Conditions: Sickle Cell Disease
Keywords: Sickle Cell Disease Young Adults Phase II Trial Hematopoietic Cell Transplantation (HCT) Human Leukocyte Antigen (HLA)
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 138
Healthy volunteers: no

Brief summary:
This is a clinical trial that will compare survival and sickle related outcomes in adolescents and young adults with severe sickle cell disease after bone marrow transplantation and standard of care. The primary outcome is 2-year overall survival.

Detailed description:
This is a prospective phase II multi-center trial of hematopoietic stem cell transplantation or standard of care based on availability of HLA-matched related or unrelated donor after confirmation of clinical eligibility. In order to minimize bias assignment to either treatment arm, clinical eligibility to both treatment arms are similar and donor availability is not known at referral. HLA typing and donor search is initiated upon confirmation of clinical eligibility for the study. Additionally, all analyses of primary and secondary endpoints will follow the Intent-to-Treat principle to address potential bias introduced by participants with donors not proceeding to transplantation or those without a matched donor receiving transplantation with less well-matched donors.

The primary outcome is 2-year overall survival. Our hypothesis is that patients who receive bone marrow transplantation will experience early deaths but that this will plateau by 2 years after transplantation. Patients who receive standard of care will not experience early death but will succumb to their disease at a rate much higher than the general population. Therefore, the goal of the study is to establish that the difference in the proportion of patients surviving is not significantly more than 15% lower in the donor arm at 2-years after assignment to treatment arm.

Secondary endpoints will compare changes in sickle cell disease related events (pulmonary hypertension, cerebrovascular events, renal function, avascular necrosis, leg ulcer) and functional outcomes \[6-minute walk distance (6MWD), health-related quality of life, cardiac function, pulmonary function, and mean pain intensity as assessed by a multidimensional electronic pain diary\] from baseline to 2-years after assignment to treatment arms.

Additionally for patients assigned to the donor arm and expected to undergo transplantation, hematopoietic recovery, graft rejection, acute and chronic graft-versus-host disease, other significant transplant-related complications and disease-free survival will be reported.

Arms:
arm 1: Donor Arm patients will undergo hematopoietic cell transplant. Patients with a matched unrelated donor will receive a bone marrow transplant (unless PBSC graft is pre-approved per section 2.5.1 using a preparative regimen with Busulfan, Fludarabine and rabbit ATG. Patients with an HLA-identical sibling donor can receive a transplant using one of three regimens:

A. Busulfan, Fludarabine, and rabbit ATG using a bone marrow graft (preferred regimen) B. Alemtuzumab/TBI 300 cGy using a peripheral blood graft C. Alemtuzumab, fludarabine, melphalan using a bone marrow graft arm 2: No-donor arm patients will continue with standard of care per their SCD physician.

Interventions: intervention 1: Busulfan intervention 2: Fludarabine intervention 3: r-ATG intervention 4: Hematopoietic Cell Transplant intervention 5: Tacrolimus intervention 6: Methotrexate intervention 7: Standard of Care intervention 8: Alemtuzumab intervention 9: Total Body Irradiation (TBI) intervention 10: Sirolimus intervention 11: Melphalan intervention 12: G-CSF
Intervention descriptions: intervention 1: A:

Busulfan dose will be 3.2 mg/kg administered as a single daily dose IV on days -8 through -5 with dosing adjusted using targeted pharmacokinetics. intervention 2: A:

Fludarabine dose will be 35 mg/m\^2/day administered IV on days -7 through -3 (total fludarabine dose is 175 mg/m\^2).

C:

Fludarabine 30mg/m2 IV dose will be given on Days -8, -7, -6, -5, -4 intervention 3: A:

r-ATG will be administered IV on day -6 at 0.5mg/kg, on day -5 at 1 mg/kg and on days -4, -3 and -2 at 1.5mg/kg (total r-ATG dose is 6 mg/kg). intervention 4: A,B,C:

Day 0 is the day of transplantation. intervention 5: A:

Tacrolimus commences on day -3 and extends through day +180 after transplantation with doses adjusted to maintain appropriate levels according to institutional guidelines.

C:

Tacrolimus at therapeutic doses through Day 180, then taper per institutional guidelines intervention 6: A:

Methotrexate will be administered intravenously on day+1 at 15mg/m\^2, day+3 at 10mg/m\^2, day+6 at 10mg/m\^2, and day+11 at 10mg/m\^2.

C:

Methotrexate IV 7.5 mg/m2 dose will be given on Days +1, 3, +6 following transplant intervention 7: Continue to receive standard of care treatment per patient's SCD physician. intervention 8: B:

Alemtuzumab 0.03 mg/kg IV dose will be given on Day -7, Alemtuzumab 0.1 mg/kg IV dose will be given on Day -6, Alemtuzumab 0.3 mg/kg IV dose will be given on Day -5,-4,-3

C:

Alemtuzumab test dose 3 mg IV once 24 hours prior to 1st dose of Alemtuzumab Alemtuzumab 10 mg IV, 15 mg IV, 20 mg IV given on Days -22 through Day -18. Alemtuzumab doses may be administered between Days -22 and -18 but are required to be on three consecutive days. intervention 9: Total Body Irradiation 300 cGY on Day -2 intervention 10: Sirolimus at therapeutic doses through day 180, then taper per institutional guidelines if donor CD3+ \>50% intervention 11: C:

Melphalan 140 mg/m2 IV dose will be given on Day -3 intervention 12: G-CSF 5 μg/kg/day continue until neutrophil engraftment.

Protocol document:
Prot_SAP_ICF_001.pdf: 
 
CONFIDENTIAL 
 
 
 
 
A Study to Compare Bone Marrow Transplantation to 
Standard Care in Adolescents and Young Adults with 
Severe Sickle Cell Disease 
(Posted on clinicaltrials.gov as NCT02766465) 
 
BMT CTN Protocol 1503 
Version 6.0 
 
Study Chairpersons 
Lakshmanan Krishnamurti, MD1; Mark C. Walters MD2 
 
 
Data Coordinating Center 
Mary Eapen, MD, MS3 
Julie Panepinto, MD3 
Adam Mendizabal, PhD4 
Nicole Ritzau, RN4 
Kris Bornholdt4 
Donna Neuberg, ScD5 
Yiwen Liu MB5 
 
 
 
NIH/NHLBI Members 
Nancy DiFronzo, PhD6 
Nahed El Kassar, MD PhD6 
Nancy Geller, PhD6 
Marlene Peters Lawrence, RN6 
 
 
Co-Investigators
 
Andrew Campbell, MD7  
 
 
 
Wally Smith, MD14 
Laura De Castro, MD8  
 
 
 
Keith Sullivan, MD15 
John Gorscan, MD8 
 
 
 
 
Edmund Waller, MD, PhD9 
Fuad El Rassi, MD9 
 
 
 
 
Catherine J. Wu, MD5 
Nitya Bakski10  
 
 
 
 
Carlton Dampier10 
Anne Haight, MD3  
 
 
 
 
Kathryn Hassell, MD6 
Naynesh Kamani, MD11 
 
 
 
Carolyn Hoppe2 
Elizabeth Klings, MD12  
 
 
 
Allistair Abraham16 
John Levine, MD13 
 
Yale (CCC) Study Coordinators 
Karissa McLaurin, MSHS1  


 
CONFIDENTIAL 
Page i 
 
 
Sponsored by the National Institutes of Health 
National Heart, Lung, and Blood Institute 
National Cancer Institute 
 
 
1YaleUniversity  
2UCSF Benioff Children’s Hospital of Oakland  
3Medical College of Wisconsin  
4The Emmes Company  
5Dana Farber Cancer Institute 
6National Heart, Lung and Blood Institute   
7University of Michigan 
8University of Pittsburgh Medical Center  
 
9Emory University 
10Children’s Healthcare of Atlanta  
11Consultant 
12 Boston Medical Center 
13Mt Sinai Medical Center 
14Virginia Commonwealth University  
15Duke University  
16Children’s National Medical Center 
 
 
 
Approval Signatures 
Mary  Eapen
Mary Eapen
Lakshmanan  Krisnamurti
I am approving this document.
I am approving this document.
Lakshmanan Krisnamurti
I am approving this document.
Mark Walters
30/Oct/2023 02:26 PM EDT
28/Sep/2023 06:53 PM EDT
Mark  Walters
09/Oct/2023 10:14 AM EDT


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Participating Centers 
Augusta University, Augusta, GA 
Baylor Methodist Hospital, Houston, TX 
Boston University, Boston, MA 
Brigham and Women’s Hospital, Boston, MA 
Children’s Healthcare of Atlanta, GA 
Children’s Hospital & Research Center, Oakland, CA 
Children’s National Medical Center, Washington, D.C. 
Children’s Hospital of New Orleans, New Orleans, LA 
Children’s Hospital of Philadelphia, Philadelphia, PA 
Cohen Children’s Medical Center, New Hyde Park, NY 
Duke University Medical Center, Durham, NC 
Emory University Hospital, Atlanta, GA 
Foundation for Sickle Cell Disease Research (FSCDR), Miami, FL 
Grady Memorial Hospital, Atlanta, GA 
Hackensack University Medical Center, Hackensack, NJ 
Karmanos Cancer Center, Detroit, MI 
Massachusetts General Hospital, Boston, MA 
MD Anderson, Houston, TX 
Medical University of South Carolina, Charleston, SC 
Montefiore Medical Center, Bronx, NY 
Mount Sinai Hospital, New York City, NY 
Newark Beth Israel Medical Center, Newark, NJ 
New York Presbyterian Hospital, Brooklyn, NY 
Ohio State University, Columbus, OH 
Oregon Health and Science University, Portland, OR 
University of Florida, Gainesville, FL 
University of Iowa, Iowa City, IA 
University of Miami Hospital, Miami, FL 
University of North Carolina, Chapel Hill, NC 
University of Texas Health Sciences Center, Houston, TX 
University of Virginia, Charlottesville, VA 
Virginia Commonwealth University, Richmond, VA 
Washington University, St. Louis, MO 
Weill Cornell University, New York, NY 
 


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PROTOCOL SYNOPSIS – BMT CTN 1503 
v6.0 
A Study to Compare Bone Marrow Transplantation to Standard Care in Adolescents and 
Young Adults with Severe Sickle Cell Disease 
 
Co-Principal Investigators:      Lakshmanan Krishnamurti, MD, Mark C. Walters, MD 
 
Study Design: 
This study is designed as a phase II, multi-center trial of 
hematopoietic cell transplantation (HCT) versus standard of care 
in adolescents and young adults with severe sickle cell disease 
(SCD). Eligible participants are biologically assigned to HCT or 
standard of care based on the availability of HLA-matched 
related or unrelated donor after confirmation of clinical 
eligibility. Insurance coverage and donor availability are not 
known at referral or consultation. 
 
Primary Objective: 
The primary objective is to compare the overall survival (OS) at 
2 years after biological assignment between those assigned to the 
donor arm and to the no donor arm. Those assigned to the donor 
arm are expected to undergo HCT and those on the no donor arm, 
to receive standard of care supportive therapy. 
 
Secondary Objectives: 
Secondary objectives will compare changes in SCD related 
events (pulmonary hypertension, cerebrovascular events, renal 
function, avascular necrosis, leg ulcer) and functional outcomes 
[6-minute walk distance (6MWD), health-related quality of life 
(HRQoL), cardiac function, pulmonary function, and mean pain 
intensity as assessed by a multidimensional electronic pain diary 
from baseline to 2-years after assignment to treatment arms. 
Additionally, some outcomes will also be measured at 1 year. 
Baseline, 1- and 2-year assessments will be done at the same sites 
to minimize variability. Secondary objectives for the donor arm 
include neutrophil recovery, platelet recovery, graft failure, 
chimerism, acute and chronic graft-versus-host disease, 
idiopathic pneumonia syndrome, veno-occlusive disease, and 
central nervous system toxicity. 
 
Eligibility Criteria: 
Eligible patients are ≥ 15 and < 41 years of age with severe sickle 
cell disease [any clinically significant sickle genotype, for 
example, Hemoglobin SS (Hb SS), Hemoglobin SC (Hb SC), 
Hemoglobin S Beta thalassemia (Hb Sβ), or Hemoglobin S-
OArab genotype] with at least one of the following 
manifestations: 


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a. Clinically 
significant 
neurologic 
event 
(stroke) 
or 
neurological deficit lasting > 24 hours; 
b. History of two or more episodes of acute chest syndrome 
(ACS) in the 2-year period preceding enrollment or referral 
despite adequate supportive care measures (i.e., asthma 
therapy); 
c. An average of three or more pain crises per year in the 2- 
year period preceding enrollment or referral (required 
intravenous pain management in the outpatient or inpatient 
hospital setting); 
d. Administration of regular red blood cell (RBC) transfusion 
therapy, defined as 8 or more transfusion events per year (in 
the 12 months before enrollment) to prevent vaso-occlusive 
clinical complications (i.e., pain, stroke, or acute chest 
syndrome); 
e. An echocardiographic finding of tricuspid valve regurgitant 
jet(TRJ)velocity≥2.7 m/sec. 
f. Ongoing high impact1 chronic pain on a majority of days per 
monthfor ≥6monthsasdefinedasONE ormore ofthe
following: Chronic pain without contributory SCD 
complications2, OR Mixed pain type in which chronic pain 
is occurring at site(s) (arms, back, chest, or abdominal pain) 
unrelated to any sites associated with Contributory SCD 
complications2 (e.g. leg ulcers and/or avascular necrosis). 
 
Adequate physical function as defined by all of the following: 
a. Karnofsky/Lanskyperformancescore≥to 60; 
b. Cardiac function: Left ventricular ejection fraction (LVEF) 
> 40%; or LV shortening fraction > 26% by cardiac 
echocardiogram or by MUGA scan; 
c. Pulmonary function: Pulse oximetry with a baseline O2 
saturation of ≥ 85% and DLCO > 40% (corrected for 
hemoglobin); 
d. Renalfunction:Serumcreatinine≤1.5xtheupperlimitof 
normal for age as per local laboratory and one of the 
following: creatinine clearance > 70 mL/min calculated 
using the CockcroftGault calculator, creatinine clearance > 
 
1High impact chronic pain is identified as those reporting “severe interference” with life activities OR “usually or 
always” experiencing a limitation of their life or work activities including household chores. (See guidelines for 
identifying HICP in the BMT CTN 1503 Manual of Procedures) 
2Contributory SCD complications are defined as clinical signs (e.g., presence of leg ulcers) or clinical assessments 
(e.g., imaging confirmation of splenic infarct or avascular necrosis). Chronic pain attributed solely to contributory 
SCD complications is excluded. 


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70 mL/min by 24-hour urine (preferred), or GFR > 70 
mL/min/1.73 m2 by radionuclide GFR; 
e. Hepatic function: ALT and AST < 5 times upper limit of 
normal as per local laboratory; serum conjugated (direct) 
bilirubin ≤ 2x upper limit of normal for age as per local 
laboratory Participants are not excluded if the serum 
conjugated (direct) bilirubin is >2x the upper limit of normal 
for age as per local laboratory and: There is evidence of a 
hyperhemolytic reaction after a recent RBC transfusion, OR 
there is evidence of moderate direct hyperbilirubinemia 
defined as direct serum bilirubin < 5 times ULN and not 
caused by underlying hepatic disease. 
 
Additional inclusion required for donor arm participants to 
proceed with transplant: 
a. Liver MRI (≤ 90 days prior to initiation of transplant
conditioning) to document hepatic iron content is required 
forparticipantswhoarecurrentlyreceiving≥8packedred
blood cell transfusions for ≥1 year or have received ≥20
packed red blood cell transfusions (cumulative). Participants 
whohavehepaticironcontent≥7mgFe/gliverdryweight
by liver MRI must have a liver biopsy and histological 
examination/documentation of the absence of cirrhosis, 
bridging fibrosis1,andactivehepatitis(≤90dayspriorto
initiation of transplant conditioning). 
b. Lack of clinical or radiologic evidence of a recent neurologic 
event (such as stroke or transient ischemic attack) by 
Cerebral MRI/MRA within 30 days prior to initiating 
transplant conditioning. Subjects with clinical or radiologic 
evidence of a recent neurologic event will be deferred for ≥ 
6 months with repeat cerebral MRI/MRA to ensure 
stabilization of the neurologic event prior to proceeding to 
transplantation 
c. Documentation of participant’s willingness to use approved 
contraception 
method 
until 
discontinuation 
of 
all 
immunosuppressive medications is to be documented in the 
medical record corresponding with the consent conference. 
 
 
 
Exclusion Criteria: 
 
1. HLA typing with donor search prior to referral (consultation 
with HCT physician). 
 
 
1The absence of bridging fibrosis will be determined using the histological grading and staging scale as described by 
Ishak and colleagues as described in the Manual of Operating Procedures. 


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a. If a subject has had HLA typing and a related donor 
search that did not identify a suitably matched relative 
(i.e., sibling) at any time, and also did not have an 
unrelated donor search, the patient will be considered 
eligible. 
b. If a subject has had HLA typing and a related donor 
search that did not identify a suitably matched relative 
(i.e., sibling) at any time and had an unrelated donor 
search that did not identify a suitably matched unrelated 
donor≥1yearpriortoenrollment,thepatientwillbe
considered eligible. 
c. If a subject has had HLA typing with no related donor 
search and had an unrelated donor search that did not 
identify a suitably matched unrelated donor ≥ 1 year
prior to enrollment, the patient will be considered 
eligible. 
d. Subjects with a known HLA-identical sibling or HLA- 
matched unrelated donor are excluded 
2. Uncontrolled bacterial, viral or fungal infection; 
3. Seropositivity for HIV; 
4. Previous HCT or solid organ transplant; 
5. Participation in a clinical trial in which the patient receives 
an investigational drug or device must be discontinued prior 
to date of enrollment; 
6. A history of substance abuse as defined by version IV of the 
Diagnostic & Statistical Manual of Mental Disorders (DSM 
IV);1 
7. Demonstrated lack of compliance with prior medical care as 
determined by referring physician; 
8. Pregnant or breast feeding females; 
9.  Inability to receive HCT due to alloimmunization, defined 
as the inability to receive packed red blood cell (pRBC) 
transfusion therapy; 
 
Treatment Description: 
Donor arm: All donor arm patients receiving an unrelated donor 
HCT will receive busulfan, fludarabine, and r-ATG as their 
preparative regimen using  a bone marrow  graft. For donor arm 
 
 
1American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. (4th 
ed.). Washington, DC American Psychiatric Association. 


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GVHD prophylaxis 
patients receiving a related donor HCT, there are 3 acceptable 
preparative regimens for this study: 
a. Regimen A: Busulfan/Fludarabine/r-ATG using a bone 
marrow graft (preferred regimen) 
b. Regimen B: Alemtuzumab/TBI 300 cGy using a peripheral 
blood graft 
c. Regimen C: Alemtuzumab/Fludarabine/Melphalan using a 
bone marrow graft 
The preparative regimen to be used for HLA-identical sibling 
transplants must be declared to the DCC by the site and used for 
all HLA-identical sibling transplants at that site. 
 
a. GVHD prophylaxis for patients receiving an unrelated 
donor transplant or Conditioning Regimen A: Tacrolimus 
commences on day -3 and extends through day +180 after 
transplantation, with methotrexate (MTX) administered 
intravenously on days +1 (15mg/m2), +3 (10mg/m2), +6 
(10mg/m2) and +11 (10mg/m2). Patients unable to tolerate 
tacrolimus may receive cyclosporine. 
b. GVHD prophylaxis for Conditioning Regimen B: Sirolimus 
commences on day -1 and extends through day +180 after 
transplantation or until donor CD3+ chimerism >50%, 
whichever is later 
c. GVHD prophylaxis for Conditioning Regimen C: 
Tacrolimus commences on day -3 and extends through day 
+180 after transplantation, with methotrexate (MTX) 7.5 
mg/m2 administered intravenously on days +1, +3, and +6. 
Patients unable to tolerate tacrolimus may receive 
cyclosporine. 
 
No-donor arm: Will continue with standard of care per their 
SCD physician. 
 
Primary Endpoint: 
The primary endpoint is a comparison of the difference in the 
observed proportion of patients surviving at 2 years post 
biological assignment between the two treatment arms. Biologic 
assignment will occur ≤ 180 days after eligibility is confirmed by 
enrollment or the eligibility review committee (ERC). 
Participants will remain in their assigned treatment arm for 
analysis of all endpoints (intent-to-treat [ITT] principle). 


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Secondary Endpoints: 
Comparison of SCD-related events and functional assessments 
by administering the 6MWD test, HRQoL and a 28-day e-pain 
diary to capture mean pain intensity. The secondary endpoints 
will examine changes between baseline, 1- year, and 2-years 
between participants on the donor and no donor arms. All 
baseline, 1-, and 2-year tests will be conducted at the same 
institution (to minimize variability). 
 
Accrual Objective: 
The sample size for the donor arm is fixed at 60 participants. 
Based on donor availability for ~30% of participants the sample 
size for the no donor arm is anticipated to be 140. 
 
Accrual Period: 
3 years. 
 
Study Duration: 
Participants will be followed for 2 years from time of biological 
assignment. Overall survival outcomes will continue to be 
measured between years 3 and 10. 
 
Interim Analysis: 
There will be no interim analyses for efficacy. 
 
Stopping Guidelines: 
Patients on the donor arm will be monitored for mortality at day 
100 and 1-year post transplant and graft rejection at day 100 post 
transplant. The stopping rules for unacceptable day 100 mortality 
considers all patients together and for 1-year mortality, separately 
for HLA-matched related and unrelated donor transplants. For 
day 100 graft rejection, patients will be considered separately for 
HLA-matched related and unrelated donor transplants. 


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Study Design 


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Treatment Schema – Donor Arm 
Unrelated Donor Transplant Conditioning Regimen, 
and HLA-identical Sibling Transplant Conditioning Regimen A 
Days 
Treatment 
-8 
IV busulfan 3.2 mg/kg 
-7 
IV busulfan 3.2 mg/kg, fludarabine 35 mg/m2 
-6 
IV busulfan 3.2 mg/kg, fludarabine 35 mg/m2, r-ATG 0.5 mg/kg
-5 
IV busulfan 3.2 mg/kg, fludarabine 35 mg/m2, r-ATG 1.0 mg/kg
-4 
IV fludarabine 35 mg/m2, r-ATG 1.5 mg/kg 
-3 
IV fludarabine 35 mg/m2, r-ATG 1.5 mg/kg 
-2 
r ATG 1.5 mg/kg 
-1 
Rest day 
0 
Infusion of bone marrow 
 
GVHD Prophylaxis for the Unrelated Donor Transplant Conditioning Regimen 
and HLA-identical Sibling Transplant Conditioning Regimen A 
Days 
Prophylactic Agent 
-3 through +180 
Tacrolimus, begin taper +180 per institutional guidelines 
0 
Infusion of bone marrow 
+1 
IV methotrexate 15 mg/m2 
+3 
IV methotrexate 10 mg/m2 
+6 
IV methotrexate 10 mg/m2 
+11 
IV methotrexate 10mg/m2 
 
HLA-identical Sibling Transplant Conditioning Regimen B 
Days 
Treatment 
-7 
IV Alemtuzumab: 0.03 mg/kg 
-6 
IV Alemtuzumab: 0.1 mg/kg 
-5 
IV Alemtuzumab: 0.3 mg/kg
-4 
IV Alemtuzumab: 0.3 mg/kg
-3 
IV Alemtuzumab: 0.3 mg/kg 
-2 
TBI 300 cGy with testicular shielding 
-1 
Rest day 
0 
Infusion of mobilized PBSC 


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GVHD Prophylaxis for Conditioning Regimen B 
Days 
Prophylactic Agent 
-1 through +180 
Sirolimus, begin taper +180 per institutional guidelines if donor 
CD3+ >50% 
 
HLA-identical Sibling Transplant Conditioning Regimen C 
Days 
Treatment 
-22 
IV Alemtuzumab: 3 mg test dose 
-21 
IV Alemtuzumab: 10 mg 
-20 
IV Alemtuzumab: 15 mg
-19 
IV Alemtuzumab: 20 mg
-8 
IV Fludarabine 30 mg/m2 
-7 
IV Fludarabine 30 mg/m2 
-6 
IV Fludarabine 30 mg/m2 
-5 
IV Fludarabine 30 mg/m2 
-4 
IV Fludarabine 30 mg/m2 
-3 
IV Melphalan 140 mg/m2 
-2 
Rest Day 
-1 
Rest day 
0 
Infusion of bone marrow 
 
GVHD Prophylaxis for Conditioning Regimen C 
Days 
Prophylactic Agent 
-3 through +180 
Tacrolimus, begin taper +180 per institutional guidelines 
0 
Infusion of bone marrow 
+1 
IV methotrexate 7.5 mg/m2 
+3 
IV methotrexate 7.5 mg/m2 
+6 
IV methotrexate 7.5 mg/m2 


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ABBREVIATIONS 
 
ACA
Affordable Care Act
HLA
Human Leukocyte Antigen
ACS
Acute Chest Syndrome
HRQoL
Health-Related Quality of Life
AE
Adverse Event
HU
Hydroxyurea
AjBW
Adjusted Body Weight
IBW
Ideal Body Weight
ANC
Absolute Neutrophil Count
ICU
Intensive Care Unit
ATG
Anti-thymocyte Globulin
ITT
Intent to Treat
AUC
Area Under Curve
IPS
Idiopathic Pneumonia Syndrome
BMT
Bone Marrow Transplant
IV
Intravenous
BU
Busulfan
MOP
Manual of Procedures
CBC
Complete Blood Count
MSH
Multicenter Study of Hydroxyurea
CCC
Clinical Coordination Center
6MWD
6 Minute Walk Distance
CIBMTR
Center for International Blood and NHLBI
National Heart Lung & Blood
Marrow Transplant Research
Institute
CMS
Center for Medicare and Medicaid
NIH
National Institutes of Health
Services
NMA
Non-myeloablative
CMV
Cytomegalovirus
NMDP
National Marrow Donor Program
CNS
Central Nervous System
OS
Overall Survival
CR1
Complete Remission 1
PCR
Polymerase Chain Reaction
Css
Concentration at Steady State
PFT
Pulmonary Function Test
CTCAE
Common Terminology for
PI
Principal Investigator
Adverse Events
PRES
Posterior Reversible
CTN
Clinical Trials Network
Encephalopathy Syndrome
CY
Cyclophosphamide
RCT
Randomized Clinical Trial
DCC
Data Coordinating Center
RBC
Red Blood Cell
DSMB
Data Safety Monitoring
SAE
Serious Adverse Event
Committee
SCD
Sickle Cell Disease
EBV
Epstein-Barr Virus
SCD-EOSI Sickle Cell Disease related event
EDC
Electronic Data Capture
of special interest
EFS
Event Free Survival
SPRT
Sequential Probability Ratio Test
ERC
Eligibility Review Committee
STRIDE
Sickle Cell Transplantation to
FEV1
Forced Vital Capacity 1 second
Prevent Disease Exacerbation in
FLU
Fludarabine
Young Adults
FVC
Forced Vital Capacity
TBI
Total Body Irradiation
GEE
Generalized Estimating Equation
TLC
Total Lung Capacity
GVHD
Graft-versus-Host Disease
TRJV
Tricuspid Regurgitant Jet Velocity
HbSC
Hemoglobin SC
TRM
Transplant Related Mortality
HbSS
Hemoglobin SS
UCB
Umbilical Cord Blood
HbSβ
S Betathalassemia(Sβ)genotype
URD
Unrelated Donor
HCT
Hematopoietic Cell
VOD
Veno-occlusive Disease
Transplantation


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Table of Contents 
 
1. 
BACKGROUND AND RATIONALE .......................................................................... 1 
1.1. 
Introduction ................................................................................................................................ 1 
1.2. 
Rapid Disease Progression in Adults with SCD ........................................................................ 1 
1.3. 
Lack of Curative -Treatments for Adults with SCD .................................................................. 2 
1.4. 
Rationale for Proposed Study .................................................................................................... 3 
1.5. 
STRIDE Consortium .................................................................................................................. 6 
2. 
STUDY DESIGN ......................................................................................................... 11 
2.1. 
Study Overview ....................................................................................................................... 11 
2.2. 
Hypothesis and Specific Objectives ......................................................................................... 11 
2.3. 
Patient Eligibility ..................................................................................................................... 12 
2.4. 
Trial Design, Screening, and Biological Assignment .............................................................. 15 
2.5. 
Donor Selection Criteria .......................................................................................................... 17 
2.6. 
Treatment Plan for Patients Assigned to the No Donor Arm ................................................... 18 
2.7. 
Treatment Plan for Patients Assigned to the Donor Arm (HCT) ............................................. 18 
2.8. 
Graft Failure ............................................................................................................................. 29 
2.9. 
Toxicities of Hematopoietic Stem Cell Transplantation .......................................................... 30 
3. 
STUDY ENDPOINTS ................................................................................................. 33 
3.1. 
Primary Endpoint ..................................................................................................................... 33 
3.2. 
Secondary Endpoints ............................................................................................................... 33 
3.3. 
Secondary Endpoints for Patients Assigned to the Donor Arm ............................................... 35 
4. 
PATIENT REGISTRATION, ENROLLMENT AND EVALUATIONS .................. 40 
4.1. 
Screening and Enrollment Procedures ..................................................................................... 40 
4.2. 
Patient Follow up and Study Assessments ............................................................................... 41 
4.3. 
Data Reporting ......................................................................................................................... 54 
4.4. 
Subject Payment....................................................................................................................... 57 
5. 
STATISTICAL CONSIDERATIONS ........................................................................ 58 
5.1. 
Study Design ............................................................................................................................ 58 
5.2. 
Accrual ..................................................................................................................................... 58 
5.3. 
Biological Assignment ............................................................................................................. 58 
5.4. 
Primary Endpoint ..................................................................................................................... 59 
5.5. 
Primary Hypothesis .................................................................................................................. 59 
5.6. 
Sample Size and Power Considerations ................................................................................... 59 
5.7. 
Interim Analysis and Stopping Guidelines .............................................................................. 60 
5.8. 
Analysis of Primary Endpoint .................................................................................................. 62 
5.9. 
Secondary Endpoints ............................................................................................................... 63 
5.10. 
Secondary Endpoints for Participants who Undergo HCT ...................................................... 66 
5.11. 
Demographics and Baseline Characteristics ............................................................................ 67 
5.12. 
Handling of Missing Data ........................................................................................................ 67 
5.13. 
Extended Follow Up ................................................................................................................ 67 


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APPENDIX A ....................................................................................................................... A-1 
APPENDIX B-1 .................................................................................................................... B-1 
APPENDIX B-2 .................................................................................................................. B-28 
APPENDIX B-3 .................................................................................................................. B-50 
APPENDIX B-4 .................................................................................................................. B-54 
APPENDIX B-5 .................................................................................................................. B-58 
APPENDIX C  ...................................................................................................................... C-1 
APPENDIX D  ...................................................................................................................... D-1 
APPENDIX E ....................................................................................................................... E-1 
APPENDIX F  ...................................................................................................................... F-1 
APPENDIX G ....................................................................................................................... G-1 
APPENDIX H ....................................................................................................................... H-1 
APPENDIX I  ........................................................................................................................ I-1 
 
 
 


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Figure 1. Steep decline in probability of 
survival in adulthood in patients with 
sickle cell disease 
 
CHAPTER 1 
 
1. BACKGROUND AND RATIONALE 
 
1.1. 
Introduction 
 
Sickle cell disease (SCD) is a hereditary anemia that affects approximately 100,000 Americans 
and millions of individuals worldwide. It is associated with early mortality and a diminished 
quality of life, with intermittent episodes of pain that are accompanied by progressive damage to 
vital organs, such as the lung, brain, spleen and kidney. Supportive health care measures instituted 
during childhood, which include newborn screening and pneumococcal prophylaxis, the 
administration of HU and regular RBC transfusions, have decreased the risk of serious infections 
and other life-threatening complications, resulting in improved survival to adulthood. This has 
shifted the demographics of SCD to a growing proportion of young adults with chronic health 
impairments. As an alternative to chronic supportive care, hematopoietic cell transplantation 
(HCT) from a human leukocyte antigen (HLA)-identical sibling donor has been used sparingly in 
children, but is curative in the majority of children treated1. This experience has been broadened 
to include alternate donors and the Blood and Marrow Transplant Clinical Trials Network (BMT 
CTN) recently completed a multicenter trial of unrelated donor HCT for children with severe SCD. 
However, there is limited experience with HCT in adults, even though the clinical need in this 
group of individuals is expanding rapidly. The possibility of conducting HCT more safely in young 
adults is strongly suggested by recent successful reports in young adults with thalassemia major 
and other hematological disorders using a reduced toxicity regimen that contain busulfan (Bu) or 
treosulfan in the preparative regimen2-5. Based in part on these results and results in our own pilot 
investigation, it is reasonable to project an acceptable safety profile after HLA-identical sibling and 
HLA-matched unrelated HCT in young adults with severe SCD, which in the long- term is 
projected to improve survival compared to adults who receive standard supportive care. 
 
1.2. 
Rapid Disease Progression in Adults with 
SCD 
 
Improved Survival of Children with 
SCD has Uncovered the Natural 
History of the Disease in Adults 
 
In 1960, SCD was a disease of childhood, and few 
survived to adulthood. Health care initiatives such as 
newborn screening, penicillin prophylaxis against 
pneumococcal sepsis and comprehensive programs 
with a focus on family education together 
dramatically improved outcomes in children with 
SCD. Currently, 90% of US newborns with SCD 
survive to 20 years of age. However, with improved 
survival to adulthood, chronic health impairments caused by 
progressive organ damage from SCD and the associated risk of 
premature death have become the dominant targets of clinical intervention for this disorder6-12. 


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Natural history studies show that in contrast to the improvements in outcomes in childhood, there 
is a rapid progression in organ damage, morbidity and premature mortality in adulthood. 
Progression of organ damage in adulthood is marked by progressive organ impairment as a 
consequence of hemolysis and vaso-occlusion. In 3 large screening studies, approximately 30% of 
patients had a tricuspid valve regurgitant jet velocity (TRV) >2.5 m/s and 10% had a TRV >3 m/s. 
In all the epidemiological studies performed to date, the risk ratio of early death in adults with a 
TRV > 2.5 m/s ranged from 9.24 to 15.9 fold9,13. Renal insufficiency with proteinuria occurs in 
70% of adults and progresses to renal failure in 11%. Abnormal pulmonary function occurs in 90% 
and progression to irreversible organ damage in 50% of patients by 50 years of age8. One third 
develop chronic pain syndrome and only 20% are employed14,15. Patients who experience a 
hemorrhagic stroke have a 26% risk of mortality within the first two-week period following the 
stroke.16 Death in adulthood is frequently related to organ damage which is not preventable or 
easily managed with current medical measures8. SCD related complications such as leg ulcers, 
stroke, priapism, avascular necrosis, anxiety, and depression further worsen the health related 
quality of life. The mortality rate of patients with SCD is 5.8-20% in the first 10 years after 
transition to adult care14,15. Premature death occurs at a median age of 38 years, a statistic that has 
not changed in 20 years8,17,18 (Figure 1). In a long-term follow-up study of patients with 
symptomatic SCD who were eligible to participate in the multicenter study of hydroxyurea (MSH), 
the annual mortality rate was 4.4 per 100 person-years among adults with SCD who satisfied 
eligibility criteria, which is 4.4%13. In another recent report, mortality was higher among those 
who have >4 pain crisis per year or those with a higher organ severity score19. Thus, if the 2-year 
mortality rate after HCT in adults is <15%, it is very likely that transplantation will confer a long- 
term survival advantage in these recipients. 
 
1.3. 
Lack of Curative -Treatments for Adults with SCD 
 
Myeloablative HLA-matched sibling HCT has excellent outcomes in children 16 years of age and 
younger. Following successful HCT there is a resolution of complications related to SCD with 
protection from episodes of pain, stroke, or acute chest syndrome and in most patients, a stable 
appearance of cerebral magnetic resonance imaging and pulmonary function tests and regeneration 
of the spleen20. The prevailing framework of clinical research in SCD shifts in the transition from 
childhood to adulthood. Among pediatric hematologists, the dominant view is that survival to 
adulthood is excellent, and that children, on average, have a very good quality of life as a result of 
supportive care measures such as antibiotics, family education, and the judicious use of 
transfusions. In addition, a great deal of effort has focused on identifying children who have high- 
risk features, so that the risk of any specific intervention might be balanced by the severity of 
disease in that individual. 
 
In contrast, the prevailing view among clinicians who care for adults is that SCD is, on average, a 
severe disease with a significant risk of sudden death and the development of chronic medical 
problems and that supportive care options for young adult patients are not adequate to address the 
overwhelming nature of this disease. Thus, clinical studies in adults with SCD have focused on 
interventions that prolong survival and improve the quality of life. Unlike children, adults with 
SCD are much more likely to have a debilitating complication. As a result, the risk/benefit ratio of 
HCT may be more favorable in adults, particularly if an approach to HCT that defines an 


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acceptable level of toxicity can be established. If successful, such an approach could significantly 
improve the outlook of many adults with SCD and broaden the therapeutic choices. 
 
1.4. 
Rationale for Proposed Study 
 
 
Novel Approaches to HCT for Hemoglobinopathies Based on a Combination of 
Reduced Intensity Conditioning and Immunosuppression 
 
Non-myeloablative (NMA) and reduced intensity conditioning regimens are now routinely used 
to establish engraftment of donor 
hematopoietic cells in adults with 
hematologic malignancies. The 
success of immunoablative but 
reduced-intensity  
regimens 
suggests that an immunologic 
barrier rather than a requirement of 
“hematopoietic 
space” 
is 
a 
primary 
factor 
to 
ensuring 
engraftment 
of 
 
donor 
hematopoietic stem cells. While 
NMA conditioning regimens have 
been successfully applied in adults 
with hematological malignancies, 
these have been far less successful 
in hemoglobin disorders. Over a 
decade ago, Lucarelli et al. 
described       the       effects      of 
conditioning regimen dose intensity on overall transplant outcome in HCT for thalassemia. 
Conditioning regimens containing less than 200 mg/kg of cyclophosphamide (CY) resulted in 
decreased transplantation-related mortality, with a concomitant increase in graft rejection.21 For 
example, in pediatric patients with class III disease, the incidence of graft rejection increased from 
10% to 30% after reducing the CY dose to 120-160 mg/kg. Sodani et al. successfully modified this 
regimen, resulting in a reduced rate of graft rejection from 30% to 8% by introducing a 
combination of intensive hypertransfusion, hydroxyurea and chelation, to reduce erythropoiesis 
and expansion of thalassemic clones well before transplantation, and by the addition of fludarabine 
(Flu) and azathioprine to increase the level of immunosuppression.22 In another series focused on 
SCD, Krishnamurti et al reduced the dose of busulfan (Bu) by 50%, substituted Flu for CY and 
included 500 cGy total lymphoid irradiation and anti-thymocyte globulin23 in the conditioning 
regimen. In this series, 6 of 7 patients had stable engraftment after HLA-ID sibling HCT and 
discontinued immunosuppression with no SCD-related symptoms at 2 to 9 years after HCT. 
Investigators from Duke University have also demonstrated encouraging results after HCT for 
SCD using the Bu-Flu backbone in 2 adults, one of whom had end stage renal disease24. Shenoy 
et al substituted the alkylator melphalan for Bu in combination with Flu and alemtuzumab and 
observed long term stable engraftment in patients with non-malignant disorders including SCD 
treated by HCT from related or unrelated donors25. Hsieh et al demonstrated stable donor 


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engraftment in adult SCD patients following non-myeloablative HCT from HLA-matched sibling 
donors. Low-dose total-body irradiation (TBI 300 cGy) and alemtuzumab were administered 
before transplantation, and sirolimus was used for GVHD prophylaxis26. However, long-term 
administration of sirolimus at a median of 30 months post HCT was necessary because patients 
developed mixed lymphohematopoietic chimerism after transplantation with a perceived risk of 
late graft rejection27. Finally, the application of haplo-identical donor transplantation is in the early 
stages of development, led by the investigative team at Johns Hopkins. Seventeen children 
received a non-myeloablative combination of ATG, fludarabine, CY and 200 cGy TBI before 
transplantation and received high-dose CY after transplant to accomplish in vivo T-cell depletion 
of alloreactive donor T-cells. While this was safe and effectively prevented severe GVHD, graft 
rejection occurred in 6 of 14 haplo-identical donor transplants28. Thus, while encouraging results 
have been observed after these non-myeloablative regimens tested in patients with sickle cell 
disease, the problems of graft rejection and a need for long-term immunosuppressive therapy after 
transplantation have not been overcome. 
 
Another approach to improve the safety profile of HCT has been to modify the myeloablative 
Bu/CY backbone of a conventional preparative regimen by substituting fludarabine for 
cyclophosphamide. This approach has successfully reduced the toxicity of the conditioning 
regimen but retains very high rates of stable donor engraftment3,4,29. Taken together, these studies 
suggest that modified preparative regimens containing a combination of myeloablative and 
immunosuppressive drugs can be safely and effectively administered in adults with non-malignant 
disorders. 
 
Safety and Efficacy of the Conditioning Regimen for HCT in Adults. 
 
Several conditioning regimens aimed at reducing the toxicity of HCT have been developed to 
support unrelated donor HCT for malignant and nonmalignant diseases (Table 1). 
 
