. 
 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
D-2 
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
T
T
T

 
)
,
(
.  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
T
1.303), and 50% 
translates into a mean survival of 0.395 years (
 
1
T
2.532). 
 
The SPRT is derived with reference to a simple null and alternative hypothesis, in this case, 
 
 
o
H
T
T
:
0
 1.303 versus
1
1 :
T
T  
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
T
T
T
T
T
T
, is a 
monotone function of ¦
n
i
iT , the power of the test is non-decreasing in T .  Thus the SPRT is a 
one-sided level .05 test of a composite null (
303
.1
:
0
 
d
o
H
T
T
) versus a composite alternative 
(
303
.1
:
1
 
t
o
H
T
T
), with power of 
80
.
1
 
 E
 at the selected alternative 
 
 
1
T
T
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
T
T
T
T
0.541, and intercepts 
 

)
/(
log
1
0
T
T
A
-2.256 
and 
 

)
/(
log
1
0
T
T
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.   
 


BMT CLINICAL TRIALS NETWORK 
 
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Version 3.0 dated January 31, 2011 
 
 
D-3 
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 
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 D  and 
E to 10% and 15%, result in empirical type I and II error rates of  about 5% and 20%.   


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
D-4 
 
Table D-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. 
 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
E-5 
APPENDIX E 
 
M.D. ANDERSON SYMPTOM INVENTORY (MDASI) 
 CORE ITEMS 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
E-1 
 
 
 


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Version 3.0 dated January 31, 2011 
 
 
E-2 
 
 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
 
APPENDIX F 
 
REFERENCES 
 
 
 


BMT CLINICAL TRIALS NETWORK 
 
Acute GVHD Treatment – Protocol 0802 
Version 3.0 dated January 31, 2011 
 
 
F-1 
APPENDIX F 
 
REFERENCES 
 
 
 
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4 MacMillan ML, Weisdorf DJ, Wagner JE et al. Response of 443 patients to steroids as primary 
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F-2 
 
14 Lee SJ, Zahrieh D, Agura E et al. Effect of up-front daclizumab when combined with steroids 
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after reduced-intensity conditioning. Blood 2003; 102(5):1915-1919. 


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Version 3.0 dated January 31, 2011 
 
 
F-3 
 
26 Le Meur Y, Buchler M, Thierry A, Caillard S, Villemain F, Lavaud S, et al.  Individualized 
mycophenolate mofetil dosing based on drug exposure significantly improves patient out-
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efficacy and safety of monitored MMF in combination with CNI in renal transplantation at 12 
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28 Paczesny S, Krijanovski OI, Braun TM et al. A biomarker panel for acute graft versus host 
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