Conditions: Sickle Cell Disease Stroke
Keywords: sickle cell disease stroke silent cerebral infarct children
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 28
Healthy volunteers: no

Brief summary:
This is a pilot study of hydroxyurea versus placebo to reduce central nervous system complications (abnormally fast blood flow to the brain, silent cerebral infarct or stroke) in young children with sickle cell disease. The investigators plan to identify children 12 to 48 months old without central nervous system complications and randomly assign 20 to treatment with hydroxyurea and 20 to treatment with placebo for 36 months. Neither the study doctors nor the participants will know which treatment they are receiving.

Detailed description:
Stroke, silent cerebral infarct (SCI), and cognitive impairment are frequent and highly morbid complications of sickle cell disease (SCD) in children. Current approaches to the prevention and treatment of neurological complications in SCD include screening by transcranial Doppler ultrasound (TCD) to identify children with elevated cerebral blood flow velocity who are at increased risk for strokes; these children are then typically treated with chronic transfusions indefinitely. Hydroxyurea (HU) may have beneficial effects on central nervous system (CNS) complications in SCD and reduces the frequency of painful crisis, acute chest syndrome and transfusion. The safety of HU in infants and children has been suggested in a National Institutes of Health (NIH) sponsored phase III trial; however, the exact indications for the use of HU in children remain unclear, as well as its efficacy in preventing central nervous system (CNS) complications of SCD. Our preliminary data suggest that, if the cumulative frequency of abnormal TCD, SCI and stroke could be reduced by 50%, the majority of pediatric hematologists would prescribe HU to all young children with SCD. The long term goal of this project is to perform a primary prevention trial to demonstrate the neuroprotective effect of HU and broaden the indications for HU in children. The goals of this proposal are to: 1) conduct an internal pilot randomized placebo-controlled trial of HU to reduce the CNS complications of SCD (the term internal pilot is used, as the results from the participants in the pilot will be analyzed as part of a definitive phase III trial to follow); 2) demonstrate the safety of hydroxyurea and study procedures in young children with SCD; and 3) create the leadership, network of clinical centers and other procedures necessary to conduct a definitive phase III trial demonstrating the efficacy of HU for primary prevention of the neurological complications of SCD.

The primary endpoint for the internal pilot and definitive phase III trials will be the development of abnormal TCD, SCI, transient ischemic attack (TIA) or stroke. To begin the internal pilot trial, the investigators obtained Clinical and Translational Science Award (CTSA) support at Johns Hopkins and Washington University; these sites will screen 40 participants 9-48 months of age and randomly assign and follow 20 participants for three years. Four additional centers (Children's Hospital of Philadelphia, Vanderbilt University, Children's Hospital Medical Center, Cincinnati and the University of Alabama, Birmingham) began enrollment (up to 20 patients screened and 10 participants randomly assigned per site), to provide a total of 80 participants screened, 40 randomly assigned, and a minimum of 70 participant years of follow-up. Additional sites have been added. Participants must have TCD measurements that are well below transfusion thresholds and magnetic resonance imaging (MRI) of the brain without evidence of SCI. Participants in the internal pilot will continue into a phase III trial, to complete 3 years on HU or placebo. The information from the internal pilot trial will be used to improve the design of the definitive phase III trial. The results of these studies could lead to true primary prevention of CNS complications of SCD, including abnormal TCD, SCI, neurocognitive impairment and stroke. In doing so, this study could also reduce the burden of chronic transfusions and change clinical practice by broadening the indications for HU.

Arms:
arm 1: Treatment with hydroxyurea 20 mg/kg/day increased by 5 mg/kg every 8 weeks to maximum of 35 mg/kg/day or hematologic toxicity or Absolute Neutrophil Count (ANC) \<4000 arm 2: Sucrose placebo 0.2 ml/kg/day increased to max of 0.35 ml/kg/day

Interventions: intervention 1: Hydroxyurea intervention 2: Placebo
Intervention descriptions: intervention 1: Hydroxyurea solution 100 mg/ml with a starting dose of 20 mg/kg/day by mouth once daily and escalation by 5 mg/kg/day every 8 weeks until hematological toxicity, an Absolute Neutrophil Count of 2000 to 4000/ul, or a maximum dose of 35 mg/kg/day. intervention 2: Sucrose solution 0.2 ml/kg/day by mouth once a day with blinded dose escalation of 0.05 ml/kg/day to match the frequency of dose escalation in the hydroxyurea arm.

Protocol document:
Prot_SAP_000.pdf: 
H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s of 
Si c kl e C ell Di s e a s e i n C hil dr e n  
( H U Pr e v e nt) 
St u d y Pr ot o c ol  
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N C T 0 1 3 8 9 0 2 4  


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1. 0   I N T R OD U C TI O N A N D H Y P O T H E S E S 
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1. 1  Pr eli mi n ar y St u di e s  
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1. 2  C urr e nt T r e at m e nt F or P ri m ar y P r e v e nti o n Of O v ert  Str o k e a n d Sil e nt C er e br al I nf ar ct   
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1. 3   S CI I s M or bi d a n d O c c ur s E arl y I n Lif e 
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1. 4  T h e R ati o n al B a si s f or th e U s e of H y dr o x y ur e a  t o T r e at N e ur ol o gi c al C o m pli c ati o n s i n  S C D  
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1. 5  D et e cti o n of S il e nt C er e br al I nf ar ct  a n d S e d ati o n 
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1. 6  Bi o m ar k er Di s c o v er y  
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1. 9  H U Pr e v e nt Tri al Or g a ni z ati o n C h art 
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2. 0  S T U D Y D E SI G N, P H A SI N G, A N D E LI GI BI LI T Y  
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2. 1  St u d y O v er vi e w  
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3. 0  C E N T R A L N E U R O R A DI O L O G Y R E VI E W of M RI/ T C D  
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4. 0  P A R T I CI P A N T E V A L U A TI O N S  
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S af et y R e p orti n g a n d A d v er s e E v e nt s  
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Wit h dr a w al fr o m t h e St u d y  
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E n d o f St u d y Pr o c e d ur e s 
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E v al u ati o n s f or p ar e nt s/ c ar e gi v er s  
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A d dr e s si n g N e w M RI T e c h n ol o g y  
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6. 0  S E D A TI O N O F C HI L D R E N WI T H S C D  
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H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
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St u d y L e a d er s hi p a n d K e y C o m p o n e n t s of t h e Tri al  
J a m e s F. C a s ell a, M D  
St u d y C h air  
Pri n ci p al I n v e sti g at or ( C o nt a ct) 
Cli ni c al C o or di n ati n g C e nt er  
J o h n s H o p ki n s U ni v er sit y S c h o ol of M e di ci n e  
P e di atri c H e m at ol o g y/ O n c ol o g y  
R o s s B uil di n g, R o o m 1 1 2 5  
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B alti m or e, M D  2 1 2 0 5  
Offi c e:  4 1 0 9 5 5 -6 1 3 2  
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j c a s ell a @j h mi. e d u 
R o b ert J. A d a m s, M. D.  
St u d y Vi c e C h air  
Pri n ci p al I n v e sti g at or ( M ulti pl e) , T C D C or e 
V a n d er bilt U ni v er sit y S c h o ol of M e di ci n e  
P e di atri c H e m at ol o g y/ O n c ol o g y  
2 2 0 0 C hil dr e n’ s W a y  
N a s h vill e, T N 3 7 2 3 2 -9 9 0 0  
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m. d e b a u n @ v a n d er bilt. e d u  
S p e ci m e n s hi p pi n g a d dr e s s f or t h e Bi ol o gi c 
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J o h n s H o p ki n s U ni v er sit y S c h o ol of M e di ci n e  
7 2 0 R utl a n d A v e n u e  
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M alli n c kr o dt I n stit ut e of R a di ol o g y  
W a s hi n gt o n U ni v er sit y S c h o ol of M e di ci n e  
5 1 0 S. Ki n g s hi g h w a y, C B 8 1 3 1  
St. L o ui s, M O  6 3 1 1 0  
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F a x  : 3 1 4-3 6 2 -6 9 7 1  
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H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
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1. 0  I N T R O D U C TI O N A N D H Y P O T H E S E S  
  
  
  
  
  
 
 
1. 1  
Pr eli mi n ar y St u di e s     
  
  
  
  
  
 
Si c kl e c ell di s e a s e ( S C D) i s o n e of t h e m o st c o m m o n g e n eti c di s e a s e s i n c hil d h o o d, aff e cti n g a p pr o xi m at el y 1 
i n 2 5 0 0  birt h s i n t h e U nit e d St at e s. 1  T h e i n ci d e n c e a m o n g Afri c a n A m eri c a n s i s 1 i n 3 0 0 , a n d t h er e i s a 
tr e m e n d o u s gl o b al b ur d e n of 2 5 0, 0 0 0 n e w c a s e s e a c h y e ar.2 ,3   C e ntr al n er v o u s s y st e m ( C N S) i nj ur y ar g u a bl y 
r e pr e s e nt s t h e m o st d e bilit ati n g fr e q u e nt c o m pli c ati o n of S C D, r e s ulti n g i n si g nifi c a nt c o g niti v e d y sf u n cti o n t h at 
li mit s l e ar ni n g a n d a c a d e mi c a c hi e v e m e nt, w or k p erf or m a n c e a n d t h e a bilit y of i n di vi d u al s wit h S C D t o l e a d 
n or m al li v e s.  Str o k e, sil e nt c er e br al i nf ar ct ( S CI), a n d c o g niti v e i m p air m e nt ar e all fr e q u e nt a n d hi g hl y m or bi d 
c o m pli c ati o n s of S C D i n c hil dr e n a n d a d ult s.  A m o n g c hil dr e n wit h H b S S, 1 1 % h a d a str o k e b y a g e 1 8 y e ar s 
b ef or e t h e i m pl e m e nt ati o n of tr a n s cr a ni al D o p pl er ( T C D) s cr e e ni n g. 4   S CI i s t h e m o st c o m m o nl y r e c o g ni z e d 
c a u s e of s eri o u s n e ur ol o gi c al di s e a s e i n H b S S, aff e cti n g a p pr o xi m at el y 2 7 % of c hil dr e n b y t h eir 5t h birt h d a y 5  
a n d 3 7 % b y a g e 1 4. 6  C hil dr e n w h o d e v el o p S CI h a v e gr e at er c o g niti v e i m p air m e nt c o m p ar e d wit h eit h er 
c hil dr e n wit h H b S S wit h o ut S CI or si bli n g s wit h o ut S C D. 7  A r e c e nt st u d y of a d ult s  d e m o n str at e d si g nifi c a nt 
c o g niti v e d y sf u n cti o n, e v e n i n p arti ci p a nt s wit h a p p ar e ntl y mil d S C D. 8  
 
H y dr o x y ur e a m a y h a v e  b e n efi ci al eff e ct s o n n e ur ol o gi c al c o m pli c ati o n s i n H b S S 9 ,1 0  a n d r e d u c e s t h e 
fr e q u e n c y of p ai nf ul cri si s, a c ut e c h e st s y n dr o m e a n d tr a n sf u si o n.  At t hi s p oi nt, h o w e v er, t h e i n di c ati o n s f or 
t he u s e of h y dr o x y ur e a  i n c hil dr e n r e m ai n u n cl e ar.  A r e c e nt NI H C o n s e n s u s C o nf er e n c e c o n cl u d e d t h at 
h y dr o x y ur e a  t h er a p y h a s n ot b e e n br o a dl y a d o pt e d i n y o u n g c hil dr e n or a d ult s.1 1   T h er e ar e c urr e ntl y n o 
F D A -a p pr o v e d i n di c ati o n s f or h y dr o x y ur e a  i n c hil dr e n.  Alt h o u g h t h e r e c e nt N H L BI B A B Y H U G st u d y ai m e d 
t o e st a bli s h t h at h y dr o x y ur e a  c o ul d pr e v e nt c hr o ni c or g a n s y st e m d a m a g e d u e t o H b S S a n d H b S β 0 , t hi s 
st u d y f ail e d t o a c hi e v e eit h er of it s pri m ar y e n d p oi nt s ( pr e v e nti o n of s pl e ni c or r e n al i nj ur y); h o w e v er,   
s e c o n d ar y a n al y s e s  s u g g e st e d t h at t h e i ntr a p ati e nt i n cr e a s e i n T C D v el o cit y fr o m e ntr y t o e xit w a s l e s s i n 
t h e h y dr o x y ur e a gr o u p t h a n i n t h e pl a c e b o gr o u p.  I n a d diti o n, t h er e w er e f e w er c hil dr e n wit h v er y l o w 
B a yl e y d e v el o p m e nt al s c or e s i n t h e h y dr o x y ur e a  gr o u p ( 0 v s. 5 i n t h e pl a c e b o gr o u p). 1 2    A s e x p e ct e d i n t h e 
v er y y o u n g gr o u p of p arti ci p a nt s i n t hi s st u d y ( 9 -4 8 m o nt h s of a g e), t h e i n ci d e n c e of str o k e w a s v er y l o w 
a n d n o diff er e n c e s w er e s e e n b et w e e n t h e h y dr o x y ur e a  a n d pl a c e b o gr o u p s.  T h e effi c a c y of h y dr o x y ur e a  
i n pr e v e nti n g S CI w a s n ot e v al u at e d.  I m p ort a ntl y, t h e e x p e ct e d st ati sti c all y si g nifi c a nt d e cr e a s e i n p ai nf ul 
e v e nt s, a c ut e c h e st s y n dr o m e a n d tr a n sf u si o n s w a s  s e e n i n t hi s st u d y.  
 
B A B Y H U G a n d ot h er st u di e s s u g g e st, b ut d o n ot pr o v e, t h at h y dr o x y ur e a  m a y pr e v e nt a b n or m al T C D a n d 
n e ur ol o gi c al i nj ur y i n c hil dr e n wit h H b S S. 1 0 ,1 3 -1 7   Pr eli mi n ar y e x p ert o pi ni o n fr o m t h e SI T Tri al i n v e sti g at or s 
pr o vi d e s s u p p ort t h at a 5 0 % r e d u cti o n i n C N S c o m pli c ati o n s w o ul d b e a c o m p elli n g r e a s o n f or m o st 
pr a ctiti o n er s t o u s e h y dr o x y ur e a  i n all c hil dr e n wit h H b S S.  T h u s, t h e p u bli c h e alt h i m pli c ati o n s of a cli ni c al 
tri al t h at e st a bli s h e s t h e a bilit y of h y dr o x y ur e a  t o pr o vi d e tr u e pri m ar y pr e v e nti o n of C N S c o m pli c ati o n s a n d 
br o a d e n s t h e u s e of h y dr o x y ur e a  i n t hi s p o p ul ati o n w o ul d b e i m m e n s e.  T h e p ur p o s e of t hi s pr o p o s al i s t o 
l a y t h e gr o u n d w or k f or s u c h a tri al b y d e m o n str ati n g t h e f e a si bilit y of r e cr uit m e nt a n d t h e s af et y of st u d y 
pr o c e d ur e s , w hil e c o m pl eti n g t h e pl a n ni n g a n d ot h er pr o c e d ur e s n e c e s s ar y f or a d efi niti v e p h a s e III tri al. 
 
1. 2  
C urr e nt Tr e at m e nt f or Pri m ar y Pr e v e nti o n of O v ert Str o k e a n d S CI  
B a s e d o n t h e hi g hl y s u c c e s sf ul S T O P Tri al, t h e c urr e nt a p pr o a c h f or pri m ar y pr e v e nti o n of o v ert str o k e i n 
H b S S i n cl u d e s m e a s ur e m e nt of T C D v el o cit y i n t h e mi d dl e c er e br al art er y or t er mi n al p orti o n of t h e i nt er n al 
c ar oti d.  If i n di vi d u al s wit h v el o citi e s gr e at er t h a n 2 0 0 c m/ s e c ar e tr a n sf u s e d wit h r e d bl o o d c ell s t o m ai nt ai n 
si c kl e h e m o gl o bi n ( H b S) < 3 0 %, t h er e i s a n 8 6 % r el ati v e ri s k r e d u cti o n f or o v ert str o k e i n t h e fir st 3 0 
m o nt h s.
1 8   Alt h o u g h hi g hl y eff e cti v e, tr a n sf u si o n t h er a p y i s a s s o ci at e d wit h si g nifi c a nt b ur d e n t o f a mili e s a n d 
m or bi dit y, i n cl u di n g e x c e s si v e ir o n st or e s r e q uiri n g c h el ati o n, ri s k of s e n siti z ati o n t o mi n or r e d c ell a nti g e n s, 
i nf e cti o n, a n d i s i n c o n v e ni e nt a n d e x p e n si v e.  I n a d diti o n, e v e n wit h o ut tr a n sf u si o n s, m a n y c hil dr e n wit h 
T C D m e a s ur e m e nt s a b o v e t h e t hr e s h ol d f or tr a n sf u si o n t h er a p y will n e v er h a v e a str o k e; h e n c e, m a n y 
u n n e c e s s ar y tr a n sf u si o n s ar e gi v e n.  C urr e nt e sti m at e s ar e t h at a p pr o xi m at el y 7. 5  c hil dr e n  n e e d t o b e 
tr a n sf u s e d f or o n e y e ar t o pr e v e nt o n e str o k e a n d t h at 6 0 % of t h o s e tr a n sf u s e d w o ul d n e v er h a v e h a d a n 
o v ert str o k e wit h o ut tr e at m e nt.  A b n or m al T C D v el o citi e s ar e n o w t h e m o st c o m m o n r e a s o n f or c hr o ni c 
tr a n sf u si o n s at m o st p e di atri c si c kl e c ell c e nt er s, pl a ci n g a gr e at b ur d e n o n p ati e nt s a n d t h e h e alt h c ar e 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 6 of 7 4  
s y st e m.  I n s e v er al l ar g e h e m at ol o g y c e nt er s, 5 0 or m or e c hil dr e n m a y b e r e c ei vi n g bl o o d tr a n sf u si o n f or 
pri m ar y pr e v e nti o n of str o k e s at a gi v e n ti m e.  If t h e n u m b er of a b n or m al T C D s c a n b e l e s s e n e d t hr o u g h 
pri m ar y pr e v e nti o n wit h h y dr o x y ur e a , t h e b ur d e n of tr a n sf u si o n will b e l e s s e n e d pr o p orti o n at el y.  A s 
h y dr o x y ur e a  i s a n or all y a d mi ni st er e d a g e nt t h at i s r el ati v el y i n e x p e n si v e c o m p ar e d t o tr a n sf u si o n, t h e 
r e d u cti o n i n c o st w o ul d al s o b e s u b st a nti al; i n a d diti o n, t h e c o m pli c ati o n s of tr a n sf u si o n w o ul d b e a v oi d e d 
f or m a n y c hil dr e n  c urr e ntl y r e c ei vi n g tr a n sf u si o n, t h e m aj orit y of w h o m d o n ot b e n efit i n t er m s of str o k e 
pr e v e nti o n.  T hi s c o ul d f a cilit at e t h e tr e at m e nt of a m u c h l ar g er pr o p orti o n of p ati e nt s at ri s k f or str o k e 
( p o s si bl y i n cl u di n g c hil dr e n i n r e s o ur c e-p o or c o u ntri e s).  A s a n i niti al e sti m at e of p o s si bl e c o st s a vi n g s, 
a p pr o xi m at el y 1 0 % of a n u n s cr e e n e d p o p ul ati o n of y o u n g c hil dr e n wit h S C D will h a v e a b n or m al T C D 
v el o citi e s.  T h er e ar e a b o ut 1 4, 0 0 0 c hil dr e n i n t h e U nit e d St at e s b et w e e n 2 a n d 1 6 y e ar s of a g e wit h H b S S 
or H B S β 0  a n d a b o ut 1 4 0 0 will h a v e a b n or m al C B F V.  A s s u mi n g t h at 1 1 2 0 ( 8 0 %) of t h e s e c hil dr e n a c c e pt 
tr a n sf u si o n s ( b a s e d o n t h e pr o p orti o n i n t h e S T O P Tri al),1 8  5 0 % of t h e s e a b n or m al T C D s c o ul d b e 
pr e v e nt e d b y h y dr o x y ur e a , a n d a c o st of $ 2 8, 5 0 0 p er y e ar f or tr a n sf u si o n s a n d c h el ati o n1 9  v er s u s $ 8 5 0 0 f or 
h y dr o x y ur e a , $ 1 1, 2 0 0, 0 0 0 c o ul d b e s a v e d p er y e ar.  A d di n g t h e r e d u cti o n i n ot h er c o st s of ir o n o v erl o a d t o 
t h e s e fi g ur e s w o ul d c o n si d er a bl y i n cr e a s e t h e c o st s a vi n g s, n ot t o m e nti o n t h e p ot e nti al r e d u cti o n i n b ur d e n 
t o t h e p ati e nt s a n d t h eir f a mili e s.  T hi s c al c ul ati o n a s s u m e s t h at a r e d u cti o n of T C D v el o citi e s will pr e v e nt 
str o k e; t hi s h a s n ot b e e n ri g or o u sl y pr o v e n, b ut i s f elt t o b e a r e a s o n a bl e a s s u m pti o n.  
  
Fi g ur e 1: Pr e v al e n c e of Sil e nt C er e br al I nf ar ct b y A g e  
1. 3  S CI i s m or bi d a n d o c c ur s e arl y i n 
lif e  
T h e hi g h e st i n ci d e n c e of S CI i s i n t h e fir st 
4 y e ar s of lif e, a s t h e c u m ul ati v e 
pr e v al e n c e i n cr e a s e s ( Fi g ur e 1) fr o m 1 2 % 
at 1 5 m o nt h s 2 0 ,2 1  t o 2 8 % at 3. 7 y e ar s5 , 
3 1 % at 9. 4 y e ar s ( D e B a u n p er s o n al 
c o m m u ni c ati o n), a n d 3 7. 4 % at 1 4 y e ar s .6  
S p e cifi c n e ur ol o gi c al m or bi diti e s 
a s s o ci at e d wit h S CI i n cl u d e d e cr e m e nt s i n 
c o g niti o n, p o or a c a d e mi c att ai n m e nt, 
pr o gr e s si o n t o o v ert str o k e, a n d n e w or 
pr o gr e s si v e S CI o n M RI. 2 2 -2 5   C hr o ni c 
tr a n sf u si o n i s b ei n g e v al u at e d f or 
s e c o n d ar y pr e v e nti o n of S CI i n t h e SI T 
Tri al, b ut pr e s e ntl y t h er e i s n o pri m ar y 
pr e v e nti o n str at e g y f or S CI.  T h e d e gr e e 
t o w hi c h H U pr e v e nt s S CI, a pr o bl e m t h at 
aff e ct s n e arl y a t hir d of c hil dr e n wit h H b S S, c o ul d b e a v er y i m p ort a nt d et er mi n a nt of h o w wi d el y t hi s a g e nt 
i s u s e d i n c hil dr e n.   
 
1. 4  
T h e R ati o n al B a si s f or t h e U s e of H y dr o x y ur e a  t o Tr e at N e ur ol o gi c al C o m pli c ati o n s i n S C D  
T h er e i s s uffi ci e nt e vi d e n c e t o s u s p e ct t h at a n i n cr e a s e i n f et al h e m o gl o bi n ( H b F) a n d t ot al H b c o ul d 
a m eli or at e t h e C N S c o m pli c ati o n s of H b S S.  Gi v e n t h at h y dr o x y ur e a  i s k n o w n t o i n cr e a s e H b F, t hi s t h er a p y 
h a s b e e n u s e d e xt e n si v el y i n a d ult p ati e nt s wit h S C D.  T h e s e mi n al st u di e s of C h ar a c h e et al., i n cl u di n g t h e 
M ulti -C e nt er St u d y  of H y dr o x y ur e a, d e m o n str at e d d efi niti v el y t h at h y dr o x y ur e a  r e d u c e d t h e fr e q u e n c y of 
cri si s, c h e st s y n dr o m e, tr a n sf u si o n s a n d h o s pit ali z ati o n i n a d ult s. 2 6   Si mil ar r e s ult s h a v e b e e n r e p ort e d i n 
c hil dr e n. 2 7   T h e u n d erl yi n g c a u s e s of el e v at e d T C D v el o citi e s a n d t h e hi g h r at e of S CI a n d str o k e a m o n g 
y o u n g c hil dr e n wit h H b S S  ar e n ot c o m pl et el y u n d er st o o d, b ut m a y b e r el at e d i n p art t o a n e mi a 2 8  a n d 
p at h ol o gi c al art eri al st e n o si s. 2 9   A ut or e g ul ati o n, a c o m p e n s at or y v a s o dil at ati o n of t h e c er e br al v a s c ul at ur e 
t o pr e s er v e o x y g e n d eli v er y t o t h e br ai n, m a nif e st s i niti all y a s i n cr e a s e d c er e br al bl o o d fl o w. 3 0 ,3 1    El e v at e d 
C B F V a s a s s e s s e d b y T C D m e a s ur e m e nt i s a ri s k  f a ct or f or o v ert str o k e a n d a n e mi a i s a ri s k f a ct or f or 
S CI. 2 9 ,3 2   Dir e ct b e n efit s of h y dr o x y ur e a  i n c hil dr e n wit h S C D i n cl u d e a n i n cr e a s e i n t h e b a s eli n e h e m o gl o bi n 
l e v el a n d a d e cr e a s e i n C B F V,1 0  r e s ulti n g i n a n i n cr e a s e i n o x y g e n d eli v er y; w e p o st ul at e t h at t h e s u m t ot al 
of t h e m ulti pl e b e n efit s of h y dr o x y ur e a  i n cl u di n g, b ut  n ot li mit e d t o, d e cr e a s e d C B F V,2 9  i n cr e as e d H b F  a n d 
W a n g 1 9 9 8/ 2 0 0 8
K wi at k o w s ki 2 0 0 9
B er n a u di n 2 0 1 1
B er n a u di n 2 0 1 1
SI T T D at a 2 0 1 0
0
1 0
2 0
3 0
4 0
5 0
Sil e nt C er e br al I nf ar ct s ( %)
0
5
1 0
1 5
A g e i n y e ar s


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 7 of 7 4  
N O pr o d u cti o n 3 3  a n d d e cr e a s e d r e d bl o o d c ell a d h e si v e n e s s  t o t h e e n d ot h eli u m3 4 -3 6  will d e cr e a s e t h e r at e 
of c o n v er si o n t o hi g h T C D m e a s ur e m e nt s a n d pr e v e nt S CI a n d str o k e.  
 
C o n si st e nt wit h t hi s h y p ot h e si s, o ur pr eli mi n ar y r e s ult s s u g g e st i n v er s e c orr el ati o n s of b ot h t ot al H b 
c o n c e ntr ati o n a n d p er c e nt a g e of H b F wit h t h e i n ci d e n c e of S CI.  I n cr e a s e s i n t ot al H b  c o n c e ntr ati o n  m a y 
al s o i m pr o v e c o g niti v e f u n cti o n, a s m or e s e v er e a n e mi a i s a s s o ci at e d wit h l o w er I Q i n b ot h c hil dr e n a n d 
a d ult s wit h S C D. 7 ,3 7   T h u s, w e f e el t h er e i s c o m p elli n g r e a s o n t o i n v e sti g at e f urt h er t h e effi c a c y of 
h y dr o x y ur e a  i n pr e v e nti n g n e ur ol o gi c c o m pli c ati o n s i n S C D.  
 
1. 5  
D et e cti o n of S CI a n d S e d ati o n  
M RI of t h e br ai n i s t h e o nl y pr e s e ntl y a v ail a bl e m et h o d t o d et e ct S CI.  F or c hil dr e n wit h t h e gr e at e st 
i n ci d e n c e of S CI (l e s s t h a n 5 y e ar s ol d), M RI u s u all y r e q uir e s s e d ati o n.  N o st a n d ar d a p pr o a c h f or s e d ati o n 
of t hi s p o p ul a ti o n e xi st s, li miti n g a c c e s si bilit y f or s cr e e ni n g f or S CI i n t h e gr o u p wit h t h e hi g h e st ri s k.  At 
s o m e m e di c al c e nt er s, h e m at ol o gi st s a n d a n e st h e si ol o gi st s el e ct t o tr a n sf u s e r e d bl o o d c ell s t o all p ati e nt s 
wit h S C D pri or t o a n y s e d ati o n, i n a n eff ort t o d e cr e a s e t h e r at e of c o m pli c ati o n s; h o w e v er, m a n y c e nt er s d o 
n ot a d mi ni st er tr a n sf u si o n s f or all s e d ati o n pr o c e d ur e s.  I n a r e c e nt s ur v e y of 2 1 of 2 5 SI T Tri al C e nt er 
I n v e sti g at or s, t h e m aj orit y i n di c at e d t h at tr a n sf u si o n w a s n ot gi v e n b ef or e all or s o m e M RI s r e q uiri n g 
s e d ati o n.  At J o h n s H o p ki n s a n d W a s hi n gt o n U ni v er siti e s, w e e v al u at e s u c h p ati e nt s o n a c a s e b y c a s e 
b a si s. B a s e d o n d at a fr o m o ur c o -i n v e sti g at or ( J. K wi at o w k si at C H O P) s u p p orti n g t h e s af et y of a str u ct ur e d 
pr ot o c ol f or p ati e nt s el e cti o n a n d  s e d ati o n wit h o ut a nt e c e d e nt tr a n sf u si o n i n o v er 6 0 c hil dr e n  wit h S C D , w e 
b eli e v e t h at it i s r e a s o n a bl e t o i m pl e m e nt a st a n d ar di z e d pr ot o c ol f or s e d ati o n at ot h er c e nt er s.  
D e m o n str ati n g t h at M RI s wit h s e d ati o n c a n b e s af el y o bt ai n e d wit h o ut tr a n sf u si o n will gr e atl y i n cr e a s e t h e 
f e a si bilit y of s cr e e ni n g f or S CI i n t h e a g e gr o u p wit h t h e hi g h e st r at e of S CI.  E arl y d et e cti o n of S CI i s 
criti c al, a s a d diti o n al e d u c ati o n al s er vi c e s, e v e n i n pr e -s c h o ol, c a n b e m a n d at e d b y f e d er al l a w.  A 
s u c c e s sf ul d e m o n str ati o n  t h at s e d ati o n wit h o ut tr a n sf u si o n u si n g o ur pr ot o c ol a n d pr o c e d ur e s i s s af e w o ul d 
pr o vi d e n e c e s s ar y i nf or m ati o n t o c o n d u ct a d efi niti v e p h a s e III tri al.  It w o ul d al s o pr o vi d e i nf or m ati o n t h at 
c o ul d b e a p pli e d t o ot h er pr o c e d ur e s a n d r e d u c e t h e u s e of tr a n sf u si o n s a n d t h eir a s s o ci at e d ri s k s.  
 
W e ar e a c ut el y a w ar e of t h e i n cr e a s e d ri s k of s e d ati o n i n p ati e nt s wit h S C D a n d t h at a d e at h o c c urr e d 
d uri n g s e d ati o n/ a n e st h e si a f or a r e s e ar c h M RI i n t h e NI H -N H L BI -f u n d e d B A B Y H U G st u d y.  E x p ert p e di atri c  
a n e st h e si ol o gi st s h a v e d e si g n e d o ur pr ot o c ol f or s e d ati o n t o mi ni mi z e t h e s e ri s k s; s p e cifi c all y, c hil dr e n wit h 
r e c e nt r e s pir at or y ill n e s s e s a n d ot h er ri s k f a ct or s will n ot u n d er g o s e d ati o n.  B a s e d o n t hi s pr ot o c ol, our 
st u d y w o ul d h a v e e x cl u d e d t h e i nf a nt w h o di e d i n  t h e B A B Y H U G st u d y fr o m o ur tri al.  S e v er al  a d diti o n al 
diff er e n c e s e xi st w h e n c o m p ari n g o ur st u d y t o  t h e B A B Y H U G st u d y: 1) O ur s e d ati o n t e a m of 
a n e st h e si ol o gi st s h a v e d efi n e d a ri g or o u s s et of crit eri a  a n d s p e cifi c s e d ati o n pr ot o c ol s  t o mi ni mi z e ri s k s 
a s s o ci at e d wit h s e d ati o n ; 2) E a c h sit e t e a m will b e r e q uir e d t o  h a v e t h eir s e d ati o n pr ot o c ol r e vi e w e d 
c e ntr all y a n d a p pr o v e d pri or t o st arti n g e nr oll m e nt; a n d 3) T h e S e d ati o n C o m mitt e e will c o nti n u e t o r e vi e w 
t h e s e d ati o n pr ot o c ol s a n d r e c or d s a n d b e a v ail a bl e t o a d dr e s s a n y A E or S A E a s s o ci at e d wit h s e d ati o n. 
 
1. 6  
Bi o m ar k er Di s c o v er y  
Pr ot e o mi c di s c o v er y a p pr o a c h e s p er mit t h e i d e ntifi c ati o n of p ot e nti al bi o m ar k er s b y a n u n bi a s e d e v al u ati o n 
of r ar e pl a s m a pr ot ei n s.  O ur gr o u p h a s i nt er e st a n d e x p erti s e i n t hi s ar e a of r e s e ar c h, a s w ell a s t h e u ni q u e 
r e s o ur c e s of t h e J o h n s H o p ki n s N H L BI Pr ot e o mi c s C e nt er.  T hi s w or k w a s  f u n d e d b y U 5 4 H L 0 9 0 5 1 5 a n d 
R 0 1 H L 0 9 1 7 5 9.  W e h a v e i d e ntifi e d el e v at e d l e v el s of G F A P i n p ati e nt s wit h S C D wit h e vi d e n c e of 
s u b cli ni c al br ai n i nj ur y. 3 8   W e h a v e al s o i d e ntifi e d t hr o m b o s p o n di n a n d L -s el e cti n a s pr ot ei n s t h at ar e 
el e v at e d i n p ati e nt s wit h S C D a n d S CI c o m p ar e d t o t h o s e wit h n or m al M RI.  T h e s a m pl e s fr o m t hi s st u d y 
will b e u s e d t o v ali d at e t h e s e bi o m a r k er s a n d f or f urt h er st u di e s.  
 
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 8 of 7 4  
1. 7  
H y p ot h e s e s:    
  
  
  
  
  
  
 
 
H y p ot h e si s 1:  H y dr o x y ur e a t h er a p y i n y o u n g c hil dr e n ( a g e 1 - 4 y e ar s ) will r e d u c e b y 5 0 % or gr e at er t h e 
C N S c o m pli c ati o n s of si c kl e c ell di s e a s e, i n cl u di n g c o n diti o n al or a b n or m al T C D, sil e nt 
c er e br al i nf ar cti o n , TI A a n d o v ert str o k e.  
 
H y p ot h e si s 2:   O f 8 0 s cr e e n e d p arti ci p a nt s, a p pr o xi m at el y 4 0 will a c c e pt r a n d o mi z ati o n t o h y dr o x y ur e a . 
 
H y p ot h e si s 3 :   Th e pr o p orti o n of s eri o u s a d v er s e r e a cti o n s attri b ut e d  t o s e d ati o n f or t h e M RI will b e < 4 %.    
 
 
1. 8  
Ai m s of t h e Tri al  
 
 
A.  
Pri m ar y O bj e cti v e :  
T o c o n d u ct a n i nt er n al pil ot, a r a n d o mi z e d pl a c e b o -c o ntr oll e d tri al of h y dr o x y ur e a  t o r e d u c e t h e C N S 
c o m pli c ati o n s of S C D, i n pr e p ar ati o n f or a  NI H-f u n d e d m ulti c e nt er, p h a s e III Tri al.  T h e pri m ar y e n d p oi nt f or 
t h e pil ot a n d d efi niti v e p h a s e III  tri al will b e pr e v e nti o n of c o n diti o n al or a b n or m al C B F V, S CI, TI A a n d str o k e.  
I n t h e pil ot tri al, fr o m a n eli gi bl e gr o u p of 2 7 0, w e will s cr e e n 8 0 c hil dr e n 9 – 4 8 m o nt h s of a g e wit h H b S S or 
H b S β 0  u si n g M RI/ M R A of t h e br ai n, T C D, a n d a s s e s s m e nt b y a p e di atri c n e ur ol o gi st.  Of t h e s e 8 0 p arti ci p a nt s, 
w e e sti m at e t h at 4 0 ( 5 0 % of t h o s e s cr e e n e d aft er e x cl u si o n s a n d r ef u s al s) will a c c e pt r a n d o mi z ati o n. T C D, 
M RI/ M R A of  t h e br ai n a n d m e a s ur e s of c o g niti o n will b e o bt ai n e d e v er y 1 2 m o nt h s f or 3 6 m o nt h s.  T h e 
s cr e e ni n g M RI a n d r a n d o mi z ati o n will n ot o c c ur u ntil t h e c hil d r e a c h e s t h e a g e of 1 2 m o nt h s  (i. e., h a s att ai n e d 
t h eir 1 st birt h d a y) . T h e r e s ult s fr o m t h e pil ot will b e i n c or p or at e d i nt o t h e d e si g n of t h e d efi niti v e P h a s e III tri al  
 
B.  
S e c o n d ar y  O bj e cti v e s  
 
O bj e cti v e 1:  
 T o  d et er mi n e t h e a c c e pt a bilit y of r a n d o mi z ati o n t o h y dr o x y ur e a  v s. pl a c e b o f or pri m ar y pr e v e nti o n of C N S 
c o m pli c ati o n s of S C D.  W e will c al c ul at e t h e pr o p orti o n of p ot e nti all y eli gi bl e p arti p a nt s u n d er g oi n g s cr e e ni n g 
a n d a c c e pti n g r a n d o mi z ati o n i nt o t h e pil ot st u d y a n d u s e t h e s e pr o p orti o n s i n t h e d e si g n of t h e d efi niti v e P h a s e 
III tri al. 
 
O bj e cti v e 2:  
T o d et er mi n e t h e s af et y of st u d y pr o c e d ur e s  u si n g st a n d ar di z e d pr ot o c ol s  i n t o d dl er s a n d pr e c h o ol c hil dr e n 
wit h S C D.    
 
O bj e cti v e 3:  
T o c oll e ct pl a s m a s p e ci m e n s t o e v al u at e p ut ati v e bi o m ar k er s of C N S i nj ur y a s a s urr o g at e o ut c o m e of 
h y dr o x y ur e a  effi c a c y i n a n o n g oi n g  pr ot e o mi c s di s c o v er y pr oj e ct .  W e will c oll e ct pl a s m a s p e ci m e n s o n all 
s cr e e n e d p arti ci p a nt s o n t h e d a y of t h eir M RI a n d e v er y 4 w e e k s o n c hil dr e n r a n d o mi z e d t o t h e st u d y.  W e will 
m e a s ur e G F A P, t hr o m b o s p o n di n, a n d L -s el e cti n b y el e ctr o c h e mil u mi n e s c e n c e d et e cti o n ( M e s o s c al e 
Di s c o v er y G ait h er s b ur g, M D) a n d a p oli p o pr ot ei n A 1 b y fl o w c yt o m etr y i m m u n o a s s a y ( Milli pl e x M A P, Milli p or e, 
St. C h arl e s, M O.  A d diti o n al p ot e nti al bi o m ar k er s will b e a s s a y e d a n d e v al u at e d, a s t h e y b e c o m e a v ail a bl e.  
 
O bj e cti v e 4 : 
C o m pl et e t h e n e c e s s ar y pr e p ar ati o n s f or a d efi niti v e p h a s e III tri al .  D uri n g t h e c o ur s e of t h e c urr e nt st u d y, 
w e will al s o pr e p ar e a m a n u al of o p er ati o n s a n d c a s e r e p ort f or m s f or t h e pr o p o s e d tri al,  d e v el o p s a m pl e 
I R B s u b mi s si o n t e m pl at e s a n d or g a ni z e all c o m mitt e e s, c oll a b or at or s a n d st u d y pr o c e d ur e s n e c e s s ar y f or 
i niti ati o n of a s u c c e s sf ul, d efi niti v e, m ulti c e nt er tri al.  
 
 
 
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 9 of 7 4  
1. 9  
H U P r e v e nt Tri al Or g a ni z ati o n C h art: Fi g ur e 2  
 
2. 0  
S T U D Y D E SI G N, P H A SI N G, A N D E LI GI BI LI T Y   
 
 
2. 1  St u d y O v er vi e w    
  
  
  
  
 
T h e st u d y i s a r a n d o mi z e d , c o ntr oll e d , d o u bl e -bli n d, i nt er n al pil ot of h y dr o x y ur e a v s. pl a c e b o f or t h e pr e v e nti o n 
of C N S i nj ur y i n c hil dr e n 1 2 t o 4 8 m o nt h s of a g e wit h si c kl e c ell a n e mi a .  T h e st u d y will b e a n al y z e d u si n g 
i nt e nti o n t o tr e at f or o ut c o m e s, w hi c h will b e gi n i m m e di at el y aft er r a n d o mi z ati o n a n d a ft er r e c ei pt of t h e fir st 
d o s e of h y dr o x y ur e a or pl a c e b o  f or s af et y.  All pr o c e d ur e s ar e r e s e ar c h pr o c e d ur e s , e x c e pt f or t h e a n n u al T C D 
( b e gi n ni n g at a g e 2), a hi st or y a n d p h y si c al e x a m i n ati o n e v ery 6 t o 1 2 m o nt h s a n d  C B C wit h diff er e nti al, 
r eti c ul o c yt e c o u nt e v er y 4 w e e k s a n d c o m pr e h e n si v e p a n el e v er y 3 m o nt h s, w hi c h ar e r o uti n e f or p arti ci p a nt s 
o n h y dr o x y ur e a.  W e pr o p o s e t o s cr e e n 8 0 c hil dr e n wit h a T C D, c o g niti v e t e sti n g, a n e ur ol o gi c al e x a m b y a 
p e di atri c n e ur ol o gi st, l a b s, a n d M RI/ M R A of t h e br ai n, t o r a n d o mi z e 4 0 of t h e a p pr o xi m at el y 1 8 0  c hil dr e n 
r e q uir e d f or t h e d efi niti v e P h a s e III tri al.  W e will al s o c oll e ct s p e ci m e n s f or a bi or e p o sit or y ( pl a s m a a n d 
l y m p h o c yt e s t o m a k e tr a n sf or m e d l y m p h o c yt e s a s a s o ur c e of D N A) a n d d e m o gr a p hi c a n d cli ni c al i nf or m ati o n 
a b o ut t h e s e p arti ci p a nt s fr o m t h e m e di c al r e c or d a n d i nt er vi e wi n g t h eir p ar e nt s/l e g al g u ar di a n s . T h e 
p ar e nt s/l e g al g u ar di a n s of t h e s e c hil dr e n will h a v e a n e d u c ati o n al s e s si o n o n t h e br ai n i nj ur y a n d tr e at m e nt o f 
si c kl e c ell di s e a s e.  T h e l a st s cr e e ni n g pr o c e d ur e will b e t h e s e d at e d M RI of t h e br ai n.  S cr e e ni n g 
pr o c e d ur e s m a y b e d o n e b e gi n ni n g at 9 m o nt h s of a g e; b ut t h e s cr e e ni n g M RI will n ot b e d o n e u ntil t h e c hil d 
r e a c h e s t h e a g e of 1 2 m o nt h s.  C hil dr e n wit h o ut e vi d e n c e of br ai n i nj ur y will b e eli gi bl e f or r a n d o mi z ati o n at 1 2 
m o nt h s of a g e t o 3 y e ar s of tr e at m e nt wit h h y dr o x y ur e a  or pl a c e b o .  


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 1 0  of 7 4  
 
2. 2  St u d y P h a s e s  
  
  
 
P H A S E I – St a n d ar di z ati o n     
  
  
  
  
  
0 8/ 11 – 0 7 / 12   ( 1 2 m o nt h s) 
D uri n g t hi s p h a s e , e a c h Cli ni c al C e nt er will o bt ai n or will alr e a d y h a v e o bt ai n e d I R B a p pr o v al of t h e pr ot o c ol, 
a n d c o n s e nt f or m a n d o bt ai n c ertifi c ati o n f or t h e st u d y pr o c e d ur e.   T hi s p h a s e of t h e st u d y m a y b e gi n at 
diff er e nt ti m e p oi nt s f or diff er e nt sit e s, a n d t h e d at e s f or t h e p h a s e s of t h e st u d y c a n b e a dj u st e d f or e a c h sit e.  
 
T h e St u d y C h air, Vi c e C h air, D at a  C o or di n ati n g C e nt er St aff a n d t h e E x e c uti v e C o m mitt e e will w or k t o g et h er t o 
c o m pl et e m ut u all y u n d er st o o d st u d y d o c u m e nt s s u c h a s t h e Pr ot o c ol, M a n u al of O p er ati o n s a n d St u d y F or m s. 
B ef or e a cli ni c al sit e i s all o w e d t o b e gi n p arti ci p a nt  r e cr uit m e nt, a cli ni c al sit e i n v e sti g at or, n e ur ol o gi st, 
p s y c h ol o gi st, n e ur or a di ol o gi st a n d st u d y c o or di n at or m u st b e c ertifi e d i n e a c h of t h e pr o c e d ur e s of k e y 
i m p ort a n c e t o t h e I R B-a p pr o v e d st u d y.  Tr ai ni n g will i n cl u d e t h e m et h o d s f or r e cr uit m e nt, o bt ai ni n g i nf or m e d 
c o n s e nt, c oll e cti o n of pr ot o c ol s p e cifi c d at a, ( e. g., T C D, M RI, p s y c h ol o gi c al e v al u ati o n, a n d n e ur ol o gi c al 
e x a mi n ati o n s), c o m pl eti o n of t h e st u d y f or m s, a n d u s e of t h e d at a e ntr y ( w e b e ntr y/f a x e ntr y) s y st e m. All st u d y 
sit e n e ur ol o gi st s m u st c o m pl et e t h e NI H Str o k e St u d y S c al e c ertifi c ati o n p a c k a g e pri or t o st u d y c e nt er e nr olli n g 
p arti ci p a nt s.  
 
T h e c o m pl eti o n of st u d y f or m s a n d c ert ai n st u d y pr o c e d ur e s ( e. g., r e cr uit m e nt)  ar e t o b e p erf or m e d o nl y b y 
cli ni c al sit e st aff t h at h a v e b e e n tr ai n e d a n d c ertifi e d t o c o m pl et e t h e s e t a s k s.  C ertifi c ati o n will b e gi v e n t o st aff 
t h at p a s s a si m pl e t e st c o n c er ni n g t h e p r ot o c ol a n d d e m o n str at e pr ofi ci e n c y i n r e q uir e d t a s k s ( e. g., c o m pl eti o n 
of f or m s a n d u s e of t h e w e b e ntr y/f a x e ntr y s y st e m s).  R e -c ertifi c ati o n will o c c ur i n a s s o ci ati o n wit h sit e vi sit s 
a n d will b e b a s e d o n pr ofi ci e n c y d e m o n str at e d i n t h e o n -g oi n g p erf or m a n c e of st u d y a cti viti e s.  
 
F or t h e ori gi n al sit e s w h o h a v e b e e n i n v ol v e d i n st u d y d e v el o p m e nt, c ertifi c ati o n m a y b e gr a nt e d at t h e 
di s cr eti o n of t h e PI, b a s e d o n p arti ci p ati o n i n E x e c uti v e a n d O p er ati o n c all s a n d d e m o n str ati o n of a d e q u at e 
k n o wl e d g e of t h e pr ot o c ol a n d pr o c e d ur e s.  
 
P H A S E II – S cr e e ni n g a n d R a n d o mi z ati o n  
0 2 / 12 – u ntil r a n d o mi z ati o n 
c o m pl et e d  
D uri n g t h e s cr e e ni n g p eri o d u p t o 8 0 c hil dr e n fr o m f o ur  or m or e  c e nt er s will b e s cr e e n e d u si n g M RI t o i d e ntif y 
c hil dr e n wit h sil e nt c er e br al i nf ar ct s. W e a nti ci p at e a p pr o xi m at el y 4 0 will a gr e e t o p arti ci p ati o n i n t h e 
r a n d o mi z ati o n p orti o n of t h e st u d y.  Writt e n i nf or m e d c o n s e nt m u st b e o bt ai n e d fr o m t h e p ar e nt s pri or t o t h e 
s cr e e ni n g pr o c e s s.  A s cr e e ni n g l o g t o i d e ntif y all i n di vi d u al s a p pr o a c h e d f or t h e tri al will b e k e pt u p t o d at e a n d 
r e vi e w e d b y t h e e xt er n al a u diti n g t e a m.  A s e c o n d l o g will b e k e pt t o i d e ntif y i n di vi d u al s w h o b e g a n, b ut di d n ot 
c o m pl et e s cr e e ni n g .  A o n e-s e nt e n c e r e a s o n will b e r e c or d e d a s t o w h y eli gi bl e p arti ci p a nt s di d n ot pr o c e e d t o 
t h e r a n d o mi z ati o n c o m p o n e nt of t h e tri al.  T h e g o al i s t o r a n d o mi z e p arti ci p a nt s wit hi n 3 m o nt h s of si g ni n g 
c o n s e nt , wit h a m a xi m u m p eri o d  of 6 m o nt h s fr o m c o n s e nt  t o r a n d o mi z ati o n ( u nl e s s ot h er wi s e a p pr o v e d b y t h e 
st u d y l e a d er s hi p).  
 
P H A S E III – A cti v e Cli ni c al Tri al   
  
  
  
  
 
5/ 1 2 – 7/ 1 7  
P arti ci p a nt s i d e ntifi e d o n s cr e e ni n g M RI wit h o ut sil e nt c er e br al i nf ar ct s will b e r a n d o ml y all o c at e d t o pl a c e b o or 
h y dr o x y ur e a t h er a p y, f oll o w e d a n d t h e n di s c h ar g e d fr o m t h e tri al or c o nti n u e d t o b e f oll o w e d i n t h e pr o p o s e d 
p h a s e III tri al, if a p pr o v e d a n d f u n d e d.  P arti ci p a nt s will r e c ei v e pl a c e b o or h y dr o x y ur e a f or 3 6  m o nt h s, or t h e 
d ur ati o n of t h e f e a si bilit y tri al.  T w el v e m o nt h s aft er st u d y e ntr y, c o g niti v e a s s e s s m e nt, M RI, T C D a n d a 
n e ur ol o g y e x a mi n ati o n m u st b e d o n e f or s af et y a n d i nt eri m a n al y si s.   
 
All p arti ci p a nt s will r e c ei v e y e arl y e v al u ati o n s t h at i n cl u d e a n M RI, T C D , c o g niti v e t e sti n g, H & P, a n d 
n e ur ol o gi c al e v al u ati o n  f or t hr e e y e ar s.  T h e e xit e v al u ati o n i n cl u d e s H & P, M RI, T C D, n e ur ol o gi c al 
e x a mi n ati o n, c o g niti v e a n d l a b or at or y t e sti n g.   
 
P H A S E I V -  St u d y Cl o s e O ut a n d D at a A n al y si s   
  
  
8/ 1 7-1 1/ 1 7  


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 1 1  of 7 4  
D uri n g t hi s p h a s e, d at a a n al y si s a n d m a n u s cri pt pr e p ar ati o n f or t h e f e a si bilit y st u d y will o c c ur ; i n t h e e v e nt t h at 
t h e p h a s e III st u d y i s a p pr o v e d a n d f u n d e d, t h e r e s ult s of t h e f e a si bilit y st u d y m a y b e r e p ort e d at t h e e n d of t h e 
p h a s e III st u d y, at t h e di s cr eti o n of t h e PI . 
 