Table 1. Summary of outcomes after Bu, Flu, ±Thymoglobulin and Bu (14)/Cy for hematological 
malignancies and thalassemia. OS- overall survival; DFS-disease free survival; TRM-Transplant related 
mortality, MRD-matched sibling donor; URD-unrelated donor; GR-graft rejection. TT-Thiotepa; Treo- 
Treosulfan 
Reference
# patients/donor 
type
Conditioning
Disease/Age range 
(median)
Outcome
Bernardo et al 
201230 
20/MRD; 40 URD
Treo (14)/TT (8)/Flu
(160) or 
Treo(14)/TT (8) 
/Flu(160)/ ATG 
Thal/ 1-37 (7 years)
OS 93%/DFS 
84% 
Russell et al 200831 
200/MRD
BU(12.8)/Flu 
(250)/rATG (4.5) 
Hem Malignancies/ 
18 – 65 (46 years) 
OS 76% / DFS 
72%/ TRM 4% 
OS 64% / DFS 
43%/ TRM 6%
Andersson et al 
200832 
148/MRD& URD
Bu (130 mg/m2 
x4d)/Flu(160)
AML/MDS/ 19 – 66 (46
years) 
TRM – 12%
La Nasa et al 20075 
53/URD
Bu(14)/TT(10)/Flu 
(160) 
Bu(14)/TT(10)/ 
Cy(120-200)
Thal/ 2 – 26 (14 years)
OS 88% / DFS 
74% 
GR 15% /TRM 
11% 


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La Nasa et al5 demonstrated that a combination of Bu/TT/CY conditioning in the initial series of 
32 patients that received unrelated related donor (URD) transplantation had a transplant related 
mortality (TRM) of 19% and an event-free survival of 69%. The Bu/TT/CY regimen was later 
replaced with Bu/Flu/TT in the subsequent series, in 17 patients who received a combination of 
Bu/Flu with thiotepa, the TRM was 0% and thalassemia free survival was 77% after HCT. 
Bernardo et al substituted busulfan with its dihydroxy derivative treosulfan and demonstrated 
updated data in 60 patients (40 URD and 20 MRD recipients) indicating an overall survival of 93% 
and thalassemia free survival of 84%30. Together, these data demonstrate incremental 
improvement in the safety of myeloablative HCT for thalassemia major in adult recipients by 
modulation of the conditioning therapy and by optimal donor selection. We also interpret these 
data to suggest that a similar approach to study the safety and efficacy of a trial of HCT following 
a conditioning regimen with Bu+Flu in patients with SCD is feasible if suitable transplant donors 
can be identified. As in the thalassemia trials cited above, we would anticipate an event-free 
survival of at least 80% using this regimen in adult recipients. 
 
The application of non-myeloablative and reduced intensity preparative regimens have been tested 
in children and adults with severe SCD as a strategy to mitigate the risk of infertility associated 
with myeloablative BU and to improve the safety profile of conditioning, particularly in adults 
with co-morbid organ function impairment related to SCD. Two conditioning regimens have 
emerged with the largest experience. The first of these was updated most recently in 2014.27 Thirty 
patients between 16 and 65 years of age received a G-CSF mobilized peripheral blood graft from 
HLA-identical sibling donors. Patients with severe SCD were prepared with a combination of 
alemtuzumab and a single fraction of 300 cGy total body irradiation (TBI). Sirolimus was 
administered for GVHD prophylaxis. Twenty-nine of 30 patients survived with a medial follow- 
up of 3.4 years and 25 (83%) had full donor-type hemoglobin. A second series of patients prepared 
for HCT by reduced intensity conditioning was reported in 2015. Forty-three children with SCD 
and 9 with thalassemia who were between 0.8 and 20.3 years of age were enrolled. They received 
a reduced intensity combination of alemtuzumab ~3 weeks before transplantation, followed by 
fludarabine and melphalan. GVHD prophylaxis consisted of a combination of tacrolimus or 
cyclosporine with methotrexate in most cases. The overall survival was 93% and the event-free 
survival was 90.7% in the recipients who had SCD. Three patients with SCD died of complications 
related to GVHD. 
 
Together, these data support the notion that myeloablative and non-myeloablative/reduced 
intensity conditioning regimens generate similar outcomes after HLA-ID sibling donor HCT for 
SCD. The potential benefits of administering a modulated regimen include a reduction in the risk 
of infertility and other toxicities related to the preparative regimen, particularly in older, fragile 
patients. However, there appears to be a higher risk of graft rejection after reduced intensity/non- 
myeloablative conditioning for SCD when an alternate or unrelated donor HCT is performed. For 
this reason, a myeloablative regimen would be preferred if it could be administered with an 
acceptable safety profile. 


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1.5. 
STRIDE Consortium (Sickle cell Transplantation to Prevent Disease Exacerbation 
in Young Adults – Preliminary Trial) 
 
Preliminary Data From the R34 NIH Planning Grant 
 
A consortium of 23 centers was developed to conduct the STRIDE demonstration study as 
supported by a R34 planning grant awarded by the NHLBI. Patients between 16-40 years of age 
were enrolled between October 2012 and June 2015 in 8 of the 23 participating transplant centers. 
Eligibility criteria included stroke; recurrent episodes of acute chest syndrome (ACS) or sickle 
pain in the past 2 years; 8 or more RBC transfusions/year; or a tricuspid valve regurgitant jet 
velocity > 2.7 m/sec. Patients received unmodified bone marrow from a human leukocyte antigen 
(HLA)-matched sibling or an unrelated donor matched for 8 of 8 HLA loci. Patients were prepared 
for HCT with Busulfan from day -8 to -5 (13.2 mg/kg), Fludarabine from day -7 to -3 (175 mg/m2) 
and Thymoglobulin from day -5 to -2 (6 mg/kg). GVHD prophylaxis consisted of cyclosporine or 
tacrolimus with methotrexate. 


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Table 2. Outcomes in Patients Undergoing HCT on Feasibility Study
GVHD
Complications
% Donor Chimerism T-cell/RBC/Whole Blood/Myeloid
Acute
Chronic
Events
PIN
Day 28
Day 100
Day 180
1 Year
Organ/Grade
301R
43/100/100
62/100/96/100
59/100/NA/100/
58 /100/NA/100
None
None
Grade 3 hypercalcemia, 
Transient elevated ALT
101R
56/100/100/NA
100/100/100/100
100/100/100/100
100/100/100/100
None
None
Bell’s Palsy, EBV 
reactivation
201R
51/100/99/100
68/100/96/100
NA/100/98/NA
87/100/98/100
GII
None
Grade 3 hypertension 
Gall bladder obstruction
302R
41/100/NA/100
88/100/NA/100
91/100/NA/100
100/100/NA/100
None
Mild
102R
100/100/NA/100
100/100/NA/100
100/100/NA/100
100/NA/100/100
None
None
Bacteremia, AIHA
901R
66/95/97/NA
72/95/98/NA
68/93/91/ NA
62/80/95/NA
Skin II
Mild
Hyperglycemia 
Grade 3 itching
303R
54/94/NA/100
66/97/NA/100
66/100/NA/100
77/87/NA/100
None
Skin 
GR 2
Persistent fever
401R
76/100/98/98
85/100/98/98
91/100/98/NA
98/NA/98/NA
Skin I
None
Pericardial effusion 
Hemolytic anemia
202R
12/100/95/100
83/100/NA/100
79/100/96/100
79/100/94/98
None
Moderate
501R
97/94/NA/100
96/97/NA/100
100/97/98/NA
100/91/NA/NA
None
None
Transient inc ALT 
Hemolytic anemia 
402R
27/95/97/99
50/*/96/NA
Not available
Not available
None
None
Dead
Intracranial hemorrhage 
304R
44/100/NA/100
79/100/NA/ 100
100/100/NA/100
100/88/NA/100
None
Liver Gr 2
403R
78/100/NA/100
10/NA/95/100
11/NA/86/100
12/80/82/100
None
None
Diabetes, Pulmonary 
edema
503U
84/96/NA/100
35/96/NA/NA
NA/96/NA/99
Not available
Skin I
Lung 
BOOP 
Dead 
VOC, pericardial 
effusion, BOOP
502R
53/97/NA/100
63/91/NA/98
37/100/NA/NA
51/79/NA/NA
None
None
305R
75/100/NA/100
81/100/NA/100
75/100/NA/100
96/NA/NA/100
None
None
Pericarditis
504R
78/100/NA/NA
86/100/NA/NA
86/100/NA/100
82/NA/NA/100
None
Skin liver 
Gr 5
Transient inc ALT
1001R
28/91/NA/100
56/93/NA/100
59/NA/NA/100
82/NA/NA/100
Liver III
None
701U
NA/90/97/NA
NA/83/97/NA
NA/NA/100/NA
100/NA/100/NA
Not available 
None
None
306U
81/NA/NA/100
100/89/NA/100
96/NA/NA/100
100/NA/NA/100
None
None
Seizure, infection
1002U
55/94/NA/100
51/71/NA/100
51/NA/NA/100
75/NA/NA/100
None
None
Transient inc ALT, 
VOC
307U
20/89/NA/100
0/24/NA/100
0/NA/NA/100
Not available
None
None
Thrombus, pneumonia
 
Outcomes and Measures: The primary endpoint was 1-year event-free survival with events defined 
as graft failure, disease recurrence, or death. The Kaplan-Meier probabilities of event-free and 
overall survival will be determined. Donor chimerism, transplant-related toxicities and clinical and 
laboratory measures of SCD were secondary endpoints obtained 1 year after HCT. 
 
Results: Twenty-two patients (13 female) who ranged in age from 17-36 (median 22) years were 
enrolled. Seventeen patients received a sibling and 5 an unrelated donor HCT (Table 2). Enrolled 


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subjects had stroke (n=2), ACS (n=3), pain (n=14), RBC transfusion ≥8 per year for ≥1 year (n=6) 
andTRJvelocity≥2.7m/sec(n=5);N=8satisfied eligibility criteria for more than 1 category. 
N=22 patients are evaluable; 20 of 22 patients are alive with stable engraftment of donor cells at a 
median 13.6 months after HCT. The overall and event-free survival probabilities are both 90% at 
12-months after HCT). Full donor myeloid chimerism was observed after HCT in all patients. 
 
Justification for Proposed Trial Design 
 
Trial design: A randomized clinical trial (RCT) is the ideal trial design when comparing treatment 
approaches. However, there are formidable challenges to conducting an RCT in this setting. The 
major challenge is limited donor availability; only a third of eligible participants will have a 
suitably HLA-matched donor. In a randomized design, only participants with a suitably HLA- 
matched donor could enroll; randomization would then determine whether an HCT were done. 
Restricting enrollment in this way would mean an accrual time of 5-6 years rather than 2-3 years, 
even if randomization did not affect patients’ willingness to participate. HCT and standard of care 
are unequal in their intensity, potential toxicity and potential for cure. HCT is an intense treatment 
with a certain number of early deaths expected from HCT-related complications. On the other 
hand, it is potentially curative. Supportive care has very low toxicity and early mortality but there 
is no cure of the underlying disease and the likelihood of death from SCD is high later in life; 
expected mortality is 4.4 per 100 person-years.13,33 , The decision to undergo HCT is a complex 
process but once physicians and patients accept the idea of a curative therapy for SCD, despite its 
risk, they are often unwilling to accept non-curative treatment (standard of care) when a suitable 
donor is available, posing a barrier to participation. Accepting randomization to a non-curative 
approach may be a particular problem in a population with demonstrated mistrust of the medical 
establishment and is likely to result in a serious impediment to timely accrual. Timely completion 
of a trial is important both scientifically and ethically. It is a key criterion used by Data Safety 
Monitoring Boards as data generated from a lengthy trial may no longer be scientifically relevant 
upon the trial’s completion, raising ethical issues of asking patients to participate in a trial that 
cannot answer a question in a timely manner. Therefore, the trial is designed as a biologic 
assignment trial with the ITT principle. 
 
Justification of primary endpoint: We hypothesize that for participants assigned to the donor arm 
HCT-related mortality may exert an early impact on survival, but that the rate of mortality should 
plateau by two years.34-36 Reports of survival for severe aplastic anemia after related and unrelated 
donor transplantation suggest early mortality is less than 15% and that this risk plateaus by two 
years.34-36 Severe aplastic anemia is the most common nonmalignant disease indication for 
transplantation in young adults. Additionally, data from the pilot trial mentioned above for young 
adults with SCD also support 1-year survival of 90%. We hypothesize as well that participants on 
the no donor arm will not be especially susceptible to early death, but will gradually succumb to 
the cumulative effects of their disease with a mortality rate higher than in the general population.13 
Published reports for SCD adults receiving standard of care with hydroxyurea suggest this occurs 
at a rate of 4.4 deaths per 100 person years.33 Consequently, the survival curves of the 2 groups 
will eventually cross, with a long-term benefit for HCT if early HCT-related mortality is 
sufficiently low. For this phase II trial, we will compare survival rates at 2-years, with the goal of 
establishing that the difference in the proportion surviving is no more than 0.15 lower in the donor 


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arm. We think that if the early survival disadvantage of HCT is modest, a long-term survival 
advantage will emerge. 
 
The study design and the acceptability of HCT as a treatment option for adolescents and young 
adults were discussed with the Sickle Cell Adult Provider Network (SCPAN). There is agreement 
amongst the SCAPN physicians (~150) that if the 2-year disease-free survival after 
HCT is 75% they would accept HCT as superior to supportive care in young adults based upon the 
long-term mortality risks associated with supportive care. Based upon the results in the pilot 
investigation, there is a strong possibility that clinical practice could change and incorporate HCT 
as a therapeutic option. 
 
Justification of bone marrow as the graft source: There are several published reports including a 
phase III randomized trial through the BMT CTN that show higher rates of chronic graft-versus- 
host disease (GVHD) after transplantation of peripheral blood.37 Further, studies in severe aplastic 
anemia, suggest higher mortality after transplantation of peripheral blood.35,38 Although data are 
lacking on the use of peripheral blood with the exception of a report from a single institution27 the 
protocol team remains concerned about study subjects trading a chronic disease (SCD) for another, 
chronic GVHD. Chronic GVHD is debilitating and associated with poor quality of life in addition 
to being at risk for opportunistic infections and death.39 
 
Justification for the use of calcineurin inhibitors (CNI): In a cohort of 488 patients (subjects were 
enrolled on BMT CTN 0401 or transplanted at the Dana Farber Cancer Institute), the use of 
sirolimus was associated with higher rates of veno-occlusive disease (VOD) in the setting of 
myeloablative transplantations; 15.8% with sirolimus containing regimens vs. 7.4% with non- 
sirolimus regimens (tacrolimus + methotrexate). Higher VOD was associated with higher 
mortality.40 In another randomized trial that studied the effects of sirolimus in 146 patients, the 
incidence of VOD was 21% with sirolimus containing regimens compared to 9% with non-
sirolimus regimens.41 Since higher rates of VOD and liver complications were also seen in HCT 
for transfused individuals with thalassemia, for safety reasons we elected not to employ sirolimus 
in this trial. 
 
Issues in biological assignment: Participants are biologically assigned, based on the presence or 
absence of a suitable donor, to donor versus no donor arms. Participants in the donor arm are 
expected to proceed to HCT and those in the no donor arm, to continue with standard of care. 
However, crossovers may occur, which may lower the statistical power to detect differences 
between the donor and no donor arms. We have undertaken measures to minimize crossovers. The 
up-front consultation with the HCT physician should screen out most participants interested in 
only one or the other treatment option. Consequently, recruitment of highly motivated participants 
will minimize crossovers and dropouts. In the pilot trial there was only 1 withdrawal after a suitable 
donor was identified (1 of 23, 4%). Denial of insurance coverage for HCT may prevent some 
participants assigned to the donor arm from receiving HCT. Based on the pilot trial and the Center 
for Medicare and Medicaid Services (CMS) guidelines, we anticipate <10% will be denied 
insurance coverage. Many SCD patients are covered by Medicare and CMS guidelines state the 
Affordable Care Act (ACA) policy is that if an indication for HCT is in the silent category (such 
as SCD) and patients are in a federally approved or sponsored clinical trial, Medicare patients are 


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eligible for HCT coverage. Participants assigned to the donor arm but subsequently unable to 
proceed to HCT for any reason will remain in the donor arm for the primary analyses. Similarly, 
there may be participants in the no donor arm who proceed to HCT at a later date with an HLA- 
mismatched or matched donor. These participants will remain in the no donor arm for primary 
analyses. A full description of crossovers on both arms will be provided. Another potential problem 
is that participants with donors may differ from those without donors. Analyses are planned to 
assess comparability of participants on the 2 treatment arms for demographic and prior sickle 
related events. Multivariable analysis will be used to adjust for imbalances in characteristics. 
Although very unlikely, any death occurring prior to identification of a donor would be assigned 
to the no donor arm. 
 
Enrollment bias: Bias can occur with biologic assignment with differential assignment of higher 
risk patients to one or the other treatment arm. This occurs when knowledge of the eventual arm 
assignment differentially influences enrollment of specific types of patients. We will minimize this 
by deferring initiation of donor search until after enrollment. We will also monitor this by 
requesting sites to submit a pre-screen log to the DCC. The log will identify potential participants 
based on their clinical eligibility and confirmation from the site that HLA typing has not been 
performed. Concurrent with this effort, the Protocol Team will educate site PIs on the importance 
of refraining from HLA typing potential participants. Participants who have been HLA typed prior 
to referral are ineligible; however if a participant has had HLA typing with accompanying 
documentation that relatives were not HLA typed or a search of the unrelated donor registry was 
not performed the participant will be considered eligible.


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CHAPTER 2 
 
 
2. STUDY DESIGN 
 
2.1. 
Study Overview 
 
The primary goal of this multicenter study is to determine the safety and efficacy of HCT in young 
adults with severe SCD compared to a cohort with severe SCD without a suitable donor. Study 
participants are assigned to one of two treatment arms: a donor arm for those with a suitable donor 
and a no donor arm for those without an available marrow donor. We will compare the difference 
in the observed proportion of patients surviving at 2 years post biologic assignment between the 
treatment arms (ITT principle). Secondary outcomes will compare changes in SCD-related events 
(pulmonary hypertension, cerebrovascular events, renal function, avascular necrosis, leg ulcer), 
functional outcomes (6MWD, HRQoL), and mean pain intensity assessed by a multidimensional 
electronic pain diary between the treatment arms. 
 
2.2. 
Hypothesis and Specific Objectives 
Primary Objective 
The primary objective of this clinical trial is to compare 2-year OS in young adults with severe 
SCD who receive HCT compared to standard of care. Participants are selected on clinical eligibility 
and without knowledge of donor availability when approached for consent. Study participants will 
be biologically assigned to one of two treatment arms, a donor arm or no donor/standard of care 
arm, based on the availability of a suitable HLA-matched sibling or 8/8 HLA-matched adult 
unrelated donor. All participants are initially assigned to the no donor/standard of care arm, and if 
a suitable donor is identified, patients are re-assigned to the donor arm. The protocol recommends 
HLA typing of study participant, sibling(s) and/or initiation of search for an unrelated donor to 
occur as soon as the potential participant is confirmed to be eligible by enrollment or the external 
eligibility review committee. Subjects assigned to the donor arm are expected to proceed to HCT 
and those on the no donor arm, to receive standard of care. Regardless of treatment received 
participants will remain in their assigned arm for analyses (Intent- to-treat principle). The primary 
endpoint is a comparison of the difference in the observed proportion of patients surviving at 2 
years post biologic assignment between the two treatment arms. 
 
We hypothesize that for participants assigned to the donor arm, HCT-related mortality may exert 
an early impact on survival, but that the rate of mortality will plateau by 2 years. Additionally, we 
hypothesize that participants on the no donor arm will not be especially susceptible to early death, 
but will gradually succumb to the cumulative effects of their disease anticipated to be at a rate of 
4.4 deaths per 100 person-years.13,33 Our goal is to establish that the difference in the proportion 
of participants surviving at 2-years is no more than 0.15 lower in the donor arm compared to the 
no donor arm. A difference of this magnitude or less at two years is likely to result in a long-term 
survival advantage.


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Secondary Objectives 
 
Secondary objectives will compare changes in SCD-related events including organ function 
(pulmonary hypertension, cerebrovascular events, renal function, avascular necrosis, leg ulcer) and 
functional outcomes (6-MWD, HRQoL assessed using the NIH’s PROMIS-57 instrument, and 
mean pain intensity assessed by an electronic pain diary), pulmonary function tests, 
echocardiogram at baseline and 2-years after assignment to treatment arm. Additionally, HRQoL, 
28 day e-pain diary, pulmonary function tests, echocardiogram and the 6MWD test will also be 
measured at 1 year. Baseline 1 and 2-year assessments will be done at the same sites to minimize 
variability. Secondary objectives for the donor arm include neutrophil recovery, platelet recovery, 
graft failure, chimerism, acute and chronic graft-versus-host disease, idiopathic pneumonia 
syndrome, veno-occlusive disease, and central nervous system toxicity. Additionally, we will 
ascertain survival status of patients annually, years 3 through 10 and compare survival between 
the treatment groups. 
 
2.3. 
Patient Eligibility 
Eligibility Criteria for Initial Screening 
Inclusion Criteria – Initial Screening 
1. Age≥15and< 41 
2. Severe sickle cell disease [any clinically significant sickle genotype, for example, 
Hemoglobin SS (Hb SS), Hemoglobin SC (Hb SC), Hemoglobin SBeta thalassemia (Hb 
Sβ),orHemoglobinS-OArab genotype] with at least 1 of the following manifestations (a-
f): 
a. Clinically significant neurologic event (stroke) or any neurological deficit lasting > 24 
hours; 
b. History of two or more episodes of acute chest syndrome (ACS) in the 2-year period 
preceding enrollment or referral despite the institution of supportive care measures (i.e. 
asthma therapy); 
c. An average of three or more pain crises per year in the 2-year period preceding 
enrollment or referral (required intravenous pain management in the outpatient or 
inpatient hospital setting) 
i. 
Clinical documentation of pain management in the outpatient or inpatient 
setting is required. 
d. Administration of regular RBC transfusion therapy, defined as receiving 8 or more 
transfusion events per year (in the 12 months before enrollment) to prevent vaso- 
occlusive clinical complications (i.e. pain, stroke, and acute chest syndrome) 
e. An echocardiographic finding of tricuspid valve regurgitant jet (TRJ) velocity≥2.7
m/sec. 


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f. Ongoing high impact1 chronic pain on a majority of dayspermonthfor≥6monthsas
defined as ONE or more of the following: 
i. 
Chronic pain without contributory SCD complications2 OR 
ii. 
Mixed pain type in which chronic pain is occurring at site(s) (arms, back, chest, 
or abdominal pain) unrelated to any sites associated with Contributory SCD 
complications2 (e.g. leg ulcers and/or avascular necrosis). 
3. Adequate physical function as measured by all of the following: 
 
a. Karnofsky/Lanskyperformancescore≥ 60 
b. Cardiac function: Left ventricular ejection fraction (LVEF) > 40%; or LV shortening 
fraction > 26% by cardiac echocardiogram or by MUGA scan. 
c. Pulmonary function: 
i. 
Pulse oximetry with a baseline O2 saturation of ≥ 85% 
ii. 
DLCO > 40% (corrected for hemoglobin) 
d. Renalfunction:Serumcreatinine≤1.5xtheupperlimitofnormalforageasperlocal
laboratory and one of the following: 
i. 
creatinine clearance >70 mL/min calculated using the Cockcroft-Gault 
calculator 
ii. 
creatinine clearance > 70 mL/min by 24 hour urine (preferred) 
iii. 
GFR > 70 mL/min/1.73 m2 by radionuclide GFR. 
e. Hepatic function: 
i. 
Serumconjugated(direct)bilirubin≤2xupperlimitofnormalforageas
per local laboratory. Participants are not excluded if the serum conjugated 
(direct) bilirubin is >2x the upper limit of normal for age as per local 
laboratory and: 
i. There is evidence of a hyperhemolytic reaction after a recent RBC 
transfusion, OR 
ii. There is evidence of moderate direct hyperbilirubinemia defined as 
direct serum bilirubin < 5 times ULN and not caused by underlying 
hepatic disease. 
ii. 
ALT and AST < 5 times upper limit of normal as per local laboratory. 
 
1 High impact chronic pain (HICP) is identified as those reporting “severe interference” with life activities OR 
“usually or always” experiencing a limitation of their life or work activities including household chores. (See 
guidelines for identifying HICP in the BMT CTN 1503 Manual of Procedures) 
2 Contributory SCD complications are defined as clinical signs (e.g. presence of leg ulcers) or clinical assessments 
(e.g. imaging confirmation of splenic infarct or avascular necrosis). Chronic pain attributed solely to contributory 
SCD complications is excluded. 


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Exclusion Criteria – Initial Screening: 
1. HLA typing with a donor search prior to referral (consultation with HCT physician). 
a. If a subject has had HLA typing and a related donor search that did not identify a 
suitably matched relative (i.e., sibling) at any time, and also did not have an 
unrelated donor search, the patient will be considered eligible. 
b. If a subject has had HLA typing and a related donor search that did not identify a 
suitably matched relative (i.e., sibling) at any time and had an unrelated donor 
searchthatdidnotidentifyasuitablymatchedunrelateddonor≥1yearpriorto
enrollment, the patient will be considered eligible. 
c. If a subject has had HLA typing with no related donor search and had an unrelated 
donor search that did not identify a suitably matched unrelated donor ≥ 1 year prior 
to enrollment, the patient will be considered eligible. 
d. Subjects with a known HLA-identical sibling or HLA-matched unrelated donor are 
excluded. 
2. Uncontrolled bacterial, viral, or fungal infection in the 6 weeks before enrollment. 
3. Seropositivity for HIV 
4. Previous HCT or solid organ transplant 
5. Participation in a clinical trial in which the patient receives an investigational drug or 
device must be discontinued prior to date of enrollment 
6. A history of substance abuse as defined by version IV of the Diagnostic & Statistical 
Manual of Mental Disorders (DSM IV).1 
7. Demonstrated lack of compliance with prior medical care as determined by referring 
physician. 
8. Pregnant or breast feeding females. 
9. Inability to receive HCT due to alloimmunization, defined as the inability to receive packed 
red blood cell (pRBC) transfusion therapy. 
 
Eligibility Criteria for Transplant after Biologic Assignment - Donor Arm 
Participants 
 
Participants assigned to the Donor Arm at the time of biologic assignment are subject to additional 
transplant eligibility criteria as specified below. Additionally, repeat clinical assessments prior to 
transplant should be obtained in accordance with institutional policies and standards of care in the 
interest of good clinical practice. If participants biologically assigned to the donor arm do not meet 
the following additional eligibility criteria, they will not be able to proceed with transplant. 
 
 
 
 
 
 
1American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. (4th 
ed.). Washington, DC American Psychiatric Association. 


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All donor arm participants must meet the following criteria to qualify for transplant: 
a. Liver MRI (≤ 90 days prior to initiation of transplant conditioning) to document hepatic 
ironcontentisrequiredforparticipantswhoarecurrentlyreceiving≥8packed red
blood cell transfusions for ≥1 year or have received ≥20 packed red blood cell
transfusions (cumulative). Participants who have hepatic iron content ≥ 7 mg Fe/g liver 
dry weight by liver MRI must have a liver biopsy and histological 
examination/documentation of the absence of cirrhosis, bridging fibrosis1, and active 
hepatitis(≤90dayspriortoinitiationoftransplant conditioning). 
 
b. Lack of clinical or radiologic evidence of a recent neurologic event (such as stroke or 
transient ischemic attack) by Cerebral MRI/MRA within 30 days prior to initiating 
transplant conditioning. Subjects with clinical or radiologic evidence of a recent 
neurologiceventwillbedeferredfor≥6monthswithrepeatcerebralMRI/MRAto
ensure stabilization of the neurologic event prior to proceeding to transplantation. 
 
c. Documentation of participant’s willingness to use approved contraception method until 
discontinuation of all immunosuppressive medications is to be documented in the 
medical record corresponding with the consent conference. 
 
2.4. 
Trial Design, Screening, and Biological Assignment 
 
In brief, potentially eligible participants are referred to a HCT physician for consultation which 
includes 1) confirmation of trial specified clinical eligibility; 2) detailed patient education about 
the trial design including biologic assignment, HCT procedure, and risks and benefits of disparate 
treatment arms (curative intent versus standard of care); 3) consent for screening tests and HLA 
typing. Sites will be provided patient-oriented education materials on the design and objectives of 
the trial for review prior to referral for screening consultation. 
 
Sites participating in this trial will accept referrals from other primary practice/private 
hematologists/SCD physicians within the community. However, for the purposes of this trial, it is 
preferred that all visits from time of initial consent through biological assignment be completed at 
the transplant center. Following biologic assignment, patients assigned to the donor arm should be 
followed by the transplant center and patients assigned to the no-donor arm may be transferred to 
the referral site for the remainder of follow up. 
 
Consenting participants are enrolled into the AdvantageEDCSM data collection system with 
relevant clinical information needed to confirm clinical eligibility without knowledge of donor or 
health care insurance status. An independent Eligibility Review Committee (ERC) will review 
clinical eligibility for some participants (see appendix G for additional details). If a participant is 
not required to be reviewed by the ERC, eligibility will be confirmed upon successful enrollment 
into AdvantageEDC. If eligibility is not confirmed, that participant will not be followed further. 
 
 
1The absence of bridging fibrosis will be determined using the histological grading and staging scale as described by 
Ishak and colleagues (1995) as described in the Manual of Operating Procedures. 


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Based on a similar screening program for BMT CTN 0601 and the pilot trial for this protocol, we 
expect this will happen in <5% of participants. For those with confirmed eligibility, the enrolling 
site will be informed and the donor search will be initiated. HLA typing and donor search is 
initiated only after confirmation of eligibility by ERC or AdvantageEDC, as applicable. In the rare 
instance a potential patient had been HLA typed but without knowledge or documentation of a 
donor search prior to referral, initiation of donor search can only occur after confirmation of 
eligibility. Biologic assignmentwilloccur≤180daysafterthiseligibilityconfirmation,basedon
identification of a suitable donor as defined in section 2.5. 
 
For participants assigned to the donor arm, consent is obtained for HCT. If no suitable donor is 
identified ≤ 180 days after confirmation of eligibility, participants remain in the no donor arm and 
will continue medical care, trial-related tests, and follow-up for 2 years. The likelihood of a 
participant dying during the waiting period is highly unlikely given the natural history of SCD. 
 
Follow-up: Follow up for participants on the donor arm is conducted by an HCT physician or 
designee and for those on the no donor arm, by a SCD physician or designee. Baseline 
characteristics and monitoring/tests are assessed after confirmation of eligibility, at time of 
assignment to treatment arm, and every 3 months for 2 years from biologic assignment. For those 
assigned to the donor arm, additional assessments are performed weekly through day-100 post- 
transplant. HCT is a very intense treatment requiring inpatient hospital care and careful monitoring 
of participants. A dedicated DCC coordinator will monitor that data are reported in a timely manner 
into AdvantageEDCSM for participants on the donor and no donor arms (Figure 4). Our experience 
suggests compliance is high for BMT CTN trials that employ a similar monitoring strategy with 
the median percent of forms due for longer than 30 days per patient at 1.2% (range 0.5–3.0% by 
center). 
 
A Visit Scheduling Calendar, an interactive 
resource for site coordinators, is available in 
AdvantageEDCSM to track participant visits. 
There will be mandatory regularly scheduled 
teleconferences 
with 
the 
DCC/CCC 
leadership and all site PIs to discuss accrual, 
data reporting and compliance. The Protocol 
Coordinator will develop quarterly reports 
on site performance metrics for discussion 
on the teleconference calls. We will foster partnerships between HCT and non-HCT physicians, a 
strategy that proved effective for follow-up of non-HCT participants in the Scleroderma: 
Cyclophosphamide or Transplantation trial.42 
 
Adopting a similar approach, when HCT and SCD physicians are at the same site (i.e., within the 
same University), a single contract is issued to that site. When the HCT and SCD physicians are 
at different sites, separate contracts are issued and “hybrid sites” created where HCT and SCD 
physicians are paired. For monitoring compliance, each hybrid site is treated as a single site, 
motivating both physicians to comply with reporting requirements. Sites recruited for this Phase 
II trial have SCD patient populations >100, are largely academic sites with HCT programs, and 
Figure 4


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have a track record for participating in national trials. Consequently, there is greater awareness and 
resources available to fulfill the rigor needed for participant retention and completeness of data 
reporting. 
 
2.5. 
Donor Selection Criteria 
All donors must meet the criteria below to be considered eligible for donation on this trial based 
upon the availability of a related or unrelated donor. An adult unrelated donor transplant is 
recommended only if an HLA-matched sibling is NOT available. HLA-matched donors that do 
not meet the donor selection criteria in section 2.5.1 are not suitable donors. 
 
Criteria Required for Assignment to the Donor Arm 
 
Participantswillbeassignedtothedonorarmifthefollowingcriteriaaremet≤180daysafter
confirmation of eligibility: 
 
1. Have a suitably matched HLA donor: 
a. Siblings must be at a minimum HLA-6/6 matched to the recipient at HLA –A, -B 
and –DRB1 at intermediate (or higher) resolution using DNA-based typing. Donors 
aged <18 years1 are allowed provided that there is no medically equivalent HLA- 
matched adult relative who is willing and able to donate 
 
b. Unrelated adult donors must be at a minimum 8/8 HLA-matched to the recipient at 
HLA -A, -B, -C and -DRB1 at high resolution using DNA-based typing 
 
2. Donor is willing and able to donate required graft source. Patients with an HLA-identical 
sibling donor can receive a transplant using one of three regimens: A) Busulfan, 
Fludarabine, and rabbit ATG using a bone marrow graft (preferred), B) Alemtuzumab/TBI 
300 cGy using a peripheral blood graft, OR C) Alemtuzumab, fludarabine, melphalan 
using a bone marrow graft. 
a. In the unlikely event the sole suitable donor is not medically fit to donate bone 
marrow, a mobilized peripheral blood graft may be permitted subject to review of 
documentation by the Medical Monitor or Protocol Officer. 
 
3. Absence of anti-donor HLA antibodies. The presence of anti-donor HLA antibodies is 
defined as a positive cross-match test of any titer (by complement-dependent cytotoxicity 
or flow cytometric testing) or the presence of anti-donor HLA antibody to HLA-A, -B, -C, 
–DRB1 or –DP with mean fluorescence intensity >1000 by solid phase immunoassay. Anti-
donor HLA antibody testing may be performed after confirmation of availability of an 
HLA-matched sibling or unrelated donor. 
 
Any participant not confirmed to meet the above criteria ≤ 180 days after the date of confirmation 
of eligibility will remain in the No Donor/SOC arm. If it is known that a potential donor is available 
 
1The minimum age of a patient eligible for this trial is 15 years. As the ages of the siblings are with ± 5 years it is 
unlikely children aged <10 years will serve as donors. 


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but they will not have been confirmed to meet criteria for assignment to the donor arm within the 
window, the Protocol Coordinator should be contacted prior to the end of the 180 day window. 
Expansions to the donor search window will be considered on a case-by-case basis and at the 
discretion of the Protocol Chairs/Officer. 
 
 
Criteria Required Prior to Donation 
 
The following must be confirmed prior to BMT for those assigned to the donor arm: 
 
1. All related donors must meet institutional criteria for donation 
 
2. All unrelated donors must fulfill their respective unrelated donor registry criteria for 
donation. 
2.6. 
Treatment Plan for Patients Assigned to the No Donor Arm 
 
Patients assigned to the no donor arm will continue to receive standard of care treatment per their 
SCD physician. Co-enrollment on another clinical trial requires the site notify the Protocol 
Coordinator at EMMES for consultation with Study PIs and Protocol Officer prior to initiating the 
co-enrollment. 
 
2.7. 
Treatment Plan for Patients Assigned to the Donor Arm (HCT) 
 
Patients with a matched unrelated donor will receive a bone marrow transplant (unless PBSC graft 
is pre-approved per section 2.5.1 using a preparative regimen with Busulfan, Fludarabine and 
rabbit ATG. 
 
Patients with an HLA-identical sibling donor can receive a transplant using one of three regimens: 
A. Busulfan, Fludarabine, and rabbit ATG using a bone marrow graft (preferred regimen) 
B. Alemtuzumab/TBI 300 cGy using a peripheral blood graft 
C. Alemtuzumab, fludarabine, melphalan using a bone marrow graft 
Prior to implementation of the version 5.0 protocol, each center will choose one regimen to use for 
all HLA-identical sibling donor transplants on BMT CTN 1503. Centers must register and receive 
approval for which of the three transplant regimens they will use with the BMT CTN DCC in 
advance of protocol version 5.0 implementation. If a center wishes to modify their conditioning 
regimen choice for HLA-identical sibling donor transplants, they must contact the BMT CTN DCC 
and obtain approval prior to administration of a new regimen. 
 
A summary of the conditioning regimen options is summarized in Table 2.7. Details on each 
conditioning regimen is available in section 2.7.2. 


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Table 2.7: Transplant Regimens for Related and Unrelated Donor Transplants
Matched Unrelated Donor
Matched Related Donor (i.e. Sibling)
Busulfan, Fludarabine, and rabbit ATG using 
a bone marrow graft 
A. Busulfan, Fludarabine, and rabbit ATG 
using a bone marrow graft 
B. Alemtuzumab/TBI 300 cGy using a 
peripheral blood graft 
C. Alemtuzumab, fludarabine, melphalan 
using a bone marrow graft 
 
Pre-Transplant Procedures 
 
Hemoglobin S Level 
HbSlevelmustbe≤30%within30dayspriortoinitiationofconditioning regimen for HCT. This 
may be achieved by exchange or simple transfusion according to local institutional practice. If 
doing an exchange transfusion, it is recommended that a hematocrit level of 30% is targeted, while 
not exceeding 36%. 
 
Hydroxyurea and Iron Chelation Therapy 
Hydroxyurea must be discontinued at least 1 week before initiation of conditioning regimen for 
HCT. Iron chelation therapy must be discontinued no later than 48 hours prior to commencement 
of the conditioning therapy. Iron chelation therapy or a program of phlebotomy may be resumed 
after neutrophil and red cell engraftment at the discretion of the transplanting center. 
 
Preparative Regimen 
 
Patients who have a matched unrelated donor will receive the preparative regimen as shown in 
Table 3. Patients who have an HLA-identical sibling donor will receive either the regimen in Table 
3 (Regimen A) or the alternative non-myeloablative regimen in Table 4 (Regimen B) or the reduced 
intensity regimen in Table 5 (Regimen C). Centers must register and receive approval for which of 
the three HLA-identical donor transplant regimens they will use per section 2.7. All patients with 
an HLA-identical matched sibling will receive a transplant with the same, single, pre-approved 
regimen for the center. 
 
Unrelated Donor HCT and HLA-Identical Sibling HCT Regimen A: 
 
 
Table 3. SCHEMA OF CONDITIONING REGIMEN 
Day 
Treatment 
–8 
BU 3.2 mg/ kg/dose IV 
–7 
BU 3.2 mg/kg/dose IV, Fludarabine 35mg/m2 IV 
–6 
BU 3.2 mg/kg/dose IV, Fludarabine 35mg/m2 IV, rabbit ATG 0.5mg/kg 
IV 


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Table 3. SCHEMA OF CONDITIONING REGIMEN 
–5 
BU 3.2 mg/kg/dose IV, Fludarabine 35mg/m2 IV, rabbit ATG 1 mg/kg 
IV 
–4 
Fludarabine 35mg/m2 IV, rabbit ATG 1.5mg/kg IV 
–3 
Fludarabine 35mg/m2 IV, rabbit ATG 1.5mg/kg IV 
–2 
rabbit ATG 1.5mg/kg IV 
–1 
Rest 
0 
Stem cell infusion 
 
Busulfan (Bu) and fludarabine dosing will be based on adjusted body weight (AjBW) in patients 
weighing >125% Ideal Body Weight (IBW). The following are dose adjustment formulas: 
 
IBW in kg is estimated as follows: 
Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet. 
Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet. 
AjBW = adjusted body weight is estimated as follows: 
AjBW = IBW + 0.25(Actual Body Weight - IBW) 
Initial busulfan dosing should be followed by pharmacokinetic dosing to ensure targeted exposure 
 
 
Fludarabine 
Fludarabine 35 mg/m2/day will be administered on Day –7 to Day –3 (for a total of 175 mg/m2 
over 5 consecutive days) and administered IV over a minimum of 30 minutes. The IV infusion 
may take longer per institutional guidelines. Preparation, administration, and monitoring will be 
according to institutional standard practice. Fludarabine will be adjusted to adjusted body weight 
(AjBW) in patients weighing > 125% IBW. 
 
 
Busulfan 
Busulfan 3.2 mg/kg as a daily single dose will be given IV on Days –8 to -5 (4 days) before 
transplantation. Busulfan injection (6 mg/mL) should be diluted with 0.9% sodium chloride or 5% 
dextrose injection to a quantity 10 times the volume of the injection (e.g. 5 mL of busulfan injection 
should be diluted in 50 mL of NS or D5W) prior to the infusion. Busulfan should be infused over 
3 hours. The line should be completely flushed with D5W or NS at the end of the infusion to ensure 
administration of the complete dose. Blood will be collected for busulfan pharmacokinetics (2 mL 
of blood in green top vacutainer). The collection time-points will be per institutional standards. 
The following schedule is recommended but not required: at the end of the infusion (+15 min), 4, 
5, 6 and 8 hours after the start of the first infusion on day -8 of the preparative regimen. 


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Busulfan dose will be targeted to achieve a concentration at steady state (Css) of 600-900 ng/mL 
(target 750 ng/mL) or a daily area under the plasma concentration curve (AUC) of 3507–5261 
µM•min (target 4384 µM•min) on the subsequent day. The total regimen AUC will be in the range 
of 14,000 – 21,000 µM•min. (Appendix D). 
Supportive care management during busulfan administration will follow institutional guidelines. 
 
 
Rabbit ATG 
Rabbit ATG (r-ATG) will be administered on day -6 at 0.5 mg/kg, day -5 at 1 mg/kg and days -4, 
-3, and -2 at 1.5 mg/kg for a total dose 6 mg/kg. Each vial of r-ATG lyophilized powder is 
reconstituted with 5 mL of soluble water for injection and transferred into the bag of infusion 
solution (saline or dextrose). It is recommended to use 50 mL of infusion solution for each vial of 
thymoglobulin. Total volume is usually between 50 to 500 mL. It is infused through a 0.22- 
micrometer filter into a high-flow vein over a minimum of 6 hours for the first dose and over at 
least 4 hours for subsequent doses. Premedication with corticosteroids, acetaminophen, and 
diphenhydramine 1 hour prior to the infusion is recommended to reduce the incidence and intensity 
of side effects during and after the infusion. Other sources of ATG are contra-indicated. Please 
notify Protocol Coordinator if patient is unable to tolerate r-ATG. 
 
