A Phase 3 Single Arm Study Evaluating the Efficacy and Safety of Gene Therapy in Subjects With Transfusion-dependent β-Thalassemia, Who do Not Have a β0/β0 Genotype, by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With a Lentiviral βA-T87Q-Globin Vector in Subjects ≤50 Years of Age
Phase: PHASE3
Conditions: Beta-Thalassemia
Sponsor: Genetix Biotherapeutics Inc.

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C LI NI C A L S T U D Y P R O T O C O L H G B - 2 0 7 
E u dr a C T N o. 2 0 1 5 -0 0 4 1 2 2 -3 3  
I N D N o. 1 5 3 2 4 
A  P h ase  3  Si n gle  Ar m  St u d y  E v al u ati n g  t he  Effic ac y  a n d  S afet y  of  Ge ne  
T her a p y i n S u bjects wit h Tr a nsf usi o n -de pe n de nt β -T h al asse mi a, w h o d o n ot 
h a ve  a  β 0/ β0 Ge n ot y pe, b y Tr a ns pl a nt ati o n of A ut ol o g o us C D 3 4 + Ste m Cells 
Tr a ns d uce d  E x  Vi v o  wit h  a  Le nti vir al  β A- T 8 7 Q -Gl o bi n  Vect or  i n  S u bjects  
≤5 0  Ye ars of A ge  
  
St u d y S p o ns or:  bl ue bir d bi o, I n c. 
6 0 Bi n ne y Street 
Ca m bri d ge, M A 0 2 1 4 2 U S A 
Res p o nsi ble Me dic al Officer:  
, M D 
Se ni or Me dical Direct or  
Cli nical Researc h De vel o p me nt  
bl ue bir d bi o, I nc. 
Office tele p h o ne: 
 
E mail: 
 
Pr ot oc ol V ersi o n:  Versi o n 6. 0  
D oc u m e nt D ate:  1 0 J u ne 2 0 2 1 
 
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M E DI C A L O F FI C E R C O N T A C T I N F O R M A TI O N  
C o u ntr y -S pecific 2 4 -h o ur E m er ge nc y C o nt act P h o ne N u m bers  
C o u ntr y  
P h o ne N u m ber  
Fra nce  
Ger ma n y  
Ital y  
T haila n d  
U nite d Ki n g d o m  
U nite d States of A merica  
 