2. 3   Eli gi bilit y  
 
I n cl u si o n Crit eri a f or S cr e e ni n g  
 
1.  P arti ci p a nt  m u st h a v e si c kl e c ell a n e mi a ( h e m o gl o bi n S S) or si c kl e β° -t h al a s s e mi a ( h e m o gl o bi n 
S β° ) a s c o nfir m e d at t h e l o c al i n stit uti o n b y h e m o gl o bi n a n al y si s aft er si x m o nt h s of a g e  or b y 
g e n ot y pi n g at a n y ti m e .    
2.  P arti ci p a nt  m u st b e 9 t o 4 8 m o nt h s of a g e (i. e., m u st n ot h a v e att ai n e d t h eir 4 t h birt h d a y).   All 
s cr e e ni n g pr o c e d ur e s e x c e pt M RI m a y b e c o m pl et e d b et w e e n 9 a n d 1 2 m o nt h s of a g e, wit h t h e 
e x c e pti o n of t h e M RI, f or w hi c h  t h e c hil d m u st h a v e att ai n e d t h eir 1 st birt h d a y . 
3.  I nf or m e d c o n s e nt i n a c c or d a n c e wit h t h e i n stit uti o n al p oli ci e s (i n stit uti o n al I R B a p pr o v al) a n d 
F e d er al g ui d eli n e s ( a p pr o v e d b y t h e U nit e d St at e s D e p art m e nt of H e alt h a n d H u m a n S er vi c e s) 
m u st b e si g n e d b y t h e p arti ci p a nt ' s l e g all y a ut h ori z e d g u ar di a n a c k n o wl e d gi n g writt e n c o n s e nt t o 
j oi n t h e st u d y.   
 
M RI of t h e br ai n wit h s e d ati o n  
1.  T h e p ar e nt s or g u ar di a n s m u st pr o vi d e c o n s e nt f or s e d ati o n, a s w ell a s si g ni n g t h e st u d y c o n s e nt 
f or m. 
2.  A d e q u at e st u d y T C D wit h C B F V  < 1 7 0  c m/ s e c a n d c o m pl eti o n of b a s eli n e c o g niti v e t e sti n g a n d 
n e ur ol o gi st e v al u ati o n wit h o ut e vi d e n c e of TI A or o v ert str o k e.  
 
E x cl u si o n Crit eri a f or S cr e e ni n g    
1.  Hi st or y of a f o c al n e ur ol o gi c e v e nt l a sti n g m or e t h a n 2 4 h o ur s wit h m e di c al d o c u m e nt ati o n or a 
hi st or y of pri or o v ert str o k e  or sil e nt c er e br a l i nf ar ct.  
2.  Ot h er n e ur ol o gi c al pr o bl e m s, s u c h a s TI A, n e ur ofi br o m at o si s, l e a d p oi s o ni n g, n o n -f e bril e s ei z ur e 
di s or d er, or t u b er o u s s cl er o si s.  
3.  K n o w n HI V i nf e cti o n.  
4.  Tr e at m e nt wit h a nti -si c kli n g dr u g s or h y dr o x y ur e a wit hi n 3 m o nt h s or a nti ci p at e r e c ei vi n g a nti 
si c kli n g dr u g s or h y dr o x y ur e a d uri n g t h e c o ur s e of t h e st u d y.  
5.  C hr o ni c bl o o d tr a n sf u si o n t h er a p y, o n g oi n g or pl a n n e d . 
6.  P o or a d h er e n c e f elt t o b e li k el y p er hi s/ h er h e m at ol o gi st a n d st u d y c o or di n at or, b a s e d o n pr e vi o u s 
c o m pli a n c e wit h  cli ni c a p p oi nt m e nt s a n d f oll o wi n g a d vi c e.  
7.  Pr e s e n c e or pl a n n e d p er m a n e nt ( or s e mi -p er m a n e nt) m et alli c str u ct ur e s att a c h e d t o t h eir b o d y. 
( e. g., br a c e s o n t e et h, b o d y pi er ci n g s), w hi c h t h eir p h y si ci a n s b eli e v e will i nt erf er e wit h t h e M RI of 
t h e h e a d t o a s s e s s t h e pr e s e n c e of sil e nt c er e br al i nf ar ct. 
8.  Hi st or y of t w o or m or e T C D st u di e s wit h a T A M M V  or T A M X  ≥1 7 0  c m/ s e c b y t h e i m a gi n g or n o n -
i m a gi n g t e c h ni q u e, or a T C D t h at i s i n d et er mi n at e (i n d et er mi n at e T C D s m e a s ur e m e nt s m a y b e 
r e p e at e d, a n d if e v al u a bl e o n r e p e at, t hi s e x cl u si o n i s lift e d). 
9.  Si g nifi c a nt c yt o p e ni a s [ a b s ol ut e n e utr o p hil c o u nt ( A N C) < 1 5 0 0/ ul, pl at el et s < 1 5 0, 0 0 0/ ul, 
r eti c ul o c yt e s < 8 0, 0 0 0/ ul, u nl e s s t h e H b i s > 9 g/ dl]. C yt o p e ni a s will b e c o n si d er e d tr a n si e nt 
e x cl u si o n s.  
1 0.  Ot h er si g nifi c a nt or g a n s y st e m d y sf u n cti o n  
1 1.  K n o w n all er g y or i nt ol er a n c e of h y dr o x y ur e a  
1 2.  Si g nifi c a nt pr e m at urit y ( g e st ati o n al a g e of < 3 2 w e e k s)  
 
M RI of t h e B r ai n wit h S e d ati o n  
1.  F ail ur e t o p a s s M RI s cr e e ni n g c h e c kli st 
2.  O b str u cti v e sl e e p a p n e a [ O S A] a n d r e c ei vi n g t h er a p y [ e. g. C P A P], or b ei n g e v al u at e d or f oll o w e d  
b y a s p e ci ali st f or m a n a g e m e nt of s e v er e O S A  
3.  L e s s t h a n 1 2 m o nt h s of a g e.  


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 1 2  of 7 4  
4.  All er gi c r e a cti o n s s u c h a s urti c ari a or br o n c h o s p a s m or pr e vi o u s a d v er s e r e a cti o n s t o pr o p of ol, 
e g g s, or s o y pr o d u ct s.  
5.  K n o w n m aj or c hr o m o s o m al a b n or m aliti e s  
6.   Kn o w n air w a y a b n or m aliti e s  t h at w o ul d i n cr e a s e t h e ri s k of s e d ati o n/ a n e st h e si a. 
 
 
T e m p or ar y E x cl u si o n s  
7.  R o o m air o x y g e n s at ur ati o n gr e at er t h a n or e q u al t o 5 % b el o w t h e p arti ci p a nt' s b a s eli n e o n t h e d a y 
of t h e M RI wit h s e d ati o n . 
8.  R o o m air o x y g e n s at ur ati o n < 9 0 % o n t h e d a y of t h e M RI wit h s e d ati o n.  
9.  H e m o gl o bi n < 6. 5 g/ dl ( m u st b e m e a s ur e d wit hi n 3 0 d a y s of M RI).  
1 0.  T e m p er at ur e > 3 8˚ C o n t h e d a y of s e d ati o n  
1 1.  U p p er or l o w er r e s pir at or y i nf e cti o n, a cti v e br o n c h o s p a s m, a c ut e c h e st s y n dr o m e, s pl e ni c 
s e q u e str ati o n or ot h er a c ut e c o m pli c ati o n s of si c kl e c ell di s e a s e ot h er t h a n p ai n i n t h e l a st 4 w e e k s  
( d efi n e d b y t h e ti m e fr o m r e s ol uti o n of s y m pt o m s t o s e d ati o n).   
1 2.  P ai n cri si s wit hi n t w o w e e k s r e q uiri n g tr e at m e nt wit h o pi at e s  
 
I n cl u si o n Crit eri a f or R a n d o mi z ati o n  
  
  
  
  
  
 
1.  P arti ci p a nt  m u st h a v e si c kl e c ell a n e mi a ( h e m o gl o bi n S S) or si c kl e β -n ull t h al a s s e mi a ( h e m o gl o bi n 
S β° ) a s c o nfir m e d at t h e l o c al i n stit uti o n b y h e m o gl o bi n a n al y si s aft er si x m o nt h s of a g e.   
2.    P a rti ci p a nt m u st b e 1 2 t o 5 4  m o nt h s of a g e (i. e., m u st h a v e att ai n e d t h eir 1 st birt h d a y , b ut n ot b e > 
4. 5 y e ar s of a g e ).  
3.  P arti ci p a nt  m u st h a v e s u c c e s sf ull y c o m pl et e d s cr e e ni n g pr o c e d ur e s ( T C D, M RI of t h e br ai n, 
n e ur ol o g y e x a m, a n d c o g niti v e e v al u ati o n) . 
 
E x cl u si o n Crit eri a f or R a n d o mi z ati o n     
  
  
 
1.  P arti ci p a nt s w h o s e M RI s h o w a sil e nt or o v ert c er e br al i nf ar ct. 
2.  P arti ci p a nt s w h o h a v e a n o n -i m a gi n g T C D st u d y wit h a T A M M V ≥ 17 0  c m/ s e c v erifi e d b y t h e st u d y 
r a di ol o gi st or a T C D t h at i s i n d et er mi n at e (i n d et er mi n at e T C D s m e a s ur e m e nt s m a y b e r e p e at e d, 
a n d if e v al u a bl e o n r e p e at, t hi s e x cl u si o n i s lift e d ). 
3.  P arti ci p a nt s wit h a b n or m al ki d n e y f u n cti o n ( cr e ati ni n e > 0. 8 m g/ dl)  
4.  Si g nif i c a nt c yt o p e ni a s [ a b s ol ut e n e utr o p hil c o u nt ( A N C) < 1 5 0 0/ ul, pl at el et s < 1 5 0, 0 0 0/ ul, 
r eti c ul o c yt e s < 8 0, 0 0 0/ ul, u nl e s s t h e H b i s > 9 g/ dl]. C yt o p e ni a s will b e c o n si d er e d tr a n si e nt 
e x cl u si o n s.  
  
 
2. 4  
C o m pli a n c e R et e nti o n Str at e gi e s    
T o f urt h er i n cr e a s e t h e li k e li h o o d of a d h er e n c e a n d r et e nti o n, w e pl a n t o u s e s e v er al e vi d e n c e-b a s e d m et h o d s 
t h at h a v e b e e n eff e cti v e i n cli ni c al tri al s. T h e u s e of si m pl e, cl e ar, d et ail e d writt e n a n d v er b al i n str u cti o n s 
r e g ar di n g t h er a p y, p o s si bl e si d e eff e ct s of h y dr o x y ur e a a n d t e st s r e q uir e d f or t h e st u d y i n cr e a s e s 
c o m pr e h e n si o n of t h e p ur p o s e a n d i m p ort a n c e of t h e st u d y, a n d yi el d s b ett er a d h er e n c e t o t h e tri al. 3 9   
 
E d u c ati o n S e s si o n s  
Gi v e n t h e i nt e n sit y a n d d ur ati o n of t hi s st u d y, w e b eli e v e t h at a s oli d p arti ci p a nt -pr o vi d er r el ati o n s hi p n e e d s t o 
b e e st a bli s h e d pri or t o t h e i nf or m e d c o n s e nt a n d r a n d o mi z ati o n pr o c e s s. Pri or t o o bt ai ni n g c o n s e nt f or t h e 
tr e at m e nt c o m p o n e nt of t h e st u d y, e a c h p ar e nt/ g u ar di a n s h o ul d b e e d u c at e d a b o ut t h e p ot e nti al s e q u el a e of 
sil e nt c er e br al i nf ar ct s a n d o v ert s tr o k e a n d t h e b e n efit s/ri s k s of h y dr o x y ur e a f or 3 6 m o nt h s.  T h e o v er all g o al 
of t h e s e e d u c ati o n al vi sit s i s t o f ull y i nf or m p ar e nt s/ g u ar di a n s a n d p arti ci p a nt s a b o ut t h e i m p ort a n c e of t h e tri al 
a n d t h e r e q uir e m e nt s of p arti ci p ati o n.  Aft er p ar e nt s/ g u ar di a n s h a v e r e c ei v e d b a s eli n e i nf or m ati o n a b o ut t h e 
p ot e nti al s e q u el a e of s tr o k e a n d ri s k s/ b e n efit s of h y dr o x y ur e a t h er a p y, t h e y will b e b ett er inf or m e d of t h e ri s k s 
a n d b e n efit s of p arti ci p ati n g i n t hi s cli ni c al tri al f or u p t o 3 6 m o nt h s.   
 
T h e pri m ar y f o c u s of t h e p ar e nt a n d p arti ci p a nt  e d u c ati o n vi sit will b e t o pr o m ot e p arti ci p a nt  r e cr uit m e nt, a s 
w ell a s p arti ci p a nt s’ a d h er e n c e t o t h e pr ot o c ol a n d l o n g -t er m r et e nti o n i n t h e st u d y.  T hi s e d u c ati o n al m et h o d 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 1 3  of 7 4  
h a s b e e n eff e cti v e i n a pr e vi o u s N ati o n al H e art, L u n g, a n d Bl o o d I n stit ut e ( N H L BI) m ulti -i n stit uti o n al tri al, t h e 
C hil d h o o d A st h m a M a n a g e m e nt Pr o gr a m ( C A M P). 4 0    Alt h o u g h att e n d a n c e i s n ot a n a s s ur a n c e of c o m pli a n c e 
i n cli ni c al tri al s, n o n-att e n d e e s ar e fr e q u e ntl y u nli k el y t o c o m pl y wit h t h e tri al. 4 1  
 
T h e fir st e d u c ati o n al vi sit s h o ul d o c c ur d uri n g i niti al s cr e e ni n g.  T o pi c s c o v er e d s h o ul d i n cl u d e a 
p ar e nt/ p arti ci p a nt  e d u c ati o n c urri c ul u m t h at c o v er s t h e f oll o wi n g s u bj e ct m att er s:  t h e n e e d f or a n d ri s k s of 
s e d ati o n t o o bt ai n a M RI of t h e br ai n  a n d T C D , i d e ntifi cati o n a n d m a n a g e m e nt of a b n or m al T C D, sil e nt 
c er e br al i nf ar ct a n d o v ert str o k e; s c h o ol -r el at e d pr o bl e m s i n c hil dr e n wit h si c kl e c ell a n e mi a, sil e nt c er e br al 
i nf ar ct s a n d o v ert str o k e ; a n d str at e gi e s t o a s si st p ar e nt s/ g u ar di a n s i n i m pr o vi n g t h e s c h o ol e n viro n m e nt  a n d 
o bt ai ni n g a d diti o n al e v al u ati o n a n d e arl y i nt er v e nti o n r e s o ur c e s f or t o d dl er s a n d pr e s c h o ol a g e c hil dr e n .  
T h e s e str at e gi e s will i n cl u d e o pti o n s f or d e cr e a si n g s c h o ol a b s e nt e ei s m, s u c h a s i nt er mitt e nt h o m e b o u n d 
i n str u cti o n, g ui d eli n e s f or i niti ati o n of a n I n di vi d u al E d u c ati o n Pl a n (I E P), a n d i nf or m ati o n r e g ar di n g h el p f or 
c hil dr e n wit h p ot e nti al d e v el o p m e nt al d el a y or c o g niti v e i m p air m e nt .  
 
D uri n g t h e s e c o n d e d u c ati o n al vi sit w hi c h s h o ul d f oll o w a q u alif yi n g s cr e e ni n g M RI, p ar e nt s/ g u ar di a n s will  b e 
i nf or m e d of t h e i m pli c ati o n s of h y dr o x y ur e a t h er a p y, i n cl u di n g r e v er si bl e b o n e m arr o w s u p pr e s si o n, 
m a cr o c yt o si s t h at m a y m a s k f oli c a ci d or B 1 2 d efi ci e n c y,  r a s h a n d  t h e pr e c a uti o n s t a k e n t o d e cr e a s e t h e s e 
a d v er s e e v e nt s.  
 
P ar e nt/ C ar e gi v er R el ati o n s hi p  
T h e st aff will c o nt a ct p ar e nt s/ g u ar di a n s i m m e di at el y a n d r e s c h e d ul e p a rtici p a nt s ’ a p p oi nt m e nt s w h e n mi s s e d.  
Cl o s el y m o nit ori n g t h e p a rti ci p a nt vi sit s a n d n e e d f or r et ur n a p p oi nt m e nt s, s e n di n g r e mi n d er c ar d s a n d m a ki n g 
f oll o w-u p t el e p h o n e c all s t o a s s ur e p arti ci p a nt  att e n d a n c e f or bl o o d t e st s a n d r e c ei vi n g h y dr o x y ur e a or pl a c e b o 
ar e k e y el e m e nt s i n k e e pi n g p arti ci p a nt s fr o m b e c o mi n g l o st t o f oll o w -u p.  Al s o, p arti ci p a nt  r a n d o mi z e d t o 
r e c ei v e h y dr o x y ur e a or pl a c e b o will r e c ei v e $2 0. 0 0  f or e v er y st u d y vi sit, a n d a n a d diti o n al $ 2 0 . 0 0 f or e v er y 
r e s e ar c h vi sit t h at i n cl u d e s a s e d at e d M RI, T C D or  c o g niti v e t e sti n g.  If t h e p arti ci p a nt c o m pl et e s all of t h e 
st u d y vi sit s ( 1 6 vi sit s i n t h e fir st y e ar, 1 5 vi sit s i n t h e s e c o n d y e ar, a n d 1 5 vi sit s i n t h e t hir d y e ar ) t his will t ot al 
u p t o $ 1 1 0 0  ( $ 9 2 0 f or t h e r e g ul ar vi sit s a n d $ 1 8 0 f or s e d at e d M RI, T C D, a n d c o g niti v e t e sti n g) o v er 3 y e ar s t o 
h el p d ef r a y a n y st u d y a s s o ci at e d c o st s.   
 
I d e ntif yi n g a st a bl e c o nt a ct p er s o n ( s u c h a s a gr a n d p ar e nt, n ei g h b or, t e a c h er, fri e n d) n ot li vi n g wit h t h e st u d y 
p arti ci p a nt s f a mil y , b ut w h o will al w a y s k n o w t h e f a mili e s w h er e a b o ut s , will a s si st i n tr a c ki n g p arti ci p a nt s a n d 
d e cr e a s e t h e n u m b er l o st t o f oll o w u p.  W e will al s o r e q uir e t h e p arti ci p a nt ’ s s o ci al s e c urit y n u m b er t o a s si st i n 
tr a c ki n g of t h e p arti ci p a nt  l o n g t er m.  T h e r e s e ar c h t e a m will u s e a n d s h ar e t h e p arti ci p a nt ’ s i nf or m ati o n u ntil 
t e n y e ar s aft er cl o s ur e of t h e st u d y.  At t h at p oi nt, t h e sit e i n v e sti g at or will r e m o v e t h e i d e ntifi er s fr o m t h e 
p arti ci p a nt ’ s i nf or m ati o n, ( k e pt o nl y at t h e l o c al sit e b y t h e l o c al pri n ci p al i n v e sti g at or) m a ki n g it i m p o s si bl e t o 
li n k t h e p arti ci p a nt  t o t h e st u d y.   
 
C o m m u nit y O utr e a c h  
T o pr o m ot e cl o s e r el ati o n s hi p s wit h all h e alt h pr o vi d er s i n v ol v e d wit h H U  Pr e v e nt at e a c h i n stit uti o n, w e will 
r e c o m m e n d t h at t h e st u d y st aff n otif y t h e p arti ci p a nt s’ pri v at e p h y si ci a n w h e n p arti ci p a nt s ar e e nt er e d o n t h e 
tri al. T h e Sit e I n v e sti g at or will k e e p t h e p e di atri c m e di c al c o m m u nit y a br e a st of t h e pr o gr e s s at gr a n d r o un d s 
a n d/ or r o uti n el y s c h e d ul e d e d u c ati o n al c o nf er e n c e s at e a c h i n stit uti o n, e m p h a si zi n g t h e i m p ort a n c e of 
f oll o wi n g t h e s e p arti ci p a nt s f or a mi ni m u m of 3 6 m o nt h s.   
 
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 1 4  of 7 4  
 
3. 0  
C E N T R A L N E U R O R A DI O L O G Y R E VI E W of M RI/ T C D  
 
3. 1  
M RI R e vi e w  
T h e N e ur or a di ol o g y C o m mitt e e i s m a d e u p of t hr e e m e m b er s. All t hr e e m e m b er s r e a d e v er y e ntr y s c a n ( M RI -
1) a n d v ot e i n d e p e n d e ntl y o n t w o i s s u e s:  1) D o e s t h e s c a n m e et q u alit y a s s ur a n c e g ui d eli n e s ? a n d 2) D o e s 
t h e s c a n r e v e al a c er e br al i nf ar ct-li k e l e si o n(s) ?  
 
Alt h o u g h a m aj orit y v ot e i s n ot c h a n g e d, t h e c o m mitt e e m a k e s e v er y att e m pt t o h ol d a m o nt hl y  c o n s e n s u s c all , 
t o di s c u s s c a s e s w h er e t h er e i s n o  c o n s e n s u s.  
 
I n a d diti o n t o a r e a di n g t o e x cl u d e p ot e nti al p arti ci p a nt s fr o m t h e H U Pr e v e nt st u d y, a n M RI i s al s o r e a d wit hi n 
2 4 h o ur s of u pl o a di n g i nt o t h e C R L  w e b sit e f or a n y e m er g e n c y m e di c al c o n diti o n t h at will r e q uir e f oll o w u p at 
t h e l o c al sit e. T h e e m er g e n c y r e a d i s p erf or m e d b y o n e a s si g n e d n e ur or a di ol o gi st. T hi s h a s b e e n b uilt i nt o t h e 
s y st e m t o a c c o m m o d at e s e v er al sit e s t h at ar e u si n g a r e s e ar c h M RI , w hi c h m e a n s t h at t h e s c a n i s n ot r e a d 
l o c all y. If a n e m er g e n c y or i n ci d e nt al fi n di n g i s f o u n d, t h e n e ur or a di ol o gi st E-m ail s a n d t el e p h o n e s eit h er Dr. 
J a m e s  C a s ell a, Dr. J o h n Str o u s e, or Dr. L ori J or d a n. 4 2  T h e criti c al m e di c al i nf or m ati o n i s r el a y e d, a n d eit h er 
t h e St u d y PI or N e ur ol o g y C o m mitt e e C h air will c all a n d E-m ail t h e l o c al sit e i n v e sti g at or. T hi s c h ai n of 
c o m m u ni c ati o n i s t o k e e p t h e n e ur or a di ol o gi st s ' bli n d' t o a n y ot h er cli ni c al c o n diti o n s t h at m a y b e di s c u s s e d 
d uri n g t h e tr a n sf er of p erti n e nt cli ni c al i nf or m ati o n.   T h e s e fi n di n g s will b e c o m m u ni c at e d t o t h e p arti ci p a nt’ s  
p h y si ci a n, p ar e nt , a n d/ or g u ar di a n  a s n e c e s s ar y b y t h e l o c al st u d y i n v e sti g at or s or p er s o n n el , r e c o g ni zi n g t h e 
c h oi c e s m a d e b y t h e p arti ci p a nt i n t h e c o n s e nt f or m.   
 
T h e c o m mitt e e p erf or m s t h e s a m e pr o c e s s f or all M RI s, st u d y cl o s e -o ut s c a n s, a n d u n s c h e d ul e d  s c a n s; 
h o w e v er, i n st e a d of s e e ki n g di s q u alif yi n g l e si o n s, n o w t h e q u e sti o n of i nt er e st i s, " D o e s t h e M RI m e et t h e 
st u d y d efi n e d e n d p oi nt ?"  
 
3. 2  
T C D R e vi e w  
T C D s m a y  b e i nt er pr et e d l o c all y b y r a di ol o g y, n e ur ol o g y, or h e m at ol o g y , i n a d diti o n t o a st u d y i nt er pr et ati o n b y 
t h e st aff of t h e c e ntr al r e a di n g f a cilit y.  T C D s will b e tr a n s mitt e d t o t h e M e di c al U ni v er sit y of S o ut h C ar oli n a 
( M U S C) f or q u alit y c o ntr ol a n d c e ntr al i nt er pr et ati o n b y t h e M U S C N e ur ol o g y C or e.  Dr. R o b ert A d a m s, 
Pr of e s s or of N e ur ol o g y at t h e M e di c al U ni v er sit y of S o ut h C ar oli n a, i s a l o n g -st a n di n g c o n s ult a nt t o o ur gr o u p 
a n d dir e ct s t h e N e ur ol o g y C or e.  Dr. A d a m s will pr o vi d e tr ai ni n g u si n g st a n d ar di z e d pr ot o c ol s t o a s s ur e t h e 
v ali dit y a n d r eli a bilit y of m e a s ur e m e nt s o bt ai n e d b y n o n -i m a gi n g T C D at p arti ci p ati n g sit e s.  P er s o n n el at e a c h 
sit e will p arti ci p at e i n a s cr e e ni n g tr ai ni n g a n d t e sti n g pr o gr a m d e v el o p e d b y t h e T C D I m a gi n g C e nt er f or n o n -
i m a gi n g T C D a s s e s s m e nt ( d e s cri b e d i n d et ail i n A p p e n di x 1 1 ).  T h e i m a g e a n al y si s q u alit y a s s ur a n c e pr o gr a m 
i n cl u d e s t w o c o m p o n e nt s: 1) i niti al tr ai ni n g o n -sit e or vi a vi d e o c o nf er e n c e/ W e b e x; a n d 2) i ntr a -o b s er v er 
v ari a bilit y t e sti n g.   E a c h r e s e ar c h st u d y r e a d er will i n d e p e n d e ntl y e v al u at e a s et of t hr e e r e a di n g s i n t h e s a m e 
i n di vi d u al wit hi n a 1 2 0 mi n ut e i nt er v al.   I ntr a-o b s er v er v ari a bilit y will b e a s s e s s e d a n d t h e d e gr e e of v ari a bilit y 
m u st n ot e x c e e d a pr e d efi n e d t hr e s h ol d.   T h e Pri n ci p al I n v e sti g at or  a n d I m a gi n g C e nt er Dir e ct or ( Dr. A d a m s) 
will a gr e e u p o n t h e e x a ct p ar a m et er s t o b e a s s e s s e d a n d t h e t hr e s h ol d t o b e s et.   If t h e r e a d er s e x c e e d t h e 
t hr e s h ol d, t h e n r e-tr ai ni n g will b e r e q uir e d.  
 
Dr. A d a m s a n d hi s t e a m will e v al u at e i m a g e s fr o m b ot h eli gi bilit y s cr e e ni n g a n d fr o m e nr oll e d p arti ci p a nt s, 
i n cl u di n g p arti ci p a nts wit h a s u s p e ct e d or c o nfir m e d pri m ar y e n d p oi nt, t h at i s, a T C D m e a s ur e m e nt of C B F V 
a b o v e a pr e -d efi n e d t hr e s h ol d ( > 1 7 0 c m/ s e c)  i n t h e di st al i nt er n al c ar oti d or mi d dl e c er e br al art eri e s.  H e will 
u s e a r ef er e n c e s et s h o wi n g e x a m pl e s of t h e v ari o u s di a g n o sti c crit eri a d e v el o p e d pri or t o t h e st art of t h e 
st u d y.   T h e M U S C N e ur ol o g y C or e will b e r e s p o n si bl e f or b ot h a q u alit ati v e a n d q u a ntit ati v e a s s e s s m e nt of t h e 
i m a g e s.   T h e q u alit ati v e a s s e s s m e nt will b e b a s e d o n t h e pr e s e n c e or a b s e n c e of T C D m e a s ur e m e nt 
r e a c hi n g t h e e n d p oi nt of t h e tri al ( 1 = d efi nit el y n ot, 2 =i n d et er mi n at e, 3 = d efi nit el y pr e s e nt).  Dr. A d a m s will 
i n d e p e n d e ntl y a s s e s s a n d r e c or d w h et h er a T C D e n d p oi nt h a s b e e n r e a c h e d.  
 
I n t h e e v e nt of a T C D i n di c ati n g a C B F V > 2 0 0 c m/ s e c a n d c o nfir m e d b y t h e i m a gi n g c e nt er , a r e p e at T C D will 
b e o bt ai n e d a n d c o nfir m e d a s q ui c kl y a s p o s si bl e, pr ef er a bl y wit hi n 4 8 hr s, b ut n o l o n g er t h at 1 w e e k .  


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 1 5  of 7 4  
C o n diti o n al T C D s will b e r e p e at e d wit hi n 6 -1 2 w e e k s, or e arli er, at t h e di s cr eti o n of  t h e sit e PI.  T w o T C D s 
a b o v e 1 7 0 c m/ s e c will b e r e q uir e d t o d et er mi n e a n e n d p oi nt, u nl e s s t h e i niti al T C D i s gr e at er t h a n or e q u al t o 
2 2 0 c m/ s e c, i n w hi c h c a s e a si n gl e T C D will s uffi c e .  I n t h e e v e nt t h at a c hil d h a s b e e n st art e d o n c hr o ni c 
tr a n sf u si o n s b y t h e l o c al tr e at m e nt t e a m, b a s e d o n a l o c al r e a d of a T C D > 2 0 0 c m/ s e c, t hi s will b e c o n si d er e d 
a n e n d p oi nt f or t h e st u d y, e v e n if t h e T C D i s n ot > 1 7 0  c m/ s e c b y t h e c e ntr al r e a d.   A s t w o p ati e nt s i n t h e 
S T O PII tri al of t h e 1 6 r e a c hi n g e n d p oi nt s d e v el o p e d str o k e b ef or e a s e c o n d T C D c o ul d b e o bt ai n e d, w e will 
a s k t h e PI s a n d c o or di n at or s t o a d h er e v er y stri ctl y t o t h e a b o v e ti m e crit eri a f or r e p e at T C D.  I n pr a cti c e, t h e 
i n v e sti g at or s i n t h e H U Pr e v e nt tri al f e el t h at r e p e ati n g a b n or m al T C D s i s t h e st a n d ard of c ar e, m a ki n g t hi s 
a p pr o a c h d e sir a bl e a n d a c c e pt a bl e.  
 
 
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 1 6  of 7 4  
 
4 
P A R TI CI P A N T  E V A L U A TI O N S    
  
  
  
  
  
 
St a n d ar d C ar e v s E x p eri m e nt al pr o c e d ur e s  
 
 Y e arl y T C D s h a v e b e e n r e c o m m e n d e d b y t h e N H L BI , b e gi n ni n g at 2 y e ar s of a g e, a n d will b e c o n si d er e d 
st a n d ar d of c ar e a n d bill e d t o t h e p arti ci p a nt ’ s i n s ur a n c e or s elf-p a y.  At s o m e sit e s, M RI s ar e r o uti n el y 
p erf or m e d at y e arl y or e v er y ot h er y e ar i nt er v al s; i n t h e s e c a s e s, t h e y will b e  c o n si d er e d st a n d ar d of c ar e a n d 
bill e d t o t h e  p arti ci p a nt ’ s i n s ur a n c e or s elf-p a y.  M o nt hl y C B C s  wit h diff er e nti al s a n d r eti c ul o c yt e c o u nt s a n d 
m et a b oli c p a n el s  e v er y t hr e e m o nt h s  ar e st a n d ar d c ar e f or c hil dr e n b ei n g tr e at e d wit h h y dr o x y ur e a.  All ot h er 
st u d y pr o c e d ur e s ar e c o n si d er e d e x p eri m e nt al.  P arti ci p a nt s will b e c o u n s el e d b y s o ci al w or k er s or m e m b er s 
of t h e t e a m r e g ar di n g t h e p ot e nti al e x p e n s e s i n c urr e d b y i n cl u si o n i n t h e st u d y a n d e n c o ur a g e d t o v erif y 
w h et h er p a y m e nt f or st a n d ar d of c ar e pr o c e d ur e s will b e a c c e pt a bl e t o t h eir i n s ur a n c e c o m p a ni e s.  
 
4. 1  
D N A a n d Pr ot e o mi c s S a m pl e  
W e h a v e a n e x c e pti o n al o p p ort u nit y t o e x p a n d t h e e xi sti n g bi ol o gi c al r e p o sit or y of s p e ci m e n s fr o m c hil dr e n 
wit h si c kl e c ell di s e a s e fr o m t h e SI T Tri al.  T hi s r e s o ur c e will b e i n v al u a bl e t o t h o s e st u d yi n g t h e g e n eti c s , 
pr ot e o mi c s  a n d bi ol o g y of si c kl e c ell di s e a s e.  T h e v al u e of t h e e xi sti n g r e p o sit or y i s i n it s l ar g e si z e ( o v er 1 2 0 0 
p arti ci p a nt s) a n d i n t h e hi g h q u alit y of t h e i nf or m ati o n a b o ut t h e p arti ci p a nt s.  All p arti ci p a nt s i n cl u d e d i n t h e 
r e p o sit or y will h a v e a n M RI of t h e br ai n a n d pr o vi d e ( wit h h el p fr o m t h eir p ar e nt s a n d h e alt h c ar e pr o vi d er s) 
d et ail e d i nf or m ati o n o n t h eir pr e vi o u s c o m pli c ati o n s fr o m si c kl e c ell di s e a s e.  L y m p h o c yt e s fr o m t h e s p e ci m e n s 
will u n d er g o E B V tr a n sf or m ati o n a n d b e st or e d i n t h e C ell C e nt er  of t h e G e n eti c R e s o ur c e s C or e F a cilit y 
( G C R F) at J o h n s H o p ki n s H o s pit al.  I n a d diti o n, pl a s m a a n d D N A i s ol at e d fr o m t h e l y m p h o c yt e s will b e st or e d 
i n t h e r e p o sit or y.  T h e vi a bilit y of l y m p h o c yt e s d e cr e a s e s o v er ti m e, s o it i s i m p ort a nt t h at w e r e c ei v e all 
s a m pl e s wit hi n 4 8 h o ur s of c oll e cti o n, pr ef er a bl y wit hi n 2 4 h o ur s. I n a d diti o n, t o t h e c oll e cti o n of g e n eti c 
s a m pl e s , w e will c oll e ct pl a s m a s a m pl e s u n d er o pti m al c o n diti o n s f or pr ot e o mi c e x p eri m e nt s. T h e H U Pr e v e nt 
St u d y will r e pr e s e nt a u ni q u e o p p ort u nit y t o st u d y a w ell -d efi n e d c o h ort of p arti ci p a nt s w h o will b e f oll o w e d 
l o n git u di n all y.  Pl e a s e r ef er t o A p p e n di c e s 14 a n d 1 5 f or s p e ci m e n pr e p ar ati o n a n d s hi p pi n g i n str u cti o n s  
 
4. 2  
H y dr o x y ur e a  
P arti ci p a nt s r a n d o mi z e d t o r e c ei v e h y dr o x y ur e a will b e gi n at 2 0 m g/ k g/ d a y r o u n d e d t o t h e n e ar e st 1 0 m g, wit h 
a st a bl e li q ui d f or m ul ati o n c o m p o u n d e d at 1 0 0 m g/ ml b y l o c al r e s e ar c h p h ar m a ci e s  u si n g a st a n d ar di z e d 
pr o c e d ur e a n d H y dr e a ™ 5 0 0 m g c a p s ul e s ( Bri st ol -M y er s S q ui b b) o bt ai n e d b y t h e l o c al sit e r e s e ar c h p h ar m a c y 
(A p p e n di x 1 7). 4 3   D o s e e s c al ati o n will o c c ur i n 5 m g/ k g/ d a y i n cr e m e nt s  e v er y ei g ht w e e k s , t o a m a xi m u m of 3 5 
m g/ k g/ d a y, if t h e A N C i s > 4. 0  x 1 0 9 / L a n d n o ot h er h e m at ol o gi c al t o xi cit y i s pr e s e nt ( H b < 7 . 0 g/ d L w h e n 
a b s ol ut e r eti c ul o c yt e c o u nt <  80 x 1 0 9 / L, or pl at el et c o u nt <  8 0 x 1 0 9 / L). Hy dr o x y ur e a  will b e h el d f or 
h e m at ol o gi c al t o xi cit y a n d a C B C wit h diff er e nti al a n d a r eti c ul o c yt e c o u nt will b e o bt ai n e d w e e kl y, u ntil 
r e s ol uti o n of t h e t o xi cit y.  H e m at ol o gi c al t o xi cit y i s d efi n e d a s a n A N C < 1 x 1 0 9 / L, H b < 7. 0 g/ d L, w h e n 
a b s ol ut e r eti c ul o c yt e c o u nt < 8 0 x 1 0 9 / L, or pl at el et c o u nt < 8 0 x 1 0 9 / L. R e c o v er y i s d efi n e d a s a n A N C >  1. 5 x 
1 0 9 / L, H b ≥ 6 . 0 g/ d L ( u nl e s s t h e p ati e nt s pr e-tr e at m e nt b a s eli n e i s < 6. 0 g/ d L, i n w hi c h c a s e t h e H b s h o ul d b e 
wit hi n 0. 5 g/ d L of b a s eli n e), a b s ol ut e r eti c ul o c yt e c o u nt > 8 0 x 1 0 9 / L a n d pl at el et c o u nt > 1 0 0 x 1 09 / L.  
H y dr o x y ur e a  will t h e n b e r e st art e d at t h e s a m e d o s e, u nl e s s h e m at ol o gi c t o xi cit y h a s pr e vi o u sl y o c c urr e d at 
t hi s d o s e; if s o, t h e d o s e will b e r e d u c e d b y 2. 5 m g/ k g/ d a y.  F urt h er d o s e e s c al ati o n will n ot o c c ur aft er d o s e 
r e d u cti o n. 
 
 
4. 3  
Pl a c e b o  
P arti ci p a nt s r a n d o mi z e d t o r e c ei v e s u cr o s e pl a c e b o ( a s i n t h e B A B Y H U G St u d y) will b e gi n 0. 2 m L / k g r o u n d e d 
t o t h e n e ar e st 0. 1 mL of pl a c e b o c o m p o u n d e d b y l o c al r e s e ar c h p h ar m a ci e s.  D o s e e s c al ati o n will o c c ur b a s e d 
o n l o c al c o u nt s a s wit h h y dr o x y ur e a i n 0. 0 5 mL / k g/ d a y i n cr e m e nt s t o a m a xi m u m of 0. 3 5 mL / k g/ d a y, e v er y 
ei g ht w e e k s , if t h e A N C i s > 4. 0 x 1 0 9 / L a n d n o ot h er h e m at ol o gi c a l t o xi cit y i s pr e s e nt ( H b < 7 . 0 g/ d L w h e n 
a b s ol ut e r eti c ul o c yt e c o u nt <  80 x 1 0 9 / L, or pl at el et c o u nt <  8 0 x 1 0 9 / L).   H y dr o x y ur e a  will b e h el d f or 
h e m at ol o gi c al t o xi cit y a n d a C B C wit h diff er e nti al a n d a r eti c ul o c yt e c o u nt will b e o bt ai n e d w e e kl y, u ntil 
re s ol uti o n of t h e t o xi cit y .  H e m at ol o gi c al t o xi cit y i s d efi n e d a s a n A N C < 1 x 1 09 / L, H b < 7. 0 g/ d L, w h e n 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 1 7  of 7 4  
a b s ol ut e r eti c ul o c yt e c o u nt < 8 0 x 1 0 9 / L or pl at el et c o u nt < 8 0 x 1 09 / L. R e c o v er y i s d efi n e d a s a n A N C >  1. 5 x 
1 0 9 / L, H b ≥ 6 . 0 g/ d L ( u nl e s s t h e p ati e nt s pr e-tr e at m e nt b a s eli n e i s < 6. 0 g/ d L, i n w hi c h c a s e t h e H b s h o ul d b e 
wit hi n 0. 5 g/ d L of b a s eli n e), a b s ol ut e r eti c ul o c yt e c o u nt >  8 0 x 1 0 9 / L a n d pl at el et c o u nt > 1 0 0 x 1 09 / L.  St u d y 
tr e at m e nt ( pl a c e b o) will t h e n b e r e st art e d at t h e s a m e d o s e, u nl e s s h e m at ol o gi c t o xi cit y h a s pr e vi o u sl y 
o c c urr e d at t hi s d o s e; if s o, t h e d o s e will b e r e d u c e d b y 0. 0 2 5 m L / k g/ d a y.  F urt h er d o s e e s c al ati o n will n ot 
o c c ur aft er d o s e r e d u cti o n.   
 
Si m ul at e d d o s e e s c al ati o n s will o c c ur at t h e s a m e fr e q u e n c y a s t y pi c all y r e q uir e d i n t h e h y dr o x y ur e a ar m ( 1 t o 
3 p er p arti ci p a nt, wit h a m e a n of 2).   
 
4. 4  
M o nit ori n g  
All p arti ci p a nt s will h a v e a C B C wit h diff er e nti al a n d r eti c ul o c yt e c o u nt 2 w e e k s aft er d o s e i niti ati o n or 
e s c al ati o n a n d e v er y 4 w e e k s ot h er wi s e.  A n u n bli n d e d, l o c al  st u d y m o nit or will r e vi e w  all l o c al c o u nt s a n d a n 
u n bl in d e d l o c al d at a m a n a g er will s u b mit t h e s e st u di e s el e ctr o ni c all y t o t h e D at a C o or di n ati n g C e nt er  ( D C C) 
a n d i s s u e l o c al h ol d s f or t o xi cit y a n d d o s e e s c al ati o n .  A c e ntr al st u d y m o nit or will b e r e s p o n si bl e f or r e vi e wi n g 
l a b or at or y r e s ult s t o a s s ur e t h at t o xi cit y a n d d o s e e s c al ati o n s ar e o c c urri n g a p pr o pri at el y.  T h e c e ntr al st u d y 
m o nit or will i nf or m sit e s of r a n d o m st o p s a n d h ol d s f or pl a c e b o p arti ci p a nt s a s w ell.  Ot h er m o nit ori n g f or 
t oxi cit y a n d t h e eff e ct of h y dr o x y ur e a will i n cl u d e a c o m pr e h e n si v e p a n el, l a ct at e d e h y dr o g e n a s e, h e m o gl o bi n 
F, F -c ell s, e v er y 3 m o nt h s  a n d  F-r eti c ul o c yt e s a n n u all y . 
 
4. 5  
S af et y R e p orti n g a n d A d v er s e E v e nt s  
S af et y a s s e s s m e nt s  
C o m pli c ati o n s of s e d ati o n f or M RI s will b e r e c or d e d b y t h e a n e st h e si ol o gi st  or ot h er pr o vi d er  p erf or mi n g t h e 
s e d ati o n  u n d er t h e s u p er vi si o n of t h e a n e st h e si ol o gi st , u si n g  a st a n d ar d f or m d e v el o p e d b y t h e S e d ati o n 
C o m mitt e e ( s e e a p p e n di x 1 8) a n d b y f oll o w -u p t el e p h o n e c all  b y t h e st u d y c o or di n at or  aft er 7 2  h o ur s a n d 
f oll o w-u p vi sit or t el e p h o n e c all at 1 4 d a y s , u si n g a st a n d ar di z e d q u e sti o n n air e ( A p p e n di x 1 9 ).  P arti ci p a nt s will 
b e e v al u at e d e v er y t w o w e e k s aft er a c h a n g e i n d o s e a n d ot h er wi s e e v er y f o ur w e e k s. A n i nt er v al hi st or y of 
m e di c al e v e nt s a n d p ot e nti al a d v er s e e v e nt s will b e o bt ai n e d at t h e s e vi sit s.  T hi s i nf or m ati o n will b e c oll e ct e d 
f or 4 w e e k s aft er t h e p arti ci p a nt h a s st o p p e d t h e st u d y m e di c ati o n.  C o n diti o n al a n d a b n or m al T C D s will b e 
r e p e at e d wit hi n d efi n e d i nt er v al s ( s e e S e cti o n 5. 1) t o d et e ct pr o gr e s si o n a n d t h e n e e d f or tr a n sf u si o n s. 
 
S af et y i nf or m ati o n will b e s e nt t o t h e c o or di n ati n g c e nt er l e d b y D a ni el H a nl e y, M D a n d s u p p ort e d b y t h e J o h n s 
H o p ki n s I C T R.  T hi s c e nt er will b e r e s p o n si bl e f or d at a m a n a g e m e nt, d at a q u alit y a s s ur a n c e, r a n d o m st o p 
or d er s a n d d o s e e s c al ati o n or d er s f or h y dr o x y ur e a, a n d pr o vi di n g i nf or m ati o n o n r e s ult s a n d a n al y s e s t o t h e 
D S M B.  
 
A d v er s e e v e nt s: D at a will b e c oll e ct e d o n a d v er s e e v e nt s ( A E), a n y a b n or m al fi n di n g ( hi st or y, p h y si c al e x a m, 
l a b or at or y, or i m a gi n g) of a p arti ci p a nt i n t h e st u d y.  U n e x p e ct e d A E s ar e a d v er s e r e a cti o n s t h at ar e n ot 
c o n si st e nt ( n at ur e or s e v erit y) wit h t h e a v ail a bl e i nf or m ati o n o n h y dr o x y ur e a or S C D.   A f ull li st of e x p e ct e d 
A E s ar e b el o w.  A E s will b e s c or e d u si n g t h e C o m m o n T o xi cit y Crit eri a f or A d v er s e E v e nt s ( C T C A E) 3. 0 of t h e 
N ati o n al C a n c er I n stit ut e a n d t h e st a n d ar d n o m e n cl at ur e f or d efi ni n g t h e c a u s al r el ati o n b et w e e n t h e A E a n d 
st u d y dr u g ( u nr el at e d, pr o b a bl y n ot r el at e d/r e m ot e, p o s si bl y r el at e d, pr o b a bl y r el at e d, d efi nit el y r el at e d) .  A E s 
will b e f oll o w e d u ntil t h e y r e s ol v e or st a bili z e.  A E s will b e cl a s sifi e d a s o n g oi n g, r e s ol v e d wit h o ut s e q u el a e, 
r e s ol v e d wit h s e q u el a e, or d e at h.  T h e r e s p o n s e t o t h e A E will b e r e c or d e d. 
 
E x p e ct e d A d v er s e E v e nt s i n C hil dr e n wit h Si c kl e C ell Di s e a s e  
A c ut e c h e st s y n dr o m e  
A pl a sti c cri si s  
A n e mi a  
B a ct er mi a  
C h ol elit hi a si s, c h ol e c y stiti s, bili ar y tr a ct o b str u cti o n  
D e h y dr ati o n  
F ail ur e t o t hri v e  
F e v er  


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 1 8  of 7 4  
G a str o e nt erititi s  
H e a d a c h e  
H e m at uri a  
H y p ot h e n uir a  
H y p er bilir u bi n e mi a  
L e u k o c yt o si s  
N o ct uri a  
O b str u cti v e sl e e p a p n e a  
O st e o m e yliti s  
Otiti s m e di a  
P ai n  
P h ar y n giti s  
P n e u m o ni a  
Pri a pi s m  
S pl e ni c s e q u e str ati o n  
U p p er r e s pir at or y tr a ct i nf e cti o n s  
Uri n ar y tr a ct i nf e cti o n 
T a c h y c ar di a  
T a c h y p n e a  
T hr o m b o c yt o si s  
 
S eri o u s a d v er s e e v e nt ( S A E)  
R e s ult s i n d e at h  
Lif e -t hr e at e ni n g ( p arti ci p a nt at ri s k of d e at h at t h e ti m e of t h e e v e nt) 
R e q uir e s or pr ol o n g s h o s pit ali z ati o n  ( u nl e s s a n e x p e ct e d e v e nt). 
I ntr a c er e br al or s u b ar a c h n oi d h e m orr h a g e 
I s c h e mi c str o k e 
C a u s e s p er si st e nt or si g nifi c a nt di s a bilit y . 
R e s ult s i n a c o n g e nit al a n o m al y.  
Ot h er m e di c al e v e nt s (i n t h e o pi ni o n of t h e i n v e sti g at or) t h at m a y p ut t h e p arti ci p a nt at ri s k or r e q uir e 
i nt er v e nti o n t o pr e v e nt a s eri o u s A E. 
 
R e p orti n g of e v e nt s  
S eri o u s s af et y i s s u e s will b e r e p ort e d t o t h e D S M B  a n d I R B, w hi c h will m a k e r e c o m m e n d ati o n s t o t h e s p o n s or 
(J o h n s H o p ki n s a n d t h e N H L BI) a b o ut t h e st u d y.  
 
U n e x p e ct e d S A E t h at ar e p o s si bl y r el at e d, pr o b a bl y r el at e d, or d efi nit el y r el at e d t o st u d y m e di c ati o n or 
pr o c e d ur e s will b e r e p ort e d t o t h e D S M B , F D A,  a n d I R B wit hi n 7 c al e n d ar d a y s, if f at al or lif e -t hr e at e ni n g, a n d 
wit hi n 1 5 c al e n d ar d a y s if n ot.   All S A E ( e x p e ct e d a n d u n e x p e ct e d) will b e pr o vi d e d t o t h e D S M B b y t h e D C C 
q u art erl y.   All A E ( s eri o u s a n d n o n -s eri o u s) will b e r e p ort e d t o t h e D S M B e v er y si x m o nt h s.  
 
4. 6  
E v al u ati o n of A d h er e n c e  
A d h er e n c e will b e a s c ert ai n e d b y a n i nt er vi e w wit h a bri ef q u e sti o n n air e a n d m e a s ur e m e nt of m e di c ati o n 
di s p e n s e d a n d r et ur n e d.  T h e p ar e nt will b e a s k e d t o e sti m at e t h e n u m b er of h y dr o x y ur e a  d o s e s mi s s e d, 
s pill e d, or ot h er wi s e l o st si n c e t h e l a st vi sit a n d t o c o m pl et e t h e m o difi e d M ori s k y M e di c ati o n a d h er e n c e 
s c al e. 4 4 ,4 5   I n a d diti o n, t h e st u d y c o or di n at or will o bt ai n i nf or m ati o n, i n cl u di n g t h e d o s e, di s p e n si n g d at e, a n d 
v ol u m e of li q ui d di s p e n s e d fr o m t h e sit e p h ar m a ci st a n d w ei g ht of t h e b ottl e b ef or e it i s gi v e n t o t h e f a mil y a n d 
u p o n it s r et ur n. T hi s i nf or m ati o n will b e u s e d t o c o m pl et e t h e h y dr o x y ur e a  l o g. W e will e v al u at e t h e pr o p orti o n 
of p arti ci p a nt s r e c ei vi n g at l e a st 8 0 % of t h eir pr e s cri b e d d o s e s of h y dr o x y ur e a  a n d c al c ul at e 9 5 % CI b y e x a ct 
m et h o d s.  
 
4. 7  
Wit h dr a w al fr o m t h e st u d y.   


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 1 9  of 7 4  
A s t h e st u d y i s b ei n g c o n d u ct e d a s i nt e n ti o n t o tr e at, p arti ci p a nt s will o nl y b e wit h dr a w n fr o m t h e st u d y if t h e y 
wit h dr a w c o n s e nt or b e c o m e u n a bl e t o c o m pl y wit h st u d y pr o c e d ur e s.  I n t h e s e i n st a n c e s, all r e a s o n a bl e 
eff ort s will b e m a d e t o c oll e ct a s m u c h e n d p oi nt i nf or m ati o n a s p o s si bl e pri or t o wit h dr a w al.  
 
4. 8  
Di s c o nti n u ati o n of h y dr o x y ur e a or pl a c e b o.  
If a p arti ci p a nt  i s b e g u n o n r e g ul arl y s c he d ul e d  tr a n sf u si o n s d uri n g t h e st u d y, h y dr o x y ur e a or pl a c e b o will 
di s c o nti n u e d  f or t h e p eri o d of c hr o ni c tr a n sf u si o n s .  If t h e p arti ci p a nt i s t a k e n off of tr a n sf u si o n s d uri n g t h e 3 
y e ar s of i nt e n d e d t h er a p y, t h e st u d y dr u g m a y b e r e s u m e d.  M o nit ori n g f or h y dr o x y ur e a  will b e di s c o nti n u e d 
d uri n g t h e p eri o d of t h e c hr o ni c tr a n sf u si o n s.  If a p arti ci p a nt  i s gi v e n  tr a n sf u si o n s d uri n g t h e st u d y, wit h o ut t h e 
int e nti o n of c o nti n ui n g c hr o ni c tr a n sf u si o n s, h y dr o x y ur e a or pl a c e b o will b e c o nti n u e d f or t h e p eri o d of t h e 
tr a n sf u si o n s; t h e st u d y dr u g c a n b e c o nti n u e d f or a p eri o d of u p t o 6 m o nt h s of a p pr o xi m at el y m o nt hl y  
tr a n sf u si o ns , aft er w hi c h it s h o ul d b e di s c o nti n u e d, if t h e p ati e nt r e m ai n s o n tr a n sf u si o n s f or a n y r e a s o n.  All 
p arti ci p a nt s will c o nti n u e t o b e f oll o w e d f or t h e d ur ati o n of t h e st u d y p eri o d  ( 3 y e ar s).  All st u d y pr o c e d ur e s , 
e x c e pt f or m o nit ori n g f or t o xi cit y fr o m h y dr o x y ur e a , s h o ul d c o nti n u e.   
 