 
Infusion of Bone Marrow 
Targettotalnucleatedcellcount(TNC):≥3.5108/kg (actual recipient body weight). Institutional 
procedures should be followed for requesting and receiving marrow units for infusion. Under no 
circumstances are the marrow cells to be irradiated. No in-line leukocyte filter should be used and 
no medications or fluids should be given through the catheter lumen that is used for infusion of 
stem cells during the infusion of bone marrow. Monitoring immediately prior to, during infusion 
of bone marrow cells, and thereafter will be according to institutional guidelines. Pre-medication 
prior to infusion of bone marrow will be according to institutional guidelines. 
 
 
HLA-Identical Sibling HCT Preparative Regimen B: 
 
 
Table 4. SCHEMA OF CONDITIONING REGIMEN B for HLA-ID 
SIB TRANSPLANTS 
Day 
Treatment 
–7 
Alemtuzumab 0.03 mg/kg IV 
–6 
Alemtuzumab 0.1 mg/kg IV 
–4 
Alemtuzumab 0.3 mg/kg IV 
–4 
Alemtuzumab 0.3 mg/kg IV 
–3 
Alemtuzumab 0.3 mg/kg IV 
–2 
TBI 300 cGy 


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Table 4. SCHEMA OF CONDITIONING REGIMEN B for HLA-ID 
SIB TRANSPLANTS 
–1 
Rest 
–0 
Stem cell infusion 
 
 
Alemtuzumab 
Alemtuzumab will be administered on day -7 (0.03 mg/kg), day -6 (0.1 mg/kg) and day -5, -4, and 
-3 (0.3 mg/kg). 
 
Pre-medication should be commenced 30 minutes prior to each infusion of alemtuzumab and 
should be continued for at least 48 hours after the last dose of alemtuzumab. 
Recommended pre-medication include the following combination of medications: 
Diphenhydramine: 25 – 50 mg IV or PO q 8 hours (maximum 50 mg/dose) 
Acetaminophen: 650 mg PO q 6 hours (maximum 4 grams qd) 
Hydrocortisone: 50 mg IV q 6 hours 
Meperidine: 50 - 75 mg IV q 4-6 hours as needed for rigors 
 
Alemtuzumab will be administered in-patient and the initial dose must be administered over 2 
hours and subsequent doses not less than 24 hours apart. If the patient has a severe or life 
threatening adverse reaction to alemtuzumab (e.g., severe hypotension, severe bronchospasm) the 
adverse event meets expedited reporting requirements (within 24 hours) through the expedited AE 
reporting system via AdvantageEDCSM. A study chair(s) may also be consulted regarding further 
doses at the discretion of treating physician. 
 
Alemtuzumab will be diluted in 100cc of 0.9% normal saline (NS) and infused intravenously over 
a minimum of 6 hours each day for 5 consecutive days. Since serious infusion reactions are not 
uncommon during alemtuzumab infusion, it is strongly recommended that vital signs should be 
recorded q 15-30 minutes during each infusion of alemtuzumab. 
Total Body Irradiation (TBI) 300 cGy on day -2 in a single dose, with testicular shielding. TBI 
may be delivered from either linear accelerator or Cobalt sources per institutional practice. 
Rest on Day -1 
Day 0 is the day of transplant; G-CSF mobilized peripheral blood stem cells is the preferred source 
of donor hematopoietic cells 
 
Testicular/Gonadal Shielding during TBI 
Testicular shielding will be administered to all male patients. 
The testis is one of the most radiosensitive tissues, and even low doses of radiation can cause 
impairment of function. In adult men, doses as low as 10 cGy can cause damage to 
spermatogonia50. At single fraction doses of 200 to 300 cGy there is overt damage to 
spermatocytes in adult men and return to pre-irradiation sperm concentrations and germinal cell 
numbers may take up to 30 months51. Fractionated doses are more toxic to spermatogenesis, and 


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complete sterilization may occur if the fractionated dose exceeds 100 – 200 cGy. However, in the 
pre-pubertal state, the impact of radiotherapy is mitigated. In one study of 12 pre-pubertal boys 
who received 2400 cGy testicular irradiation to treat ALL, it was observed that testosterone levels 
were normal in all 12 and basal LH was normal in 9 and elevated in 352. Nonetheless, to preserve 
fertility and Leydig cell function in post-pubertal males, we propose to administer testicular 
shielding to all males during the single fraction of TBI. This shielding will have no impact on the 
immunosuppressive effect of the radiotherapy. 
There will be no gonadal shielding in female patients. 
The effects of radiotherapy on ovarian function and fertility are dose- and age-dependent. 
However, ovarian doses of less than 400 cGy do not result in permanent ovarian dysfunction and 
the calculated LD50 of the human oocyte dose is approximately 400 cGy53 54 55. Thus, ovarian 
shielding to preserve ovarian function will not be necessary for the dose of TBI administered in 
this investigation; moreover, shielding in this setting could reduce the immunosuppressive effects 
of TBI if intra-abdominal lymph nodes were inadvertently shielded. 
 
Infusion of fresh mobilized donor peripheral blood stem cells (PBSC) 
Targettotalnucleatedcellcount(TNC):≥3.5108/kg (actual recipient body weight) and >3 x 106 
CD34+ cells/kg recipient weight. Institutional procedures should be followed for mobilizing PBSC 
and collecting via apheresis. Under no circumstances are the PBSC to be irradiated. No in- line 
leukocyte filter should be used and no medications or fluids should be given through the catheter 
lumen that is used for infusion of stem cells during the infusion of PBSC. Monitoring immediately 
prior to, during infusion of PBSC, and thereafter will be according to institutional guidelines. Pre-
medication prior to infusion of PBSC will be according to institutional guidelines. 
HLA-identical Sibling HCT Preparative Regimen C: 
 
TABLE 5: SCHEMA OF CONDITIONING REGIMEN C FOR HLA-ID SIB 
TRANSPLANTS
Day
Treatment
24 hours prior to 1st dose of 
Alemtuzumab
Alemtuzumab test dose 3 mg IV once 
–22
Alemtuzumab 10 mg IV1 
Alemtuzumab 15 mg IV1 
Alemtuzumab 20 mg IV1 
–21
–20
–19
–18
–8
Fludarabine 30mg/m2 IV
–7
Fludarabine 30mg/m2 IV
–6
Fludarabine 30mg/m2 IV
–5
Fludarabine 30mg/m2 IV
–4
Fludarabine 30mg/m2 IV
–3
Melphalan 140 mg/m2 IV
–2
Rest
–1
Rest
0
Stem cell infusion
+7
G-CSF5μg/kg/daycontinueuntilneutrophilengraftment
1Alemtuzumab doses may be administered between Days–22 and –18 
but are required to be on three consecutive days. 


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The cytoreductive medications fludarabine and melphalan will be adjusted to the ideal body weight 
(IBW) in patients weighing > 125% IBW, as above. 
Pre-medication 
 
Pre-medication should be commenced 30 minutes prior to each infusion of alemtuzumab and 
including the test dose and should be continued for at least 48 hours after the last dose of 
alemtuzumab. 
 
Recommended pre-medication include the following combination of medications: 
Diphenhydramine: 1 mg/kg IV or PO q 8 hours (maximum 50 mg/dose) 
Acetaminophen: 10-15mg/kg PO q 6 hours (maximum 4 grams qd) 
Hydrocortisone: 1-2 mg/kg IV q 6 hours 
Meperidine: 0.5 mg/kg IV q 4-6 hours may be used as needed for rigors 
 
Test dose and administration 
 
Alemtuzumab 10 – 15- 20 mg may be administered between Days –22 and –18 but are required to 
be on three consecutive days. Alemtuzumab will be administered in-patient and the patient may 
be discharged the day after completion of Alemtuzumab infusions. The test dose of alemtuzumab 
(3 mg IV) must be administered over 2 hours and not less than 24 hours prior to administration of 
the first dose. It is recommended that the test dose be administered Monday through Thursday, in 
the morning, to allow for time for notification of the Study Chair in the case of a severe adverse 
reaction. 
 
If the test dose is not tolerated: 
 
If the patient has a severe or life threatening adverse reaction to alemtuzumab (e.g., severe 
hypotension, severe bronchospasm) the adverse event meets expedited reporting requirements 
(within 24 hours) through the expedited AE reporting system via AdvantageEDCSM. The study 
chair(s) may also be consulted regarding further doses at the discretion of treating physician. 
 
If the test dose is tolerated: 
 
Alemtuzumab will be diluted in 100cc of 0.9% normal saline (NS) and infused intravenously over 
a minimum of 6 hours each day for three consecutive days beginning between Days –22 and –18. 
 
Since serious infusion reactions are not uncommon during alemtuzumab infusion, it is strongly 
recommended that vital signs should be recorded q 15-30 minutes during each infusion of 
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Fludarabine 
Fludarabine 30mg/m2 will be administered IV, on Day –8 to Day –4 (for a total of 5 days) given 
over a minimum of 30 minutes daily. The infusion can take longer per institutional guidelines. 
 
Preparation, administration, and monitoring will be according to institutional standard practice. 
Fludarabine will be adjusted to the ideal body weight (IBW) in children weighing > 125% IBW. 
Melphalan 
Melphalan 140 mg/m2 will be given IV on Day –3 given over a minimum of 30 minutes. The 
infusion can take longer per institutional guidelines. 
 
Melphalan will be adjusted to the ideal body weight (IBW) in children weighing > 125% IBW. 
 
Infusion of Bone Marrow 
 
Under no circumstances is the bone marrow stem cell product to be irradiated. Vital signs should 
be monitored before beginning the infusion and periodically during administration. Pre- 
medications and hydration prior to stem cell infusion will be administered per institutional 
procedure. Diphenhydramine, epinephrine, and hydrocortisone should be available at the bedside 
for emergency use if infusion reactions occur. Oxygen with nasal prongs for standby use should 
be present in the room. 
 
GVHD Prophylaxis 
 
GVHD prophylaxis should be given in accordance with the preparative regimen received by the 
patient. 
A. Patients who received a matched unrelated donor transplant or who received an HLA- 
identical sibling transplant using regimen A (BU/Flu/r-ATG) will receive the GVHD 
prophylaxis regimen described in Table 2.7.4A. Therapeutic levels of tacrolimus must be 
maintained at all times (per institutional standard). Those unable to tolerate tacrolimus may 
receive cyclosporine with therapeutic levels maintained per institutional standard. 
B. Patients who received an HLA-identical sibling transplant using regimen B 
(Alemtuzumab/TBI 300 cGy) will receive the GVHD prophylaxis regimen described in 
Table 2.7.4.B. 
C. Patients who received an HLA-identical sibling transplant using regimen C 
(Alemtuzumab/Flu/Mel) will receive the GVHD prophylaxis regimen described in Table 
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Additional details on each GVHD prophylaxis medication is below. 
 
Table 2.7.4.A GVHD prophylaxis
Day
GVHD Regimen
-3 
Tacrolimus at therapeutic doses through day 180, then 
taper per institutional practice
0
Stem cell infusion
+1
Methotrexate 15 mg/m2 IV
+3
Methotrexate 10 mg/m2 IV
+6
Methotrexate 10 mg/m2 IV
+11
Methotrexate 10 mg/m2 IV
 
Table 2.7.4.B GVHD Prophylaxis for Regimen B (HLA-ID Sibling transplantation)
Day
GVHD Regimen
-1 
Sirolimus at therapeutic doses through day 180, then taper per 
institutional guidelines if donor CD3+ >50%
 
Table 2.7.4.C GVHD Prophylaxis for Regimen C (HLA-ID sibling transplantation)
Day
GVHD Regimen
-3 
Tacrolimus at therapeutic doses through day 180, then taper per 
institutional practice
0
Infusion of bone marrow
+1
IV methotrexate 7.5 mg/m2 
+3
IV methotrexate 7.5 mg/m2 
+6 
IV methotrexate 7.5 mg/m2 
 
Calcineurin Inhibitor 
Tacrolimus will be administered beginning on Day –3 and doses will be adjusted to maintain 
appropriate levels according to institutional guidelines. Tacrolimus can be administered by 
continuous or intermittent infusion per institutional guidelines. Dose adjustments will be made 
based on toxicity and blood levels. Tacrolimus will be converted to an oral form, preferably 
microemulsion, at 2-3x the IV dose when oral medications are tolerated. Tacrolimus dosing will 
be monitored and altered as clinically appropriate (per institutional standard). Patients will receive 
tacrolimus until day +180 and tapered thereafter in the absence of GVHD. A suggested taper in 
the absence of GVHD is 10% per week. In case of unstable mixed donor chimerism or GVHD, the 
duration of tacrolimus alone or in combination with additional immunosuppressive agents may be 
modified at investigator’s discretion/institutional guidelines as dictated by patient’s condition. A 
similar schedule will apply for those receiving cyclosporine. Please see section 3.3.7.1 about PRES 
prevention. If PRES occurs in a study subject, administration of the calcineurin inhibitor 


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should be suspended until there is clinical stabilization. In addition, if an episode of PRES occurs 
beyond the typical risk period for VOD/SOS, the calcineurin inhibitor may be replaced by 
sirolimus. Administering sirolimus and tacrolimus together is not recommended. 
 
Methotrexate 
Methotrexate will be given IV at a dosage of 15mg/m2 on day +1 and 10mg/m2 on days +3, +6, 
and +11. The day +1 dose of methotrexate will not be administered until 24 hours following 
completion of the marrow infusion. Mucositis is treated symptomatically. Methotrexate doses used 
in the setting of marrow transplantation are not sufficient to cause liver disease. In the absence of 
renal impairment, third space fluid collection (ascites, pleural effusion, etc.), or severe mucositis, 
all planned doses of methotrexate should be administered. The attending transplant physician 
should assess patient prior to delivery of each dose and decide if any methotrexate dose 
adjustments are necessary. Guidelines for methotrexate dose adjustments are provided in 
Appendix E. 
 
Sirolimus: 
Sirolimusforparticipants≥18.00yearsold: A one-time sirolimus loading dose, 6 mg PO, is 
given on Day -1. Sirolimus is then continued at a maintenance dose (start 2 mg PO QD) with 
dose adjustments to maintain a trough of 10-15 ng/mL for the first 3-4 months and ~10 ng/ml for 
the remainder of year 1. Sirolimus may be tapered at end of year 1 if donor T cell chimerism is 
>50% in the absence of GVHD. 
 
Sirolimus for participants <18.00 years old: Sirolimus dosing is based on actual body weight; 
however, an adjusted body weight may be used if the actual weight is > 50% greater than IBW. 
A one-time sirolimus loading dose, 3 mg/m2 PO with the dose not to exceed 6 mg, is given on 
Day -1. Sirolimus is then continued at a maintenance dose (start 1 mg/m2 PO QD maximum 2 
mg QD) with dose adjustments to maintain a trough of 10-15 ng/mL for the first 3-4 months and 
~10 ng/ml for the remainder of year 1. Sirolimus may be tapered at end of year 1 if donor T cell 
chimerism is >50% in the absence of GVHD. 
 
Supportive Care 
 
Institutional practice guidelines should be followed after transplantation for nutritional support, 
treatment of infections, blood products, and treatment for acute or chronic GVHD. Institutional 
practice guidelines should be followed regarding determination of caregiver status during and after 
transplantation. 
 
Additional supportive care guidelines are recommended below. The treating investigator or 
appropriate research team designee may contact the Emmes protocol coordinator with questions 
(i.e. treatment plans for mixed chimerism). 
 
Treatment of a transplant-related complication such as GVHD, interstitial pneumonitis, veno- 
occlusive disease, or a complication that is NOT an endpoint for the trial is at the discretion of the 
treating physician or institutional standard. 


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Any consideration of enrollment on a clinical trial for non-treatment related purposes (i.e. addition 
of an immunosuppressive agent for GVHD prophylaxis or to facilitate engraftment) requires 
approval from the Protocol Chairs/Protocol Officer. Please contact Emmes protocol coordinator 
with any inquiries. 
 
Venous Access 
Recipients will have appropriate long-term central venous access placed, per institutional standard 
practice, prior to beginning the conditioning regimen. The placement of a double lumen tunneled 
catheter is recommended. 
 
Blood Products 
The hemoglobin level must be maintained between 9.0 and 11.0 g/dL and platelet count 
> 50,000/mL after transplantation to minimize the risk of neurological adverse events. Irradiated 
blood products should be administered universally, and cytomegalovirus (CMV) negative or 
leuko-filtered blood products are recommended for CMV sero-negative recipients. In those 
patients who do not receive chronic RBC transfusions or who have a Hgb S fraction > 30%, a 
partial exchange transfusion will be performed to reduce the hemoglobin (Hgb) S to ≤ 30% before 
commencing the conditioning regimen. The Hgb and % Hgb S should be re-checked 4 hours after 
the exchange transfusion. 
 
Hypertension 
Hypertension should be strictly controlled to prevent central nervous system (CNS) toxicity. Blood 
pressure should be monitored closely and both systolic and diastolic hypertension should be treated 
promptly to maintain blood pressure at the patient’s pre-transplant baseline. Explicit orders must 
be written to intervene if systolic or diastolic blood pressure exceeds 10% over baseline. Refer to 
section 3.3.7 for additional information. 
 
Treatment of Fever/Infections 
Patients should be monitored closely for clinical manifestations of infection and treated per 
institutional guidelines with broad-spectrum antibacterial, antiviral, and antifungal agents. Early 
and severe immunosuppression of the patient necessitates prompt and adequate treatment of 
infections to prevent systemic spread. Patients are especially susceptible to bacterial and viral 
infections in the early post-transplant period. 
 
Infection Surveillance and Prophylaxis 
Please use institutional guidelines for infection surveillance and prophylaxis. Where institutional 
guidelines do not exist, the following guidelines are recommended. 
 
Antiviral Prophylaxis 
Acyclovir prophylaxis is recommended after transplantation until immune reconstitution in 
patients who are sero-positive for Herpes Simplex or Varicella Zoster Virus. If unable to tolerate 
oral medications, IV therapy will be necessary. 


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Pneumocystis Prophylaxis 
Trimethoprim-sulfamethoxazole or an equivalent drug should be administered beginning after 
neutrophil recovery and continued until there is full immune reconstitution. 
 
Fungal Prophylaxis 
Due to the level of immune suppression, anti-fungal prophylaxis for candida and invasive mold 
infection is recommended with agents such as itraconazole, voriconazole, or posaconazole until 
Day 180. Frequent monitoring of tacrolimus levels will be necessary during azole therapy to avoid 
toxic drug levels. 
 
Bacterial Prophylaxis 
Prophylaxis against bacterial infections is generally not recommended. However, antibiotic 
prophylaxis according to institutional guidelines is acceptable. 
 
Cytomegalovirus (CMV) 
It is recommended that recipients be tested weekly using the polymerase chain reaction (PCR) 
method beginning a week after commencing conditioning regimen and until Day 100. Antiviral 
therapy for CMV reactivation should commence preemptively if CMV testing reveals a high or 
rising viral load. Treatment of CMV should be undertaken per institutional guidelines. If CMV 
reactivation occurs at or before engraftment, foscarnet may be considered as an alternative to 
ganciclovir mitigate marrow suppression. 
 
Adenovirus 
It is recommended that testing for adenovirus infection in the blood by PCR method is 
recommended in the event of symptoms suspicious for infection such as diarrhea, hepatic 
dysfunction, or respiratory symptoms. If an active systemic infection is diagnosed, therapy should 
be instituted with cidofovir or other active agents per institution guidelines. 
 
Epstein-Barr Virus (EBV) 
It is recommended that Patients will have EBV DNA quantitative PCR testing on peripheral blood 
every two weeks from Day 14 to Day 100. In the event of persistent EBV virema or 
signs/symptoms consistent with EBV-related Post-transplant lymphoproliferative disease (PTLD, 
adenopathy, fever, etc.) therapy with rituximab is recommended. 
 
Intravenous Immune Globulin 
Intravenous immune globulin may be administered according to institutional practice guidelines. 
 
2.8. 
Graft Failure 
 
Graft failure may occur following HCT in patients with sickle cell disease and is usually associated 
with autologous reconstitution of the bone marrow with host hematopoiesis. Both in related and 
unrelated donor settings the data suggest most patients experience autologous reconstitution of the 
bone marrow with host hematopoiesis. It is associated with a steady decline in donor chimerism, 
increasing representation of hemoglobin S (in the absence of ongoing RBC transfusion therapy), 
and clinical manifestations of sickle cell disease. The management of graft failure is at the 


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discretion of the treating physician / transplant center. Autologous bone marrow harvest is not 
recommended. Most SCD patients experience autologous reconstitution, and second 
transplantation from a haplo-identical relative has been reported as an acceptable treatment. 
 
Please contact the protocol chairs with any questions on the management of patients with declining 
donor chimerism. 
2.9. 
Toxicities of Hematopoietic Stem Cell Transplantation 
Toxicities Related to the Preparative Regimen 
Pancytopenia 
The administration of fludarabine and busulfan is expected to produce pancytopenia with absolute 
neutrophil count (ANC) < 500/μL, hemoglobin < 7-8 g/dL and platelet < 50,000/μL for as long as 
several weeks in most patients. Thus, these patients will require RBC and platelet transfusions 
until hematological recovery after BMT. In addition, many patients will develop fever and 
approximately 30% will develop a documented infection during the period of neutropenia. 
Complications related to pancytopenia may be life threatening or fatal. 
 
Chemotherapy-Specific Toxicities 
The clinical management of chemotherapy-specific toxicities will be at the discretion of the 
treating physician and institutional guideline/protocols. 
 
Busulfan 
Administration can cause decreased blood counts, nausea, vomiting, diarrhea, oral ulcers, 
decreased immunity, sterility, interstitial pneumonitis, lung fibrosis, allergic reactions, and rarely 
seizures (with very high doses). We recommend counseling patients for infertility including 
gamete cryopreservation in accordance with institutional practice. 
 
Fludarabine 
Administration can cause hemolytic anemia, neutropenia or thrombocytopenia, low blood counts 
secondary to bone marrow suppression, nausea, vomiting, diarrhea, stomatitis, skin rash, 
pneumonitis, edema, fever, chills, fatigue, blurred vision, peripheral neuropathy, confusion, coma, 
decreased immunity and rarely encephalopathy. 
 
Rabbit Anti-Thymocyte Globulin 
Thymoglobulin (r-ATG) is a purified, pasteurized, gamma immune globulin obtained by 
immunization of rabbits with human thymocytes, and thus contains cytotoxic antibodies directed 
against antigens expressed on human T-lymphocytes. Infusion toxicities include leukopenia, 
malaise, and post-transplant lymphoproliferative disease (PTLD). Chills and fever commonly 
occur in patients receiving ATG. Minor toxicities can usually be managed by symptomatic 
treatment and temporary slowing of the infusion. Pruritus and erythema occasionally develop. 
These symptoms are generally controlled with diphenhydramine. Respiratory distress and 
hypotension may be signs of anaphylaxis. In such cases, the infusion should be discontinued. If 
reaction persists, diphenhydramine, epinephrine, or hydrocortisone or a combination should be 


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administered. Serum sickness syndrome may present with fever, arthralgias, and rash. Symptoms 
usually occur with some delay after initial ATG administration. Treatment is with steroids. Other 
toxicities include pain in chest, flank, or back which may be a sign of anaphylaxis or hemolysis. 
Infusion should be discontinued if anaphylaxis is suspected. 
 
Alemtuzumab 
Alemtuzumab side effects include: 
• Cardiovascular: dysrythmias (most commonly tachycardia), hypotension, hypertension, 
cardiomyopathy, congestive heart failure 
• Dermatologic: rash, itching 
• Endocrine: Thyroid disorders 
• Gastrointestinal: anorexia, nausea, vomiting, abdominal pain, diarrhea, acute acalculous 
cholecystitis 
• Hematologic: anemia, thrombocytopenia, leukopenia 
• Musculoskeletal: myalgia, arthralgia muscle weakness, muscle spasms 
• Neurologic: headache, dizziness, insomnia, anxiety, tremor, progressive multifocal 
leukoencephalopathy 
• Miscellaneous: infection, infusion reaction, allergic reaction, cough, sweating, lower 
extremity swelling 
Melphalan 
Melphalan side effects include: 
• Cardiac and vascular: edema, heart failure, vasculitis 
• Gastrointestinal: mucositis, nausea, vomiting, diarrhea General: fatigue 
• Hematologic: anemia, thrombocytopenia, neutropenia 
• Hepatic: abnormal liver function tests, hepatitis 
• Pulmonary: shortness of breath, pulmonary fibrosis 
• Renal: renal impairment 
• Miscellaneous: allergic reaction including anaphylaxis, secondary malignancy 
 
Total Body Irradiation 
Total body irradiation will be administered (300 cGy) in Regimen B. This dose is a fraction of the 
irradiation delivered in a myeloablative conditioning regimen, thus modulated toxicity is anticipated. 
Nonetheless, irradiation can cause short-term and long-term toxicities, particularly in children. The 
long-term toxicities include a risk of malignancy secondary to the exposure and a risk of infertility. 
 
Low dose (less than 400cGy) Total Body Irradiation side effects include: 
• Cutaneous: erythema, hyperpigmentation, alopecia 
• Gastrointestinal: nausea, vomiting, diarrhea, parotitis, mucositis, abdominal cramping 
• General: fever, fatigue 
• Genitourinary: gonadal impairment 
• Hepatic: hepatic sinusoidal obstruction syndrome 


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• Hematologic: myelosuppression, anemia, thrombocytopenia 
• Pulmonary: interstitial pneumonitis 
• Renal: nephropathy 
• Miscellaneous: infection, short stature, vertebral deformities, cataracts, secondary 
malignancy, hormonal impairment 
 
Toxicities Related to Hematopoietic Stem Cell Infusion 
 
Infusion of allogeneic BM cells can result in shortness of breath, fever, hemolysis with renal 
dysfunction and back pain, or anaphylaxis. To reduce the risk of reactions to product infusion, 
patients will be hydrated before and after administration of allogeneic BM, and will be monitored 
closely before, during, and after infusion. 
Toxicities Related to GVHD Prophylaxis 
Tacrolimus 
Tacrolimus (or cyclosporine) may cause nephrotoxicity, seizures, hypertension, hirsutism, 
thrombotic 
microangiopathy, 
electrolyte 
imbalances, 
paresthesias/neuropathy, 
gingival 
hyperplasia, transient-blindness, and hepatic dysfunction. 
 
Methotrexate 
Myelosuppression and stomatitis are the most common dose-limiting side effects. At the dosage 
used in this study, no other significant side effects are anticipated. 
 
Sirolimis 
Sirolimus side effects include: 
• Cardiovascular: hypertension, tachycardia, venous thromboembolism (which can cause 
pulmonary embolism or deep vein thrombosis) 
• Cutaneous: itching, rash, acne, exfoliative dermatitis, impaired wound healing 
• Endocrine and metabolic: hyperglycemia, hypokalemia, hypertriglyceridemia, 
hypercholesterolemia 
• Gastrointestinal: constipation, diarrhea, nausea, abdominal pain, mouth sores 
• Hematologic: anemia, thrombocytopenia, leukopenia, thrombotic thrombocytopenic 
purpura, hemolytic uremic syndrome, transplant associated thrombotic microangiopathy 
• Musculoskeletal: bone necrosis, myalgia, arthralgia 
• Neurologic: headache dizziness 
• Pulmonary: interstitial lung disease 
• Renal: proteinuria, increased creatinine, edema 
• Miscellaneous: infection, allergic reaction, epistaxis, secondary malignancy 


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CHAPTER 3 
 
 
3. STUDY ENDPOINTS 
 
3.1. 
Primary Endpoint 
 
The primary endpoint is to compare the difference in the observed proportion of patients surviving 
at 2 years post-biologic assignment between the donor and the no donor arms. 
 
3.2. 
Secondary Endpoints 
 
In addition to comparing the observed proportion of patients surviving at 2 years post-biologic 
assignment using the ITT approach, we will also compare the difference in the observed proportion 
of patients surviving at 2 years post-biologic assignment between groups by treatment received 
(i.e., as treated). The “as treated” approach will compare OS between patients who received a 
transplant to patients who received standard of care. Secondary endpoints will examine record- 
based assessment of sickle-related events using the system identified by Elmariah and colleagues 
(pulmonary hypertension, cerebrovascular events, renal function, avascular necrosis of 
hip/shoulder, and leg ulcers)19; cardiac function, pulmonary function, functional assessment by 
administration of 6MWD test, HRQoL and mean pain intensity over a 28-day period. Additionally, 
HRQoL, 28-day e-pain diary, and the 6MWD test will also be measured at 1-year. We will examine 
changes between baseline, at 1-year and at 2-years between participants on the donor and no donor 
arms. Additionally, changes within assigned group will also be reported. Extended follow up for 
survival status is planned years 3 through 10 from biologic assignment. 
Occurrence of Sickle-Related Events 
Elmariah and colleagues have created a severity score on five parameters.19 We will track 
occurrence of these events over two years and compare the proportion of patients experiencing 
each component within two years. The events are pulmonary (pulmonary hypertension as 
measured by TRV or O2 saturation < 92%); cerebrovascular (stroke, transient ischemic attack, or 
seizure); renal (proteinuria or creatinine >1); avascular necrosis of the hip or shoulder; and leg 
ulcers. The prevalence of these events will be extracted from the histories of subjects at study 
entry, noting that these events can constitute eligibility criteria for the study. We will also examine 
and describe the occurrence of these events on study (i.e., for the period between biologic 
assignment and 2-years). 
 
HRQoL 
 
We will assess health related quality of life using the PROMIS-57 instrument and the stiffness 
impact short form from ASCQ-Me for all participants. The PROMIS-57 and ASCQ-Me Stiffness 
Scale are available in Spanish and English. Participants who do not speak Spanish or English will 
not complete the HRQoL surveys. 


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We will focus on changes from baseline, assuming, on average, no change in the no donor group 
and improvement in the donor group. The results on these instruments are scaled to a mean of 50 
and a standard deviation of 10, with the directionality of the interpretation reflecting the wording 
of the domain (high scores indicate worse sleep disturbance, but better physical function). We have 
assumed no correlation to maximize the variability of the estimate of change. PROMIS-57 and 
ASCQ-Me Stiffness Scale will be administered within the last 3 weeks of the electronic pain diary 
as PROMIS-57 and ASCQ-Me Stiffness Scale capture data for the last 7 days prior to 
administration. This will permit a direct comparison of these two approaches to assessing pain. 
While our primary endpoint is the change between the baseline and two-year assessments, we will 
also examine HRQoL at one year in order to better understand the trajectory of changes, should 
they occur, during the two-year follow up period. 
 
Mean Pain Intensity 
Based on estimates of daily pain in adults with SCD43, we anticipate that patients in the no donor 
arm will report pain with a mean pain intensity of 3.9 on a scale of 10 at baseline. We expect that 
this will be unchanged at follow-up. We anticipate that baseline pain assessments will be similar 
in the donor cohort but that these patients will demonstrate a clinically significant decline in mean 
pain intensity to a level of 1.3 units on a scale of 10 two-years later. While our primary endpoint 
is the change between the baseline and two-year assessments, we will also examine pain at one 
year, in order to better understand the trajectory of changes during the two year follow up period. 
 
Pain data will be recorded over time using the pain diary. The pain diary will be utilized in 
assessing and determining the burden of pain pre-transplant, post-transplant and with standard of 
care. The diary will be administered at baseline, 1 year and 2 years for 28 days at each time point. 
The pain diary enables real time data capture which allows us to capture pain metrics in real time 
and in the participant’s natural environment. Additionally, we will be able to compare diary data 
to NIH-PROMIS measures of pain. 
 
The pain diary electronic application is only available for English speaking participants. Non- 
English speaking participants will not complete the pain diary. Additionally, the pain diary is only 
available in electronic format. Participants who do not have access to an internet enabled device 
will not complete the pain diary. Please contact the BMT CTN 1503 Pain Diary Coordinator in the 
event a study participant will not be completing the pain diary. 
 
Exercise Capacity 
 
We will use the 6MWD, testing under standardized procedures, to assess exercise capacity (see 
guidelines as outlined in the BMT CTN 1503 Manual of Procedures). This endpoint will measure 
absolute change from baseline with increased distance identified as positive change. We anticipate 
an improvement of at least 50 m for subjects in the donor arm on average, compared to subjects in 
the no donor arm, in whom we anticipate no improvement. While our primary endpoint is the 
change between the baseline and two-year assessments, we will also examine 6MWD test at one 
year in order to better understand the trajectory of changes during the two-year follow up period. 


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Cardiac Function 
 
Tricuspid regurgitant velocity (TRJV) is a marker for the severity and progression of SCD. While 
our primary endpoint is the change between the baseline and two-year assessments, we will also 
examine TRJV at one year in order to better understand the trajectory of changes during the two- 
year follow up period. All cardiac function evaluations obtained and/or reported for study purposes 
must include adequate documentation of TRJV. It is recommended that cardiac evaluations are 
obtained at the same institution to minimize variability. 
 
Pulmonary Function 
 
There is a growing body of evidence to indicate that the pulmonary toxicity of SCD is 
progressive.44,45 We anticipate changes in Forced Expiratory Volume 1 second (FEV1) of 49 
cc/year45 for participants on the no donor arm, compared to half that rate in the donor arm, based 
on Field’s observation of a general population decrease of 20 to 26 cc/year.44,45 We will also assess 
the proportion of participants on the treatment arms in whom we find evidence of restrictive lung 
disease, defined as total lung capacity (TLC) below the 5th percentile adjusted for age, gender, 
race, and height. The complete pulmonary function test will include FVC, FEV1, FEV1/FVC, VC, 
TLC, RV, ERV, IC, FRC, DLCO, and oxygen saturation. It is recommended that pulmonary 
evaluations are obtained at the same institution to minimize variability. 
 
Renal Function 
 
Guasch reported that 61% of SCD subjects between 18 to 30 years of age had either micro- or 
macroalbuminuria based on a single measurement.46 We will assess renal function through 
measurements of albuminuria (urine-albumin creatinine ratio) and serum creatinine. 
 
3.3. 
Secondary Endpoints for Patients Assigned to the Donor Arm 
Neutrophil and Platelet Recovery 
Absolute Neutrophil Count (ANC) recovery: defined as the first day of 3 measurements on 
different days when the patient has an absolute neutrophil count of ≥ 500/µL after conditioning. 
 
Platelet Recovery: defined as the first day of a minimum of 3 measurements on different days that 
the patient has achieved a platelet count > 50,000/µL AND did not receive a platelet transfusion 
in the previous 7 days. Platelet data will be collected via the CIBMTR. 
 
Primary Graft Failure: defined as never achieving ANC ≥ 500/µLorneverachieving≥5%donor
whole blood or myeloid chimerism (myeloid is preferable) assessed by bone marrow or peripheral 
blood chimerism assays by day +42 post-transplant. Second infusion of hematopoietic cells is also 
considered indicative of primary graft failure by day +42 post-transplant. 
 
Secondary Graft Failure: defined as < 5% donor whole blood or myeloid chimerism (myeloid is 
preferable) in peripheral blood or bone marrow beyond day +42 post-transplant in patients with 
prior documentation of hematopoietic recovery with ≥ 5% donor cells by day +42 post-transplant. 


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Second infusion of hematopoietic cells is also considered indicative of secondary graft failure. 
 
Lineage Specific Chimerism 
 
Chimerism studies are recommended on whole blood, CD3 sorted mononuclear cells as well 
CD15, or CD33 sorted mononuclear cells as per institutional practice. Erythroid chimerism assays 
will be performed at the Blood Center of Wisconsin (See BMT CTN 1503 MOP for more info). 
The assay involves reverse transcription of total RNA followed by digital droplet PCR with 
fluorescently-labeled hydrolysis probes specific for the HBB gene HbA and HbS transcripts. The 
percent chimerism is calculated taking into account the genotype of the donor (AA or AS). The 
results of these assays will not be used for clinical care. 
 
Grade II-IV and Grade III-IV Acute GVHD 
 
Acute GVHD will be graded according to the BMT CTN Technical Manual of Operating 
Procedures (MOP). The time of onset of acute GVHD grades II-IV and III-IV will be recorded as 
well as the maximum grade achieved (including the date of maximum grade). 
 
Chronic GVHD 
 
Data will be collected according to the recommendations of the NIH Consensus Conference. Eight 
organs will be scored on a 0-3 scale to reflect degree of chronic GVHD involvement. Liver and 
pulmonary function test results and use of systemic therapy for treatment of chronic GVHD will 
also be recorded. These data will allow calculation of the NIH global severity scores of mild, 
moderate, and severe chronic GVHD, which has been associated with transplant related mortality 
and overall survival. 
 
Idiopathic Pneumonia Syndrome (IPS) 
 
Evidence of widespread alveolar injury in the absence of documented active lower respiratory tract 
infection: 
a. Radiographic evidence of bilateral, multi-lobar infiltrates (by chest x-ray or CT scan), 
AND 
b. Evidence for abnormal respiratory physiology, based upon oxygen saturation (SpO2) 
< 93% on room air, or the need for supplemental oxygen to maintain oxygen saturation 
≥ 93%. 
Veno-Occlusive Disease (VOD) 
 
Veno-occlusive disease (VOD) is diagnosed by the presence of two or more of the following with 
no other identifiable cause for liver disease: 
a. Jaundice (direct bilirubin > 2 mg/dL or > 34 μmol/L) 
b. Hepatomegaly with right upper quadrant pain 
c. Ascites and/or weight gain (> 5% over baseline) 


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Central Nervous System (CNS) Toxicity 
 
CNS toxicity will be defined as seizures, CNS hemorrhage, or posterior reversible 
leukoencephalopathy syndrome (PRES), which is defined as an increased diffusion coefficient in 
areas of T2 hyper intensities on diffusion-weighted imaging in the context of clinical symptoms or 
physical findings including headache, seizures, visual disturbances, and/or altered level of 
consciousness. PRES results from endothelial injury related to abrupt blood pressure changes or 
direct effects of cytokines on the endothelium, which leads to the breakdown of the blood–brain 
barrier and subsequent brain edema. With early diagnosis and appropriate management, PRES is 
reversible, both radiographically and clinically, and generally has a favorable prognosis. PRES 
commonly occurs in the first month following HCT although patients remain at risk during the 
course of immune suppression therapy. 
 
Measures for prevention of PRES include extended duration of anticonvulsant prophylaxis, 
intensified antihypertensive management (including mean arterial pressure if indicated), and 
aggressive platelet support. Blood pressure values must be compared against published normal 
values appropriate for age and race (African Americans have normal blood pressure adjusted for 
age compared to Caucasians). Blood pressure values in SCD patients are lower compared to 
population norms adjusted for age and race. 
 
Prevention of Posterior Reversible Leukoencepaholpathy Syndrome (PRES): 
Recommended Guidelines 
In addition to the recommended guidelines below, refer to Appendix G for additional guidelines 
regarding the prevention and/or management of PRES. 
 
• Control of Blood Pressure 
Blood pressure in patients with SCD has been reported to be lower than published 
standards for age, sex, and race-matched controls. Pressures above the 90th percentile for 
HbSS may overlap levels considered normal in non-SCD patients. Blood pressure (BP) 
may be elevated with fluid infusions or use of medications such as corticosteroids or CNIs. 
Supportive care orders must indicate the importance of keeping BP within 10% above the 
median for age for HbSS patients as described by Pegelow et al (Table 5)47 or the baseline 
BP for the patient, whichever is lower. Mean arterial pressure (MAP) should be 
maintained at < 70mmHg. Close monitoring and aggressive management with anti- 
hypertensive agents will be required to prevent PRES. 
 
Table 5. Median and 90th percentiles of systolic (SYS BP) and diastolic (DIA BP) blood 
pressure for sickle cell anemia subjects by age (years) in the Cooperative Study of Sickle 
Cell Disease 
 
Age 
2-3 
4-5 
6-7 
8-9 
10-11 
12-13 
14-15 
16-17 
18-24 
25-34 
35-44 
Female N 
257 
97 
72 
68 
57 
71 
89 
81 
227 
199 
66 
SYS BP 
Median 
90 
95 
96 
104 
106 
110 
110 
110 
110 
110 
110 
90th 
100 
110 
110 
110 
110 
118 
120 
122 
122 
125 
130 


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Age 
2-3 
4-5 
6-7 
8-9 
10-11 
12-13 
14-15 
16-17 
18-24 
25-34 
35-44 
DIA BP 
Median 
52 
60 
60 
60 
60 
62 
70 
70 
64 
68 
70 
90th 
62 
70 
70 
70 
74 
74 
80 
78 
80 
80 
84 
Male N 
276 
111 
78 
66 
75 
61 
75 
53 
179 
166 
41 
SYS BP
Median
90
95
100
100
100
110
108
112
112
114
110
90th 
104 
110 
108 
116 
112 
120 
120 
128 
130 
130 
132 
DIA BP 
Median 
54 
60 
60 
60 
60 
64 
64 
70 
68 
70 
70 
90th 
66 
68 
68 
70 
70 
72 
78 
80 
80 
80 
84 
 
• Maintenance of Adequate Platelet Count 
Thrombocytopenia and coagulopathy may be associated with increased risk of PRES- 
related intra-cranial hemorrhage. It is therefore recommended to keep platelet count > 
50,000. 
 
• Maintenance of Euvolemic State 
Large fluid shifts should be avoided. Close attention must be paid to fluid balance since 
fluid overload with weight gain associated with increased blood pressure and consequently, 
increased risk of PRES. 
 
