STRIDE Biorepository

A subset of sites for the main study "Bone Marrow Transplantation vs Standard of Care in
Patients with Severe Sickle Cell Disease (BMT CTN 1503) (STRIDE)" (NCT02766465) will also
participate in the biorepository portion of the study. The purpose of the biorepository is to
examine DNA to learn if certain genes predict who will have serious complications of sickle
cell disease. The STRIDE Biorepository is an optional substudy available to individuals
enrolled in the main study, who are at a participating site. Participants in the main study
who consent to take part in the biorepository will have blood drawn at the Baseline Visit.
This blood will be shipped to Emory University in Atlanta Georgia and stored for future
research.

Inclusion Criteria:

- Age 15.00 - 40.99 years

- Severe sickle cell disease [Hemoglobin SS (Hb SS), Hemoglobin SC (Hb SC) or Hemoglobin
SBeta thalassemia (Hb Sβ) genotype] with at least 1 of the following manifestations:

1. Clinically significant neurologic event (stroke) or any neurological deficit
lasting > 24 hours;

2. History of two or more episodes of acute chest syndrome (ACS) in the 2-year
period preceding enrollment despite the institution of supportive care measures
(i.e. asthma therapy);

3. Three or more pain crises per year in the 2-year period preceding referral
(required intravenous pain management in the outpatient or inpatient hospital
setting);

4. Administration of regular red blood cell (RBC) transfusion therapy, defined as
receiving 8 or more transfusions per year for ≥ 1 year to prevent vaso-occlusive
clinical complications (i.e. pain, stroke, and acute chest syndrome);

5. An echocardiographic finding of tricuspid valve regurgitant jet (TRJ) velocity ≥
2.7 m/sec.

- Adequate physical function as measured by all of the following:

1. Karnofsky/Lansky performance score > or equal to 60

2. Cardiac function: Left ventricular ejection fraction (LVEF) > 40%; or LV
shortening fraction > 26% by cardiac echocardiogram or by Multi Gated Acquisition
(MUGA) Scan

3. Pulmonary function: Pulse oximetry with a baseline O2 saturation of ≥ 85% and
diffusing capacity of the lung for carbon monoxide (DLCO) > 40% (corrected for
hemoglobin)

4. Renal function: Serum creatinine ≤ 1.5 x the upper limit of normal for age as per
local laboratory and 24 hour urine creatinine clearance >70 mL/min; or GFR > 70
mL/min/1.73 m2 by radionuclide Glomerular Filtration Rate (GFR)

5. Hepatic function: Serum conjugated (direct) bilirubin < 2x upper limit of normal
for age as per local laboratory; alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) < 5 times upper limit of normal as per local laboratory.
Patients with hyperbilirubinemia as a consequence of hyperhemolysis, or who
experience a sudden, profound change in the serum hemoglobin after a RBC
transfusion are not excluded.

Exclusion Criteria:

- Human Leukocyte Antigen (HLA) typing prior to referral (consultation with
hematopoietic cell transplantation (HCT) physician). However, 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.

- Uncontrolled bacterial, viral or fungal infection in the 6 weeks before enrollment.

- Seropositivity for HIV.

- Previous HCT.

- Participation in a clinical trial in which the patient received an investigational
drug or device must be discontinued at enrollment.

- A history of substance abuse as defined by version IV of the Diagnostic & Statistical
Manual of Mental Disorders (DSM IV).

- Demonstrated lack of compliance with prior medical care (determined by referring
physician).

- Pregnant or breast feeding females.

- Inability to receive HCT due to alloimmunization, defined as the inability to receive
packed red blood cell (pRBC) transfusion therapy.

- Unwillingness to use approved contraception method from time of biologic assignment
until discontinuation of all immunosuppressive medications if assignment at biologic
assignment would be to donor arm.

Additional Eligibility Criteria for Transplant after Biologic Assignment to the Donor Arm:

Participants assigned to the Donor Arm at the time of biologic assignment are subject to
additional transplant eligibility criteria as specified below. Additional, 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.

- Participants who are receiving ≥8 packed red blood cell transfusions for ≥1 year or
have received ≥20 packed red blood cell transfusions (cumulative) will undergo liver
magnetic resonance imaging (MRI) for estimation of hepatic iron content. Liver biopsy
is indicated for hepatic iron content ≥7 mg Fe/gm liver dry weight. Histological
examination must document the absence of cirrhosis, bridging fibrosis and active
hepatitis. The 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.

- Cerebral MRI/magnetic resonance angiogram (MRA) within 30 days prior to initiation of
transplant conditioning. If there is clinical or radiologic evidence of a recent
neurologic event (such as stroke or transient ischemic attack) subjects will be
deferred for at least 6 months with repeat cerebral MRI/MRA to ensure stabilization of
the neurologic event prior to proceeding to transplantation.

- Absence of donor specific HLA antibodies

- Documentation of participant's willingness to use approved contraception method until
discontinuation of all immunosuppressive medications. This is to be documented in the
medical record corresponding with the consent conference.

- The HLA-matched donor must be medically fit to donate and willing to donate bone
marrow.