If a pr o vi d er  d e ci d e s t o b e gi n h y dr o x y ur e a o n a p arti ci p a nt  d uri n g t h e tri al, a di s c u s si o n will b e h el d wit h t h e PI 
a n d t h e pr o vi d er , t o r e vi e w t h e i n di c ati o n s f or d oi n g s o.  W e e x p e ct t h e s e e v e nt s t o b e r ar e, a s t h e st u d y 
i n v e sti g at or s f e el t h at t h er e ar e pr e s e ntl y n o a b s ol ut e i n di c ati o n s f or h y dr o x y ur e a u s e i n t hi s a g e gr o u p.  T h e s e 
d e ci si o n s will al w a y s b e m a d e wit h t h e b e st i nt er e s t s of t h e p arti ci p a nt  i n mi n d a n d t h e fi n al d et er mi n ati o n of 
t h er a p y will b e m a d e b y t h e p arti ci p a nt ’ s p h y si ci a n i n all c a s e s. 
 
If t h e p arti ci p a nt h a s tw o or m or e e pi s o d e s of h e m at ol o gi c al t o xi cit y d e s pit e r e d u cti o n of t h e st u d y m e di c ati o n 
t o < 0. 1 2 5 ml/ k g/ d a y ( 1 2. 5 m g/ k g/ d a y of h y dr o x y ur e a or e q ui v al e nt v ol u m e of pl a c e b o) or Gr a d e 4 t o xi cit y or 
r e c urr e nt gr a d e 3 t o xi cit y, pr o b a bl y or d efi nit el y r el at e d t o st u d y m e di c ati o n, t h e st u d y d r u g will b e 
di s c o nti n u e d.  
 
 
5. 0  
E V A L U A TI O N S a n d F O L L O W U P  
 
5. 1   O v er vi e w of st u d y pr o c e d ur e s   
Aft er s cr e e ni n g pr o c e d ur e s, w hi c h i n cl u d e a T C D, M RI, n e ur ol o gi c al e v al u ati o n a n d n e ur o p s y c h ol o gi c al 
t e sti n g, c hil dr e n wit h o ut S CI, str o k e, TI A or el e v at e d C B F V ( > 1 7 0  c m/ s e c) a n d m e eti n g t h e ot h er crit eri a will 
b e eli gi bl e f or r a n d o mi z ati o n.  R a n d o mi z e d p arti ci p a nt s will h a v e st u d y vi sit s e v er y 4 w e e k s wit h a hi st or y a n d 
e x a m, st u d y m e di c ati o n r efill, a d h er e n c e m e a s ur e s, a n d a C B C wit h diff er e nti al a n d r eti c ul o c yt e c o u nt.   A 
C B C wit h diff er e nti al a n d r eti c ul o c yt e  c o u nt will al s o b e o bt ai n e d 2 w e e k s aft er e a c h d o s e i n cr e a s e a n d a s 
n e e d e d t o m o nit or t o xi cit y.  Wit h l o c al i n stit uti o n al r e vi e w b o ar d a p pr o v al, t h e s e vi sit s m a y o c c ur at s at ellit e 
sit e s.  A d diti o n al l a b s ( H b F a n d S q u a ntifi c ati o n, L D H, a n d c o m pr e h e n si v e  p a n el will b e o bt ai n e d 4 ti m e s a 
y e ar  a n d pr ot e o mi c s e v er y 4 w e e k s).  T h e T C D, s e d at e d M RI/ M R A of t h e br ai n, n e ur ol o g y a n d c o g niti v e 
e v al u ati o n s will b e r e p e at e d y e arl y.   P arti ci p a nt s wit h c o n diti o n al T C D s ( C B F V 1 7 0 -1 9 9  c m/ s e c ) or a b n or m al 
T C D ( C B F V > 2 0 0 c m/ s e c)  b y n o n -i m a gi n g T C D or c o m p ar a bl e C B F V b y i m a gi n g T C D) will h a v e t h e T C D  
c o nfir m e d b y a r e p e at st u d y f or t h e e n d p oi nt .   E xit st u di e s ar e d e s cri b e d , al o n g wit h a s u m m ar y of pr o c e d ur e s 
i n t h e t a bl e b el o w.  T a bl e s of e v al u ati o n s b y y e ar ar e i n cl u d e d a s a p p e n di c e s 4 -6.  
T a bl e 1: S c h e d ul e of St u d y Pr o c e d ur e s  
Pr o c e d ur e  
S cr e e ni n g  
Pr e r a n d o mi z ati o n  
Q 4 w e e k s  
Y e arl y  
E xit  
Hi st or y a n d E x a m  
X X  
 
X X  
 
X X  
Tr a n s cr a ni al D o p pl er  
X X +  
 
 
X X  
X X  
M RI of br ai n  
X X ^  
 
 
X X  
X X  
St u d y M e di c ati o n r efill  
 
 
X X  
 
 
A d h er e n c e m e a s ur e s  
 
E d u c ati o n S e s si o n  
X X  
 
 
N e ur ol o g y E v al u ati o n  
X X  
 
 
X X  
X X  
C o g niti v e e v al u ati o n  
X X  
 
 
X X  
X X  
C B C, diff., r eti c ul o c yt e s  
X X  
 
Q 2 -4 w e e k s  
 
 
C o m pr e h e n si v e p a n el, L D H  
X X  
 
4 p er y e ar  
X X  


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 2 0  of 7 4  
Bi or e p o sit or y s a m pl e s  
X X*  
 
X X  
 
X X  
H b F a n d S, q u a ntifi c ati o n  
X X  
 
4 p er y e ar  
X X  
+ T h e T C D s h o ul d n ot b e d o n e wit hi n 2 m o nt h s of tr a n sf u si o n  
^ T o mi ni mi z e ri s k, t h e M RI m u st b e t h e l a st s c h e d ul e d s cr e e ni n g pr o c e d ur e, u nl e s s p erf or m e d a s a cli ni c al c ar e st u d y  
* at ti m e of M RI of t h e br ai n 
 
5. 2  S cr e e ni n g Vi sit s  
Vi sit 1  
S cr e e ni n g vi sit s f or p arti ci p a nt s m e eti n g e ntr y r e q uir e m e nt s of t hi s pr ot o c ol will b e s c h e d ul e d b y t h e st u d y 
c o or di n at or at e a c h sit e. T h e fir st s cr e e ni n g vi sit will c o n si st of a c o m pr e h e n si v e hi st or y ( m e di c al a n d 
e d u c ati o n al), a s cr e e ni n g T C D, a p h y si c al e x a mi n ati o n , i n cl u di n g n e ur ol o gi c e v al u ati o n b y t h e h e m at ol o gi st, 
a n d c oll e cti o n of bl o o d f or a C B C wit h diff er e nti al, r eti c ul o c yt e c o u nt, L D H, h e m o gl o bi n el e ctr o p h or e si s a n d 
q u a ntifi c ati o n of H b F , H b S , H b A , a n d  ot h er h e m o gl o bi n s , F-c ell s a n d F -r eti c ul o c yt e s. T h e T C D s h o ul d n ot b e 
d o n e wit hi n 2 m o nt h s of si m pl e or e x c h a n g e tr a n sf u si o n s .  T h e bl o o d dr a w s h o ul d pri oriti z e t h e C B C wit h 
diff er e nti al,  r eti c ul o c yt e c o u nt a n d q u a ntifi c ati o n of h e m o gl o bi n s, t h e n t h e L D H, F-c ell s, a n d F -r eti c ul o c yt e s.  
T hi s vi sit will al s o i n cl u d e e d u c ati o n a b o ut n e ur ol o gi c al c o m pli c ati o n s of si c kl e c ell di s e a s e a n d t h e r ati o n al e f or 
t h e st u d y. 
 
 
Vi sit 2  
If t h e p arti ci p a nt m e et s i n cl u si o n crit eri a, a s e c o n d vi sit will b e s c h e d ul e d, i n cl u di n g t h e e x a m b y a p e di atri c 
n e ur ol o gi st a n d n e ur o c o g niti v e a s s e s s m e nt, a s w ell a s t h e s e c o n d h o ur of e d u c ati o n a b o ut h y dr o x y ur e a a n d 
t h e st u d y.  Bl o o d f or D N A a n d t o m a k e tr a n sf or m e d l y m p h o c yt e s  f or t h e bi ol o gi c r e p o sit or y will b e dr a w n at t hi s 
ti m e ( s e e a p p e n di x 14 ).  Vi sit 1 a n d Vi sit 2  m a y b e c o m bi n e d or s plit i nt o a d diti o n al vi sit s.  
 
Vi sit 3  
T hi s vi sit will i n cl u d e t h e s e d at e d M RI of t h e br ai n, if t h e p arti ci p a nt still m e et s all eli gi bilit y r e q uir e m e nt s f or t h e 
st u d y, a n d a bl o o d dr a w f or a pr ot e o mi c s a m pl e ( s e e a p p e n di x 1 5 ).   Vi sit 3 ( a n d th e s e d at e d M RI f or r e s e ar c h) 
s h o ul d n ot o c c ur u ntil aft er all ot h er st u d y pr o c e d ur e s (fr o m Vi sit s 1 a n d 2) h a v e b e e n c o m pl et e d a n d t h e 
p arti ci p a nt  h a s b e e n c o nfir m e d t o  still b e eli gi bl e f or t h e st u d y . 
 
T h e sit e i n v e sti g at or c a n u s e a n M RI ( wit hi n 2 w e e k s of i nf or m e d c o n s e nt) or T C D ( wit hi n 6 w e e k s of c o n s e nt), 
if d o n e f or cli ni c al r e a s o n s a n d  if t h e M RI a n d T C D m e et s t h e q u alif yi n g crit eri a, a s j u d g e d b y t h e 
n e ur or a di ol o g y c o m mitt e e (f or M RI) a n d T C D r e a di n g c e nt er (f or t h e T C D).   N ot e t h at t h e cli ni c al T C D m u st b e 
b y t h e n o n -i m a gi n g t e c h ni q u e t o q u alif y. 
 
T h e p arti ci p a nt s h o ul d b e r a n d o mi z e d wit hi n 2 w e e k s of t h e M RI, if at all p o s si bl e, t o a v oi d t h e o c c urr e n c e of 
e n d p oi nt e v e nt s b ef or e tr e at m e nt i s i nit i at e d. 
 
5. 3  R a n d o mi z ati o n E v al u ati o n  
All p arti ci p a nt s will h a v e a C B C wit h diff er e nti al, r eti c ul o c yt e c o u nt, c o m pr e h e n si v e p a n el  (if n ot o bt ai n e d i n t h e 
l a st 2 w e e k s f or t h e C B C wit h diff er e nti al a n d r eti c ul o c yt e c o u nt or l a st 8 w e e k s f or c o m pr e h e n si v e p a n el ) at 
t h e ti m e of r a n d o mi z ati o n a n d st art t h e st u d y tr e at m e nt t h e s a m e d a y.  If bl o o d f or t h e D N A or pr ot e o mi c 
s p e ci m e n s c o ul d n ot b e o bt ai n e d o n pr e vi o u s vi sit s, it m a y b e o bt ai n e d at t hi s ti m e.  
 
5. 4 P o st -R a n d o mi z ati o n E v al u ati o n s  
T h e f oll o wi n g e v al u ati o n s will b e r e q uir e d at e a c h cli ni c al c e nt er f or all p arti ci p a nt s 2 w e e k s aft er a d o s e 
i n cr e a s e of t h e st u d y m e di c ati o n: 
C B C wit h diff er e nti al, r eti c ul o c yt e c o u nt  
 
T h e f oll o wi n g e v al u ati o n s will b e r e q uir e d e v er y  4 w e e k s at e a c h cli ni c al c e nt er f or all p arti ci p a nt s:  
Hi st or y a n d p h y si c al e x a m , i n cl u di n g w ei g ht, l e n gt h, bl o o d pr e s s ur e, r e s pir at or y r at e, h e art r at e, 
t e m p er at ur e, a n d p ul s e o xi m etr y 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 2 1  of 7 4  
M o difi e d M ori s k y, r e vi e w of mi s s e d, s pill e d, or ot h er wi s e l o st d o s e s, a n d w ei g hi n g of t h e r et ur n e d st u d y 
m e di c ati o n  
C B C wit h diff er e nti al, r eti c ul o c yt e c o u nt, pr ot e o mi c s s p e ci m e n.  
A 3 w or ki n g d a y wi n d o w o n eit h er si d e i s all o w a bl e f or t h e e v er y 4 w e e k vi sit s ( 2 5 -3 1 d a y s aft er t h e l a st 
vi sit )  
 
T h e f oll o wi n g e v al u ati o n s will b e r e q uir e d e v er y 3 m o nt h s at e a c h cli ni c al c e nt er f or all p arti ci p a nt s:  
C o m pr e h e n si v e p a n el, L D H,  h e m o gl o bi n el e ctr o p h or e si s a n d q u a ntifi c ati o n of H b F , H b S , H b A a n d 
ot h er h e m o gl o bi n s , a n d F- c ell s  
 
T h e f oll o wi n g st u di e s will  b e p erf or m e d a n n u all y o n all p arti ci p a nt s:  
N e ur ol o gi c al e x a mi n ati o n b y p e di atri c n e ur ol o gi st  
C o g niti v e e v al u ati o n b y a n e ur o p s y c h ol o gi st  
M RI of t h e br ai n  
T C D  
F- r eti c ul o c yt e s  
A 4 w e e k  wi n d o w o n eit h er si d e i s all o w a bl e f or a n n u al e v al u ati o n s ( u si n g t h e r a n d o mi z ati o n d at e a s 
ti m e 0) 
 
 
If a p arti ci p a nt  r e c ei v e s a cli ni c al M RI of t h e br ai n  ( n ot st u d y m a n d at e d) d uri n g t h e c o ur s e of t h e st u d y, it 
s h o ul d b e s u b mitt e d t o C R L  f or r e vi e w b y t h e N e ur or a di ol o g y C o m mitt e e. 
 
5. 5  E n d of st u d y pr o c e d ur e s:  
Aft er 3 y e ar s of t h er a p y, or i n t h e e v e nt of a n e n d p oi nt, t h e a n n u al vi sit pr o c e d ur e s will b e r e p e at e d , wit h a fi n al 
p hl e b ot o m y of 1 0 ml of v e n o u s bl o o d  f or t h e bi or e p o sit or y. 
 
5. 6   E v al u ati o n s f or p ar e nt s/ c ar e gi v er s  
E d u c ati o n  
P ar e nt s/ c ar e gi v er s will p arti ci p at e i n a si c kl e c ell di s e a s e e d u c ati o n pr o gr a m i n t h e pr e -r a n d o mi z ati o n p h a s e of 
t hi s st u d y.  T hi s pr o gr a m will i n cr e a s e t h eir k n o wl e d g e of si c kl e c ell di s e a s e ( S C D) a n d it s c o m pli c ati o n s, 
r e vi e w s c h o ol r el at e d pr o bl e m s i n c hil dr e n wit h S C D, t e a c h i d e ntifi c ati o n a n d m a n a g e m e nt of o v ert str o k e, 
a b n or m al T C D, di s c u s s sil e nt c er e br al i nf ar ct a n d t h e e x pl a n ati o n of it s i m p a ct o n t h e e d u c ati o n al a n d 
v o c ati o n al att ai n m e nt f or c hil dr e n wit h si c kl e c ell di s e a s e, a n d d e s cri b e t h e ri s k s a n d b e n efit s of tr e at m e nt wit h 
h y dr o x y ur e a i n c hil dr e n wit h S C D. T h e s e s e s si o n s will o c c ur d uri n g t w o r e g ul arl y s c h e d ul e d st u d y vi sit s.  
 
B e h a vi or al S c al e s  
P ar e nt s/ C ar e gi v er s will c o m pl et e b e h a vi or s c al e s a b o ut t h eir c hil dr e n , i n cl u di n g t h e A B A S-II ( all a g e s, B RI E F-
P ( 2 - 5. 9 9 y e ar s ol d), a n d B RI E F ( > 6 y e ar s ol d), d e p e n di n g o n t h e a g e of t h e c hil d.  
 
A d h er e n c e  
P ar e nt s/ C ar e gi v er s will c o m pl et e t h e M o difi e d M ori s k y S c al e t o e v al u at e m e di c ati o n a d h er e n c e , a s w ell a s 
pr o vi di n g i nf or m ati o n o n mi s s e d, l o st, or s pill e d d o s e s of t h e st u d y m e di c ati o n.  
 
5. 7 St u d y e xit e v al u ati o n s f or all p arti ci p a nt s  
 
M RI of br ai n  
 
T C D  
 
C o g niti v e a n d b e h a vi or al a s s e s s m e nt  
 
Hi st or y a n d p h y si c al  
 
N e ur ol o gi c al A s s e s s m e nt  
 
C B C wit h diff er e nti al, r eti c ul o c yt e s, c o m pr e h e n si v e p a n el, L D H, q u a ntifi c ati o n of H b F , H b S , H b A,  a n d 
ot h er h e m o gl o bi n s , F- c ell s, a n d F -r eti c ul o c yt e s 
 
D e m o gr a p hi c/ p h e n ot y pi c e xit f or m   
 
O bt ai n bl o o d f or t h e bi ol o gi c r e p o sit or y f or pr ot e o mi c st u di e s  


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 2 2  of 7 4  
 
5. 8  Pr o c e d ur e f or mi s s e d a p p oi nt m e nt s  
I n t h e c a s e of a p arti ci p a nt mi s si n g a n a p p oi nt m e nt, t h e st u d y n ur s e s h o ul d i m m e di at el y att e m pt t o c o nt a ct t h e 
p arti ci p a nt ’ s c ar e gi v er b y t el e p h o n e, t o d et er mi n e w h y t h e a p p oi nt m e nt w a s mi s s e d a n d r e s c h e d ul e it.  All 
c o nt a ct att e m pt s, e v e n u n s u c c e s sf ul, s h o ul d b e r e c or d e d i n t h e cli ni c r e c or d.  W h e n c o nt a ct i s e st a bli s h e d, t h e 
r e a s o n w h y t h e a p p oi nt m e nt w a s mi s s e d s h o ul d b e r e c or d e d i n t h e cli ni c r e c or d.  A m a k e-u p a p p oi nt m e nt 
s h o ul d b e s c h e d ul e d a s pr o m ptl y a s p o s si bl e. I n c a s e s w h er e n o n -c o m pli a n c e i s b e c o mi n g a n i s s u e t h at will  
i m p a ct t h e p arti ci p a nt ’ s w ell-b ei n g a n d d at a, w e i n vit e t h e i n v e sti g at or or c o or di n at or t o c o nt a ct t h e St u d y C h air 
or Vi c e C h air , t o a s si st t h e sit e i n cr e ati v e w a y s t o i m pr o v e c o m pli a n c e.  W e d efi n e n o n -c o m pli a n c e a s mi s si n g 
t w o a p p oi nt m e nt s i n a r o w, or t w o a p p oi nt m e nt s i n a f o ur-m o nt h p eri o d.  
 
5. 9 
A d dr e s si n g N e w M RI T e c h n ol o g y:  
If d uri n g t h e c o ur s e of t h e tri al, u p gr a d e s t o a 3. 0 T e sl a M RI s c a n n er fr o m a 1. 5 T e sl a s c a n n er ar e pl a n n e d at a 
sit e a n d a  1. 5 T e sl a s c a n n er i s n o l o n g er a c c e s si bl e, a n a d diti o n al t w o M RI s c a n s will b e r e q uir e d: o n e M RI 
s c a n o n t h e 1. 5 T e sl a s c a n n er b ef or e it i s di s c o nti n u e d, f oll o w e d wit hi n 3 m o nt h s b y a n a d diti o n al M RI s c a n o n 
t h e 3. 0 T e sl a s c a n n er.  T h e s e e xtr a M RI s c a n s will o nl y b e o bt ai n e d if s e d ati o n i s n ot r e q uir e d s o a s t o 
mi ni mi z e ri s k t o t h e p arti ci p a nt.  T h e n e ur or a di ol o g y c o m mitt e e will u s e t h e s e i nt eri m 1. 5 & 3. 0 T e sl a s c a n s t o 
c o m p ar e t o t h e st u d y e xit M RI ( al s o c o m pl et e d o n a 3. 0 T e sl a s c a n n er) , t o d et er mi n e w het h er pr o gr e s si o n h a s 
o c c urr e d fr o m t h e b a s eli n e s c a n.  T hi s will n ot b e n e c e s s ar y f or sit e s t h at u s e a 3 T e sl a s c a n n er f or all 
i m a gi n g, t h e pr ef err e d fi el d str e n gt h f or n e ur oi m a gi n g of t hi s st u d y. 
 
6. 0  S E D A TI O N O F C HI L D R E N WI T H S C D  
M RI of t h e br ai n i s t h e o nl y pr e s e ntl y a v ail a bl e m et h o d t o d et e ct S CI.  F or c hil dr e n wit h t h e gr e at e st 
i n ci d e n c e of S CI (l e s s t h a n 5 y e ar s ol d), M RI u s u all y r e q uir e s s e d ati o n.  N o st a n d ar d a p pr o a c h f or s e d ati o n 
of t hi s p o p ul ati o n e xi st s, li miti n g a c c e s si bilit y f or s cr e e ni n g f or S CI i n t h e gr o u p wit h t h e hi g h e st ri s k.  At 
s o m e m e di c al c e nt er s, h e m at ol o gi st s a n d a n e st h e si ol o gi st s el e ct t o tr a n sf u s e r e d bl o o d c ell s t o all p ati e nt s 
wit h S C D pri or t o a n y s e d ati o n, i n a n eff ort t o d e cr e a s e t h e r at e of c o m pli c ati o n s; h o w e v er, m a n y c e nt er s d o 
n ot a d mi ni st er tr a n sf u si o n s f or all s e d ati o n pr o c e d ur e s.  I n a r e c e nt s ur v e y of 2 1 of 2 5 SI T Tri al C e nt er 
I n v e sti g at or s, t h e m aj orit y i n di c at e d t h at tr a n sf u si o n w a s n ot gi v e n b ef or e all or s o m e M RI s r e q uiri n g 
s e d ati o n.  At J o h n s H o p ki n s a n d W a s hi n gt o n U ni v er siti e s, w e e v al u at e s u c h p ati e nt s o n a c a s e b y c a s e 
b a si s. B a s e d o n d at a fr o m o ur c o -i n v e sti g at or ( J. K wi at o w k si at C H O P) s u p p orti n g t h e s af et y of a str u ct ur e d 
pr ot o c ol f or p ati e nt s el e cti o n a n d s e d ati o n wit h o ut a nt e c e d e nt tr a n sf u si o n i n o v er 6 0  c hil dr e n, w e b eli e v e 
t h at it i s r e a s o n a bl e t o i m pl e m e nt a st a n d ar di z e d pr ot o c ol f or s e d ati o n at ot h er c e nt er s.  D e m o n str ati n g t h at 
M RI s wit h s e d ati o n c a n b e s af el y o bt ai n e d wit h o ut tr a n sf u si o n will gr e atl y i n cr e a s e t h e f e a si bilit y of 
s cr e e ni n g f or S CI i n t h e a g e gr o u p wit h t h e hi g h e st r at e of S CI.  E arl y d et e cti o n of S CI i s criti c al, a s 
a d diti o n al e d u c ati o n al s er vi c e s, e v e n i n pr e -s c h o ol, c a n b e m a n d at e d b y f e d er al l a w.  A s u c c e s sf ul 
d e m o n str ati o n t h at s e d ati o n wit h o ut tr a n sf u si o n u si n g o ur pr ot o c ol a n d pr o c e d ur e s i s s af e w o ul d pr o vi d e 
n e c e s s ar y i nf or m ati o n t o c o n d u ct a d efi niti v e p h a s e III tri al.  It w o ul d al s o pr o vi d e i nf or m ati o n t h at c o ul d b e 
a p pli e d t o ot h er pr o c e d ur e s a n d r e d u c e t h e u s e of tr a n sf u si o n s a n d t h eir a s s o ci at e d ri s k s.  
 
W e ar e a c ut el y a w ar e of t h e i n cr e a s e d ri s k of s e d ati o n i n p ati e nt s wit h S C D a n d t h at a d e at h o c c urr e d 
d uri n g s e d ati o n/ a n e st h e si a f or a r e s e ar c h M RI i n t h e B A B Y H U G st u d y.  O ur pr ot o c ol f or s e d ati o n h a s b e e n 
d e si g n e d t o mi ni mi z e t h e s e ri s k s; s p e cifi c all y, c hil dr e n wit h r e c e nt r e s pir at or y ill n e s s e s a n d ot h er ri s k f a ct or s 
will n ot u n d er g o s e d ati o n.  T hi s w o ul d h a v e e x cl u d e d t h e i nf a nt w h o di e d i n t h e B A B Y H U G st u d y fr o m o ur 
tri al.  T h er e will b e s e v er al a d diti o n al diff er e n c e s fr o m t h e B A B Y H U G st u d y: 1) O ur s ed ati o n t e a m of 
a n e st h e si ol o gi st s h a v e d efi n e d a ri g or o u s s et of crit eri a a n d pr ot o c ol s t o mi ni mi z e ri s k s a s s o ci at e d wit h 
s e d ati o n;  2) T h e sit e s will b e e x p e ct e d t o a d h er e t o t h e g ui d eli n e s f or s e d ati o n t h at ar e i n cl u d e d i n 
A p p e n di c e s 1 2 a n d 1 3.  A n y  sit e t e a m wi s hi n g t o u s e a l o c al pr ot o c ol d eri v e d fr o m t h e s e g ui d eli n e s will b e 
r e q uir e d t o  h a v e t h eir s e d ati o n pr ot o c ol r e vi e w e d c e ntr all y a n d a p pr o v e d pri or t o st arti n g e nr oll m e nt; a n d 3) 
T h e S e d ati o n C o m mitt e e will c o nti n u e t o r e vi e w t h e s e d ati o n pr ot o c ol s a n d r e c or d s a n d b e a v ail a bl e t o 
a d dr e s s a n y A E or S A E a s s o ci at e d wit h s e d ati o n .  
 
T h e  a d mi ni str ati o n of a n e st h eti c s a n d s e d ati v e s t o p ati e nt s wit h S C D i s c o ntr o v er si al a n d t h er e i s n ot 
c o n si st e nt a gr e e m e nt a m o n g st a n e st h e si ol o gi st s or h e m at ol o gi st s a s t o t h e b e st a p pr o a c h. T h e f oll o wi n g 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 2 3  of 7 4  
a s pir e s t o b e st pr a cti c e pri n ci pl e s w hi c h c e nt er o n cl e ar a n d c o n si st e nt c o m m u ni c ati o n b et w e e n t h e v ari o u s 
pr o vi d er s fr o m h e m at ol o g y, a n e st h e si ol o g y a n d t h e s e d ati o n t e a m a n d, m o st i m p ort a ntl y, wit h t h e f a mil y. 
T h e s e g ui d eli n e s w er e r e vi e w e d a n d a p pr o v e d b y t h e S e d ati o n C o m mitt e e f or t h e H U Pr e v e nt Tri al a n d ar e 
i nt e n d e d t o pr o vi d e a mi ni m al  st a n d ar d of  s af et y. T h e a ct u al m a n a g e m e nt of p arti ci p a nt s s h o ul d b e 
i n di vi d u ali z e d a s n e c e s s ar y, wit h t h e s af et y of t h e p arti ci p a nt  b ei n g t h e hi g h e st pri orit y at all ti m e s; h o w e v er, 
t h e u s e of pr o p of ol  a s t h e pri m ar y a g e nt s f or s e d ati o n/ a n e st h e si a, t h e e x cl u si o n crit eri a a n d mi ni m u m 
r e q uir e m e nt s, s u c h a s d ur ati o n of N P O a n d b a s eli n e o x y g e n s at ur ati o n s h o ul d b e a d h er e d t o stri ctl y.  T h e s e 
r e q uir e m e nt s m a y al s o b e e x c e e d e d ( e. g., l o n g er d ur ati o n s of N P O) b a s e d o n l o c al j u d g m e nt s. 
 
T h e c hil dr e n e nr oll e d f or i m a gi n g will b e pr e -s cr e e n e d b ef or e t h e y r e c ei v e s e d ati o n f or a n M RI, a s t h e g o al of 
t hi s pr ot o c ol i s t o pr o vi d e t h e s af e st e n vir o n m e nt f or t h e s e c hil dr e n, mi ni m al di sr u pti o n f or t h e p ar e nt s a n d 
c o n si st e nt c ar e wit h r ar e c a n c ell ati o n s. C hil dr e n wit h S C D m a y h a v e h a d r e c urr e nt h o s pit ali z ati o n s a n d b e 
w ar y of c ar e pr o vi d er s; t h e y m a y al s o h a v e h a d m a n y pr e vi o u s i ntr a v e n o u s ( I V) c at h et er s a n d p o or v a s c ul ar 
a c c e s s. T h e c hil dr e n will b e c ar e d f or i n a w ar m a n d s u p p orti v e m a n n er a n d t h e M RI, it s i n di c ati o n a n d t h e 
p er s o n r e q u e sti n g it s h o ul d b e c o nfir m e d wit h t h e p ar e nt or g u ar di a n.  
 
O bt ai ni n g a n M RI of t h e br ai n  i s c o n si d er e d a r e s e ar c h pr o c e d ur e at s o m e sit e s; h o w e v er, t h e s e d ati o n 
pr o c e d ur e s pl a n n e d f or t hi s st u d y ar e st a n d ar d of c ar e, b a s e d o n t h e e x p eri e n c e of m a n y c e nt er s a n d t h e 
o v er w h el mi n g m aj orit y of i n v e sti g at or s i n t h e SI T Tri al.  T h e d et ail e d c oll e cti o n of i nf or m ati o n o n  t h e MRI s a n d 
s e d ati o n i n t hi s pr ot o c ol i s f or s af et y, b ut s h o ul d h el p s et a st a n d ar d f or s e d ati o n of p ati e nt s wit h S C D i n r o uti n e 
pr a cti c e.   
 
F or t h e d et ail e d d e s cri pti o n  of t h e H U Pr e v e nt s e d ati o n pr o c e s s f or M RI s i n c hil dr e n, pl e a s e s e e A p p e n di x 1 2 .   
 
7. 0  
I M A GIN G C E N T E R A N D N E U R O R A DI O L O G Y G UI D E LI N E S   
  
  
  
 
P arti ci p a nt s wit h h e m o gl o bi n S S or h e m o gl o bi n S β°  1 2  t o 5 4 m o nt h s of a g e wit h o ut e vi d e n c e of o v ert str o k e 
will b e s cr e e n e d f or t h e pr e s e n c e of a q u alif yi n g i nf ar ct -li k e l e si o n u si n g M RI.   
 
T h e I m a gi n g C e nt er will pr o vi d e sit e s wit h a pr o c e d ur e m a n u al wit h st a n d ar di z e d a c q ui siti o n g ui d eli n e s a n d 
pr o c e d ur e s f or h a n dli n g of i m a gi n g d at a. T h e I m a gi n g C e nt er will c oll e ct i m a g e s i n dir e ct di git al f or m.  E a c h 
sit e will o bt ai n d e -i d e ntifi e d i m a g e s fr o m t h eir r a di ol o g y d e p art m e nt or u s e st u d y-pr o vi d e d s oft w ar e t o d e -
i d e ntif y t h e i m a g e s et s. P arti ci p a nt d e m o gr a p hi c i nf or m ati o n will b e r e m o v e d a n d r e pl a c e d wit h t h e st u d y 
a s si g n e d p arti ci p a nt i d e ntifi er a n d sit e -a s si g n e d 3 l ett er p arti ci p a nt c o d e. T h e s e d e -i d e ntifi e d i m a g e s will b e 
tr a n s mitt e d t o t h e I m a gi n g C e nt er u si n g a s e c ur e HI P P A c o m pli a nt I R B a c c e pt a bl e m et h o d, e n cr y pt e d V P N 
c o n n e cti o n (f or t h o s e c e nt er s alr e a d y wit h t hi s c a p a cit y fr o m t h e SI T Tri al, a s e c ur e d fil e s h ari n g s er vi c e, or b e 
s e nt b y e x pr e s s m ail o n di git al m e di a). Sit e s will c o m pl et e a n i m a g e tr a c ki n g w or k s h e et t h at m at c h e s e a c h 
DI C O M s eri e s pr o d u c e d b y t h e M R d e vi c e t o o n e of t h e p ul s e s e q u e n c e s i d e ntifi e d i n t h e i m a gi n g pr ot o c ol. 
T h e I m a gi n g C e nt er will r e vi e w a n d c o nfir m t h e q u alit y of all i m a g e s u p o n r e c ei pt ar e a c c e pt a bl e a n d will 
c o m m u ni c at e r e c ei pt of all i n c o mi n g d at a t o t h e cli ni c al c e nt er, t h e Pri n ci p al I n v e sti g at or, Vi c e C h air, D at a 
C o or di n ati n g C e nt er, a n d t h e Sit e I n v e sti g at or.  P arti ci p a nt i d e ntifi er, p arti ci p a nt c o d e, st u d y d at e a n d st u d y 
ti m e o n t h e i m a g e s will b e c o m p ar e d wit h t h e a c c o m p a n yi n g f or m s a n d i m a gi n g w or k s h e et f or c o n si st e n c y.  
T h e Pri n ci p al I n v e sti g at or a n d I m a gi n g C e nt er will e n s ur e t h at a n y c o nfi d e nti al i nf or m ati o n h a s b e e n m a s k e d.   
 
W h e n i m a g e s ar e r e c ei v e d at t h e C R L t h e y will u n d er g o s e c ur e pr o c e s si n g i m m e di at el y a n d  tr a n sf er i m a g e s 
o nt o i m a g e r e vi e w w or k st ati o n a n d c o nfir m i m a g e q u alit y a n d d at a c o m pl et e n e s s o n a di a g n o sti c w or k st ati o n. 
T h e I m a gi n g C e nt er will m a n a g e t h e c e ntr ali z e d di git al i m a g e ar c hi v e, st u d y d at a b a s e, a n d b a c k -u p st or a g e. 
T h e I m a gi n g C e nt er p er s o n n el will d et er mi n e w h et h er i m a g e s ar e e v al u a bl e f or p ur p o s e s of t h e st u d y.  I n t h e 
e v e nt t h at a pr o bl e m wit h a n i m a gi n g st u d y i s i d e ntifi e d, t h e sit e will b e n otifi e d i m m e di at el y a b o ut t h e n a t ur e of 
a n y pr o bl e m s a n d t h e st e p s r e q uir e d f or c orr e cti v e a cti o n.  
T h e I m a gi n g C e nt er will pr o vi d e di git al i m a g e s a n d el e ctr o ni c C a s e R e p ort F or m s ( e C R F) t o t h e t hr e e -st u d y 
n e ur or a di ol o gi st s ( n e ur or a di ol o g y p a n el m e m b er s). T h e n e ur or a di ol o g y p a n el will p erf or m t h e e v al u ati o n of t h e 
i m a g e s f or eli gi bilit y s cr e e ni n g a n d a n al y si s of e nr oll e d p arti ci p a nt s.  T h e pr e s e n c e or a b s e n c e of c er e br al 
i nf ar ct s will b e gr a d e d a c c or di n g t o a 3-p oi nt c o nfi d e n c e s c al e. T h e n e ur or a di ol o g y p a n el will b e bli n d e d t o 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 2 4  of 7 4  
tr e at m e nt, p arti ci p a nt d e m o gr a p hi c s a n d cli ni c al hi st or y ( ot h er t h a n hi st or y of si c kl e c ell a n e mi a).  T h e y will 
e nt er t h eir fi n al e v al u ati o n s i nt o e C R F s.  
 
T h e I m a gi n g C e nt er will f or w ar d t h e fi n al i m a gi n g e v al u ati o n d at a t o t h e Pri n ci p al I n v e sti g at or, D e p ut y Dir e ct or, 
a n d t h e D at a C o or di n ati n g C e nt er w e e kl y.  D at a c o n c er ni n g p arti ci p a nt eli gi bilit y a n d n e e d f or r ef err al will b e 
tr a n s mitt e d t o t h e Pri n ci p al I n v e sti g at or i m m e di at el y. 
 
7. 1  
I m a gi n g C e nt er 
A k e y c o m p o n e nt of t h e I m a gi n g C e nt er i s t h e Cli ni c al R e s e ar c h L a b or at or y ( C R L) l o c at e d at M alli n c kr o dt 
I n stit ut e of R a di ol o g y, W a s hi n gt o n U ni v er sit y, i n St. L o ui s, M O.  T h e C R L will pr o vi d e s e c ur e offi c e s p a c e f or 
t h e st u d y a n d h a s a c c e s s t o all f a ciliti e s a n d r e s o ur c e s n e c e s s ar y t o s u c c e s sf ull y m a n a g e H U Pr e v e nt i m a gi n g 
a cti viti e s. T h e C R L i s c o nfi g ur e d wit h n e w q u a ntit ati v e i m a gi n g a n al y si s t e c h ni q u e s al o n g wit h i m a gi n g I T 
s y st e m s n e c e s s ar y t o s u p p ort q u a ntit ati v e i m a gi n g. . T h e C R L will u s e a c o m m er ci all y a v ail a bl e i m a g e-
pr o c e s si n g s uit e of s oft w ar e  pr o gr a m s f or s e c ur e i m a g e a cti viti e s.     
 
T h e I m a gi n g C e nt er will c u st o mi z e a pr o c e d ur e m a n u al f or it s c or e -i m a gi n g l a b or at or y t o s u p p ort t h e st u d y.  
T h e pr o c e d ur e m a n u al will pr o vi d e t h e i m a gi n g c e nt er st aff wit h g ui d eli n e s f or p erf or mi n g q u alit y a s s ur a n c e 
c h e c k s o n t h e r e c ei v e d c a s e s a n d o n h a n dli n g i m a g e d at a.  All sit e i n v e sti g at or s will r e c ei v e writt e n 
d o c u m e nt ati o n f or m a n a gi n g t h e i m a g e -pr o c e s si n g t e c h n ol o g y.   
 
F or d et ail e d di s c u s si o n of I m a gi n g C e nt er pr o c e s s f or M RI a n d T C D pr ot o c ol, pl e a s e s e e A p p e n di c e s 1 0  a n d 
1 1 .  W e will u s e m o difi c at i o n s of t h e i m a gi n g pr ot o c ol s f or M RI a s t h e M ulti c e nt er Sil e nt I nf ar ct Tr a n sf u si o n 
Tri al ( SI T T) f u n d e d b y NI N D S ; f or T C D , w e will u s e t h e s a m e pr ot o c ol a s t h e S T O P II st u d y f u n d e d b y N H L BI  
gr a nt 2 U O 1 H L 5 2 1 9 3 -0 6 1 A.   
 
7 . 2 
D efi niti o n of a n I nf ar ct-Li k e L e si o n  
A n i nf ar ct -li k e l e si o n i s a n M RI si g n al a b n or m alit y vi si bl e o n t w o vi e w s o n t h e T 2 w ei g ht e d i m a g e s. T h e si g n al 
a b n or m alit y m u st m e a s ur e at l e a st 3 m m i n o n e  di m e n si o n.  T h e l e si o n m u st b e i n d e p e n d e ntl y d et er mi n e d t o 
b e n e ur ol o gi c all y sil e nt b y t h e n e ur ol o g y c o m mitt e e.  T h e d efi niti o n of a sil e nt i nf ar ct i n cl u d e s t h e pr e s e n c e of a 
sil e nt i nf ar ct - li k e l e si o n b a s e d, o n t h e r e vi e w of t w o of t h e t hr e e st u d y n e ur or a di ol o gi st s a n d a n or m al 
n e ur ol o gi c e x a mi n ati o n or a n a b n or m alit y o n n e ur ol o gi c e x a m t h at c a n n ot b e e x pl ai n e d b y t h e l o c ati o n of t h e 
M RI l e si o n.  T hi s d efi niti o n of sil e nt c er e br al i nf ar ct i s o p er ati o n all y t h e s a m e a s t h at u s e d i n t h e St. L o ui s 
C hil dr e n’ s H o s pit al/ W a s hi n gt o n U ni v er sit y S c h o ol of M e di ci n e Str o k e St u d y Gr o u p, 4 6  t h e SI T Tri al, a s w ell a s 
t h e d efi niti o n u s e d i n m ulti pl e C o o p er ati v e St u d y of Si c kl e C ell Di s e a s e ( C S S C D ) st u di e s.  
 
7 . 3  
I nt er pr et ati o n of M RI St u di e s  
A p a n el c o n si sti n g of t hr e e n e ur or a di ol o gi st s ( R o b ert C. M c Ki n str y, III, M D, P h D, W a s hi n gt o n U ni v er sit y S c h o ol 
of M e di ci n e, Mi c h a el Kr a ut, M D, P h D, J o h n s H o p ki n s U ni v er sit y S c h o ol of M e di ci n e, a n d D e n ni s S h a w , M D, 
S e attl e C hil dr e n’ s H o s pit al ) will p erf or m t h e e v al u ati o n of i m a g e s f or b ot h eli gi bilit y s cr e e ni n g a n d a n al y si s of 
i m a gi n g fr o m e nr oll e d p arti ci p a nt s, i n cl u di n g t h o s e wit h a s u s p e ct e d or c o nfir m e d e v e nt.  
T h e n e ur or a di ol o gi st i n c oll a b or ati o n wit h t h e I m a gi n g C e nt er will d e v el o p a r ef er e n c e s et s h o wi n g e x a m pl e s of 
t h e v ari o u s di a g n o sti c crit eri a u s e d i n i nt er pr et ati o n pri or t o t h e st art of t h e st u d y.  T h e n e ur or a di ol o gi st s will b e 
r e s p o n si bl e f or b ot h a q u alit ati v e a n d q u a ntit ati v e a s s e s s m e nt of t h e i m a g e s.   T h e q u alit ati v e a s s e s s m e nt will 
b e b a s e d o n t h e pr e s e n c e or a b s e n c e of n e w c er e br al i nf ar ct s a n d will b e o n a 3 -p oi nt c o nfi d e n c e s c al e 
( 1 = d efi nit el y n ot pr e s e nt, 2 =i n d et er mi n at e, 3 = d efi nit el y pr e s e nt).  T hi s i s t h e s a m e d efi niti o n t h at w a s u s e d b y 
t h e C S S C D d e m o n str ati n g a 2 4 % i n cr e a s e i n t h e i n ci d e n c e of sil e nt c er e br al i nf ar ct s i n c hil dr e n wit h sil e nt 
c er e br al i nf ar ct s o v er 4. 8 y e ar s. 4 7   E a c h n e ur or a di ol o gi st will i n d e p e n d e ntl y a s s e s s a n d r e c or d t h e pr e s e n c e of 
a sil e nt c er e br al i nf ar ct li k e l e si o n( s).  W h e n t h er e i s c o m pl et e a gr e e m e nt, t h er e i s n o  n e e d f or a di s c u s si o n.  
W h e n t h er e i s di s c or d a n c e a  c o n s e n s u s c all will b e h el d a n d a m aj orit y v ot e will d e ci d e t h e st at u s of t h e 
p arti ci p a nt  a s t o t h e pr e s e n c e or a b s e n c e of a sil e nt i nf ar ct li k e l e si o n.  T h e fi n al d e ci si o n will b e b a s e d o n a 
c o n s e n s u s.  Q u art erl y ( c al e n d ar y e ar) m o nit ori n g c o m p ari n g c o n s e n s u s d e ci si o n wit h t h e i n d e p e n d e nt r e vi e w 
will b e c o m pl et e d b y D at a  C o or di n ati n g C e nt er .   
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 2 5  of 7 4  
All M RI e x a mi n ati o n s will b e a s s e s s e d f or pr e s e n c e of a n a b n or m alit y , i n cl u di n g pr e s e n c e of i nf ar cti o n, i nf ar ct 
l o c ati o n s, n u m b er of i nf ar ct s, si z e i n milli m et er s a n d si g nifi c a nt c oi n ci d e nt al fi n di n g s. T h e q u a ntit ati v e 
a s s e s s m e nt of t h e s cr e e ni n g M RI b y t h e n e ur or a di ol o gi st s will c o n si st of i n d e p e n d e nt m e a s ur e m e nt of t h e 
gr e at e st li n e ar di m e n si o n of e a c h i nf ar ct -li k e l e si o n.  At t h e ti m e of t h e c o n s e n s u s c all, t h e n e ur or a di ol o gi st s 
will s el e ct b y c o n s e n s u s t h e b e st m e a s ur e m e nt of t h e t hr e e f or  p o sti n g fi n al d at a t o t h e d at a b a s e.  
 
B a s eli n e M RI i m a g e s will b e c o m p ar e d si d e -t o-si d e t o all s u b s e q u e nt M RI i m a g e s , t o e st a bli s h if t h er e h a s 
b e e n n e w c er e br al i nf ar cti o n.  All ti m e -p oi nt s f or e nr oll e d p arti ci p a nt s will b e r e a d b y all t hr e e r e vi e w er s.    
 
7 . 4 
Q u alit y A s s ur a n c e f or M RI E x a mi n ati o n  
Pri or t o c o m m e n c e m e nt of s cr e e ni n g M RI s, e a c h n e ur or a di ol o gi st will p arti ci p at e i n a s cr e e ni n g tr ai ni n g a n d 
t e sti n g pr o gr a m d e v el o p e d b y t h e I m a gi n g C e nt er.  T h e i m a g e a n al y si s q u alit y a s s ur a n c e pr o gr a m i n cl u d e s 
t w o c o m p o n e nt s: 1) i niti al tr ai ni n g; 2) i nt er-o b s er v er v ari a bilit y t e sti n g.  E a c h r e a d er will t h e n i n d e p e n d e ntl y 
e v al u at e a s e c o n d s et of 1 0 M RI s c a n s i n c o n s e n s u s f a s hi o n.   I nt er -o b s er v er v ari a bilit y will b e a s s e s s e d a n d 
t h e d e gr e e of v ari a bilit y m u st n ot e x c e e d a pr e d efi n e d t hr e s h ol d.  T h e Pri n ci p al I n v e sti g at or  a n d C h air of t h e 
N e ur or a di ol o g y C o m mitt e e will a gr e e u p o n t h e e x a ct p ar a m et er s t o b e a s s e s s e d a n d t h e t hr e s h ol d t o b e s et.  If 
t h e r e a d er s e x c e e d t h e t hr e s h ol d, t h e n r e-tr ai ni n g will b e r e q uir e d.   
 
7 . 5  
I m a g e Ar c hi vi n g 
T h e I m a gi n g C e nt er will m ai nt ai n a c e ntr ali z e d i m a g e ar c hi v e t h at will c o nt ai n e v er y i m a g e r e c ei v e d fr o m t h e 
cli ni c al i n v e sti g at or s f or t h e cli ni c al tri al. T h e I m a gi n g C e nt er will pr o vi d e i m a g e s t h at m a y b e u s e d f or s ci e ntifi c 
pr e s e nt ati o n s or p u bli c ati o n s. M e a s ur e m e nt s ar e al s o st or e d s o t h at t hi s d at a m a y b e a u dit e d , if n e c e s s ar y.  All 
st u d y d at a, a s w ell a s s u p p orti n g d o c u m e nt ati o n a n d a d mi ni str ati v e r e c or d s, will b e r et ai n e d f or a p eri o d of 
ti m e m ut u all y a gr e e d u p o n. 
 
7 . 6 
S e c urit y of D at a  
All i m a gi n g d at a will b e m ai nt ai n e d i n a s e c ur e e n vir o n m e nt.  I n cr e m e nt al b a c k -u p s of t h e st u d y d at a b a s e will 
b e p erf or m e d o n a ni g htl y b a si s.  C o m pl et e b a c k -u p s ar e p erf or m e d o n a w e e kl y b a si s.  D u pli c at e s y st e m 
b a c k -u p t a p e s will b e st or e d i n a s e c ur e, o ff-sit e f a cilit y.  A c c e s s t o t h e s y st e m will b e c o ntr oll e d b y p a s s w or d 
pr ot e cti o n.   
 
7. 7 
M a s ki n g Pr o c e d ur e s  
Aft er e a c h fil m i s r e a d a c c or di n g t o t h e pr e s cri b e d pr ot o c ol o utli n e d a b o v e, e a c h r a di ol o gi st will r e c or d t h e 
fi n di n g s o n a C R F.   E a c h r a di ol o gi st  will b e u n a w ar e of t h e r e s ult s of cli ni c al hi st or y ( ot h er t h a n hi st or y of 
si c kl e c ell a n e mi a), n e ur ol o gi c al e x a mi n ati o n a n d ot h er i m a gi n g st u di e s ( s u c h a s C T or T C D).  A si d e -b y -si d e 
c o m p ari s o n of t h e pr e -r a n d o mi z ati o n M RI will b e m a d e t o t h e e xit M RI e x ami n ati o n.  
 
7. 8   
R ei n s erti o n St u di e s  
 
T o m o nit or a s s e s s m e nt of t h e M RI r e a di n g s, 1 0 % of pr e vi o u sl y r e a d st u di e s will b e r ei n s ert e d r a n d o ml y, t o 
a s s e s s t h e i ntr a-o b s er v er  a n d i nter -o b s er v er  r eli a bilit y a n d i n s ur e fi d elit y of t h e S CI e n d p oi nt.  
 
8. 0  
Tr a n s cr a ni al D o p pl er  
T C D s m a y  b e i nt er pr et e d l o c all y b y r a di ol o g y  or a n ot h er a p pr o pri at el y cr e d e nti al e d cli ni c al s er vi c e , i n a d diti o n 
t o a st u d y i nt er pr et ati o n b y t h e st aff of t h e c e ntr al r e a di n g f a cilit y.  T C D s will b e s e nt b y e x pr e s s m ail o n di git al 
m e di a t o  t h e M e di c al U ni v er sit y of S o ut h C ar oli n a ( M U S C) f or q u alit y c o ntr ol a n d c e ntr al i nt er pr et ati o n b y t h e 
M U S C N e ur ol o g y C or e.  Dr. R o b ert A d a m s, Pr of e s s or of N e ur ol o g y at t h e M e di c al U ni v er sit y of S o ut h 
C ar oli n a, i s a l o n g -st a n di n g c o n s ult a nt t o o ur gr o u p a n d dir e ct s t h e N e ur ol o g y C or e.  Dr. A d a m s will pr o vi d e 
tr ai ni n g u si n g st a n d ar di z e d pr ot o c ol s t o a s s ur e t h e v ali dit y a n d r eli a bilit y of m e a s ur e m e nt s o bt ai n e d b y b ot h 
i m a gi n g a n d n o n-i m a gi n g T C D at p arti ci p ati n g sit e s.  I m a gi n g p er s o n n el at e a c h sit e will p arti ci p at e i n a 
s cr e e ni n g tr ai ni n g a n d t e sti n g pr o gr a m d e v el o p e d b y t h e T C D I m a gi n g C e nt er f or n o n -i m a gi n g T C D 
a s s e s s m e nt ( d e s cri b e d i n d et ail i n A p p e n di x 1 1 ).  T h e i m a g e a n al y si s q u alit y a s s ur a n c e pr o gr a m i n cl u d e s t w o 
c o m p o n e nt s: 1) i niti al tr ai ni n g  o n – sit e or vi a vi d e o c o nf er e n c e/ W e b e x; a n d 2) i ntr a -o b s er v er v ari a bilit y 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 2 6  of 7 4  
t e sti n g.  E a c h r e s e ar c h st u d y r e a d er will i n d e p e n d e ntl y e v al u at e a s et of t hr e e r e a di n g s i n t h e s a m e i n di vi d u al 
wit hi n a 1 2 0 mi n ut e i nt er v al.    I ntr a-o b s er v er v ari a bilit y will b e a s s e s s e d a n d t h e d e gr e e of v ari a bilit y m u st n ot 
e x c e e d a pr e d efi n e d t hr e s h ol d.   T h e Pri n ci p al I n v e sti g at or  a n d I m a gi n g C e nt er Dir e ct or ( Dr. A d a m s) will a gr e e 
u p o n t h e e x a ct p ar a m et er s t o b e a s s e s s e d a n d t h e t hr e s h ol d t o b e s et.   If t h e r e a d er s e x c e e d t h e t hr e sh ol d, 
t h e n r e-tr ai ni n g will b e r e q uir e d.  
 