• Maintenance of Adequate Level of Serum Magnesium 
The association between hypomagnesemia and cyclosporine toxicity was first observed 
during the initial clinical trials of the drug for GVHD prophylaxis.48,49 Magnesium 
sulphate is considered the drug of choice in the treatment of PRES associated with 
eclampsia. It is therefore recommended that patients receive magnesium supplementation 
in order maintain magnesium level at 1.8mg/dL Maintenance of mild hypermagnesemia 
with serum magnesium 2-3mg/dL may be advisable, but may be difficult to achieve. 
 
• Seizure Prophylaxis 
Seizure prophylaxis should be commenced prior to conditioning therapy (therapeutic level 
prior to initiation of conditioning) and continued at least until immunosuppression is 
withdrawn. 
 
• Platelets 
Platelet counts should be monitored frequently after starting conditioning therapy, and 
platelet transfusions shouldbeadministeredtokeepcounts≥50x109/L 
Infection 
Significant infections will be recorded including but not limited to bacterial or fungal sepsis, CMV 
reactivation with/without clinical disease, adenovirus infection, EBV PTLD, other significant viral 
reactivations or community-acquired viral infections, and invasive mold infections. The incidence 


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of definite and probable viral, fungal, and bacterial infections will be tabulated for each 
intervention arm. The cumulative incidence of CMV reactivation in the first 100 days post HSCT 
will be described. All Grade 2 and 3 infections will be reported according to the BMT CTN 
Technical MOP. 
 
Long-Term Follow Up 
Survival status of all participants will be collected annually, years 3 through 10. The probability 
of survival annually beginning year 3 will be calculated for each treatment arm. 


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CHAPTER 4 
 
4. PATIENT REGISTRATION, ENROLLMENT AND EVALUATIONS 
 
4.1. 
Screening and Enrollment Procedures 
 
Participants are identified and recruited by the site investigator, an SCD physician. If initial 
consultation with the potential participant confirms interest in the proposed phase II trial, the 
patient is referred to a HCT physician for further consultation. This consultation includes a detailed 
review of the trial design including the concept of biologic assignment to treatment arms based on 
donor availability, the anticipated benefits and complications of both treatment arms, importance 
of adherence to assigned treatment arm, and compliance including availability at 1- and 2-years 
later for trial assessments. The order of events for patient enrollment is as follows: 
1. Interested participants will sign a study informed consent form which will include 
consent for screening assessments, HLA typing, and all non-transplant related follow up. 
Following local assessment of eligibility criteria, the potential participant will be enrolled 
into Segment 0 in AdvantageEDC, a web-based data collection system. The time period 
from initial consent for eligibility screening to biological assignment is defined as 
Segment 0 of the protocol. 
 
2. Following Segment 0 enrollment, as applicable, the Eligibility Review Committee (ERC) 
will independently review the clinical eligibility data regarding disease severity to 
confirm or deny eligibility according to procedures outlined in Appendix G. All 
participants enrolled under the neurologic deficit SCD severity criteria will be reviewed. 
For participants who do not require ERC review, confirmation of eligibility will be 
confirmed upon enrollment into Segment 0. If the participant is not confirmed to be 
clinically eligible then he/she is off-study and no further follow up is required. Criteria 
for clinical eligibility are described in Section 2.3.1. 
 
3. If clinical eligibility is confirmed, the site is notified and will proceed with HLA typing 
and donor search. All patients will be assigned to the no donor arm upon confirmation of 
eligibility. HLA typing is performed on the participant and full siblings (if applicable) to 
determine donor status. While it is acceptable to wait to initiate the search for an adult 
unrelated donor after establishing an HLA-matched sibling is not available, it is 
recommended that the related and unrelated donor searches occur simultaneously to 
avoid delays in identifying a suitable donor. Any participant for whom a suitable sibling 
or unrelated donor as defined in section 2.5.1 is not confirmed ≤ 180 days from 
confirmation of eligibility will remain in the no donor/standard of care arm. 
 
4. Followingadonorsearch,biologicassignmentisdetermined≤180daysfromthedate
of confirmation of eligibility; those with an HLA-matched donor meeting requirements 
in section 2.5.1 are assigned to the donor arm, and those without a donor are assigned to 
the no donor/standard of care arm. 


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a. For donor arm patients, the date of biologic assignment is the date a suitable 
donor (defined as meeting all criteria outlined in section 2.5.1 of the protocol) 
is confirmed. Donor arm participants should be approached with the transplant 
consent as soon as possible after identification of a suitable donor. Initiation of 
transplantconditioningforthoseassignedtothedonorarmshouldoccur≤30
days after signature on the transplant consent. Workup is a continuum rather 
than an interrupted process. 
b. For no donor arm patients, the date of biologic assignment is the date the site 
becomes aware that the patient does not have a suitable related or unrelated 
donor. 
 
5. Once the participant has been biologically assigned, they will be enrolled into Segment 
A in AdvantageEDC. The time period from biological assignment to the end of the study 
is defined as Segment A of the protocol. It is recommended that enrollment in Segment 
A occur ≤ 30 days after biologic assignment. For donor arm patients, consent for
transplant should be obtained prior to Segment A enrollment. 
 
4.2. 
Patient Follow up and Study Assessments 
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. 
 
TABLE 4.2.1: FOLLOW-UP SCHEDULE 
 
Study Visit
Target Day
Pre-Enrollment
Pre-Enrollment* 
≤1yearpriortoSegment0Enrollment
≤3monthspriortoSegment0Enrollment
≤30dayspriortoSegment0Enrollment
Screening Segment
PBA 
≤30daysfollowingconfirmationofEligibility;
prior to biologic assignment
Pre-Transplant Visits for Donor Arm Participants Only
Pre-conditioning** 
≤90dayspriortoinitiation of transplant 
conditioning
Pre-conditioning 
≤30dayspriortoinitiationoftransplant
conditioning
Pre-conditioning 
Within 7-14 days prior to initiation of transplant 
conditioning


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Post-Transplant Visits for Donor Arm Participants Only
Week 1
7 ± 3 days
Week 2
14 ± 3 days
Week 3
21 ± 3 days
Week 4
28 ± 3 days
Week 5
35 ± 3 days
Week 6
42 ± 3 days
Week 7
49 ± 3 days
Week 8
56 ± 3 days
Week 9
63 ± 3 days
Week 10
70 ± 3 days
Week 11
77 ± 3 days
Week 12
84 ± 3 days
Week 13
91 ± 3 days
Day 100
100 ± 3 days
Day 180
180 ± 14 days
Day 365
365 ± 14 days
Day 730
730 ± 14 days
Post-Biologic Assignment Visits
Day 0 post-BA
0 ± 14 days
Day 100 post-BA
100 ± 14days
Day 180 post-BA
180 ± 14 days
Day 270 post-BA
270 ± 14 days
Day 365 post-BA
365 ± 14 days
Day 450 post-BA
450 ± 14 days
Day 540 post-BA
540 ± 14 days
Day 630 post-BA
630 ± 14 days
Day 730 post-BA
730 ± 14 days
* Refer to section 4.2.2 for the required timing of each pre-enrollment assessment 
**Pre-conditioningvisit≤90dayspriortoinitiationoftransplantconditioningonlyrequiredin
the event a liver biopsy is needed (see section 4.2.5.1 for additional information) 
 
Required Assessments PRIOR to enrollment in Segment 0: 
 
Prior to enrollment in Segment 0, patients must meet the clinical eligibility for referral to an HCT 
physician as described in section 2.3.1. Screening assessments should be completed after obtaining 
consent for eligibility screening with the exception of the cardiac and pulmonary assessments 
whichcanbeahistoricalassessmentperformed≤1-year prior to enrollment. These assessments 
are summarized below and in Table 6. 
 
The following assessments must be completed for all participants ≤ 1-year prior to enrollment into 
Segment 0:


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- 
Cardiac: LVEF or LV shortening fraction by echocardiogram or by MUGA, evaluation 
must include documentation of tricuspid valve jet velocity (TRJV). Refer to Section 3.2.5. 
- 
Pulmonary: The complete pulmonary function test will include FVC, FEV1, FEV1/FVC, 
DLCO, and oxygen saturation. 
 
Thefollowingassessmentsmustbecompletedforallparticipants≤3monthspriortoenrollment
into Segment 0 unless otherwise noted below: 
- 
History and physical examination, height and weight. The baseline history should reference 
participant’s sickle cell genotype and all relevant past medical history in relation to his/her 
severe SCD. 
- 
Karnofsky/Lansky performance score 
- 
Renal: serum creatinine and one of the following: 
o creatinine clearance calculated using the Cockcroft-Gault calculator, 
o creatinine clearance by 24 hour urine (preferred), OR 
o Radionuclide GFR including assessment for albumin 
- 
Hepatic: direct bilirubin, alkaline phosphatase, ALT, and AST 
- 
CBC with differential 
- 
Assessment of Hemoglobin S percent per institutional methods with documentation of the 
date of last packed red blood cell transfusion is required. 
- 
Infectious disease testing per institutional standards. Infectious disease testing must include 
HIV. 
- 
Pregnancy test per institutional practices (serum or urine) for females of child-bearing 
potential(required≤30dayspriortoenrollmentinSegment 0). 
- 
Sickle Cell Disease Genotyping: Assessment of SCD genotype can be done at any time but 
must be known prior to enrollment in segment 0. 
 
Eligibility Review Committee Approval & Initiation of HLA Typing 
 
As detailed in Section 4.1, potential BMT CTN 1503 participants may be screened and approved 
for protocol eligibility by a three-member review panel comprised of experts in sickle cell disease 
and transplantation (Appendix G) following Segment 0 enrollment into AdvantageEDC. All 
participants enrolled under the neurologic deficit SCD severity criteria will be reviewed, and 
participants enrolled under the other SCD severity criteria will be reviewed as necessary. For 
participants who do not undergo ERC review, confirmation of eligibility will be confirmed upon 
enrollment into Segment 0. Potential participants are reviewed by the ERC after signing of the 
study informed consent and completion of screening eligibility evaluations as defined in section 
4.2.2, and prior to initiation of HLA typing and subsequent biologic assignment. The ERC’s 
adjudication decision is based on data contained in the patient registration (Segment 0) form as 
well as uploaded source documentation establishing protocol eligibility as defined in Section 2.3.1. 
Additional details regarding the 1503 ERC adjudication process are available in Appendix G. 
 
Initiation of HLA typing and donor search is permitted only after the confirmation of eligibility 
and notification is received from the DCC in writing. Refer to section 2.5 for further details 


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regarding HLA typing standards and donor selection criteria. The Protocol Officer or his/her 
designee will review and confirm all HLA typing for donor-recipient pairs assigned to the Donor 
Arm of the study. 
 
Additional screening tests prior to transplant for participants on the donor arm are described in 
section 2.3.2. These tests are not subject to review/adjudication by the ERC. 
 
Required Assessments Prior to Biologic Assignment for ALL Participants 
 
The following assessments are required for all participants after confirmation of eligibility and 
prior to date of biologic assignment: 
- 
6-minute walk distance test (6MWD) 
- 
HRQoL: PROMIS-57 and ASCQ-ME Stiffness Scale 
- 
Review and documentation of SCD Events of Special Interest (SCD-EOSI) at baseline. 
Refer to section 4.3.4.2. for additional details on SCD EOSI and defining a single 
occurrence of any given SCD-EOSI. 
- 
Review and documentation of compliance with medical treatment 
- 
28 day pain diary (begins following initiation of donor search and continues for 28 days) 
o Please contact the BMT CTN 1503 Pain Diary Coordinator in the event a study 
participant will not be completing the pain diary for the duration of the study. 
- 
Assessment for toxicities 
 
Required Assessments Following Biologic Assignment for ALL Participants 
 
The following assessments are required for all participants following biologic assignment. These 
are also summarized in Table 7. 
- 
History and Physical Examination 
- 
Karnofsky/Lansky performance score 
- 
Assessment of Hemoglobin S percent per institutional methods with documentation of the 
date of last packed red blood cell transfusion is required. 
- 
Renal1: serum creatinine and 24-hour urine creatinine clearance; or Radionuclide GFR 
including assessment for albumin 
- 
Hepatic Function Tests: direct bilirubin, alkaline phosphatase, ALT, and AST 
- 
CBC with differential, electrolytes, and serum creatinine 
- 
Pulmonary function tests1 FVC, FEV1, FEV1/FVC, VC, TLC, RV, ERV, IC, FRC, DLCO, 
and oxygen saturation. 
- 
Echocardiogram1 with documentation of TRJV 
 
 
 
 
1 Any renal, pulmonary, and cardiac assessmentsthathavebeenperformed≤180dayspriortobiologicassignment
as part of screening do not need be repeated after biologic assignment. 


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- 
OPTIONAL Research samples to be sent to the YSM BioBank1: 
o Peripheral Blood collection (31.5mL) (see BMT CTN 1503 MOP for details) 
o Urine Sample (50mL) (see BMT CTN 1503 MOP for details) 
- 
Assessment for toxicities 
Additional Required Assessments Following Biologic Assignment for Patients 
Assigned to the Donor Arm: 
The following assessments are required for Donor Arm participants following signature of the 
Transplant consent: 
- 
Cerebral MRA/MRI (≤ 30 days prior to initiation of transplant conditioning). Cerebral MRI 
images will be uploaded for central MRI review. Refer to the BMT CTN 1503 MOP for 
details. 
o If there is clinical or radiologic evidence of a recent neurologic event (such as stroke 
or transient ischemic attack), subjects will be deferred ≥ 6 months with repeat
cerebral MRI/MRA to ensure stabilization of the neurologic event prior to 
proceeding to transplantation. Please notify DCC when deferring HCT for this or 
any reason. 
- 
Liver MRI (≤ 90 days prior to initiation of transplant conditioning)2 for estimation of 
hepaticironcontentforparticipantswhoarecurrentlyreceiving≥8packedredbloodcell
transfusionsfor≥1yearorhavereceived≥20packedredbloodcelltransfusions(lifetime
cumulative) 
o Ifhepaticironcontent≥7mgFe/g,aliverbiopsyisrequired to document absence 
of absence of cirrhosis, bridging fibrosis3,andactivehepatitis(≤90dayspriorto
initiation of transplant conditioning). 
- 
Pregnancy test (7 - 14 days prior to initiation of transplant conditioning) 
Required Assessments for patients assigned to the No-Donor Arm after Segment 
A enrollment 
 
The follow up assessments noted below are required for all participants assigned to the no-donor 
arm as outlined below following enrollment in Segment A. Date of biologic assignment is Day 0. 
The mandatory follow up assessments are also summarized in Table 7. 
The following assessments are required at every 3 months post biological assignment starting 
at Day 100 and continuing through Day 730: 
- 
Survival status, history, and physical examination 
 
 
 
1 Collected≤14daysafterbiologicassignmentandpriortotheinitiationofstudyarm-specific therapies 
2May use prior [liver] MRI if done within 6 months prior to initiation of conditioning; otherwise this imaging is 
required within 90 days prior to initiation of transplant conditioning 
3The absence of bridging fibrosis will be determined using the histological grading and staging scale as described by 
Ishak and colleagues (1995) as described in the Manual of Operating Procedures. 


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- 
Review and documentation of all interim occurrences of SCD-EOSI.  Refer to section 
4.3.4.2 for details on SCD EOSI and defining a single occurrence of any given SCD-EOSI. 
- 
Review and documentation of compliance with medical treatment 
- 
Assessment for toxicities 
The following additional assessments are required at Day 100 AND Day 180 post biologic 
assignment: 
- 
Assessment of Hemoglobin S percent per institutional methods with documentation of the 
date of last packed red blood cell transfusion is required. 
The following additional assessments are required at Day 365 post biologic assignment: 
- 
6MWD test 
- 
HRQoL: PROMIS-57 and ASCQ-ME Stiffness Scale 
- 
Pain diary over a 28-day period (Year 1: day 337 to 365) 
- 
Pulmonary function tests: FVC, FEV1, FEV1/FVC, VC, TLC, RV, ERV, IC, FRC, DLCO, 
and oxygen saturation 
- 
Assessment of Hemoglobin S percent per institutional methods with documentation of the 
date of last packed red blood cell transfusion is required. 
- 
Echocardiogram with documentation of TRJV. 
The following additional assessments are required at Day 730 post biologic assignment: 
- 
Karnofsky/Lansky performance score 
- 
Assessment of Hemoglobin S percent per institutional methods with documentation of the 
date of last packed red blood cell transfusion is required. 
- 
Renal: serum creatinine and 24-hour urine creatinine clearance; or Radionuclide GFR 
including assessment for albumin 
- 
Liver Function Tests: direct bilirubin, alkaline phosphatase, ALT, and AST 
- 
CBC with differential, electrolytes, and serum creatinine 
- 
6MWD test 
- 
HRQoL: PROMIS-57 and ASCQ-ME Stiffness Scale 
- 
Pain diary over a 28-day period (Year 2: day 702 to 730) 
- 
Pulmonary function tests: FVC, FEV1, FEV1/FVC, VC, TLC, RV, ERV, IC, FRC, DLCO, 
and oxygen saturation 
- 
Echocardiogram with documentation of TRJV 
- 
6MWD test 
- 
OPTIONAL Research samples to be sent to the YSM BioBank: 
o Peripheral Blood collection (31.5mL) (see BMT CTN 1503 MOP for details) 
o Urine Sample (50mL) (see BMT CTN 1503 MOP for details) 


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Required Assessments for patients assigned to the Donor Arm 
 
The follow up assessments noted below are required for all participants assigned to the donor arm 
following enrollment in Segment A. Assessments are either tied to date of transplant or date of 
biologic assignment as outlined below. These mandatory follow up assessments are also 
summarized in Table 7. 
 
Required Assessments Post Transplant 
The follow up assessments noted below are required for all participants assigned to the donor arm 
following enrollment in Segment A. Date of transplant is Day 0. These mandatory follow up 
assessments are also summarized in Table 7. 
- 
Physical examination and appropriate lab evaluations to assess GVHD and other morbidity 
weekly starting at day 7 post-transplant through Day 100 post-transplant in accordance 
with the BMT CTN Technical MOP. 
- 
Chimerism analysis (peripheral blood or bone marrow) at Days 28, Day 421, and 100 post- 
transplant. 
- 
Whole Blood (10mL) OR Marrow (3-5mL) Research Sample for Erythroid Chimerism 
Testing at Day 100 and Day 730 post-transplant to be sent to Blood Center of Wisconsin 
(see BMT CTN 1503 MOP for details) 
 
Required Assessments Post Biologic Assignment 
The follow up assessments noted below are required for all participants assigned to the donor arm 
following enrollment in Segment A. Date of biologic assignment is Day 0. These mandatory follow 
up assessments are also summarized in Table 7. 
The following assessments are required at every 3 months post biological assignment starting 
at Day 100 and continuing through Day 730: 
- 
Survival status, physical examination, and appropriate lab evaluations to assess GVHD and 
other morbidity in accordance with the BMT CTN Technical MOP. 
- 
Review and documentation of all interim occurrences of SCD-EOSI. Refer to section 
4.3.4.2. for additional details on SCD EOSI and defining a single occurrence of any given 
SCD-EOSI. 
- 
Review and documentation of compliance with medical treatment 
- 
Assessment for toxicities 
The following additional assessments are required at Day 100 and Day 180 post biologic 
assignment: 
- 
Assessment of Hemoglobin S percent per institutional methods with documentation of the 
date of last packed red blood cell transfusion is required. 
 
 
1In the event that the chimerism assessment at day 28 reflects >5% donor hematopoietic cells by whole blood or 
myeloid chimerism (myeloid is preferable) in peripheral blood or bone marrow, the day 42 chimerism does not need 
to be done. 


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The following additional assessments are required at Day 365 post biologic assignment: 
- 
6MWD test 
- 
HRQoL: PROMIS-57 and ASCQ-ME Stiffness Scale 
- 
Pain diary over a 28-day period (Year 1: day 337 to 365) 
- 
Pulmonary function tests: FVC, FEV1, FEV1/FVC, VC, TLC, RV, ERV, IC, FRC, DLCO, 
and oxygen saturation 
- 
Assessment of Hemoglobin S percent per institutional methods with documentation of the 
date of last packed red blood cell transfusion is required. 
- 
Echocardiogram with documentation of TRJV. 
- 
Chimerism analysis (peripheral blood or bone marrow) 
The following additional assessments are required at Day 730 post biologic assignment: 
- 
Karnofsky/Lansky performance score 
- 
Assessment of Hemoglobin S percent per institutional methods with documentation of the 
date of last packed red blood cell transfusion is required. 
- 
Renal: serum creatinine and one of the following: 
o creatinine clearance calculated using the Cockcroft-Gault calculator, 
o creatinine clearance by 24-hour urine (preferred), OR 
o 
Radionuclide GFR including assessment for albumin 
- 
Hepatic: direct bilirubin, alkaline phosphatase, ALT, and AST 
- 
CBC with differential, electrolytes, and serum creatinine 6 MWD test 
- 
HRQoL: PROMIS-57 and ASCQ-ME Stiffness Scale 
- 
Pain diary over a 28-day period (Year 2: day 702 to 730) 
- 
Pulmonary function tests: FVC, FEV1, FEV1/FVC, VC, TLC, RV, ERV, IC, FRC, DLCO, 
and oxygen saturation 
- 
Echocardiogram with documentation of TRJV 
- 
6MWD test 
- 
Chimerism analysis (peripheral blood or bone marrow) at Days 28 and 100 post-transplant. 
- 
Cerebral MRA/MRI (Cerebral MRI images will be uploaded for central MRI review. Refer 
to the BMT CTN 1503 MOP for details.) 
- 
OPTIONAL Research samples to be sent to YSM BioBank: 
o Peripheral Blood collection (31.5mL) (see BMT CTN 1503 MOP for details) 
o Urine Sample (50mL) (see BMT CTN 1503 MOP for details) 
Follow Up for Patients who are not Biologically Assigned 
 
Patients who are found to be ineligible following enrollment will be considered off-study and will 
not be followed for any study related assessments. The DCC will track the number of cases enrolled 
and number of ineligible and eligible cases as determined by the ERC (required for 


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CONSORT diagram upon study completion). All eligible patients will be followed for the primary 
endpoint. 
 
Should a patient withdraw consent prior to biologic assignment, no further follow up is permitted. 
The site is expected to submit written documentation of the patient’s withdrawal of consent to the 
DCC. The numbers of patients withdrawing consent will be tracked by the DCC (CONSORT 
diagram). 
 
In the event HLA typing/donor search does not occur after enrollment, the physician/site is 
expected to provide written documentation to the DCC for review by the Protocol team. 
 
Follow Up for Patients who are Biologically Assigned 
 
All eligible patients will be followed for at least 2 years from biologic assignment for survival 
status (the primary endpoint) unless the patient withdraws consent (documentation submitted to 
DCC). In the event a patient has only a single suitable donor for assignment to the donor arm 
(meeting all criteria in section 2.5.1) who is subsequently deemed ineligible to donate (does not 
meet all criteria in section 2.5.2), that patient will remain assigned to the donor arm and be counted 
as a crossover. Patients who have a suitable donor and are assigned to the donor arm may decline 
to proceed with transplantation. Such patients will be followed on the donor arm for at least 2 years 
for survival and will complete all assessments (except the transplant-specific assessments). 
Similarly, a patient assigned to the no donor arm may opt for HLA-mismatched related or HLA- 
mismatched unrelated donor transplantation. As noted above, these patients will remain in the no 
donor arm of the study, report survival status for at least 2 years and complete other no donor/SOC 
arm assessments as specified in the protocol. With continued education, we hope to minimize 
crossovers and withdrawal of consent. Any participant that receives a fully matched transplant 
using the BMT CTN 1503 conditioning regimen with or without the protocol specified GVHD 
prophylaxis will follow the Donor Arm Follow up Schedule in sections 4.2.5.1, 4.2.7, and Table 
8. 
 
The protocol team has taken steps to minimize crossovers in the 2 years after biologic assignment 
as follows: 1) instituting the screening visit with an HCT physician who is expected to discuss the 
rationale for the study design (i.e., we do not know if HCT will result in a survival advantage long- 
term) and 2) describing the burden of morbidity and mortality associated with transplantation 
especially the up front risks. Further, we believe only committed providers and patients will subject 
themselves to a trial that biologically assigns subjects to a treatment option. Providers and patients 
who favor one treatment approach over another are unlikely to participate in a trial such as this. 
During the course of the trial we will monitor for crossovers (overall and by site) and maintain a 
log. As this is a relatively modest sized phase II trial, should a patient crossover from the assigned 
treatment arm, the DCC will enter into discussions with the site to ascertain the cause for the 
crossover. The trial has met criteria for “coverage with evidence” (CED) as determined by the 
Centers for Medicare and Medicaid Services, an incentive for trial participation. 
 
Should a patient withdraw consent after to biologic assignment, no further follow up is permitted. 
The site is expected to submit written documentation of the patient’s withdrawal of consent to the 
DCC. The number of patients withdrawing consent will be tracked by the DCC (CONSORT 
diagram). 
 


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Table 6: Study Assessments from prior to Segment 0 Enrollment through HLA typing 
and donor search initiation for ALL PARTICIPANTS 
Study Assessments/Testing 
After Screening 
Consent 
After eligibility 
confirmation 
History, physical examination1 
X 
Karnofsky/Lansky performance score1 
X 
Renal and Hepatic Function Assessment1 
(per section 4.2.2) 
X 
Cardiac and Pulmonary Function Assessment2 
(per section 4.2.2) 
X 
CBC with differential1 
X 
Hemoglobin S Level and date of last packed red 
blood cell transfusion is required1 
X 
Infectious disease markers1 
X 
Pregnancy test3 
X 
Sickle Cell Disease Genotyping4 
X 
HLA Typing and Donor Search 
X5 
1 Must be done within 3 months prior to enrollment into Segment 0 
2 Must be done within 1-year prior to enrollment into Segment 0 
3 Must be done within 30 days prior to enrollment into Segment 0 
4 Can be done any time prior to enrollment in Segment 0 
5 If a subject has had HLA typing with accompanying documentation that relatives were not HLA typed 
and that a search of the unrelated donor registry was not performed the subject will be considered eligible. 
Documentation will be reviewed and adjudicated by the Protocol Officer or his/her designee. (See 
guidelines as outlined in BMT CTN 1503 Manual of Procedures.) 


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Table 7: Study Assessments after initiating HLA typing for No-Donor Arm Participants 
Study Assessments/Testing 
 
Prior to 
Biologic 
Assignment1 
 
After 
Biologic 
Assignment2 
Days Post Biologic Assignment 
100 
180 
270 
365 
450 
540 
630 
730 
History, physical examination3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Karnofsky/Lansky performance score3 
 
X 
 
 
 
 
X 
Renal and Hepatic Function Assessment 
 
X4 
 
 
 
 
X 
Pulmonary Function Assessment 
 
X4 
 
X 
 
 
X 
CBC with differential, electrolytes, and 
serum creatinine 
 
X 
 
 
 
 
X 
Hemoglobin S Level and date of last packed 
red blood cell transfusion is required 
 
X 
X 
X 
X 
 
 
X 
Echocardiogram with documentation of 
TRJV 
 
X4 
 
X 
 
 
X 
6MWD Test 
X 
 
 
X 
 
 
X 
HRQoL5 
X 
 
 
X 
 
 
X 
28-day Pain Diary 
X 
 
 
X6 
 
 
X6 
Review and Documentation of compliance 
with medical treatment 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Review and Documentation of SCD Events 
of Special Interest 
(per section 4.3.4.2) 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
Assessment for reportable adverse events and 
toxicities 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Optional Research Samples 
 
X7 
 
 
 
 
X8 
1Must be performed after eligibility confirmation and prior to Biologic Assignment 
2Must be performed after biologic assignment and prior to initiating any study-arm specific therapies 
3The performance score and History/Physical examination at Biologic Assignment should be obtained on at the same visit. 
4Any renal, pulmonary, andcardiacassessmentsthathavebeenperformed≤180dayspriortobiologicassignmentaspartofscreeningdonotneedberepeated after biologic 
assignment. 
5Mustbeconductedatasinglevisitfrom≥7daysand≤28daysfrominitiatingthepaindiary 
6Must be conducted during 28 days leading up to the patient’s yearly visit. 
7Samplesshouldbecollected≤14daysafterBiologicAssignmentandpriortotheinitiationofstudy-arm specific therapies 
8Samples should be collected on Day 730 + 30 days 


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Table 8: Study Assessments after initiating HLA typing for Donor Arm Participants 
Study Assessments/Testing 
Prior to 
Biologic 
Assignment1 
After Biologic 
Assignment2 
Days Post Transplant 
Days Post Biologic Assignment 
Weekly from 
Day 7- Day 
100 
 
28 
42 
1009 
 
730 
 
1009 
180 
270 
 
365 
 
450 
540 
630 
 
730 
History, physical examination3 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Karnofsky/Lansky performance score3 
 
X 
 
 
 
 
 
X 
Renal and Hepatic Function Assessment  
X4 
 
 
 
 
 
X 
Pulmonary Function Assessment 
 
X4 
 
 
 
X 
 
X 
CBC with differential, electrolytes, and 
serum creatinine 
 
X 
 
 
 
 
 
X 
Hemoglobin S Level and date of last 
packed red blood cell transfusion is 
required 
 
X 
 
 
 
X 
X 
 
X 
 
 
X 
Echocardiogram with documentation of 
TRJV 
 
X 
 
 
 
X 
 
X 
GVHD Assessment 
 
X 
 
 
 
 
 
 
Chimerism Analysis 
 
X 
X5 
X 
 
 
X 
 
X 
6MWD Test 
X 
 
 
 
X 
 
X 
HRQoL6 
X 
 
 
 
X 
 
X 
28-day Pain Diary 
X 
 
 
 
X7 
 
X7 
Cerebral MRA/MRI8 
 
X 
 
 
 
 
 
X 
Pregnancy Test 
 
X 
 
 
 
 
 
 
Liver MRI10 
 
X 
 
 
 
 
 
 
Liver biopsy11 
 
X 
 
 
 
 
 
 
Review and Documentation of 
compliance with medical treatment 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Review and Documentation of SCD 
Events of Special Interest (per section 
4.3.4.2) 
 
X 
 
 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
Assessment for reportable adverse events 
and toxicities 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Required Research Sample for Erythroid 
Chimerism Testing 
 
 
X 
X13 
 
 
 
 
Optional Research Samples 
 
X12 
 
 
 
 
 
X13 


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1Must be performed after eligibility confirmation and prior to Biologic Assignment 
2Must be performed after biologic assignment and prior to initiating any study-arm specific therapies 
3The performance score and History/Physical examination at Biologic Assignment should be obtained on at the same visit. 
4Anyrenal,pulmonary,andcardiacassessmentsthathavebeenperformed≤180dayspriortobiologicassignmentaspartofscreening do not need be repeated after biologic 
assignment. 
5 If the chimerism assessment at day 28 reflects >5% donor hematopoietic cells in peripheral blood or bone marrow, the day 42 chimerism does not need to be done 
6Mustbeconductedatasinglevisitfrom≥7daysand≤28daysfrominitiatingthepaindiary 
7Must be conducted during the 28 days leading up to the patient’s yearly visit. 
8If there is clinical or radiologic evidence of a recent neurologic event (such as stroke or transient ischemic attack), subjectswillbedeferred≥6monthswithrepeatcerebral
MRI/MRA to ensure stabilization of the neurologic event prior to proceeding to transplantation. Please notify DCC when deferring HCT for this or any reason. 
9If Day 100 post-transplant and Day 100 post-biologic assignment visits are within 14 days of one another, they can be conducted at the same visit. 
10Forparticipantswhoarecurrentlyreceiving≥8packedredbloodcelltransfusionsfor≥1yearorhavereceived≥20packedred blood cell transfusions (lifetime cumulative) 
11Ifhepaticironcontent≥7mgFe/g,aliverbiopsyisrequiredtodocumentabsenceofabsenceofcirrhosis,bridgingfibrosis,andactivehepatitis(≤90dayspriortoinitiation
of transplant conditioning). 
12Samples should be collected≤30daysafterBiologicAssignmentandpriortotheinitiationofstudy-arm specific therapies 
13Samples should be collected on Day 730 + 30 days 


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4.3. 
Data Reporting 
 
Criteria for Forms Submission 
Forms that are not entered into AdvantageEDCSM within 30 days of the calculated target date will 
be considered delinquent. A missing form will continue to be requested either until the form is 
entered into the AdvantageEDCSM and integrated into the Data and Coordinating Center’s (DCC) 
master database, or until an exception is granted and entered into the Missing Form Exception File. 
 
CIBMTR Data Reporting (Patients Assigned to the Donor Arm and Receive 
HCT) 
 
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.) Enrollment on BMT CTN #1503 must be indicated on the SCTOD pre-transplant 
registration form. Additionally, CIBMTR pre- and post-transplant Report Forms must also be 
submitted for all patients enrolled on this trial. CIBMTR forms will be submitted directly to the 
CIBMTR at the times specified on the Form Submission Schedule. 
 
Follow Up Beyond 2 Years 
 
The informed consent will include consent from all patients for extended follow-up annually to 
determine survival status (years 3 through 10). For patients on the donor arm, survival status will 
be obtained through the CIBMTR. The CIBMTR tracks HCT recipients until death or loss to 
follow up and has several publications that report late mortality after HCT.50 For patients on the 
no donor arm and for those assigned to the donor arm but did not proceed to HCT, the sites will 
be contacted annually for survival status. If patients are lost to follow up (either treatment arm) the 
participating site is requested to search the National Death Index (NDI), a centralized database of 
death record information in state vital statistics offices. The NDI assists in determining whether a 
person is dead and, if so, will provide the name of the state in which the death occurred, the date, 
and the corresponding death certificate numbers. The team (through the participating site) will 
contact the appropriate state office to review the death certificate for cause of death. Alternatively, 
the cause of death is available through the NDI with about a 12-month lag period. Adopting these 
strategies, we plan to compare 5-year and 10-year survival of patients enrolled on both treatment 
arms. We will also explore differences in pattern of survival by donor type for those patients 
enrolled on the donor arm. Operationally, the clinical trial dataset (at the end of the trial funding 
period – 5 years) will be transferred to the Medical College of Wisconsin for maintenance and 
extended follow up of patients assigned to the donor and no donor treatment arms. The CIBMTR 
will assume responsibility for long-term follow up of patients enrolled on the donor and no-donor 
arms of the trial. 


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Adverse Event (AE) Reporting 
 
Adverse event reporting requirements as detailed in this section become effective at the time of 
the participant’s biologic assignment. Events occurring prior to biologic assignment do not require 
expedited reporting as detailed in this section. Participant death occurring prior to biologic 
assignment requires prompt completion of the event driven Death form only. Refer to the 1503 
Forms Guide for further details. 
 
Required Adverse Event Reporting 
Adverse event reporting will be consistent with BMT CTN procedures (BMT CTN Administrative 
Manual of Procedures, Chapter 6). Unexpected, serious adverse events (SAEs) will be reported 
through an expedited AE reporting system via AdvantageEDC. Unexpected, life-threatening and 
fatal (grade 4-5) SAEs must be reported within 24 hours of knowledge of the event. All other 
unexpected SAEs must be reported within three business days of knowledge of the event. Events 
entered in AdvantageEDC will be reported as a single event using NCI’s Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.0. Expected AEs will be reported using NCI’s 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as 
defined on the Form Submission Schedule (e.g., the Re-Admission, Infection, GVHD and Toxicity 
Forms). Any expected life-threatening SAE not collected on another study form must be reported 
through the expedited AE reporting system via AdvantageEDC. 
 
Expectedness of AEs should be determined based on treatment received rather than treatment 
assignment. For participants that receive standard of care, the expectedness of AEs will be 
determined by the institutional PI based upon the toxicity profile of the treatment received and 
those listed in section 4.3.4.3. Any participant that receives a fully matched transplant using the 
BMT CTN 1503 conditioning regimens with or without the protocol specified GVHD prophylaxis 
will report expectedness of AEs relative to the Donor Arm, regardless of biologic assignment. AEs 
will not be collected on participants that receive a transplant with an alternative graft source or 
other experimental therapy. AE reporting on patients that receive a transplant with an alternative 
graft source or other experimental therapy will continue until the date of transplant or start date of 
experimental therapy. 
 
In addition to the standard BMT CTN Unexpected SAE reporting, all deaths, diagnosis of posterior 
reversible encephalopathy syndrome (PRES)/reversible posterior leukoencephalopathy syndrome 
(RPLS), and/or events requiring advanced care interventions or admission/transfer to an intensive 
care unit (ICU) for an indication below are required to be reported via the expedited AE reporting 
system in AdvantageEDC. All event reporting is to be expedited. Grade 4-5 events should be 
reported within 24 hours of knowledge of the event. All other events should be reported within 
three business days of the event. 
 
For the purposes of this protocol, examples of “intensive care unit (ICU)” or “advanced care 
intervention” requiring expedited AE reporting are one or more of the following: 
• 
The patient is transferred to an advanced care unit or the ICU* (see footnote below) 
• 
Continuous Renal Replacement Therapy (CRRT) by dialysis (CAVHD) or filtration 
(CAVH) 


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• 
Non-invasive positive pressure ventilation: continuous positive airway pressure (CPAP), 
bi-level positive airway pressure (BIPAP), intermittent positive pressure ventilation 
(IPPV) 
• 
Endotracheal intubation with mechanical ventilation 
• 
Pressor support 
• 
Organ failure – acute renal failure, acute liver failure, acute respiratory distress 
syndrome, respiratory failure, or multi-organ failure. 
 
* Elective transfer to an advanced care/ICU unit for a scheduled intervention does not need 
to be reported via the Adverse Event forms in AdvantageEDC. 
 
Sickle Cell Disease Related Events of Special Interest Reporting 
The following sickle cell disease related events of special interest (SCD-EOSI) are expected events 
for all participants, regardless of biologic assignment: 
• pulmonary hypertension1 
• significant cerebrovascular events, including: 
o stroke 
o transient ischemic attack 
o seizure 
• renal function compromise1, including: 
o proteinuria 
o increasedcreatininegrades≥2perCTCAEversion 4.0 
• avascular necrosis of the hip or shoulder1 
• leg ulcers1 
• acute chest syndrome (ACS) requiring hospitalization 
• vaso-occlusive pain crisis (VOC) requiring hospitalization or administration of 
parenteral opioid drugs in an outpatient setting. Self-reported events without 
clinical documentation should not be included. 
 
While these events may not require expedited reporting via completion of the Adverse Events 
forms, each occurrence of any SCD-EOSI must be reported on the SCD-EOSI Targeted Toxicities 
form at each regularly scheduled follow up interval. A single event occurrence is defined as a new 
onset of any of the above listed SCD-EOSIs after screening evaluations are completed. A single 
occurrence resolves once the SCD-EOSI returns to the participant’s baseline. Therefore, multiple 
occurrences of the same or several SCD-EOSIs may be reported in one reporting interval. The 
completion of the SCD-EOSI Targeted Toxicities form is required for all participants regardless 
of biological assignment. 
 
No-Donor Arm Expected Event Reporting 
For participants assigned to the no-donor arm, there are expected toxicities associated with the 
standard of care. These expected toxicities do not require expedited reporting on the Adverse 
Event Forms. These toxicities may include but are not limited to: 
 
1 Each new onset event 


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• Transfusions 
o Transfusion reaction, including but not limited to: fever, rash, hives, itching, 
allergic reaction, bronchospasm, hypotension, hypoxia, anaphylaxis, hematuria, 
hemolysis, renal impairment 
o Infection 
o Iron overload 
o Development of allo-antibodies 
• Hydroxyurea 
o Decreased blood cell counts, which can lead to infection or bleeding 
o Nausea 
o Diarrhea 
o Constipation 
o Hyperpigmentation of skin under nails 
o Thinning hair 
o Reduced sperm production 
Expedited AE reporting requirements for the no donor arm are described in section 4.3.4.1. 
 
4.4. 
Subject Payment 
 
Patients on both treatment arms will be paid $25 at baseline, 1 year and two years (total of $75) 
for their time to complete the HRQoL assessment. Payments are made only upon completion of 
required HRQoL forms. 
 
Patients will be paid $1.00 for each electronic pain diary entry. This compensation will be the same 
for all three of the 28-day reporting periods. The potential compensation for completing the pain 
diary at all of these time points is $168. 
 
The total possible compensation is $243. 


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CHAPTER 5 
 
5. STATISTICAL CONSIDERATIONS 
 
5.1. 
Study Design 
 
This study is designed as a phase II, multi-center trial of hematopoietic transplantation (HCT) 
versus standard of care for sickle cell disease. Eligible participants will be biologically assigned to 
HCT or standard of care based on the availability of an HLA-matched related or unrelated donor by 
day 180 after confirmation of clinical eligibility. Insurance coverage and donor availability are not 
known at referral or consultation. Availability of HLA typing prior to referral makes the potential 
subject ineligible for the trial. However, if a subject has had HLA typing with accompanying 
documentation that full siblings were not HLA typed and a search of the unrelated donor registry 
was not performed, the subject will be considered eligible. Documentation will be reviewed and 
adjudicated by the Protocol Officer or his/her designee. 
 
5.2. 
Accrual 
 
It is estimated that 36 months of accrual will be necessary to enroll approximately 200 patients. 
The sample size for the donor arm is fixed at 60 based on donor availability for ~30% of 
participants. The sample size for the no donor arm is anticipated to be approximately 140 but may 
vary according to true availability rate. Accrual will be reported by gender and age. 
 