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S U M M A R Y O F C H A N G E S  
D oc u me nt c o ncer ne d: Pr ot oc ol H G B‑ 2 0 7  
N u m ber
 a n d
 dat e
 of
 t he
 pre vi o us
 v ersi o n:
 Versi o n
 5. 0
 ( 0 6
 Oct o ber
 2 0 2 0)  
N u m ber a n d d ate of t he n e w versi o n:  Versi o n 6. 0 ( 1 0 J u ne 2 0 2 1) 
T his pr ot oc ol ( Versi o n 6. 0, 1 0 J u ne 2 0 2 1) re pl aces pre vi o us Versi o n 5. 0 ( 0 6 Oct o ber 2 0 2 0). 
S u bsta ntial c ha n ges c o m pare d t o St u d y H G B -2 0 7 Pr ot oc ol v 5. 0 are des cri be d i n t he ta ble bel o w, 
a n d i ncl u de u p d ate d cli nical w or k -u p criteria, pr o ce d ure, a n d f oll o w -u p i n t he secti o n d escri bi n g 
i nte grati o n site a n al yses, i ntr o d ucti o n of o pti o nal arc hi val a n d ge n etic testi n g o n b o ne marr o w 
sa m ples, a d de d c o nsi der ati o ns  f or  vacci nes  as  c o nc o mita nt  me dicati o ns,  a n d  re m o val  of  t he  
state me nt t hat a s u bject ma y be wit h dra w n fr o m t he st u d y if t he y ha ve u n detecta ble V C N i n 
peri p her al bl o o d cells f or 2 c o nsec uti ve mea s ure m e nts at least 1 m o nt h a part. 
N o n -s u bsta ntial c ha n ges i m ple me nte d are d escri be d i n t he f oll o wi n g list. I n a d diti o n, se veral 
mi n or c ha n ges were ma de t o c orrect t y p o gra p hi cal err ors a n d ali g n t he use of ter mi n ol o g y a n d 
f or matti n g wit h c urre nt sta n dar ds. 
N ote: i n t he f oll o wi n g ta ble, a d de d te xt is i n b ol d it alics  a n d delete d te xt is i n stri ket hr o u g h.
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D E S C RI P TI O N O F E A C H S U B S T A N TI A L C H A N G E  
I niti al w or di n g 
A m e n de d or Ne w W or di n g  
Re as o n/ J ustific ati o n f or c h a n ge  
Secti o n(s) c o ncer ne d:  
Secti o n 4. 5 S u bject Wit h dra wal fr o m t he St u d y  
I n a d diti o n, after s u bjects ha ve bee n treate d wit h 
Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct, t he y ma y be wit h dra w n 
fr o m t he st u d y if t he s u bject has u n detecta ble V C N 
( < 0. 0 0 0 3 vect or c o pies per di pl oi d ge n o me) i n peri p heral 
bl o o d cells f or 2 c o nsec uti ve meas ure me nts at least 1 
m o nt h a part. T his deter mi nati o n is base d o n a ver y 
se nsiti ve q u a ntitati ve p ol y merase c hai n reacti o n  ( q P C R) 
assa y.  
Secti o n(s) c o ncer ne d:  
Secti o n 4. 5 S u bject Wit h dra wal fr o m t he St u d y  
I n a d diti o n, after s u bjects ha ve bee n treate d wit h 
Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct, t he y ma y be wit h dra w n 
fr o m t he st u d y if t he s u bject has u n detecta ble V C N 
( < 0. 0 0 0 3 vect or c o pies per di pl oi d ge n o me) i n peri p heral 
bl o o d cells f or 2 c o nsec uti ve meas ure me nts at least 1 
m o nt h a part. T his deter mi nati o n is base d o n a ver y 
se nsiti ve q ua ntitati ve p ol y merase c hai n reacti o n  ( q P C R) 
assa y.  
Treate d s u bj ects s h o ul d re mai n i n t he 
st u d y re gar dless of t heir vect or c o p y 
n u m ber after treat me nt t o e ns ure 
c o m pre he nsi ve f oll o w -u p of safet y 
a n d efficac y.  
Secti o n(s) c o ncer ne d:  
Secti o n  5. 9. 2  C o nc o mita nt  Me dicati o ns  a n d  T hera pies:  
Ge neral  
[ …] 
Secti o n(s) c o ncer ne d:  
Secti o n 5. 9. 2 C o nc o mita nt Me dicati o ns a n d T hera pies: 
Ge neral  
 