Dr. A d a m s a n d hi s t e a m will e v al u at e i m a g e s fr o m b ot h eli gi bilit y s cr e e ni n g a n d fr o m e nr oll e d p arti ci p a nt s, 
i n cl u di n g t h o s e wit h a s u s p e ct e d or c o nfir m e d pri m ar y e n d p oi nt,  t h at i s, T C D m e a s ur e m e nt a b o v e a pr e -
d efi n e d t hr e s h ol d ( 1 7 0  c m/ s e c f or n o n -i m a gi n g T C D).  H e will u s e a r ef er e n c e s et s h o wi n g e x a m pl e s of t h e 
v ari o u s di a g n o sti c crit eri a d e v el o p e d pri or t o t h e st art of t h e st u d y.   T h e M U S C N e ur ol o g y C or e will b e 
r e s p o n si bl e f or b ot h a q u alit ati v e a n d q u a ntit ati v e a s s e s s m e nt of t h e i m a g e s.    T h e q u alit ati v e a s s e s s m e nt will 
b e b a s e d o n t h e pr e s e n c e or a b s e n c e of T C D m e a s ur e m e nt r e a c hi n g t h e e n d p oi nt of t h e tri al ( 1 = d efi nit el y n ot, 
2 =i n d et er mi n at e, 3 = d efi nit el y pr e s e nt).   Dr. A d a m s will i n d e p e n d e ntl y a s s e s s a n d r e c or d w h et h er a T C D 
e n d p oi nt h a s b e e n r e a c h e d.  
 
8. 1  
Q u alit y A s s ur a n c e a n d R e pr o d u ci bilit y  
E a c h c e nt er will m e et q u alit y a s s ur a n c e i n o n e of t w o w a y s.  C e nt er s t h at p arti ci p at e d i n S T O P or h a v e 
c ertifi e d -S T O P , S T O PII, S Wi T C H or T Wi T C H T C D t e c h ni ci a n s will a ut o m ati c all y m e et q u alit y a s s ur a n c e, aft er 
o n e a d e q u at e e x a m  i s s u b mitt e d a n d r e vi e w e d.  All ot h er sit e s m u st s e n d i n at l e a st t hr e e T C D e v al u ati o n s f or 
q u alit y a s s e s s m e nt b y Dr. R o b ert A d a m s.  T h e pr a cti c e e v al u ati o n will b e a s s e s s e d f or q u alit y a n d t h e 
t e c h ni q u e of a c q uiri n g a ti m e-a v er a g e d m e a n m a xi m u m v el o cit y.  
 
8. 2  
Ti mi n g of T C D  
U s u all y t h e T C D will b e o bt ai n e d at t h e fir st st u d y vi sit.  P arti ci p a nt s wit h a c o n diti o n al or a b n or m al T C D 
( C B F V> 1 7 0  c m/ s e c b y n o n -i m a gi n g T C D) will n e e d t o h a v e a s e c o n d T C D wit h a n a v er a g e v el o cit y < 1 7 0  
c m/ s e c t o  b e eli gi bl e t o c o nti n u e i n t h e st u d y.  P erf or mi n g T C D a n d all ot h er s cr e e ni n g pr o c e d ur e s b ef or e t h e 
M RI a s s ur e s t h at p arti ci p a nt s w h o d o n ot q u alif y o n t h e b a si s of ot h er m e a s ur e s will n ot b e  e x p o s e d t o 
s e d ati o n u n n e c e s s aril y.  
 
 
9. 0  
P S Y C H O L O GI C A L E V A L U A TI O N    
 
9 . 1  
C o g niti v e A s s e s s m e nt T o ol s   
  
  
  
  
  
  
  
 
B a yl e y S c al e s of I nf a nt a n d T o d dl er D e v el o p m e nt ( B a yl e y -III) 
T h e B a yl e y -III pr o vi d e s a c o m pr e h e n si v e a s s e s s m e nt of e arl y c o g niti v e d e v el o p m e nt i n c hil dr e n t o o y o u n g f or 
t h e m e a s ur e m e nt of I Q u si n g t h e W e c h sl er Pr e s c h o ol a n d Pri m ar y S c al e of I nt elli g e n c e  (W P P SI -III).  It 
i n cl u d e s a m ot or, m e nt al, a n d b e h a vi or r ati n g s c al e.  W e will u s e t h e B a yl e y-III [ e x c e pt f or t h e A d a pti v e 
B e h a vi or S u bt e st , a s t hi s will b e r e pl a c e d b y t h e A d a pti v e B e h a vi or A s s e s s m e nt S y st e m ( A B A S -II)] f or c hil dr e n 
9 t hr o u g h 2 9 m o nt h s of a g e.  
 
T h e W e c h sl er Pr e s c h o ol a n d Pri m ar y S c al e of I nt elli g e n c e -III ( W P P SI-III)  
T h e W e c h sl er S c al e s ar e t h e m o st wi d el y r e c o g ni z e d a n d a d mi ni st er e d t o ol s f or t h e a s s e s s m e nt of I Q. F or 
c hil dr e n w h o ar e 2 y e ar s a n d 6  m o nt h s  u p t o 3 y e ar s  1 1 m o nt h s  of a g e, w e will a d mi ni st er t h e R e c e pti v e 
V o c a b ul ar y, Bl o c k D e si g n, I nf or m ati o n, a n d O bj e ct A s s e m bl y c or e s u bt e st s of t h e W P P SI -III.  If t h e p arti ci p a nt 
i s l e s s t h a n 3 y e ar s a n d 6 m o nt h s  ol d a n d r a w s c or e s of 0 ar e o bt ai n e d f or t h e fir st t w o s u bt e st s, t h e e x a mi n er 
s h o ul d st o p a d mi ni st eri n g t h e W P P SI -III a n d a d mi ni st er t h e B a yl e y-III.  F or c hil dr e n 4 t o 7  y e ar s  a n d 4 m o nt h s  
of a g e , w e will a d mi ni st er t h e Bl o c k D e si g n, I nf or m ati o n, M atri x R e a s o ni n g, V o c a b ul ar y, Pi ct ur e C o n c e pt s, 
W or d R e a s o ni n g, a n d C o di n g c or e s u bt e st s .  F or c hil dr e n t h at i niti all y r e c ei v e d t h e B a yl e y -III, w e will 
a d mi ni st er t h e W P P SI -III, if t h e c hil d i s 3 y e ar s a n d 6  m o nt h s  of a g e  or ol d er.  T h e s e c or e s u bt e st s t a k e 3 0 t o 
4 5 mi n ut e s i n c hil dr e n 2 y e ar s a n d 6  m o nt h s  u p t o 4 y e ar s of a g e a n d 4 5 t o 6 0 mi n ut e s i n c hil dr e n 4 t o 7  y e ar s 
a n d 3 m o nt h s  of a g e.   
 
9. 2   
B e h a vi or R ati n g s  
A d a pti v e B e h a vi or A s s e s s m e nt S y st e m ( A B A S -II) 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 2 7  of 7 4  
T h e A B A S -II will b e u s e d a s s e s s b e h a vi or i n all c hil dr e n at b a s eli n e a n d, f or t h o s e r a n d o mi z e d, at t h e a n n u al 
a n d e xit vi sit  r e g ar dle s s of a g e .  C hil dr e n u p t o a g e 5 y e ar s a n d 1 1 m o nt h s will b e a d mi ni st er e d t h e I nf a nt a n d 
Pr e s c h o ol A B A S -II i n cl u di n g t h e m ot or s c al e; c hil dr e n 6 y e ar s or ol d er will b e a d mi ni st er e d t h e S c h o ol A B A S. 
T hi s s y st e m eli cit s p ar e nt s’ r ati n g of b e h a vi or t hr o u g h a  q u e sti o n n air e . 
 
B e h a vi or R ati n g I n v e nt or y of E x e c uti v e F u n cti o n Pr e s c h o ol V er si o n  ( B RI E F-P)  
T h e B RI E F -P (f or c hil dr e n 2 t o 5. 9 9 y e ar s of a g e) a n d B RI E F (f or c hil dr e n 6 y e ar s of ol d er) ar e  s e n siti v e t o 
c o g niti v e c h a n g e s i n c hil dr e n wit h n e ur ol o gi c d e cli n e. 4 8  F or e x a m pl e, t h e B RI E F - P h a s r e c e ntl y b e e n 
d e m o n str at e d t o b e s e n siti v e a n d s p e cifi c f or r e d u c e d i n hi biti o n a n d w or ki n g m e m or y i n c hil dr e n.  T h e B RI E F 
a s s e s s e s i m p air m e nt of e x e c uti v e f u n cti o n i n c hil dr e n a g e 5 t hr o u g h 1 8  y e ar s .4 9  F or t h e s e r e a s o n s, t h e B RI E F -
P or B RI E F will b e a d mi ni st er e d at b a s eli n e  (i n c hil dr e n at l e a st 2 y e ar s ol d) a n d e v er y y e ar a n d at e xit f or 
r a n d o mi z e d p arti ci p a nt s i n t h e st u d y. 
 
  
  
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 2 8  of 7 4  
T a ble 2: C o g niti ve a n d Be h a vi or al Testi n g 
 
9 m o - 2 9 m o  
2 yr 6 m o - 3 yr 1 1 m o  
B a yl e y -III 
W P P SI -III ( y o u n g er) 
 
    R e c e pti v e V o c a b ul ar y  
 
    Bl o c k D e si g n  
 
    I nf or m ati o n 
A B A S -II  I nf a nt a n d Pr e s c h o ol     O bj e ct A s s e m bl y  
B RI E F -P (if ≥ 2 4 m o)  
A B A S -II  I nf a nt a n d Pr e s c h o ol 
  
B RI E F -P  
4 yr  - 5 yr 1 1 m o  
≥ 6 yr  
W P P SI -III ( ol d er) 
W P P SI -III ( ol d er) 
    Bl o c k D e si g n  
    Bl o c k D e si g n  
    I nf or m ati o n 
    I nf or m ati o n 
    M atri x R e a s o ni n g  
    M atri x R e a s o ni n g  
    V o c a b ul ar y  
    V o c a b ul ar y  
    Pi ct ur e C o n c e pt s  
    Pi ct ur e C o n c e pt s  
    W or d R e a s o ni n g   
    W or d R e a s o ni n g   
    C o di n g  
    C o di n g  
A B A S -II  I nf a nt a n d Pr e s c h o ol A B A S -II  S c h o ol 
B RI E F -P  
B RI E F  
 
 
1 0. 0  
N E U R O L O GI C E V A L U A TI O N  
A st a n d ar di z e d n e ur ol o gi c al e x a mi n ati o n b a s e d o n t h e P e di atri c Str o k e O ut c o m e M e a s ur e ( P S O M) will b e 
p erf or m e d b y a p e di atri c n e ur ol o gi st d uri n g vi sit o n e o n a ll p arti ci p a nt s w h o h a v e a T C D b el o w t h e tr a n sf u si o n 
t hr e s h ol d, a s w ell a s o n a n a n n u al b a si s a n d u p o n e xiti n g t h e st u d y.  T h e sit e m a y c h o o s e t o c o m pl et e t h e 
n e ur ol o gi c al a s s e s s m e nt b ef or e a T C D.  T h e st a n d ar di z e d e x a mi n ati o n i s al s o c o m pl et e d at m o nt h s 1 2, 2 4, 
a n d at st u d y e xit. T h e st a n d ar di z e d e x a mi n ati o n a n d NI H Str o k e S c al e will al s o b e c arri e d o ut aft er a n y 
e pi s o d e i n w hi c h n e ur ol o gi c al s y m pt o m s o c c ur.  T h e n e ur ol o gi c al e x a mi n ati o n h a s b e e n st a n d ar di z e d , i n or d er 
t o mi ni mi z e v ari a bilit y t h at c o ul d b e cr e at e d b y h a vi n g m ulti pl e e x a mi n er s at v ari o u s sit e s. F or p arti ci p a nt s 
e x p eri e n ci n g a n e v e nt s u s pi ci o u s  f or o v ert str o k e or a n y e pi s o d e i n w hi c h n e ur ol o gi c al s y m pt o m s o c c ur,  
r e s ult s of t h eir n e ur ol o gi c e x a mi n ati o n at t h e ti m e of t h e a c ut e e v e nt will b e s c or e d u si n g t h e NI H Str o k e S c al e.    
 
T h e n e ur ol o gi c al e x a mi n ati o n , i n cl u di n g l e v el of c o n s ci o u s n e s s, cr a ni al n er v e t e sti n g, t o n e, c o or di n ati o n, a n d 
s e n s ati o n (li g ht t o u c h, pi n pri c k, vi br ati o n, a n d pr o pri o c e pti o n) i s  sc or e d a s b ei n g n or m al or a b n or m al.  
Str e n gt h, pr o xi m al a n d di st al i n e a c h e xtr e mit y, i s a s s e s s e d o n t h e M e di c al R e s e ar c h C o u n cil s c al e , a n d 
t e n d o n r efl e x e s ar e e x pr e s s e d o n a 0-4 gr a di n g s y st e m. A g e a p pr o pri at e c o g niti v e s kill s ar e e v al u at e d u si n g 
n a mi n g, c o m pr e h e n si o n, r e p etiti o n, a n d ori e nt ati o n. C hil dr e n  a bl e t o r e a d a n d writ e will b e a s k e d t o r e a d a n d 
writ e st a n d ar di z e d w or d s a n d/ or s e nt e n c e s ; e a c h of t h e s e t w o s u bt e st s c o nt ai n s it e m s wit h a n i n cr e a si n g l e v el 
of diffi c ult y.  Fi n all y, s e v er al a g e -s p e cifi c t a s k s  a s s e s si n g o v er all f u n cti o n will b e u s e d,  i n cl u di n g c o p yi n g of 
g e o m etri c d e si g n s, w al ki n g o n ti pt o e s, a n d v ari o u s a s p e ct s of g ait.   
 
T h e e v al u ati o n of a n e v e nt wit h n e ur ol o gi c al s y m pt o m s will d et er mi n e t h e o n s et a n d d ur ati o n of t h e e v e nt, a s 
w ell a s p erti n e nt i nf or m ati o n a b o ut t h e s y m pt o m s.  S p e cifi c all y, t h e n e ur ol o gi c al e v e nt f or m c o nt ai n s q u e sti o n s 
t o d et er mi n e w h et h er t h er e w a s a n alt er e d l e v el of c o n s ci o u s n e s s, he a d a c h e, h e mi p ar e si s/ w e a k n e s s, c h a n g e 
i n vi si o n, alt er ati o n i n s p e e c h, cl u m si n e s s, s e n s or y di st ur b a n c e, or p o s si bl e s ei z ur e.  If t h e a n s w er t o a n y of 
t h e s e q u e sti o n s i s affir m ati v e, d et ail s m u st b e pr o vi d e d.  At t h e c o n cl u si o n of t h e hi st or y a n d n e ur ol o gi cal  
e x a mi n ati o n i n p arti ci p a nt s wit h n e ur ol o gi c al s y m pt o m s, t h e e x a mi ni n g p e di atri c n e ur ol o gi st m u st m a k e a 
d et er mi n ati o n a s t o t h e pr o b a bilit y t h at t h e e v e nt w a s a str o k e.  T h e r e s p o n s e of t h e p e di atri c n e ur ol o gi st i s 
i n di c at e d b y a 5-p oi nt s c al e r a n gi n g fr o m ‘ d efi nit el y y e s’ t o ‘ d efi nit el y n o’.  T h e fi n al d e ci si o n t o c at e g ori z e a 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 2 9  of 7 4  
n e ur ol o gi c al e v e nt a s a str o k e will b e m a d e b y t hr e e m e m b er s of t h e a d v er s e a d v er s e  c o m mitt e e.  T h e 
n e ur ol o g y c o m mitt e e i s c o m pri s e d of L ori J or d a n, M D , P h D – V a n d er bilt U ni v er sit y , R e b e c c a N. I c h or d, M D - 
C hil dr e n’ s H o s pit al of P hil a d el p hi a  a n d Mi c h a el N o et z el , M D, W a s hi n gt o n U ni v er sit y  S c h o ol of M e di ci n e.  
 
F or p arti ci p a nt s wit h a n o v ert str o k e a s j u d g e d b y t h e tr e ati n g p h y si ci a n s a n d t h e sit e n e ur ol o gi st, t h e  st u d y  
n e ur ol o gi st will p erf or m t h e s a m e n e ur ol o gi c e x a mi n ati o n a s t h e a n n u al m o nit ori n g e x a mi n ati o n.  I n t h e c o ur s e 
of p erf or mi n g t hi s e x a mi n ati o n, t h e p arti ci p a nt ’ s d efi cit s will b e gr a d e d u si n g t h e P S O M a n d NI H Str o k e 
S c al e .5 0  Dail y n e ur ol o gi c e x a mi n ati o n u si n g t h e st a n d ar di z e d pr ot o c ol will b e p erf or m e d t hr o u g h t h e fir st 3 
d a y s, or l o n g er a s n e e d e d , u ntil t h e s e v erit y of t h e d efi cit i s m a xi m al, at w hi c h ti m e t h e NI H Str o k e S c al e will b e 
r e p e at e d.  F oll o w-u p n e ur ol o gi c e x a mi n ati o n will b e p erf or m e d u si n g t h e st a n d ar d pr ot o c ol a n d gr a di n g o n t h e 
NI H Str o k e S c al e 6 m o nt h s a n d 1 2 m o nt h s aft er t h e e v e nt, a n d u p o n e xit fr o m t h e tri al.    
 
1 0 . 1   D efi niti o n of Tr a n si e nt I s c h e mi c Att a c k s a n d Str o k e  
T a bl e 2 pr o vi d e s t h e st u d y d efi niti o n of TI A a n d str o k e f or p arti ci p a nt s pr e s e nti n g wit h n e w n e ur ol o gi c fi n di n g s.  
 
T a bl e 3 D efi niti o n  of tr a n si e nt i s c h e mi c att a c k a n d str o k e  
< 2 4 h o ur s  
N e ur ol o gi c al D efi cit*  
< 2 4 h o ur s  
N e ur ol o gi c al D efi cit*  
> 2 4 h o ur s  
N e ur ol o gi c al D efi cit*  
> 2 4 h o ur s  
N e ur ol o gi c al D efi cit*  
N e g ati v e M RI  
P o siti v e M RI  
( n e w v a s c ul ar l e si o n w hi c h 
c o ul d e x pl ai n d efi cit)  
P o siti v e M RI  
( n e w v a s c ul ar l e si o n w hi c h 
c o ul d e x pl ai n d efi cit)  
N e g ati v e M RI or P o siti v e 
M RI a n d v a s c ul ar l e si o n 
d o e s n ot e x pl ai n a d efi cit  
 
Di a g n o si s = Tr a n si e nt 
i s c h e mi c att a c k ( TI A) 
 
Di a g n o si s = Cli ni c al Str o k e  
 
Di a g n o si s = Cli ni c al Str o k e  
 
Di a g n o si s = Cli ni c al Str o k e  
* T h e i nfl u e n c e of bl o o d tr a n sf u si o n o n a c ut e s y m pt o m s of str o k e h a s n ot b e e n w ell d efi n e d.  Tr a n sf u si o n 
t h er a p y m a y d e cr e a s e t h e p er si st e n c e of n e ur ol o gi c al fi n di n g s.  N e ur ol o gi c d efi cit i n t hi s s etti n g m e a n s a n 
a b n or m alit y c o n si st e nt wit h a str o k e.  
 
1 0 . 2 
D et er mi n ati o n of Str o k e  
T h e  H U Pr e v e nt pr ot o c ol h a s b e e n d e si g n e d t o i d e ntif y all i nt er c urr e nt n e ur ol o gi c al e v e nt s, eit h er a c ut e, or 
s u b a c ut e, t h at c o ul d b e c o n si st e nt wit h a n o v ert str o k e.  I nf or m ati o n a b o ut t h e si g n s a n d s y m pt o m s of str o k e 
will b e gi v e n t o all p ar e nt s/ p arti ci p a nt s w h o ar e s cr e e n e d a n d r ei nf or c e d wit h t h o s e w h o ar e r a n d o mi z e d.  I n 
a d diti o n, f a mil y a n d p arti ci p a nt s will b e i n str u ct e d t o r e p ort a n y si g nifi c a nt n e ur ol o gi c al s y m pt o m s.  T hi s s h o ul d 
mi ni mi z e a n y d el a y i n r e p orti n g.  W e a nti ci p at e t h at t h e m aj orit y of p arti ci p a nt s wit h n e ur ol o gi c e v e nt s will b e 
e v al u at e d i n cl o s e pr o xi mit y t o t h e e v e nt b y t h e l o c al n e ur ol o gi c al c o n s ult a nt at t h e i n di vi d u al st u d y sit e.  
P arti ci p a nt s wit h a c ut e n e ur ol o gi c e v e nt s s u s pi ci o u s f or a str o k e m u st r e c ei v e a n i m m e di at e M RI, pr ef er a bl y 
f oll o wi n g t h e H U Pr e v e nt i m a gi n g pr ot o c ol a n d i n cl u di n g diff u si o n w ei g ht e d s e q u e n c e s ( wit hi n 2 4 h o ur s of t h e 
n e ur ol o gi c e v e nt) a s p art of st a n d ar d c ar e, a s  p arti ci p a nt s m a y b e c a n di d at e s f or er yt hr o c yt a p h er e si s  or 
m a n u al e x c h a n g e tr a n sf u si o n.  I n a d diti o n , t h e p arti ci p a nt  s h o ul d b e e x a mi n e d b y t h e st u d y n e ur ol o gi st i n cl o s e 
pr o xi mit y t o t h e M RI, a n d pr ef er a bl y pri or t o t h e d e ci si o n t o pr o c e e d wit h er yt hr o c yt a p h er e si s  or m a n u al 
e x c h a n g e . If t h e st u d y n e ur ol o gi st i s u n a v ail a bl e, e v er y eff ort s h o ul d b e m a d e b y t h e sit e t o h a v e t h e 
n e ur ol o gi st pr o vi di n g cli ni c al c ar e d o c u m e nt t h e n e ur ol o gi c e x a m a n d NI H Str o k e S c al e b ef or e p erf or mi n g t h e 
tr a n sf u si o n. Hi st ori c al i nf or m ati o n a n d t h e n e ur ol o gi c al e x a mi n ati o n d o c u m e nt e d i n t h e n e ur ol o gi c al e v e nt f or m 
will t h e n b e r e vi e w e d b y t h e n e ur ol o g y c o m mitt e e c o n si sti n g of t hr e e p e di atri c n e ur ol o gi st s, e a c h of w h o m h a s 
e x p eri e n c e wit h str o k e s i n p arti ci p a nt s wit h si c kl e c ell a n e mi a.  I n a d diti o n t o t h e n e ur ol o gi c al e v e nt f or m, t h e 
n e ur ol o g y c o m mitt e e will r e vi e w all c urr e nt a n d pri or n e ur ol o gi c al c o n s ult ati o n f or m s, a c o p y of a n y i nt eri m 
pr o gr e s s f or m s, t h e i nt a k e hi st or y f or m, a n d all c urr e nt a n d pri or H U Pr e v e nt  c o n s e n s u s r a di ol o g y r e p ort s.  A n y 
i nf or m ati o n all u di n g t o t h e c o ntr ol or tr e at m e nt st at u s of t h e p arti ci p a nt  u n d er c o n si d er ati o n will b e d el et e d  fr o m 
d at a s e nt t o t h e n e ur ol o gi c al c o m mitt e e m e m b er s b y t h e D at a C o or di n ati n g C e nt er .   
 
T hr e e n e ur ol o gi st s  will i n d i vi d u all y r e vi e w all of t h e m at eri al s a n d m a k e a d et er mi n ati o n, b a s e d o n t h e d at a , a s 
t o w h et h er t h e n e ur ol o gi c al e v e nt i n q u e sti o n w a s a n o v ert str o k e. W h e n t h er e i s c o m pl et e a gr e e m e nt, t h er e i s 
n o n e e d f or a di s c u s si o n.  W h e n t h er e i s di s c or d a n c e , a c o n s e n s u s c all will b e h el d a n d a m aj orit y v ot e will 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 3 0  of 7 4  
d e ci d e t h e st at u s of t h e p arti ci p a nt  a s t o t h e pr e s e n c e or a b s e n c e of a str o k e.  It i s a nti ci p at e d t h at a fi n al 
d et er mi n ati o n of w h et h er a n e ur ol o gi c al e v e nt w a s str o k e will b e c o m pl et e d wit hi n 4 w e e k s of t h e ti m e of t h e 
i niti al r e p ort of t h e n e ur ol o gi c al e v e nt.  I n a d diti o n, t h e n e ur or a di ol o g y c o m mitt e e will r e vi e w t h e e v e nt M RI t o 
a s c ert ai n w h et h er or n ot t h er e ar e n e w i nf ar ct -li k e l e si o n s f oll o wi n g t h e n e ur ol o gi c al e v e nt. T h e 
n e ur or a di ol o gi st s will c o m p ar e  all s u b s e q u e nt M RI i m a g e s t o t h e i niti al b a s eli n e i m a g e a n d will r e c or d t h eir 
fi n di n g s o n c a s e r e p ort f or m s.  A n e ur or a di ol o g y r e vi e w will b e f or w ar d e d t o all m e m b er s of t h e n e ur ol o g y 
c o m mitt e e a n d will b e i n cl u d e d a s p art of t h e m at eri al , t o d e v el o p a c o n s e n s u s o pi ni o n d et er mi ni n g w h et h er 
t h e n e ur ol o gi c al e v e nt w a s a str o k e.  
 
1 0 . 3  Cli ni c al E v e nt s or C o n diti o n s t h at S h o ul d Tri g g er a n E v e nt -R el at e d U n s c h e d ul e d N e ur ol o gi c 
A s s e s s m e nt  
F oll o wi n g r a n d o mi z ati o n, if t h e p arti ci p a nt  e x p eri e n c e s a n y of t h e f oll o wi n g sit u ati o n s, t h e sit e n e ur ol o gi st 
s h o ul d e x a mi n e t h e p arti ci p a nt  a s s o o n a s p o s si bl e, pr ef er a bl y wit hi n 2 4 h o ur s of t h e s u s p e ct e d e v e nt.  T h e 
sit e n e ur ol o gi st or t h eir d e si g n e e s h o ul d c o m pl et e t h e St a n d ar di z e d N e ur ol o g y E x a mi n ati o n C R F  1 0 f or 
p arti ci p a nt s < 2 y e ar s ol d or C R F 1 1 f or p arti ci p a nt s > 2 y e ar s ol d  f or a cli ni c al e v e nt or c o n diti o n t h at tri g g er s a n 
e v e nt -r el at e d, u n s c h e d ul e d n e ur ol o gi c a s s e s s m e nt.  T h e f or m s s h o ul d b e c o m pl et e d a n d s e nt t o st ati sti c al 
c e nt er wit hi n o n e w e e k.  
 
S u s p e ct e d e v e nt s s h o ul d i n cl u d e , b ut n ot b e li mit e d t o:   
 
•  
A c ut e n e ur ol o gi c d efi cit s u c h a s  c o nf u si o n, l o s s of c o n s ci o u s n e s s, h e mi p ar e si s, l o s s of or sl urri n g of 
s p e e c h, vi s u al l o s s, s e n s or y l o s s, at a xi c g ait t h at h a s n o o b vi o u s e x pl a n ati o n.   
•  
A n y c h a n g e i n n e ur ol o gi c al f u n cti o n l a sti n g m or e t h a n 2 4 h o ur s , e v e n wit h a n ot h er e x pl a n ati o n.  
•  
S ei z ur e  
•  
H e a d a c h e wit h dr o w si n e s s or alt er e d l e v el of c o n s ci o u s n e s s, u nl e s s t h er e i s a hi st or y of mi gr ai n e s wit h 
si mil ar m a nif e st ati o n s.  
•  
N e w -o n s et h e a d a c h e s or i n cr e a si n g s e v erit y or fr e q u e n c y  ( d a y s t o w e e k s) of h e a d a c h e s 
•  
D e cli n e or r e gr e s si o n of a m aj or lif e f u n cti o n ( s c h o ol p erf or m a n c e, a cti viti e s of d ail y li vi n g, s o ci al 
r el ati o n s hi p s, c o m m u ni c ati o n) e v ol vi n g o v er a s h ort ti m e i nt er v al ( d a y s t o w e e k s), wit h o ut cl e ar 
e x pl a n ati o n.  
 
T h e a b o v e- d e s cri b e d g ui d eli n e s s h o ul d s er v e t o a u g m e n t t h e sit e n e ur ol o gi st’ s cli ni c al a c u m e n a n d n ot 
s u b stit ut e f or cli ni c al j u d g m e nt.  
 
I n a d diti o n, t h e sit e PI a n d st u d y l e a d er s hi p ( C h air or vi c e-C h air)  sh o ul d b e n otifi e d a s s o o n a s p o s si bl e, 
pr ef er a bl y wit hi n 2 4 h o ur s, if:  
•  
If t h e c hil d i s s u s p e ct e d b y t h e p ar e nt t o h a v e a n a c ut e n e ur ol o gi c e v e nt or c h a n g e i n n e ur ol o gi c al 
or f u n cti o n al st at u s, a n d i s br o u g ht t o t h e st u d y sit e f or cli ni c al c ar e.  
•  
T h e c hil d i s s u s p e ct e d b y t h e p ar e nt t o h a v e a n a c ut e n e ur ol o gi c e v e nt or c h a n g e i n n e ur ol o gi c al or 
f u n cti o n al st at u s, a n d i s br o u g ht t o a f a cilit y ot h er t h a n t h e st u d y sit e f or cli ni c al c ar e.  
o  
T h e f a mil y or tr e ati n g p h y si ci a n s at t hi s o ut si d e f a cilit y n otif y t h e sit e st aff t h at t hi s e v e nt h a s 
o c c urr e d c o n c urr e nt wit h a s s e s s m e nt a n d tr e at m e nt.  
o  
T h e f a mil y or tr e ati n g p h y si ci a n s at t hi s o ut si d e f a cilit y d o n ot n otif y t h e sit e st aff t h at t hi s 
e v e nt h a s o c c urr e d, or o nl y aft er si g nifi c a nt d el a y ( > 1 w e e k).  
•  
T h e st u d y c o or di n at or, sit e i n v e sti g at or or a n y ot h er st u d y p er s o n n el l e ar n s a b o ut a p o s si bl e a c ut e 
n e ur ol o gi c e v e nt or c h a n g e i n n e ur ol o gi c al or f u n cti o n al st at u s d uri n g t h e m o nt hl y s cr e e n; or t h e 
st u d y n e ur ol o gi st l e ar n s a b o ut a p o s si bl e n e ur ol o gi c e v e nt or c h a n g e i n n e ur ol o gi c al or f u n cti o n al 
st at u s d uri n g t h e a n n u al s cr e e n.  
•  
T h e c hil d d e v el o p s a n a c ut e n e ur ol o gi c e v e nt or c h a n g e i n n e ur ol o gi c al or f u n cti o n al st at u s, w hil e 
b ei n g tr e at e d f or a n o n -n e ur ol o gi c ill n e s s.  
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 3 1  of 7 4  
P ar e nt s/ g u ar di a n s will b e gi v e n a c ar d  t h at t h e y c arr y wit h t h e m at all ti m e s pr o vi di n g i n str u cti o n s dir e ct e d t o 
a n y h e alt h c ar e pr o vi d er w h o s e e s t h e p arti ci p a nt  f or a n a c ut e, u n s c h e d ul e d m e di c al c ar e vi sit, i n di c ati n g t h at 
t h e pr o vi d er s h o ul d c o nt a ct t h e o n-c all h e m at ol o gi st of t h e st u d y sit e.   
 
T h e p ar e nt s/ g u ar di a n s will b e i n str u ct e d t o c all t h e st u d y c o or di n at or i m m e di at el y , t o n otif y h er/ hi m of a n y 
i n st a n c e t h at t h e y s o u g ht m e di c al att e nti o n f or a n a c ut e ( u n s c h e d ul e d) m e di c al pr o bl e m. 
 
F or cli ni c al e v e nt s c o n si d er e d s u s pi ci o u s f or a n o v e rt str o k e or TI A,  a s d e s cri b e d i n t h e li st a b o v e, a  
n e ur ol o gi c al e v al u ati o n a n d a n M RI of t h e br ai n f oll o wi n g t h e  H U Pr e v e nt  i m a gi n g pr ot o c ol s h o ul d b e 
c o m pl et e d wit hi n 2 4 h o ur s aft er c o n s ult ati o n wit h t h e p e di atri c sit e n e ur ol o gi st a n d sit e pri n ci p al i n v e sti g at or.  
 
P arti ci p a nt s wit h a c ut e n e ur ol o gi c al e v e nt s s u s pi ci o u s f or a str o k e ( d efi nit el y Y e s, Pr o b a bl y Y e s or U n cl e ar, i n 
a n s w er t o q u e sti o n 3 2 o n H U Pr e v e nt  C R F 1 0) s h o ul d t h e n h a v e t h e NI H P e di atri c Str o k e S c al e S u m m ar y 
c o m pl et e d a n d t h e y m u st r e c ei v e a n i m m e di at e M RI, pr ef er a bl y f oll o wi n g t h e H U Pr e v e nt i m a gi n g pr ot o c ol a n d 
i n cl u di n g diff u si o n w ei g ht e d s e q u e n c e s a n d M R V ( wit hi n 2 4 h o ur s of t h e n e ur ol o gi c al ev e nt), a s p art of 
st a n d ar d c ar e, a s p arti ci p a nt s m a y b e c a n di d at e s f or er yt hr o c yt a p h er e si s or m a n u al e x c h a n g e tr a n sf u si o n.  A 
f oll o w u p M RI, 3 0-6 0 d a y s aft er t h e e v e nt i s str o n gl y r e c o m m e n d e d, i n cl u di n g M R A (if n ot d o n e a c ut el y t o 
a s s e s s t h e e v al u ati o n of v a s c ul o p at h y).  
 
If o v ert str o k e s or n e w or pr o gr e s si v e sil e nt c er e br al i nf ar ct s ar e i d e ntifi e d, t h e n t h e p arti ci p a nt  w o ul d b e 
cl a s sifi e d a s m e eti n g t h e pri m ar y o ut c o m e m e a s ur e of t h e st u d y  a n d a r e p e at M RI will b e d o n e a n n u all y a s 
p art of st a n d ar d c ar e . We will c o nti n u e t o tr a c k t h e c o ur s e of t h e p arti ci p a nt  t hr o u g h o ut t h e tri al, a n d a s k t h at 
t h e y c o nti n u e t o r e c ei v e t h e s c h e d ul e d c o g niti v e a n d b e h a vi or al a s s e s s m e nt.  I n t h e e v e nt of a n o v ert str o k e, 
t h e p arti ci p a nt will b e off er e d bl o o d tr a n sf u si o n t h er a p y.  
 
If n o o v ert str o k e di a g n o si s i s m a d e or n o sil e nt c er e br al i nf ar ct i s i d e ntifi e d, t h e p arti ci p a nt  will r e s u m e t h eir 
r a n d o ml y all o c at e d ar m a n d ti m e p oi nt i n t h e st u d y. 
 
1 0. 4  
Tr a n si e nt I s c h e mi c Att a c k s  
I n s o m e p arti ci p a nt s wit h a c ut e n e ur ol o gi c al e v e nt s, a di a g n o si s of a TI A m a y b e m a d e ( Q u e sti o n 3 2 A o n C R F 
1 0). At pr e s e nt t h er e i s li mit e d e vi d e n c e t o dir e ct s u b s e q u e nt tr e at m e nt d e ci si o n s f or t h e s e i n di vi d u al s. T h e 
m o st i nf or m ati v e d at a c a n b e f o u n d i n:  
 
1) O h e n e -F e m p o n g, et. al. ’s r e p ort o n C o o p er ati v e St u d y of Si c kl e C ell Di s e a s e d at a i n Bl o o d  1 9 9 8; 9 1: 2 8 8 -
9 4.  Pri or TI A w a s o n e of fi v e ri s k f a ct or s f or i nf ar cti v e str o k e, i n cl u di n g r e c e nt a c ut e c h e st s y n dr o m e a n d 
el e v at e d s y st oli c bl o o d pr e s s ur e; h o w e v er, sil e nt i nf ar cti o n w a s n ot m e a s ur e d, t h e st u d y i n cl u d e d m a n y 
a d ult p arti ci p a nt s a n d t h e r el ati v e ri s k of TI A w a s a s s e s s e d o nl y i n t h e e ntir e c o h ort; y o u n g p arti ci p a nt s 
w er e n ot e v al u at e d s e p ar at el y.  
2)  Mill er et. al. a n d t h e  C o o p er ati v e St u d y of Si c kl e C ell Di s e a s e i n J P e di atr  2 0 0 1; 1 3 9: 3 8 5- 9 0. A g ai n, u si n g 
o v erl a p pi n g d at a t o # 1, pri or TI A str o n gl y w a s a s s o ci at e d wit h s u b s e q u e nt str o k e; h o w e v er, all st o k e 
p arti ci p a nt s wit h TI A al s o h a d a sil e nt i nf ar ct.  I n a m ulti v ari at e a n al y si s, sil e nt str o k e a n d n ot TI A w a s 
a s s o ci at e d wit h a n i n cr e a s e r at e of o v ert str o k e.  
3)  A H A/ A S A G ui d eli n e s ( Str o k e  2 0 0 6; 3 7: 5 7 7 -6 1 7) r e c o m m e n d ( o n p a g e 6 0 0) t h at “F or  a d ult s wit h S C D a n d 
i s c h e mi c str o k e or TI A ( e m p h a si s a d d e d) … A d diti o n al t h er a pi e s t h at m a y b e c o n si d er e d i n cl u d e r e g ul ar 
bl o o d tr a n sf u si o n t o r e d u c e h e m o gl o bi n S …”  ( Cl a s s II b, l e v el of e vi d e n c e C); h o w e v er, t h e s e g ui d eli n e s 
s h o ul d b e c o n si d er e d e x p ert o pi ni o n, b e c a u s e TI A i s m e nti o n e d o nl y i n t h e r e c o m m e n d ati o n a n d n ot i n t h e 
d at a a n al y si s.  
 
Gi v e n t h at t h e m aj orit y of i n di vi d u al s wit h S C D pr e s e nti n g wit h a f o c al n e ur ol o gi c al d efi cit h a v e a M RI of t h e 
br ai n, t h e d e ci si o n t o p erf or m a n e x c h a n g e tr a n sf u si o n i s oft e n b a s e d  o n t h e r e s ult s of a n a c ut e diff u si o n 
w ei g ht e d i m a g e ( D WI) M RI a n d t h e f o c al n e ur ol o gi c al e x a mi n ati o n ; ho w e v er, i n t h e s etti n g of f o c al n e ur ol o gi c al 
d efi cit, e x pli cit c ar e m u st b e t a k e n t o e n s ur e t h at t h er e i s n ot o v er r eli a n c e o n a n e g ati v e M RI  ( a b s e n c e of a n 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 3 2  of 7 4  
a b n or m alit y o n diff u s e w ei g ht e d i m a gi n g)  t o f or g o e x c h a n g e tr a n sf u si o n. S e v er al st u di e s h a v e d o c u m e nt e d 
t h at p ati e nt s wit h f o c al n e ur ol o gi c al d efi cit s m a y h a v e a n e g ati v e M RI-D WI s c a n, s p e cifi c all y n e g ati v e diff u si o n 
w ei g ht e d i m a g e s wit hi n 2 4 h o ur s of t h e o n s et of s y m pt o m s. 5 1 ,5 2   S u c h p ati e nt s m a y b e r ef err e d t o a s h a vi n g a 
TI A; h o w e v er, a pr o p orti o n of p ati e nt s t h at pr e s e nt wit h a f o c al n e ur ol o gi c al d efi cit a n d n e g ati v e M RI, m a y h a v e 
r e p e at M RI of t h e br ai n 3 0 d a y s l at er r e v e ali n g t h e l e si o n c orr e s p o n di n g t o t h e f o c al d efi cit. 5 2   Aft er e x cl u si o n of 
str o k e mi mi c s a s s o ci at e d wit h a n e g ati v e M RI of t h e br ai n, s u c h a s mi gr ai n e h e a d a c h e or a s ei z ur e t h at w a s 
n ot wit n e s s e d, t h e p o s si bilit y of a str o k e still e xi st s.  Ulti m at el y t h e di a g n o si s of a n a c ut e o v ert str o k e a n d t h e 
d e ci si o n t o p erf or m a ti m el y e x c h a n g e tr a n sf u si o n i s a m ulti -di s ci pli n ar y b e d si d e d e ci si o n , r e q uiri n g i n p ut fr o m 
t h e n e ur ol o gi st, n e ur or a di ol o gi st a n d h e m at ol o gi st.  Fi g ur e 3 d e s cri b e s a s c h e m ati c of t h e n e ur oi m a gi n g 
st u di e s a n d t h e diff er e nti al di a g n o si s of f o c al n e ur ol o gi c al d efi cit s . 
 
Fi g ur e 3: E v al u ati o n of a F o c al N e ur ol o gi c al D efi cit   
N ot e:  M RI  or C T m a y b e t h e fir st st u d y d o n e, d e p e n di n g t h e e a s e a n d s p e e d wit h w hi c h e a c h st u d y m a y b e 
d o n e at e a c h i n stit uti o n.  M RI i s r e q uir e d f or c o m pl et e e v al u ati o n w h e n a v ail a bl e.   A C T of t h e br ai n i s n ot 
r e q uir e d, d e p e n di n g o n t h e a v ail a bilit y a n d r e s ult s of t h e M RI. 
 
 D V S T i n di c at e s d ur al v e n o u s si n u s t hr o m b o si s; P R E S, p o st eri or r e v er si bl e e n c e p h al o p at h y s y n dr o m e  
 
T h e t hr e s h ol d t o m a n d at e a n i niti al e x c h a n g e tr a n sf u si o n i n t h e s etti n g of a n a c ut e f o c al n e ur ol o gi c al d efi cit 
s h o ul d b e l o w , t a ki n g i nt o a c c o u nt t h e d at a n ot e d a b o v e; ho w e v er, t h e t hr e s h ol d t o c o nti n u e e x c h a n g e 
tr a n sf u si o n b e y o n d t h e i niti al tr a n sf u si o n t h er a p y s h o ul d b e hi g h, if t h e f oll o w u p 3 0 d a y M RI i s n e g ati v e, d o e s 
n ot r e v e al a n y i nf ar ct a n d t h e p ati e nt r e m ai n s a s y m pt o m ati c. T h er e m a y b e cir c u m st a n c e s w h er e t h e sit e PI 
a n d n e ur ol o gi st ar e c o m p ell e d t o tr e at a p ati e nt  o n st u d y tr e at m e nt wit h c hr o ni c bl o o d tr a n sf u si o n t h er a p y.   
W e r e c o m m e n d t h at a st u d y p arti ci p a nt wit h m ulti pl e di s cr et e TI A s i n v ol vi n g t h e s a m e v a s c ul ar s h o ul d b e 
c o n si d er e d f or c hr o ni c bl o o d tr a n sf u si o n t h er a p y. S u c h p ati e nt s b y d efi niti o n will n ot h a v e a n y e vi d e n c e of a 
c er e br al i nf ar ct o n M RI, si n c e a n e w l e si o n i s a n e n d p oi nt t o t h e H U Pr e v e nt Tri al.  W e al s o w o ul d r e c o m m e n d 
t h at a r e p e at M RI b e o bt ai n e d aft er t h e st art of c hr o ni c bl o o d tr a n sf u si o n, a p pr o xi m at el y 3 0 t o 6 0 d a y s aft er t h e 
pr e ci pit ati n g e v e nt. T hi s M RI s h o ul d b e c o n si d er e d st a n d ar d c ar e t o a s s e s s t h e pr e s e n c e of t h e n e w l e si o n 
a s s o ci at e d wit h t h e TI A. Fi n all y, if t h e d e ci si o n i s m a d e t o pl a c e a c hil d o n c hr o ni c  tr a n sf u si o n, t h e n it i s 
i m p er ati v e t o di s c u s s t hi s d e ci si o n wit h t h e st u d y l e a d er s hi p.  T h e u s e of h y dr o x y ur e a h a s n ot b e e n s h o w n t o 
b e eff e cti v e i n pr e v e nti n g TI A s; t h e d e ci si o n t o b e gi n t hi s t h er a p y f or n e ur ol o gi c s y m pt o m s s h o ul d al w a y s b e 
di s c u s s e d b ef or e h a n d wit h st u d y l e a d er s hi p.  
 
If t h e p arti ci p a nt  r e c ei v e s a di a g n o si s of a n o v ert str o k e d uri n g t h e c o ur s e of t h e tri al, w e r e q u e st bl o o d 
s a m pl e s f or t h e bi ol o gi c r e p o sit or y b e o bt ai n e d.  Ti mi n g of t h e s e bl o o d dr a w s will v ar y, b a s e d o n p arti ci p a nt  
cir c u m st a n c e s.  I n s o m e c a s e s, it m a y b e f e a si bl e t o dr a w d ail y s a m pl e s f or t h e fir st s e v er al d a y s; f or 
h o s pit ali z e d p arti ci p a nt s, w e w o ul d t h e n dr a w s a m pl e s e v er y 2 -3 d a y s, a n d t h e n w e e kl y f or u p t o 6 w e e k s , if 
f e a si bl e.  A t y pi c al s c h e d ul e mi g ht b e s a m pl e s at ti m e 0, 3, 7, a n d 1 4 d a y s, b ut m or e fr e q u e nt s a m pli n g w o ul d 
b e d o n e, if p o s si bl e.   
 
If t h e p arti ci p a nt  r e c ei v e s a di a g n o si s of a n o v ert str o k e d uri n g t h e c o ur s e of t h e tri al, e v al u ati o n p er t h e 
i n stit uti o n’ s st a n d ar d of c ar e  i s r e c o m m e n d e d 
 
 
1 1. 0   
SA M P L E SI Z E A N D S T A TI S TI C A L A N A L Y SI S  
 
1 1. 1  
Pri m ar y o ut c o m e v ari a bl e  
 
T h e pri m ar y e n d p oi nt f or t h e pil ot a n d d efi niti v e p h a s e III  tri al will b e pr e v e nti o n of a b n or m al 
C B F V, S CI , TI A a n d str o k e.   
 
1 1. 2  
S e c o n d ar y o ut c o m e v ari a bl e s  
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 3 3  of 7 4  
O bj e cti v e 1:  
T h e s e c o n d ar y o ut c o m e v ari a bl e s will b e t h e pr o p orti o n of s cr e e n e d p arti ci p a nt s a c c e pti n g 
r a n d o mi z ati o n a n d t h e pr o p orti o n of r a n d o mi z e d p arti ci p a nt s wit h > 8 0 % a d h er e n c e. 
 
O bj e cti v e 2:  
S e c o n d ar y o ut c o m e s will b e t h e pr o p orti o n of c hil dr e n wit h: 1) s eri o u s a d v er s e e v e nt s 2) s eri o u s 
a d v er s e e v e nt s attri b ut e d t o t h e st u d y i nt er v e nti o n or st u d y pr o c e d ur e s.  
 
 
O bj e cti v e 3:  
T h e s e c o n d ar y o ut c o m e s will b e t h e l e v el s of G F A P, t hr o m b o s p o n di n, L -s el e cti n , a n d 
a p oli p o pr ot ei n A 1  i n c hil dr e n wit h a n d wit h o ut S CI.  W e will al s o c oll e ct pl a s m a s p e ci m e n s t o 
e v al u at e p ut ati v e bi o m ar k er s of C N S i nj ur y a s a s urr o g at e o ut c o m e of h y dr o x y ur e a  effi c a c y i n a n 
o n g oi n g, pr ot e o mi c s di s c o v er y pr oj e ct .   
 
 
O bj e cti v e 4 : 
C o m pl et e t h e n e c e s s ar y pr e p ar ati o n s f or a d efi niti v e p h a s e III tri al.  D uri n g t h e c o ur s e of t h e 
c urr e nt st u d y, w e will al s o pr e p ar e a m a n u al of o p er ati o n s a n d c a s e r e p ort f or m s f or t h e 
pr o p o s e d tri al,  d e v el o p s a m pl e I R B s u b mi s si o n t e m pl at e s a n d or g a ni z e all c o m mitt e e s, 
c oll a b or at or s a n d st u d y pr o c e d ur e s n e c e s s ar y  f or i niti ati o n of a s u c c e s sf ul, d efi niti v e, m ulti c e nt er 
tri al.  
 
1 1. 3  R a n d o mi z ati o n s c h e m e.  
R a n d o mi z ati o n will b e p erf or m e d u si n g a n a d a pti v e r a n d o mi z ati o n s c h e m e, wit h str atifi c ati o n f or a g e ( < 3 0 
m o nt h s v s. > 3 0 m o nt h s)  a n d  C B F V < 1 5 5  v s. 1 5 5 -1 6 9  c m/ s e c b y n o n -i m a gi n g T C D.  T h e r a n d o mi z ati o n will b e 
p erf or m e d b a s e d o n i nf or m ati o n e nt er e d b y t h e c o or di n at or u si n g a w e b -b a s e d a p pli c ati o n , wit h t h e 
r a n d o mi z ati o n c o d e pr o vi d e d t o t h e r e s e ar c h p h ar m a ci st. Si bli n g s ( a d o pti v e or bi ol o gi c al) will b e r a n d o mi z e d t o 
t h e s a m e tr e at m e nt t o a v oi d h a vi n g t h e p arti ci p a nt s a n d t h eir p ar e nt s c o m p ar e st u d y tr e at m e nt s or h a v e 
a n xi et y r el at e d t o p o s si bl e diff er e nti al tr e at m e nt.   Alt h o u g h t hi s will d e cr e a s e t h e i n d e p e n d e n c e of t h e 
o b s er v ati o n s, t h e st ati sti c al eff e ct o n  t h e st u d y i s a nti ci p at e d t o b e s m all a n d t hi s c o ul d e n h a n c e r e cr uit m e nt 
effi ci e n c y.  
 
1 1. 4   St ati sti c al P l a n 
Pri m ar y o ut c o m e v ari a bl e:  D at a a n al y si s  will i n cl u d e p oi nt e sti m at e s a n d 9 5 % c o nfi d e n c e i nt er v al s u si n g e x a ct 
m et h o d s of t h e pr o p orti o n a c hi e vi n g t h e pri m ar y e n d p oi nt f or t h e pl a n n e d d efi niti v e p h a s e III tri al ( a c o m p o sit e 
of S CI, C B F V > 1 7 0  c m/ s e c, TI A or o v ert str o k e, b a s e d o n M RI, n o n -i m a gi n g T C D, a n d n e ur ol o g y e x a m) i n 
e a c h gr o u p.  
 