5.3. 
Biological Assignment 
 
Participants are biologically assigned, based on the presence or absence of a suitable donor, to 
donor versus no donor arms.51,52 Participants in the donor arm are expected to proceed to HCT and 
those in the no donor arm, to continue with standard of care. However, crossovers may occur, which 
may lower the statistical power to detect differences between the donor and no donor arms. There 
may be participants in the no donor arm who proceed to HCT at a later date with an HLA- 
mismatched or matched donor. These participants will remain in the no donor arm for primary 
analyses. There may be participants on the donor arm with a suitable donor who may decline HCT. 
However, we anticipate such crossovers to be <5% based on our planned intensive counseling by 
a SCD physician prior to referral and an HCT physician at referral but prior to enrollment in 
AdvantageEDC for confirmation of clinical eligibility. At all steps of enrollment as shown in 
Figure 4, the protocol coordinator will keep a tally of potential participants who did not proceed 
as indicated in figure 4. Additionally, a full description of crossovers on both arms will be 
provided. The DSMB will be provided with data describing the crossovers at the regularly 
scheduled meetings. The DCC will consult the DSMB if the crossover rate exceeds 5% for 
consideration of the necessity of increasing accrual due this level of failure to adhere to protocol 
assignment. Another potential problem is that participants with donors may differ from those 
without donors, although this is not anticipated. Analyses are planned to assess comparability of 
participants on the 2 treatment arms for demographic and sickle-related events at baseline. 
Multivariable analysis will be used to adjust for imbalances in characteristics. Although very 


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unlikely, any death occurring prior to identification of a donor would be assigned to the no donor 
arm. 
 
5.4. 
Primary Endpoint 
 
The primary endpoint is the estimate of overall survival at two years after biologic assignment. 
Participants on the donor arm are expected to receive HCT and those on the no donor arm, standard 
of care. Regardless of treatment received, subjects will remain in their assigned treatment arm for 
analysis of survival (ITT principle.).51,52 As donor availability is not known at enrollment, all 
patients are assigned to the “no donor arm”. Upon donor search, those with a suitable donor will 
be re-assigned to the “donor arm”. All participants will remain in their assigned treatment arm 
regardless of treatment received. Participants who withdraw consent prior to the site’s 
determination of whether or not there is a suitable donor found will not be considered on study if 
the site provides documentation that the donor search and eligibility qualification process were 
stopped before determining whether a suitable donor was available; these participants will also not 
be part of the statistical analysis. 
 
A consort diagram (number of eligible patients who consented for the study, their biologic 
assignment and treatment received) will be maintained. Patients will not be treated as failures in 
the unlikely event they do not receive treatment per their biologic assignment. 
 
5.5. 
Primary Hypothesis 
 
We hypothesize that for participants assigned to the donor arm HCT-related mortality may exert 
an early impact on survival, but that the rate of mortality should plateau by two years.34-36 Mortality 
after HCT for severe aplastic anemia is less than 15% at 2 years and thereafter, plateaus.34-36 For 
young adults with SCD, the available data suggest mortality after HCT is about 10%. We 
hypothesize as well that participants on the no donor arm will not be especially susceptible to early 
death, but will gradually succumb to the cumulative effects of their disease with a mortality rate 
higher than in the general population.23 Published reports suggest this occurs at a rate of 4.4 deaths 
per 100 person years. Consequently, the survival curves of the 2 groups will eventually cross, with 
a long-term benefit for HCT if early HCT-related mortality is sufficiently low. For this phase II 
trial, we will compare survival rates at 2-years, with the goal of establishing that the difference in 
the proportion surviving is no more than 0.15 lower in the donor arm. We think that if the early 
survival disadvantage of HCT is modest, a long-term survival advantage will emerge. We therefore 
propose the following approach: PD is the probability of overall survival at 2-years on the donor 
arm and PND is the probability of overall survival on the no donor arm. We can write the hypothesis 
as follows: 
H0: PND – PD ≤0.15;H1 PND – PD > 0.15. 
 
5.6. 
Sample Size and Power Considerations 
 
For our calculations, we assume 60 participants on the donor arm and 140 on the no donor arm 
and that at 2 years 0.95 participants on the no donor arm and 0.80 participants on the donor arm 
will remain alive. We will test at the 0.10 one-sided significance level which means that we will 


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define a rejection region that is 1.282 standard deviations beyond the null. Our test will yield more 
than 80% power to reject an alternative difference of 0.30. We chose an expanded one-sided 
significance level of 0.10 to control the size of the rejection region. Under our assumptions, the 
standard error estimate of the difference is 0.0548; this leads us to reject the null hypothesis if the 
observed difference in two-year survival between the groups is 0.22 or higher. That is, we will 
reject the null hypothesis of no more than a 0.15 difference if the observed difference is 
significantly larger than 0.15, and the point at which the difference is considered significantly 
larger is 0.22. We postulate that to be able to demonstrate a survival advantage long-term, the 
difference in survival between the groups of participants cannot exceed 22% at 2-years. There is a 
potential for bias resulting from biologic assignment, and we will compare the two groups to 
identify factors that may differ. If such factors are identified, we will extend our comparison of 
survival between the donor and no donor arms to adjust for such factors, using a multivariable Cox 
model. Our survival estimate of 80% for the donor arm is based on two-year overall survival of 
80% in young adults after HLA-matched related and unrelated HCT for severe aplastic anemia34,35 
and 93% for thalassemia after related and unrelated HLA-matched HCT in children and young 
adults.30 Our survival estimate for the no donor arm is based on a mortality rate of 4.4 deaths per 
100 person-years in SCD patients receiving supportive care.33 In a long-term study of patients with 
severe aplastic anemia who underwent HCT, the risk of death after 2 years was only modestly 
higher than, and by the 6th year after HCT did not differ significantly from, an age- and sex- 
matched general population.36 With a mortality rate of 4.4 deaths per 100 person-years in SCD 
patients receiving supportive care we expect the survival curves to cross beyond year 6. 
 
5.7. 
Interim Analysis and Stopping Guidelines 
Interim Analysis for Efficacy 
There will be no interim analyses for efficacy. 
 
Guidelines for Safety Monitoring 
 
Monitoring of key safety endpoints will be conducted monthly, and if rates significantly exceed 
pre-set thresholds, the NHLBI will be notified so that the DSMB can be advised. Policies and 
composition of the DSMB are described in the BMT CTN's Administrative Manual of Procedures. 
The stopping guidelines serve as triggers for consultation with the DSMB for additional review. 
Guidelines have been prepared using a sequential probability ratio test (SPRT) for day-100 
mortality for participants on the donor arm; 1-year mortality and day 100 graft rejection will be 
monitored separately for participants transplanted from HLA-matched related and unrelated 
donors. 
 
Overall Mortality by Day 100 
For the donor arm, overall mortality in this trial is projected to be less than 20% at day 100 post- 
transplant. The stopping rule for overall mortality will be triggered if there is significant evidence 
that the 100 day overall mortality rate exceed 15% based on the truncated sequential probability 
ratio test (SPRT). The truncated SPRT is based on contrasting 15% versus 30% 100 day mortality, 
with nominal type I and type II error rates of 10% and 20%, respectively. The common slope of 
the parallel lines is 0.219 and the intercept for the upper boundary is 2.344. The stopping rule is 
summarized in the following table. 


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Table 10. Stopping Rules for Overall Mortality by Day 100 for Participants on the Donor 
Arm 
 
Number of evaluable patients enrolled*
Stop if death occurs in:
3
3
4-7
4
8-12
5
13-16
6
17-21
7
22-25
8
26-30
9
31-34
10
35-39
11
40-44
12
45-48
13
49-53
14
54-57
15
58-60
16
*An evaluable patient is one who starts the conditioning regimen 
 
Overall Mortality at 1-Year 
For the donor arm, the stopping rule for overall mortality at 1 year post transplant will be triggered 
if there is significant evidence that the 1-year overall mortality rate exceeds 15% for participants 
with matched related donors and 15% for participants with matched unrelated donors based on the 
truncated SPRT. The truncated SPRT is based on contrasting 15% versus 30% 1-year mortality 
with nominal type I and type II error rates of 15% and 20%. The common slope of the parallel 
lines is 0.219 and the intercept for the upper boundary is 1.887. The stopping rule is summarized 
in the following table. We anticipate that 40% of participants on the donor arm will have matched 
related donors. 
 
Table 11. Stopping Rules for Overall Mortality at 1-Year for Participants on the Donor 
Arm 
 
A. Participants with matched related donors (N=24)
Number of evaluable patients enrolled*
Stop if death occurs in:
3-5
3
6-9
4
10-14
5
15-18
6
19-24
7
*an evaluable patient is one who starts the conditioning regimen 
 
B. Participants with matched unrelated donors (N=36)
Number of evaluable patients enrolled*
Stop if death occurs in:
3-5
3
6-9
4
10-14
5
15-18
6
19-23
7
24-27
8


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B. Participants with matched unrelated donors (N=36)
28-32
9
33-36
10
*An evaluable patient is one who starts the conditioning regimen 
 
Graft Rejection by Day-100 
For participants with matched related donors (N=24 expected), failure to engraft donor cells 
(defined as having primary or secondary graft failure per section 3.3.1) by day-100 post-transplant 
should occur in <10% of patients. The stopping rule for graft rejection by day-100 will be triggered 
if there is significant evidence that the day-100 graft rejection rate exceed 10% based on truncated 
SPRT. The truncated SPRT is based on contrasting 10% versus 20% 100-day graft rejection, with 
nominal type I and type II error rates of 15% and 20%. The common slope of the parallel lines is 
0.14524 and the intercept for the upper boundary is 2.06427 for late rejection. The stopping rule 
is summarized in Table 12. For the participants with matched unrelated donors (N=36 expected), 
failure to engraft donor cells (defined as having primary or secondary graft failure) by day-100 
should occur in < 15% of participants. The stopping rule for graft rejection by day-100 will be 
triggered if there is significant evidence that the day-100 graft rejection rate exceed 15% based on 
the truncated SPRT. The truncated SPRT is based on contrasting 15% versus 30% 100-day graft 
rejection, with nominal type I and type II error rates of 15% and 20%. The common slope of the 
parallel lines is 0.219 and the intercept for the upper boundary is 1.8866 for late rejection. The 
stopping rule is summarized in Table 12. 
 
Table 12: Stopping Rules for Graft Rejection by Day-100 for Participants on the Donor 
Arm 
 
A) Participants with matched related donors (N=24)
Number of evaluable patients enrolled
Stop if graft rejection occurs in:
3-6
3
7-13
4
14-20
5
21-24
6
*An evaluable patient is one who starts the conditioning regimen 
 
B) Participants with matched unrelated donors (N=36)
Number of evaluable patients enrolled
Stop if graft rejection occurs in:
3-5
3
6-9
4
10-14
5
15-18
6
19-23
7
24-27
8
28-32
9
33-37
10
*An evaluable patient is one who starts the conditioning regimen 
5.8. 
Analysis of Primary Endpoint 
 
The primary outcome will be assessed in a final analysis to be performed after the last enrolled 
patient has been followed for two years post-biological assignment. The two-year overall survival 


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probability and confidence interval will be calculated. The event is death from any cause. Patients 
alive at the time of the last observation are censored at the time of the last observation; however, 
all patients are expected to have survival status reported at or beyond 2 years. Overall survival will 
be compared between treatment arms using a point-wise comparison at 2-years, and the survival 
curves will be estimated using the Kaplan Meier product limit estimator. 
 
In addition to comparing the difference in the observed proportion of patients surviving at 2 years 
post-biologic assignment using the ITT approach, we will also compare the difference in the 
observed proportion of patients surviving at 2 years post-biologic assignment between groups by 
treatment received (i.e., as treated). The “as treated” approach will compare OS between patients 
who received a transplant to patients who received standard of care. The 2-year OS probability and 
confidence interval will be calculated. OS will be compared between treatment arms using a point-
wise comparison at 2-years and the survival curves will be estimated using the Kaplan-Meier 
product limit estimator. 
 
Exploratory analysis comparing the difference in the observed proportion of patients surviving at 
2 years post-biologic assignment among recipients of HLA-matched sibling and HLA-matched 
unrelated donor transplantations will be performed. We will focus on descriptive analyses, as the 
statistical power will be lacking for alternatives of interest. We will explore both the point estimate 
of overall survival at two years, and the full survival curves estimated using the method of Kaplan 
and Meier, as the tempo of deaths with different donor types may differ even if the two-year 
estimates do not. We will also report patient and disease characteristics on the two donor arms, 
and, if the data support it, fit models to explore the impact donor source and other features on the 
overall survival of transplanted patients. Because our hypothesis is that the survival curves will 
ultimately cross, we will continue our assessment of overall survival in the donor and no donor 
arms, using data submitted to the CIBMTR augmented by information obtained from the National 
Death Index, at 3, 4, 5, and 10 years of follow up. 
 
Additionally, we will describe outcomes separately for any matched related donor conditioning 
regimen used for 5 or more patients. Similarly, we will describe outcomes separately for patients 
for whom peripheral blood is the stem cell source, should there be 5 or more such patients. 
 
There is a potential for bias resulting from biologic assignment, and we will compare the two 
groups to identify factors that may differ. If such factors are identified, we will extend our 
comparison of survival between the donor and no donor arms to adjust for such factors, using a 
multivariable Cox model.53 
 
5.9. 
Secondary Endpoints 
 
The secondary endpoints will examine changes in record-based assessment of sickle-related events 
using the system developed by Elmariah and colleagues19; cardiac function, pulmonary function, 
and functional assessments by administering the 6MWD test, HRQoL, and a 28-day electronic 
pain diary to capture mean pain intensity. The secondary endpoints will examine changes between 
baseline and 2-years between participants on the donor and no donor arms. Additionally, HRQoL, 
28-day e-pain diary, and the 6MWD test will be measured at 1-year; therefore changes between 


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baseline, 1- and 2-years will be examined. Additional endpoints for patients undergoing HCT will 
be analyzed. 
 
Occurrence of Sickle-Related Events 
We will examine the occurrence of the sickle-related events identified by El Mariah on study.19 
Exact logistic regression will be used to estimate an odds ratio of each of these events between 
treatment groups, assuming that at least one event occurs on study in each of the treatment groups, 
controlling for other patient related characteristics and individual history of the event of interest. 
 
HRQoL 
 
We will measure HRQoL using the PROMIS-57 and the stiffness impact short form from ASCQ- 
Me. We will focus on changes from baseline, and assume on average no change in the no donor 
group and improvement in the donor group. We have assumed no correlation to maximize the 
variability of the estimate of change. Using a two-sample t-test, we will have power of 0.98 to 
identify a 10-point difference in changes within a domain between donor and no donor, testing at 
the two-sided 0.05 significance level. This calculation is based on 45 participants on the donor arm 
and 113 on the no donor arm completing the two-year assessment; power to identify as statistically 
significant an even smaller difference will be increased if adherence to the two-year measurements 
is higher than we have assumed. We will also analyze the trajectory of change using baseline, year 
1, and year 2 measurements, using either a generalized linear model or generalized estimating 
equations, as appropriate, and adjusting the assessment of the trajectory, in addition of the primary 
question of donor/no donor, by incorporating additional demographic factors as well as adjusting 
for whether the assigned treatment was delivered. More complex models may be required if the 
changes over time are strongly nonlinear. 
 
Mean Pain Intensity 
 
The electronic pain diary is administered twice daily for 28 consecutive days. As the pain diary is 
administered twice/day, an average value will be computed for each day on which the diary shows 
two entries. Should the diary reflect only a single entry for a day that value will be used and if a 
patient did not enter a value on a given day, that non-adherence will be tallied separately. The 
mean pain intensity from the diary will be the sum of the reported daily pain intensities averaged 
over the number of days on which at least one pain intensity was reported. 
 
The PROMIS-57 HRQoL instrument asks the patient to rate his/her pain intensity over the past 7 
days. The PROMIS-57 will be administered at least 7 days into the daily electronic pain diary so 
that reporting periods overlap and the two measures can be compared. The ASCQ-Me instrument 
should be administered on the same day as the PROMIS-57 instrument. 
 
Based on estimates of daily pain in adults with SCD43, we anticipate that all patients will report 
pain with a mean pain intensity of 3.9 on a scale of 10 at baseline. We expect that this will be 
unchanged at follow-up for patients in the no donor arm. We anticipate however that patients in 
the donor arm will demonstrate a clinically significant decline in mean pain intensity to a level of 
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94% power to detect this difference, testing at the one-sided 0.05 significance level. We will also 
analyze the trajectory of change using baseline, year 1 and year 2 measurements, using either a 
generalized linear model or generalized estimating equations, as appropriate, and adjusting the 
assessment of the trajectory, in addition of the primary donor/no donor question, by incorporating 
additional demographic factors as well as whether the assigned treatment was delivered. More 
complex models may be required if changes in pair do not occur early making changes over time 
strongly nonlinear. 
 
Exercise Capacity 
 
We will use the 6MWD, testing under standardized procedures, to assess exercise capacity. The 
ATS guidelines indicate sensitivity of this test to a number of subject characteristics, but we will 
be focusing on the change between two time points, and this orientation will permit us to make a 
more straightforward comparison. This endpoint will measure absolute change from baseline, with 
increased distance identified as positive change. We anticipate an improvement of at least 50 m in 
the subjects in the donor arm on average, compared to subjects in the no donor arm, in whom we 
anticipate at best no improvement. However, we have not identified an estimate of variability of 
the change in for 6MWD over a one- or two-year period. We will use the two-sample t-test to 
examine the changes in distance walked between the groups of subjects, and will also examine 
linear mixed models to understand how other factors, in addition to transplant/control, may affect 
those changes. Finally, we will interrogate the impact of baseline distance on the magnitude of 
change at one- and two-years; this may lead to a parallel analysis based on the percentage change 
from baseline. 
 
Cardiac Function 
 
Tricuspid regurgitant velocity (TRV) is an important marker for the severity and progression of 
SCD. In a series of 148 adults with SCD followed over 9 years, patients with a progressive increase 
in TRV during follow-up had increased mortality54 In another series of 54 adults with SCD a linear 
mixed effects model indicated an overall rate of increase in the TRV of 0·02 m/s per year.55,56 
Desai and colleagues55 found that, using a linear mixed model, the estimated average increase per 
year in TRV was 0.02 m/s, and that 56% of the subjects experienced an increase in TRV over time 
(with 4.5 years median follow up). They also report, using the same model, that administration of 
hydroxyurea was responsible for an estimated reduction in change in TRV of -0.20 m/s. Again, 
using the model, they report that among the subjects whose TRV increased, the estimated average 
increase per year was 0.07 m/s. We note that the subjects in that study were older than those in the 
present study. Increase in TRV over time was not associated with whether the TRV was above 
2.5 at baseline. We will measure changes in TRV jet velocity (TRJV) over time (at 1-year and 2- 
years) using a two sample t-test as well as on a linear mixed model for the rate of change in TRJV 
while incorporating both transplant status and baseline value. We will also use a linear mixed 
model incorporating time and transplant/control status to estimate the rate of change in TRV. We 
will use the model for obtaining estimates for the group as a whole, with an estimate of the impact 
of transplant on change in TRV. We will also examine the proportion of patients with increases in 
TRV as a planned subset analysis, in the context of the same model. Finally, we will examine the 
relationship of increases in TRV as a function of whether the baseline TRV was ≤ 2.7 m/s or 
> 2.7 m/s, using the Fisher exact test. 


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Pulmonary Function 
 
There is a growing body of evidence to indicate that the pulmonary toxicity of SCD is 
progressive.44,45 In a series from the Cooperative Study of Sickle Cell disease, only 10% of adults 
had normal pulmonary function test (PFT) results.6 The rate of progression of pulmonary function 
abnormalities is not certain, but in 1 series of children and adolescents tested over 42 +/- 23 months, 
56% had normal PFTs at the baseline, and only 29% stayed normal at the second testing, with 
obstructive patterns being observed more frequently than restrictive.57 In another series of 413 
children with SCD who had pulmonary function testing results analyzed by a linear mixed effects 
model, showed significant serial decline in the percent predicted values for FEV1, forced vital 
capacity (FVC), and forced expiratory flow (FEF25-75) across age.58 Thus, these data strongly 
suggest that the negative impact of sickle vasculopathy on pulmonary function is progressive. This 
type of pulmonary injury appears to be halted by successful HCT.1 We anticipate changes in FEV1 
of 49 cc/year45 for participants on the no donor arm, compared to half that rate in the donor arm, 
based on Field’s observation of a general population decrease of 20 to 26 cc/year.44,45 We will also 
assess the proportion of participants on the treatment arms in whom we find evidence of restrictive 
lung disease, defined as total lung capacity below the 5th percentile adjusted for age, gender, race, 
and height, as is also reported by Field et al.45 used generalized estimating equation models on the 
serial PFT measurements for 92 subjects with SCD, and reported that the average loss in FEV1 
was 49 cc/year. This paper also cites a general population drop with age of 20 to 26 cc/year. Based 
on this we would also use a generalized linear mixed model as we will have only two time points, 
and feel that we will be able to assess the variance/covariance structure, rather than the Generalized 
Estimating Equation (GEE) which Field used with 2 to 4 time points per subject. We will also 
assess the proportion of subjects in both arms in which we find evidence of restrictive lung disease, 
defined as TLC below the 5th percentile adjusted for age, gender, race, and height, as is also 
reported in the Field paper. 
 
Renal Function 
Guasch et al.46 report that 61% of SCD subjects aged 18 to 30 had either micro- or 
macroalbuminuria; for subjects aged 30 to 40, this percentage was 66%, based on a single 
measurement. We will examine changes in albuminuria at the two time points separately for the 
transplanted and control subjects using the McNemar test, and we will compare the proportions of 
subjects at the each measurement time using the Fisher exact test. 
 
5.10. Secondary Endpoints for Participants who Undergo HCT 
 
For participants assigned to the donor arm (expected to undergo HCT) the following outcomes 
will be monitored and described: 
1. Cumulative Incidence of neutrophil and platelet recovery will be reported 
2. Cumulative Incidence of primary graft failure will be reported 
3. Cumulative Incidence of secondary graft failure will be reported 
4. Lineage specific chimerism will be described taking into account the genotype of the donor 
(AA or AS). 
5. The cumulative incidence of grade II-IV and III-IV aGVHD at day-100 will be reported. 


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6. The cumulative incidence of chronic GVHD and the severity of chronic GVHD at 1- and 
2-years will be reported. 
7. The occurrence of other HCT-related complications will be described. 
8. IPS, VOD, CNS toxicity including hemorrhage and PRES, significant infections (bacterial, 
viral, fungal including mold infections), CMV reactivation and EBV-PTLD will be 
reported. 
9. The incidence of definite and probable viral, fungal and bacterial infections will be 
tabulated for separately for HLA-matched related and unrelated transplants. The 
cumulative incidence of CMV reactivation in the first 100 days post HSCT will be 
described. All Grade 2 and 3 infections will be reported according to the BMT CTN 
Technical MOP. 
5.11. Demographics and Baseline Characteristics 
 
Demographics and baseline characteristics will be summarized for all patients. Characteristics to 
be examined are: age, gender, race/ethnicity, performance status and other baseline characteristics. 
Between group comparisons will be performed for continuous variables via a Kruskal-Wallis test 
and for categorical variables, via the chi-square test. 
 
5.12. Handling of Missing Data 
 
Two-year measurements can only be obtained on surviving subjects who return for testing at two 
years. We will not impute values for subjects with missing data. We recognize the challenges 
in retaining control subjects in whom no intervention beyond enrollment and measurement is 
performed, and therefore assume that 15 % of surviving control subjects will not be evaluable at 
both time points. 
 
5.13. Extended Follow Up 
 
The probability of survival of patients in both treatment groups will be calculated annually years 
3 through 10 using the Kaplan-Meier estimator and the 95% confidence interval generated using 
the Greenwood formula. Comparative p-values will be generated at time-points 3 through 10 years 
using point-wise estimator rather than the log rank test as we except the survival curves will over 
time cross. We anticipate crossing hazards as most deaths in the donor group will occur within the 
first 2 years; however, most deaths in the no-donor group will occur beyond 2-years. 


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APPENDIX A 
 
HUMAN SUBJECTS PROTECTION 


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APPENDIX A 
 
HUMAN SUBJECTS PROTECTION 
 
 
Risks to Subjects 
 
Subjects Involvement and Characteristics: 200 patients with severe SCD will be recruited; we 
anticipate 60 will be enrolled on the donor arm based on ~30% having a HLA-matched related or 
unrelated donor and 140, on the no donor arm. 
 
Recruitment of Women and Minorities as Research Subjects: Equal number of women and 
men are likely to be recruited. Majority of the patients will be of minority ethnic origin because of 
the demographics of distribution of SCD. The racial, gender and ethnic characteristics of the 
proposed subject population reflects the demographics of the study sites. We shall attempt to 
recruit subjects in respective proportion to these demographics. No exclusion shall be based on 
race, ethnicity, or gender. 
 
Inclusion of Children as Research Subjects: Previous studies have demonstrated the benefit of 
HCT for children from matched sibling donor in children up to age 16 years. There is currently an 
ongoing study of HCT for children up to age 16 years from unrelated donors. We therefore propose 
a study for children above age 15 years and for adults up to age 40 years. This study attempts to 
further reduce toxicity in patients, age 15-40 years, receiving HCT for SCD. The risk involved in 
the participation of the study is greater than minimal, but has the potential for direct benefit to the 
individual. The risk is justified by the extent of potential benefit to the involved children and the 
relation of the risk to the potential benefit is at least as favorable to the subject as that presented 
by alternative approaches. As such this study fulfills criterion 2 of 45CFR 46 .405. 
 
Expertise of the Investigative Team in Dealing with Patients of the Specific Age Ranges: 
Investigators are Board Certified in Pediatric or Adult Hematology/Oncology/HCT with 
experience in taking care of SCD patients and HCT patients. PIs of the study have previously 
conducted IRB approved multicenter trials of HCT for SCD. 
 
Adequacy of Facilities to Accommodate Patients of Specified Age Ranges: All the participating 
sites have dedicated inpatient oncology units, Blood and Marrow Transplant (BMT) rooms and 
outpatient clinics equipped with high efficiency air and water purification systems, seamless floors 
and drywall ceilings. These units accommodate patients in the acute phase of HCT and offer 
intensive care for returning patients with serious complications related to HCT. The units are 
equipped with state-of-the-art air handling capabilities and are staffed by clinical nurses with a 
primary interest in blood and marrow HCT, HCT research nurses as well as staff physicians with 
experience in HCT. 
 
Potential Risks: HCT is the only modality that can cure severe hemoglobinopathy. If HCT is 
successful, it is anticipated that patients will not have symptoms related to the disease, have no 
requirement of transfusion and have stabilization of organ damage. The risk of mortality is low in 


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patients <16 years of age receiving HCT from matched siblings (4-5%) 59. Risks are higher among 
older patients and those receiving HCT from an unrelated donor. Preliminary data suggest that this 
protocol is well tolerated in recipients of HCT from an unrelated donor. However, serious viral or 
bacterial infections and acute and chronic graft versus host disease pose significant risks of 
morbidity and mortality even in patients receiving HCT following a non-myeloablative 
conditioning regimen. While there is no information available on the effect of busulfan alone on 
fertility, the use of high doses of another alkylator, cyclophosphamide alone in HCT conditioning 
regimens is associated with recovery of ovarian function in all patients under the age of 26 years 
and in 61% of patients over the age of 26 years60,61. At least half of the patients with aplastic anemia 
who received high doses of cyclophosphamide for HCT and survived ≥2 years preserved or 
regained the ability to become pregnant or father children62. With the regimen used in this trial, 
there is a small risk (<5%) for a malignancy, and the potential for other late toxicities including 
infertility. 
 
Discussion of Alternatives to Participation in the Study: Patients will be clearly apprised of 
alternatives to participation on the study, which is continuation of standard of care (chronic 
transfusion, hydroxyurea, pain management). 
 
Adequacy of Protection Against Risks: Subjects for this study will be recruited from among 
patients followed at or referred to the clinical sites. The study will be discussed with the patient or 
family members by one of the investigators and informed consent obtained. All potential subjects 
will sign informed consent according to guidelines of the local Institutional Review Boards. 
Patients will be evaluated and, if eligible for the trial, consent will be obtained for enrollment. 
Enrollment prompts ad hoc review of clinical eligibility by an Eligibility Review Committee 
(ERC). If eligibility is confirmed by successful enrollment into AdvatageEDC or review by the 
ERC, patients undergo HLA typing and donor search is initiated. Patients with a suitably HLA-
matched donor are assigned to the donor arm for transplantation. Those without a donor are 
assigned to the no donor arm. 
 
Protection Against Risk: This protocol will be reviewed and approved by the IRB of record for 
each site, as defined by FDA regulations (21CFR Part 56) and DHHS regulations (45 CFR part 
46). Sites may choose to use the NMDP IRB of record or institutional IRB for this study. Reporting 
of unanticipated events, protocol deviations, protocol amendments, and other information to the 
IRB of record should follow institutional or NMDP IRB practice. Reporting of events to the DSMB 
and federal agencies by the BMT CTN will follow the BMT CTN Administrative MOP. 
 
External Data Safety and Monitoring Board: An external Data safety monitoring board will be 
constituted by NHLBI. The External DSMB will convene via an in-person meeting or 
teleconference at a minimum of twice a year to assess progress on patients enrolled on the study. 
Administrative reports from these meetings will be available to site staff. 
 
Risk Management Procedures: Procedures for minimizing specific risks associated with study 
procedures are outlined above. Patients assigned to the donor arm will be admitted to the HCT 
beds and will receive standard care. Once engraftment has been demonstrated the patients will be 
followed closely in the outpatient clinic. In addition, the protocol chairs and protocol officer are to 


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address trial-related concerns from physicians. Patents assigned to the no donor arm will continue 
to receive standard of care administered by their hematologist. At individual institutions, a 
physician or designee is available 24/7 for patient-related queries; these will follow institutional 
guidelines. Confidentiality will be maintained throughout the study. Subjects will be identified by 
research study numbers, which will be the only identifying information to appear on data and 
documents used for evaluation or statistical analysis. No verbal or written information concerning 
any subject will be released without the written consent of the subject. Records will be maintained 
only in anonymous research files, kept in locked quarters and made available only to qualified 
research personnel. 
 
Potential Benefits of the Proposed Research to the Subjects and Others: Potential benefits to 
patients include cure of the severe SCD and alleviation of chronic morbidity and possibly reversal 
of organ damage. 
 
Importance of the knowledge to be gained: It is anticipated that a safe and effective reduced 
toxicity approach to HCT for severe SCD in young adults will greatly enhance the applicability of 
this modality of treatment to this group of patients. By comparing with a group of similarly affected 
patients we will compare overall survival and sickle-related events 2-years after enrollment. 
 
Donor Human Subject Protection 
 
In the interest of safeguarding the safety of the clinical procedure of bone marrow donation by 
minor donors, and in keeping with the American Academy of Pediatrics Guidelines for minors as 
hematopoietic stem cell donors (Pediatrics Vol. 125 No. 2 February 1, 2010 pp. 392 -404), 
informed consent for a marrow harvest in minors who meet donor eligibility is sought only when 
all 5 criteria below are satisfied: 
1. There is no medically equivalent histocompatible adult relative who is willing and able to 
donate 
2. There is a strong personal and emotionally positive relationship between the donor and 
recipient 
3. There is a reasonable likelihood that the recipient will benefit 
4. The clinical, emotional, and psychosocial risks to the donor are minimized and are 
reasonable in relation to the benefits expected to accrue to the donor and to the recipient; 
a child mental health professional as well as donor advocate will be involved to help 
clarify the child's concerns 
5. Parental permission and, when appropriate, child assent are obtained. 
 
Additionally, the work-up and consenting of all minor donors are subject to the laws in the state 
in which they reside including but not limited to the designation of an independent advocate. 
 
All donors will be evaluated for eligibility by an independent physician separate from the research 
team. Related donor eligibility (minors and adults) is subject to established clinical practice at 


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participating sites and compliant with state and federal laws. Adult unrelated donors are identified 
through the NMDP and subject to NMDP’s policy and procedures. 
 
All donors will undergo screening procedures including blood tests (approximately 10-15ml); a 
urinalysis, pregnancy test (for female donors of child bearing potential), and any tests clinically 
indicated for the safety of the donor during general anesthesia. The risks involved in the screening 
procedures include discomfort from phlebotomy. Since the bone marrow donation occurs under 
general anesthesia, there is some risk associated with anesthesia. The most common side effects 
related to the collection of bone marrow are: pain in the hip bones, back stiffness and bruising and 
bleeding in the skin where the needles were placed. Rare complications include infections in the 
skin and bone or major bleeding problem. It is possible that a blood transfusion will be necessary 
so that the donor is not too anemic after the bone marrow collection. In some cases, it will be 
possible to collect blood in advance from the donor and store it so that it can be given after the 
bone marrow collection. There is also a potential for psychological distress to the donor in case of 
serious HCT related complications to the recipient. 
 
Measures that will be taken to minimize the risks of procedures to the donors: 
a. Every effort will be made to use aseptic technique as well as measures to minimize the 
discomfort from phlebotomy, including the use of topical analgesia. 
b. Pregnancy tests will be done prior to any radiological procedure. 
c.  Adequate pre, intra, and post-operative analgesia will be ensured in order to minimize 
the risk of pain. Appropriate aseptic technique will be used to minimize the risk of 
infections. Appropriate anesthetic technique and monitoring will be ensured to 
minimize the risk from anesthesia. 
d. Where the patient is eligible for autologous blood donation (e.g., children>16 years of 
age, weighs > 50 kg), we would recommend that this be done so as to limit the 
possibility of requiring transfusion from an Allogeneic donor. 
e. Blood will be placed on hold with the Blood Bank should the patient become anemic 
and require a transfusion. 
f.  A psychologist will be available to see the donor prior to donation and will be available 
subsequently to address any behavioral and/or psychological consequences of bone 
marrow donation. 
 
Donation of bone marrow has no prospect of direct benefit to individual subjects, but represents 
an opportunity to understand, prevent, and alleviate sickle cell disease, which is a serious problem 
that affects the health and welfare of those with sickle cell disease. There is no research conducted 
on donors; only donor demographic data (gender and age), donor’s relationship to subject 
(sibling/unrelated) and donor HLA typing will be collected. 
 
Protected health information will be obtained for subjects enrolled on the study research purposes. 
This study involves reviewing patients’ medical records. The consent form will be reviewed with 
the subject prior to accessing the potential subject’s information. We will require that the subject 
sign these forms prior to enrollment. 


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Each prospective subject will be told during the consent process that he or she can withdraw at any 
time from the study. The investigator will inform each potential subject that participation is 
voluntary and declining to participate in the study will not affect the medical care they receive at 
the institution. 
 
In the event a subject also received care at another institution, the subject will be asked to sign a 
Release of Information form. Written consent and release of information forms will be reviewed 
with participants during the consent process. Prospective participants will be given the contact 
information of the principal investigator if further questions arise. Prior to review of the medical 
records the PI will require that the subject has returned and signed a copy of this consent and that 
each participant has received a copy of the written consent and release of information form. 
 
Protected Health Information: 
 
Protected health information will be obtained for research purposes. This study involves 
reviewing patients’ medical records. We will review the written consent with the subject prior to 
accessing the potential subject’s information. We will require that the patient sign these forms 
before enrolling them in this study and will be encouraged to ask questions. Prospective 
participants will not have to enroll immediately after they are approached. 
 
Each prospective subject will be told during the consent process that he or she can withdraw at any 
time from the study. The investigator will inform each potential subject that participation is 
voluntary. In the event a subject also received care at another institution, the subject will be asked 
to sign a Release of Information form. Written consent and release of information forms will be 
reviewed with participants during the consent process. Prior to review of the medical records the 
PI will require that the subject has returned and signed a copy of this consent and that each 
participant has received a copy of the written consent and release of information form. 


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APPENDIX B-1 
 
INFORMED CONSENT AND ASSENT FORMS 
TO PARTICIPATE IN RESEARCH 


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Informed Consent to Participate in Research 
 
 
 
 
TITLE: A Study to Compare Bone Marrow Transplantation to Standard Care in 
Adolescents and Young Adults with Severe Sickle Cell Disease 
 
Principal Investigator: 
[Insert site PI] 
Co-Investigators: 
[Insert site co-I] 
 
Study Coordinators: 
[Insert site study coordinator/s] 
 
[Insert site department/facility name, address, and phone number] 
 
 
Source of Support: National Heart, Lung, and Blood Institute (NHLBI) of the National 
Institutes of Health (the NIH), Bethesda, Maryland 
 
CONSENT FOR AN ADULT TO BE A SUBJECT IN CLINICAL RESEARCH AND 
AUTHORIZATION TO PERMIT THE USE AND DISCLOSURE OF IDENTIFIABLE 
MEDICAL INFORMATION (PROTECTED HEALTH INFORMATION) FOR 
RESEARCH PURPOSES. 
 
 
[Insert site logo and/or address] 
This is a clinical trial, which is a research study to answer specific medical questions. 
The information from this study may also help future patients. The Study doctor (the person in 
charge of the research) will explain the study to you. This research study will include only people 
who choose to take part in the study. Please take your time to make your decision about taking 
part in the study. You may discuss your decision with family and friends. You should also 
discuss this with your healthcare team. If you have any questions, you can ask the Study doctor 
for more explanation. 


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1. Introduction 
 
You are being invited to be part of a research study at [Insert institution]. The people who take 
part in research studies are called “participants”. This study is called a clinical trial. A clinical 
trial is a research study involving treatment of a disease in human patients. Before you decide if 
you would like to participate, we want you to know why we are doing this study. Being in this 
study is voluntary. You do not have to take part in this study. You have a choice between a 
standard treatment for sickle cell disease and this clinical trial. Do not join this study unless all 
of your questions are answered. 
 
After reading and discussing the important information in this consent form you should know: 
• Why this research study is being done 
• What will happen during the study 
• Any possible benefits to you 
• The possible risks to you 
• How your personal health information will be treated during the study and after the study 
is over 
• Whether being in this study could involve any costs to you 
• What to do if you have problems or questions about this study 
 
Please read, or have read to you, this consent form carefully. After you finish, talk with the 
study doctor and ask questions. You may also want to talk to family, friends, your primary care 
doctor, or other health care provider about joining this study. If you decide that you would like 
to take part in the study, you will be asked to sign this form. You will be given a copy of the 
signed form to keep. 
 
Please ask the study doctor or the study staff to explain any words or information that you do not 
clearly understand. You may take home an unsigned copy of this consent form to read and 
discuss with family or friends before making your decision. There are also names and telephone 
numbers of people you can call to get answers to any questions you may have now or at any time 
during or after the study. You may change your mind about staying in the study at any time. 
However, due to the nature of the treatment provided during this study, it might not be safe for 
you to immediately stop being in the study. If you have any questions about your staying in the 
study, please talk with the study doctor or study team. 
 
This research study is sponsored by National Heart, Lung, and Blood Institute of the National 
Institutes of Health (the “Sponsor”). [Insert institution] is being paid by the Sponsor to conduct 
this study. 
 
If you choose to take part in this study, it is important that you give a true and complete 
medical history. You must be honest about your past and present use of medications. 
Information that is untrue or incomplete could have very serious effects on your health and 
safety during the study. 


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2. Background 
 
As you know, SCD is an inherited blood disorder. It is caused by a change in the hemoglobin 
protein that helps red blood cells (RBC) carry oxygen in the body. This change in hemoglobin 
leads to blockage of blood flow in small blood vessels that can cause severe pain. It also 
damages body organs, such as the lungs, brain, spleen, and kidneys. The treatment known as 
hematopoietic cell or bone marrow transplant (HCT/BMT) can replace the defective blood cells 
with blood cells from a healthy donor who could be a sibling or an unrelated donor with a tissue- 
type match that is similar to yours. Unrelated adult volunteer donors are persons who list 
themselves with a donor registry for the purpose of donating their blood or bone marrow cells to 
patients who may benefit from HCT/BMT but do not have a sibling who is a tissue-type match to 
the patient and able to donate blood or bone marrow. This treatment (HCT/BMT) may stop the 
disease and its health problems. HCT/BMT for SCD is successful in children but has not yet 
been tested in very many adults. 
 
We are conducting this trial to study if adolescents and young adults who are treated with 
HCT/BMT live longer than those who are not treated with HCT/BMT. The clinical trial is 
designed to have two groups. In one group are patients who have a donor and expected to be 
treated with HCT/BMT (donor arm) and in the other group (no donor arm), patients without a 
donor who will receive standard of care (this is the same treatment you now receive for your 
SCD). 
 
Neither you or your doctors know whether you have a donor until your doctors confirm you are 
eligible for the clinical trial. After you have heard about the trial and are interested, your doctor 
will submit test results and other documents to confirm you are eligible for the trial. Then your 
blood will be sent for tissue typing along with blood from any available full siblings (brother or 
sister, from same set of parents) that agree to be typed. If your brother or sister is not a tissue 
match or if you do not have a brother or sister, your doctor will search the unrelated donor 
registry for a donor who is tissue matched to you. 
 
• If the tests confirm you have a suitable donor (no longer than 6 months from when you 
were confirmed eligible), you will be moved to the “donor arm” of the trial. 
• If you do not have a donor (no longer than 6 months from when you were confirmed 
eligible), you will remain in the “no donor arm” for 2 years. 
 
The study will recruit 200 subjects with severe SCD from approximately 40 hospitals in the 
United States. Approximately a third of subjects (60 subjects) are likely to have a tissue 
matched donor. These subjects will be assigned to the donor arm and are eligible for transplant 
(HCT/BMT). The remaining 140 subjects will be assigned to the ‘no donor arm’ and will 
continue to receive ongoing standard of care treatment for SCD. 
 
This study is open to males and females between 15 - 40 years old with SCD and have one or 
more serious problems that include: 
• stroke or another serious brain complication 
• 2 or more episodes of acute chest syndrome in the last 2 years even though treatment 
such as hydroxyurea to stop acute chest syndrome was given to you 


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• 6 or more episodes of severe vaso-occlusive pain (pain crises) in the last 2 years 
• Receiving regular RBC transfusions (receiving 8 or more blood transfusions per year to 
prevent sickle related health problems) 
• Anechocardiographicfindingoftricuspidvalueregurgitant(TRJ)velocity≥2.7 m/sec 
• ChronicPainonamajorityofdayspermonthfor≥6 months 
 
You cannot be in this study if you: 
• Have cirrhosis of the liver (a very serious condition of liver failure) 
• Have now or have had a very serious bacterial, viral or fungal infection in the past six 
weeks 
• Have human immunodeficiency virus (HIV) infection 
• Have already received a HCT/BMT 
• Are currently pregnant or breast feeding 
 
In order for you to qualify to participate in this research study, your medical history and the 
results of your screening evaluation will be checked to see if the sickle cell disease (SCD) 
complications that you have had and the results of your screening evaluation make you eligible 
to take part in this trial. If you are eligible for this trial, we need to first find out if we can 
identify an individual who can serve as a blood or bone marrow donor for your transplant. This is 
done by determining your HLA type. 
 