F or t he p ur p oses of t his st u dy, v acci nes (e. g., C O VI D -1 9 
v acci nes) are c o nsi dere d c o nc o mit a nt me dic ati o ns. 
Alt h o u g h i nter acti o ns bet wee n a v acci ne a n d 
Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct are n ot e x pecte d, t he 
pr ot oc ol i ncl u des use of i m m u n o m o d ul at ory ( pleri x af or) 
a n d i m m u n os u p pressive me di c ati o n ( b us ulf a n). L oc al 
g ui deli nes s h o ul d be f oll o we d re g ar di n g a mi ni m u m ti me 
peri o d  bet wee n a ny me dic ati o n t o be pr ovi de d as p art of 
tre at me nt wit h Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct a n d 
a ny v acci ne; it is rec o m me n de d t h at v acci nes are n ot 
a d mi nistere d t o s u bjects wit hi n 1 m o nt h of i niti ati n g 
m o biliz ati o n f or ste m cell c ollecti o n, wit hi n 1 w ee k after 
receivi n g m o biliz ati o n a ge nts, wit hi n 1 m o nt h of 
i niti ati n g myel o a bl ative c o n diti o ni n g, or wit hi n 6 m o nt hs 
after dr u g pr o d uct i nf usi o n. Rev acci n ati o n p ost -dr u g 
pr o d uct i nf usi o n s h o ul d be c o nsi dere d per I nvesti g at or's 
discreti o n d ue t o p ote nti al l oss of i m m u nity after 
Pr o vi de d c o nsi derati o ns f or vacci nes 
as c o nc o mita nt me dicati o ns per 
g ui da nce fr o m re g ulat or y a ge nc y.  
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I niti al w or di n g 
A m e n de d or Ne w W or di n g  
Re as o n/ J ustific ati o n f or c h a n ge  
myel o a bl ative c o n diti o ni n g a n d m ay be a d mi nistere d 
f oll o wi n g l oc al g ui deli nes. 
T he prescri bi n g i nf or m ati o n of t he v acci ne a d mi nistere d 
s h o ul d be referre d t o f or t he l atest i n dic ati o n, 
c o ntr ai n dic ati o ns a n d s afety i nf or m ati o n as well a s t he 
l atest ge ner al cli nic al rec o m me n d ati o ns o n v acci ne 
a d mi nistr ati o n i n t he c o u ntry or re gi o n.  
All  v acci n ati o ns  d uri n g  t h e  st u dy  peri o d  s h o ul d  be  
d oc u me nte d i n t he C R F.  
Secti o n(s) c o ncer ne d:  
Secti o n 6. 1 Sc he d ule of E ve nts  
Ta ble 4 Sc he d ule of E ve nts: Scree ni n g a n d C D 3 4 + Cell 
Har vest; F o ot n ote 1 5  
B o ne marr o w c ollecti o n f or m or p h ol o g y, cell ularit y, cell 
c o u nt a n d ir o n stai ns. F or s u bj ects u n der g oi n g re -scree ni n g, 
b o ne marr o w c ollecti o n d oes n ot nee d t o be perf or me d.  
Secti o n(s) c o ncer ne d:  
Secti o n 6. 1 Sc he d ule of E ve nts  
Ta ble 4 Sc he d ule of E ve nts: Scree ni n g a n d C D 3 4 + Cell 
Har vest; F o ot n ote 1 5  
B o ne marr o w c ollecti o n f or m or p h ol o g y, cell ularit y, cell 
c o u nt a n d ir o n stai ns. F or s u bjects u n der g oi n g re -scree ni n g, 
b o ne marr o w c ollecti o n d oes n ot nee d t o be perf or me d. If 
s ufficie nt  s a m ple  is  av ail a bl e,  s a m ple  m ay  be  arc hive d 
a n d/ or ot her rese arc h tests (e. g., ge netic testi n g) m ay be 
perf or me d.  
S peci fie d t hat b o ne marr o w sa m ples 
ma y be arc hi ve d a n d t hat ge netic 
testi n g ma y be perf or me d if cli nicall y 
i n dicate d. 
Secti o n(s) c o ncer ne d:  
Secti o n 6. 1 Sc he d ule of E ve nts  
Ta ble 6 Sc he d ule of E ve nts: F oll o w -u p; F o ot n ote 1 0  
B o ne marr o w f or d yser yt hr o p oiesis st u dies (retic ul oc ytes, 
n ucleate d R B C, ser u m tra nsferri n rece pt or, he pci di n, a n d 
er yt hr o p oieti n),  as  well  as  m or p h ol o g y,  cell ularit y,  cell  
c o u nt, a n d ir o n c o nte nt; ot her researc h tests (e. g., V C N, 
I S A,  H P L C)  ma y  be  perf or me d if  s ufficie nt sa m ple  is  
a vaila ble  
Secti o n(s) c o ncer ne d:  
Secti o n 6. 1 Sc he d ule of E ve nts  
Ta ble 6 Sc he d ule of E ve nts: F oll o w -u p; F o ot n ote 1 0  
B o ne marr o w f or d yser yt hr o p oiesis st u dies (retic ul oc ytes, 
n ucleate d R B C, ser u m tra nsferri n rece pt or, he pci di n, a n d 
er yt hr o p oieti n) ,  as  well  as  m or p h ol o g y,  cell ularit y,  cell  
c o u nt, a n d ir o n c o nte nt; if s ufficie nt s a m ple is av ail a ble, 
s a m ple m ay be arc hive d a n d/ or ot her researc h tests (e. g., 
V C N, I S A, H P L C , ge netic t esti n g) ma y be perf or me d if 
s ufficie nt sa m ple is a vaila ble 
 