1 1. 5   S e c o n d ar y o ut c o m e s  
O bj e cti v e  1  
T h e pr o p orti o n of p arti ci p a nt s a c c e pti n g r a n d o mi z ati o n.  W e e x p e ct t h at ~ 3 0 % will a gr e e t o b e s cr e e n e d, 
a p pr o xi m at el y 8 0 % of s cr e e n e d p arti ci p a nt s will b e eli gi bl e a n d at l e a st 6 3 % will a gr e e t o b e r a n d o ml y 
all o c at e d. If < 4 0 of t h e a nti ci p at e d eli gi bl e 8 0 S CI n e g ati v e p arti ci p a nt s s cr e e n e d at all  c e nt er s ar e u n willi n g t o 
u n d er g o r a n d o m a s si g n m e nt, t h e n o ur pr e vi o u s e sti m at e s of p arti ci p ati o n i n cli ni c al tri al s m a y n e e d t o b e 
a dj u st e d f or t h e l ar g e m ulti c e nt er s etti n g. F or c o g niti v e m e a s ur e s, r e p e at e d m e a s ur e s a n al y si s of v a ri a n c e will 
b e u s e d t o a s s e s s c h a n g e fr o m b a s eli n e b et w e e n t h e t w o tr e at m e nt gr o u p s. I n a d diti o n t o u si n g st ati sti c al 
t e c h ni q u e s t o e v al u at e d e cli n e s i n c o g niti v e m e a s ur e s, cli ni c al si g nifi c a n c e will b e e v al u at e d u si n g s c or e s 
b a s e d o n n or m ati v e d at a. T h e s e  r e s ult s will b e u s e d t o r efi n e t h e s a m pl e si z e of t h e d efi niti v e P h a s e III tri al. 
 
O bj e cti v e  2  
T o d et er mi n e t h e s af et y of st u d y pr o c e d ur e s.  W e wi ll c al c ul at e pr o p orti o n s a n d 9 5 % c o nfi d e n c e i nt er v al s of 
p arti ci p a nt s h a vi n g s e v er e a d v er s e e v e nt s u si n g e x a ct m et h o d s , a s w ell a s t h e r at e of a d v er s e e v e nt s.  W e 
e x p e ct t h e pr o p orti o n a n d r at e of s eri o u s a d v er s e e v e nt s t o b e si mil ar i n t h e t w o gr o u p s.  
 
O bj e cti v e  3 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 3 4  of 7 4  
E v al u ati o n of Bi o m ar k er s of C N S i n jur y.  W e will c o m p ar e t h e l e v el s of G F A P, t hr o m b o s p o n di n, a n d L -s el e cti n 
i n c hil dr e n wit h a n d wit h o ut S CI b y st u d e nt’ s t-t e st or aft er tr a n sf or m ati o n or wit h t h e Wil c o x o n r a n k-s u m t e st , if 
n ot n or m all y di stri b ut e d.  T h e s e r e s ult s will pr o vi d e t h e n e c e s s ar y pr eli mi n ar y d at a o n t h e m e a n a n d v ari ati o n 
of t h e s e v al u e s  i n t o d dl er s a n d pr e s c h o ol c hil dr e n wit h S C A, t o e sti m at e t h e n e c e s s ar y s a m pl e si z e of 
bi o m ar k er s u b -st u di e s of t h e pl a n n e d P h a s e III st u d y.   
 
1 1. 6  
I nt eri m D at a A n al y si s a n d E arl y St o p pi n g R ul e s 
W e will al s o c o nti n u o u sl y m o nit or t h e s af et y of st u d y pr o c e d ur e s, wit h r e p orti n g t o t h e I R B aft er e v er y 1 0 
s e d at e d M RI s a n d pl a n n e d r e vi e w b y t h e D S M B aft er 1 0, 2 0, 4 0, 8 0, a n d 1 2 0 M RI s (t hi s i n cl u d e s s cr e e ni n g 
a n d f oll o w u p M RI s); If t h e n u m b er of S A E s wit hi n 7 2 h o ur s of s e d ati o n e x c e e d s t h e n u m b er i n T a bl e 3 , t h e n 
t h e tr u e pr o p orti o n of S A E s i s li k el y ≥4 %; at t hi s p oi nt, t h e M RI s wit h s e d ati o n w o ul d b e h alt e d t e m p or aril y, a n d 
w e w o ul d r e c o n si d er t h e s e d ati o n pr ot o c ol, wit h D S M B r e vi e w.  T h e t hr e s h ol d s w er e  d et er mi n e d b y fi n di n g t h e 
9 5 % c o nfi d e n c e i nt er v al ( o n e -si d e d) f or t h e r at e of S A E s t h at di d n ot c o nt ai n 4 %, a dj u sti n g f or m ulti pl e 
c o m p ari s o n s t o gi v e a 5 % err or r at e.  W e will u s e u ni v ari a bl e a n d m ulti v ari a bl e l o gi sti c r e gr e s si o n t o i d e ntif y 
p ot e nti al ri s k f a ct or s f or S CI a s e x pl or at or y a n al y s e s, a s t h e n e xt p h a s e of st u d y will c o n si d er a d a pti v e 
r a n d o mi z ati o n t o b al a n c e t h e s e f a ct or s ( a g e, H b c o n c e ntr ati o n, a n d/ or H b F) b et w e e n tr e at m e nt ar m s. A D S M B 
will b e f or m e d pri or t o t h e tri al a n d will i n cl u d e a h e m at ol o gi st wit h e x p erti s e i n S C D, a p e di atri c 
a n e st h e si ol o gi st, a n d a bi o st ati sti ci a n.  
 
T a bl e 3 : N u m b er of S e v er e A d v er s e E v e nt s t o E x cl u d e a Pr o p orti o n < 4 % wit h 9 5 % C o nfi d e n c e   
S e v er e A d v er s e E v e nt s  
3  
4  
6  
9  
1 1  
M RI s  
1 0  
2 0  
4 0  
8 0  
1 2 0  
 
I n a d diti o n, d at a o n t h e i n ci d e n c e of S A E s i n t h e h y dr o x y ur e a a n d pl a c e b o ar m will b e r e p ort e d t o t h e D S M B at 
i nt eri m bli n d e d a n al y s e s e v er y 6 m o nt h s aft er t h e fir st 1 0 p arti ci p a nt-y e ar s of f oll o w -u p h a s b e e n c o m pl et e d , or 
at t h e di s cr eti o n of t h e D S M B .  If t h er e i s a si g nifi ca ntl y gr e at er pr o p orti o n  of S A E s i n o n e ar m ( u si n g p < 0 . 0 1 
t o a c c o u nt f or t h e m ulti pl e c o m p ari s o n s, t h e d e ci si o n t o h alt t h e tri al will b e at t h e di s cr eti o n of t h e D S M B.  
 
 
T h e D S M B will al s o r e vi e w t h e effi c a c y o ut c o m e s  e v er y 6 m o nt h s  or at t h eir di s cr eti o n , aft er t h e fir st 1 0, b ut w e 
d o n ot e x p e ct t hi s s m all st u d y t o i d e ntif y a si g nifi c a nt diff er e n c e b et w e e n gr o u p s .  Gi v e n t h e s m all si z e f or t h e 
i nt er n al pil ot, w e will n ot a s s e s s effi c a c y: t h er ef or e, w e will n ot b e a bl e t o d et er mi n e f utilit y f or t h e pri m ar y 
e n d p oi nt . W e  d o n ot pl a n s c h e d ul e d i nt eri m a n al y s e s f or t h e pri m ar y e n d p oi nt  ot h er t h a n t h e D S M B’ s r e vi e w .    
  
  
  
  
  
 
1 2. 0 R E GI S T R A TI O N, S T U D Y M O NI T O RI N G A N D S T U D Y O R G A NI Z A TI O N   
 
 
1 2 . 1 
C o n s e nt F or m   
  
T h e p ar e nt/l e g al g u ar di a n of e a c h p ot e nti al p arti ci p a nt  will b e gi v e n c o n s e nt f or m s t o r e a d a n d si g n pri or t o t h e 
p arti ci p a nt ’ s e ntr y i nt o t h e s cr e e ni n g a n d r a n d o mi z ati o n a n d tr e at m e nt p h a s e s, if eli gi bl e.  T h e s e f or m s will 
c o nt ai n a d e s cri pti o n of t h e o bj e cti v e s of t h e tri al, a d e s cri pti o n of t h e e x a mi n ati o n s a n d t e st s w hi c h will b e 
gi v e n t o t h e p arti ci p a nt  a s e a c h p art of t h e tri al, a s w ell a s e x p e ct ati o n s of t h e p arti ci p a nt  a s a tri al p arti ci p a nt.  
T hi s c o n s e nt f or m s will b e gi v e n t o t h e p arti ci p a nt ’ s p ar e nt or l e g al g u ar di a n b y a m e m b er of t h e cli ni c al c e nt er 
st aff , w h o will a ct a s a wit n e s s a n d si g n t h e f or m b el o w t h e si g n at ur e of t h e p ar e nt or l e g al g u ar di a n.  All l o c al 
c o n s e nt f or m s will n e e d t o b e a p pr o v e d b y t h e cli ni c al c o or di n ati n g c e nt er f or e s s e nti al c o nt e nt.  
 
1 2. 2   P arti ci p a nt  R e gi str ati o n  
P arti ci p a nt s will b e e nt er e d i nt o t hi s cli ni c al tri al d uri n g t h e  1 2 m o nt h s of a cti v e s cr e e ni n g  at e a c h sit e . Sit e s 
wit h l o w a c cr u al aft er 6 m o nt h s will h a v e a c o nf er e n c e c all or sit e vi sit b y a m e m b er of t h e E x e c uti v e 
C o m mitt e e t o ai d i n t h e i d e ntifi c ati o n of b arri er s t o r e cr uit m e nt a n d t o d e v el o p s ol uti o n s t o o v er c o m e t h e s e 
b arri er s.  If e nr oll m e nt r e m ai n s l o w, t h e sit e m a y b e r e m o v e d fr o m t h e st u d y , b a s e d o n a d e ci si o n b y t h e st u d y 
l e a d er s hi p.  E nr oll m e nt m a y b e e xt e n d e d f or 6 m o nt h s or l o n g er f or i n stit uti o n s d e m o n str ati n g l o w, b ut 
i m pr o vi n g, a c cr u al. All p arti ci p a nt s will b e e nt er e d a n d d at a c a pt ur e d vi a a w e b -b a s e d d at a s y st e m o p er at e d 
a n d m ai nt ai n e d b y t h e D at a C o or di n ati n g C e nt er. T h e st u di e s ar e t o b e p erf or m e d at t h e p arti ci p ati n g 
i n stit uti o n s a n d c e ntr all y r e vi e w e d b y t h e r e s p e cti v e s u b c o m mitt e e s ( N e ur ol o g y, N e ur or a di ol o g y, a n d 
P s y c h ol o g y) or at t h e I m a gi n g C e nt er.   


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 3 5  of 7 4  
 
1 2 . 3  St u d y Or g a ni z ati o n  
T h e H U Pr e v e nt St u d y will h a v e ni n e or g a ni z ati o n al c o m p o n e nt s: ( 1) 2 i niti al p arti ci p ati n g Cli n i c al Sit e s, 
p e di atri c h e m at ol o g y f a ciliti e s i n t h e U nit e d St at e s ( wit h a d diti o n al sit e s t o b e a d d e d) ( 2) Cli ni c al C o or di n ati n g 
C e nt er, ( 3) D at a C o or di n ati n g C e nt er,  ( 4) O p er ati o n s C o m mitt e e, ( 5) E x e c uti v e C o m mitt e e ( 6) N e ur ol o g y 
C o m mitt e e, ( 7) P s y c h ol o g y C o m mitt e e, ( 8) N e ur or a di ol o g y C o m mitt e e, ( 9) D at a a n d S af et y M o nit ori n g B o ar d.   
 
T h e C h air s of t h e Cli ni c al C o or di n ati n g C e nt er, D at a C o or di n ati n g C e nt er, a n d t h e Bi ol o gi c R e p o sit or y will b e 
l o c at e d at J o h n s H o p ki n s U ni v er sit y S c h o ol of M e di ci n e, B alti m ore, M D.  
 
T h e C h air s of t h e N e ur or a di ol o g y, S e d ati o n a n d P s y c h ol o g y C o m mitt e e s will b e l o c at e d at W a s hi n gt o n 
U ni v er sit y S c h o ol of M e di ci n e i n St. L o ui s, M O.  
 
T h e C h air of t h e N e ur ol o g y C o m mitt e e will b e l o c at e d at V a n d er bilt U ni v er sit y, N a s h vill e, T N.  
 
Cli ni c al sit e s w er e s el e ct e d o n t h e b a si s of t h eir cli ni c al e x p erti s e, t h eir p a st p erf or m a n c e i n cli ni c al st u di e s 
i n v ol vi n g si c kl e c ell di s e a s e, t h eir m a n a g e m e nt a n d tr e at m e nt of str o k e i n p ati e nt s wit h si c kl e c ell di s e a s e, t h e 
n u m b er s of p e di atri c p ati e nt s wit h si c kl e c ell di s e a s e tr e at e d at t h eir i n stit uti o n s a n n u all y, a n d t h e pr e s e n c e of 
pr e -e xi sti n g r el ati o n s hi p s of w or ki n g wit h Dr s . C a s ell a a n d ot h er m e m b er s of st u d y l e a d er s hi p   b a s e d o n 
c oll a b or ati v e pr oj e ct s a d dr e s si n g q u e sti o n s r e g ar di n g t h e e pi d e mi ol o g y a n d tr e at m e nt of str o k e s i n si c kl e c ell 
di s e a s e.   
 
 
1 2 . 4  D A T A  M O NI T O RI N G A N D R E VI E W C O M MI T T E E   
I n d e p e n d e nt l o c al st u d y m o nit or s will b e r e s p o n si bl e f or r e vi e wi n g l a b r e s ult s a n d i nf or mi n g t h e D at a 
C o or di n ati n g C e nt er a n d r e s e ar c h t e a m at t h eir c e nt er a b o ut h ol d s f or t o xi cit y or d o s e e s c al ati o n.  T o m ai nt ai n 
bli n di n g, si m ul at e d d o s e e s c al ati o n a n d h ol d s f or t o xi cit y b y t h e c e ntr al st u d y m o nit or will o c c ur f or t h e pl a c e b o 
ar m, a s i n pr e vi o u s h y dr o x y ur e a  tri al s.5 3   M or e d et ail e d di s c u s si o n of t h e st u d y m o nit or s r e s p o n si biliti e s a n d 
i nt er a cti o n s ar e d e s cri b e d i n A p p e n di x 2 0.  A d v er s e e v e nt s will b e r e c or d e d at st u d y vi sit s e v er y 4 w e e k s, 
u si n g  a str u ct ur e d f or m f or c o m m o n si d e eff e ct s of h y dr o x y ur e a  a n d c o m pli c ati o n s of S C D a n d cl a s sifi e d 
b a s e d o n s eri o u s n e s s, e x p e ct e d n e s s, a n d r el at e d n e s s b y p h y si ci a n s n ot ot h er wi s e i n v ol v e d i n t hi s st u d y. 5 4   
U n e x p e ct e d s e v er e a d v er s e e v e nt s t h at ar e r elat e d t o st u d y m e di c ati o n or pr o c e d ur e s will b e r e p ort e d t o t h e 
D S M B, F D A, a n d I R B wit hi n 7 c al e n d ar d a y s, if f at al or lif e -t hr e at e ni n g, a n d wit hi n 1 5 c al e n d ar d a y s, if n ot,  of 
t h e i n v e sti g at or s’ k n o wl e d g e of t h e m.  All S A E ( e x p e ct e d a n d u n e x p e ct e d) will b e pr o vi d e d t o t h e D S M B b y t h e 
D C C q u art erl y.   All A E ( s eri o u s a n d n o n -s eri o u s) wil l b e r e p ort e d t o t h e D S M B e v er y si x m o nt h s, or at t h e 
di s cr eti o n of t h e D S M B.  
 
M e m b er s of t h e i n d e p e n d e nt D at a a n d S af et y M o nit ori n g B o ar d ( D S M B) will  b e s el e ct e d b y t h e PI s of t h e st u d y , 
s u bj e ct t o N H L BI a p pr o v al.  T h e D S M B will m o nit or a c cr ui n g d at a i n or d er t o c o nfir m t h at t h e p arti ci p a nt s i n t h e 
trial ar e b ei n g c ar e d f or s af el y. T h e D S M B will b e r e s p o n si bl e f or:  
 
 
1.  
R e vi e wi n g a n d a p pr o vi n g t h e st u d y pr ot o c ol  
 
2.  
R e vi e wi n g a n d a n al y zi n g t h e pr o gr e s s of t h e st u d y;  
  
3. 
A p pr o vi n g a m e n d m e nt s t o t h e tri al pr ot o c ol, if w arr a nt e d;  
  
4. 
M o nit ori n g t h e s af et y of t h e st u d y pr o c e d ur e s a n d tr e at m e nt s; 
 
5.  
R e vi e wi n g d at a q u alit y;  
  
6. 
R e vi e wi n g i nt eri m a n al y s e s a n d r e c o m m e n di n g e arl y st o p pi n g or c o nti n u ati o n of t h e tri al;  
  
7. 
R e vi e wi n g r e cr uit m e nt, cr o s s o v er r at e s, a n d e v e nt r at e s  
 
T h e Cli ni c al C o or di n ati n g C e nt er a n d St ati sti c al a n d D at a C o or di n ati n g C e nt er will pr o vi d e i nf or m ati o n t o t hi s 
c o m mitt e e a s r e q u e st e d  a n d e v er y 6 m o nt h s f or all A E s.  T h e D S M B will r e vi e w st u d y d at a r e p ort s, i n cl u di n g 
pri m ar y e n d p oi nt a n al y si s, e v er y si x m o nt h s , eit h er i n a m e eti n g or o n a c o nf er e n c e c all .  T h e y will r e vi e w b y 
c o nf er e n c e c all wit hi n 2 w e e k s of o bt ai ni n g t h e r e q uir e d n u m b er of st u di e s t h e s e v er e a d v er s e e v e nt s r el at e d 
t o s e d ati o n f or  M RI s , f oll o wi n g t h e s c h e d ul e i n S e cti o n 1 1.6 . 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 3 6  of 7 4  
 
1 3. 0  H u m a n S u bj e ct s C o n si d er ati o n s  
 
1 3. 1  G e n er al i s s u e s of d e si g n  
 
Bli n di n g, a n d j u stifi c ati o n . 
T hi s st u d y will b e bli n d e d wit h a pl a c e b o c o ntr ol t o mi ni mi z e cr o s s -o v er s a n d bi a s i n t h e cl a s sifi c ati o n of 
o ut c o m e s a n d a d v er s e eff e ct s s e c o n d ar y t o h y dr o x y ur e a.  
 
J u stifi c ati o n f or i n cl u si o n of a pl a c e b o or n o n -tr e at m e nt gr o u p. 
A pl a c e b o or n o n -tr e at m e nt gr o u p i s e s s e nti al t o h a v e a n a p pr o pri at e c o m p ari s o n gr o u p, a s t h er e m a y b e 
u n k n o w n c o nf o u n d er s t h at c o ul d n ot b e a dj u st e d f or d uri n g a n al y si s.  R a n d o mi z ati o n all o c ati o n t o tr e at m e nt 
wit h h y dr o x y ur e a or pl a c e b o will mi ni mi z e t h e pr o b a bilit y of bi a s.  
 
Pr o c e d ur e s r e g ar di n g tr e at m e nt f or p arti ci p a nt s w h e n t h e st u d y e n d s or if a p arti ci p a nt’ s p arti ci p ati o n i n t h e 
st u d y e n d s pr e m at ur el y . 
P arti ci p a nt s will b e a bl e t o c o nti n u e or di s c o nti n u e h y dr o x y ur e a aft er t h eir p arti ci p ati o n i n t h e st u d y e n d s at t h e 
di s cr eti o n of t h eir pri m ar y h e m at ol o gi st a n d p ar e nt s or g u ar di a n s, a s t hi s m e di c ati o n i s i n cli ni c al u s e f or 
c hil dr e n wit h S C D.  T h e st u d y l e a d er s hi p will f a cilit at e t h eir a c c e s s t o h y dr o x y ur e a.  
 
S o ur c e s of M at eri al s:  
I nf or m ati o n c o n c er ni n g t h e c hil d' s m e di c al, f a mil y, a n d d e v el o p m e nt al hi st or y will b e o bt ai n e d b y i nt er vi e w of 
t h e p ar e nt or g u ar di a n a n d r e vi e w of t h e m e di c al r e c or d. B e h a vi or al q u e sti o n n air e s a n d c o g niti v e t e sti n g will b e 
c o m pl et e d f or r e s e ar c h p ur p o s e s.  Vit al si g n s a n d ot h er el e m e nt s of t h e p h y si c al e x a m, l a b or at or y a n d i m a gi n g 
st u di e s ( M RI of t h e br ai n a n d T C D ultr a s o u n d) will b e c oll e ct e d a n d u s e d f or r e s e ar c h p ur p o s e s.  S o m e of 
t h e s e r e s ult s will b e r el e a s e d t o t h e p arti ci p a nt s or t h eir p ar e nt s a n d s h ar e d wit h t h eir d o ct or s or s c h o ol s ( b ut 
o nl y wit h t h e c o n s e nt of t h e p ar e nt or g u ar di a n).  S o m e of t hi s i nf or m ati o n ( hi st or y a n d p h y si c al e x a m s fr o m 
st u d y vi sit s, cli ni c al i nt er pr et ati o n s of T C D s a n d M RI s a n d r o uti n e l a b or at or y t e st s) will b e i n cl u d e d i n t h e 
m e di c al r e c or d of t h e p arti ci p a nt a n d t h er ef or e dir e ctl y li n k e d b y n a m e a n d m e di c al r e c or d n u m b er.  
I nf or m ati o n c oll e ct e d s p e cifi c all y f or t hi s r e s e ar c h pr oj e ct ( c o g niti v e t e sti n g, b e h a vi or al q u e sti o n n air e s, 
bi or e p o sit or y s p e ci m e n s) will b e dir e ctl y li n k e d t o t h e st u d y I D.  O nl y t h e n e c e s s ar y r e s e ar c h p er s o n n el will 
h a v e a c c e s s t o t h e li st li n ki n g t h e st u d y I D t o p er s o n al i d e ntifi er s of t h e p arti ci p a nt.  
 
1 3. 2   P ot e nti al Ri s k s  
T C D:  T h er e ar e n o k n o w n si g nifi c a nt ri s k s t o T C D t e sti n g i n c hil dr e n.  C hil dr e n m a y b e u n c o mf ort a bl e h a vi n g 
t o h ol d still or h a v e a n xi et y a b o ut t h e r e s ult s. 
 
P hl e b ot o m y:   At v ari o u s vi sit s fr o m 2 t o 1 0 ml of bl o o d will b e dr a w n t hr o u g h a p eri p h er al v ei n f or t e st s a n d 
st or a g e i n a bi ol o gi c al r e p o sit or y.  P hl e b ot o m y i s oft e n a s s o ci at e d wit h mil d p ai n a n d o c c a si o n all y wit h a s m all 
br ui s e at t h e sit e.  R ar el y, p arti ci p a nt s f e el li g ht h e a d e d or h a v e s y n c o p e.  T h er e i s al s o a v er y s m all ri s k of 
i nf e cti o n at t h e sit e of t h e n e e dl e p u n ct ur e. T h e m a xi m u m a m o u nt r e m o v e d i s 1. 5 % of t h e bl o o d v ol u m e f or a n 
8. 6 k g c hil d wit h S C D ( 5 t h p er c e ntil e of w ei g ht f or a 1 y e ar ol d), a n d h a s n o a d diti o n al ri s k s, e v e n i n a n a n e mi c 
c hil d.  
 
Hi st or y a n d p h y si c al e x a m:  S o m e c hil dr e n will b e c o m e u n c o mf ort a bl e or a n xi o u s d uri n g t h e q u e sti o n s or 
e x a mi n ati o n.  
 
N e ur o p s y c h ol o gi c al t e st s: C hil dr e n m a y o c c a si o n all y e x p eri e n c e s o m e mil d a n xi et y d uri n g t e sti n g.  T h e r e s ult s 
of t e st s m a y aff e ct s c h o ol pl a c e m e nt, b ut t h e r e s ult s ar e o nl y r el e a s e d b y p ar e nt al r e q u e st.  A r el a x e d 
e n vir o n m e nt wit h fr e q u e nt br e a k s will mi ni mi z e a n xi et y.  
 
M RI/ M R A of t h e br ai n:  P ot e nti al ri s k s d u e t o M R i m a gi n g i n cl u d e ( 1) cl a u str o p h o bi a, ( 2) m o v e m e nt of 
p ar a m a g n eti c m at eri al s, ( 3) i d e ntifi c ati o n of a n i n ci d e nt al fi n di n g.   Cl a u str o p h o bi a i n t h e M RI s c a n n er i s 
u n c o m m o n i n c hil dr e n.  M o v e m e nt of p ar a m a g n eti c m at eri al ( eit h er wit hi n t h e p arti ci p a nt  or i n t h e s c a n n er 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 3 7  of 7 4  
r o o m) i s r ar e s e c o n d ar y t o t h e pr e c a uti o n s d e cri b e d b el o w.   All i ntr a cr a ni al  i n ci d e nt al fi n di n g s (i d e ntifi e d i n 
a p pr o xi m at el y 5 % of c hil dr e n wit h S C D) will b e di s c u s s e d wit h t h e p ar e nt of g u ar di a n a n d a d diti o n al t e sti n g 
m a y b e r e c o m m e n d e d.   S o m e c hil dr e n ar e s c ar e d b y t h e n oi s e or b ei n g al o n e i n t h e s c a n n er.  
 
S e d ati o n : P ot e nti al c o m pli c ati o n s of s e d ati o n i n cl u d e r e s pir at or y d e pr e s si o n l e a di n g t o h y p o x e mi a a n d 
r e q uiri n g a d diti o n al s u p p ort, i n cl u di n g or al air w a y, n a s o p h ar y g e al tr u m p et, l ar y n g e al m a s k or e n d otr a c h e al 
i nt u b ati o n t o m ai nt ai n t h e air w a y, p o siti v e pr e s s ur e v e ntil ati o n b y m a s k, or a v e ntil at or.  R ar el y t h e s e 
c o m pli c ati o n s c a n i n cl u d e r e s pir at or y or c ar di a c arr e st a n d e v e n d e at h.  S e d ati o n m a y al s o l e a d t o d el a y e d 
c o m pli c ati o n s of S C D i n t h e n e xt 4 8 h o ur s, i n cl u di n g a c ut e c h e st s y n dr o m e, p ai n, or v er y r ar el y str o k e.  
C o n c er n h a s b e e n r ai s e d o v er  a p o s si bl e i n cr e a s e d ri s k of d e v el o p m e nt al d el a y aft er a n e st h e si a , b a s e d o n 
a ni m al st u di e s wit h pr ol o n g e d hi g h d o s e e x p o s ur e a n d c a s e -c o ntr ol st u di e s of y o u n g c hil dr e n u n d er g oi n g 
a n e st h e si a.   T h e si g nifi c a n c e of t h e s e fi n di n g s i s c o ntr o v er si al a n d u n d er a cti v e i n v e sti g ati o n i n c o ntr oll e d 
tri al s.  Se d ati o n will r e q uir e pl a c e m e nt of a p eri p h er al i ntr a v e n o u s c at h et er ( PI V).  T hi s i s oft e n a s s o ci at e d wit h 
mil d p ai n a n d o c c a si o n all y wit h a s m all br ui s e at t h e sit e or p hl e biti s.  R ar el y, p arti ci p a nt s f e el li g ht h e a d e d or 
h a v e s y n c o p e.  T h er e i s al s o a v er y s m all ri s k of i nf e cti o n.  A d v er s e eff e ct s r el at e d t o t h e m e di c ati o n s u s e d f or 
s e d ati o n ar e li st e d b el o w.  
 
Mi d a z ol a m : T hi s a g e nt i s gi v e n pri or t o s e d ati o n t o r e d u c e a n xi et y a n d t o c a u s e a m n e si a. C o m m o n a d v er s e 
eff e ct s i n cl u d e h y p o v e ntil ati o n, s h ort p eri o d s of a p n e a, a n d s o m n ol e n c e.  U n c o m m o n a d v er s e eff e ct s ar e 
n a u s e a, v o miti n g, hi c c o u g h s, i n v ol u nt ar y m o v e m e nt s, a n d h e a d a c h e.   R ar e a d v er s e eff e ct s i n cl u d e 
r e s pir at or y arr e st a n d h y p ot e n si o n.  
 
Pr o p of ol : T hi s i s a fr e q u e ntl y u s e d a g e nt f or d e e p s e d ati o n f or pr o c e d ur e s C o m m o n a d v er s e eff e ct s i n cl u d e 
h y p ot e n si o n, s h ort p eri o d s of a p n e a, a n d p ai n at t h e i nf u si o n sit e.  U n c o m m o n a d v er s e eff e ct s ar e m y o cl o n u s 
a n d pri a pi s m, a n d r ar e a d v er s e eff e ct s i n cl u d e d y st o ni a.  
 
Li d o c ai n e : T hi s m e di c ati o n i s oft e n a d mi ni st er e d b ef or e t h e pr o p of ol t o r e d u c e p ai n. A d v er s e eff e ct s i n cl u d e 
n a u s e a ( c o m m o n), dr o w si n e s s, l a bil e m o o d, ti n nit u s, di z zi n e s s, vi si o n c h a n g e s, tr e m or s, n u m b n e s s, 
h e a d a c h e, b a c k a c h e ( u n c o m m o n), a n d f e v er, t a c h y c ar di a or br a d y c ar di a, r e s pir at or y di str e s s, s ei z ur e s, or 
c h e st p ai n (r ar e).  
 
S e v ofl ur a n e : T hi s m e di c ati o n will b e u s e d t o i n d u c e s e d ati o n i n c hil dr e n t h at c a n n ot h a v e a PI V pl a c e d e a sil y 
w hil e a w a k e.  C o m m o n a d v er s e eff e ct s ar e n a u s e a, cr yi n g, c o nf u si o n, hi c c u p s, a n d h y p er s ali v ati o n.  
U n c o m m o n a d v er s e eff e ct s ar e e m e si s, dr y m o ut h, pr urit u s, r a s h, f e v er, a n d t e m p or ar y di s c o nj u g at e g a z e.  
R ar e a d v er s e eff e ct s i n cl u d e arr h yt h mi a s , a git ati o n, diffi c ult y br e at hi n g, h y p ot e n si o n, f ati g u e, or s hi v eri n g. 
 
Nitr o u s o xi d e :  Thi s i n h al ati o n a g e nt i s c o m m o nl y u s e d f or s h ort p ai nf ul pr o c e d ur e s.  C o m m o n a d v er s e eff e ct s 
i n cl ud e h e a d a c h e, di z zi n e s s, c o nf u si o n, a n d h y p ot e n si o n a n d u n c o m m o n a d v er s e eff e ct s ar e n a u s e a, e m e si s, 
i n cr e a s e d mi d dl e e ar pr e s s ur e, a n d a p n e a.  R ar e a d v er s e e v e nt s i n cl u d e el e v at e d tr a n s a mi n a s e s a n d 
i n cr e a s e d i ntr a cr a ni al pr e s s ur e. 
 
H y dr o x y ur e a : H y dr o x y ur e a  h a s b e e n i n cli ni c al u s e f or o v er 3 0 y e ar s a n d h a s s e v er al w ell -r e c o g ni z e d p ot e nti al 
ri s k s, i n cl u di n g r e v er si bl e b o n e m arr o w s u p pr e s si o n a n d  m a cr o c yt o si s t h at m a y m a s k f oli c a ci d or B 1 2 
d efi ci e n c y. It i s k n o w n t o c a u s e birt h d ef e ct s i n a ni m al s.  S o m e p ati e nt s will h a v e mil d n a u s e a or v o miti n g a n d 
r ar el y d ar k e ni n g of t h e s ki n a n d n ail s, ul c er ati o n of t h e s ki n of t h e l e g s, or h e p ati c t o xi cit y ( el e v at e d 
tr a n s a mi n a s e s).  S ki n n e cr o si s h a s r e c e ntl y b e e n r e p ort e d a s a r ar e si d e eff e ct i n p ati e nt s r e c ei vi n g 
h y dr o x y ur e a f or m y el o pr olif er ati v e di s or d er s a n d m e n wit h S C D t a ki n g h y dr o x y ur e a m a y h a v e d e cr e a s e d 
s p er m c o u nt s a n d s p er m q u alit y.  
 
Di s cl o s ur e of c o nfi d e nti al i nf or m ati o n: T h er e i s a s m all ri s k of br e a c h e s i n c o nfi d e nti alit y. T hi s m a y aff e ct t h e 
p arti ci p a nt’ s f ut ur e a bilit y t o o bt ai n e m pl o y m e nt or m e di c al, di s a bilit y, or lif e i n s ur a n c e. 
 
Alt er n ati v e tr e at m e nt s:  T h e alt er n ati v e t o p arti ci p ati o n i n t hi s tri al i s t o h a v e u s u al c ar e , wit h a n M RI of t h e 
br ai n if r e c o m m e n d e d b y y o ur p h y si ci a n a n d T C D a n n u all y b e gi n ni n g at a g e 2.  If a c hil d d e v el o p s a n 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 3 8  of 7 4  
a b n or m al T C D or str o k e, tr a n sf u si o n a p pr o xi m at el y e v er y 4 w e e k s i s u s u all y r e c o m m e n d e d t o d e cr e a s e t h e 
ri s k of fir st or r e c urr e nt str o k e.  M o nt hl y tr a n sf u si o n h a s w ell-d o c u m e nt e d ri s k s (tr a n sf u si o n r e a cti o n s, ir o n 
o v er l o a d, tr a n s mi s si o n of i nf e cti o u s a g e nt s, a n d v ol u m e o v erl o a d). 
 
R e cr uit m e nt a n d C o n s e nt: P arti ci p a nt s will b e r e cr uit e d t hr o u g h t h e s e v e n  cli ni c al c e nt er s. A d dit o n al c e nt er s 
m a y b e a d d e d, if r e cr uit m e nt r e q uir e s t hi s.  T h e p ar e nt or g u ar di a n of t h e pr o s p e cti v e p arti ci p a nt will r e c ei v e a 
m aili n g a b o ut t h e st u d y a n d al s o b e i nf or m e d a b o ut t h e st u d y d uri n g cli ni c a p p oi nt m e nt s a n d a d mi s si o n s.  T h e 
st u d y will b e e x pl ai n e d t o i nt er e st e d p ar e nt s. If t h e p ar e nt a gr e e s t o p arti ci p at e, i nf or m e d c o n s e nt fr o m t h e 
p ar e nt or l e g al g u ar di a n will b e o bt ai n e d a n d d o c u m e nt e d o n c o n s e nt f or m s a p pr o v e d b y t h e I n stit uti o n al 
R e vi e w B o ar d.  C o n s e nt will b e o bt ai n e d b y t h e l o c al i n v e sti g at or s, u s u all y i n t h e o ut p a ti e nt cli ni c.  
 
1 3 . 3 
A d e q u a c y of pr ot e cti o n a g ai n st ri s k s  
 
P hl e b ot o m y :  V e n o u s bl o o d will b e c oll e ct e d b y tr ai n e d p er s o n n el wit h e x p eri e n c e i n p e di atri c p hl e b ot o m y.  
T h e y will f oll o w st a n d ar d h o s pit al pr o c e d ur e s t o mi ni mi z e ri s k.  
 
Hi st or y a n d p h y si c al e x a m:  T h e e x a m  will b e o bt ai n e d b y e x p eri e n c e d p e di atri c pr o vi d er s s kill e d at mi ni mi zi n g 
di s c o mf ort or e m b arr a s s m e nt f or t h e p arti ci p a nt s a n d t h eir p ar e nt s.  
 
N e ur o p s y c h ol o gi c al t e st s:  A n e x p eri e n c e d p e di atri c n e ur o p s y c h ol o gi st or p s y c h o m etri ci a n will pr o vi d e a 
r el a x e d e n vir o n m e nt wit h fr e q u e nt br e a k s t o mi ni mi z e a n xi et y.  
 
M RI/ M R A of t h e br ai n:  C hil dr e n will b e s cr e e n e d f or f err o m a g n eti c m at eri al s a n d i m pl a nt s t h at m a y b e u n s af e 
d uri n g M RI a n d r e q uiri n g e x cl u si o n.  
 
S e d ati o n : T hi s will b e p erf or m e d u si n g a st a n d ar di z e d pr ot o c ol d e v el o p e d b y a n e st h e si ol o gi st s a n d p e di atri c 
s e d ati o n e x p ert s.  S e d ati o n will b e p erf or m e d b y e x p eri e n c e d p e di atri c pr o vi d er s ( a n e st h e si ol o gi st s, 
i nt e n si vi st s, or h o s pit ali st s) cli ni c all y cr e d e nti al e d t o p erf or m s e d ati o n at t h eir r e s p e cti v e i n stit uti o n s, wit h dir e ct 
s u p er vi si o n b y a n att e n di n g a n e st h e si ol o gi st.  P arti ci p a nt s will b e s cr e e n e d b y a q u e sti o n n air e a n d s e d ati o n 
p o st p o n e d or c a n c ell e d if t h e p arti ci p a nt i s at i n cr e a s e d ri s k of c o m pli c ati o n s.  All p arti ci p a nt s will b e e x a mi n e d 
b ef or e t h e s e d ati o n pr o c e d ur e b y a p e di atri c h e m at ol o gi st a n d i m m e di at el y b ef or e t h e s e d ati o n b y t h e s e d ati o n 
pr o vi d er t o i d e ntif y f a ct or s t h at m a y i n cr e a s e ri s k a n d r e q uir e t h at t h e s e d ati o n f or t h e M RI b e p o st p o n e d or n ot 
u n d ert a k e n.  
W e will al s o mi ni mi z e t h e ri s k of  p erf or mi n g s e d at e d M RI s i n c hil dr e n t h at ar e n ot eli gi bl e f or r a n d o mi z ati o n b y 
t h e f oll o wi n g: 
C o nfir mi n g t h at p ot e nti al p arti ci p a nt s m e et  all ot h er eli gi bilit y r e q uir e m e nt s f or r a n d o mi z ati o n ( e. g., n o pri or 
str o k e or ot h er m aj or n e ur ol o gi c al di s or d er, n o si g nifi c a nt c yt o p e ni a s or or g a n d y sf u n cti o n, c er e br al bl o o d fl o w 
v el o cit y b y tr a n s cr a ni al D o p pl er ultr a s o u n d b el o w t h e t hr e s h ol d f or tr e at m e nt wit h tr a n sf u si o n s) b ef or e 
p erf or mi n g t h e s e d at e d M RI of t h e br ai n.   B y p erf or mi n g t h e M RI a s t h e l a st pr o c e d ur e, a s t hi s i s t h e o nl y st u d y 
pr o c e d ur e a s s o ci at e d wit h si g nifi c a nt ri s k,   p arti ci p a nt s w h o w o ul d ot h er wi s e n ot q u alif y o n  ot h er gr o u n d s will 
n ot u n d er g o t hi s pr o c e d ur e u n n e c e s s aril y.   
 I n a d diti o n, aft er t h e fir st t e n p arti ci p a nt s ar e s cr e e n e d, w e will e v al u at e all cli ni c al d at a, t o s e e if a n y 
si g nifi c a nt pr e di ct or s of Sil e nt C er e br al I nf ar cti o n ( S CI) c a n  b e i d e ntifi e d t h at w o ul d t ell u s t h e s e p arti ci p a nt s 
s h o ul d n ot b e s cr e e n e d.  W e will t h e n c o nti n u e t o d o t hi s p er t h e s a m e s c h e d ul e a s m o nit ori n g f or a d v er s e 
e v e nt s a s s o ci at e d wit h t h e s e d at e d M RI.  
H y dr o x y ur e a:    T h e ri s k of b o n e m arr o w s u p pr e s si o n will b e mi ni mi z e d b y fr e q u e nt m o nit ori n g of t h e 
p arti ci p a nt s wit h a C B C wit h diff er e nti al a n d r eti c ul o c yt e c o u nt e v er y t w o t o f o ur w e e k s.  T h e p arti ci p a nt s will 
b e c ar ef ull y f oll o w e d t o i d e ntif y ot h er a d v er s e eff e ct s ( c o m pr e h e n si v e p a n el e v er y t hr e e m o nt h s t o e v al u at e 
h e p ati c a n d r e n al f u n cti o n) fr o m t h e m e di c ati o n a n d t o i nt er v e n e e arl y t o mi ni mi z e t h e ri s k of s eri o u s a d v er s e 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 3 9  of 7 4  
e v e nt s.  W e will a s k t h e p ar e nt s of t h e p arti ci p a nt s t o u s e pr e c a uti o n s w hil e a d mi ni st eri n g t h e st u d y m e di c ati o n 
t o a v oi d dir e ct c o nt a ct wit h it. 
 
P arti ci p a nt  c o nfi d e nti alit y :  T o pr ot e ct of t h e c o nfi d e nti alit y of t h e p arti ci p a nt s, n a m e s will b e r e m o v e d fr o m 
e a c h p arti ci p a nt' s fil e a n d r e pl a c e d wit h a n i d e ntifi c ati o n c o d e.  All t e sti n g pr ot o c ol s will u s e t h e s e c o d e s t o 
i d e ntif y s u bj e ct s. A li st t h at c o nt ai n s t h e m at c h b et w e e n t h e c o d e a n d n a m e will b e k e pt i n a s e c ur e l o c ati o n 
o nl y a c c e s si bl e t o t h e i n v e sti g at or s a n d st u d y p er s o n n el.   All d at a will b e r etri e v e d u si n g t h e i d e ntifi c ati o n 
c o d e.  D at a  will b e m ai nt ai n e d o n c o m p ut er d at a b a s e o nl y a c c e s si bl e t o t h e i n v e sti g at or s a n d st u d y p er s o n n el.  
 
1 3. 4  
P ot e nti al b e n efit s of t h e pr o p o s e d r e s e ar c h t o t h e s u bj e ct s a n d ot h er s  
 
P r o b a bl e b e n efit s f or t h e p arti ci p a nt a n d f or s o ci et y. 
 
T hi s st u d y will h el p t o e v al u at e t h e effi c a c y of h y dr o x y ur e a f or t h e pri m ar y pr e v e nti o n of a b n or m al T C D, sil e nt 
c er e br al i nf ar ct, c o g niti v e i m p air m e nt a n d str o k e i n c hil dr e n wit h H b S S.  If h y dr o x y ur e a i s effi c a ci o u s i n 
pr e v e nti n g t h e C N S c o m pli c ati o n s of S C D, t h e p arti ci p a nt s t a ki n g t h e dr u g will b e n efit.  If h y dr o x y ur e a i s 
effi c a ci o u s, it c o ul d al s o pr e v e nt t h e n e e d t o i niti at e tr a n sf u si o n i n m a n y c hil dr e n wit h H b S S.  M a n y p ati e nt s 
w h o d o n ot m e et t h e c urr e nt crit eri a f or tr a n sf u si o n al s o s uff er t h e s e c o m pli c ati o n s, a n d h y dr o x y ur e a m a y 
d e cr e a s e t h e ri s k of str o k e i n t hi s gr o u p.  Ulti m at el y, m a n y m or e C N S c o m pli c ati o n s c o ul d b e pr e v e nt e d t h a n 
wit h c hr o ni c tr a n sf u si o n s, gi v e n t h e l o w er c o st a n d r el ati v e e a s e of a d mi ni str ati o n of h y dr o x y ur e a c o m p ar e d t o 
tr a n sfu si o n s.  Al s o, t h e si d e eff e ct s of h y dr o x y ur e a a n d b ur d e n t o p ati e nt s m a y b e p er c ei v e d t o b e l o w er a n d 
l e s s s e v er e b y m a n y p ati e nt s t h a n c hr o ni c tr a n sf u si o n s.  T h e p ati e nt s w h o r e c ei v e pl a c e b o will b e f oll o w e d 
m or e cl o s el y ( vi sit s e v er y 4 w e e k s) a n d t hi s will pr o vi d e a d diti o n al o p p ort u nit y f or e d u c ati o n a b o ut S C D, 
pr o m pt r e c o g niti o n of c o m pli c ati o n s of t h eir di s e a s e a n d di s e a s e pr e v e nti o n.  T h e p ot e nti al dir e ct b e n efit s t o 
t h e p arti ci p a nt s a n d f or ot h er p ati e nt s wit h S C D a p p e ar t o o ut w ei g h t h e ri s k s of t h e st u d y.  
 
1 3. 5   I m p ort a n c e of k n o wl e d g e t o b e g ai n e d 
 
T h e effi c a c y of h y dr o x y ur e a  i n tr e ati n g n e ur ol o gi c c o m pli c ati o n s of S C D i s n ot w ell e st a bli s h e d, n or ar e t h e 
i n di c ati o n s f or h y dr o x y ur e a  i n c hil d h o o d.  T hi s st u d y will e v al u at e t h er a p y t o pr e v e nt pr o gr es si o n t o a b n or m al 
T C D, sil e nt c er e br al i nf ar ct, c o g niti v e i m p air m e nt a n d str o k e.  T hi s st u d y will al s o pr o vi d e t h e n e c e s s ar y 
f e a si bilit y d at a t o p ot e nti all y e v al u at e h y dr o x y ur e a f or t h e pri m ar y pr e v e nti o n of C N S c o m pli c ati o n s of H b S S i n 
a d efi niti v e P h a s e III tri al.  F urt h er st u di e s will b e n e c e s s ar y t o d et er mi n e w h et h er p ati e nt s p er c ei v e t h e b ur d e n 
of h y dr o x y ur e a t o b e l e s s t h a n t h at of tr a n sf u si o n s, b ut t h e pr e s e nt st u d y m a y h el p s h e d s o m e li g ht o n t hi s a s 
w ell.  It i s e x p e ct e d t h at a l ar g er gr o u p of p ati e nt s at ri s k c o ul d b e tr e at e d wit h h y dr o x y ur e a t h a n tr a n sf u si o n s.  
T hi s w o ul d b e a tr e m e n d o u s b e n efit i n t h e tr e at m e nt of S C D a n d pr e v e nti o n of C N S c o m pli c ati o n s.  It m a y al s o 
cl arif y w h et h er all c hil dr e n wit h S C D s h o ul d b e tr e at e d wit h h y dr o x y ur e a , b arri n g c o ntr ai n di c ati o n s. 
 
C oll e cti o n of s p e ci m e n s f or a bi ol o gi c al r e p o sit or y wit h d et ail e d i nf or m ati o n o n M RI, c er e br al bl o o d fl o w v el o cit y 
a n d ot h er p h e n ot y p e i nf or m ati o n will i m pr o v e o ur u n d er st a n di n g of S C D a n d p ot e nti all y pr o vi d e c o m p elli n g 
e vi d e n c e t h at h y dr o x y ur e a c a n pr e v e nt c hr o ni c n e ur ol o gi c al c o m pli c ati o n s of S C D.  T h e st u di e s u si n g t hi s 
r e p o sit or y m a y i d e ntif y n e w pr o g n o sti c f a ct or s, bi o m ar k er s a n d t ar g et s f or t h er a p y. 
 
Ri s k/ B e n efit:  T hi s st u d y will h o p ef ull y pr o vi d e t h e n e c e s s ar y f e a si bilit y d at a t o pr o c e e d wit h a P h a s e III tri al of 
h y dr o x y ur e a t o pr e v e nt C N S c o m pli c ati o n s i n c hil dr e n wit h H b S S a n d H B S β 0 .  Tr e at m e nt wit h h y dr o x y ur e a 
a n d s e d ati o n i s a s s o ci at e d wit h m o d er at e ri s k, b ut t hi s ri s k c a n b e mi ni mi z e d wit h st a n d ar di z e d pr ot o c ol s a n d 
m o nit or i n g.  T h e d e gr e e of ri s k i s r e a s o n a bl e, gi v e n t h e m or bi dit y of n e ur ol o gi c al i nj ur y i n c hil dr e n wit h S C D, 
t h e m or bi dit y of c urr e nt tr e at m e nt s f or str o k e a n d i m p e n di n g str o k e (tr a n sf u si o n s a n d c h el ati o n), t h e p ot e nti al 
f or dir e ct b e n efit f or t h e c hil dr e n a n d t h e p o s si bl e i m p ort a n c e of t h e r e s ult s. 
 
1 3. 6  
D at a a n d s af et y m o nit ori n g pl a n  
 
S af et y a s s e s s m e nt s  


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 4 0  of 7 4  
 
P arti ci p a nt s will b e e v al u at e d e v er y t w o w e e k s aft er a c h a n g e i n d o s e a n d ot h er wi s e e v er y f o ur w e e k s. A n 
i nt er v al hi st or y of m e di c al e v e nt s a n d p ot e nti al a d v er s e e v e nt s will b e o bt ai n e d at t h e s e vi sit s.  T hi s i nf or m ati o n 
will b e c oll e ct e d f or 4 w e e k s aft er t h e p arti ci p a nt h a s st o p p e d t h e st u d y m e di c ati o n.  C o n diti o n al a n d a b n or m al 
T C D s will b e r e p e at e d wit hi n d efi n e d i nt er v al s t o d et e ct pr o gr e s si o n a n d t h e n e e d f or tr a n sf u si o n s.  
 
S af et y i nf or m ati o n will b e s e nt t o t h e c o or di n ati n g c e nt er l e d b y D a ni el H a nl e y, M D a n d s u p p ort e d b y t h e J o h n s 
H o p ki n s I C T R.  T hi s c e nt er will b e r e s p o n si bl e f or d at a m a n a g e m e nt, d at a q u alit y a s s ur a n c e, r a n d o m st o p 
or d er s a n d d o s e e s c al ati o n or d er s f or h y dr o x y ur e a, a n d pr o vi di n g i nf or m ati o n o n r e s ult s a n d a n al y s e s t o t h e 
D S M B.  
 
A d v er s e e v e nt s: D at a will b e c oll e ct e d o n a d v er s e e v e nt s ( A E), a n y a b n or m al fi n di n g ( hi st or y, p h y si c al e x a m, 
l a b or at or y, or i m a gi n g) of a p arti ci p a nt i n t h e st u d y. 
 
U n e x p e ct e d A E s ar e a d v er s e r e a cti o n s t h at ar e n ot c o n si st e nt ( n at ur e or s e v erit y) wit h t h e a v ail a bl e 
i nf or m ati o n o n h y dr o x y ur e a or S C D. 
 
S eri o u s a d v er s e e v e nt ( S A E)  
R e s ult s i n d e at h  
Lif e -t hr e at e ni n g ( p arti ci p a nt at ri s k of d e at h at t h e ti m e of t h e ev e nt)  
R e q uir e s or pr ol o n g s h o s pit ali z ati o n.  
C a u s e s p er si st e nt or si g nifi c a nt di s a bilit y.  
R e s ult s i n a c o n g e nit al a n o m al y.  
Ot h er m e di c al e v e nt s (i n t h e o pi ni o n of t h e i n v e sti g at or) t h at m a y p ut t h e p arti ci p a nt at ri s k or r e q uir e 
i nt er v e nti o n t o pr e v e nt a s eri o u s A E. 
 
A E s will b e s c or e d u si n g t h e C o m m o n T o xi cit y Crit eri a f or A d v er s e E v e nt s ( C T C A E) 3. 0 of t h e N ati o n al C a n c er 
I n stit ut e a n d t h e st a n d ar d n o m e n cl at ur e f or d efi ni n g t h e c a u s al r el ati o n b et w e e n t h e A E a n d st u d y dr u g 
( u nr el at e d, pr o b a bl y n ot r el at e d/r e m ot e, p o s si bl y r el at e d, pr o b a bl y r el at e d, d efi nit el y r el at e d) 
 
A E s will b e f oll o w e d u ntil t h e y r e s ol v e or st a bili z e.  A E s will b e cl a s sifi e d a s o n g oi n g, r e s ol v e d wit h o ut 
s e q u el a e, r e s ol v e d wit h s e q u el a e, or d e at h.  T h e r e s p o n s e t o t h e A E will b e r e c or d e d.  
 