Human Leukocyte Antigen (HLA) typing is done to learn your tissue type. Your immune system 
uses the HLA genes to tell the difference between your own tissues, which are not attacked, and 
germs and other foreign cells, which should be attacked. A transplant is most likely to be 
successful when the donor and recipient share the same HLA type. The person most likely to be 
HLA matched is a brother or sister from the same parents. It is also possible to search for a 
volunteer donor who by chance has the same HLA genes as you. In order to receive a 
HCT/BMT, a suitable HLA-matched donor must be identified and be willing to donate blood or 
bone marrow. 
 
If you have previously undergone HLA typing and your doctor found a donor, you will not be 
able to take part in this study. We are informing you of all the risks and benefits of participating 
in this study if you do not have a donor at this time. If you do have a donor, you will be given a 
second consent form explaining the risks and benefits of HCT/BMT so that you can make a 
decision as to whether you will be willing to undergo a transplant. 
 
3. Purpose 
 
The purpose of this research study is to compare transplant (HCT/BMT) to standard of care 
treatment in young adults with SCD. 
 
We recommend that you participate in this study only if you have decided that you wish to take 
part in a study whose results will help us better understand the best treatment option for severe 
SCD. This means that if you have a donor, you will be assigned to the donor treatment group 
and will receive HCT/BMT. If you don’t have a donor, you will remain in the no donor 


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treatment group and will continue to receive the care you are currently receiving. Both 
treatment groups will be followed for 2 years. There are scheduled tests now and for 2 years 
after we determine if you have a donor so we can compare how both groups are doing. This 
comparison allows physicians to compare the two treatment approaches. It is very important 
that you carefully consider whether assignment to one of two treatment groups is acceptable to 
you and that you are willing to be followed by 2 years. Between years 3 and 10 from 
enrollment, we will ask your doctor annually whether you are alive or dead and the date of last 
contact with your doctor. If you are not alive, we will ask for the date of death and the cause of 
death. If you doctor has lost contact with you, we will search the National Death Index, 
maintained by the government to record all deaths that occur in the U.S. Through the National 
Death Index, we will obtain the date of death and the cause of death. 
 
4. Study Treatments and Tests 
 
 
 
When you first enroll in the study: 
• During this consultation, the BMT physician will review and confirm that you meet the 
eligibility criteria for the study which is based on your disease (SCD). 
• If the BMT physician confirms you meet the eligibility criteria based on your disease and 
you agree to participate in this study, a series of screening evaluations will be conducted 


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to determine if your body can tolerate the treatment called transplant (BMT). These 
screening assessments include: 
o History, Physical exam, height and weight 
o Assessment of your performance status (how well you are able to do your normal 
activities) 
o Urinalysis to check for protein and/or infection in your urine 
o Blood Samples (about 3 teaspoons, or 1 tablespoon) will be drawn from one of 
the veins to conduct routine laboratory blood tests of your … 
 Blood counts (number of each type of blood cell), 
 Blood chemistries (elements and minerals in your blood, as well as 
elements that show kidney and liver health and check your blood clotting). 
 Hemoglobin S percent (a measure of the different kinds of hemoglobin in 
the blood such as transfused hemoglobin and sickle hemoglobin) 
 Blood drawn for HLA typing (about 1 tablespoon and tested only when 
eligibility is confirmed) 
o If you are a female who can bear children, a pregnancy test will be performed 
using a sample of your blood or urine 
o Echocardiogram (a test that takes numerous pictures of your heart to make sure 
the heart is functioning properly) 
o Pulmonary function test (a test that measures how well the lungs work) 
o 24-hour urine collection (a test to measure the amount of water and chemicals 
present in the urine) and/or a Radionuclide GFR (a blood test to measure kidney 
function) 
• After you complete your screening assessments, your clinical information and SCD 
history will be verified to determine whether you are eligible for the study. 
o In the unlikely event you are not eligible for the study, you will not be enrolled on 
study, and you will no longer be asked to provide follow up. 
o If you are confirmed eligible for the study, we will perform tissue typing and 
search for a donor. 
• If you are confirmed eligible, HLA typing (tissue-typing) will be done to determine if 
you have a suitably matched donor (related or unrelated) who can donate blood or bone 
marrow cells for HCT/ BMT. If you have full siblings (i.e., from the same parents), we 
will contact them, and if interested, HLA type them to determine whether you are tissue 
matched to any of your siblings. If you do not have any full siblings, we will search 
among unrelated donors to determine if someone is matched to you. We will search for a 
donor for 180 days. If we are not able to find a donor within 180 days, you will be on the 
no donor arm for the remainder of the study. 
• While we are searching for a donor, we will perform baseline assessments so we can 
have a better idea of your organ function and quality of life. Some of these baseline 
assessments are done before we know if you have a donor or not. These include: 
o 6-minute walk distance test: a test to measure how far you can walk in 6 minutes 
o Questionnaires about your health and quality of life: surveys to measure health 
outcomes from the patient perspective. Your doctor and/or the research team will 
provide the instructions and materials you will need to complete the survey at 


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each time point it is due Whenever possible, this questionnaire will be completed 
electronically during your study visits. 
o Pain diary: You will document your pain twice daily for 28 days via an electronic 
application. Your doctor and/or research team will provide the instructions you 
will need to complete the pain diary. 
• The rest of the baseline assessments are done after we know if you have a donor or not. 
These include: 
o History, Physical exam, height and weight 
o Assessment of your performance status (how well you are able to do your normal 
activities) 
o Urinalysis to check for protein and/or infection in your urine 
o 24-hour urine collection (a test to measure the amount of water and chemicals 
present in the urine) and/or a Radionuclide GFR (a blood test to measure kidney 
function) 
o Blood Samples (about 3 teaspoons, or 1 tablespoon) will be drawn from one of 
the veins to conduct routine laboratory blood tests of your … 
 Blood counts (number of each type of blood cell), 
 Blood chemistries (elements and minerals in your blood, as well as 
elements that show kidney and liver health and check your blood clotting). 
 Hemoglobin S percent (a measure of the different kinds of hemoglobin in 
the blood such as transfused hemoglobin and sickle hemoglobin) 
o A blood and urine sample for future genetic testing (optional) 
o Echocardiogram (if it was not already done within the last 60 days) 
o Pulmonary function test (if it was not already done within the last 60 days) 
 
If you have a donor: 
• If the HLA typing shows that you have a suitably matched donor who is available, you 
will be re-assigned to the donor arm treatment group. 
• You will be asked to sign a second consent form explaining the risks and procedures 
related to HCT/BMT. The detailed information about the risks and benefits of HCT/BMT 
will be explained by a doctor who performs the HCT/BMT. 
• You will undergo additional assessments in preparation for HCT/BMT and for 
monitoring your health after HCT/BMT. 
• You will receive chemotherapy drugs to prepare your body to receive stem cells from 
your donor. 
• You will have a HCT/BMT 
• We will study the side effects of transplant (HCT/BMT) including those that are expected 
and unexpected with additional follow up assessments. You will be followed weekly for 
the first 100 days after your transplant, and every 3 months thereafter 
 
If you do not have a donor: 
• You will remain in the no donor arm 
• You will receive standard of care for your SCD (same treatment as you are receiving, or 
your sickle cell doctor may change that treatment depending on whether there are new 
medications available) 


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• You will be followed every 3 months for 2 years after it is determined you do not have a 
suitable donor 
 
Follow up for all participants: 
• You will be asked to come in for a study visit every 3 months for 2 years after we 
determine if you have a donor or not. We will measure the health of your body organs 
(lungs, brain, and kidneys) and functional outcomes. These tests will be done at baseline, 
one, and two years to compare the results between patients who receive standard of care 
treatment and patients who receive transplant. The following assessments will be 
performed regardless of whether you have a donor or not: 
Day 100, 180, and 270 Follow up Assessments: 
o History and Physical Exam 
o Review of any SCD events that have occurred since your last visit 
o [only at day 100 and day 180] Blood test to measure your hemoglobin S percent 
(a measure of the different kinds of hemoglobin in the blood such as transfused 
hemoglobin and sickle hemoglobin) 
Follow up Assessments at 1 year (Day 365): 
o 6-minute walk distance test: a test to measure how far you can walk in 6 minutes 
o Questionnaires about your health and quality of life: surveys to measure health 
outcomes from the patient perspective. Your doctor and/or the research team will 
provide the instructions and materials you will need to complete the survey at 
each time point it is due Whenever possible, this questionnaire will be completed 
electronically during your study visits. 
o Pain diary: You will document your pain twice daily for 28 days via an electronic 
application. Your doctor and/or research team will provide the instructions you 
will need to complete the pain diary. 
o Echocardiogram 
o Pulmonary function test and oxygen saturation by pulse oximetry 
Day 450, 540, and 630 Follow up Assessments: 
o History and Physical Exam 
o Review of any SCD events that have occurred since your last visit 
Follow up Assessments at 2 years (Day 730): 
o History and Physical Exam 
o Blood Samples (about 3 teaspoons, or 1 tablespoon) will be drawn from one of 
the veins to conduct routine laboratory blood tests of your … 
 blood counts (number of each type of blood cell), 
 blood chemistries (elements and minerals in your blood, as well as 
elements that show kidney and liver health and check your blood clotting). 
 Hemoglobin S percent (a measure of the different kinds of hemoglobin in 
the blood such as transfused hemoglobin and sickle hemoglobin) 
o Pulmonary function test and oxygen saturation by pulse oximetry 
o 6-minute walk distance test: a test to measure how far you can walk in 6 minutes 
o Urine test for protein (albumin) in your urine 
o Echocardiogram 


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o Questionnaires about your health and quality of life: surveys to measure health 
outcomes from the patient perspective. Your doctor and/or the research team will 
provide the instructions and materials you will need to complete the survey at 
each time point it is due. Whenever possible, this questionnaire will be completed 
electronically during your study visits. 
o Pain diary: You will document your pain twice daily for 28 days via an electronic 
application. Your doctor and/or research team will provide the instructions you 
will need to complete the pain diary. 
• Between years 3 and 10 from enrollment we will ask your doctor annually whether you are 
alive and the date you last talked with your doctor. If you are not alive, we will ask for the 
date of death and the cause of death. If you doctor has lost contact with you, we will search 
the National Death Index, maintained by the government to record all deaths that occur in the 
U.S. Through the National Death Index, we will obtain the date of death and the cause of 
death. 
 
5. Risks and Discomforts 
 
All participants will be asked to come in for a study visit every 3 months for 2 years after we 
determine if you have a donor or not. We will collect information including blood and other tests 
at follow up visits for 2 years. These tests are associated with no more than minimal risk 
although you may experience minor discomfort with blood draw. Participating in the health 
survey will not cause any physical discomfort but you may find some of the questions or topics 
on the survey upsetting. If this is the case, your doctor will refer you to a psychologist for 
counseling. 
 
HCT/BMT and Standard of Care (SOC) are not the same in their chance of causing serious 
health problems, chance of early death, or chance of curing your sickle cell disease. The 
Standard of Care (SOC) treatment you receive for supportive care of your sickle cell disease has 
very low chance of causing health problems, and the chance of early death from your sickle cell 
disease is very low but does increase as you get older. The Standard of Care (SOC) treatment 
you are receiving for your sickle cell disease will not cure the disorder. HCT/BMT is a procedure 
that has a higher risk of causing serious health problems and early death. However, HCT/BMT 
may cure your disease. 
 
If you do not have a donor, there are no treatments that are research. Your condition may not get 
better or may get worse during the course of the study. Your doctor will treat you as before or 
may offer other treatment options. If your condition gets worse, your doctor will determine the 
best treatment for care. 
 
All the procedures and potential risks associated with HCT/BMT will be outlined in a separate 
consent form that will be given to you if you have a donor and are assigned to the donor arm. If 
you have questions about the procedures, risks, and benefits associated with HCT/BMT you 
should ask your doctor now. 
 
You will be promptly notified if, during the conduct of this research study, any new information 
develops which may cause you to change your mind about continuing to participate. If new 


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information is provided to you after you have joined the study, it is possible that you may be 
asked to sign a new consent form that includes the new information. 
 
6. Possible Benefits 
 
You may or may not receive medical benefit from taking part in this study. If you are assigned 
to the transplant arm and the transplant is successful, you may benefit by not having further 
symptoms and complications of severe sickle cell disease. 
 
Allowing us to collect SCD-related information at enrollment and 2 years later would allow us to 
directly compare the health outcomes for patients who receive HCT/ BMT to those patients who 
receive standard of care (regular/routine care). This is very important as this is the first time that 
SCD physicians will be able to do a direct comparison of patients with severe SCD to determine 
whether HCT/BMT is a better or worse treatment than routine care for severe SCD. In other 
words, even though you may not benefit directly, you will contribute towards helping treat future 
patients with severe SCD. 
 
7. Optional Research Samples 
 
This section of the Consent Form is about collection of optional blood and urine research 
samples from patients who are taking part in the trial. These research samples will be used for 
future research studies on patients with SCD. 
You can choose to give blood and urine samples if you want to. You can still be a part of the 
main study even if you say “no” to giving optional blood and urine samples for these studies. 
You and/or your insurance will not have to pay for these samples to be collected or for any of the 
important research tests to be performed on these samples. Please mark your choice at the end of 
this section. 
 
We would like to collect two (2) blood and urine samples over the course of the primary study 
for future research. If you agree, these samples will be collected at two different times during 
the primary study. 
 
1. Within a few days after your specific primary study therapy is determined, we would collect 
about 6 teaspoons (31.5 mL) of blood and 10 teaspoons of urine (50 mL). Usually, the blood 
can be drawn from a vein in your arm at the same time as other blood collections. 
 
2. And about 2 years after your primary study therapy was determined, we would once again 
collect about 6 teaspoons (31.5 mL) of blood and 10 teaspoons of urine (50 mL). 
 
The blood and urine samples collected for future research purposes will be sent to the YSM 
BioBank. The samples will be labeled with unique codes that do not contain information that 
could identify you. A link to this code does exist.  The link is stored at the Data and Coordinating 
Center for the Blood and Marrow Transplant Clinical Trials Network (BMT CTN DCC). The 
staff at the BioBank where your samples are being stored do not have a link to this code. Your 
de-identified research samples may also be given to investigators outside of Yale University for 
approved research studies. However, these laboratory investigators will not be able to trace the 
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Your research samples will continue to be stored at the YSM BioBank until they are used up for 
research. They will be kept unless you happen to change your mind and request to have your 
samples destroyed by withdrawing from the study or the Sponsor requests use of stored samples 
to be discontinued. If you stop being in the primary study before it is finished, upon your written 
request to [Insert site investigator] any remaining research samples you have given will be 
discarded when you tell us that you want to stop being in the study. Results we get before you 
stop being in the study will be kept. 
 
Genetic Studies 
DNA from your stored blood samples might be used in future genetic studies. We would like to 
test your DNA (or genes) to learn if some genes predict who will have serious complications of 
sickle cell disease. DNA is inherited information like a blueprint about the structure and 
functions of human body traits that make up the color of our hair and eyes and may affect the 
way our bodies respond to things that happen outside the body such as smoking, an illness, or 
infections. Based on genetic studies of patients with sickle cell disease that have been done 
already, we believe that common differences in genes that control inflammation (entry of white 
blood cells into tissue) are important reasons for differences in sickle cell disease symptoms. 
Thus, we are interested in the possibility that there are genes besides the sickle hemoglobin 
mutation that also contribute to problems with blood flow in your arteries and veins that cause 
pain and other sickle cell symptoms. In the course of these studies, we may find new genes that 
are inherited and predict the development of other sickle cell disease symptoms. 
 
Risks of Genetic Testing 
In the course of these studies, we may find new genes that are inherited and predict the 
development of sickle cell disease related illnesses. Once we have obtained your DNA (or genes) 
from the white blood cells, we will put the DNA in tubes. These tubes will be labeled with a 
code and will have no markings to link the tube with you specifically. If we learn anything of 
importance to our research from this testing, we may publish the results in a medical journal. 
However, you will not be identified in the article as the patient who provided the blood sample 
for our testing. 
 
In rare instances, it is possible that we could find out information about a specific gene that could 
affect you or other members of your family in terms of insurability, employability, or paternity. 
We will do everything possible to ensure that your identity and confidentiality will not be 
breached. As previously mentioned, the code linking your identifying information to the sample 
will be kept secure by the BMT CTN DCC staff in a password protected file on a secure 
location. 
 
Genome-Wide Association Studies 
DNA from your stored blood samples might be used in genome-wide association (GWA) studies 
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wide association studies are a way for scientists to find genes that have a role in human disease 
or treatment. Each study can look at hundreds of thousands of genetic changes at the same time 
 
If your coded samples are used in such a study, the researcher is required to add your test results 
and sample information into a shared, 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, although the results of genetic 
studies could theoretically include identifying information about you. 
 
Benefits of Genetic Testing 
There will be no direct benefit to you for providing this additional blood sample for genetic 
testing. We hope that the information learned from the study treatment trial and these genetic 
research tests will help us understand what genes are important. This may further our 
understanding of the possible treatments to patients with sickle cell disease. 
 
You will be given an additional choice to indicate whether or not your research samples can be 
used in these important genetic studies. You may choose not to participate in the genetic testing 
study and still have your blood and urine samples used for other important research. Once again, 
your decision does not affect your care and participation in the primary study. 
 
Things to Think About: 
The choice to let us have blood and urine samples for future research is up to you. No matter 
what you decide to do, it will not affect your care. 
 
If you decide now that your blood and urine can be kept for future research, you can change your 
mind at any time. Just contact your study doctor and let him or her know that you do not want us 
to use your blood sample. Then any blood that remains will no longer be used for research. 
 
In the future, people who do research on these blood and urine samples may need to know more 
about your health. While the study doctor or others involved in running this study may give the 
researchers reports about your health, it will not give them your name, address, phone number, or 
any other information that will let the researchers know who you are. 
 
Your blood and urine will be used only for research and will not be sold. The research done with 
your blood and urine may help to develop new products in the future. 
 
Benefits: 
The benefits of research using blood and urine include learning more about how your body’s 
immune system recovers after a transplant, as well as to gain knowledge that may help people in 
the future and make transplants even more successful. 
 
Risks: 
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The greatest risk to you is the release of information from your health records. We will do our 
best to make sure that your personal information will be kept private. The chance that this 
information will be given to someone else is very small. 
 
Making Your Choice: 
Please read each sentence below and think about your choice. After reading each sentence, 
please indicate your choice below. If you have any questions, please talk to your doctor or nurse, 
or call our research review board at [Insert institution]. 
 
No matter what you decide to do, it will not affect your care. 
 
Statement of Consent 
The purpose of storing blood and urine samples, the procedures involved, and the risks and 
benefits have been explained to me. I have asked all the questions I have at this time, and I 
have been told whom to contact if I have more questions. I have been told that I will be given a 
signed copy of this consent form to keep. 
 
I understand that I do not have to allow the use of my blood and urine for research. If I decide to 
not let you store research samples now or in the future, it will not affect my medical care in any 
way. 
 
I voluntarily agree that blood and urine samples may be collected and that my blood, urine 
and related health information can be stored indefinitely by the YSM BioBank and used 
for transplant-related and sickle cell disease research. 
 
 I do agree to give optional blood samples for future research which may include DNA 
genetic studies. 
 I do not agree to give optional blood samples for future research which may include DNA 
genetic studies. 
 I do agree to give optional urine samples for future research. 
 I do not agree to give optional urine samples for future research. 
 
 
 
 
 
Signature 
Date 
 
                                              


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8. Other Treatments 
 
You do not have to participate in this study. Your participation is voluntary.  If you choose not 
to participate in the study, you will not be missing out on any standard therapy for sickle cell 
disease.  You will receive the same excellent care from the doctors and nurses whether or not 
you decide to take part in this study. In addition, other types of transplants are currently available 
to you. You may also choose to receive a transplant that uses a different combination of 
medications or a higher or lower dosage of the same medications. The different transplant 
treatment plans each will have different risks and benefits. Your doctors can discuss each type of 
transplant with you in greater detail. If you do not have a suitably matched related or unrelated 
donor and want to still consider HCT/BMT as an option, you may be eligible for other clinical 
trials that utilize mismatched related or unrelated donors. 
 
9. Costs and Reimbursements 
 
Most of the care given in this study is standard care; it will be billed to you or  your insurer 
in the usual way. This study is also approved by Centers for Medicare and Medicaid 
Services (CMS) for reimbursement. Standard costs include those of your hospitalization, 
doctor's visits, standard laboratory tests, medications, and the cost of the donor’s blood or 
bone marrow. There will be no charge for research tests. 
 
The study will pay for the research-related items or services that are provided only because you 
are in the study as outlined above. If you get a bill you think is wrong, call the researchers. 
 
You or your health plan will pay for all the things you would have paid for even if you were not 
in the study, like: 
• Health care given during the study as part of your regular care 
• Items or services needed to give you study drugs or devices 
• Monitoring for side effects or other problems 
• Treatment of complications 
• Deductibles or co-pays for these items or services. 
 
If you do not have a health plan or if you think your health plan may not cover these costs during 
the study, please talk to the research team or call your health plan’s medical reviewer. 
 
If you receive a bill, or believe your health insurance has been billed for something that is part of 
the study, notify a member of the research team or [Insert institution] Patient Billing Services. 
 
You and/or your health insurance will be charged, in the standard manner, for services and 
procedures provided for your routine care. Any deductibles, co-insurances or co-payments that 
are a part of your insurance coverage will apply. 
 
 
 
 
 
 
 
 


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10. Compensation of Payment 
 
You will be paid $25 for completing the health-related quality of life questionnaires. You will be 
asked to complete these questionnaires when you first enroll and at 1 and 2 years later. You can 
earn up to a total of $75 for completing the health-related quality of life questionnaire. 
 
You will receive $1.00 for each electronic pain diary entry. If you complete the pain diary twice 
daily, you will receive $2.00/day. This compensation will be the same for all three of the 28-day 
reporting periods. The potential compensation for completing the pain diary at all of these time 
points is $168. 
 
The total amount of money you can earn for being in this trial is $243. 
 
11. Physical Injury as a Result of Participation 
 
[Insert institution] researchers and their associates who provide services at the [Insert institution] 
recognize the importance of your voluntary participation in their research studies. These 
individuals and their staff will make reasonable efforts to minimize, control, and treat any 
injuries that may arise as a result of this research. 
 
If you believe that you are injured as a result of the research procedures being performed, please 
contact [Insert site PI name] immediately. Emergency medical treatment for injuries solely and 
directly related to your participation in this research study will be provided to you by the 
hospitals [Insert institution]. The study sponsor, the National Heart, Lung, and Blood Institute, 
does not offer financial compensation or payment if you are injured as a result in participating in 
this research study. However, you are not giving up any legal rights by signing this form. 
 
It is possible that [Insert institution] may bill your insurance provider for the costs of this 
emergency treatment, but none of these costs will be charged directly to you. If your research- 
related injury requires medical care beyond this emergency treatment, you will be responsible for 
the costs of this follow-up care unless otherwise specifically stated below. 
 
12. Rights as a Participant 
 
Your participation in this research study, including the use and disclosure of your identifiable 
information for the purposes described above, is completely voluntary. (Note, however, that if 
you do not provide your consent for the use and disclosure of your identifiable information for 
the purposes described above, you will not be allowed, in general, to participate in the research 
study.) Whether or not you provide your consent for your participation in this research study will 
have no effect on your current or future relationship with the [Insert institution]. Whether or not 
you provide your consent for participation in this research study will have no effect on your 
current or future medical care at a [Insert institution] hospital or affiliated health care provider or 
your current or future relationship with a health care insurance provider. 
 
Your physician is involved as an investigator in this research study. As both your physician and 
a research investigator, s/he is interested both in your medical care and the conduct of this 
research study. Before agreeing to participate in this research study, or at any time during your 
study participation, you may discuss your care with another doctor who is not associated with 


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this research study. You are not under any obligation to participate in any research study offered 
by your doctor. 
 
If you have questions about your rights as a research participant or if you have questions, concerns 
or complaints about the research, you may contact the [Insert institution] Institutional Review 
Board (IRB) at the toll-free number [Insert IRB Number]. 
 
13. Ending Your Participation 
 
You may withdraw your consent, at any time, for your participation in this research study, to 
include the use and disclosure of your identifiable information for the purposes described above. 
Any identifiable research or medical information recorded for, or resulting from, your 
participation in this research study prior to the date that you formally withdrew your consent may 
continue to be used and disclosed by the investigators for the purposes described above. 
 
To formally withdraw your consent for your participation in this research study, you should 
provide a written and dated notice of this decision to the principal investigator of this research 
study at the address listed on the first page of this form. Your decision to withdraw your consent 
for your participation in this research study will have no effect on your current or future medical 
care at [Insert institution] hospital or affiliated health care provider or your current or future 
relationship with a health care insurance provider. 
 
If you are thinking about withdrawing from this study, talk with one of the research team 
members and your regular doctor first so they can help you decide what may be best for your 
medical care once you are off study. If you leave the study before the planned final visit, the 
study doctor may ask to have some of the end of study procedures done for your safety and well- 
being. 
 
Your study doctor or NHLBI may decide to take you out of the study if: 
• The researcher believes that it is not in your best interest to stay in the study. 
• You become ineligible to participate. 
• Your condition changes and you need treatment that is not allowed while you are 
taking part in this study. 
• You do not follow instructions from the researchers. 
• The study is suspended or canceled. 
 
14. Privacy, Confidentiality, and Use of Information 
 
By signing this consent form, you are giving the researchers your permission to obtain, use, and 
share information about you for this study. Information about you may be obtained from any 
hospital, doctor, and other health care provider involved in your care. This may include 
information about hospital admissions or visits during this study, so that we know about any 
possible problems or side effects. If health information is needed from your doctors or hospitals 
from other institutions, you will be asked to give permission for these records to be sent to the 
researchers. 


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Any information about you obtained from this research will be kept as confidential (private) as 
possible. Federal Privacy Regulations protect your privacy, restrict who is allowed to look at 
your records, and require security to protect your records. All records related to your 
involvement in this research study will be stored in a locked file cabinet. Your identity on these 
records will be indicated by a unique study ID number rather than by your name, and the 
information linking these case numbers with your identity will be kept separate from the research 
records. You will not be identified by name in any publication of the research results unless you 
sign a separate consent form giving your permission (release). 
 
Information gathered during this study and your medical records may be inspected and verified 
by staff of the study sponsor (the National Heart, Lung, and Blood Institute/National Institutes of 
Health), Office for Human Research Protections, [Insert institution], or the Institutional Review 
Board (IRB). Except when required by law, you will not be identified by name, social security 
number, address, telephone number, or any other direct personal identifier in study records 
shared outside of [Insert institution].  For records shared outside of [Insert institution], you will 
be given a study ID number. The list that can match you to the study ID number will be kept in a 
locked file cabinet in [Insert location]. 
 
In addition to the investigators listed on the first page of this authorization (consent) form and 
their research staff, the following individuals will or may have access to identifiable information 
(which may include your identifiable medical information) related to your participation in this 
research study: 
 
Authorized representatives of the sponsor of this research study, the National Institutes of 
Health, or the Office for Human Research Protections or the Blood and Marrow 
Transplant Clinical Trials Network will review and/or obtain identifiable information 
(which may include your identifiable medical information) related to your participation in 
this research study for the purpose of monitoring the accuracy and completeness of the 
research data and for performing required scientific analyses of the research data. 
 
In unusual cases, the investigators may be required to release identifiable information 
(which may include your identifiable medical information) related to your participation in 
this research study in response to an order from a court of law. 
 
While the study sponsor understands the importance of maintaining the confidentiality of 
your identifiable research and medical information, the [Insert institution] cannot 
guarantee the confidentiality of this information after it has been obtained by the study 
sponsor. The investigators involved in the conduct of this research study may receive 
funding from the sponsor to perform the research procedures and to provide the sponsor 
with identifiable research and medical information related to your participation in the 
study. 
 
Authorized representatives of the [Insert institution] or other affiliated health care 
providers may have access to identifiable information (which may include your 
identifiable medical information) related to your participation in this research study for 


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the purpose of: (1) fulfilling orders, made by the investigators, for hospital and health 
care services (e.g., laboratory tests, diagnostic procedures) associated with research study 
participation; (2) addressing correct payment for tests and procedures ordered by the 
investigators; and/or (3) for internal hospital operations (i.e., quality assurance). 
 
Peripheral blood and urine samples will be collected on all consenting study patients receiving biologic 
assignment to either arm of the trial and shipped agent of Yale University that will manage the 
pain diary. DWC will have access to your phone number, email address, IP Address and 
data that is entered in the pain diary application. 
 
At the end of the study, the study sponsor, the National Heart, Lung, and Blood Institute 
(NHLBI) will be given data from the study, without personal identifying information such as 
your name, address, Social Security number, or Medicare number. The data and/or materials may 
be shared with other scientists who meet NHLBI requirements. These requirements include 
treating the data or materials as medically confidential, obtaining approval from their Human 
Subjects review boards, and agreeing not to share the data or materials with other parties. 
 
The investigators may continue to use and disclose, for the purposes described above, 
identifiable information (which may include your identifiable medical information) related to 
your participation in this research study for ten years from enrollment on to study. Beyond the 
finding period (5-years), the dataset will be transferred to the Center for International Blood and 
Marrow Transplant Research at the Medical College of Wisconsin for extended follow up. Data 
regarding your clinical situation, including follow-up after 2 years, may be obtained from the 
CIBMTR, which captures information on all US transplants. 
 
Extended follow up: Between years 3 and 10 from enrollment, we will ask your doctor annually 
whether you are alive or dead and the date of last contact with your doctor. If you are not alive, 
we will ask for the date of death and the cause of death. If you doctor has lost contact with you, 
we will search the National Death Index annually using your Social Security number. The 
National Death Index is maintained by the government to record all deaths that occur in the U.S. 
Through the National Death Index, we will obtain the date of death and the cause of death. This 
follow up will apply to all subjects regardless of assigned treatment arm. 
 
In accordance with the [Insert institution] Notices of Privacy Practices document that you have 
been provided, you are permitted access to information (including information resulting from 
your participation in this research study) contained within your medical records filed with your 
health care provider. 
 
Your privacy is very important to us. The study doctors will make every effort to protect it. The 
study doctors have a privacy permit to help protect your records if there is a court case. 
However, some of your medical information may be given out if required by law. If this should 
happen, the study doctors will do their best to make sure that any information that goes out to 
others will not identify who you are. 
 
 
 
 


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15. Health Insurance Portability and Accountability Act (HIPAA) 
 
HIPAA authorization to use and disclose individual health information for research 
purposes: 
 
a. Purpose: As a research participant, I authorize the Principal Investigator and the 
researcher’s staff to use and disclose my individual health information for the purpose 
of conducting the research study entitled Bone Marrow Transplantation for 
Adolescents and Young Adults with Severe Sickle Cell. 
b. Individual Health Information to be Used or Disclosed: My individual health 
information that may be used or disclosed to conduct this research includes: 
demographic information (e.g., age, date of birth, sex, weight), medical history (e.g., 
diagnosis, complications with prior treatment), physical examination findings, and 
laboratory test results obtained at the time of work up and after transplantation (e.g., 
blood tests, biopsy results). The identities of individuals such as names and addresses 
will not be shared or de-identified to make sure information cannot be linked to you. 
c. Parties Who May Disclose My Individual Health Information: The researcher and the 
researcher’s staff may obtain 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: 
Members of the BMT CTN Data and Coordinating Center and BMT CTN #1503 
Protocol Team 
National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute 
(NCI), both of the National Institutes of Health (NIH), study sponsors 
The National Marrow Donor Program and the Center for International Blood and 
Marrow Transplant Research 
 
The Blood Center of Wisconsin (BCW), which is a central lab that will do specialized 
testing on blood samples required during the study 
 
Data Warehouse Consultants (DWC) which is an agent of Yale University that will 
manage the pain diary. DWC will have access to your phone number, email address, IP 
Address and data that is entered in the pain diary application. 
 
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) 
 
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 


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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 research-related treatment that is provided through the study. However, 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 the 
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. 
h. This authorization does not have an expiration date. However, you can elect at any time to 
withdraw your authorization to participate in the study. 
 
16. For More Information 
 
If you‘d like more information about this study, or if you have any problems while you’re 
participating in this study, you can contact the study doctor or staff. They may be contacted at 
the telephone numbers listed here: 
 
[Insert name and contact details] 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 


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VOLUNTARY CONSENT 
 
All of the above has been explained to me and all of my current questions have been answered. I 
understand that I am encouraged to ask questions about any aspect of this research study during 
the course of this study, and that such future questions will be answered by the researchers listed 
on the first page of this form. 
 
I understand that I may contact the Human Subjects Protection Advocate of the IRB Office, 
[Insert institution and number] to discuss problems, concerns, and answer any questions I have 
about my rights as a research participant, to obtain information; offer input; or discuss situations 
in the event that the research team is unavailable. 
 
By signing this form, I agree to participate in this research study. A copy of this consent form 
will be given to me. 
 
 
 
Signature of Participant 
Participant’s Printed Name 
Date 
 
 
CERTIFICATION of INFORMED CONSENT 
 
I certify that I have explained the nature and purpose of this research study to the above-named 
individual(s), and I have discussed the potential benefits and possible risks of study participation. 
Any questions the individual(s) have about this study have been answered, and we will always be 
available to address future questions as they arise. I further certify that no research component of 
this protocol was begun until after this consent form was signed. 
 
 
 
Printed Name of Person Obtaining Consent 
Role in Research Study 
 
 
 
Signature of Person Obtaining Consent 
Date 


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Assent to Participate in Research 
 
 
 
 
 
TITLE: A Study to Compare Bone Marrow Transplantation to Standard Care in 
Adolescents and Young Adults with Severe Sickle Cell Disease 
 
Principal Investigator: 
[Insert site PI] 
Co-Investigators: 
[Insert site co-I] 
 
Study Coordinators: 
[Insert site study coordinator/s] 
 
[Insert site department/facility name, address, and phone number] 
 
 
Source of Support: National Heart, Lung, and Blood Institute (NHLBI) of the National 
Institutes of Health (the NIH), Bethesda, Maryland 
 
CONSENT FOR A MINOR TO BE A SUBJECT IN CLINICAL RESEARCH AND 
AUTHORIZATION TO PERMIT THE USE AND DISCLOSURE OF IDENTIFIABLE 
MEDICAL INFORMATION (PROTECTED HEALTH INFORMATION) FOR 
RESEARCH PURPOSES. 
 
 
[Insert site logo and/or address] 
This is a clinical trial, which is a research study to answer specific medical questions. 
The information from this study may also help future patients. The Study doctor (the person in 
charge of the research) will explain the study to you. This research study will include only people 
who choose to take part in the study. Please take your time to make your decision about taking 
part in the study. You may discuss your decision with family and friends. You should also 
discuss this with your healthcare team. If you have any questions, you can ask the Study doctor 
for more explanation. 


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A. Why am I here? 
 
We are inviting you to join our study because you have severe sickle cell disease. You are 
now receiving blood transfusions, hydroxyurea and/or pain medicines. There is another 
treatment called hematopoietic cell transplant or bone marrow transplant (HCT/BMT). A 
transplant uses blood-making cells from another person (donor) to replace your cells that are 
not healthy (the sickle red blood cell). A donor is the name for a person who gives some of 
their blood-making cells for a transplant and their tissue has to match your tissue. Only 3 out 
of 10 persons will have a tissue-matched donor, so most people do not have a donor. In this 
study, if you have a donor, you will receive the treatment called HCT/BMT. If you don’t 
have a donor, you will continue receiving blood transfusion, hydroxyurea, and/or pain 
medications. 
 
B. Why are you doing this study? 
 
We know transplant works to cure your disease, but we don’t know if this is a better 
treatment than blood transfusions, hydroxyurea, and/or pain medicines. 
 
C. What will happen to me if I receive a transplant? 
 
Before your transplant, you will have check-ups with the study doctors and find out if you 
have a donor.  If you have a donor, you will get a small tube put in your chest in the 
operating room (you will be asleep for this). The small tube makes it easier for you to get 
your medicines. It will also make it easier for drawing blood for tests because you will not be 
poked. 
 
We will give you medicines that will help make the cells from your donor grow in your body. 
These medicines might make you feel sick. You might throw up, lose your hair, or get sores 
in your mouth. 
 
After you’re done taking the medicines, you will get cells from your donor. This is your 
transplant. Your donor can be your sister or brother (related) or someone you don’t know 
(unrelated). Your new cells will come from your donor's blood or bone marrow. The cells will 
make new and healthy cells in your body. 
 
Sometimes the donor cells can cause a problem called graft versus host disease (GVHD). 
GVHD happens when the donor cells attack your body. It can give you diarrhea, a skin rash, 
make you feel sick and throw up, or make you not feel hungry. Your doctors will give you 
medicines to try to make sure you don’t get GVHD. 
 
You will stay in the hospital for several days before your transplant and for about 4 weeks 
after your transplant. After you go home, you will need to go back to see your doctor often. 
 
It is possible that your disease will come back. If this happens, your doctor will find another 
way to treat you. 


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You will be followed for two years with tests for follow up scheduled weekly for the first 
100 days and then every 3 months. 
 
D. What will happen to me if I do not receive a transplant? 
 
If you don’t have a donor, you will continue receiving blood transfusion, hydroxyurea, and/or 
pain medications. 
 
You will be followed for two years with tests for follow up scheduled every 3 months. 
 
E. Will it hurt? 
 
For your transplant, we will put a small tube in your chest. It might hurt a little and you 
might bleed a little. Your doctor and nurses will make sure you feel as little pain as possible. 
 
F. Will the study help me? 
 
We know HCT/BMT can cure sickle cell disease. What we don’t know is whether some of 
the problems from transplant like GVHD can cause more harm than if you did not have a 
transplant and continued to receive the care you are receiving now. 
 
G. 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. 
 
H. Do I have to be in this study? 
 
You don't have to be in this study. Your doctor and nurses will not be mad at you if you don't 
want to join. If you decide you don't want to be in this study, you should talk to your doctor, 
nurses and parents about other ways to treat your disease. 
 
You can say yes now and change your mind later. 
 
Be sure to talk this over with your parents before you decide if you want be in the study. We 
will also ask your parents to give their permission for you to join this study. 


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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 your doctor. 
 
You and your parent or guardian will get a copy of this form after you sign it. 
 
 
Printed Name of Child 
Date 
 
 
Signature of Child 
Age of Child 
 
 
Certification of Counseling Healthcare Professional: I certify that the nature and purpose, the 
potential benefits, and possible risks associated with participation in this study have been 
explained to the above individual and that any questions about this information have been 
answered. 
 
 
Printed Name of Person Obtaining Assent 
Role in Research Study 
 
 
Signature of Person Obtaining Assent 
Date 


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APPENDIX B-2 
 
INFORMED CONSENT AND ASSENT FORMS 
FOR TRANSPLANT AND ADDITIONAL FOLLOW UP 
AS PART OF A RESEARCH STUDY 


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Informed Consent form for Transplant and Additional Follow Up as Part of a 
Research Study 
 
 
 
 
TITLE: A Study to Compare Bone Marrow Transplantation to Standard Care in 
Adolescents and Young Adults with Severe Sickle Cell Disease 
 
Principal Investigator: 
[Insert site PI] 
Co-Investigators: 
[Insert site co-I] 
 
Study Coordinators: 
[Insert site study coordinator/s] 
 
[Insert site department/facility name, address, and phone number] 
 
 
Source of Support: National Heart, Lung, and Blood Institute (NHLBI) of the National 
Institutes of Health (the NIH), Bethesda, Maryland 
 
 
CONSENT FOR AN ADULT TO BE A SUBJECT IN CLINICAL RESEARCH AND 
AUTHORIZATION TO PERMIT THE USE AND DISCLOSURE OF IDENTIFIABLE 
MEDICAL INFORMATION (PROTECTED HEALTH INFORMATION) FOR 
RESEARCH PURPOSES. 
 
 
 
[Insert site logo and/or address] 
This is a clinical trial, which is a research study to answer specific medical questions. 
The information from this study may also help future patients. The Study doctor (the 
person in charge of the research) will explain the study to you. This research study 
will include only people who choose to take part. Please take your time to make your 
decision about taking part in the study. You may discuss your decision with family and friends. 
You should also discuss this with your healthcare team. If you have any questions, you can ask 
the Study doctor for more explanation. 


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1. Introduction 
 
You previously agreed to be part of a research study at [Insert institution]. The people who take 
part in research studies are called “participants”. This study is called a clinical trial. A clinical 
trial is a research study involving treatment of a disease in human patients. You are being asked 
to sign this consent form because you have been assigned to the “donor arm” of the clinical trial. 
Before you decide if you would like to participate on the “donor arm” of the study, we want you 
to know why we are doing this study. Being in this study is voluntary. You do not have to take 
part in this study. If you decide not to participate on the “donor arm” we will continue follow 
you for two years unless you tell your doctor you do not want to be followed. Do not join this 
study unless all of your questions are answered. 
 
After reading and discussing the important information in this consent form you should know: 
• Why this research study is being done 
• What will happen during the study 
• Any possible benefits to you 
• The possible risks to you 
• How your personal health information will be treated during the study and after the study 
is over 
• Whether being in this study could involve any costs to you 
• What to do if you have problems or questions about this study 
 
Please read, or have read to you, this consent form carefully. After you finish, talk with the study 
doctor and ask questions. You may also want to talk to family, friends, your primary care doctor 
or other health care provider about joining this study. If you decide that you would like proceed 
with HCT/BMT, you will be asked to sign this form. You will be given a copy of the signed 
form to keep. 
 