 
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Secti o n (s) c o ncer ne d:  
Secti o n
 6. 2. 1 0
 B o ne
 Marr o w
 a n d
 Bl o o d
 f or
 
D yser yt hr o p oiesis St u dies  
B o ne marr o w will be c ollecte d f or d yser yt hr o p oiesis 
st u dies (see Secti o n  6. 2. 1 6. 2 ), as well as m or p h ol o g y, 
cell ularit y, cell c o u nt a n d ir o n c o nte nt, at Scree ni n g a n d 
M o nt h 1 2 a n d M o nt h 2 4 Visits. If s ufficie nt sa m ple is 
a vaila ble, b o ne marr o w ma y als o be teste d f or vect or c o p y 
n u m ber ( V C N), a n d f or β A- T 8 7 Q -gl o bi n e x pressi o n i n 
er yt hr oi d b urst f or mi n g u nits ( B F U -E).  
If a n u nsc he d ule d b o ne marr o w c ollecti o n is perf or me d at 
a n y p oi nt d uri n g st u d y, s uc h sa m ples ma y als o be use d f or 
t he deter mi nati o n of V C N, a n d f or βA- T 8 7 Q -gl o bi n 
e x pressi o n i n B F U -Es.  
Secti o n(s) c o ncer ne d:  
Secti o n
 6. 2. 1 0
 B o ne
 Marr o w
 a n d
 Bl o o d
 f or
 
D yser yt hr o p oiesis St u dies  
B o ne marr o w will be c ollecte d f or d yser yt hr o p oiesis 
st u dies (see Secti o n  6. 2. 1 6. 2 ), as well as m or p h ol o g y, 
cell ularit y, cell c o u nt a n d ir o n c o nte nt, at Scree ni n g a n d 
M o nt h 1 2 a n d M o nt h 2 4 Visits. If s ufficie nt sa m ple is 
a vaila ble, t he b o ne marr o w s a m ple ma y als o  be teste d 
f orarc hive d a n d/ or ot her rese arc h tests (e . g., vect or c o p y 
n u m ber ([V C N ]), a n d f or  β A- T 8 7 Q -gl o bi n e x pressi o n i n 
er yt hr oi d b urst f or mi n g u nits ([B F U - E).], I S A, H P L C, 
ge netic testi n g) m ay be perf or me d.  
If a n u nsc he d ule d b o ne marr o w c ollecti o n is perf or me d at 
a n y p oi nt d uri n g st u d y, s uc h sa m ples ma y als o be use d f or 
t he deter mi nati o n ofarc hive d a n d/ or ot her rese arc h tests 
(e. g., V C N, a n d f or β A- T 8 7 Q -gl o bi n e x pressi o n i n B F U -Es , 
I S A, H P L C, ge netic testi n g) m ay be perf or me d. 
 