R e p orti n g of e v e nt s  
S eri o u s s af et y i s s u e s will b e r e p ort e d t o t h e D S M B, w hi c h will m a k e r e c o m m e n d ati o n s t o t h e s p o n s or ( N H L BI) 
a b o ut t h e st u d y.  
 
U n e x p e ct e d S A E will b e r e p ort e d t o t h e D S M B  a n d F D A  wit hi n 7 c al e n d ar d a y s, if f at al or lif e -t hr e at e ni n g, a n d 
wit hi n 1 5 c al e n d ar d a y s if n ot.  
 
All S A E ( e x p e ct e d a n d u n e x p e ct e d) will b e pr o vi d e d t o t h e D S M B b y t h e D C C q u art erl y.  
 
All A E ( s eri o u s a n d n o n -s eri o u s) will b e r e p ort e d t o t h e D S M B e v er y si x m o nt h s  or at t h eir di s cr eti o n . 
 
S af et y m o nit ori n g  
T h e D S M B will i n cl u d e a p e di atri c h e m at ol o gi st, p e di atri c a n e st h e si ol o gi st, a n d a bi o st ati sti ci a n wit h e x p erti s e 
i n cli ni c al tri al s.  T h e D S M B will r e vi e w t h e s af et y d at a, a s w ell a s i nf or m ati o n o n e nr oll m e nt at t h eir m e eti n g 
a p pr o xi m at el y e v er y si x m o nt h s  aft er t h e fir st p arti ci p a nt i s e nr oll e d  or at t h e di s cr eti o n of t h e D S M B, b a s e d o n 
p ati e nt a c c ru al .  U p o n t h e r e vi e w of t h e s af et y d at a a s w ell a s i nt eri m d at a a n al y si s of e nr oll e d s u bj e ct s, t h e y 
will m a k e a r e c o m m e n d ati o n t o c o nti n u e or st o p t h e tri al.  
 
1 3. 7  
P a y m e nt a n d R e m u n er ati o n  
 
T h e p arti ci p ati n g f a mili e s will r e c ei v e $ 2 0 at e a c h vi sit a n d a n a d diti o n al $ 2 0 f or e a c h vi sit t h at r e q uir e s e xtr a 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 4 1  of 7 4  
ti m e ( s e d at e d M RI, T C D, a n d c o g niti v e t e sti n g) t o a s si st wit h t h e e x p e n s e of m e al s, p ar ki n g, a n d b a b y sitti n g.   
W e e sti m at e t h at t h e a v er a g e r a n d o mi z e d p arti ci p a nt  will h a v e 1 6 vi sit s i n t h e fir st y e ar a n d 1 5 vi sit s i n t h e 
s e c o n d a n d t hir d y e ar s.   If t h e p arti ci p a nt c o m pl et e s all of t h e st u d y vi sit s, t h e y will r e c ei v e $ 1 1 0 0 ( $ 9 2 0 f or t h e 
r e g ul ar vi sit s a n d $ 1 8 0 f or s e d at e d M RI, T C D, a n d c o g niti v e t e sti n g) o v er 3 y e ar s  t o h el p d efr a y a n y st u d y 
a s s o ci at e d c o st s.   
 
 C o st s  
T h e f oll o wi n g will b e p ai d f or b y t h e st u d y: Hi st or y a n d P h y si c al, N e ur ol o g y e v al u ati o n, N e ur o p s y c h ol o gi c al 
e v al u ati o n, S e d ati o n  ( e x c e pt w h e n cli ni c all y i n di c at e d), St u d y m e di ci n e ( h y dr o x y ur e a or pl a c e b o),  L D H, 
q u a ntifi c ati o n of H b S a n d F, bi or e p o sit or y s p e ci m e n c oll e cti o n, pr o c e s si n g, a n d st or a g e, T C D ( e x c e pt w h e n 
cli ni c all y i n di c at e d), a n d M RI/ M R A of t h e br ai n  ( e x c e pt w h e n cli ni c all y i n di c at e d). 
 
1 3. 8  
I n cl u si o n of W o m e n a n d Mi n oriti e s 
 
T h e st u d y s h o ul d i n cl u d e a si mil ar n u m b er of m al e s a n d f e m al e s, b a s e d o n t h e s e x of p arti ci p a nt s wit h H b S S 
s e e n at t h e P e di atri c H e m at ol o g y cli ni c s. W e will i n vit e a n y eli gi bl e p arti ci p a nt s ( m al e or f e m al e) t o p arti ci p at e.  
W e e x p e ct t h at m o st of o ur p arti ci p a nt s will b e of Afri c a n d e s c e nt, gi v e n t h e et h ni c di stri b uti o n of S C D i n t h e 
U nit e d St at e s.  W e will i n vit e p arti ci p a nt s of ot h er et h ni c b a c k gr o u n d s t o p arti ci p at e, if t h e y m e et t h e eli gi bilit y 
r e q uir e m e nt s f or t h e st u d y. 
 
1 3. 9  
I n cl u si o n of C hil dr e n 
 
W e pl a n t o e nr oll o nl y c hil dr e n wit h S C D a g e s ≥ 1 2 a n d < 4 8 m o nt h s of a g e, gi v e n t h e hi g h i n ci d e n c e of 
pr o gr e s si o n t o a b n or m al T C D, fir st sil e nt c er e br al i nf ar ct, a n d str o k e i n t hi s a g e gr o u p.  Ol d er c hil dr e n h a v e a 
l o w er i n ci d e n c e of t h e s e c o m pli c ati o n s.  W e d o n ot i n cl u d e a d ult s, b e c a u s e t h e o v er all i n ci d e n c e of t h e s e 
e v e nt s i s m u c h l o w er or u n k n o w n a n d m a n y a d ult s h a v e e st a bli s h e d v a s c ul o p at h y t h at m a y n ot r e s p o n d t o 
tr e at m e nt wit h h y dr o x y ur e a or tr a n sf u si o n s.  
 
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 4 2  of 7 4  
  
 
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cell a ne mia: t he H U S O F T e xte nsi o n st u d y. Bl o o d 1 0 6: 2 2 6 9- 7 5, 2 0 0 5 
  
1 8.  
A da ms RJ, Mc Kie V C, Hs u L, et al: Pre ve nti o n of a first str o ke b y tra nsf usi o ns i n c hil dre n wit h 
sic kle cell a ne mia a n d a b n ormal res ults o n tra nscra nial D o p pler ultras o n o gra p h y. N E n gl J Me d 3 3 9: 5- 1 1, 1 9 9 8 
  
1 9. 
Delea T E, Ha gi wara M, T h o mas S K, et al: O utc o mes, utilizati o n, a n d c osts a m o n g t halass e mia 
a n d sic kle cell disease patie nts recei vi n g def er o x a mi ne t hera p y i n t he U nite d S tates. A m J He mat ol 8 3: 2 6 3- 7 0, 
2 0 0 8 
  
2 0.  
Wa n g W C, Pa vla kis S G, Helt o n KJ, et al: M RI a b n or malities of t he brai n i n o ne-year - ol d 
c hil dre n wit h sic kle cell a ne mia. Pe diatr Bl o o d Ca ncer 5 1: 6 4 3- 6, 2 0 0 8 
  
2 1.  
Wa n g W C, La n gst o n J W, Stee n R G, et al: A b n or malities of t he ce ntral n er v o us s yste m i n ver y 
y o u n g c hil dr e n wit h sic kle cell a n e mia. J Pe diatr 1 3 2: 9 9 4- 8, 1 9 9 8 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 4 3  of 7 4  
  
2 2. 
Miller S T, Mac kli n E A, Pe gel o w C H, et al: Sile nt i nfarcti o n as a ris k fact or f or o vert str o ke i n 
c hil dre n wit h sic kle cell a ne mia: a r e p ort fr o m t h e C o o perati ve St u d y of Si c kle Cell Disease. J Pe diatr 1 3 9: 3 8 5-
9 0, 2 0 0 1 
  
2 3. 
Sc hatz J: Brief re p ort: Aca de mic attai n me nt i n c hil dre n wit h sic kle cell disease. J Pe diatr Ps yc h ol 
2 9: 6 2 7- 3 3, 2 0 0 4 
  
2 4.  
Wa n g W, E n os L, Galla g her D, et al: N e ur o ps yc h ol o gic perf or ma n ce i n sc h o ol-a ge d c hil dre n 
wit h sic kle cell disease: a re p ort fr o m t he C o o perati ve St u d y of Sic kle Cell Disease. J Pe diatr 1 3 9: 3 9 1- 7, 2 0 0 1 
  
2 5.  
Pe gel o w C H, M ac kli n E A, M oser F G, et al: L o n git u di nal c ha n ges i n brai n ma g n etic res o n a nce 
i ma gi n g fi n di n gs i n c hil dre n wit h sic kle cell disease. Bl o o d 9 9: 3 0 1 4- 8, 2 0 0 2 
  
2 6.  
C harac h e S, Terri n M L, M o ore R D, et al: Effect of h y dr o x y urea o n t he fre q ue nc y of pai nf ul 
crises i n sic kle cell a ne mia. I n v esti gat ors of t he M ultice nter St u d y of H y dr o x y urea i n Sic kle Cell A ne m ia. N 
E n gl J Me d 3 3 2: 1 3 1 7- 2 2, 1 9 9 5 
  
2 7. 
Ware R E: H o w I use h y dr o x y urea t o treat y o u n g p atie nts wit h sic kle cell a n e mia. Bl o o d 
1 1 5: 5 3 0 0- 1 1, 2 0 1 0 
  
2 8.  
Brass L M, Pa vla kis S G, De Vi v o D, et al: Tra nscra nial D o p pler meas ure m e nts of t he mi d dle 
cere bral arter y. Ef fect of he mat ocrit. Str o ke 1 9: 1 4 6 6- 9, 1 9 8 8 
  
2 9.  
A da ms RJ, Mc Kie V, Nic h ols F, et al: T he us e of tra nscra ni al ultras o n o gra p h y t o pre dict str o ke 
i n sic kle cell disease. N e w E n gla n d J o ur nal of Me dici ne 3 2 6: 6 0 5- 6 1 0, 1 9 9 2 
  
3 0. 
Brass L M, Pr o h o v ni k I, Pa vla kis S G, et al: Mi d dle cere bral arter y bl o o d vel ocit y a n d cere bral 
bl o o d fl o w i n sic kle cell disease. Str o ke 2 2: 2 7- 3 0, 1 9 9 1 
  
3 1.  
Pr o h o v ni k I, H urlet-J e nse n A, A da ms R, et al: He m o d y na mic eti ol o g y of ele vate d fl o w vel o cit y 
a n d str o ke i n sic kle- cell disease. J Cere b Bl o o d Fl o w Meta b 2 9: 8 0 3- 1 0, 2 0 0 9 
  
3 2. 
Ki n ne y T R, Slee p er L A, Wa n g W C, et al: Sile nt cere bral i nfarcts i n sic kle cell a ne mia: a ris k 
fact or a nal ysis. T he C o o perati ve St u d y of Sic kle Cell Disease. Pe diatrics 1 0 3: 6 4 0- 5, 1 9 9 9 
  
3 3.  
L o u T F, Si n g h M, Mac ki e A, et al: H y dr o x y urea ge nerat es nitric o xi de i n h u ma n er yt hr oi d cells: 
mec ha nis ms f or ga m ma - gl o bi n ge ne acti vati o n. E x p Bi ol Me d ( Ma y w o o d) 2 3 4: 1 3 7 4- 8 2, 2 0 0 9 
  
3 4.  
Bart ol ucci P, C haar V, Pi c ot J, et al: Decreas e d sic kle re d bl o o d cell a d h esi o n t o la mi ni n b y 
h y dr o x y urea is ass ociate d wit h i n hi biti o n of L u/ B C A M pr otei n p h os p h or yl ati o n. Bl o o d 1 1 6: 2 1 5 2- 9, 2 0 1 0 
  
3 5. 
Ca nalli A A, Fr a nc o - Pe nt ea d o C F, Saa d S T, et al: I n crease d a d h esi ve pr o p erties of ne utr o p hils i n 
sic kle cell disease m a y b e re verse d b y p har mac ol o gical nitric o xi de d o nati o n. Hae mat ol o gica 9 3: 6 0 5- 9, 2 0 0 8 
  
3 6.  
Ha y nes J, Jr., O bia k o B, Hester R B, et al: H y dr o x y urea atte n u ates acti vate d ne utr o p hil-me diate d 
sic kle er yt hr oc yt e me m br a ne p h os p hati d yls eri ne e x p os ure a n d a d hesi o n t o p ul m o nar y v asc ular e n d ot heli u m. 
A m J P h ysi ol Heart Circ P h ysi ol 2 9 4: H 3 7 9 - 8 5, 2 0 0 8 
  
3 7.  
Vic hi ns k y E P, Ne u m a yr L D, G ol d JI, et al: Ne ur o ps yc h ol o gical d ysf u ncti o n a n d ne ur oi ma gi n g 
a b n or malities i n ne ur ol o gicall y i ntact a d ults wit h sic kle cell a ne mia. J A M A 3 0 3: 1 8 2 3 - 3 1, 2 0 1 0 
  
3 8. 
Sa va ge WJ, F u Z, Barr o n- Casella E, et al: Glial Fi brillar y Aci dic Pr otei n as a Plas ma Bi o mar k er 
of Brai n I nj ur y i n C hil dre n wit h Sic kle Cell Disease, A S H A n n ual Meeti n g A bstracts, 2 0 0 9, p p 1 5 1 2 
  
3 9.  
At w o o d J R, Gi or da n o L, Var gas P, et al: A d h ere n ce e n h a ncers i n pill -relat e d cli nical trials:  a 
healt h be ha vi or i n ca ncer pre ve nti o n m o del- bas e d a p pr oac h. Patie nt E d u c C o u nsel 2 8: 1 5- 2 3, 1 9 9 6 
  
4 0.  
Szefler S, Oli ver S, Be n d er B, et al: Desi g n a n d i m ple me ntati o n of a patie nt e d ucati o n ce nter f or 
t he c hil d h o o d ast h ma ma na ge me nt pr o gr a m. A n n of Aller g y Ast h ma I m m u n ol 8 1: 5 7 1- 5 8 1, 1 9 9 8 
  
4 1. 
B o u des P: Dr u g c o m plia nce i n t hera p e utic trials:  a re vie w. C o ntr olle d Cli nical Trials 1 9: 2 5 7 -
2 6 8, 1 9 9 8 
  
4 2.  
J or da n L C, Mc Ki nstr y R C, Kra ut M A, et al: I nci d e ntal Fi n di n gs o n Brai n Ma g n etic Res o na nce 
I ma gi n g of C hil dre n Wit h Sic kle Cell Disease. Pe diatrics, 2 0 1 0 
  
4 3.  
Hee ne y M M, W h ort o n M R, H o war d T A, et al: C he mical a n d f u ncti o nal a nal ysis of h y dr o x y urea 
oral s ol uti o ns. J Pe diatr He mat ol O nc ol 2 6: 1 7 9- 8 4, 2 0 0 4 
  
4 4.  
T h or n b ur g C D, Calatr o ni A, Tele n M, et al: A d h ere nce t o h y dr o x y urea t h era p y i n c hil dre n wit h 
sic kle cell a ne mia. J Pe diatr 1 5 6: 4 1 5- 9, 2 0 1 0 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 4 4  of 7 4  
  
4 5. 
M oris k y D E, A n g A, Kr o usel -W o o d M, et al: Pre dicti ve vali dit y of a m e dicati o n a d here n ce 
meas ure i n a n o ut p atie nt setti n g. J Cli n H y perte ns ( Gree n wic h) 1 0: 3 4 8-5 4, 2 0 0 8  
  
4 6. 
De Ba u n M R, Sc hatz J, Sie gel MJ, et al: C o g niti ve scree ni n g e x a mi nati o ns f or sile nt cere bral 
i nfarcts i n sic kle cell disease. Ne ur ol o g y 5 0: 1 6 7 8- 8 2, 1 9 9 8 
  
4 7. 
Miller S T, Mac kli n E, Slee per L, et al: Ris k Fact ors f or Str o ke i n  C hil dre n wit h Sic kle Cell 
Disease: A Re p ort fr o m t he C o o perati ve St u d y ( C S S C D). J o ur nal of Pe diatrics 1 3 9: 3 8 5- 9 0, 2 0 0 1 
  
4 8.  
Gi oia G A, Is q uit h P K, G u y S C, et al: Be ha vi or rati n g i n ve nt or y of e x ec uti ve f u ncti o n. C hil d 
Ne ur o ps yc h ol 6: 2 3 5- 8, 2 0 0 0 
  
4 9.  
Is q uit h P K, Gi oia G: Pre dicti o ns of A D H D: Cli nical Utilit y of t he Be h a vi oral Rati n g I n v e nt or y 
of E x ec uti ve F u ncti o n f or Detecti n g A D H D S u bt y pes i n C hil dre n., Nati o nal Aca de m y of Ne ur o ps yc h ol o g y. 
Orla n d o, F L, 2 0 0 0 
  
5 0.  
de Ve ber G A, Mac Gr e g or D, C urtis R, et al: Ne ur ol o gic o utc o me i n s ur vi v ors of c hil d h o o d 
arterial isc h e mic str o ke a n d si n o ve n o us t hr o m b osis. J o ur nal of c hil d ne ur ol o g y 1 5: 3 1 6- 2 4, 2 0 0 0 
  
5 1.  
O p pe n hei m C, Sta nesc u R, D or m o nt D, et al: Fals e- ne gati ve diff usi o n- wei g hte d M R fi n di n gs i n 
ac ute isc he mic str o k e.  AJ N R. A merica n j o ur n al of ne ur ora di ol o g y 2 1: 1 4 3 4- 4 0, 2 0 0 0 
  
5 2.  
S yl aja P N, C o utts S B, Kr ol A, et al: W he n t o e x pect ne gati ve diff usi o n- wei g hte d i ma ges i n 
str o ke a n d tra nsie nt isc h e mic attac k. Str o ke; a j o ur nal of cere bral circ ulati o n 3 9: 1 8 9 8- 9 0 0, 2 0 0 8 
  
5 3.  
C harac h e S, Terri n M L, M o ore R D, et al: Effect of h y dr o x y urea o n t he fre q ue nc y of pai nf ul 
crises i n sic kle cell a ne mia. T he Ne w E n gla n d J o ur nal of Me dici ne 3 3 2: 1 3 1 7- 1 3 2 2, 1 9 9 5 
  
5 4. 
Sil ver ma n DI, Cir ull o L, De Marti nis N A, et al: S yste matic i de ntificati o n a n d classificati o n of 
a d verse e ve nts i n h u ma n researc h. C o nte m p orar y Cli nical Trials 2 7: 2 9 5- 3 0 3, 2 0 0 6 
 
 
 
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 4 5  of 7 4  
A p p e n di x  1   
Par e nt a n d P arti ci p a nt  Si c kl e C ell Di s e a s e E d u c ati o n Pr o gr a m  
 
P ar e nt s p arti ci p ati n g i n t hi s pr o gr a m will i n cr e a s e t h eir k n o wl e d g e of si c kl e c ell di s e a s e ( S C D) a n d it' s 
c o m pli c ati o n s, l e ar n t h e s c h o ol -r el at e d pr o bl e m s i n c hil dr e n wit h S C D, o bt ai n h el p f or a c hil d wit h e d u c ati o n 
pr o bl e m s i n s c h o ol, l e ar n a b o ut t h e i d e ntifi c ati o n a n d m a n a g e m e nt of o v ert str o k e, di s c u s s sil e nt c er e br al 
i nf ar ct a n d t h e e x pl a n ati o n of it s i m p a ct o n t h e e d u c ati o n al a n d v o c ati o n al att ai n m e nt f or c hil dr e n wit h si c kl e 
c ell di s e a s e a n d b e c o m e f a mili ar wit h t h e ri s k s a n d b e n efit s of bl o o d tr a n sf u si o n a n d h y dr o x y ur e a t h er a p y i n 
c hil dr e n wit h S C D.  
 
Vi sit I -1 h o ur  
Si c k l e C ell Di s e a s e O v er vi e w - St u d y C o or di n at or , S o ci al W or k er, & Pri n ci p al I n v e sti g at or 
O bj e cti v e s:  
 
Pr o vi d e d efi niti o n of sil e nt a n d o v ert str o k e s  
 
E x pl ai n t h e i m p ort a n c e of T C D s cr e e ni n g i n str o k e pr e v e nti o n  a n d t h e r ol e of bl o o d tr a n sf u si o n f or 
tr e at m e nt i n str o k e pr e v e nti o n  
 
E x pl ai n sil e nt c er e br al i nf ar ct a n d r a mifi c ati o n s f or e d u c ati o n  
 
Di s c u s s b arri er s t o t h e e d u c ati o n al pr o c e s s f or c hil dr e n wit h si c kl e c ell di s e a s e , p arti c ul arl y t h o s e wit h 
sil e nt c er e br a l i nf ar ct s 
 
Pr o vi d e r e c o m m e n d ati o n s t o i m pr o v e e d u c ati o n al a c hi e v e m e nt s u c h a s d e v el o p m e nt al a s s e s s m e nt a n d 
e arl y i nt er v e nti o n pr o gr a m s f or at ri s k t o d dl er s a n d pr e s c h o ol c hil dr e n, i nt er mitt e nt h o m e b o u n d e d u c ati o n, 
a n d a n e v al u ati o n f or a n i n di vi d u al e d u c ati o n al pl a n (I E P)  
 
Vi sit II  - 1 h o ur  
Di s c u s si o n of h y dr o x y ur e a a n d s e d ati o n r i s k s & b e n efit s  - St u d y C o or di n at or  & Pri n ci p al I n v e sti g at or  
O bj e cti v e s:  
 
Di s c u s s i m pli c ati o n s of h y dr o x y ur e a t h er a p y  
 
Di s c u s s t h e p ot e nti al b e n efit of h y dr o x y ur e a t h e r a p y, i n cl u di n g t h e d e cr e a s e i n t h e fr e q u e n c y of p ai nf ul 
e pi s o d e s, a c ut e c h e st s y n dr o m e s, a n d p o s si bl y d e cr e a si n g t h e pr o gr e s si o n of n e ur ol o gi c i nj ur y  
 
Di s c u s s ri s k s a s s o ci at e d wit h s e d at e d M RI a n d pr e c a uti o n s t a k e n t o d e cr e a s e t h e s e a d v er s e e v e nt s  
 
Di s c u s s p o s si bl e fi n a n ci al i m pli c ati o n s of st u d y p arti ci p ati o n t o t h e f a mil y a n d e n c o ur a g e di s c u s si o n wit h 
t h eir i n s ur a n c e pr o vi d er s 
 
R e vi e w t h e H U Pr e v e nt Tri al a n d r e s p o n d t o q u e sti o n s fr o m p ar e nt s a n d p ot e nti al p arti ci p a nt s 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 4 6  of 7 4  
A p p e n di x  2    
 Im a gi n g C e nt er   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Ste p 1  P atie nt  Visit  
Sites will o btai n M RI a n d T C Ds acc or di n g t o 
g ui deli nes.  
Ste p 2  
Sites fa x i ma ge trac ki n g w or ks heet t o I ma gi n g Ce nter.  
De -i de ntifie d di gital i ma ges ar e se nt t o I ma gi n g Ce nter 
fr o m via a sec ure I nter net c o n necti o n or maile d o n 
di gital me dia .   
Ste p 3  
I ma ges are c hec ke d f or pr o per la beli n g, l o g ge d i nt o a 
trac ki n g data base, a n d re vie we d f or i ma ge q ualit y.  If 
t here are a n y pr o ble ms wit h i ma ge q ualit y or 
c o m plete ness, t he i n vesti gat or site is n otifie d a n d 
re me dial acti o ns are rec o m me n de d 
Ste p 4   
Di gital i ma ges are tra nslate d i nt o a sta n dar dize d f or mat 
a n d ass ociate d patie nt a n d st u d y i de ntifiers are e ntere d 
b y t he i ma gi n g s pecialist.  I ma ges are c hec ke d a gai n f or 
q ualit y, c o m plete ness, a n d acc urac y  of  i de ntif yi n g 
i nf or mati o n. 
Ste p 5  
F oll o w -U p I ma ges   
I ma ges are pre pare d f or fi nal r e vie w a n d tra nsferre d t o 
t he t hree ne ur ora di ol o g y rea ders.   
Ste p 6  
F or M RIs, t hree ne ur ora di ol o gists will perf or m e val uati o ns 
a n d e nter t he res ults i nt o e C F R.  T he t hree e C R F’s are 
verifie d b y a n i ma gi n g researc h ass ociate at t he I ma gi n g 
Ce nter.  F or T C Ds, Dr. R o bert A da ms will pr o vi de t he 
fi nal rea di n g.  A n y necessar y q ueries are ge nerate d a n d  
f oll o we d u p t hr o u g h res ol uti o n.  T he I ma gi n g Ce nter 
f or war ds t he res ults t o t he Pri nci pal I n vesti gat or, De p ut y 
Direct or a n d Statistical C o or di nati n g Ce nter.  
T he I ma gi n g Ce nter will pr o vi d e sites wit h  sta n d ar dize d 
ac q uisiti o n g ui deli nes a n d pr o ce d ures f or h a n dli n g of 
i ma gi n g data.  T he I ma gi n g Ce nter will c ollect i ma ges i n 
direct di gital f or m. Eac h site will d ei d e ntif y i ma ges a n d 
t he n se n d i ma ges usi n g a sec ure V P N, a sec ure d file 
s hari n g ser vice or o n di gital me dia t o t h e I ma gi n g Ce nter.  
A c o or di nat or at eac h site will use s oft ware pr o vi d e d b y 
t he I ma gi n g Ce nter or i nstit uti o n al s oft ware t o d e -i d e ntif y 
t he i ma ge sets or ot her wise d e -i d e ntif y t h e i ma ges.  
P a rtici pa nt’s de m o gra p hic i nf or mati o n will b e re m o ve d 
a n d re place d wit h t he st u d y- assi g n e d p artici p a nt i d e ntifier 
a n d site-assi g ne d 3 letter p artici pa nt c o d e.  T h e la pt o p 
s yste m will tra ns mit t he d e-i d e ntifie d i ma g es t o t h e 
I ma gi n g Ce nter usi n g a sec ure, e n cr y pte d V P N c o n n ecti o n 
or it will be se nt b y e x press mail o n di gital me dia.  Sites 
will c o m plete a n i ma ge trac ki n g w or ks h eet t h at matc h es 
eac h DI C O M ser ies pr o d u ce d b y t h e M R d e vice t o o n e o f 
t he p ulse se q ue nces i de ntifie d i n t h e i ma gi n g pr ot o c ol.  
T he I ma gi n g Ce nter will c h ec k t h e q u alit y of all i ma ges 
u p o n recei pt a n d will c o m m u nicate recei pt of all i n c o mi n g 
data t o t he cli nical ce nter, t h e Pri n ci p al I n vesti gat or , Vice  
C hair, Data C o or di nati n g  Ce nter, a n d t h e site i n vesti gat or.  
P artici pa nt i de ntifier, partici p a nt c o d e, st u d y d ate a n d 
st u d y ti me o n t he i ma ges will b e is c o m p are d wit h t h e 
acc o m pa n yi n g f or ms a n d i ma gi n g w or ks h eet f or 
c o nsiste nc y.  T he Pri nci p al I n vesti gat or a n d I ma gi n g 
Ce nter will e ns ure t hat a n y c o nfi d e ntial i nf or mati o n h as 
bee n mas ke d.   
 
T he I ma gi n g Ce nter will t h e n tra nsfer i ma ges o nt o 
i ma ge re vie w w or kstati o n a n d c o nfir ms i ma ge q u alit y 
a n d data c o m plete ness o n dia g n ostic w or kstati o n. T h e 
I ma gi n g Ce nter will ma na ge ce ntralize d di gital i ma ge 
arc hi ve, st u d y data base, a n d off -site b ac k-u p st ora ge.   
 
T he I ma gi n g Center ne ur ora di ol o g y re vie wers will 
deter mi ne w het her i ma ges ar e e v al u a ble f or p ur p oses of 
t he st u d y.  I n t he e ve nt t h at a pr o ble m wit h a n i ma gi n g 
st u d y is i de ntifie d, t he site is i m me diatel y n otifie d 
c o ncer ni n g t he nat ure of a n y pr o ble ms a n d t h e ste ps 
re q uire d f or c orrecti ve acti o n.  
 
T he I ma gi n g Ce nter will pr o vi d e di gital M RI i ma ges 
a n d  electr o nic Case Re p ort F or ms (e C R F) t o t h e  t hree- 
st u d y ne ur ora di ol o gist ( n e ur ora di ol o g y p a n el 
me m bers) a n d t he cli nical c o or di n ati n g ce nter 
Pri nci pal I n vesti gat or . T h e n e ur ora di ol o g y p a n el will 
perf or m t he e val uati o n of t h e i ma ges f or eli gi bilit y 
scree ni n g a n d a nal ysis of e nr olle d p atie nts.  T h e 
prese nce or a bse nce of cere bral i nfar cts will b e gra d e d 
acc or di n g t o a 3 -p oi nt c o nfi d e n ce scale. T h e 
ne ur ora di ol o g y pa nel will b e bli n d e d t o treat me nt, 
patie nt de m o gra p hics a n d cli nical hist or y ( ot h er t h a n 
hist or y of sic kle c ell a ne mi a).  T h e y will e nter t h eir 
fi nal e val uati o ns i nt o electr o nic Case Re p ort F or ms 
(e C R F). 
 
T C Ds i ma ges will be se nt t o t h e Ne ur ol o g y C ore at t h e 
U ni versit y of S o ut h Car oli n a f or re vie w.  
T he i ma gi n g c e nter will f or war d t h e fi n al i ma gi n g 
e val uati o n data t o t he Pri n ci p al I n vesti gat o r, De p ut y 
Direct or, a n d t he Statistical C o or di n ati n g Ce nter wee kl y.  
Data c o ncer ni n g patie nt eli gi bilit y a n d n ee d f or referral 
will be tra ns mitte d t o t he Pri n ci p al I n vesti gat or 
i m me diatel y.  


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 4 7  of 7 4  
  
  
  
 
A p p e n di x 3.  E v al u ati o n s f or s cr e e ni n g / pr e -r a n d o mi z ati o n 
  
 
 
 
All p arti ci p a nt s 
 
S cr e e ni n g  Vi sit 1 + 
 
 
S cr e e ni n g Vi sit 
2 +  
 
 
S cr e e ni n g Vi sit 
3 
M RI  
 
I nf or m e d c o n s e nt  
 
X  
 
 
 
D e m o gr a p hi c/ p h e n ot y pi c f or m  
 
X  
 
 
 
R e p o sit or y St u di e s ( D N A S p e ci m e n s)  
 
X ^  
 
 
 
C B C, Diff, R eti c, L D H, C o m pr e h e n si v e P a n el, H e m o gl o bi n 
a n al y si s  
 
X  
 
 
 
M e di c al hi st or y a n d p h y si c al e x a m  b y h e m at ol o gi st  
 
X  
 
 
 
T C D  
 
X  
 
 
 
† N e ur ol o g y E x a m wit h n e ur ol o gi c al e v e nt f or m aft er T C D 
(if T C D <1 7 0 c m/ s e c)  
 
 
 
X  
 
 
C o g niti v e T e sti n g  
 
 
 
 
X  
 
 
S e d ati o n e v al u ati o n  
 
X  
X  
 
 
S e d ati o n c h e c kli st  
 
 
X  
 
 
M RI  
 
 
 
X  
 
* P ar e nt & P arti ci p a nt  E d u c ati o n  
 
X  
 
X  
 
X  
 
R e p o sit or y St u di e s ( Pl a s m a S p e ci m e n s f or Pr ot e o mi c s)  
 
 
X  
† Sit e n e ur ol o gi st bli n d e d t o l o c ati o n of l e si o n  
 
* P ar e nt s a n d p arti ci p a nt s will b e e n c o ur a g e d t o p arti ci p at e i n t h e s e f or m al s e s si o n s pri or t o e nr oll m e nt o n t hi s st u d y ; 
h o w e v er , si c kl e c ell di s e a s e e d u c ati o n, m a n a g e m e nt a n d e m p h a si s o n k e e pi n g t h e p arti ci p a nt  o n tr a c k f or pr e s c h o ol 
d e v el o p m e nt a n d i n s c h o ol  a s a n ol d er c hil d  s h o ul d c o nti n u e t hr o u g h o ut t h e d ur ati o n of t h e st u d y a s st a n d ar d of c ar e f or  
p ati e nt s wit h si c kl e di s e a s e.  
+ T h e pr o c e d ur e s i n t h e fir st a n d s e c o n d vi sit s c a n b e c o m bi n e d or s plit i nt o a d diti o n al vi sit s.  L a b or at or y v al u e s n ot 
o bt ai n e d s u c c e s sf ull y at t h e fir st vi sit m a y b e d o n e o n t h e s e c o n d or a n a d diti o n al vi sit or vi sit, a s l o n g a s n o m or e t h a n 
1 0 c c of bl o o d i s dr a w n o n a gi v e n d a y.  
^ T hi s s p e ci m e n c a n b e o bt ai n e d at a n y of t h e s cr e e ni n g vi sit s, i n cl u di n g t h e M RI


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 4 8  of 7 4  
A p p e n di x 4    
S c h e d ul e of St u d y Pr o c e d ur e s  Aft er Tr e at m e nt I niti ati o n- Y e ar 1  
 
 
Vi sit  0 
R a n d o mi z ati o n  
Vi sit  1 
Vi sit  2 
Vi sit  3 
Vi sit  4 
Vi sit  5 
Vi sit  6 
Vi sit  7 
Vi sit  8 
Vi sit  9 
Vi sit  
1 0  
Vi sit  
1 1  
Vi sit  
1 2  
Vi sit 
1 3  
H & P b y H e m at ol o gi st  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
St u d y M e di c ati o n R efill  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
A d h er e n c e M e a s ur e s  
 
 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
* C B C, diff, r eti c 
 
x 
R e p e at i n 2 
w e e k s  
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
E d u c ati o n  
 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
C o m pr e h e n si v e p a n el, L D H  
 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
H b F a n d S, a n d Ot h er 
H e m o gl o bi n Q u a ntifi c ati o n  
 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
S a m pl e s f or Pr ot e o mi c s   
   x + 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
Tr a n s cr a ni al D o p pl er  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
S e d ati o n E v al u ati o n  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
M RI of Br ai n  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
C o g niti v e E v al u ati o n  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
N e ur ol o g y E v al u ati o n  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
R a n d o mi z ati o n  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
*C B C Diff, R eti c m a y n e e d t o b e d o n e e v er y 2 w e e k s  
+ Pr ot e o mi c s a m pl e n ot n e c e s s ar y, if d o n e wit h t h e M RI a n d r a n d o mi z ati o n i s ≤ 2 w e e k s aft er M RI  
 
 
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 4 9  of 7 4  
 
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 5 0  of 7 4  
A p p e n di x 5   
S c h e d ul e of St u d y Pr o c e d ur e s Y e ar - 2 
  
 
 
Vi sit 
1 4  
Vi sit 
1 5  
Vi sit 
1 6  
Vi sit 
1 7  
Vi sit 
1 8  
Vi sit 
1 9  
Vi sit 
2 0  
Vi sit  
2 1  
Vi sit 
2 2  
Vi sit 
2 3  
Vi sit 
2 4  
Vi sit 
2 5  
Vi sit 
2 6  
H & P b y H e m at ol o gi st  
 
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
St u d y M e di c ati o n R efill  
 
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
A d h er e n c e M e a s ur e s  
 
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
* C B C, diff, r eti c  
 
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
E d u c ati o n  
 
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
C o m pr e h e n si v e p a n el, L D H  
 
 
 
x  
 
 
x  
 
 
x  
 
 
 
x  
H b F a n d S, a n d Ot h er H e m o gl o bi n 
Q u a ntifi c ati o n  
 
 
 
x  
 
 
x  
 
 
x  
 
 
 
x  
S a m pl e s f or Pr ot e o mi c s   
 
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
Tr a n s cr a ni al D o p pl er  
 
 
 
 
 
 
 
 
 
 
 
 
 
x  
S e d ati o n E v al u ati o n  
 
 
 
 
 
 
 
 
 
 
 
 
 
x  
M RI of Br ai n  
 
 
 
 
 
 
 
 
 
 
 
 
 
x  
C o g niti v e E v al u ati o n  
 
 
 
 
 
 
 
 
 
 
 
 
 
x  
N e ur ol o g y E v al u ati o n  
 
 
 
 
 
 
 
 
 
 
 
 
 
x  
* C B C Diff, R eti c m a y n e e d t o b e d o n e e v er y 2 w e e k s 
 
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 5 1  of 7 4  
A p p e n di x 6    
S c h e d ul e of St u d y Pr o c e d ur e s Y e ar – 3 
 
 
Vi sit 
2 7  
Vi sit 
2 8  
Vi sit 
2 9  
Vi sit 
3 0  
Vi sit 
3 1  
Vi sit 
3 2  
Vi sit 
3 3  
Vi sit  
3 4  
Vi sit 
3 5  
Vi sit 
3 6  
Vi sit 
3 7  
Vi sit 
3 8  
Vi sit 
3 9  
H & P b y H e m at ol o gi st  
 
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
St u d y M e di c ati o n R efill  
 
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
A d h er e n c e M e a s ur e s  
 
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
* C B C, diff, r eti c 
 
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
E d u c ati o n  
 
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
C o m pr e h e n si v e P a n el, L D H  
 
 
 
x  
 
 
x  
 
 
x  
 
 
 
x  
H b F a n d S Q u a ntifi c ati o n  
 
 
 
x  
 
 
x  
 
 
x  
 
 
 
x  
S a m pl e s f or Pr ot e o mi c s  
 
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
Tr a n s cr a ni al D o p pl er  
 
 
 
 
 
 
 
 
 
 
 
 
 
x  
S e d ati o n E v al u ati o n  
 
 
 
 
 
 
 
 
 
 
 
 
 
x  
M RI of Br ai n  
 
 
 
 
 
 
 
 
 
 
 
 
 
x  
C o g niti v e E v al u ati o n  
 
 
 
 
 
 
 
 
 
 
 
 
 
x  
N e ur ol o g y E v al u ati o n  
 
 
 
 
 
 
 
 
 
 
 
 
 
x  
* C B C Diff, R eti c m a y n e e d t o b e d o n e e v er y 2 w e e k s 
 
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 5 2  of 7 4  
A p p e n di x 7 S c h e d ul e of T o xi cit y E v al u ati o n s Aft er Tr e at m e nt I niti ati o n  - Y e ar 1  
 
Vi sit  
0 
Vi sit  
1 
Vi sit  
2 
Vi sit  
3 
Vi sit  
4 
Vi sit  
5 
Vi sit  
6 
Vi sit  
7 
Vi sit  
8 
Vi sit  
9 
Vi sit  
1 0  
Vi sit  
1 1  
Vi sit  
1 2  
Vi sit 
1 3  
H & P b y 
H e m at ol o gi st , 
P A or N P  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
* C B C, diff, 
r eti c 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
C o m pr e h e n si v e 
p a n el,  
 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
S e d ati o n 
E v al u ati o n  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
S e d ati o n 
F oll o w -u p c all s  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
* C B C Diff, R eti c m a y n e e d t o b e d o n e e v er y 2 w e e k s 
 
A p p e n di x 8  S c h e d ul e of T o xi cit y  E v al u ati o n s - Y e ar 2  
 
Vi sit 
1 4  
Vi sit 
1 5  
Vi sit 
1 6  
Vi sit 
1 7  
Vi sit 
1 8  
Vi sit 
1 9  
Vi sit 
2 0  
Vi sit 
2 1  
Vi sit 
2 2  
Vi sit 
2 3  
Vi sit 
2 4  
Vi sit 
2 5  
Vi sit 
2 6  
H & P b y 
H e m at ol o gi st , 
P A or N P  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
* C B C, diff, 
r eti c 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
C o m pr e h e n si v e 
p a n el,  
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
S e d ati o n 
E v al u ati o n  
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
S e d ati o n 
F oll o w -u p c all s  
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
* C B C Diff, R eti c m a y n e e d t o b e d o n e e v er y 2 w e e k s 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 5 3  of 7 4  
 
A p p e n di x 9  S c h e d ul e of T o xi cit y E v al u ati o n s - Y e ar 3  
 
 
Vi sit 
2 7  
Vi sit 
2 8  
Vi sit 
2 9  
Vi sit 
3 0  
Vi sit 
3 1  
Vi sit 
3 2  
Vi sit 
3 3  
Vi sit 
3 4  
Vi sit 
3 5  
Vi sit 
3 6  
Vi sit 
3 7  
Vi sit 
3 8  
Vi sit 
3 9  
H & P b y 
H e m at ol o gi st  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
* C B C, diff, 
r eti c 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
C o m pr e h e n si v e 
p a n el,  
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
S e d ati o n 
E v al u ati o n  
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
S e d ati o n 
F oll o w -u p c all s  
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
* C B C Diff, R eti c m a y n e e d t o b e d o n e e v er y 2 w e e k s 
 
 
  
  
  
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 5 4  of 7 4  
A p p e n di x 1 0  
Cr a ni al M a g n eti c R e s o n a n c e I m a gi n g Pr ot o c ol  
 
M a g netic Res o n a nce I m a gi n g of t he br ai n perf or me d at 1. 5 o r 3 Tesl a 
 
I. 
Re q uire d Se q ue nces  
a. Sc o ut l ocat or- 3 pla nes 
b.  A xial T 2 W F L AI R  
i.  3 m m c o nti g u o us slices f or w h ole brai n c o vera ge 
ii. C o ncate nate d ac q uisiti o ns f or e ve n/ o d d slices 
c. C or o nal T 2 W F L AI R 
i.  3 m m c o nti g u o us slices f or w h ole brai n c o vera ge 
ii. C o ncate nate d ac q uisiti o ns f or e ve n/ o d d slices  
d.  T 2 W a xial- F S E or l ocal e q ui vale nt 
i.  3 m m c o nti g u o us slices f or w h ole brai n c o vera ge 
ii. 2 1 c m F O V 
e. A xial a n d c or o nal T 1 W [ca n be re place d b y T 1 W 3 D se q ue nce (II b u n der s u p ple me ntal)] 
f. Diff usi o n wei g hte d  i ma gi n g wit h A D C Ma ps [(ca n be re place d b y D TI  (IIc u n der s u p ple me ntal)] 
 
II. 
S u p ple me nt al se q ue nces (i n or der of pri ori t y) 
a. 3 D Ti me - of-Fli g ht ( T O F) M R A - T his se q ue nce will pr o vi de i nf or mati o n a b o ut cere bral 
vasc ul o pat h y, a c o m m o n fi n di n g a n d t he m aj or mec ha nis m of isc he mic str o ke i n c hil dre n wit h 
S C D  
i. 4 o verla p pi n g sla bs f or c o vera ge fr o m C 2  t hr o u g h t he le vel of t he ce ntr u m se mi o vale 
ii. 3 2 0 x 1 0 0 matri x wit h s u b milli meter res ol uti o n  (i deall y v o x el of 0. 3 x 0. 3 x 0. 6 m m) 
iii. Slice t hic k ness 0. 6 m m  
i v. 2 0 c m F O V 
v.  S o mersa ult (t u m bli n g) a n d E x orcist (s pi n ni n g) MI P rec o ns tr ucti o n 
b.  Sa gittal T 1 W M P R A G E T 1 W 3 D is otr o pic ( or l ocal e q ui vale nt-I R- F S P G R o n G E sca n ners. T his 
se q ue nce will pr o vi de i ma ges f or v ol u metri c a nal ysis of brai n str uct ures t hat ma y c orrel ate wit h 
c o g niti ve d eficits.  
i. 1 x 1 x 1 m m res ol uti o n (ca n  re place a xial a n d c or o nal T 1 W se q ue nces)  
c. Diff usi o n te ns or i ma gi n g ( D TI) (ca n re place diff usi o n wei g hte d i ma gi n g wit h A D C Ma ps) .  T he 
D TI se q ue n ces will per mit a nal ysis of fi b er trac ki n g a n d w hite matter i nte grit y, t w o p ote ntial 
c o ntri b ut ors t o t he c o m m o n deficits i n atte nti o n a n d ot her as pects of e x ec uti ve f u ncti o n i n 
c hil dre n wit h S C D. 
i. 2 x 2 x 2 m m res ol uti o n at 3 T, 2. 5 x 2. 5 x 2. 5 m m res ol uti o n at 1. 5 T  
ii. 1 2 or m ore diff usi o n e n c o di n g directi o ns  
iii. A ut o matic c o m p utati o n of A D C a n d F A  
d.  S usce pti bilit y Wei g hte d I ma gi n g ( S WI) .  T hese se q ue nces are v er y se nsiti ve f or t he d etecti o n of 
ac ute or c hr o nic h e m orr h a ge.  
i. S o urce i ma ges  
ii. P hase ma ps  
iii. S o urce i ma ges mas ke d b y p has e ma ps  
i v. Mi ni m u m I nt e nsit y pr oj ecti o n rec o nstr ucti o n  
e. Arterial S pi n La beli n g  ( A S L).  T h e vari o us A S L tec h ni q ues ( p ulse d, c o nti n u o us, 
pse u d oc o nti n u o us) ar e us e d t o meas ure cere bral bl o o d fl o w, a p ote ntial pre dict or of t he ris k of 
sile nt a n d o vert str o ke t h at ma y c orrelate wit h perf or ma nce o n c o g niti ve testi n g. 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 5 5  of 7 4  
f. F u ncti o nal C o n necti vit y Ma p pi n g wit h M RI ( fc M RI, a 4 t o 8 mi n ute B O L D r u n wit h o ut sti m uli) .  
T his se q ue nce is use d t o st u d y t he resti n g state c orrelati o ns of t he B O L D si g nal a m o n g v ari o us 
brai n re gi o ns. 
g.  M R  ve n o gr a p h y ( M R V)- T his se q ue nce is use d t o e val uate f or cere bral si n us t hr o m b osis a n d 
s h o ul d be o btai ne d i n c hil dre n wit h a cli nical pres e ntati o n c o ncer ni n g f or str o ke, cere bral si n us 
t hr o m b osis or i ntracer e br al he m orr ha ge. 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 5 6  of 7 4  
A p p e n di x 1 1  
Tr a n s cr a ni al D o p pl er ( T C D) Pr ot o c ol    
D uri n g t h e T C D  r e c or di n g I D E N TI F Y t h e v e s s el a n d O P TI MI Z E t h e w a v ef or m s.  T h e f oll o wi n g d e s cri b e s t h e 
Tr a n st e m p or al I d e ntifi c ati o n L a b el s & Fl o w Dir e cti o n:   
 
 
L a b el  
V e s s el  
Fl o w Dir e cti o n  
1.  M -1  
S h all o w e st d e pt h of t h e M C A  
T o w ar d t h e pr o b e  
2.  M C A  
Mi d dl e C er e br al Art er y      
T o w ar d t h e pr o b e  
3.  BI F  
I C A bif ur c ati o n 
Bi -dir e cti o n al si g n al  
4.  
A C A  
A nt eri or C er e br al Art er y  
A w a y fr o m t h e pr o b e  
5.  
dI C A  
Di st al I nt eri or C ar oti d Art er y  
T o w ar d t h e pr o b e  
6.  
P C A  
P o st eri or C er e br al Art er y  
T o w ar d t h e pr o b e  
7.  T O B  
T o p of t h e B a sil ar  
Bi -dir e cti o n al si g n al  
 
R e c or di n g t h e T C D E x a m St e p -b y -St e p  
 
T h e M - 1 a n d t h e Mi d dl e C er e br al Art er y ( M C A):  
B e gi n t h e T C D e x a m b y d et e cti n g a si g n al t hr o u g h t h e t e m p or al wi n d o w wit h a d e pt h s etti n g of ~ 5 0 m m.  O n c e 
t hi s si g n al i s d et e ct e d, i n cr e a s e or d e cr e a s e t h e d e pt h u ntil a bi dir e cti o n al “ bif ur c ati o n” ( BI F) si g n al i s i d e ntifi e d.  
O n c e t h e BI F h a s b e e n i d e ntifi e d v erif y t h at t h e art er y b ei n g i n s o n at e d i s t h e M C A b y tr a c ki n g t h e v e s s el t o it s 
s h all o w e st d e pt h.   T h e s h all o w e st p orti o n of t h e M C A i s l a b el e d M -1.   R e c or d O N E s c a n of t h e M -1.  
 
Aft er r e c or di n g t h e M -1, i n cr e a s e t h e d e pt h of i n s o n ati o n i n 2 m m st e p s a n d r e c or d o n e s c a n of e a c h w a v ef or m 
u si n g t h e M C A l a b el u ntil t h e Bif ur c ati o n i s r e a c h e d. If HI G H V E L O CI T Y i s f o u n d t h e n t a k e a s m a n y s c a n s a s 
n e c e s s ar y t o r e c or d t h e HI G H V E L O CI T Y.  
 
T h e Bif ur c ati o n ( BI F)  
T h e i ntr a cr a ni al i nt er n al c ar oti d art er y (I C A) t er mi n at e s b y di vi di n g i nt o t h e M C A a n d t h e A C A.  T hi s bif ur c ati o n, 
k n o w n a s t h e “ BI F”, i s i d e ntifi e d a s a bi -dir e cti o n al si g n al.   T h e fl o w a b o v e t h e z er o li n e a n d fl o wi n g t o w ar d s t h e 
pr o b e r e pr e s e nt s t h e M C A w hil e t h e fl o w b el o w t h e z er o li n e a n d a w a y fr o m t h e pr o b e r e pr e s e nt s t h e 
A C A.   O n c e t h e BI F i s i d e ntifi e d, att e m pt t o o bt ai n a si g n al wit h e q u al "i nt e n sit y" a b o v e a n d b el o w t h e li n e.   
R e c or d T W O s c a n s of t h e BI F at t h e s a m e d e pt h.  
 
T h e A nt eri or C er e br al Art er y ( A C A)  
Aft er i d e ntif yi n g t h e A C A v e s s el a s t h e fl o w a w a y fr o m t h e pr o b e b el o w t h e Z er o li n e at t h e Bif ur c ati o n, 
i n cr e a s e t h e d e pt h b y 4 m m a n d r e c or d t h e A C A. T o b ett er i s ol at e t h e A C A, a n gl e t h e pr o b e 
a nt eri orl y/ s u p eri orl y.  R e c or d T W O A C A w a v ef or m s: o n e s c a n s h o ul d b e r e c or d e d at 4 m m p a st t h e 
bif u r c ati o n, t h e n a s e c o n d s c a n at 6 m m p a st t h e bif ur c ati o n U N L E S S t h e A C A at 6 m m p a st t h e bif ur c ati o n i s 
n ot a g o o d si g n al.  I n t hi s c a s e, r e c or d t w o s c a n s of t h e A C A at 4 m m p a st t h e bif ur c ati o n.  
 
T h e Di st al I nt er n al C er e br al Art er y ( dI C A)  
R et ur n t o t h e BI F l a n d m ar k a n d a n gl e sli g htl y i nf eri orl y t o l o c at e t h e dI C A. I n cr e a s e t h e d e pt h 4 m m t o i s ol at e 
a n d o pti mi z e t h e si g n al. R e c or d T W O dI C A w a v ef or m s : o n e s c a n s h o ul d b e r e c or d e d at 4 m m p a st t h e 
bif ur c ati o n, t h e n a s e c o n d s c a n at 6 m m p a st t h e  bif ur c ati o n U N L E S S t h e dI C A at 6 m m p a st t h e bif ur c ati o n i s 
n ot a g o o d si g n al.  I n t hi s c a s e, r e c or d t w o s c a n s of t h e dI C A at 4 m m p a st t h e bif ur c ati o n.  D u e t o t h e 
u nf a v or a bl e a n gl e of i n s o n ati o n, t h e dI C A si g n al i s oft e n “ d a m p e d” or di mi ni s h e d a s c o m p ar e d t o t h e M C A 
si g n al a n d m a y h a v e a “ gr uff” a u di o q u alit y.  
 