Please ask the study doctor or the study staff to explain any words or information that you do not 
clearly understand. You may take home an unsigned copy of this consent form to read and 
discuss with family or friends before making your decision. There are also names and telephone 
numbers of people you can call to get answers to any questions you may have now or at any time 
during or after the study. You may change your mind about staying in the study at any time. 
However, due to the nature of the treatment provided during this study, it might not be safe for 
you to immediately stop being in the study. If you have any questions about your staying in the 
study, please talk with the study doctor or study team. 
 
This research study is sponsored by National Heart, Lung, and Blood Institute of the National 
Institutes of Health (the “Sponsor”). [Insert institution] is being paid by the Sponsor to conduct 
this study. 
 
If you choose to take part in this study, it is important that you give a true and complete 
medical history. You must be honest about your past and present use of medications. 
Information that is untrue or incomplete could have very serious effects on your health and 
safety during the study. 


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2. Background 
 
Your doctor has already explained your Sickle Cell Disease (SCD) and how a hematopoietic cell 
transplant (HCT/BMT) (also referred to as a bone marrow transplant or BMT) can be used to 
treat your SCD when you first joined the study. The HCT/BMT replaces the defective Sickle 
blood cells with blood cells from a healthy donor who could be a sibling or an unrelated donor 
with a tissue-type match that is similar to yours. HCT/BMT may stop the disease and its health 
problems. HCT/BMT for SCD is successful in children but has not yet been tested in very many 
adults. 
 
In this study, we assign patients to two treatment options: HCT/BMT or standard of care (this is 
the same treatment you now receive for your SCD). The treatment is assigned based on whether 
you have a tissue-type matched (also known as HLA-matched) donor; if you have a donor, you 
are assigned to the donor treatment arm and will be offered HCT/BMT. If you do not have a 
donor, you are assigned to the no donor treatment arm and will continue with on-going care. By 
comparing the health outcomes for patients who receive HCT/BMT to those patients who receive 
standard of care (regular/routine care), we will be able to determine whether the two treatments 
are the same, or if one is better than the other. 
 
The study will recruit 200 subjects with severe SCD from approximately 40 hospitals in the 
United States. Approximately a third of subjects (60 subjects) will be assigned to the donor arm 
and are eligible for transplant (HCT/BMT). The remaining 140 subjects will be assigned to the 
‘no donor arm’ and will continue to receive ongoing standard of care treatment for SCD. 
 
We found a tissue-type matched donor for you. Therefore, you are assigned to the donor 
treatment arm and will undergo a hematopoietic cell transplant if you sign this consent 
form. 
 
Your doctor already determined you were eligible for this study, but to be eligible for transplant: 
• Your liver must be healthy enough for transplant 
• Your brain MRI must show that you have not had a recent neurologic event (such as 
stroke) within 30 days of starting transplant conditioning. If you did have a neurologic 
event, your transplant will be put on hold for 6 months. After the 6 months, the brain 
MRI will be repeated to see if your brain has healed. 
• You must not have HLA (tissue-specific) antibodies against your donor 
• You must be willing to use approved contraception until you have stopped taking all the 
medicines that work against your immune system 
• Your donor must be healthy enough to donate and willing to donate hematopoietic cells. 
 
3. Purpose 
 
The purpose of this research study is to: 
• To compare outcomes in patients with SCD who undergo HCT/BMT with those who do 
not undergo HCT/BMT because of the lack of a donor. 


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• To learn if it is possible and safe to treat persons with severe SCD by HCT/BMT from 
related and unrelated donors and to document serious side effects due to HCT/BMT (both 
expected and unexpected). 
 
For 2 years from enrollment, you will undergo study-related tests and results will be made 
available to study team. Between years 3 and 10 from enrollment, we will ask your doctor 
annually whether you are alive or dead and the date of last contact with your doctor. If you are 
not alive, we will ask for the date of death and the cause of death. If you doctor has lost contact 
with you, we will search the National Death Index, maintained by the government to record all 
deaths that occur in the U.S. Through the National Death Index, we will obtain the date of 
death and the cause of death. 
 
4. Study Treatments and Tests 
 
We found a tissue-type matched donor for you, so you have been assigned to the donor arm. You 
have already signed a consent which told you about the study procedures and follow up. This 
consent form will go over transplant and additional donor-arm specific follow up. 
 
Before your transplant: 
• Before your transplant, the BMT doctor will need to determine if you are healthy enough 
for transplant. These transplant-related screening assessments include: 
o If you are a female who can bear children, a blood pregnancy test (about 1 
teaspoon of blood will be drawn for this purpose) 
o MRA/MRI of the brain (tests that show a detailed view of the brain and its blood 
vessels) 
o MRI of your liver may be required if you meet certain criteria based on this 
history of your SCD. 
 A liver biopsy may be required based on the results of your [liver] MRI. 
• If you are determined to be healthy enough, you will proceed to transplant. If you are not 
healthy enough, you will not have a transplant and will continue receive standard of care 
from your SCD doctor. 
 
Preparation for your transplant and transplant conditioning: 
• Transplant Conditioning is the chemotherapy and other medicines given to prepare you 
to receive donor hematopoietic cells. It will help stop your immune system from 
attacking the donor cells and blocking engraftment or the donor cells ‘taking’. You will 
receive these medications before the HCT/BMT. These medications will be given in the 
hospital. 
• If you are taking hydroxyurea, this medication will be discontinued at least one week 
before you start the conditioning therapy. 
• To help with providing medicines, blood transfusions and obtaining blood for lab tests, a 
central venous catheter will be used. This is a hollow tube that is placed by a surgeon or 
radiologist, usually in the operating room. The tube is placed in the chest and allows 
medicines, transfusions, etc. to be given painlessly into the vein without the need for 
repeated sticking of needles in your arms. Once the catheter is placed, it will need daily 
care at home with cleaning and injection of medicines to prevent catheter-related blood 


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clots. The doctor doing the procedure and the anesthesiologist will describe the risks of 
the procedure before the surgery. You or your family members will be instructed on the 
care of this catheter. 
• Transplant Conditioning Regimen: 
o [Insert 1, Conditioning Regimen Drugs, from Appendix B-3, B-4, or B-5] 
 
Transplant and Post-Transplant Care: 
• On the day of transplantation, you will receive the hematopoietic cell infusion that will 
be given through the central venous catheter. Your blood pressure, heart rate, respiration 
rate, and temperature, will be taken before and during the infusion. The study doctor may 
also give you medications before the infusion to prevent side effects or discomfort. 
• After transplant, you will receive additional medications to help prevent a condition 
called graft-versus-host disease (GVHD). GVHD will be explained more later on in this 
document. 
o [Insert 2, GVHD Prophylaxis Drugs, from Appendix B-3, B-4, or B-5] 
 
Additional Donor Arm Follow-Up: 
• We will study the side effects of transplant (BMT) including those that are expected and 
unexpected in addition to the assessments described in the consent form you already 
assigned. These additional follow up assessments include: 
o Weekly physicals and GVHD assessments from day 7 to day 100 post-transplant. 
o White blood cell chimerism assessment at day 28, day 100, 1 year, and 2 years. 
o Red blood cell chimerism assessment for research at day 100 and 2 years 
o MRA/MRI of the brain (tests that show a detailed view of the brain and its blood 
vessels) at 2 years 
 
5. Risks and Discomforts 
 
You may experience discomfort, injury, and other risks as a result of taking part in this study, 
some of which are not currently known at this time. You may also learn medical information 
about you that you were previously unaware of and would rather not know. Also, your condition 
may not get better or may get worse during this study. 
 
By taking part in this research study, you are at risk to a number of complications, some of which 
can be severe and sometimes fatal. The most serious and commonly encountered include: 
 
Graft-versus-Host Disease (GVHD): 
This condition results from white cells called T cells in the donor’s hematopoietic cell cells 
recognizing your body as foreign and attacking it. You are more likely to get GVHD if the 
donor’s tissue type does not match your tissue type well. There are two forms of GVHD: acute 
GVHD (usually occurs in the first 3 months after transplant) and chronic GVHD (usually occurs 
later and lasts longer). Acute GVHD may produce a skin rash, nausea, vomiting, diarrhea, 
abdominal pain, abnormalities of liver function and an increased risk of infection. 
Chronic GVHD may produce skin rashes, hair loss, thickened skin, joint stiffness, dry eyes, dry 
mouth, liver disease, weight loss, diarrhea, and an increased risk of infection. Some patients 


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who have GVHD have developed collections of fluid around the heart (known as a pericardial 
effusion) or other body spaces such as around the lungs. These fluid collections may interfere 
with heart or lung function and may require surgical drainage or other treatments. To confirm the 
diagnosis of acute or chronic GVHD, you may be asked to have a skin biopsy (i.e., taking a 
small sample of skin tissue to look at under the microscope) and possibly an intestinal biopsy 
and rarely a liver biopsy. 
 
There is at least a 10-20% chance that you will develop GVHD after the transplant. The risk of 
GVHD is higher after an unrelated donor transplant. You will be watched closely for this 
complication and given treatment to treat it further if it occurs despite the medicines given to 
prevent it. In most cases, GVHD can be successfully treated. If GVHD does not respond to the 
medicines listed above, treatment can involve combinations of many other medicines with 
different side effects. Chronic GVHD can also occur 3 or more months after transplantation and 
may be associated with a prolonged course. GVHD can range from mild to life-threatening. 
Treatment may be necessary for many years as GVHD symptoms can last for many months or 
years. Prolonged treatment for chronic GVHD can result in a weak immune system and 
infections and may need frequent medical care and hospitalization. It is possible that GVHD can 
leave you with chronic medical problems which are worse than symptoms or disability you 
currently experience due to sickle cell disease. Sometimes GVHD is severe or difficult to treat 
and may lead to death. 
 
Susceptibility to bacterial and viral infections in the early post-transplant period: 
In the early post-transplant period, you will have an increased chance of getting bacterial or viral 
infections. This is because your ability to fight infections will be greatly limited due to the drugs 
given to prepare you for the BMT/HCT. 
 
Potential risk of reversible brain injury RPLS/PRES and bleeding in the brain: 
Patients with sickle cell disease who have a HCT/BMT have a higher than expected occurrence 
of a usually uncommon (< 5%) complication called reversible posterior leukoencephalopathy 
syndrome (RPLS) also known as posterior reversible encephalopathy syndrome (PRES) a form 
of injury to the brain, which is usually reversible. Patients with RPLS/PRES have confusion and 
other changes in their ability to think. Sometimes, they experience seizures, sleepiness or, 
rarely, loss of consciousness. RPLS is diagnosed with an MRI of the brain. It is a disorder that 
is sometimes seen in patients with sickle cell disease even if they do not  have a transplant.  In 
transplant patients, it is usually caused by some of the drugs used to prevent or treat graft versus 
host disease. It can often, but not always, be prevented by very careful control of blood 
pressure. It is treated by changing graft versus host disease drugs, controlling blood pressure 
and/or giving anti-seizure medicines. It is likely that about a quarter of the patients are at risk to 
develop RPLS/PRES. All sickle cell patients who develop RPLS/PRES typically can be 
successfully treated for this complication. We do not anticipate RPLS/PRES in any patient more 
than 6 months from their date of transplant. We believe that patients who are on prednisone or 
other corticosteroids, or immunosuppressive drugs such as cyclosporine or tacrolimus or have 
high blood pressure are more likely to develop RPLS/PRES. 


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A very small number of patients with sickle cell disease have experienced bleeding in the brain 
after an HCT/BMT. While this complication is rare, it is very serious because it can cause 
permanent brain damage or death. Your doctors will keep your platelet count in a safe range and 
monitor you carefully to keep you safe and prevent bleeding in the brain. 
 
If you experience any of these side effects or changes in mental status, you should contact 
your transplant physician right away, since early treatment is important. It is also 
important that any blood pressure medication be taken as prescribed to decrease the risk 
of RPLS/PRES. 
 
Potential risk of drugs used to ensure engraftment of new hematopoietic cells: 
To reduce the risk that the new hematopoietic cells will not "take" or grow, you will receive the 
medications listed previously, called the conditioning regimen, before transplantation. These drugs 
have possible side effects which include: 
 
[Insert 3, Conditioning Regimen Risks, from Appendix B-3, B-4 or B-5] 
Potential Side Effects of Drugs used to prevent GVHD: 
Although we have learned much about how to prevent the disease, graft-versus-host disease may be 
difficult to treat once it occurs and the complications associated with it can be life-threatening. You 
will be given drugs to prevent graft-versus-host disease. These drugs have possible side effects 
which include: 
 
[Insert 4, GVHD Prophylaxis Risks, from Appendix B-3, B-4 or B-5] 
Damage to the vital organs in your body 
The conditioning or GVHD treatment could result in problems in the heart, lungs, liver, intestine, 
kidneys and bladder, brain etc. Lung problems can be the result of infections or chemotherapy 
and sometimes as a complication of GVHD. Some patients can have veno-occlusive disease of the 
liver (VOD). This complication usually results from high doses of chemotherapy. Patients with 
VOD become jaundiced (yellowish skin), have liver function abnormalities, fluid retention, 
abdominal swelling, and abdominal pain. If organ damage symptoms are severe, you may have 
to stay in the hospital longer or be re-hospitalized after transplant. Although many patients 
recover completely, these complications may cause permanent damage or even death. 
 
Serious infections 
Full and complete recovery of your immune system may take many months following the initial 
recovery of your cell counts. During this time, there is an increased risk of infections. You 
w il l be prescribed certain medications to reduce the chance of those infections. However, 
preventive treatments are not always effective. If you have an infection, you may have to stay 
in the hospital longer or be re-hospitalized after transplant. Although most infections can be 
successfully treated, some infections are fatal. 
 
Recurrence of disease and graft rejection. 
There is a risk that the new marrow will fail to “take” and grow after transplantation. This is called 
graft rejection. If this happens, your own marrow will recover meaning that symptoms of your 


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sickle cell disease such as pain crises and other complications will return. Your blood will be 
evaluated frequently after transplantation to determine if the new donor hematopoietic cells are 
recovering. In the event that your marrow does not recover as expected, stimulating the 
hematopoietic cells by drugs, performing second HCT/BMT or giving hematopoietic cells from 
another donor are treatment options. If you develop graft rejection, you will stop being in this 
study, but you will continue to receive the standard medical care. Delay or failure of 
hematopoietic cell recovery increases the risk period of infection and the need for blood 
transfusions. 
 
Central venous catheter complications 
The most common complications associated with central venous catheters are blood clots in the 
catheter and infection. If clots form, a medicine will be injected to dissolve the clot. If it cannot 
dissolve, the catheter may need to be replaced. Infections will be treated with medicines; 
sometimes, removal of the infected catheter is required, and a new catheter will need to be placed. 
 
Pregnancy: 
For Women: 
The treatment on this study can affect an unborn child. You should not become pregnant 
or breast feed your baby while being treated in this study. If you are sexually active and are at 
risk of getting pregnant, you and your male partner(s) must use an effective method to avoid 
pregnancy, or you must not have sex. The study doctor will talk to you about acceptable methods 
of contraception to avoid pregnancy while you are being treated in this study. You will have to 
use the chosen method to avoid pregnancy or abstain (not have sexual intercourse) the whole 
time you are being treated in this study. Since treatments may alter/disrupt normal menstrual 
cycles, resulting in missed or absent periods, natural methods of family planning should not be 
used. If you have questions about this or want to change your method to avoid pregnancy during 
therapy, please ask your doctor. If you become pregnant during the research study, please tell the 
study doctor and your doctor immediately. 
 
If you are nursing a baby, the medications used in this research could pass into the breast milk. 
You should not nurse your baby for the whole time you are getting the study medicines. You 
may need to continue this for a while, even after you finish the treatment, so talk to your doctor 
about the length of time you need to avoid nursing. 
 
For Men: 
The treatment on this study can damage testicular function. You should not father a child while 
in this study as the treatment may indirectly affect an unborn child. If you are sexually active and 
are at risk of causing a pregnancy, you and your female partner(s) must use an effective method 
of contraception to avoid pregnancy, or you must not have sex. The study doctor will talk to you 
about the acceptable methods to avoid pregnancy while you are being treated in this study. You 
will have to use the chosen method to avoid pregnancy or abstain (not have sexual intercourse) 
the whole time you are being treated in this study. Natural family planning and the rhythm 
method will not be permissible means of avoiding pregnancy during study participation. If you 
have questions about this or want to change your method to avoid pregnancy during therapy, 
please ask your doctor. If your partner becomes pregnant during the research study, please tell 
the study doctor and your doctor immediately. 


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Impact on reproductive hormone function and sexuality 
High doses of chemotherapy can cause sterility (inability to have children) and decreased 
hormone levels. Some patients with chronic GVHD have reported impaired sexual function due 
to decreased sexual desire and vaginal dryness. Since the chemotherapy doses used in the 
preparative regimen for this study are lower, the risk of sterility may be lower. However, it is 
difficult to know the exact risk of sterility after transplant with the use of this conditioning 
regimen. Since there is a high risk of infertility after an HCT/BMT in both males and females 
we will refer you to a fertility preservation center to discuss your options. These may include 
storage of sperm/eggs or tissue from ovary or testes. 
 
Risk of death 
Some of the side effects of an unrelated donor transplant may be very severe and may cause 
death despite using all supportive care. Though all precautions will be taken to make the 
transplant as safe as possible for you, there is still a 10% - 20% chance of death following 
unrelated donor transplantation. 
 
Oher Risks 
As with any procedure, there may be adverse events or side effects that are currently unknown and 
certain of these unknown risks could be permanent, severe or life-threatening. You will be 
promptly notified if, during the conduct of this research study, any new information develops 
which may cause you to change your mind about continuing to participate. If new information is 
provided to you after you have joined the study, it is possible that you may be asked to sign a 
new consent form that includes the new information. 
 
6. Possible Benefits 
 
You may or may not benefit from taking part in this study. If the transplant is successful, you 
may benefit by not having any further symptoms and complications of severe sickle cell 
disease. The information obtained from your participation in this study will help doctors treat 
future patients with severe sickle cell disease who require a transplant. 
 
7. Other Treatments 
 
You do not have to participate in this study. Your participation is voluntary. If you choose not to 
participate in the study, you will not be missing out on any standard therapy for sickle cell 
disease. You will receive the same excellent care from the doctors and nurses whether or not you 
decide to take part in this study. In addition, other types of transplants are currently available to 
you. You may also choose to receive a transplant that uses a different combination of 
medications or a higher or lower dosage of the same medications. The different transplant 
treatment plans each will have different risks and benefits. Your doctors can discuss each type of 
transplant with you in greater detail. 
 
8. Costs and Reimbursements 
 
Several of the tests and treatments given in this study are considered standard care and will 
be billed to you or your insurer in the usual way. This study is also approved by Centers for 


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Medicare and Medicaid Services (CMS) for reimbursement. Standard costs include those of 
your hospitalization, doctor's visits, standard laboratory tests, medications, and the cost of 
the donor’s hematopoietic cells. There will be no charge for research tests. 
 
The study will pay for the research-related items or services that are provided only because you 
are in the study as outlined above. If you get a bill you think is wrong, call the researchers. 
 
You or your health plan will pay for all the things you would have paid for even if you were not 
in the study, like: 
• Health care given during the study as part of your regular care 
• Items or services needed for your care 
• Monitoring for side effects or other problems 
• Treatment of complications 
• Deductibles or co-pays for these items or services. 
 
If you do not have a health plan or if you think your health plan may not cover these costs during 
the study, please talk to the researchers or call your health plan’s medical reviewer. It is 
recommended that you work with your health care team to find out about costs in advance. 
 
If you receive a bill, or believe your health insurance has been billed for something that is part of 
the study, notify a member of the research team or [Insert institution] Patient Billing Services. 
 
You and/or your health insurance will be charged, in the standard manner, for services and 
procedures provided for your routine care. Any deductibles, co-insurances or co-payments that 
are a part of your insurance coverage will apply. 
 
9. Compensation of Payment 
 
You will not receive additional compensation for participating on the transplant portion of this 
clinical trial. You will continue to receive compensation for the health-related questionnaire and 
the electronic pain diary as was explained to you when you previously agreed to participate on 
this trial. 
 
10. Physical Injury as a Result of Participation 
 
[Insert institution] researchers and their associates who provide services at the [Insert institution] 
recognize the importance of your voluntary participation in their research studies. These 
individuals and their staff will make reasonable efforts to minimize, control, and treat any 
injuries that may arise as a result of this research. 
 
In the event that this research activity results in an injury, treatment will be available, 
including first-aid, emergency treatment and follow-up care as needed. Care for such injuries 
will be billed in the ordinary manner, to your insurance company. If you think that you have 
suffered a research-related injury, let the study doctors know right away. It is important that 
you tell your doctor, [Insert Investigator], if you feel that you have been injured because of 
taking part in this study. You can tell the doctor in person or call him/her at [Insert 


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telephone]. You will receive medical treatment if injured as a result of taking part in this study. 
Your insurance will be charged for this treatment. The study sponsor, the National Heart, Lung, 
and Blood Institute, does not offer financial compensation or payment if you are injured as a 
result in participating in this research study. However, you are not giving up any legal rights by 
signing this form. 
 
It is possible that [Insert institution] may bill your insurance provider for the costs of this 
emergency treatment, but none of these costs will be charged directly to you. If your research- 
related injury requires medical care beyond this emergency treatment, you will be responsible for 
the costs of this follow-up care unless otherwise specifically stated below. 
 
11. Rights as a Participant 
 
Your participation in this research study, including the use and disclosure of your identifiable 
information for the purposes described above, is completely voluntary. (Note, however, that if 
you do not provide your consent for the use and disclosure of your identifiable information for 
the purposes described above, you will not be allowed, in general, to participate in the research 
study.) Whether or not you provide your consent for your participation in this research study will 
have no effect on your current or future relationship with the [Insert institution]. Whether or not 
you provide your consent for participation in this research study will have no effect on your 
current or future medical care at a [Insert institution] hospital or affiliated health care provider or 
your current or future relationship with a health care insurance provider. 
 
Your physician is involved as an investigator in this research study. As both your physician and a 
research investigator, s/he is interested both in your medical care and the conduct of this research 
study. Before agreeing to participate in this research study, or at any time during your study 
participation, you may discuss your care with another doctor who is not associated with this 
research study. You are not under any obligation to participate in any research study offered by 
your doctor. 
 
You may choose to either take part or to not take part in the study. If you decide to take part   in 
this study, you may leave the study at any time. No matter what decision is made, there will be 
no penalty and you will not lose any of your regular benefits. If you leave the study, you   can 
still get medical care from your doctor and transplant center. We will tell you about new 
information or changes in the study that may affect your health or your willingness to continue 
in the study. In the case of injury resulting from this study, you do not lose any legal rights to 
seek payment by signing this form. 
 
If you have questions about your rights as a research participant or if you have questions, concerns 
or complaints about the research, you may contact the [Insert institution] Institutional Review 
Board (IRB) at the toll-free number [Insert IRB Number]. 
 
12. Ending Your Participation 
 
You may withdraw your consent, at any time, for your participation in this research study, to 
include the use and disclosure of your identifiable information for the purposes described above. 
(Note, however, that if you withdraw your consent for the use and disclosure of your identifiable 


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medical record information for the purposes described above, you will also be withdrawn, in 
general, from further participation in this research study.) Any identifiable research or medical 
information recorded for, or resulting from, your participation in this research study prior to the 
date that you formally withdrew your consent may continue to be used and disclosed by the 
investigators for the purposes described above. 
 
To formally withdraw your consent for your participation in this research study you should 
provide a written and dated notice of this decision to the principal investigator of this research 
study at the address listed on the first page of this form. 
 
If you are thinking about withdrawing from this study, talk with one of the research team 
members and your regular doctor first so they can help you decide what may be best for your 
medical care once you are off study. However, withdrawal after initiation of treatment could 
be life-threatening or even fatal, and may not be reasonable. 
 
If you leave the study before the planned final visit, the study doctor may ask to have some of the 
end of study procedures done for your safety and well-being. 
 
Your study doctor or NHLBI may decide to take you out of the study if: 
• The researcher believes that it is not in your best interest to stay in the study. 
• You become ineligible to participate. 
• Your condition changes and you need treatment that is not allowed while you are 
taking part in this study. 
• You do not follow instructions from the researchers. 
• The study is suspended or canceled. 
 
13. Privacy, Confidentiality, and Use of Information 
 
By signing this consent form, you are giving the researchers your permission to obtain, use, and 
share information about you for this study, and are required in order for you to take part in the 
study. Information about you may be obtained from any hospital, doctor, and other health care 
provider involved in your care, including: 
• Information from your hospital or office health records that may be reasonably related 
to the conduct and oversight of the research study. This may include information 
about hospital admissions or visits during this study, so that we know about any 
possible problems or side effects. If health information is needed from your doctors or 
hospitals from other institutions, you will be asked to give permission for these 
records to be sent to the researchers. 
• New health information from tests, procedures, visits, interviews, or forms filled out 
as part of this research study. 
 
Any information about you obtained from this research will be kept as confidential (private) as 
possible. Study records that identify you will be kept confidential as required by law. Federal 
Privacy Regulations protect your privacy, restrict who is allowed to look at your records, and 
require security to protect your records. All records related to your involvement in this research 


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study will be stored in a locked file cabinet. Your identity on these records will be indicated by a 
unique study ID number rather than by your name, and the information linking these case 
numbers with your identity will be kept separate from the research records. You will not be 
identified by name in any publication of the research results unless you sign a separate consent 
form giving your permission (release). 
 
We will do our best to make sure that the personal information in your medical record 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. 
 
Information gathered during this study and your medical records may be inspected and verified 
by staff of the study sponsor (the National Heart, Lung, and Blood Institute/National Institutes of 
Health), Office for Human Research Protections, [Insert institution], or the Institutional Review 
Board (IRB). Except when required by law, you will not be identified by name, social security 
number, address, telephone number, or any other direct personal identifier in study records 
shared outside of [Insert institution].  For records shared outside of [Insert institution], you will 
be given a study ID number. The list that can match you to the study ID number will be kept in a 
locked file cabinet in [Insert location]. 
 
Organizations that may look at and/or copy your medical records and protected health 
information for research, quality assurance, and data analysis include: 
• Members of the Blood and Marrow Transplant Clinical Trials Network (BMT 
CTN), which is conducting this study 
• The EMMES Corporation, a research organization that is helping to coordinate this 
study 
• The National Marrow Donor Program (NMDP) and the Center for International 
Blood and Marrow Transplant Research (CIBMTR), organizations involved in 
research on blood and marrow transplantation and in the coordination of this study 
• The National Heart, Lung, and Blood Institute (NHLBI), the National Cancer 
Institute (NCI) and other government agencies, like the Food and Drug 
Administration (FDA), involved in keeping research safe for people 
 
In addition to the investigators listed on the first page of this authorization (consent) form and 
their research staff, the following individuals will or may have access to identifiable information 
(which may include your identifiable medical information) related to your participation in this 
research study: 
 
Authorized representatives of the sponsor of this research study, the National Institutes of 
Health, or the Office for Human Research Protections or the Blood and Marrow 
Transplant Clinical Trials Network will review and/or obtain identifiable information 
(which may include your identifiable medical information) related to your participation in 
this research study for the purpose of monitoring the accuracy and completeness of the 
research data and for performing required scientific analyses of the research data. 


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While the study sponsor understands the importance of maintaining the confidentiality of 
your identifiable research and medical information, the [Insert institution] cannot 
guarantee the confidentiality of this information after it has been obtained by the study 
sponsor. The investigators involved in the conduct of this research study may receive 
funding from the sponsor to perform the research procedures and to provide the sponsor 
with identifiable research and medical information related to your participation in the 
study. 
 
Authorized representatives of the [Insert institution] or other affiliated health care 
providers may have access to identifiable information (which may include your 
identifiable medical information) related to your participation in this research study for 
the purpose of: (1) fulfilling orders, made by the investigators, for hospital and health 
care services (e.g., laboratory tests, diagnostic procedures) associated with research study 
participation; (2) addressing correct payment for tests and procedures ordered by the 
investigators; and/or (3) for internal hospital operations (i.e. quality assurance). 
 
At the end of the study, the study sponsor, the National Heart, Lung, and Blood Institute 
(NHLBI) will be given data from the study, without personal identifying information such as 
your name, address, Social Security number, or Medicare number. The data and/or materials may 
be shared with other scientists who meet NHLBI requirements, including treating the data or 
materials as medically confidential, obtaining approval from their Human Subjects review 
boards, and agreeing not to share the data or materials with other parties. 
 
The investigators may continue to use and disclose, for the purposes described above, 
identifiable information (which may include your identifiable medical information) related to 
your participation in this research study for a minimum of seven years after final reporting or 
publication of a project. The study results will stay in your research record at (insert Institution) 
for ten years from enrollment. Beyond the funding period (5-years), the dataset will be 
transferred to the Center for International Blood and Marrow Transplant Research at the Medical 
College of Wisconsin for extended follow up. Research information  in your medical record will 
be kept indefinitely. Data regarding your clinical situation, including follow-up after 2 years, may 
be obtained from the CIBMTR, which captures information on all US transplants. 
 
 
In accordance with the [Insert institution] Notices of Privacy Practices document that you have 
been provided, you are permitted access to information (including information resulting from 
your participation in this research study) contained within your medical records filed with your 
health care provider. 
 
Your privacy is very important to us. The study doctors will make every effort to protect it. The 
study doctors have a privacy permit to help protect your records if there is a court case. 
However, some of your medical information may be given out if required by law. If this should 
happen, the study doctors will do their best to make sure that any information that goes out to 
others will not identify who you are. 
 
 
 


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14. Health Insurance Portability and Accountability Act (HIPAA) 
 
HIPAA authorization to use and disclose individual health information for research 
purposes: 
 
a. Purpose: As a research participant, I authorize the Principal Investigator and the 
researcher’s staff to use and disclose my individual health information for the purpose 
of conducting the research study entitled Bone Marrow Transplantation for 
Adolescents and Young Adults with Severe Sickle Cell. 
b. Individual Health Information to be Used or Disclosed: My individual health 
information that may be used or disclosed to conduct this research includes: 
demographic information (e.g., age, date of birth, sex, weight), medical history (e.g., 
diagnosis, complications with prior treatment), physical examination findings, and 
laboratory test results obtained at the time of work up and after transplantation (e.g., 
blood tests, biopsy results). The identities of individuals such as names and addresses 
will not be shared or de-identified to make sure information cannot be linked to you. 
c. Parties Who May Disclose My Individual Health Information: The researcher and the 
researcher’s staff may obtain 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: 
Members of the BMT CTN Data and Coordinating Center and BMT CTN #1503 
Protocol Team 
National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute 
(NCI), both of the National Institutes of Health (NIH), study sponsors 
The National Marrow Donor Program and the Center for International Blood and 
Marrow Transplant Research 
 
The Blood Center of Wisconsin (BCW), which is a central lab that will do specialized 
testing on blood samples required during the study 
 
Data Warehouse Consultants (DWC) which is an agent of Yale University that will 
manage the pain diary. DWC will have access to your phone number, email address, IP 
Address and data that is entered in the pain diary application. 
 
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) 


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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 research-related treatment that is provided through the study. However, 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 the 
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. 
h. This authorization does not have an expiration date. However, you can elect at any time to 
withdraw your authorization to participate in the study. 
 
 
15. For More Information 
 
If you’d like more information about this study, or if you have any problems while you’re 
participating in this study, you can contact the study doctor or staff. They may be contacted at 
the telephone numbers listed here: 
 
[Insert name and contact details] 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 


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****************************************************************************** 
VOLUNTARY CONSENT 
 
All of the above has been explained to me and all of my current questions have been answered. I 
understand that I am encouraged to ask questions about any aspect of this research study during 
the course of this study, and that such future questions will be answered by the researchers listed 
on the first page of this form. 
 
I understand that I may contact the Human Subjects Protection Advocate of the IRB Office, 
[Insert institution and number] to discuss problems, concerns, and answer any questions I have 
about my rights as a research participant, to obtain information; offer input; or discuss situations 
in the event that the research team is unavailable. 
 
By signing this form, I agree to participate in this research study. A copy of this consent form 
will be given to me. 
 
 
 
Signature of Participant 
Participant’s Printed Name 
Date 
 
 
CERTIFICATION of INFORMED CONSENT 
 
I certify that I have explained the nature and purpose of this research study to the above-named 
individual(s), and I have discussed the potential benefits and possible risks of study participation. 
Any questions the individual(s) have about this study have been answered, and we will always be 
available to address future questions as they arise. I further certify that no research component of 
this protocol was begun until after this consent form was signed. 
 
 
 
Printed Name of Person Obtaining Consent 
Role in Research Study 
 
 
 
Signature of Person Obtaining Consent 
Date 


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Assent to Participate in Transplant and 
Additional Follow Up as Part of a Research Study 
 
 
 
 
 
TITLE: A Study to Compare Bone Marrow Transplantation to Standard Care in 
Adolescents and Young Adults with Severe Sickle Cell Disease 
 
Principal Investigator: 
[Insert site PI] 
Co-Investigators: 
[Insert site co-I] 
 
Study Coordinators: 
[Insert site study coordinator/s] 
 
[Insert site department/facility name, address, and phone number] 
 
 
Source of Support: National Heart, Lung, and Blood Institute (NHLBI) of the National 
Institutes of Health (the NIH), Bethesda, Maryland 
 
CONSENT FOR A MINOR TO BE A SUBJECT IN CLINICAL RESEARCH AND 
AUTHORIZATION TO PERMIT THE USE AND DISCLOSURE OF IDENTIFIABLE 
MEDICAL INFORMATION (PROTECTED HEALTH INFORMATION) FOR 
RESEARCH PURPOSES. 
 
 
[Insert site logo and/or address] 
This is a clinical trial, which is a research study to answer specific medical questions. 
The information from this study may also help future patients. The Study doctor (the person in 
charge of the research) will explain the study to you. This research study will include only people 
who choose to take part in the study. Please take your time to make your decision about taking 
part in the study. You may discuss your decision with family and friends. You should also discuss 
this with your healthcare team. If you have any questions, you can ask the Study doctor for more 
explanation. 


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A. Why am I here? 
 
We are inviting you to join our study because you have severe sickle cell disease. You are 
now receiving blood transfusions, hydroxyurea, and/or pain medicines. There is another 
treatment called hematopoietic cell transplant or bone marrow transplant (HCT/BMT). A 
transplant uses blood-making cells from another person (donor) to replace your cells that are 
not healthy (the sickle red blood cell). A donor is the name for a person who gives some of 
their blood-making cells for a transplant and their tissue has to match your tissue. We have 
identified a donor for you and inviting you participate in this study to receive the treatment 
called bone marrow transplant HCT/BMT. 
 
B. Why are you doing this study? 
 
We know transplant works to cure your disease, but we don’t know if this is a better 
treatment than blood transfusions, hydroxyurea, and/or pain medicines. 
 
C. What will happen to me? 
 
Before your transplant, you will get a small tube put in your chest in the operating room (you 
will be asleep for this). The small tube makes it easier for you to get your medicines. It will 
also make it easier for drawing blood for tests because you will not be poked. 
 
We will give you medicines that will help make the cells from your donor grow in your body. 
These medicines might make you feel sick. You might throw up, lose your hair, or get sores 
in your mouth. 
 
After you’re done taking the medicines, you will get cells from your donor. This is your 
transplant. Your new cells will come from your donor's blood or bone marrow. The cells will 
make new and healthy cells in your body. 
 
Sometimes the donor cells can cause a problem called graft versus host disease (GVHD). 
GVHD happens when the donor cells attack your body. It can give you diarrhea, a skin rash, 
make you feel sick and throw up, or make you not feel hungry. Your doctors will give you 
medicines to try to make sure you don’t get GVHD. 
 
You will stay in the hospital for several days before your transplant and for about 4 weeks 
after your transplant. After you go home, you will need to go back to see your doctor often. 
 
It is possible that your disease will come back. If this happens, your doctor will find another 
way to treat you. 
 
D. Will it hurt? 
 
For your transplant, we will put a small tube in your chest. It might hurt a little and you 
might bleed a little. Your doctor and nurses will make sure you feel as little pain as possible. 


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E. Will the study help me? 
 
We know HCT/BMT can cure sickle cell disease. What we don’t know is whether some of 
the problems from transplant like GVHD can cause more harm that if you did not have a 
transplant and continued to receive the care you are receiving now. 
 
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? 
 
You don't have to be in this study. Your doctor and nurses will not be mad at you if you don't 
want to join. If you decide you don't want to be in this study, you should talk to your doctor, 
nurses, and parents. You will receive the care you are receiving now (pain medication, blood 
transfusion, or hydroxyurea). 
 
You can say yes now and change your mind later. 
 
Be sure to talk this over with your parents before you decide if you want be in the study. We 
will also ask your parents to give their permission for you to join this study. 


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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 your doctor. 
 
You and your parent or guardian will get a copy of this form after you sign it. 
 
 
Printed Name of Child 
Date 
 
 
Signature of Child 
Age of Child 
 
 
Certification of Counseling Healthcare Professional: I certify that the nature and purpose, the 
potential benefits, and possible risks associated with participation in this study have been 
explained to the above individual and that any questions about this information have been 
answered. 
 
 
Printed Name of Person Obtaining Assent 
Role in Research Study 
 
 
Signature of Person Obtaining Assent 
Date 


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APPENDIX B-3 
 
Consent Information for Conditioning Regimen A 


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APPENDIX B-3 
 
CONSENT INFORMATION FOR CONDITIONING REGIMEN A 
 
 
Insert 1, Conditioning Regimen Drugs 
o The first medication you will be given for conditioning is called fludarabine, 
which will be given intravenously or IV (using the central venous catheter) for a 
total of 5 days prior to the transplant. 
o The second medication is called busulfan. This drug will also be given IV 
through the central catheter for 4 days prior to the transplant. 
o The third medication is called anti-thymocyte globulin (ATG), and will also be 
given IV. The ATG will also be given for 5 days before the transplant. 
Each of these drugs are routinely used as part of a conditioning regimen before transplant and to 
prevent graft versus host disease. 
 
Insert 2, GVHD Prophylaxis Drugs: 
o The first medication is called methotrexate. Methotrexate will be given on Days 
1, 3, 6, and 11 following the bone marrow transplantation. 
o The second medication that you will receive is a class of medicines called a 
calcineurin inhibitor (Cyclosporine A or Tacrolimus). The calcineurin 
inhibitor will be given IV starting on Day 3 before the bone marrow 
transplantation and will be given until Day 180. After Day 180, a tapering of this 
medicine (gradual decreasing of the amount given) will start and will continue 
until it has been stopped. The dose may be modified by the study doctor if there is 
evidence of GVHD or if there is worry about the possibility of a graft rejection. 
 
Insert 3, Conditioning Regimen Risks: 
Fludarabine: Can cause rare side effects such as: temporary blindness, confusion, and coma. 
Infrequent side effects such as poor kidney function, common side effects such as mouth sores and 
likely side effects such as nausea, vomiting, and diarrhea. 
 
Fludarabine 
 
Likely 
(“Likely” refers to a side effect 
that is expected to occur in 
more than 20% of patients.) 
Less Likely 
(“Less likely” refers to a side 
effect that is expected to occur 
in 20% or fewer patients.) 
Rare, but Serious 
(These possible risks have been 
reported in rare occurrences, 
typically less than 2% of patients. 
They may be serious if they 
occur.)
Anemia due to decreased 
number of red cells 
Infection due to decreased 
number of white blood 
cells 
Bleeding due to decreased 
numbers of platelets
Pneumonia 
Diarrhea 
Mouth sores 
Skin rash 
Fever 
Swelling of hands and feet 
Numbness and tingling in hands 
and/or feet related to 
irritation of nerves of the 
hand and/or feet 
Changes in vision 
Agitation/nervousness 


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Tiredness 
Nausea 
Vomiting 
Weakened immune system 
Confusion 
Cough 
Difficulty breathing 
Weakness 
Severe brain injury and death 
 
Busulfan: Can cause rare side effects such as: infertility (inability to have children) and lung injury 
when used at high doses or for prolonged periods of time. Infrequent side effects such as seizures, 
common side effects such as sores in the mouth and darkening of the skin, and likely side effects 
include nausea, vomiting, and hair loss. 
Busulfan 
 
Likely 
(“Likely” refers to a side effect 
that is expected to occur in 
more than 20% of patients.) 
Less Likely 
(“Less likely” refers to a side 
effect that is expected to occur 
in 20% or fewer patients.) 
Rare, but Serious 
(These possible risks have been 
reported in rare occurrences, 
typically less than 2% of patients. 
They may be serious if they 
occur.)
Loss of appetite 
Nausea 
Vomiting 
Skin breakdown if drug 
leaks from vein 
Anemia due to decreased 
number of red cells 
Infection due to decreased 
number of white 
blood cells 
Bleeding due to decreased 
numbers of platelets 
Mouth sores 
Temporary hair loss 
Diarrhea
Inflammation of the lung 
Weakness 
Weight loss 
Low blood pressure 
Excessive perspiration 
Allergic reaction 
Damage/ scarring of lung 
tissue 
Sterility 
Seizure 
 
Anti-Thymocyte Globulin: Is an antibody (made in rabbits) which can cause rare side effects such 
as seizures and increased risk of infection, infrequent side effects such as joint pain or allergic 
reaction (with low blood pressure, fast heart and breathing rate, difficulty breathing, and hives) and 
anemia, and common side effects such as fever and rash. 
 
Anti-Thymocyte Globulin 
 
Likely 
(“Likely” refers to a side effect 
that is expected to occur in 
more than 20% of patients.) 
Less Likely 
(“Less likely” refers to a side 
effect that is expected to occur 
in 20% or fewer patients.) 
Rare, but Serious 
(These possible risks have been 
reported in rare occurrences, 
typically less than 2% of patients. 
They may be serious if they 
occur.)