Secti o n(s) c o ncer ne d:  
6. 2. 1 6. 7.  Cli nical  W or k -u p  f or  U ne x pecte d  Bl o o d  Test  
R es ults  
•  
B o ne marr o w bi o ps y  
Secti o n(s) c o ncer ne d:  
6. 2. 1 6. 7.  Cli nical  W or k -u p  f or  U ne x pecte d  Bl o o d  Test  
Res ults  
•  
B o ne marr o w bi o ps y a n d/ or as pir ati o n ( m ay 
als o be arc hive d f or a d diti o n al a n alysis i n 
t he f ut ure, see Secti o n  6. 2. 1 0 ) 
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Secti o n(s) c o ncer ne d:  
Secti o n  6. 2. 1 8. 2. Ot her Crite ria t hat ca n  Tri g ger Cli nical 
W or k -u p f or Mali g na nc y  
•  
A n y cli nical s us pici o n of mali g na nc y 
i ncl u di n g le u ke mia or l y m p h o ma 
•  
U ne x plai ne d W B C c o u nt > 3 0, 0 0 0 (cells/ μ L) 
o n t w o c o nsec uti ve meas ure me nts  
•  
After ac hie ve me nt of a W B C c o u nt wit hi n t he 
n or mal ra n ge p ost -dr u g pr o d uct i nf usi o n a n d 
e n graft me nt of ge ne -m o difie d cells, t he 
de vel o p me nt of a W B C < 1 0 0 0 (cells/ μ L) o n 2 
c o nsec uti ve meas ure me nts  
Secti o n(s) c o ncer ne d:  
Secti o n  6. 2. 1 8. 2. Ot her Criteria t hat ca n  Tri g ger  Cli nical 
W or k
u p f or Mali g na nc y  
•  
A n y cli nical s us pici o n of mali g na nc y 
i ncl u di n g le u ke mia or l y m p h o ma 
•  
U ne x plai ne d W B C c o u nt > 3 0, 0 0 0 (cells/ μ L) 
o n t w o c o nsec uti ve meas ure me nts  
•  
After ac hie ve me nt of a W B C c o u nt wit hi n t he 
n or mal ra n ge p ost dr u g pr o d uct i nf usi o n a n d 
e n graft me nt of ge ne m o difie d cells, t he 
de vel o p me nt of a W B C < 1 0 0 0 (cells/ μ L) o n 2 
c o nsec uti ve meas ure me nts   
 
 
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Secti o n(s) c o ncer ne d:  
Secti o n 6. 2. 1 8. 3 Cli nical W or k -U p f or Mali g na nc y  
If a n y of t he a bo ve criteria is met, t he Me dical M o nit or will 
be n otifie d, a n d a w or k -u p will be perf or me d t hat ma y 
occ ur i n sta ges a n d ma y i ncl u de s o me of t he f oll o wi n g at 
eac h sta ge:  
•  
P h ysical e xa m  
•  
C B C wit h differe ntial  
•  
L y m p h oc yte s u bsets  
•  
St u dies t o r ule o ut i nfecti o us ca use  
•  
St u dies t o r ule o ut a ut oi m m u ne disease  
•  
I ma gi n g st u dies 
•  
B o ne marr o w a nal ysis  
If cli nical res ults i n dicate a dia g n osis of a mali g na nc y or 
m yel o d ys plasia, e nr oll me nt i nt o t his st u d y will be 
s us pe n de d, a n d f urt her a nal yses will be deter mi ne d b y t he 
S p o ns or, i n c o ns ultati o n wit h t he D M C (see als o 
Secti o n  3. 2 ). It s h o ul d be n ote d t hat it ma y n ot be p ossi ble 
t o disti n g uis h t he s o urce of mali g na nc y (e. g. arisi n g fr o m 
tra ns pla nt-relate d me dicati o ns or pr oce d ures, or fr o m 
e x pa nsi o n of ge ne -m o difie d cells d ue t o i nserti o nal 
m uta ge nesis), a n d all eff orts s h o ul d be ma de t o c o nfir m t he 
s o urce of mali g na nc y bef ore deter mi ni n g t o halt or 
alter nati vel y t o res u me t he st u d y.  
If t here is n o e vi de nce of mali g na nc y or m yel o d ys plasia, 
t he s u bject will c o nti n ue t o be m o nit ore d as per t he 
pr ot oc ol -defi ne d S O E, or m ore fre q ue ntl y at discreti o n of 
t he I n vesti gat or a n d S p o ns or. 
Secti o n(s) c o ncer ne d:  
Secti o n  6. 2. 1 8. 3 2  Cli nical  W or k -U p  f or  P ote nti al 
Mali g na nc y  
If a n y of t he a b o ve criteria is metI n the eve nt of cl o n al 
pre d o mi n a nce, persiste nt cl o n al pre d o mi n a nce, or a ny 
cli nic al s us pici o n of myel o dys pl asi a, le u ke mi a, or 
ly m p h o m a, t he Me dical M o nit or will be n otifie d, a n d a 
w or k -u p will be perf or me d t hat ma y occ ur i n sta ges a n d 
ma y i ncl u de s o me of t he f oll o wi n g at eac h sta ge: 
•  
P h ysical e xa m  
•  
C B C wit h differe ntial  
•  
L y m p h oc yte s u bsets  
•  
St u dies t o r ule o ut i nfecti o us ca use  
•  
St u dies t o r ule o ut a ut oi m m u ne disease  
•  
I ma gi n g st u dies 
•  
B o ne marr o w a nal ysis  
•  
Cyt o ge netic a n d m olec ul ar a n alyses  
If cli nical res ults i n dicate a dia g n osis of a mali g na nc y or 
m yel o d ys plasia, e nr oll me nt i nt o t his st u d y will be 
s us pe n de d, a n d f urt her a nal yses will be deter mi ne d b y t he 
S p o ns or, i n c o ns ultati o n wit h t he D M C (see als o 
Secti o n  3. 2 ). It s h o ul d be n ote d t hat it ma y n ot be p ossi ble 
t o disti n g uis h t he s o urce of mali g na nc y (e. g. arisi n g fr o m 
tra ns pla nt relate d me dicati o ns or pr oce d ures, or fr o m 
e x pa nsi o n of ge ne m o difie d cells d ue t o i nserti o nal 
m uta ge nesis), a n d all eff orts s h o ul d be ma de t o c o nfir m t he 
s o urce of mali g na nc y bef ore deter mi ni n g t o halt or 
alter nati vel y t o res u me t he st u d y.  
 