 
T h e P o st eri or C er e br al Art er y ( P C A)  


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 5 7  of 7 4  
R et ur n t o t h e BI F l a n d m ar k.   I n cr e a s e t h e d e pt h 4 m m a n d a n gl e t h e tr a n s d u c er p o st eri orl y/ i nf eri orl y t o r e c or d 
t h e P C A. Tr a c k a n d r e c or d t h e P C A i n 2 m m st e p s u ntil r e a c hi n g t h e T o p of t h e B a sil ar.  T h e m e a n v el o cit y of 
t h e P C A i s n or m all y a b o ut 1/ 2 t o 2/ 3 of t h e m e a n v el o cit y of t h e M C A. 
 
T h e T o p of t h e B a sil ar ( T O B)  
T h e t o p of t h e b a sil ar i s i d e ntifi e d b y tr a c ki n g t h e P C A i n 2 m m i n cr e m e nt s u ntil bi dir e cti o n al fl o w i s i d e ntifi e d at 
t h e mi dli n e.  R e c or d T W O s c a n s of t h e T O B at eit h er o n e or t w o d e pt h s. 
 
T h e f oll o wi n g d e s cri b e s t h e Tr a n sf or a mi n al  E x a mi n ati o n:  
L a b el  
V e s s el  
Fl o w Dir e cti o n  
P R -B A S  
Pr o xi m al B a sil ar        
A w a y fr o m pr o b e  
DI S -B A S  
Di st al B a sil ar  
A w a y fr o m  pr o b e  
 
R e c or d o n e s c a n of t h e Pr o xi m al B a sil ar ( P R -B A S) a n d o n e s c a n of t h e Di st al B a sil ar ( DI S -B A S)  
 
F oll o w t h e s a m e i n str u cti o n s f or e a c h t e m p or al si d e of t h e h e a d.  E X A M P L E of T C D S c a n ni n g & L a b eli n g 
w h e n t h e H e a d Di a m et er i s 1 2 0 m m ( Mi dli n e = 6 0 m m; Bif ur c ati o n will b e s e e n ar o u n d 5 0 m m)  
 
Ri g ht T e m p or al Si d e  : 
 
L eft T e m p or al Si d e  : 
R -M 1  
4 0  
L -M 1  
4 0  
R -M C A  
4 2  
L -M C A  
4 2  
R -M C A  
4 4  
L -M C A  
4 4  
R -M C A  
4 6  
L -M C A  
4 6  
R -M C A  
4 8  
L -M C A  
4 8  
R -BI F  
5 0  
L -BI F  
5 0  
R -BI F  
5 0  
L -BI F  
5 0  
R -A C A  
5 4  
L -A C A  
5 4  
R -A C A  
5 6  
L -A C A  
5 6  
R -dI C A  
5 4  
L -dI C A  
5 4  
R -dI C A  
5 6  
L -dI C A  
5 6  
R -P C A  
5 4  
L -P C A  
5 4  
R -P C A  
5 6  
L -P C A  
5 6  
R -P C A  
5 8  
L -P C A  
5 8  
R -T O B  
6 0  
L -T O B  
6 0  
R -T O B  
6 0 or 6 2  
L -T O B  
6 0 or 6 2  
 
P R O X -B A S  
 
7 2  
 
 
 
DI S T -B A S  
7 4  
 
 
 
 
A p p e n di x 1 2  
S e d ati o n Pr ot o c ol  U si n g Pr o p of ol or P e nt o b ar bit al a s t h e  Pri m ar y A g e nt  


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 5 8  of 7 4  
T h e  a d mi ni str ati o n of a n e st h eti c s a n d s e d ati v e s t o p ati e nt s wit h S C D i s c o ntr o v er si al a n d t h er e i s n ot 
c o n si st e nt a gr e e m e nt a m o n g st a n e st h e si ol o gi st s or h e m at ol o gi st s a s t o t h e b e st a p pr o a c h. T h e f oll o wi n g 
a s pir e s t o b e st  pr a cti c e pri n ci pl e s w hi c h c e nt er o n cl e ar a n d c o n si st e nt c o m m u ni c ati o n b et w e e n t h e v ari o u s 
pr o vi d er s fr o m h e m at ol o g y, a n e st h e si ol o g y a n d t h e s e d ati o n t e a m a n d, m o st i m p ort a ntl y, wit h t h e f a mil y. 
T h e s e g ui d eli n e s w er e r e vi e w e d a n d a p pr o v e d b y t h e S e d ati o n C o m mitt e e f or t h e H U Pr e v e nt Tri al a n d ar e 
i nt e n d e d t o pr o vi d e a mi ni m al  st a n d ar d of  s af et y. T h e a ct u al m a n a g e m e nt of p arti ci p a nt s s h o ul d b e 
i n di vi d u ali z e d a s n e c e s s ar y, wit h t h e s af et y of t h e p arti ci p a nt  b ei n g t h e hi g h e st pri orit y at all ti m e s; h o w e v er, 
th e u s e of pr o p of ol or a s t h e pri m ar y a g e nt s f or s e d ati o n/ a n e st h e si a, t h e e x cl u si o n crit eri a a n d mi ni m u m 
r e q uir e m e nt s, s u c h a s d ur ati o n of N P O a n d b a s eli n e o x y g e n s at ur ati o n s h o ul d b e a d h er e d t o stri ctl y.  I n 
a d diti o n, t h e a d mi ni str ati o n of pr o p of ol s h o ul d b e p erf or m e d b y or o c c ur u n d er t h e dir e ct s u p er vi si o n of a n 
a n e st h e si ol o gi st.   T h e s e r e q uir e m e nt s m a y al s o b e e x c e e d e d ( e. g., l o n g er d ur ati o n s of N P O) b a s e d o n l o c al 
j u d g m e nt s. 
 
T h e c hil dr e n e nr oll e d f or i m a gi n g will b e pr e -s cr e e n e d b ef or e t h e y r e c ei v e s e d ati o n f or a n M RI, a s t h e g o al of 
t hi s pr ot o c ol i s t o pr o vi d e t h e s af e st e n vir o n m e nt f or t h e s e c hil dr e n, mi ni m al di sr u pti o n f or t h e p ar e nt s a n d 
c o n si st e nt c ar e wit h r ar e c a n c ell ati o n s. C hil dr e n wit h S C D m a y h a v e h a d r e c urr e nt h o s pit ali z ati o n s a n d b e 
w ar y of  c ar e pr o vi d er s; t h e y m a y al s o h a v e h a d m a n y pr e vi o u s i ntr a v e n o u s ( I V) c at h et er s a n d p o or v a s c ul ar 
a c c e s s. T h e c hil dr e n will b e c ar e d f or i n a w ar m a n d s u p p orti v e m a n n er a n d t h e M RI, it s i n di c ati o n a n d t h e 
p er s o n r e q u e sti n g it s h o ul d b e c o nfir m e d wit h t h e p ar e nt or g u ar di a n.  
 
1)  S e d ati o n E x cl u si o n Crit eri a:  
A b o v e a n d b e y o n d a d h eri n g t o all pr e v aili n g l o c al st a n d ar d s a n d pr o c e d ur e s f or M RI s cr e e ni n g a n d s af et y, t h e 
f oll o wi n g e x cl u si o n crit eri a will b e f oll o w e d: 
a.  C hil dr e n w h o d o  n ot  p a s s t h e M RI s cr e e ni n g c h e c kl i st. 
b.  C hil dr e n wit h o b str u cti v e sl e e p a p n e a [ O S A] w h o ar e r e c ei vi n g t h er a p y [ e. g.  c o nti n u o u s p o siti v e air w a y 
pr e s s ur e  (C P A P )], or w h o ar e b ei n g e v al u at e d or f oll o w e d b y a s p e ci ali st f or m a n a g e m e nt of s e v er e 
O S A .  
c. C hil dr e n w h o pr e s e nt wit h r o o m air o x y g e n s at ur ati o n s 5 % b el o w t h eir b a s eli n e will n ot b e a n e st h eti z e d 
o n t h at d a y a n d will b e r ef err e d t o t h eir h e m at ol o gi st.  
d.  C hil dr e n w h o pr e s e nt wit h r o o m air o x y g e n s at ur ati o n l e s s t h a n 9 0 % will n ot a n e st h eti z e d o n t h at d a y 
a n d will b e r ef err e d t o t h eir h e m at ol o gi st. 
e.  C hil dr e n wit h a n all er gi c r e a cti o n s u c h a s urti c ari a or br o n c h o s p a s m, or pr e vi o u s a d v er s e r e a cti o n t o 
pr o p of ol, e g g s or s o y pr o d u ct s.  
f.  Chil dr e n wit h k n o w n m aj or c hr o m o s o m al a b n or m aliti e s . 
g.  C hil dr e n wit h k n o w n air w a y a b n or m aliti e s  t h at w o ul d i n cr e a s e t h e ri s k of s e d ati o n/ a n e st h e si a. 
h.  T h e c a s e will b e c a n c ell e d i n t h e e v e nt t h at t h e p arti ci p a nt h a s a t e m p er at ur e of > 3 8˚ C, s y m pt o m s of 
a n u p p er or l o w er r e s pir at or y i nf e cti o n i n t h e pr e vi o u s 4 w e e k s, a cti v e br o n c h o s p a s m, a c ut e c h e st 
s y n dr o m e, s e q u e str ati o n or ot h er a c ut e c o m pli c ati o n s of S C D i n t h e l a st 4 w e e k s, or p ai n cri si s wit hi n 
t w o w e e k s r e q uiri n g tr e at m e nt wit h o pi at e s. 
i. 
C hil dr e n w h o s e p ar e nt s r ef u s e t o p arti ci p at e . 
 
2)  N P O Ti m e s a n d Pr e -S e d ati o n H y dr ati o n:  
a.  T h e N P O ti m e will b e k e p t t o a mi ni m al d ur ati o n a n d t h e c hil d s h o ul d b e e n c o ur a g e d t o t a k e or al 
h y dr ati o n s o a s t o r e m ai n h y dr at e d pri or t o pr o p of ol a d mi ni str ati o n.  
b.  N P O  f or 2 h o ur s f or cl e ar li q ui d s  a n d at l e a st 6 h o ur s f or s oli d s . 
c. It i s i m p er ati v e t h at t h e c hil d r e m ai n s w ell h y dr at e d pri or t o t h e N P O p eri o d. T o a c hi e v e t hi s g o al, t h e 
f a mil y will b e r e q u e st e d t o a d mi ni st er cl e ar li q ui d s u p u ntil t h e ti m e of a b s ol ut e N P O.  
 
d.  If t h e c hil d i s d e e m e d i n a d e q u at el y h y dr at e d u p o n arri v al, o n e of t h e f oll o wi n g will o c c ur: 
1)  
A n I V will b e p l a c e d a n d t h e c hil d will b e h y dr at e d wit h a n i s ot o ni c i ntr a v e n o u s fl ui d. 
2)  
T h e c hil d will b e or all y h y dr at e d a n d t h e s e d ati o n ti m e will b e d el a y e d . 
3)  
If t h e a b o v e c a n n ot b e p erf or m e d, t h e c a s e will b e c a n c ell e d a n d r e s c h e d ul e d. 
 
3) Pr e - Se d ati o n:  


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 5 9  of 7 4  
a.  T h e c hil d m u st  h a v e a  hi st or y a n d  p h y si c al d o c u m e nt e d wit h t h e l a st 3 0 d a y s . 
b.  D u e t o t h e i n cr e a s e d ri s k of p eri o p er ati v e c o m pli c ati o n s i n c hil dr e n wit h S C D, t h e c hil d m u st b e 
ot h er wi s e w ell at t h e ti m e of t hi s el e cti v e M RI . 
c. Pri or t o t h e d a y of t h e M RI, t h e c hil d will b e s cr e e n e d b y a c h e c kli st f or a c ut e ill n e s s e s, c o e xi sti n g 
di s e a s e s, or O S A . T hi s will u s u all y b e d o n e b y t el e p h o n e. 
d.  T h e c a s e will b e c a n c ell e d i n t h e e v e nt of a n u p p er or l o w er r e s pir at or y i nf e cti o n i n t h e pr e vi o u s 4 
w e e k s, a cti v e br o n c h o s p a s m, or a c ut e c h e st s y n dr o m e i n t h e l a st 4 w e e k s, or p ai n cri si s  r e q uiri n g 
tr e at m e nt wit h o pi at e s wit hi n t w o w e e k s, s e q u e str ati o n or ot h er a c ut e c o m pli c ati o n s of si c kl e c ell 
di s e a s e.  
e.  A t h or o u g h pr e o p er ati v e hi st or y a n d p h y si c al, i n cl u di n g b a s eli n e vit al si g n s [ w ei g ht, h e art  r at e, 
r e s pir at or y r at e, t e m p er at ur e, bl o o d pr e s s ur e, r o o m air p ul s e o xi m etr y a n d p ai n s c or e], s h all b e 
p erf or m e d a n d d o c u m e nt e d i n t h e c hil d’ s m e di c al r e c or d.  
f. A h e m o gl o bi n will b e o bt ai n e d wit hi n t h e pr e vi o u s 3 0 d a y s; if t h e h e m o gl o bi n i s < 6. 5  g/ d L t h e c hil d will 
n ot b e s e d at e d a n d i n st e a d will b e r ef err e d t o t h eir h e m at ol o gi st.  
g.  It will b e c o nfir m e d t h at a h o s pit al b e d i s a v ail a bl e, i n t h e e v e nt of c o m pli c ati o n s. 
h.  I nf or m e d c o n s e nt f or a d mi ni str ati o n of s e d ati o n will b e o bt ai n e d fr o m t h e c hil d’ s p ar e nt or g u ar di a n 
a c c or di n g t o l o c al pr a cti c e. T hi s will i n cl u d e t h e p ot e nti al f or t h e d e v el o p m e nt of a b n or m al vit al si g n s, 
t h e p o s si bilit y of h o s pit ali z ati o n a n d a ri s k of si c kl e c ell cri si s. T h er e i s al s o a l o w p ot e nti al ri s k f or 
c ar di o p ul m o n ar y arr e st, str o k e or d e at h. T h e c a s e will b e c a n c ell e d if t h e f a mil y d o e s n ot c o n s e nt t o t h e 
M RI or t o t h e a d mi ni str ati o n of t h e s e d ati v e s t o b e u s e d a s p art of t hi s pr ot o c ol . 
i. 
If t h e p ar e nt i n di c at e s t h at t h e c hil d t y pi c all y t ol er at e s pl a c e m e nt of a n I V c at h et er, a t o pi cal l o c al 
a n e st h eti c p at c h [ e. g. S y n er a , E L A-M a x ] or l o c al a n e st h eti c i nfiltr ati o n will b e pl a c e d at t h e p ot e nti al sit e 
f or v e n o u s a c c e s s. Aft er  t h e s ki n i s a n e st h eti z e d, t h e I V will b e pl a c e d.  
j. 
Mi d a z ol a m  m a y b e u s e d a s a n or al pr e m e di c ati o n f or I V pl a c e m e nt at a d o s e of 0. 5 m g/ k g [t o a 
m a xi m al d o s e of 1 0 m g] . 
 
4)  S e d ati o n R e gi m e n u si n g Pr o p of ol  
a.  Pr e a d mi s si o n vit al si g n s will b e r e vi e w e d a n d r e c or d e d a s p art of t h e pr e -s e d ati o n e v al u ati o n.  
b.  T h e p arti ci p a nt  will h a v e c o nti n u o u s m o nit ori n g of vit al si g n s d uri n g t h e i n d u cti o n, m ai nt e n a n c e, a n d 
r e c o v er y p eri o d i n t h e r e c o v er y ar e a. 
c. St a n d ar d A m eri c a n S o ci et y of A n e st h e si ol o g y [ A S A] m o nit ori n g will b e utili z e d i n cl u di n g E K G, p ul s e 
o xi m etr y, r e s pir at or y r at e, bl o o d pr e s s ur e, t e m p er at ur e a n d e n d ti d al c ar b o n di o xi d e. Vit al si g n s will b e 
d o c u m e nt e d at l e a st e v er y 5 mi n ut e s u si n g t h e i n stit uti o n' s f or m.  
d.  Vit al si g n s will b e m ai nt ai n e d wit hi n a n a g e a p pr o pri at e r a n g e a s d et er mi n e d b y t h e att e n di n g 
a n e st h e si ol o gi st or pr o p of ol -tr ai n e d h o s pit ali st, or ot h er a p pr o pri at e p er s o n n el u n d er t h e dir e ct 
s u p er vi si o n of a n a n e st h e si ol o gi st  
e.  O x y g e n will b e a d mi ni st er e d b y n a s al c a n n ul a or m a s k t o m ai nt ai n o x y g e n s at ur ati o n a b o v e 9 5 %.  
f. F oll o wi n g i ntr a v e n o u s pl a c e m e nt, i ntr a v e n o u s li d o c ai n e, 1 m g/ k g u p t o 2 0 m g, will b e gi v e n 
i ntr a v e n o u sl y f oll o w e d b y a b ol u s of pr o p of ol, 2 m g/ k g. A d diti o n al pr o p of ol at 1 m g/ k g i n cr e m e nt s m a y  
b e a d mi ni st er e d at t h e a n e st h e si ol o gi st’ s/ pr o p of ol -tr ai n e d h o s pit ali st’ s di s cr eti o n u ntil a n a d e q u at e l e v el 
of a n e st h e si a i s o bt ai n e d.  
g.  If t h e p ar e nt i n di c at e s t h at t h e c hil d d o e s n ot t ol er at e I V c at h et er  pl a c e m e nt, a m a s k i n h al ati o n 
i n d u cti o n will b e p erf or m e d b y a n a n e st h e si ol o gi st  a n d a n I V c at h et er pl a c e d w h e n t h e c hil d i s 
s uffi ci e ntl y a n e st h eti z e d.  
h.  F or c hil dr e n w h o r e q uir e a m a s k i n d u cti o n f or I V c at h et er  pl a c e m e nt, all m o nit or s will b e pl a c e d, 
f oll o wi n g b y a n i n h al ati o n i n d u cti o n u ntil a n a d e q u at e d e pt h of a n e st h e si a i s a c hi e v e d. Aft er t h e I V i s 
i n s ert e d, t h e c hil d will b e gi v e n 1 0 0 % o x y g e n a n d t h e b ol u s of pr o p of ol a d mi ni st er e d.  
i. 
Pr o p of ol will b e titr at e d b et w e e n 0 a n d 2 5 0 mi cr o gr a m s/ k g/ mi n ut e a s n e e d e d t o m ai nt ai n n or m al vit al 
si g n s  a n d a d e q u at e s e d ati o n . 
j. 
A d diti o n al pr o p of ol at 0. 5 m g/ k g i n cr e m e nt s will b e a d mi ni st er e d at t h e a n e st h e si ol o gi st’ s or pr o p of ol -
tr ai n ed h o s pit ali st’ s  or ot h er a p pr o pri at el y tr ai n e d p er s o n n el’ s  di s cr eti o n , u n d er t h e dir e ct s u p er vi si o n of 
a n a n e st h e si ol o gi st u ntil a n a d e q u at e l e v el of a n e st h e si a i s o bt ai n e d.  


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 6 0  of 7 4  
k. F oll o wi n g c o m pl eti o n of t h e n o n -c o ntr a st  M RI of t h e br ai n, pr o p of ol will b e di s c o nti n u e d a n d t h e c hil d 
will pr o m ptl y b e br o u g ht t o t h e r e c o v er y ar e a.  
l. 
F oll o wi n g st a n d ar d r e c o v er y, wit h t h e c hil d a c hi e vi n g pr e -pr o c e d ur e vit al si g n s, h a vi n g n o n a u s e a or 
v o miti n g, a n d t ol er ati n g cl e ar li q ui d s, t h e c hil d will b e di s c h ar g e d t o h o m e.  
m.  T h e f a mil y will b e gi v e n t h e p h o n e n u m b er of t h e a n e st h e si ol o gi st or pr o p of ol -tr ai n e d h o s pit ali st a n d t h e 
h e m at ol o gi st t o c all f or a n y q u e sti o n s or c o n c er n s.  
n.  T h e f a mil y will b e c o nt a ct e d t h e f oll o wi n g d a y b y t h e a n e st h e si ol o gi st or pr o p of ol -tr ai n e d h o s pit ali st or 
t h eir r e pr e s e nt ati v e t o a s c ert ai n a n y pr o bl e m s or c o n c er n s of t h e c hil d’ s p ar e nt. 
 
A p p e n di x 1 3   C h e c kli st f or M RI wit h S e d ati o n  
 
 ** E x cl u d e s p arti ci p ati o n u ntil r e s ol v e d** 
 
T o b e c o m pl et e d b y p h o n e s cr e e n er o n t h e  d a y pri or t o t h e s e d ati o n.  
 
 P ar e nt r ef u s al t o p arti ci p at e  
 O b str u cti v e sl e e p a p n e a  ( O S A) a n d r e c ei vi n g t h er a p y ( e. g. C P A P), or b ei n g e v al u at e d or f oll o w e d 
b y a s p e ci ali st f or m a n a g e m e nt of s e v er e O S A.  
 A st h m a e x a c er b ati o n i n pr e vi o u s 4 w e e k s  
 U p p er r e s pir at or y i nf e cti o n i n pr e vi o u s 4 w e e k s  
  Ac ut e c h e st s y n dr o m e, s e q u e str ati o n or ot h er a c ut e c o m pli c ati o n s of si c kl e c ell di s e a s e i n t h e 
pr e vi o u s 4 w e e k s  or p ai n cri si s wit hi n t h e l a st 2 w e e k s  r e q uiri n g o pi at e tr e at m e nt 
 H o s pit ali z ati o n i n t h e pr e vi o u s 4 w e e k s  
 U nr e p air e d c o m pl e x c o n g e nit al h e art di s e a s e  
 Si n gl e v e ntri cl e p h y si ol o g y   
 P ul m o n ar y h y p ert e n si o n  
 C hr o m o s o m al a b n or m aliti e s  
 
 K n o w n air w a y a b n or m aliti e s  t h at w o ul d i n cr e a s e t h e ri s k of s e d ati o n/ a n e st h e si a 
 C urr e nt f e v er or ot h er si g n s of a c ut e ill n e s s 
 M or bi d o b e sit y  
 A S A P S ≥ 3   
 H e m o gl o bi n ≥ 6. 5  g/ dl  n ot d o c u m e nt e d wit hi n 3 0 d a y s of pr o c e d ur e  
 
 
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 6 1  of 7 4  
A p p e n di x 1 4   D N A S a m pl e Pr ot o c ol                  
 
G e n eti c r e p o sit or y s p e ci m e n – 
 
T e n t o fift e e n millilit er s ( ml) of bl o o d i s t o b e dr a w n a n d a d d e d t o A C D ( 6  ml y ell o w t o p, fill c o m pl et el y) a n d 
K 3 E D T A v a c ut ai n er t u b e s ( 5 ml p ur pl e ( l a v e n d er) t o p, fill t o 4 ml).  I m m e di at el y f oll o wi n g bl o o d c oll e cti o n, A C D 
a n d E D T A t u b e s s h o ul d b e g e ntl y i n v ert e d 8 -1 0 ti m e s, t o mi x bl o o d wit h pr e s er v ati v e or a nti -c o a g ul a nt. If l e s s 
t h a n 1 0 ml of bl o o d i s o bt ai n e d, pr ef er e nti all y fill t h e A C D t u b e. If 1 3-1 5 ml of bl o o d i s o bt ai n e d, fill a s e c o n d 
A C D t u b e wit h 3 -5 ml s , aft er p utti n g 4 ml i n t h e K 3 E D T A t u b e. S e e t a bl e b el o w.  
 
Bl o o d dr a w  
6 ml A C D v a c ut ai n er 
( y ell o w t o p) 
5 ml K 3 E D T A v a c ut ai n er 
( p ur pl e t o p) 
E xtr a 6 ml A C D 
v a c ut ai n er ( y ell o w t o p)  
1 0 ml  
6 ml  
4 ml  
 
< 1 0 ml  
6 ml  
R e st of bl o o d a v ail a bl e  
 
1 3 -1 5 ml  
6 ml  
4 ml  
3 -5 ml  
 
 
T h e A C D a n d E D T A t u b e s s h o ul d b e p a c k e d a n d s hi p p e d t h e s a m e d a y a s c oll e cti o n u si n g t h e pr o vi d e d 
m at eri al s  a n d f oll o wi n g D e p art m e nt of Tr a n s p ort ati o n  ( d o m e sti c) or I A T A (i nt er n ati o n al) g ui d eli n e s f or t h e 
s hi p m e nt of h u m a n bl o o d. Bl o o d s h o ul d b e s hi p p e d at r o o m t e m p er at ur e ( 2 2 -2 4 o C).  A n a m bi e nt s hi p pi n g b o x 
will b e u s e d. It c a n c o nt ai n u p t o 8 t u b e s. Si n c e e a c h st u d y p arti ci p a nt t h at i s s cr e e n e d will pr o vi d e 2 t o 3 
t u b e s, e a c h s hi p pi n g b o x c a n c o nt ai n t u b e s f or u p t o 4 st u d y p arti ci p a nt s. 
 
S hi p pi n g  / tr a c ki n g C R Fs ( C R F 0 3 a n d 0 4) n e e d t o b e c o m pl et e d f or e a c h st u d y p arti ci p a nt ( e. g., if t h er e i s 
o nl y o n e st u d y p arti ci p a nt h a vi n g t u b e s s hi p p e d , t h e n o nl y o n e s et of C R F s i s r e q uir e d; if t w o st u d y p arti ci p a nt s 
ar e h a vi n g t u b e s s hi p p e d , t h er e n e e d s t o b e t w o s et s of C R F s e n cl o s e d i n t h e b o x).    
 
O n e a c h s hi p pi n g / tr a c ki n g C R F, a d u pli c at e t u b e l a b el n e e d s t o b e aff i x e d f or e a c h s et of t u b es b ei n g 
s hi p p e d).  
 
T h e cli ni c al sit e will al s o f a x or s c a n a n d e -m ail t h e s hi p pi n g / tr a c ki n g C R F t o Dr. B arr o n-C a s ell a’ s l a b  at 4 1 0 -
9 6 6 -8 2 0 8. Pl e a s e al s o e m ail E mil y B arr o n -C a s ell a at e b arr o n 1 @j h mi. e d u  a n d Ki m J o n e s at 
kj o n e s 6 2 @j h mi. e d u , t h at a s hi p m e nt i s t o b e e x p e ct e d. T hi s a p pr o a c h pr o vi d e s a d v a n c e d n oti c e t o Dr. B arr o n -
C a s ell a’ s l a b t h at a p arti c ul ar st u d y p arti ci p a nt will b e h a vi n g a c ert ai n n u m b er of t u b e s s hi p p e d t o t h e l a b 
s o o n.  
 
Pl a c e e a c h p arti ci p a nt’ s t u b e i n a bi o h a z ar d s b a g wit h p a p er t o w el s i n si d e t h e b a g a n d arr a n g e d s o t h at t h e y 
will fit i n sl ot s i n t h e m ultit u b e St yr of o a m c o nt ai n er  of t h e s hi p p er .  Cl o s e a n d s e al t h e  St yr of o a m c o nt ai n er wit h 
s e v er al wr a p s of t a p e. T h e St yr of o a m b o x, t o g et h er wit h t h e fill e d C R F s, s h o ul d b e sli p p e d i nt o t h e o ut er 
c ar d b o ar d b o x of t h e s hi p p er.  T h e c ar d b o ar d b o x s h o ul d b e cl o s e d a n d t h e e n d s s e al e d wit h t a p e.   
 
Affi x t h e Bi ol o gi c al  S u b st a n c e C at e g or y B U N 3 3 7 3 l a b el o n t h e o ut er c ar d b o ar d b o x a n d p ut t h e s hi p p er i n t h e 
U N 3 3 7 3 b a g, s e al, att a c h t h e fill e d air bill a n d s c h e d ul e t h e F e d E x pi c k -u p.  
 
Pl e a s e s hi p all s p e ci m e n s M o n d a y t hr o u g h T h ur s d a y t o:  
 
Att n: Ki m J o n e s / E mil y B arr o n-C a s ell a,  P h D  
 
D e p art m e nt of P e di atri c H e m at ol o g y  
J o h n s H o p ki n s U ni v er sit y S c h o ol of M e di ci n e  
R o s s 1 1 2 5  
7 2 0 R utl a n d A v e n u e  
B alti m or e, M D 2 1 2 0 5  
P h o n e 4 1 0 -9 5 5 -6 1 3 2  


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 6 2  of 7 4  
 
If a Fri d a y s hi p m e nt i s n e e d e d, pl e a s e c o nt a ct Ki m J o n e s or E mil y B arr o n-C a s ell a b ef or e s hi p pi n g, if at 
all p o s si bl e ( 4 1 0 -6 1 4 -0 7 0 8 or 4 1 0 -9 5 5 -6 1 3 2).  
 
All s p e ci m e n s m u st arri v e b y 2 P M o n Fri d a y, u nl e s s alt er n ati v e arr a n g e m e nt s ar e m a d e .  I nt er n ati o n al 
s p e ci m e n s s h o ul d o nl y b e c oll e ct e d o n M o n d a y, T u e s d a y, or W e d n e s d a y, s o t h at t h e y will arri v e b ef or e t hi s  
d e a dli n e.  
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 6 3  of 7 4  
A p p e n di x 1 5  
Pl a s m a S a m pl e s F or Pr ot e o mi c A n al y si s  
 
T h e p ur p o s e of t hi s pr ot o c ol i s t o g et t h e fr e s h e st a n d b e st pr e s er v e d pl a s m a s a m pl e s a s p o s si bl e fr o m t hi s 
i m p ort a nt gr o u p of p arti ci p a nt s.   Pl e a s e d o n ot r u s h t h e pr o c e d ur e; h o w e v er, t h e f a st er t h e bl o o d s a m pl e s ar e 
pr o c e s s e d a n d t h e pl a s m a i s fr o z e n, t h e l e s s pr ot e ol y si s will o c c ur.  T h e s e v er y hi g h q u alit y s a m pl e s will b e 
u s e d b y l a b or at ori e s t o di s c o v er p ot e nti al pr ot ei n m ar k er s f or sil e nt c er e br al i nf ar ct s.  
 
R e q uir e d m at eri al s o n sit e:   
•  
L o w s p e e d c e ntrif u g e ( m u st b e a bl e t o s pi n 5 ml V a c ut ai n er t u b e s 1 8 0 0 -2 0 0 0 x g)  
•   -8 0 o C Fr e e z er   
•  
Dr y i c e  
 
R e q uir e d m at eri al s fr o m J H U:  T o b e o bt ai n e d fr o m E mil y B arr o n -C a s ell a.  Pl e a s e s u b mit r e q u e st v i a e m ail 
e b arr o n 1 @j h mi. e d u or f a x 4 1 0 9 5 5 8 2 0 8.  
 
•  
P ur pl e ( L a v e n d er ) t o p, 5 ml gl a s s V a c ut ai n er t u b e s ( 2 t u b e s; o n e i s s p ar e) . 
•  
2. 0 ml s cr e w c a p fr e e z er t u b e s ( 1 2 t u b e s; t w o ar e s p ar e)  
•  
1 5 ml p ol y pr o p yl e n e t u b e ( 1 2 X 7 5 m m) ( 2 t u b e s; o n e i s s p ar e)  
•  
Di s p o s a bl e gr a d u at e d tr a n sf er pi p et s ( 2 pi p et s)  
•  
Pr e -pri nt e d w hit e  l a b el s f or fr e e z er t u b e s  
•  
Fr e e z er b o x l a b el e d H U Pr e v e nt Pr ot e o mi c s S a m pl e s   
•  
C o nt ai n m e nt bi o h a z ar d b a g wit h a d s or b e nt p a d  
•  
St yr of o a m c arri er o ut er c ar d b o ar d b o x  
•  
Dr y i c e l a b el  
•  
Bi ol o gi c al S u b st a n c e C at e g or y B U N 3 3 7 3 l a b el 
•  
F e d E x air bill wit h H o p ki n s s hi p -t o i nf or m ati o n fill e d o ut 
 
1.  B ef or e st arti n g  
a.  P arti ci p a nt ’ s i d e ntit y s h o ul d b e c o nfir m e d v er b all y.   
b.  Pl e a s e m ar k p arti ci p a nt ’ s I D n u m b er o n 1 x 1 5 ml p ol y pr o p yl e n e t u b e 
c. Pl e a s e c o m pl et e l a b el s f or 1 0 s cr e w t o p 2. 0 ml fr e e z er t u b e s.  T h e y s h o ul d c o nt ai n : 
 
P arti ci p a nt ’ s I D a n d b ar c o d e ( gi v e n) 
 
Pl e a s e fill i n d at e  
 
Pl e a s e e nt er w hi c h vi sit (i e. 0, 3, 6, 9, 1 2, 1 8, 2 4, 3 0 or 3 6 m o nt h s) or f or a c ut e str o k e p arti ci p a nt s 
t h e d a y s p o st-e v e nt (i e. 0, 3, 7, 1 4, … d a y s) 
d.  L a b el s s h o ul d b e affi x e d t o 1 0 s cr e w t o p 2. 0 ml fr e e z er t u b e s  ( N ot e t h at t h e b ar c o d e o n t h e l a b el 
s h o ul d g o d o w n, n ot ar o u n d, t h e t u b e).  M a k e s ur e y o u c a n cl e arl y s e e t h e gr a d u ati o n m ar k s o n t h e 
s m all fr e e z er t u b e s.  
e.  W e ar e s u p pl yi n g a n d pr ef er t h at all bl o o d b e c oll e ct e d i n gl a s s  V a c ut ai n er s, b ut if pl a sti c t u b e s ar e 
u s e d, pl e a s e m a k e a n ot ati o n o n t h e c a s e r e p ort f or m.  
  
U ntil t h e s a m pl e s ar e ali q u o tt e d, all s a m pl e s s h o ul d b e k e pt at r o o m t e m p er at ur e ( 2 1 oC).  
 D o N O T p ut s a m pl e o n i c e at a n y ti m e d uri n g pr ot o c ol.  Fr e e z e at -8 0 o C aft er ali q u oti n g.     
Pl a s m a s a m pl e s s h o ul d b e c o m pl et el y pr o c e s s e d  wit hi n 4 h o ur s.  
 
  2.  P hl e b ot o m y  
a.  I d e ntif y v ei n, a n d cl e a n s e s urr o u n di n g ar e a t h or o u g hl y wit h et h a n ol 
b.  V e ni p u n ct ur e s h o ul d b e p erf or m e d u si n g a 2 3 g a u g e ( or l ar g er) n e e dl e, a n d s uffi ci e nt bl o o d s h o ul d b e 
o bt ai n e d t o fill o n e p ur pl e  t o p V a c ut ai n er t u b e (5 ml s) . 
c. G e ntl y i n v ert t u b e s e v er al ti m e s t o mi x.    
 
3.  C e ntrif u g ati o n  


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 6 4  of 7 4  
a.  C e ntrif u g e  t h e  V a c ut ai n er  t u b e f or  8  mi n ut e s  at  3 0 0 0  R P M  ( 1 9 0 0  x  g)  at  r o o m  t e m p er at ur e  ( 2 1o C).  
( R e m e m b er t o b al a n c e t u b e s i n t h e c e ntrif u g e. 
b.  Tr a n sf er a s m u c h pl a s m a (i. e. t o p cl e ar l a y er) a s p o s si bl e ( a b o ut 3  ml s) i nt o t h e l a b el e d 1 5 ml 
p ol y pr o p yl e n e t u b e ( 1 2 X 7 5 m m).  
c. If a cl e a n tr a n sf er of pl a s m a i s o bt ai n e d, pr o c e e d t o ali q u otti n g t h e pl a s m a.  If c o nt a mi n at e d wit h s o m e 
c ell s, t hi s t u b e c a n b e s p u n at s a m e s p e e d f or 8 mi n a n d pl a s m a c ar ef ull y tr a n sf err e d t o r e m o v e c ell s.   
 
4.  Pl a s m a ali q u otti n g  
a.  G e ntl y mi x t h e pl a s m a i n t h e p ol y pr o p yl e n e t u b e  s o t h at it i s h o m o g e n e o u s i n c ol or. Ali q u ot pl a s m a wit h 
di s p o s a bl e tr a n sf er pi p et i nt o 2. 0 ml s cr e w t o p fr e e z er t u b e s a s f oll o w s:  
 
Fi v e t u b e s wit h 2 5 0 ul e a c h  
 
R e m ai n d er of pl a s m a s h o ul d b e di stri b ut e d i n 5 0 0 ul ali q u ot s  
 
If t h er e i s a d diti o n al pl a s m a, pl e a s e a d d t hi s r e m ai n d er t o t h e fi n al 5 0 0 ul t u b e a n d p ut a pl u s ( +) 
si g n o n t h e c a p t o i n di c at e m or e t h a n 5 0 0 ul  
b.  Fr e e z er t u b e s s h o ul d b e pl a c e d H U Pr e v e nt Pr ot e o mi c s S a m pl e s fr e e z er b o x a n d i m m e di at el y fr o z e n 
b y pl a ci n g i n a -8 0 o C fr e e z er.  Pl e a s e n ot e t h e l o c ati o n of t h e b o x ( pr ef er a bl y i n a r a c k).  B o x e s ar e 
e a sil y l o st i n bi g, m ulti -u s er fr e e z er s. S a m pl e s m u st b e fr o z e n s oli d pri or t o s hi p pi n g.    
 
5.  A d diti o n al n ot e s  
a.  Fr o m t h e ti m e t h e pl a s m a i s wit h dr a w n fr o m V a c ut ai n er s , pl a s m a s a m pl e s s h o ul d b e c o m pl et el y 
pr o c e s s e d (i. e. ali q u ot e d a n d pl a c e d i n -8 0 o C f or st or a g e) wit hi n 4 h o ur s.    
b.  S a m pl e s t h at r e m ai n at r o o m t e m p er at ur e f or a l o n g er t h a n 4 h o ur s c a n b e pr o c e s s e d, b ut t h e a ct u al 
ti m e r e q uir e d t o pr o c e s s t h e s a m pl e s c o m pl et el y s h o ul d b e r e c or d e d o n C R F.  
c. S a m pl e s s h o ul d b e st or e d at -8 0 o C u ntil it i s a g o o d d a y t o s hi p.  G o o d d a y s ar e M o n d a y s, T u e s d a y s, 
a n d W e d n e s d a y s ( d o m e sti c) or M o n d a y s a n d T u e s d a y s (i nt er n ati o n al).  S a m pl e s m u st b e t a k e n fr o m 
-8 0 o C fr e e z er a n d dir e ctl y  p ut o n dr y i c e f or s hi p pi n g.  D o n ot l et t h a w or p ut o n w et i c e . 
d.  S a m pl e s s h o ul d b e s hi p p e d t o J o h n s H o p ki n s U ni v er sit y S c h o ol of M e di ci n e i n b at c h e s e v er y t hr e e 
m o nt h s.  
e.  V a c ut ai n er s s h o ul d b e fill e d c o m pl et el y t o e n s ur e a d e q u at e pl a s m a s a m pl e.  
f. W h e n filli n g V a c ut ai n er , u s e t h e v a c u u m t o all o w t h e t u b e t o fill wit h bl o o d.  D o n ot f or c e bl o o d i nt o t h e 
t u b e wit h a s yri n g e, w hi c h m a y c a u s e h e m ol y si s.  
g.    If a cl ot f or m s i n t h e n e e dl e a n d  pr e v e nt s pl a s m a tr a n sf er, c h a n g e n e e dl e s a n d pr o c e e d.  
 
 
6.  S hi p pi n g  
 
D o m e sti c s hi p m e nt s  
1.  Pl e a s e c o nt a ct u s a h e a d of ti m e a b o ut s hi p pi n g.  Pl e a s e e m ail E mil y B arr o n -C a s ell a at 
e b arr o n 1 @j h mi. e d u , Ki m J o n e s at kj o n e s 6 2 @j h mi. e d u , a n d Di a n e W ei s s at d w ei s s 1 4 @j h mi. e d u  t h at a 
s hi p m e nt i s t o b e e x p e ct e d.  
2.  Pl e a s e st or e s a m pl e s at -8 0 o C u ntil it i s a g o o d d a y t o s hi p.  G o o d d a y s ar e M o n d a y s, T u e s d a y s, a n d 
W e d n e s d a y s ( d o m e sti c).   
3.  S hi p pi n g m u st f oll o w t h e g ui d eli n e s of D O T/I A T A f or “ Bi ol o gi c al S u b st a n c e C at e g or y B U N 3 3 7 3 .”  
T h er e m u st b e 3 l e v el s of c o nt ai n m e nt.  
4.  Pl a c e H U Pr e v e nt S a m pl e s fr e e z er b o x c o nt ai ni n g s a m pl e s i n s m all c o nt ai n m e nt b a g wit h p a d.  T h e 
p a d i s t o a b s or b a n y bi o h a z ar d o u s m at eri al if c o m pr o mi s e d.  P ut b a g g e d b o x i n t h e b ott o m of t h e 
St yr of o a m c arri er/ c ar d b o ar d b o x.   
5.  A d d a p pr o xi m at el y 5 l b s ( = 2. 5 k g)  of dr y i c e o n t o p of b a g g e d b o x.  P ut St yr of o a m t o p o n c arri er, b ut 
d o N O T t a p e ( C O 2  fr o m dr y i c e m u st b e a bl e t o e s c a p e).   
6.  B et w e e n St yr of o a m a n d c ar d b o ar d  b o x, t u c k i n t h e c o m pl et e d C a s e R e p ort F or m.  Cl o s e c ar d b o ar d t o p 
a n d t a p e.   
7.  C o m pl et e a n d a p pl y dr y i c e l a b el a n d “ Bi ol o gi c al S u b st a n c e C at e g or y B U N 3 3 7 3” l a b el s t o o ut si d e of 
c ar d b o ar d b o x.   
8.  C o m pl et e a n d a p pl y U S A F e d E x Air bill a n d s c h e d ul e a pi c k -u p.  


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 6 5  of 7 4  
 
 
I nt er n ati o n al s hi p m e nt s 
1.  Pl e a s e c o nt a ct u s a h e a d of ti m e a b o ut s hi p pi n g. Pl e a s e e m ail E mil y B arr o n -C a s ell a at 
e b arr o n 1 @j h mi. e d u , Ki m J o n e s at kj o n e s 6 2 @j h mi. e d u , a n d P a ul K a m at e at p k a m at e 1 @j h mi. e d u t h at a 
s hi p m e nt i s t o b e e x p e ct e d.  
2.  Pl e a s e st or e s a m pl e s at -8 0 o C u ntil it i s a g o o d d a y t o s hi p.  G o o d d a y s ar e M o n d a y s a n d T u e s d a y s.   
3.  S hi p pi n g m u st f oll o w t h e g ui d eli n e s of D O T/I A T A f or “ Bi ol o gi c al S u b st a n c e C at e g or y B U N 3 3 7 3 ” 
s hi p m e nt s.  T h er e m u st b e 3 l e v el s of c o nt ai n m e nt.  
4.  Pl a c e H U Pr e v e nt S a m pl e s fr e e z er b o x c o nt ai ni n g s a m pl e s i n s m all c o nt ai n m e nt b a g wit h p a d.  T h e 
p a d i s t o a b s or b a n y bi o h a z ar d o u s m at eri al if c o m pr o mi s e d.  P ut b a g g e d b o x i n t h e b ott o m of t h e 
St yr of o a m c arri er/ c ar d b o ar d b o x.   
5.  A d d a p pr o xi m at el y 1 5 l b s ( = 7. 5 k g) of dr y i c e  o n t o p of b a g g e d b o x f or s hi p pi n g.  P ut St yr of o a m t o p 
o n c arri er, b ut d o N O T t a p e ( C O 2  fr o m dr y i c e m u st b e a bl e t o e s c a p e).   
6.  B et w e e n St yr of o a m a n d c ar d b o ar d b o x, t u c k i n t h e c o m pl et e d C R F.  Cl o s e c ar d b o ar d t o p a n d t a p e.   
7.  C o m pl et e a n d a p pl y dr y i c e l a b el a n d “ Bi ol o gi c al S u b st a n c e C at e g or y B U N 3 3 7 3” l a b el s t o o ut si d e of 
c ar d b o ar d b o x.   
8.  C o m pl et e a n d a p pl y I nt er n ati o n al F e d E x Air bill , t h e c o m m er ci al i n v oi c e a n d a n y c o u ntr y -s p e cifi c 
r e q uir e d f or m s a n d s c h e d ul e a pi c k -u p.  
 
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 6 6  of 7 4  
 
  
  
  
  
  
  
 
A p p e n di x 1 6 :  C o m mitt e e s  
 
E x e c uti v e C o m mitt e e:   T hi s i s t h e d a y -t o-d a y d e ci si o n -m a ki n g b o d y a n d i s r e s p o n si bl e f or t h e s u c c e s sf ul 
c o m pl eti o n of t h e st u d y , i n cl u di n g s u st ai ni n g t ar g et e nr oll m e nt a n d pr ot o c ol a d h er e n c e. M e m b er s i n cl u d e t h e 
St u d y C h air, w h o will h e a d t h e c o m mitt e e, t h e Pri n ci p al I n v e sti g at or ( PI) fr o m t h e D C C, t h e st u d y Vi c e -C h air, 
J o h n Str o u s e, C o -I n v e sti g at or, t h e C h air s of t h e N e ur ol o g y , N e ur or a di ol o g y , N e ur o p s y c h ol o g y, I m a gi n g a n d 
S e d ati o n  C o m mitt e e s , a s w ell a s a r e pr e s e nt ati v e fr o m t h e T C D R e a di n g C e nt er, 3 r ot ati n g st u d y c e nt er 
Pri n ci p al I n v e sti g at or s a n d t h e N H L BI Pr oj e ct Offi c er.  O n i s s u e s r e q uiri n g a v ot e, o n e v ot e p er m e m b er will b e 
all o w e d. D uri n g e arl y p h a s e s of t h e Tri al, t hi s C o m mitt e e will m e et b y c o nf er e n c e c all n o l e s s t h a n e v er y ot h er 
w e e k d uri n g t h e st u d y, t o r e vi e w tri al e nr oll m e nt, c o n d u ct of t h e pr ot o c ol, f e a si bilit y ( p arti ci p a nt  b ur d e n, sit e 
b ur d e n a n d c o st), s ci e ntifi c  m erit, a n d i s s u e s r ai s e d b y t h e Cli ni c al Sit e s, a n d n o l e s s t h a n m o nt hl y t h er e aft er .  
 
T h e E x e c uti v e C o m mitt e e will m e et  i n p er s o n at l e a st e v er y t w el v e m o nt h s, i n B alti m or e.  Fr e q u e nt c o nf er e n c e 
c all s will e n s ur e s m o ot h d a y -t o-d a y o p er ati o n s of t h e tri al  a n d h el p t o i d e ntif y i s s u e s t h at n e e d t o b e br o u g ht 
b ef or e t h e O p er ati o n s  C o m mitt e e , w hi c h will m e et bi w e e kl y.  T h e E x e c uti v e C o m mitt e e will al s o m a k e 
r e c o m m e n d ati o n s o n tri al-r el at e d i s s u e s a n d p u bli c ati o n s.  
 
P u bli c ati o n C o m mitt e e:  A P u bli c ati o n s C o m mitt e e c o n si sti n g of t h e E x e c uti v e C o m mitt e e a n d t h e Sit e 
I n v e sti g at or s will r e vi e w a n d r e p ort r e s ult s f or d at a a n al y s e s fr o m t h e D C C a n d will r e vi e w all pr o p o s al s f or a n d 
fi n al v er si o n s of r e s e ar c h a b str a ct s, pr e s e nt ati o n s, a n d m a n u s cri pt s t o b e s u b mitt e d t o j o ur n al s a n d n ati o n al 
m e eti n g s.  A Sit e I n v e sti g at or C o m mitt e e will di s c u s s a n d fi n d s ol uti o n s t o pr o bl e m s t h at m a y ari s e at e a c h 
Cli ni c al Sit e.  
 
C o m mitt e e M e eti n g S c h e d ul e F or H U Pr e v e nt Tri a l 
C o m mitt e e  
P arti ci p a nt s  
S c h e d ul e  
E x e c uti v e  
Pri n ci p al I n v e sti g at or, Vi c e-C h air, 
St ati sti c al C o or di n at i n g C e nt er PI, C o -
I n v e sti g at or, Di s ci pli n e C h air s, I m a gi n g 
C or e  a n d T C D R e a di n g C e nt er  
R e pr e s e nt ati v e s , C o n s ult a nt s, 
A d mi ni str ati v e Offi c e St aff (if n e e d e d)  
P h o n e c o nf er e n c e e v er y m o nt h , m e eti n g 
i n B alti m or e ev er y 1 2  m o nt h s f or o n e d a y 
m e eti n g  
O p er ati o n s  
Pri n ci p al  I n v e sti g at or, Vi c e C h air, J o h n 
Str o u s e, C o -i n v e sti g at or, 
R e pr e s e nt ati v e fr o m St ati sti c al 
C o or di n ati n g C e nt er, L e a d St u d y 
C o or di n at or.  
 
Sit e 
H e m at ol o gi st s / 
N e ur ol o gi st s  
Sit e I n v e sti g at or s M e eti n g  
A n n u al I n v e sti g at or s M e eti n g i n 
B alti m or e or vi a W e bi n ar  
N e ur ol o g y  
Sit e N e ur ol o gi st s & N e ur ol o g y 
C o m mitt e e  
A n n u al I n v e sti g at or s M e eti n g i n 
B alti m or e  
N e ur o p s y c h ol o g y  N e ur o p s y c h ol o g y C o m mitt e e  
A n n u al I n v e sti g at or s M e eti n g i n 
B alti m or e  
N e ur or a di ol o g y  
N e ur or a di ol o g y C o m mitt e e M e m b er s, 
a n d I m a gi n g C or e I n v e sti g at or s  
A n n u al I n v e sti g at or s M e eti n g i n 
B alti m or e  


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 6 7  of 7 4  
S e d ati o n  
S e d ati o n c o m mitt e e  
A n n u al I n v e sti g at or s M e eti n g i n 
B alti m or e  
 
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 6 8  of 7 4  
A p p e n di x 1 7 : H y dr o x y ur e a a n d Pl a c e b o F or m ul ati o n  
 
H Y D R O X Y U R E A O R A L S O L U TI O N ( 1 0 0 M G/ M L)     
 
I n gr e di e nt s 
H y dr o x y ur e a c a p s ul e s 5 0 0 m g # 1 0  
Di still e d w at er q s a d 2 5 m L  
Si m pl e S yr u p 5 0 m L  
 
Dir e cti o n s  
1. E m pt y c a p s ul e s i nt o 2 5 m L w at er t o f or m a sl urr y i n a 3 0 m L W h e at o n vi al.  
 
2. S h a k e w ell f or 1 -2 mi n ut e s c o nti n u o u sl y e v er y 1 0 -1 5 mi n ut e s f or 1 h o ur u ntil all gr a n ul e s ar e i n s ol uti o n.  
 
3. Filt er s ol uti o n u si n g a 5 mi cr o n filt er (t h e a cti v e i n gr e di e nt i s s ol u bl e a n d will b e i n t h e filtr at e). 
 
4. A d d 2 5 m L si m pl e s yr u p ( m e a s ur e d wit h s yri n g e) a n d s h a k e w ell . 
 
L a b eli n g  
K e e p r efri g er at e d.  S p e ci al h a n dli n g r e q uir e d.  
 
E x pir ati o n  
3 m o nt h s  
 
R ef er e n c e  
H e e n e y , M att h e w, " C h e mi c al a n d F u n cti o n al A n al y si s of H y dr o x y ur e a Or al S ol uti o n s," J P e di atr H e m at ol O n c ol 
2 0 0 4, V ol 2 6 ( 3): 1 7 9 -1 8 4.  
 