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Fever 
Chills 
Anemia due to decreased 
number of red cells 
Infection due to 
decreased number of 
white blood cells 
Bleeding due to 
decreased numbers of 
platelets 
Weakened immune 
system 
Nausea 
Vomiting 
Diarrhea 
Rash 
Headache 
Sweating 
Back pain 
Severe itching 
Allergic reaction of skin and 
blood vessels 
Tiredness 
Loss of appetite
Abdominal pain 
Dizziness 
High blood pressure 
Blisters 
Pain in the muscles 
Herpes simplex infection 
Inflammation of the throat 
 
Insert 4, GVHD Prophylaxis Risks: 
 
Calcineurin inhibitor (Cyclosporine or Tacrolimus): Can cause rare side effects such as 
temporary blindness, seizures, confusion and coma, common side effects such as poor kidney 
function and in some cases a need for dialysis (rare), increased risk of infection, swelling of the 
gums, infrequent side effects include numbness/tingling/tremors in hands and feet, and some 
likely side effects include high blood pressure, increased body hair, and chemical imbalances. 
 
Cyclosporine: This drug may be used for all patients. 
 
Likely 
(“Likely” refers to a side effect 
that is expected to occur in 
more than 20% of patients.) 
Less Likely 
(“Less likely” refers to a side 
effect that is expected to occur 
in 20% or fewer patients.) 
Rare, but Serious 
(These possible risks have been 
reported in rare occurrences, 
typically less than 2% of patients. 
They may be serious if they 
occur.)
High blood pressure 
Kidney problems 
Headaches 
Nausea 
Vomiting 
Stomach pain or 
indigestion 
Swelling of the hands or 
feet
Tremors
Increased hair growth 
Muscle cramps
Numbness and tingling of the 
hands or feet 
Seizure 
 
 
 
Tacrolimus: This drug may be used for all patients. 
 
Likely
(“Likely” refers to a side effect 
that is expected to occur in 
more than 20% of patients.)
Less Likely
(“Less likely” refers to a side 
effect that is expected to occur 
in 20% or fewer patients.)
Rare, but Serious 
(These possible risks have been 
reported in rare occurrences, 
typically less than 2% of patients.


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They may be serious if they 
occur.)
Anemia
Loss of appetite 
Diarrhea 
High potassium levels 
High blood pressure 
Nausea 
Fever 
Headache 
High blood sugar 
Hair loss 
Vomiting 
Tingling sensation in the 
extremities 
Itching 
Rash 
Abdominal pain 
Confusion 
Painful joints 
Increased sensitivity to light 
Blurred vision 
Insomnia 
Infection 
Jaundice 
Kidney injury 
Seizures 
 
Methotrexate: Can cause depression of the white blood count early after transplant, transient 
alteration in liver function and can result in severe mouth sores. 
 
Methotrexate 
 
Likely 
(“Likely” refers to a side effect 
that is expected to occur in 
more than 20% of patients.) 
Less Likely 
(“Less likely” refers to a side 
effect that is expected to occur 
in 20% or fewer patients.) 
Rare, but Serious 
(These possible risks have been 
reported in rare occurrences, 
typically less than 2% of patients. 
They may be serious if they 
occur.)
High levels of liver 
enzymes 
Nausea 
Vomiting 
Loss of appetite 
Diarrhea 
Mouth sores 
Sensitivity to sunlight 
Increased risk of 
sunburn 
Decreased number of red 
and white blood 
cells and platelets 
Hair loss 
Dizziness 
Redness, tenderness, 
darkening, and peeling of 
skin 
Blurred vision 
Allergic reaction 
Damage to nerve tissue 
Kidney damage 
Seizures 
Decreased lung function 
Decreased liver function - 
temporary 
Bone and tissue damage 
Loss of memory, 
concentration, balance, 
and walking 
Poor nervous system 
function


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APPENDIX B-4 
 
Consent Information for Conditioning Regimen B 


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APPENDIX B-4 
 
CONSENT INFORMATION FOR CONDITIONING REGIMEN B 
 
 
Insert 1, Conditioning Regimen Drugs 
o The medication you will be given for conditioning is called Alemtuzumab, 
which will be given intravenously or IV (using the central venous catheter) for a 
total of 5 days prior to the transplant. 
o After that, you will get a low dose of total body irradiation (TBI). A single 
dose will be given while you are put in front of a machine two days before your 
transplant. 
• This conditioning regimen is routinely used before transplant. 
 
Insert 2, GVHD Prophylaxis Drugs: 
o The medication called Sirolimus will be given to you one day before your 
transplant until Day 180. After Day 180, a tapering of this medicine (gradual 
decreasing of the amount given) will start and will continue until it has been 
stopped. The dose may be modified by the study doctor if there is evidence of 
GVHD or if there is worry about the possibility of a graft rejection. 
• This drug is routinely used for GVHD prevention. 
 
Insert 3, Conditioning Regimen Risks: 
 
Alemtuzumab 
Likely (May happen in more 
than 20% of patients) 
Less Likely (May happen in 
20% or fewer patients, but 
more than 2%)
Rare, but Serious (May 
happen in 2% or fewer 
patients)
•
Infection, which may 
cause fever and chills 
• Joint pain 
• Low platelet levels, 
which may cause 
bruising, bleeding 
• Low red blood cell 
counts, which may 
cause tiredness or may 
require blood 
transfusions 
• Low white blood 
cells, which may 
cause increased 
•
Cough
• Feeling anxious 
• Feeling tired 
• Headache 
• Hypertension 
• Irregular heartbeat, 
most commonly fast 
heart rate 
• Muscle stiffness, 
spasms, tremor or 
pain 
• Problems sleeping 
• Rash, itching 
•
Allergic reaction 
which may cause rash, 
low blood pressure, 
wheezing, shortness 
of breath, dizziness, 
swelling of the face or 
throat 
• Heart problems 
including heart 
enlargement, or 
impaired heart 
pumping 
• Inflammation of the 
brain 


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infections and slower 
wound healing 
• Nausea, vomiting, 
abdominal pain, 
diarrhea, loss of 
appetite 
• Reaction to the 
medication infusion, 
which may include 
itching, fever, chills, 
low blood pressure 
and problems 
breathing 
• Sweating 
• Swelling of ankles 
and feet 
• Thyroid function 
decreased 
•
Inflammation of the 
gallbladder 
 
 
Low Dose TBI 
Common, some may be 
serious (>20%)
Occasional, some may be 
serious (4 - <20%)
Rare and serious (3% or 
fewer)
• Anemia (low red blood 
cells) which may require 
blood transfusions 
• Infection, especially when 
white blood cell count is 
low 
• Low platelet counts, 
which may cause bruising 
or bleeding 
• Mouth sores 
• Nausea, vomiting, 
stomach pain, diarrhea 
• Eye cloudiness 
• Hair loss 
• Inability to have children 
• Painful swelling of the 
salivary glands under the 
ears for a few days 
• Redness of the skin 
• A new cancer resulting 
from treatment of a prior 
cancer 
• Back pain 
• Difficulty swallowing 
• Hormone problems (such 
as thyroid disease or 
diabetes) 
• Kidney problems 
• Learning problems 
• Liver problems 
• Lung inflammation 
• Risk of developing other 
cancers in the future 
• Slowing of growth (body 
height) 


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Insert 4, GVHD Prophylaxis Risks: 
Sirolimus 
Common, some may be 
serious (>20%)
Occasional, some may be 
serious (4 - <20%)
Rare and serious (3% or 
fewer)
•
Change of lab values 
that may need to be 
corrected: high 
cholesterol, high 
triglycerides 
• Constipation, 
diarrhea, nausea, , 
abdominal pain 
• Headache 
• High blood pressure 
• Increased creatinine 
levels 
• Low platelet levels, 
which may cause 
bruising, bleeding 
• Low red blood cell 
counts, which may 
cause tiredness or may 
require blood 
transfusions 
• Painful Joints 
• Rash, skin breakouts 
• Swelling of the body 
•
A new cancer 
resulting from 
treatment of earlier 
cancer 
• Blood clots in the 
veins that can cause 
blood clots in the 
lungs and legs 
especially 
• Brittle bones that 
break easier 
• Change of lab values 
that may need to be 
corrected: low 
potassium, high 
glucose 
• Damage to lungs, 
which may cause 
shortness of breath, 
fluid arounds lungs 
• Embolism and 
clotting of the small 
blood vessels in the 
brain and kidneys and 
other organs 
• Fast heart rate 
• Low white blood 
cells, which may 
cause increased 
infections and slower 
wound healing 
• Mouth sores 
•
Allergic reaction 
which may cause rash, 
low blood pressure, 
wheezing, shortness 
of breath, swelling of 
the face or throat 


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APPENDIX B-5 
 
Consent Information for Conditioning Regimen C 


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APPENDIX B-5 
 
CONSENT INFORMATION FOR CONDITIONING REGIMEN C 
 
 
Insert 1, Conditioning Regimen Drugs 
o The first medication you will be given for conditioning is called alemtuzumab 
which will be given intravenously or IV (using the central venous catheter) for 
three days in a row about 20 days before the transplant. 
o The second medication is called fludarabine. This drug will also be given IV 
through the central catheter for 5 days about a week before the transplant. 
o The third medication is called melphalan and will also be given IV for one day 
three days before the transplant. 
Each of these drugs is routinely used as part of a conditioning regimen before transplant. 
 
Insert 2, GVHD Prophylaxis Drugs: 
o The first medication is called methotrexate. Methotrexate will be given on Days 
1, 3, and 6 following the transplant. 
o The second medication that you will receive is tacrolimus. Tacrolimus will be 
given IV starting on Day 3 before the transplant and will be given until Day 180. 
After Day 180, a tapering of this medicine (gradual decreasing of the amount 
given) will start and will continue until it has been stopped. The dose may be 
modified by the study doctor if there is evidence of GVHD or if there is worry 
about the possibility of a graft rejection. 
 
Insert 3, Conditioning Regimen Risks: 
 
Alemtuzumab 
Likely (May happen in more 
than 20% of patients) 
Less Likely (May happen in 
20% or fewer patients, but 
more than 2%)
Rare, but Serious (May 
happen in 2% or fewer 
patients)
•
Infection, which may 
cause fever and chills 
• Joint pain 
• Low platelet levels, 
which may cause 
bruising, bleeding 
• Low red blood cell 
counts, which may 
cause tiredness or may 
require blood 
transfusions 
• Low white blood 
cells, which may 
cause increased
•
Cough
• Feeling anxious 
• Feeling tired 
• Headache 
• Hypertension 
• Irregular heartbeat, 
most commonly fast 
heart rate 
• Muscle stiffness, 
spasms, tremor or 
pain 
• Problems sleeping 
• Rash, itching 
•
Allergic reaction 
which may cause rash, 
low blood pressure, 
wheezing, shortness 
of breath, dizziness, 
swelling of the face or 
throat 
• Heart problems 
including heart 
enlargement, or 
impaired heart 
pumping 
• Inflammation of the 
brain 


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infections and slower 
wound healing 
• Nausea, vomiting, 
abdominal pain, 
diarrhea, loss of 
appetite 
• Reaction to the 
medication infusion, 
which may include 
itching, fever, chills, 
low blood pressure 
and problems 
breathing 
• Sweating 
• Swelling of ankles 
and feet 
• Thyroid function 
decreased 
•
Inflammation of the 
gallbladder 
 
Fludarabine: Can cause rare side effects such as: temporary blindness, confusion, and coma. 
Infrequent side effects such as poor kidney function, common side effects such as mouth sores and 
likely side effects such as nausea, vomiting, and diarrhea. 
 
Fludarabine 
 
Likely 
(“Likely” refers to a side effect 
that is expected to occur in 
more than 20% of patients.) 
Less Likely 
(“Less likely” refers to a side 
effect that is expected to occur 
in 20% or fewer patients.) 
Rare, but Serious 
(These possible risks have been 
reported in rare occurrences, 
typically less than 2% of patients. 
They may be serious if they 
occur.)
Anemia due to decreased 
number of red cells 
Infection due to decreased 
number of white blood 
cells 
Bleeding due to decreased 
numbers of platelets 
Tiredness 
Nausea 
Vomiting 
Weakened immune system 
Pneumonia 
Diarrhea 
Mouth sores 
Skin rash 
Fever 
Swelling of hands and feet 
Numbness and tingling in hands 
and/or feet related to 
irritation of nerves of the 
hand and/or feet 
Changes in vision 
Agitation/nervousness 
Confusion 
Cough 
Difficulty breathing 
Weakness 
Severe brain injury and death 
 
Melphalan 


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Common, some may be 
serious (>20%)
Occasional, some may be 
serious (4 - <20%)
Rare and serious (3% or 
fewer)
•
Anemia (low red 
blood cells) which 
may require blood 
transfusions 
• Diarrhea 
• Feeling of being tired 
• Infection, especially 
when white blood cell 
count is low 
• Nausea, vomiting 
• Sores in mouth which 
may cause difficulty 
swallowing 
• Swelling of the body 
•
Inflammation of blood 
vessels 
• Kidney problems 
which may require 
dialysis 
• Liver problems which 
may cause yellow 
eyes and skin 
• Low platelet counts, 
which may cause 
bruising or bleeding 
• Scarring of the lungs 
which 
may 
cause 
shortness of breath 
•
A new cancer 
resulting from 
treatment of a prior 
cancer 
• Allergic reaction 
which may cause rash, 
low blood pressure, 
wheezing, shortness 
of breath, swelling of 
the face or throat 
• Heart failure which 
may cause shortness 
of breath, swelling of 
ankles, and tiredness 
 
 
Insert 4, GVHD Prophylaxis Risks: 
 
Methotrexate: Can cause depression of the white blood count early after transplant, transient 
alteration in liver function and can result in severe mouth sores. 
 
Methotrexate 
 
Likely 
(“Likely” refers to a side effect 
that is expected to occur in 
more than 20% of patients.) 
Less Likely 
(“Less likely” refers to a side 
effect that is expected to occur 
in 20% or fewer patients.) 
Rare, but Serious 
(These possible risks have been 
reported in rare occurrences, 
typically less than 2% of patients. 
They may be serious if they 
occur.)
High levels of liver 
enzymes 
Nausea 
Vomiting 
Loss of appetite 
Diarrhea 
Mouth sores 
Sensitivity to sunlight 
Increased risk of 
sunburn 
Decreased number of red 
and white blood 
cells and platelets 
Hair loss 
Dizziness 
Redness, tenderness, 
darkening, and peeling of 
skin 
Blurred vision 
Allergic reaction 
Damage to nerve tissue 
Kidney damage 
Seizures 
Decreased lung function 


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Decreased liver function -
temporary 
Bone and tissue damage 
Loss of memory, 
concentration, balance, 
and walking 
Poor nervous system 
function
 
Tacrolimus: This drug may be used for all patients. 
 
Likely 
(“Likely” refers to a side effect 
that is expected to occur in 
more than 20% of patients.) 
Less Likely 
(“Less likely” refers to a side 
effect that is expected to occur 
in 20% or fewer patients.) 
Rare, but Serious 
(These possible risks have been 
reported in rare occurrences, 
typically less than 2% of patients. 
They may be serious if they 
occur.)
Anemia
Loss of appetite 
Diarrhea 
High potassium levels 
High blood pressure 
Nausea 
Fever 
Headache 
High blood sugar 
Hair loss 
Vomiting 
Tingling sensation in the 
extremities 
Itching 
Rash 
Abdominal pain 
Confusion 
Painful joints 
Increased sensitivity to light 
Blurred vision 
Insomnia 
Infection 
Jaundice 
Kidney injury 
Seizures 


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APPENDIX C 
LABORATORY PROCEDURES 


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APPENDIX C 
LABORATORY PROCEDURES 
Hematopoietic progenitor cell transplantation (HCT) remains the only curative therapy for severe 
sickle cell disease (SCD) and is associated with high rates of survival with stabilization of organ 
function and amelioration of sickle cell related complications. The impact of SCD on the long term 
survival and outcomes in SCD patients remains unclear because of the lack of studies comparing 
outcomes between SCD patients who undergo HCT or standard of care. BMT CTN 1503 STRIDE 
2 is the first ever comparative clinical trial of a well-characterized group of adult patients with 
SCD biologically assigned to receive HCT or standard of care according to the availability of a 
suitable donor. As such it provides a unique opportunity. Biological specimens from patients 
enrolled in this study, therefore, represent a valuable resource to interrogate mechanisms of SCD 
related and HCT related complications and the long term effects of HCT. 
 
A. Required Research Samples for Erythroid Chimerism Testing 
Sickle cell disease (SCD) is a common and severe autosomal recessive disorder caused by a 
missense mutation in the hemoglobin gene (HBB) resulting in hemoglobin S. 
Nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) is increasingly 
being used to treat severely affected patients. Mixed chimerism is observed in a large 
proportion of patients after HSCT. Most patients transition to complete donor chimerism. Some 
patients have long-term persistent mixed chimerism without need of red cell support even with 
a low percentage of donor-derived nucleated cells since an adequate amount of the normal 
HBB transcript, HbA, is being made. 
Several studies have demonstrated that chimerism measured in the nucleated cell compartment 
does not always reflect the engraftment in the erythroid lineage. Assessment of the chimerism 
in the erythroid lineage may be a better indicator of donor erythropoiesis. As red cells do not 
contain DNA, chimerism in the erythroid compartment can be monitored using quantitative 
measurements of HbA and HbS transcripts produced from the hemoglobin gene (HBB) 
expressed in red cell progenitors. 
 
Required molecular testing will be performed on Day +100 and Day +730 post-transplant 
samples to monitor erythroid chimerism and the effects of allogenic transplantation in SCD 
patients. Sample collection is limited to study patients assigned to the allogeneic donor arm 
of the trial. Either peripheral blood or marrow aspirate samples are acceptable sample types to 
be submitted for this required testing. Research samples will be scheduled for collection on 
Day +100 (±14) and on Day +730 (±14) post-transplant. Biologic samples will be shipped on 
the day of collection to the Molecular Diagnostics Laboratory at the Blood Center of 
Wisconsin. 


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Required Erythroid Chimerism Sample Collection Summary 
Tube 
Specimen
Type 
Specimen
Purpose 
Amount
(mL) 
Time Points 
Sample
Shipping 
BD 
Vacutainer® 
EDTA Tube 
Whole Blood 
or 
Bone Marrow 
Aspirate 
Research 
Sample 
(Erythroid 
Chimerism) 
10 mL
(blood) 
Or 
3-5 mL 
(marrow) 
Day 100 & Day 730 
Post-Transplant 
 
Ambient 
 
Detailed procedures regarding specimen collection schedules, collection procedures, and 
sample shipping instructions will be provided in the BMT CTN 1503 MOP. 
 
B. Optional Research Samples for Planned and Future Laboratory Studies 
Peripheral blood and urine samples will be collected on all consenting study patients receiving 
biologic assignment to either arm of the trial and shipped to the YSM BioBank processing and 
sample storage. The samples will be used for planned lymphocyte population analysis and for 
future BMT-related cellular, proteomic, transcriptomic, and DNA-based genetic studies and 
sickle cell disease related research. 
 
The optional peripheral blood (31.5 mL) and urine (50 mL) research samples will be collected 
on all consenting study patients at two study time points: 
• At the time of biologic assignment. Baseline research samples will be collected within 14 
days after biologic assignment and prior to the initiation of study arm-specific therapy. 
• Day +730 (±14) post-biologic assignment 
 
Samples will be shipped on the day of collection to the YSM BioBank for processing and long-
term sample storage. Detailed procedures regarding specimen collection schedules, collection 
procedures, sample tube centrifugation and shipping instructions will be found in the BMT 
CTN 1503 MOP. 
 
Optional Research Sample Collection Summary 
Tube 
Specimen 
Type 
Specimen 
Purpose 
Amount 
(mL) 
Time Points 
Clinical Site 
Blood 
Tube 
Centrifugation 
Required 
Stored 
Biospecimen 
Type 
BD Vacutainer® 
SST Serum Tube 
Whole 
Blood 
Research Sample 
(Serum) 
5 
Baseline 
& 
Day 730 
YES 
Serum 
BD Vacutainer® 
PPT™ Plasma 
Preparation Tube 
Whole 
Blood 
Research Sample 
(Plasma) 
5 
YES 
EDTA 
Plasma 


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Optional Research Sample Collection Summary 
Tube 
Specimen 
Type 
Specimen 
Purpose 
Amount 
(mL) 
Time Points 
Clinical Site 
Blood 
Tube 
Centrifugation 
Required 
Stored 
Biospecimen 
Type 
BD Vacutainer® 
CPT™ 
Mononuclear Cell 
Preparation Tube 
Whole 
Blood 
Research Sample 
(PBMC) 
Post-Biologic
Assignment
8
YES
PBMC
BD Vacutainer®
EDTA Tube 
Whole
Blood 
Research Sample
(Whole Blood) 
6 
No 
Whole Blood 
PAXgene Blood 
RNA Tube 
Whole 
Blood 
Research Sample 
(PAXgene) 
2.5 
No 
Blood RNA 
Lysate 
Cyto-Chex BCT 
Whole
Blood 
Research Sample
(Cyto-Chex) 
5 
No 
N/A 
Polypropylene
Centrifuge Tube 
Urine 
Research Sample
(Urine) 
50 
No 
Urine 


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APPENDIX D 
BUSULFAN DOSING CALCULATION 


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APPENDIX D 
BUSULFAN DOSING CALCULATION 
Busulfan dose will be targeted to achieve a concentration at steady state (Css) of 600-900 ng/ml ( 
target 750 ng/ml) or a daily area under the plasma concentration curve (AUC) of 3507–5261 
µM•min ( target 4384 µM•min) on the subsequent day. The total regimen AUC will be in the range 
of 14,000 – 21,000 µM•min. 
Css does not change according to the dosing interval, but AUC does. Css can be converted to AUC 
using the following formula: 
Css (ng/mL) = AUC (in umol*min/L) * molecular weight 
Dosing interval (in min) 
Busulfan MW = 246.3 g/mol 
For Q24H dosing, the dosing interval in minutes in 24 hours = 1440 min) 
So an AUC of 4400 umol*min/L Css can be calculated as follows: 
Css (in ng/mL) = 4400 * 246.3 
= 753 (rounding to the nearest ng/mL) 
1440 


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APPENDIX E 
 
METHOTREXATE DOSING ADJUSTMENT GUIDELINES 


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APPENDIX E 
 
METHOTREXATE DOSING ADJUSTMENT GUIDELINES 
 
 
Dose reduction of methotrexate due to worsening creatinine clearance after initiation of 
conditioning regimen, elevated serum bilirubin or oral mucositis is allowed according to 
institutional practice. The Table below offer doing guidelines based on serum bilirubin and 
creatinine. 
 
Table 1. Dosing Guidelines for Methotrexate
Laboratory 
parameters 
MTX dose
Full
75%
50%
25%
Hold dose
Serum bilirubin
< 2.0
NA
2.1-3.0
3.1 – 5.0
>5.0 mg/dL
Serum creatinine
<1.5
1.5 – 1.7
1.8 - 2.0
NA
>2


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APPENDIX F 
 
GUIDELINES FOR PREVENTION AND 
MANAGEMENT OF PRES 


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APPENDIX F 
 
GUIDELINES FOR PREVENTION AND MANAGEMENT OF PRES 
 
 
Mission Statement: 
To describe the pathophysiology, clinical diagnosis, prevention and management of Posterior 
reversible encephalopathy syndrome (PRES). PRES is a disorder of reversible subcortical 
vasogenic brain edema with a constellation of acute neurological symptoms and brain imaging 
findings of vasogenic edema predominantly involving the bilateral parieto-occipital regions. 
Patients with sickle cell disease are particularly susceptible to PRES.63,64 
 
Pathophysiology 
PRES results from endothelial injury related to abrupt blood pressure changes or direct effects  of 
cytokines on the endothelium, which leads to the breakdown of the blood–brain barrier and 
subsequent brain edema. With early diagnosis and appropriate management, PRES is reversible, 
both radiographically and clinically, and generally has a favorable prognosis. 
 
Clinical Presentation 
Clinical presentation of PRES include65-71 seizure (60–75%), encephalopathy (50–80%), headache 
(50%), visual disturbances (33%), focal neurological deficit (10–15%), and Status epilepticus (5– 
15%). Symptoms  typically  occur  in  the  setting  of  renal  failure,  blood  pressure  fluctuations, 
cytotoxic drugs, autoimmune disorders, and pre-eclampsia or eclampsia.67 Calcineurin inhibitor 
(CNI)-induced PRES may occur with elevated blood pressure within days to weeks of CNI 
initiation and typically occurs without elevated medication levels.72 Clinical and radiographic 
recovery occur in 75–90% of patients with a mean time to full clinical recovery range of 2–8 days, 
although some patients can take several weeks to achieve full recovery.72-75 Concomitant GVHD 
with the use of steroids is an important risk factor for PRES.76 
 
Imaging 
Brain imaging is useful to confirm the diagnosis of PRES and to exclude alternative diagnoses. 
Although vasogenic edema can be visualized using non-contrast CT in some patients, brain MRI 
(particularly T2-weighted sequences such as fluid-attenuated inversion recovery [FLAIR]) is much 
more  sensitive.73,77  Brain  imaging  usually  reveals  vasogenic  edema  in   the parieto-   occipital 
regions of both cerebral hemispheres. The subcortical white matter is always affected, and the 
cortex is also often involved. The edema is usually asymmetric, but almost always bilateral. Three 
primary descriptive variations exist in approximately 70% of patients: a dominant parieto- occipital 
pattern, holo-hemispheric watershed pattern, and superior frontal sulcus pattern. Neither the 
pattern nor the severity of brain edema, is associated with the type or severity of clinical 
presentation.67,73 
 
Differential Diagnosis 
The symptoms and signs are non-specific, thus necessitating brain imaging with the primary intent 
to exclude alternative diagnoses. However, the diagnosis of PRES is not solely radiological; the 
clinical context and the judgment of the clinician are crucial to making the correct diagnosis. 


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Differential diagnoses to be considered include infectious encephalitis, vasculitis, post transplant 
lymphoproliferative disorder and progressive multifocal leukoencephalopathy. 
 
Risk Factors in HCT/BMT Predisposing to PRES 
Incidence of PRES in allo-HCT/BMT is 7-9% with greater risks with myeloablative than with non- 
myeloablative regimens (16%vs 3%). PRES commonly occurs in the first month following 
HCT/BMT and is associated with increased HLA mismatch and with acute GVHD. Low –level 
neurotoxicity such as tremors, anxiety, and psychiatric dysfunction has been observed in 10%- 
40% of patients receive CNIs. Cyclosporine can induce endothelial injury/dysfunction leading to 
enhanced vasoconstrictive effects, increased sympathetic activation, and coagulation effects. 
Blood levels of Cyclosporine do not appear to correlate with severe neurotoxicity or PRES. 
Immune challenge from the transplant such as rejection and GVHD, effects of chemotherapy, and 
sepsis may all contribute to the risk of PRES. Discontinuation or switch of CNIs usually results in 
clinical improvement. 
 
Unique Risk for PRES in Patients with SCD Undergoing HCT/BMT 
Patients with SCD have impaired dynamic cerebrovascular auto regulation with decreased ability 
to buffer the transfer of blood pressure surges to cerebral tissue78 as well as reduced 
cerebrovascular reserve capacity or vasodilatory capacity.79 This may place them at unique risk for 
developing PRES. PRES has been reported in patients with SCD following severe acute chest 
syndrome, blood transfusion, hyper-transfusion with rapid increase in hemoglobin, recent use of 
 
Pegelow, C et al Am J Med 102 p171-177) 1997


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corticosteroids, hypomagnesaemia, and in the absence of any precipitating factors.80-84 The 
prevalence of seizures in children with SCD is 10 times that of the general population.85-87 The 
observation of neurological complications in 30% of patients including intracranial hemorrhages 
in 38% of those with a previous history of stroke in an early series of patients with SCD undergoing 
HCT/BMT led to the universal adoption of measures for the prevention of PRES.64 Measures for 
prevention of PRES include extended duration of anticonvulsant prophylaxis, intensified 
antihypertensive management and aggressive platelet support.64 
 
Prevention of PRES in HCT/BMT for SCD 
Prevention of PRES requires careful attention to the following measures (Table 2): 
 
a. Control of blood pressure. Blood pressure in patients with SCD has been reported to be 
lower than published standards for age, sex, and race-matched controls .88-90 Decreased 
survival has been observed for patients with SCD whose systolic or diastolic pressures 
were above the 90th percentile for HbSS subjects.85 Pressures above the 90th percentile for 
HbSS may overlap levels considered normal in non-SCD patients. Blood pressures may be 
elevated with fluid infusions or use of medications such as corticosteroids or CNIs. 
Supportive care orders must indicate the importance of keeping BP within 10% above the 
median for age for HbSS patients as described by Pegelow et al (Table I)88 or the baseline 
BP for the patient, whichever is lower. Mean arterial pressure (MAP) should be maintained 
at <70mmHg. Close monitoring and aggressive management with anti-hypertensive agents 
will be required to prevent PRES. 
 
b. Maintenance of adequate platelet count. Thrombocytopenia and coagulopathy may be 
associated with increased risk of PRES-related ICH.64,90 It is therefore recommended to 
keepplateletcount>50,000/μL. 
 
Table 2. Measures for Prevention of PRES
Measure
Action
Control of Blood pressure
Physician to be notified and PRN anti-
hypertensives to be administered if systolic or 
diastolic BP exceeds 10% above median for 
age in HbSS patients or > 10% baseline for 
patient, whichever is lower. 
Maintenance of adequate platelet count.
TransfusetokeepPlatelets>50,000/μL
Maintenance of euvolemic state
Avoid rapid fluid shifts. Maintain weight as 
close to baseline as possible.
Maintenance of adequate magnesium level
Maintainserummagnesiumlevel≥1.8mg/dL
(0.75mmol/L) when lab normal range (1.7– 
2.4 mg/dL or 0.7–1 mmol/L) 
Prevention of seizures
Institute anticonvulsant therapy before 
Busulfan and continue through the duration of 
administration of any calcineurin inhibitor. 


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c. Maintenance of euvolemic state. Large fluid shifts should be avoided.86 Close attention 
must be paid to fluid balance since fluid overload with weight gain associated with 
increased blood pressure and consequently, increased risk of PRES. 
 
d. Maintenance of adequate level of serum Magnesium. The association between 
hypomagnesemia and cyclosporine toxicity was first observed during the initial clinical 
trials of the drug for GVHD prophylaxis.91 Severe hypomagnesemia can also present with 
clinical and radiological features similar to PRES.92,93 Magnesium sulphate is considered 
the drug of choice in the treatment of PRES associated with Eclampsia.94 It is therefore 
recommended that patients receive magnesium supplementation in order maintain patient 
Maintain serum magnesium level ≥ 1.8mg/dL ( 0.75mmol/L) when lab normal range (1.7– 
2.4 mg/dL or 0.7–1 mmol/L). Maintenance of mild hypermagnesemia with serum 
Magnesium 2-3mg/dL may be advisable, but maybe difficult to achieve because of side 
effects of P.O Magnesium. Bioavailability of magnesium in the aspartate, citrate, lactate, 
diglycinate and chloride forms is higher than magnesium oxide or sulfate.95-99. 
 
Table 3. Measures for Treatment and Management of PRES
Measure
Action
Supportive care
Immediately admit to ICU and initiate 
management as below while evaluating cause 
for neurological manifestations. High index of 
suspicion and early diagnosis are key. Obtain 
MRI with FLAIR. Monitor neurological status 
closely.
Removal of drug precipitating PRES
Stop cyclosporine or tacrolimus immediately. 
After 48 hours washout period may consider 
adding sirolimus. Tacrolimus may then be 
started in place of cyclosporine. Caution is 
advised in adding steroids because of the risk of 
hypertension and progression of PRES.
Control of Blood pressure
Institute intravenous medications to control 
Blood pressure. Labetalol is drug of choice. 
Decrease BP by 25% over 6 hours. Gradual 
reduction of BP thereafter.
Maintenance of adequate platelet
count.
TransfusetokeepPlatelets>50,000/μL
Maintenance of euvolemic state
Avoid rapid fluid shifts. Maintain weight as 
close to baseline as possible. Close attention to 
intake and output. Avoid hypertransfusion. 
Keep Hb <12g/dL.
Maintenance of adequate magnesium 
level 
Correct hypomagnesemia. Maintain serum 
magnesiumlevel≥1.8mg/dL(0.75mmol/L)
when lab normal range (1.7–2.4 mg/dL or 0.7–1 
mmol/L)
Treatment of seizures
Institute anticonvulsant therapy immediately.


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Table 3. Measures for Treatment and Management of PRES
Measure
Action
Management of concurrent illness
Treat sepsis, or fluid overload.
Rehabilitation
Consider early introduction of physical and 
occupational therapy as appropriate
 
Treatment and Management of PRES 
The management of PRES consists of eliminating the precipitating cause, control of blood pressure 
and the institution of comprehensive supportive measures (Table 3). If PRES is caused by a 
specific medication such as Cyclosporine or Tacrolimus, this medication should be discontinued. 
Failure to do so can perpetuate the syndrome. Alternative immunosuppression might be 
considered, but corticosteroids should be avoided. Following a suitable period for washout of 
cyclosporine, tacrolimus and/or sirolimus may be added. If steroids are added, careful 
consideration must be given to aggressive management of blood pressure. While it is important to 
treat the hypertension, the initial goal in treating patients with severe hypertension is to reduce 
blood pressure by 25% within the first few hours. Pronounced fluctuations of blood pressure 
should be avoided, and continuous infusions of intravenous drugs might be required. Excessive or 
rapid blood pressure reduction could provoke cerebral ischemia. Seizures are treated with 
antiepileptic medications. Other underlying disorders, such as sepsis, and flare-ups of autoimmune 
disorders, should be treated. 
 
Prognosis 
Despite its name, PRES is not always fully reversible. Early diagnosis and prompt management is 
crucial since the most severe forms of the PRES result in death, or chronic neurological sequelae. 
Severe neurological injury and death can be attributed to intracranial hemorrhage, posterior fossa 
edema with brainstem compression, acute hydrocephalus, or marked diffuse cerebral edema and 
increased global intracranial pressure. Persistent neurological sequelae are reported in 10–20% of 
patients with PRES. 


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APPENDIX G 
ELIGIBILITY REVIEW COMMITTEE 


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APPENDIX G 
ELIGIBILITY REVIEW COMMITTEE 
 
Potential BMT CTN 1503 participants may be screened and approved for protocol eligibility on 
an as needed basis by a three member review panel comprised of experts in sickle cell disease and 
transplantation. All participants enrolled under the neurologic deficit SCD severity criteria will be 
reviewed by the ERC; participants enrolled under the other SCD severity criteria will be reviewed 
on an ad hoc basis if deemed necessary by the BMT CTN 1503 Protocol Leadership. Potential 
participants requiring review are reviewed by the ERC after consultation with a transplant 
physician at a participating clinical site and informed consent for screening. The ERC’s 
confirmation of eligibility and approval for initiation of HLA typing in the interest of proceeding 
to biologic assignment is based on data contained in the patient registration (Segment 0) forms as 
well as uploaded source documentation. All of the following items must be completed in 
AdvantageEDC prior to review: 
 
1. Completion of Segment 0 Enrollment Form 
 
2. Upload of de-identified source documentation establishing all of the following eligibility 
criteria have been achieved: 
 
a. Baseline History & Physical Examination with study physician including 
documentation of performance score and vital signs to include pulse oximetry with a 
baseline O2 saturation of ≥ 85% on room air. 
b. Eligibility labs establishing acceptable organ function as outlined in Section 2.3.1.1. 
c. Echocardiogram results confirming left ventricular ejection fraction (LVEF) > 40%; or 
LV shortening fraction > 26% by cardiac echocardiogram or by MUGA scan; 
d. Progress notes, admission notes and/or similar documentation from the participant’s 
medical records denoting a past medical history including one or more of the following 
SCD complications: 
i. 
Clinically significant neurologic event (stroke) or neurological deficit 
lasting > 24 hours; 
ii. 
Two or more episodes of acute chest syndrome (ACS) in the 2-year period 
preceding referral despite adequate supportive care measures (i.e. asthma 
therapy and/or hydroxyurea [HU]); 
iii. 
An average of three or more vaso-occlusive crises per year in the 2-year 
period preceding referral despite adequate supportive care (i.e. a pain 
management plan and/or treatment with HU); 
iv. 
Regular red blood cell (RBC) transfusions, defined as 8 or more transfusions 
per year for ≥1 year or ≥ 20 cumulative transfusions to prevent vaso-
occlusive clinical complications (i.e. pain, stroke, or ACS); 


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v. 
An echocardiographic finding of tricuspid valve regurgitant jet (TRJ) 
velocity≥2.7 m/sec. 
vi. 
ChronicPainonamajorityofdaysfor≥6 months 
 
All uploaded source documentation must be de-identified, including redaction of all participant 
identifiers and/or PHI (name, patient initials, medical record number, date of birth) as well as 
redaction of institutional name and physician/advanced practice provider name(s). 
 
Following completion of Segment 0 enrollment form and upload of source documentation, the 
DCC protocol coordinator will be notified via email. The protocol coordinator will review the data 
and source documentation in AdvantageEDC within 24 business hours. If all case information is 
present, the protocol coordinator will alert the ERC reviewers and the Protocol Officer. The panel 
then has 5 business days to review the case and confirm eligibility. The turn-around-time for 
review and adjudication should be no longer than 5 business days. In the event the case under 
review and an ERC member are from the same clinical site, the ERC member is recused and a 
substitute from another site is assigned to the ERC. In the event there is a discrepancy, the Protocol 
Officer or the Medical Monitor (if the Protocol Officer has a conflict) will adjudicate. This 
adjudication may require a teleconference call with the ERC members tasked with reviewing the 
case. The protocol coordinator will notify the enrolling center in writing once the panel has 
completed their review for patients requiring ERC review. Please refer to the BMT CTN 1503 
MOP for additional information on the ERC. 
 
 
For participants not reviewed by the ERC, successful enrollment into Segment 0 of 
AdvantageEDC will confirm eligibility and no further notification will be provided. All relevant 
source documents related to patient eligibility must be uploaded to the enrollment form regardless 
of ERC review requirement. 


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APPENDIX H 
 
GUIDELINES FOR PRE-AND POST- TRANSPLANT CARE 
FOR PATIENTS WITH SICKLE CELL DISEASE 


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APPENDIX H: 
 
Pre- and Post- Transplant Guidelines Specific for Sickle Cell Disease 
 
1. Blood pressure management: Probably the single most important effector in preventing PRES 
and seizures after BMT for SCD is the prompt and effective treatment of systemic 
hypertension. Refer to Appendix F of the protocol for additional information on hypertension 
parameters in this population. 
a. Parameters for treating hypertension should be included in the admission order set; in 
SCD patients, it is recommended to have strict guidelines for ceiling systolic/diastolic 
BPs that prompt a call to MD and administration of a short-acting anti-hypertensive 
drug. 
b. A typical anti-hypertensive order might be nifedipine orally or hydralazine 
intravenously. 
c. Do not ‘repeat BP until normal’ or wait until the patient is ‘calm’ before treatment; 
instruct the nursing staff to call MD and institute treatment promptly. An in-service 
presentation or other targeted education for nursing staff about this issue can be helpful. 
d. Patients who receive >2 – 3 doses of prn nifedipine in a 24 – 48 hour period should 
begin a long acting Calcium-channel blocker, such as amlodipine once or twice daily, 
or another anti-hypertensive agent that is administered on a scheduled basis. 
e. Patients who develop GVHD that is treated by a combination of a calcineurin inhibitor 
and corticosteroids should receive empirical anti-hypertensive therapy; these patients 
often will require multi-drug combinations for strict control of hypertension. 
f. Some patients as above will need combination anti-hypertensive therapy for adequate 
BP control – secondary agents such as clonidine, enalapril, and/or a beta-blocker should 
be considered to ensure there is adequate control. Nephrology consultation can be very 
helpful with management of these challenging cases. 
2. Other Neurological guidelines: refer to the Appendix F of the protocol about prompt repletion 
of magnesium and the importance of maintaining platelet >50,000/mm3 to prevent intra-cranial 
hemorrhage, which are also very important for preventing neurological events after BMT. 
3. RBC transfusions: An exchange transfusion before BMT to reduce the HbS < 30% is required. 
At a minimum, patients should receive ABO compatible RBC units, but extended antigen 
matching for C, E, Kell, and rH phenotype of the recipient also is recommended to prevent 
RBC alloimmunization. 
a. In patients who have extensive RBC alloimmunization, it is necessary to have access a 
sufficient number of compatible RBC donors or units in the blood bank pre-BMT to 
support the patient through recovery after BMT; in some cases, this will limit the 
feasibility of myeloablative BMT. 
b. In patients who have RBC alloimmunization before BMT, it is recommended that 
extended phenotypically-matched RBC units should be administered before and after 
BMT to reduce the risk of developing a new allo-antibody. 
c. The routine post-transplant administration of corticosteroid or IVIg in patients with 
existing RBC alloimmunization is not recommended due to uncertain efficacy and in 
the case of corticosteroids, the potential for exacerbating hypertension. 


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4. Pain control: Many patients will have a history of acute and chronic pain related to SCD that 
can strongly influence the treatment and control of pain after BMT. In addition, patients with 
chronic pain syndrome treated previously by BMT can experience pain with extended opioid 
treatment with a taper that can extend months after transplant. 
a. Create a pain management plan that is tailored to an individual’s past experience; if a 
pain plan has been effective, it is important to extend this experience through BMT. 
b. Expectation of a rapid opioid taper after acute painful stimuli related to transplant 
complications might not be reasonable in some cases; instituting a gradual taper and 
seeking advice from Pain Management specialty services should be considered. 
c. Routine use of non-steroidal anti-inflammatory drugs should be deferred until after 
platelet engraftment. 


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APPENDIX I 
REFERENCES 


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