 
P L A C E B O O R A L S O L U TI O N  
 
i n gr e di e nt s 
Di still e d w at er 5 0 ml  
Si m p l e S yr u p 5 0 ml 
 
Mi x all i n gr e di e nt t o m a k e 1 0 0 ml of pl a c e b o s ol uti o n  
 
L a b eli n g  
K e e p r efri g er at e d. S p e ci al h a n dli n g r e q uir e d.  
 
E x pir ati o n  
3 m o nt h s  
 
 
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 6 9  of 7 4  
A p p e n di x 1 8: A n e st h e si a/ S e d ati o n D at a C oll e cti o n I n str u m e nt   
 
A ge  
   years      m o nt hs  
Wei g ht    .  k g  
Ge n der  
○ male  
○ fe male   
 
Dia g n osis  
○ H b S S  
○ H b S β 0 
C oe xisti n g Ill nesses  ○ Ast h ma  
○ Ot her _ _ _ _ _ _ _ _ _ _  
A S A Stat us  
  ( 1-5)     
 
H o me me dicati o ns  ○ Pe nicilli n  ○ F olic aci d  
○ I b u pr ofe n  
○ Al b uter ol  
 
○ Ot her  _ _ _ _ _ _ _ _ _    ○ Ot her  _ _ _ _ _ _ _ _ _  
○ Ot her  _ _ _ _ _ _ _ _  ○ 
Ot her  _ _ _ _ _ _ _ _ _   
 
○ Ot her  _ _ _ _ _ _ _ _ _  
○ Ot her  _ _ _ _ _ _ _ _  
N P O d urati o n   
   h o urs  f or clear li q ui ds      h o urs  f or s oli ds 
Case Ca ncellati o n  
○n o  
○ yes   
 
Ca ncellati o n Reas o n  
○ N P O vi olati o n  
○ Ac ute Ill ness  
○ Ot her   
  
  
 
Pre me dicati o n   
○ N o ne    
○ L oraze pa m  
○ Ot her  _ _ _ _ _ _ _ _ _  
I V place d   
○Bef ore a nest hesia  ○After i n halati o nal a ge nt  ○U n k n o w n  
Start of pr oce d ure  
  :   ( 2 4 h o ur ti me) 
Intra ve n o us  a ge nt 
D ose f or i n d ucti o n  
T otal D ose f or t he Pr oce d ure  
○ Li d ocai ne  
    m g     
 
    m g  
○ Pr o p of ol    
    m g     
 
    m g  
○ Pe nt o bar bital  
    m g     
 
    m g   
 
 
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 7 0  of 7 4  
I n halati o nal a ge nt 
 
○ Se v ofl ura ne  
C o nce ntrati o n     %   D urati o n       mi n utes  
○ Nitr o us O xi de  
C o nce ntrati o n     % 
D urati o n     mi n utes  
A d diti o nal a ge nts use d  
○ Ot her _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Details  
    
  
  
 
○ Ot her _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Details  
    
  
  
 
Air wa y de vice  
○ N o ne  
○ L M A  ○E n d otrac heal T u be  
○ Trac he ost o m y T u be  
C ha n ge i n air wa y de vice  
○n o  
○ yes  
T y pe of air wa y c ha n ge  ○ N o ne t o L M A  ○ N o ne t o E T T  ○L M A t o E T T  ○ Trac h t o E T T  
Reas o n f or c ha n ge    
○ C o u g hi n g  
○ Secreti o ns  
○ Lar y n g os pas m   
  
  
 
○ U p per air wa y o bstr ucti o n  
○ ot her     
      
 
D urati o n of M RI  
   mi n utes   
 
D urati o n of a nest hetic/se dati o n     mi n utes   
 
D urati o n of rec o ver y  
   mi n utes    
C o m plicati o ns  
 
Desat urati o n < 9 0 %  f or > 6 0s  
○ n o  
○ yes    
○ u n k n o w n/ missi n g  
Desat urati o n > 1 0 % fr o m baseli ne  > 6 0s  
○ n o  ○ yes    
○ u n k n o w n/ missi n g  
L o west desat urati o n   
   %    
 
D urati o n of l o west desat urati o n  
  sec o n ds 
  mi n utes     
  
 
Res pirat or y  
○ A p nea  
○ As pirati o n  
○ Br o nc h os pas m  
  
 
○ Stri d or  
○ Lar y n g os pas m  
  
 
○ Ot her      
  
  
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 7 1  of 7 4  
Car di o vasc ular   ○ Bra d ycar dia 
○ Tac h ycar dia  
○ H y p ote nsi o n  ○ H y perte nsi o n  
  
 
○ Ot her   
 
 
   
 
C ore Te m perat ure  
○ < 3 6. 0°  
○ 3 6. 0° -3 8. 1°  
○ > 3 8. 1°  
○u n k n o w n/ missi n g  
 
E mer ge nce Deliri u m  
○n o  
○ yes   
  
 
○ u n k n o w n/ missi n g  
 
E mesis    
○ n o  
○ o nce  
○ > 2 ti mes  ○ u n k n o w n/ missi n g  
Ot her  
○n o  
○ yes  
If yes please descri be  
  
  
  
  
  
  
  
 
 
Ac ute Seri o us A d verse E ve nts  
H os pitalizati o n   
○ n o  
○ yes  
○ u n k n o w n/ missi n g  
 
Pai n  
○ n o  
○ yes  
○ u n k n o w n/ missi n g  
 
Ac ute c hest  
○ n o  
○ yes  
○ u n k n o w n/ missi n g  
 
Str o ke  
○ n o  
○ yes  
○ u n k n o w n/ missi n g  
 
Fe ver  
○ n o  
○ yes  
○ u n k n o w n/ missi n g  
 
As pirati o n  
○ n o  
○ yes  
○ u n k n o w n/ missi n g  
 
H y p o xe mia  
○ n o  
○ yes  
○ u n k n o w n/ missi n g  
 
Ot her  
○ n o  
○ yes  
○ u n k n o w n/ missi n g  
   
If yes, descri be   
  
 
  
 
C P R  
○ n o  
○ yes  
○ u n k n o w n/ missi n g  
Deat h  
○ n o  
○ yes  
○ u n k n o w n/ missi n g  
Per ma ne nt ne ur ol o gic i nj ur y   
○ n o  ○ yes  ○ u n k n o w n/ missi n g  
Per ma ne nt e n d -or ga n i nj ur y   
○ n o  ○ yes  ○ u n k n o w n/ missi n g  
U na ntici pate d e n d otrac heal i nt u bati o n   ○ n o  ○ yes  ○ u n k n o w n/ missi n g  
Ot her  
○ n o  ○ yes  ○ u n k n o w n/ missi n g  
If yes, descri be   
  
  
  
  
  
  
  
  
 
 
Electi ve H os pit aliz ati o n f or O bser v ati o n is n ot c o nsi dere d i n itself a n a d verse e ve nt 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 7 2  of 7 4  
A p p e n di x 1 9 : S e d ati o n F oll o w-u p Q u e sti o n n air e  
 
T h e f oll o wi n g s cri pt i s t o b e u s e d f or t el e p h o n e f oll o w -u p 2 4 h o ur s aft er s e d ati o n i s a d mi ni st er e d f or a st u d y 
M RI.  T h e s a m e q u e sti o n s s h o ul d b e a d mi ni st er e d at 1 4 d a y s eit h er at a f oll o w -u p vi sit or b y t el e p h o n e.  
 
H ell o, t hi s i s n a m e of c all er  fr o m n a m e of PI, n a m e of i n stit uti o n .  M a y I pl e a s e s p e a k t o n a m e of 
p arti ci p a nt  m ot h er or f at h er ( or ot h er c ar e gi v er).   I a m c alli n g t o s e e h o w n a m e of p arti ci p a nt  i s d oi n g aft er 
t h eir M RI o n d at e of M RI.   I s n o w a n O K ti m e t o a s k y o u a f e w q u e sti o n s ? 
 
1)  H a s n a m e of p arti ci p a nt  h a d a n y p ai n ? -Y e s, N o, U n k n o w n, Mi s si n g  
a.  If y e s, w h er e w a s t h e p ai n ?  ( c h o o s e m ulti pl e fr o m li st-h e a d, ar m s,  h a n d s, l e g s, c h e st, b a c k, 
a b d o m e n/ b ell y, f e et, ot h er)  
b.  If y e s, w h e n di d it st art ? D a y/ m o nt h/ y e ar milit ar y ti m e 
c. If y e s, w h e n di d it st o p ? D a y/ m o nt h/ y e ar milit ar y ti m e 
d.  If y e s, h o w s e v er e ( 0 n o p ai n, 1 0 w or st p ai n e v er) ( dr o p d o w n m e n u 0-1 0, 9 9 f or mi s si n g  
e.  If y e s, w er e t h e y gi v e n a n y p ai n m e di ci n e ? Y e s/ N o/ U n k n o w n/ Mi s si n g 
f. If y e s, w h at t y p e of m e di ci n e-c h o o s e all fr o m li st  
i. T yl e n ol/ a c et a mi n o p h e n  
ii. M otri n/ A d vil/I b u pr of e n  
iii. Al e v e/ N a pr o x e n  
i v. A c et a mi n o p h e n wit h c o d ei n e/ T yl e n ol wit h c o d ei n e, T yl e n ol # 3  
v.  O x y c o d o n e  
vi.  M or p hi n e  
vii.  Dil a u di d/ h y dr o m or p h o n e  
viii.  Ot h er     
  
  
 
2)  H a s n a m e of p arti ci p a nt  h a d a n y br e at hi n g pr o bl e m s -Y e s, N o, U n k n o w n, Mi s si n g  
a.  If y e s, w h e n di d it st art ? D a y/ m o nt h/ y e ar milit ar y ti m e 
b.  If y e s, w h e n di d it st o p ? D a y/ m o nt h/ y e ar milit ar y ti m e 
c. If y e s, t y p e-m ar k a s m a n y  
i. C o u g h  
ii. S h ort n e s s of br e at h  
iii. W h e e zi n g  
i v. Br e at hi n g h ar d  
v.  Ot h er     
  
  
 
d.  If y e s, di d y o ur c hil d r e c ei v e a n y tr e at m e nt f or it 
i. N o n e  
ii. Al b ut er ol/ Pr o v e ntil  
iii. A nti bi oti c s  
i v. O v er t h e c o u nt er c o u g h m e di ci n e  
v.  Pr e s cri pti o n c o u g h m e di ci n e  
vi.  C orti c o st er oi d s b y m o ut h ( pr e d ni s o n e, pr e d ni s ol o n e, Pr el o n e, P e di a pr e d)  
vii.  Ot h er     
  
  
 
3)  H a s n a m e of p arti ci p a nt  h a d a n y ot h er h e alt h pr o bl e m s si n c e t h e M RI ? Y e s/ N o/ U n k n o w n/ Mi s si n g  
a.  If y e s, pl e a s e d e s cri b e  
  
  
  
 
4)  H a s n a m e of p arti ci p a nt  h a d a n y h e alt h c ar e vi sit s si n c e t h e M RI ? 
a.  N o n e  
b.  R e g ul ar vi sit -If Y e s 
i. D at e ( d a y/ m o nt h/ y e ar)  


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 7 3  of 7 4  
ii. R e a s o n -f oll o w-u p of pr o bl e m, h e alt h c ar e m ai nt e n a n c e, ot h er   
  
 
iii. D e s cri pti o n -h e m at at o g y, pri m ar y c ar e, ot h er    
  
 
c. Si c k vi sit t o d o ct or’ s offi c e, if y e s  
i. D at e ( d a y/ m o nt h/ y e ar)  
ii. R e a s o n -f oll o w-u p of pr o bl e m, h e alt h c ar e m ai nt e n a n c e, ot h er   
  
 
iii. D e s cri pti o n -h e m at at o g y, pri m ar y c ar e, ot h er    
  
 
d.  Si c k vi sit t o ur g e nt c ar e, if y e s – d at e, r e a s o n, d e s cri pti o n    
  
  
 
i. D at e ( d a y/ m o nt h/ y e ar)  
ii. R e a s o n -f oll o w-u p of pr o bl e m, h e alt h c ar e m ai nt e n a n c e, ot h er   
  
 
iii. D e s cri pti o n -h e m at at o g y, pri m ar y c ar e, ot h er    
  
 
e.  Si c k vi sit t o e m er g e n c y d e p art m e nt, if y e s – d at e, r e a s o n, d e s cri pti o n   
  
  
 
i. D at e ( d a y/ m o nt h/ y e ar)  
ii. R e a s o n -f oll o w-u p of pr o bl e m, h e alt h c ar e m ai nt e n a n c e, ot h er   
  
 
iii. D e s cri pti o n -h e m at at o g y, pri m ar y c ar e, ot h er    
  
 
f. H o s pit ali z ati o n, if y e s – st art  a n d e n d d at e, r e a s o n, d e s cri pti o n   
  
  
  
 
i. D at e ( d a y/ m o nt h/ y e ar)  
ii. R e a s o n -f oll o w-u p of pr o bl e m, h e alt h c ar e m ai nt e n a n c e, ot h er   
  
 
iii. D e s cri pti o n -h e m at at o g y, pri m ar y c ar e, ot h er    
  
 
 
 


H y dr o x y ur e a t o Pr e v e nt C N S C o m pli c ati o n s  of Si c kl e C ell Di s e a s e i n C hil dr e n  ( H U Pr e v e nt) 
 
2- 1 0 -1 6  
 
 
p a g e 7 4  of 7 4  
A p p e n di x 2 0: M e di c al M o nit or R e s p o n si biliti e s  
1. L a b or at or y M o nit ori n g  
•  
P ati e nt s will h a v e l a b t e sti n g d o n e l o c all y.  
•  
E a c h sit e will h a v e a l o c al m e di c al m o nit or ( L M M) w h o will r e vi e w all bli n d e d l a b or at or y t e sti n g. T h e 
L M M will still b e bli n d e d t o tr e at m e nt a s si g n m e nt.  
•  
T h e L M M will i s s u e st o p or d er s f or p ati e nt s ( o n H U or o n pl a c e b o) w h o m e et t o xi cit y crit eri a.  
•  
T h e L M M will n otif y D o n n a W h yt e -St e w art, M D, t h e c e ntr al m e di c al m o nit or ( C M M) a b o ut all t o xi citi e s 
t h at r e s ult i n st o p or d er s. D o n n a W h yt e-St e w art’ s c ell p h o n e n u m b er i s 3 1 5 -3 7 8 -2 4 5 5.   
•  
T hi s will all o w:  
a.  C e ntr al r e vi e w of crit eri a f or st o p pi n g st u d y dr u g.  
b.  P airi n g of pl a c e b o p ati e nt s f or r a n d o m st o p s.  
•  
T h e L M M will al s o n otif y t h e C M M w h e n r e st art o c c ur s.  
•  
T h e C M M will r e vi e w all l a b s i n R E D C a p w e e kl y, t o b e s ur e t h at n o t o xi citi e s ar e mi s s e d.  
 
2. R a n d o m St o p Or d er s  
•  
W h e n a pl a c e b o p ati e nt i s e nr oll e d, t h e C M M will a s si g n a H U p ati e nt at a n ot h er sit e t o b e a “ mirr or” 
s u bj e ct.  
•  
If t h e H U p ati e nt i n t h e p air i s i s s u e d a st o p or d er, t h e C M M ( w h o will b e n otifi e d of t h e st o p a s a b o v e) 
will c all t h e l o c al m o nit or f or t h e p air e d pl a c e b o p ati e nt a n d h a v e t h e L M M i s s u e a  st o p or d er f or t h at 
p ati e nt aft er t h e n e xt s et of l a b s, r e g ar dl e s s of t h e l a b r e s ult s.   
•  
R e st art will b e si mil arl y p air e d.  
•  
If a pl a c e b o p ati e nt h a s a t o xi cit y ( vir al s u p pr e s si o n f or e x a m pl e) a n d r e c ei v e s a st o p or d er, t h e p air e d 
H U p ati e nt will N O T b e i s s u e d a st o p or d er.  
 
3. D o s e E s c al ati o n  
•  
W h e n a n H U p ati e nt h a s a d o s e e s c al ati o n, t h e L M M will n otif y t h e C M M.  T h e C M M will k e e p tr a c k of 
t h e ti mi n g of t hi s e s c al ati o n ( w e e k s fr o m st u d y i niti ati o n) a n d will n otif y t h e L M M a b o ut ti mi n g of d o s e 
e s c al ati o n s o n  t h e pl a c e b o p ati e nt p air e d t o t h at H U p ati e nt. 
 
4. S u m m ar y P oi nt s/ Fl o w of C o m m u ni c ati o n  
•  
L M M s will c all C M M ( 3 1 5 -3 7 8 -2 4 5 5) a b o ut:  
a.  T o xi citi e s r e q uiri n g st o p or d er s  
b.  R e st art s  
c. D o s e e s c al ati o n s  
•  
T h e C M M will c all L M M s r e g ar di n g:  
a.  R a n d o m st o p s o n pl a c e b o p ati e nt s  
b.  R e -st art s o n pl a c e b o p ati e nt s  
c. D o s e e s c al ati o n s o n pl a c e b o p ati e nt s  
d.  Mi s s e d t o xi citi e s aft er w e e kl y r e vi e w  
•  
T h e C M M will b e n otifi e d of all n e wl y r a n d o mi z e d p ati e nt s t o all o w mirr or s u bj e ct p airi n g s.  
 
 
 

ICF_001.pdf: 
Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 7, 2013 
Principal Investigator: James F. Casella, MD 
Application No.: NA_00041623 
 
 Page 1 of 15 
 Combined Informed Consent/Authorization March 2012 Version 13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hydroxyurea for the Prevention of Brain Injury of Sickle Cell Disease 
(HU Prevent) 
 
 
 
 
 
 
RESEARCH PARTICIPANT INFORMED CONSENT AND  
PRIVACY AUTHORIZATION FORM 
 
March 7, 2013 
 
 
 
NCT01389024 
 
 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 7, 2013 
Principal Investigator: James F. Casella, MD 
Application No.: NA_00041623 
 
 Page 2 of 15 
 Combined Informed Consent/Authorization March 2012 Version 13 
 
 
 
 
 
 
 
 
RESEARCH PARTICIPANT INFORMED CONSENT AND PRIVACY 
AUTHORIZATION FORM 
Protocol Title:  
 
Hydroxyurea for the Prevention of Brain Injury of Sickle Cell Disease 
 
Application No.:  
NA_00041623 
 
Sponsor: 
 
 
National Center for Research Resources 
Johns Hopkins Institute for Clinical and Translational Research - 
Clinical Research Unit (ICTR-CRU) 
National Heart, Lung, and Blood Institute 
 
Principal Investigator: James F. Casella, MD 
 
 
 
 
720 Rutland Avenue 
Ross 1125 
Baltimore, MD 21205 
410-955-6132 (office) 
410-955-8208 (fax) 
 
1. 
What you should know about this study:   
• You are being asked to allow your child to join a research study. 
• This consent form explains the research study and your child’s part in the study.   
• Please read it carefully and take as much time as you need.  
• Please ask questions at any time about anything you do not understand.   
• You are a volunteer.  If you allow your child join the study, you can change your mind later. You 
can decide not to allow your child to take part or you can quit at any time. There will be no penalty 
or loss of benefits if you decide to quit the study.   
• During the study, we will tell you if we learn any new information that might affect whether you 
wish to continue to allow your child to be in the study. 
• Ask your study doctor or the study team to explain any words or information in this informed 
consent that you do not understand. 
• For clinical trials: A description of this clinical trial will be available at 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 the Web site at any time. 
• If children and adults can join this study, the word “you” in this consent form will refer to both you    
and your child. 
• A statement will be added to your medical record that you are in this research study. Results from 
any clinical tests you have will be included in your medical record.  Doctors outside of Johns 
Hopkins may not have access to this information.  You can ask the research team to send this 
information to any of your doctors. 
 
 
 
 
 
 
 
 
                               Patient I.D. Plate 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 7, 2013 
Principal Investigator: James F. Casella, MD 
Application No.: NA_00041623 
 
 Page 3 of 15 
 Combined Informed Consent/Authorization March 2012 Version 13 
• During this study, you will not have access to certain medical information and test results collected 
for study purposes.  If an emergency occurs while you are in the study, medical information needed 
for your treatment can be made available to your study physician and other physicians who treat you.  
When the study is completed, all the information in your medical record will be available to you. 
 
2. 
Why is this research being done? 
Sickle cell disease is an inherited disease of the blood.  We do not know why some people have more 
problems related to sickle cell disease than others.  Our overall goal of this study is to see if treatment 
with hydroxyurea will help prevent brain problems like strokes in children with sickle cell disease.  
Children with sickle cell disease are at high risk for strokes.  Strokes can lead to problems with learning, 
mental development, and school work. 
This study has 3 goals.  These goals are: 
    
1. To compare hydroxyurea to placebo (a placebo is a substance that looks like the study drug, but does 
not affect you) for the prevention of brain problems like stroke.   This is a small study at two 
hospitals in preparation for a larger study. 
 
 
2. To determine the safety of the study medicine and other study procedures for infants and children 
with sickle cell disease.  
 
3. To collect and store blood for testing at a later date.  We plan to study genes and proteins in the 
blood that may be markers of brain injury or an increased risk of brain injury. 
 
Other things you should know about this study include: 
 
Hydroxyurea is approved by the Food and Drug Administration (FDA) for the treatment of frequent 
painful crisis in adult patients with sickle cell disease.  It is not approved to prevent or treat central 
nervous system complications such as fast blood flow in the brain and stroke in sickle cell disease 
therefore the use of hydroxyurea in this study is investigational. The FDA is allowing the use of 
hydroxyurea in this research study. 
 
Lidocaine is approved by the Food and Drug Administration (FDA) for local anesthesia.  It is routinely 
used intravenously to reduce the pain from infusion of propofol, but it is not specifically approved by the 
FDA for this use. 
 
Nitrous oxide is approved by the Food and Drug Administration (FDA) for procedural sedation in 
children. 
 
Propofol is approved by the Food and Drug Administration (FDA) for procedural sedation and 
anesthesia in children.  
 
Sevoflurane is approved by the Food and Drug Administration for anesthesia in children. 
 
Midazolam is approved by the Food and Drug Administration to reduce anxiety in children before 
procedures. 
 
Children with sickle cell disease between the ages of 12 to 48 months (1-4 years) may join this study; 
they may begin screening for this study at age 9 months. 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 7, 2013 
Principal Investigator: James F. Casella, MD 
Application No.: NA_00041623 
 
 Page 4 of 15 
 Combined Informed Consent/Authorization March 2012 Version 13 
This is a randomized double blind study.  There is a 50% chance your child will receive the study drug, 
hydroxyurea and a 50% chance your child will receive a placebo.  A placebo is a substance that looks 
like the study drug, but does not contain hydroxyurea.  Neither you nor the study doctors will know 
which your child will be getting. This information can be gotten in an emergency. 
 
How many people will be in this study? 
We expect about 20 children at Johns Hopkins Hospital and about 60 children at three other hospitals to 
take part in the study. 
 
3. 
What will happen if you join this study? 
If you agree to allow your child to be in this study, we will ask you to allow your child to have the 
following tests. 
 
Visit 1: Screening visit 
This visit will last about 4 to 5 hours. 
• You will learn about hydroxyurea and the study. 
• A hematologist or nurse practitioner will perform a history and physical exam.   
• Your child will have a transcranial Doppler ultrasound (TCD).   This test measures the speed of the 
blood flowing through the blood vessels in the neck and brain. Your child will be required to lie on 
their back while a small microphone is placed on various parts of their head. This test takes 
approximately 30 minutes and does not cause any discomfort.  
• A pediatric neurologist will perform a neurologic history and physical exam.  
• Your child will take a series of learning and thinking tests.  A trained staff member will give your 
child a group of standard tests.  These tests will measure learning, thinking and memory.  We will 
ask you some questions about your child’s behavior and environment.  Responses to these questions 
will be coded so no one will know who you are.  You have the right to refuse to answer any question 
for any reason.   The series of tests may take up to 1 hour.   
• About one tablespoon of blood will be taken from your child to check their blood counts, amount of 
Hb F and Hb S, liver and kidney function, and to be stored for testing in the future. This blood will 
be used for genetic testing and proteomics testing.  The blood is used to obtain DNA (the blueprint 
for a person’s identity) and to learn about the genes (the part of the DNA that tells your body how to 
make proteins) that may be associated with strokes and other factors that change how SCD affects 
your child.   We will modify and store some of the cells so that they can be used as a long term 
source of DNA.  Proteomics is the study of proteins that are found in blood and may be associated 
with stroke and other complications of SCD. 
  
 Visit 2: MRI of the brain with sedation (being put to sleep) 
• This study requires four MRI scans of the brain. Your child will have to be sedated (put to sleep) for 
some or all of the MRI scans. The MRI scan is commonly used in children with sickle cell anemia to 
take pictures of the brain. The MRI of the brain will show doctors if your child has had a silent 
stroke.  The MRI will take approximately 50 minutes.   
• Prior to your child’s MRI, you will be asked to complete a standard questionnaire. The purpose of 
this questionnaire is to make sure that your child is able to safely enter the MRI area.  If your child 
has a history of metal in their head or eyes, they cannot take part in this study. 
• To start your child’s MRI test, your child will lie on a padded table. A head/neck coil will be placed 
around your child’s head, face, and neck.  The coil is necessary to help the MRI machine take 
pictures. The table on which your child is lying will be moved to the center of an MRI magnet, 
which looks like a long narrow tube. Even though the tube is open, some people feel confined in 
small places.  If this bothers your child, please notify the MRI staff. You may end your child’s 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 7, 2013 
Principal Investigator: James F. Casella, MD 
Application No.: NA_00041623 
 
 Page 5 of 15 
 Combined Informed Consent/Authorization March 2012 Version 13 
participation in this study at any time by telling the MRI staff.  When MRI pictures are taken, radio-
signals and magnetic fields are used.  When this happens, it is normal for the MRI machine to make 
loud, banging, and clicking noises.  Your child will be asked to wear earplugs or headphones for 
their comfort during the exam.   
• During the exam, the MRI staff is able to see and hear your child.   
 
• Sedation evaluation: 
- 
Prior to the day of the MRI, you will be asked questions about recent illnesses, and other medical 
problems including obstructive sleep apnea. This will usually be done by telephone. 
- 
Due to the increased risk of problems from sedation in children with sickle cell disease, your 
child must be otherwise well at the time of the sedation and MRI. 
- 
The MRI will be cancelled if your child has had pain from sickle cell disease in the last two 
weeks or a cough or other cold symptoms, trouble breathing, or an asthma attack, acute chest 
syndrome, splenic sequestration or other acute complication (other than pain) of sickle cell 
disease in the last 4 weeks. 
- 
The sedation may cause abnormal vital signs or other problems that could lead to hospitalization 
or a sickle cell crisis. There is also a very small risk for cardiopulmonary arrest, stroke or death. 
The MRI will be cancelled if you do not consent to the sedation or the MRI. Consent for this will 
also be done on standard Hospital consent forms. 
- 
If your child usually can get an intravenous [IV] line, a numbing medicine will be placed on the 
best site or two. When the skin is numb, the IV will be placed. If your child does not tolerate IV 
line placement, your child will be placed under general anesthesia first. The IV will then be 
placed.  
- 
Midazolam- This medicine may be given by mouth before sedation to help the child relax and to 
forget being put to sleep.  
 
• Sedation procedure: 
- 
 Standard American Society of Anesthesiology [ASA] monitoring will be done including heart 
activity, blood oxygen and pressure, breathing rate, temperature, and exhaled carbon dioxide. An 
anesthesiologist will remain with your child for the entire procedure. 
- 
Your child’s vital signs will be taken and be documented at least every 5 minutes throughout the 
procedure.   
- 
Your child may be given midazolam (a medicine to help people relax) by mouth before the 
sedation to reduce anxiety and help your child forget about the sedation. 
- 
Your child will be given oxygen to maintain oxygen saturation above 95% throughout the 
procedure. 
- 
If an IV can be easily placed, lidocaine (pain medicine) will be given through the IV followed by 
propofol (sedation medication).  Additional propofol doses will be given by the anesthesiologist 
until enough sedation is obtained. We will draw a teaspoon of blood to be stored for proteomic 
testing. 
- 
If an IV cannot be easily placed, your child will be sedated with a mixture of nitrous oxide 
(laughing gas), oxygen and sevoflurane (sedation gas) given by a facemask until 
unconsciousness is achieved.  Your child will be monitored continuously during this process. 
Then the IV is placed and your child will be given oxygen and the propofol (sedation 
medication) as described above.  
- 
When the MRI is completed, the propofol will be stopped and your child will be brought to the 
recovery area.  
  
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 7, 2013 
Principal Investigator: James F. Casella, MD 
Application No.: NA_00041623 
 
 Page 6 of 15 
 Combined Informed Consent/Authorization March 2012 Version 13 
Visit 3: Randomization visit (this visit will take about 1.5 hours)   
• Randomization (like a flip of a coin by a computer) will decide if your child is given hydroxyurea or 
a placebo.  A placebo is a substance that looks like hydroxyurea, but does not affect you.  We are 
using a placebo in this study so that no one, except the pharmacy, will know who is receiving the 
drug.  This way, the results of the study will be fair.   
• We will meet with you to provide further education about hydroxyurea and the study.  You will be 
able to ask any questions.   
• We will take your child’s vital signs and review of any illnesses they may have had.  This will take 
about 1 hour. 
• Your child will have 1 teaspoon of blood draw to measure blood counts  
• We will collect urine for routine analysis. 
• Your child will begin to take the study drug (hydroxyurea or placebo) once a day for 36 months.   
• We will watch your child’s blood counts closely at each study visit (listed below) and we will make 
adjustments to your child’s dose based on blood counts as necessary.  If your child’s blood counts 
become low due to the study drug, we may have your child come in for additional blood draws (1/2 
teaspoon) weekly until their blood counts improve.  We will ask your child to come in for an 
additional blood draw (1/2 teaspoon) two weeks after any changes in their study drug. 
 
Follow-up Visits 
•  Every 4 weeks (this visit will take about 1.5 hours) 
- 
A hematologist or nurse practitioner will perform a history and physical exam.   
- 
You will be asked questions about your family and medical history and use of medicine by our 
study staff.  
- 
Approximately 1/2 teaspoon of blood will be taken from to check your child’s blood counts and 
½ teaspoon to store for proteomic testing.   
- 
You will need to bring your child’s study medication to clinic so we can measure the amount of 
remaining in the bottle. 
• In addition, at months 3, 6, and 9, 12, 15, 18, 21, 24, 27, 30, 33, and 36 
- 
We will collect 2 teaspoons of blood to measure fetal hemoglobin, kidney and renal function and 
to save for proteomics. 
 
Once a year visits  
These tests will be done over two separate visits: 
• A pediatric neurologist will perform a neurologic history and physical exam. This will take about 45 
minutes.    
• A hematologist or nurse practitioner will perform a history and physical exam.  You will be asked 
questions about your family and medical history and use of medicine by our study staff.   
• Your child will have a transcranial Doppler ultrasound (TCD).  This test takes approximately 30 
minutes and does not cause any discomfort.   
• Your child will take a series of learning and thinking tests.  A trained staff member will give your 
child a group of standard tests.  These tests will measure learning, thinking and memory.  We will 
also ask you some questions about your child’s behavior and environment.  Your responses to these 
questions will be coded so no one will know who you are.  These tests will take up to 1 hour.   
• 
Your child will have a sedated MRI of the brain as described above.  
 
 
 
 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 7, 2013 
Principal Investigator: James F. Casella, MD 
Application No.: NA_00041623 
 
 Page 7 of 15 
 Combined Informed Consent/Authorization March 2012 Version 13 
Schedule of study tests and visits: 
 
Screening 
 
Randomization 
Every 4 weeks 
Annual Visit 
Hydroxyurea education 
X 
X 
X 
X 
MRI of Brain with sedation  
X 
 
 
X 
Sedation evaluation 
X 
 
 
X 
Neurological exam 
X 
 
 
X 
Neurocognitive testing 
X 
 
 
X 
History and Physical exam 
X 
X 
X 
X 
Blood samples 
X 
X 
X 
X 
Transcranial Doppler (TCD) 
X 
 
 
X 
Medication Adherence Questionnaire 
 
 
X 
X 
 
How long will you be in the study? 
Your child will be in the study for three years. 
 
Future Contact  
We would like your permission to contact you about other studies that your child may be eligible for in 
the future.  
 
Please initial your choice below:  
       Yes, you may contact me in the future about other studies.  
       No, I do not want you to contact me about other studies.  
 
Future Use of Blood, Tissue, or Data 
Your child’s tissue and information (which includes your child’s study data and blood samples for 
protein markers) that goes with it will not have your child’s name on it, only a code number.  We may 
share your child’s blood and information with other investigators doing research in a similar field.  
These investigators may be at Johns Hopkins University or at other research centers.  To protect your 
child’s privacy, your child’s name and any identifying information will always be kept separate from 
their blood and study information. 
 
You will not hear from us unless we find information that may be important for your child’s care. 
  
The blood and data that goes into the repository will be used for this study, and also may be used for 
future studies. 
 
We will keep your child’s blood and any information collected on your child for at least 20 years, unless 
you request we remove your child’s information. 
 
Primary care physician / specialist notification option 
You and your child’s physician will not get these study results.  We will try to contact you if we learn 
your child has a life-threatening medical disorder that current treatment can stop or lessen. We will 
make every reasonable effort to do so, but you must make sure that we have an accurate and current 
address or telephone number to allow us to do this. 
 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 7, 2013 
Principal Investigator: James F. Casella, MD 
Application No.: NA_00041623 
 
 Page 8 of 15 
 Combined Informed Consent/Authorization March 2012 Version 13 
Please indicate below whether you want us to notify your child’s primary care physician or your child’s 
specialist of any life-threatening medical disorder that current treatment can stop or lessen. 
 
 Yes, I want the study doctor to inform my child’s primary care physician 
 No, I do not want the study doctor to inform my child’s primary care physician 
 My child does not have a primary care physician/specialist. 
 The study doctor is my child’s primary care physician/specialist. 
 
PHYSICIAN CONTACT INFORMATION 
 
Name:   
 
 
 
 
 
 
 
 
 
 
 
Phone Number:   
 
 
 
 
 
 
 
 
 
 
Address:   
 
 
 
 
 
 
 
 
 
 
 
Incidental Findings 
The MRI your child is having as part of this research study will be reviewed by a qualified person, just 
as it would be if your child were having the MRI or CT as part of their routine medical care. 
 
There is a possibility that while reviewing your MRI we may see an abnormality that we did not expect 
to see in this study. This is what is called an “incidental finding.” 
 
We will let your child’s doctor know if we see such an incidental finding.  Depending on the type of 
incidental finding, we may contact you by mail or by phone. In the case of a potential serious 
emergency, someone may go to your home. 
 
A qualified person (usually a member of the research team) will talk to you if there is an incidental 
finding. You do not have an option to decline information about an incidental finding. 
 
If you want, we will give information about this incidental finding to your child’s primary doctor or we 
will refer your child to an appropriate doctor for further evaluation. 
• 
An incidental finding may cause you to feel anxious.   
• 
Since an incidental finding will be part of your child’s medical record, your child could face 
greater difficulty in getting health or life insurance.  
• 
The costs for any care that will be needed to diagnose or treat an incidental finding would not be 
paid for by this research study.  These costs would be your responsibility. 
 
4. 
What are the risks or discomforts of the study? 
There are two main risks to this study: sedation (required for the MRI) and hydroxyurea. 
 
Sedation  
The Food and Drug Administration (FDA) is conducting an ongoing review of the use of anesthesia and 
sedatives in infants and children. This review is taking place because several studies in animals show 
that commonly used anesthetics when given for a long time and at very high doses (much longer time 
and higher doses than for the sedation planned in this study) may affect the development of the brain.  
There is no direct evidence that anesthesia or sedation are unsafe for children, or that anesthesia should 
not be given to children; however, caution is suggested in the use of anesthesia for purely elective 
procedures in children under the age of 4 years. You should balance these theoretical risks against the 
benefit of knowing whether your child has suffered or is at risk for brain injury due to sickle cell disease. 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 7, 2013 
Principal Investigator: James F. Casella, MD 
Application No.: NA_00041623 
 
 Page 9 of 15 
 Combined Informed Consent/Authorization March 2012 Version 13 
If you have any questions about the use of sedation in this study, you should talk to the anesthesiologist 
who is on the research team for this study. 
 
Less Likely: Inadequate sedation may make it more difficult to get good pictures of the brain.  Need for 
help breathing, including repositioning the head or using a small piece of plastic to help the flow of air 
or a mask to push air into the lungs. Low levels of oxygen in blood during sedation may also cause 
delayed problems, including pain or acute chest syndrome (pneumonia-like changes in the lungs from 
sickle cell disease).  
Rare: Severe breathing problems or cardiac arrest (sudden loss of heart function), stroke, brain injury or 
death. 
 
Hydroxyurea 
Likely: Low blood counts including low levels of white blood cells (neutropenia), platelets 
(thrombocytopenia), or red blood cells, (anemia), low sperm counts (causes decreased ability to have 
children) in men (which reverses after the medication is stopped).   
Less Likely: Darkening of the skin and nails, mild nausea or vomiting, open sores of the skin of the legs 
(ulcerations), increased numbers or severity of headaches. 
Rare: Injury to kidneys or liver, skin necrosis (death of skin cells or tissue). 
 
Other risks related to study drugs and procedures: 
Midazolam 
Likely: Short periods of no or slow breathing, sleepiness. 
Less Likely: Upset stomach, vomiting, hiccoughs, agitation, or involuntary moments, headache. 
Rare: Stopping breathing, low blood pressure. 
 
Propofol 
Likely: Decreased blood pressure, short periods of no breathing, pain at the place it is given. 
Less Likely: Myoclonic movements (brief twitching of a muscle or muscles), priapism (prolonged 
erection). 
Rare: Dystonia (movement problem with sustained muscle contractions, twisting and repeated 
movements). 
 
Lidocaine 
Likely: Nausea 
Less Likely: Drowsiness, mental/mood changes, ringing in ears, dizziness, vision changes, tremors, 
numbness, headache, backache. 
Rare: Fever, unusually fast or slow pulse, trouble breathing, seizures, chest pain. 
 
Sevoflurane 
Likely:  Nausea, crying, confusion, hiccups, increased saliva. 
Less Likely: Vomiting, dry mouth, itching, rash, fever, temporary lazy eye. 
Rare: Changes in heart rhythm, agitation, difficulty breathing, decrease in blood pressure, shivering, 
tiredness. 
 
Nitrous Oxide (laughing gas) 
Likely:  Headache, dizziness, confusion, low blood pressure. 
Less Likely: Upset stomach, vomiting, ear pressure, short periods of no breathing. 
Rare: Irritation of the liver, increased pressure inside the skull. 
 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 7, 2013 
Principal Investigator: James F. Casella, MD 
Application No.: NA_00041623 
 
 Page 10 of 15 
 Combined Informed Consent/Authorization March 2012 Version 13 
MRI of the brain 
The effects of magnetic fields in an MRI scanner have been extensively studied, and there are no known 
significant risks with an MRI exam.  Your child may, however, be bothered by feelings of confinement 
(claustrophobia), and by the noise made by the magnet during the procedure. Your child will be asked to 
wear earplugs or earphones while in the magnet. Your child may not participate in this study if they 
have a pacemaker, an implanted defibrillator or certain other implanted electronic or metallic devices. It 
is important for you to advise the MRI staff if your child has had brain surgery for a cerebral aneurysm, 
or if your child has implanted medical or metallic devices, shrapnel, or other metal.  
 
Blood Sampling 
Likely:  Pain and bruising at the site of the needle puncture.   
Less Likely: Lightheadedness or fainting. 
Rare: Bleeding or infection of the skin at the puncture site. 
 
Genetic Testing 
The Genetic Information Nondiscrimination Act (GINA) generally protects employability and the ability 
to obtain health insurance. However, in spite of the protections provided by GINA and the best efforts of 
the research team, there may still be a risk if  information about your child were to become known to 
people outside of this study. 
 
Certain genetic research may reveal that your child is a carrier of a genetic disorder.  This could mean 
that your child or members of your child’s extended family may have an increased chance of developing 
the disorder, or may pass on increased risk to his/her children. 
 
If your child’s participation in a genetic study becomes known outside of the research in spite of efforts 
to keep this information private (for example, if your child’s participation and results were to be noted in 
your child’s medical record) your child and your family members may be unable to obtain health, life, or 
disability insurance.  Your child might also be refused a job or be fired from his/her current job.  This 
could happen if you/your child choose to talk about your child’s participation with your doctor without 
asking that the information be kept out of your child’s medical record.  If genetic (or any other) 
information is noted in your child’s medical record, insurance providers may get access to such 
information. 
 
The genetic studies that will be done are for research purpose only and will not be reported to you.  In 
the very unlikely event that we discover genetic information about your child through these studies that 
indicates your child has a life-threatening disorder that current treatment can stop or lessen, we will 
notify you and your child’s physician(s) as we would for any other life-threatening medical disorder as 
discussed earlier in this consent form under “Primary care physician/specialist notification option”.  We 
would ask you to have these studies confirmed in a clinical laboratory that performs this testing and 
recommend a genetic counselor to you, as medical decisions cannot be based on laboratory research 
studies that do not have certain certifications.  The study would not pay for the additional testing or 
genetic counselor. 
 
Transcranial Doppler Ultrasound (TCD) 
There are no known major risks to TCD testing in children.  Some children do not like staying still or 
become uncomfortable or scared during the test. 
 
 
 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 7, 2013 
Principal Investigator: James F. Casella, MD 
Application No.: NA_00041623 
 
 Page 11 of 15 
 Combined Informed Consent/Authorization March 2012 Version 13 
Neuropsychological Tests 
Children may occasionally experience some mild anxiety during testing. The results of tests may affect 
school placement, but the results are only released by parental request. A relaxed environment with 
frequent breaks will minimize anxiety. 
 
Questionnaires 
You may experience emotional discomfort when answering some questions. If a particular question 
makes you uncomfortable, you can discuss its importance and the need to answer it with us. Completing 
the questionnaire may be inconvenient because of the time it takes to complete them. 
 
Confidentiality 
One potential risk of participating in this study is that confidential information about your child may be 
accidentally disclosed.  We will use our best efforts to keep the information about your child secure, and 
we think the risk of accidental disclosure is very small.   
 
Some side effects stated in this consent document, if severe, may cause death. Your child may 
experience all or some of the risks listed above.  There may also be unknown risks.  
 
Throughout the study the study team will watch very closely for any possible risks.  The study 
coordinators and other providers are experienced in care of children and have medications and 
equipment available to care for possible problems. 
 
5. 
Are there benefits to being in the study? 
Your child may or may not benefit from being in this study.  If your child takes part in this study, they 
may help others with sickle cell disease in the future. 
 
6. 
What are your options if you do not want to be in the study? 
• You do not have to allow your child join this study.  If your child does not take part in the study, 
your child’s care at Johns Hopkins will not be affected. 
• Your child could get the MRI, TCD, or other testing outside of this study. 
 
7. 
Will it cost you anything to be in this study? 
You will receive a separate Insurance and Research Participant Financial Responsibility Information 
Sheet (Sheet).  
 
This Sheet will give you the following information: 
• The procedures, tests, drugs or devices that are part of this research and that will be paid for by 
the study (no cost to you).   
 
• The procedures, tests, drugs or devices that will be billed to you and/or your health insurer.  If 
you have health insurance, you will be responsible for any co-pays or deductibles not covered by 
your insurance.  
 
8. 
Will you be paid if you join this study? 
You will receive $20 for each study visit and an additional $20 for visits that require extra time (sedated 
MRI, TCD, and cognitive testing).   If your child completes all of the study visits (16 visits in the first 
year, 15 visits in the second year, and 15 visits in the third year) you will receive a total of $1100 over 
three years. 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 7, 2013 
Principal Investigator: James F. Casella, MD 
Application No.: NA_00041623 
 
 Page 12 of 15 
 Combined Informed Consent/Authorization March 2012 Version 13 
 
9. 
Can you leave the study early? 
• You can agree to allow your child to be in the study now and change your mind later. 
• If you wish to stop, please tell us right away. 
• Leaving this study early will not stop your child from getting regular medical care.  
• If your child leaves the study early, Johns Hopkins may use or give out your child’s health 
information that it already has if the information is needed for this study or any follow-up activities. 
 
10. 
Why might we take you out of the study early? 
Your child may be taken out of the study if: 
• Staying in the study would be harmful. 
• Your child needs treatment not allowed in the study. 
• You or your child fail to follow instructions. 
• The study is cancelled. 
• There may be other reasons to take your child out of the study that we do not know at this time.  
  
11. 
How will your child’s privacy be protected? 
Johns Hopkins has rules to protect information about you.  Federal and state laws also protect your 
privacy.   
 
The research team working on the study will collect information about you.  This includes things learned 
from the procedures described in this consent form.  They may also collect other information including 
your name, address, date of birth, and other details. 
 
Generally, only people on the research team will know your identity and that you are in the research 
study.  However, sometimes other people at Johns Hopkins may see or give out your information.  These 
include people who review research studies, their staff, lawyers, or other Johns Hopkins staff. 
 
People outside of Johns Hopkins may need to see your information for this study.  Examples include 
government groups (such as the Food and Drug Administration), safety monitors, other hospitals in the 
study and companies that sponsor the study. 
 
We cannot do this study without your permission to use and give out your information.  You do not have 
to give us this permission.  If you do not, then you may not join this study. 
 
We will use and disclose your information only as described in this form and in our Notice of Privacy 
Practices; however, people outside Hopkins who receive your information may not be covered by this 
promise.  We try to make sure that everyone who needs to see your information keeps it confidential – 
but we cannot guarantee this. 
 
The use and disclosure of your information has no time limit. You may cancel your permission to use 
and disclose your information at any time by notifying the Principal Investigator of this study by phone 
or in writing.  If you contact the Principal Investigator by phone, you must follow-up with a written 
request that includes the study number and your contact information.  The Principal Investigator’s name, 
address, phone and fax information are on page one of this consent form.   
 
If you do cancel your permission to use and disclose your information, your part in this study will end 
and no further information about you will be collected. Your cancellation would not affect information 
already collected in the study. 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 7, 2013 
Principal Investigator: James F. Casella, MD 
Application No.: NA_00041623 
 
 Page 13 of 15 
 Combined Informed Consent/Authorization March 2012 Version 13 
12. 
Will the study require any of your other health care providers to share your health 
information with the researchers of this study?    
As a part of this study, the researchers may ask to see your child’s health care records from his/her other 
health care providers.  We will ask these other health care providers to give us ALL information about 
your child’s health status or your child’s health care.  
 
13. 
What treatment costs will be paid if you are injured in this study?  
Johns Hopkins does not have a program to pay you if your child is hurt or has other bad results from 
being   in the study.  However, medical care at Johns Hopkins is open to your child as it is to all sick or 
injured people. 
   
• If you have health insurance:  The costs for any treatment or hospital care your child receives as the 
result of a study-related injury will be billed to your health insurer. Any costs that are not paid for by 
your health insurer will be billed to you.  
 
• If you do not have health insurance:  You will be billed for the costs of any treatment or hospital care 
your child receives as the result of a study-related injury. 
 
By signing this form you will not give up any rights you have to seek compensation for injury. 
 
14. 
What other things should you know about this research study? 
 
a. What is the Institutional Review Board (IRB) and how does it protect you?  
The Johns Hopkins Medicine IRB is made up of: 
• Doctors 
• Nurses 
• Ethicists 
• Non-scientists 
• and people from the local community.  
 
The IRB reviews human research studies. It protects the rights and welfare of the people taking part 
in those studies.  You may contact the IRB if you have questions about your rights as a participant or 
if you think you have not been treated fairly.  The IRB office number is 410-955-3008. You may 
also call this number for other questions, concerns or complaints about the research.  
 
b. What do you do if you have questions about the study?    
Call the principal investigator, Dr. Casella at 410-955-6132. If you wish, you may contact the 
principal investigator by letter or by fax. The address and fax number are on page one of this consent 
form.  If you cannot reach the principal investigator or wish to talk to someone else, call the IRB 
office at 410-955-3008.  
  
c. What should you do if you are injured or ill as a result of being in this study?  
Call the page operator at 410-955-6070 and ask them to page Dr. James Casella if your child has an 
urgent medical problem related to your child’s taking part in this study. If Dr. Casella is not 
available ask for the pediatric hematologist on-call. 
 
 
 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 7, 2013 
Principal Investigator: James F. Casella, MD 
Application No.: NA_00041623 
 
 Page 14 of 15 
 Combined Informed Consent/Authorization March 2012 Version 13 
d. What happens to Data, Tissue, Blood and Specimens that are collected in the study?  
Scientists at Johns Hopkins work to find the causes and cures of disease. The data, tissue, blood and 
specimens collected from you during this study are important to both this study and to future 
research. 
 
If you join this study: 
• You will not own the data, or the tissue, blood, or other specimens given by you to the 
investigators for this research. 
• Both Johns Hopkins and any sponsor of this research may study your data and the tissue, blood 
or other specimens collected from you. 
• If data, tissue, blood, or other specimens are in a form that identifies you, Johns Hopkins may 
use them for future research only with your consent or IRB approval. 
• If data, tissue, blood or other specimens are in a form that we believe does not identify you, they 
may be shared with other academic medical centers, non-profit organizations, corporate sponsors 
and other commercial companies without your consent or IRB approval. 
• You will not own any product or idea created by the researchers working on this study. 
• You will not receive any financial benefit from the creation, use or sale of such a product or idea. 
 
e. What are the Organizations that are part of Johns Hopkins?  
Johns Hopkins includes the following:  
• The Johns Hopkins University 
• The Johns Hopkins Hospital 
• Johns Hopkins Bayview Medical Center 
• Howard County General Hospital 
• Johns Hopkins Community Physicians.  
• Suburban Hospital 
• Sibley Memorial Hospital 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 7, 2013 
Principal Investigator: James F. Casella, MD 
Application No.: NA_00041623 
 
 Page 15 of 15 
 Combined Informed Consent/Authorization March 2012 Version 13 
15. 
What does your signature on this consent form mean? 
 
Your signature on this form means that: 
• you understand the information given to you in this form  
• you accept the provisions in the form 
• you agree to join the study  
 
You will not give up any legal rights by signing this consent form.  
 
WE WILL GIVE YOU A COPY OF THIS SIGNED AND DATED CONSENT FORM 
 
 
 
__________________________________________________________________________________________ 
Signature of Person Obtaining Consent                                                                                                                  
Date/Time 
                                                                           
 
__________________________________________________________________________________________ 
Signature of Parent/Guardian                                                                                                                                 
Date/Time 
 
 
___________________________________________________________________________________________________ 
Signature of Legally Authorized Representative (LAR) for CHILD RESEARCH PARTICIPANT                  Date/Time   
 
 
_________________________________________________________________________________________________ 
 
 
Description of LAR’s authority under Maryland Law to act as surrogate health care                                               Date/Time 
decision-maker for child research participant (for example, Legal Guardian, court-ordered representative) 
 
 
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE PRINCIPAL 
INVESTIGATOR; A COPY MUST BE GIVEN TO THE PARTICIPANT; AND, IF APPROPRIATE A COPY OF 
THE CONSENT FORM MUST BE PLACED IN THE PARTICIPANT’S MEDICAL RECORD 
 
ONLY CONSENT FORMS THAT INCLUDE THE JOHNS HOPKINS MEDICINE LOGO CAN BE USED FOR 
CONSENTING RESEARCH PARTICIPANTS.  IF THIS CONSENT FORM DOES NOT HAVE A JOHNS 
HOPKINS MEDICINE LOGO, DO NOT USE IT TO CONSENT RESEARCH PARTICIPANTS.