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If t here is If t he cli nic al w or k-u p i n dic ates n o e vi de nce of 
mali g na nc y or  m yel o d ys plasia , le u ke mi a, or ly m p h o m a, 
t he s u bject will c o nti n ue t o be m o nit ore d as per t he 
pr ot oc ol -de fi ne d S O E, or m ore fre q ue ntl y at discreti o n of 
t he I n vesti gat or a n d S p o ns or. If t he cli nic al w or k-u p 
i n dic ates a di a g n osis of myel o dys pl asi a, le u ke mi a, or 
ly m p h o m a, t he S p o ns or will c o nve ne a n ur ge nt s afety 
revie w meeti n g. F urt her a n al yses will be deter mi ne d by 
t he S p o ns or, i n c o ns ult ati o n wit h t he D M C. It s h o ul d be 
n ote d t h at it m ay n ot be p ossi ble t o disti n g uis h t he s o urce 
of m ali g n a ncy (e. g., arisi n g fr o m u n derlyi n g 
p at h o p hysi ol o gy of t he dise ase, tr a ns pl a nt -rel ate d 
me dic ati o ns or pr oce d ures, or fr o m e x p a nsi o n of ge ne -
m o difie d cells d ue t o i nserti o n al o nc o ge nesis), a n d all 
eff orts s h o ul d be m a de t o c o nfir m t he s o urce of 
m ali g n a ncy.  
F or  cli nic al  w or k -u p  after  i de ntific ati o n  of  a  persiste nt  
pre d o mi n a nt cl o ne a n d c o nfir me d prese nce of a b n or m al 
C B C,  b o ne  m ar r o w  a n alysis  is  rec o m me n de d  if  n ot  
previ o usly perf or me d as p art of t he cli nic al w or k -u p.  
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D E S C RI P TI O N O F E A C H N O N -S U B S T A N TI A L C H A N G E  
•  M o difie d la n g ua ge t hr o u g h o ut t he pr ot oc ol t o i n dicate t hat s u bjects w h o c o m plete 
t his st u d y will be e x pecte d t o e nr oll i n t he l o n g-ter m f oll o w- u p st u d y L T F- 3 0 3.  
•  N u m bers f or s u bject e nr oll me nt as of 0 3 Marc h 2 0 2 0 were u p d ate d i n t he Secti o n 1 
I ntr o d u cti o n. 
•  U p date d t he title pa ge t o reflect c ha n g e i n Res p o nsi ble Me dical Offi cer  
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C LI NI C A L S T U D Y P R O T O C O L S Y N O P SI S  
Pr ot oc ol Title:  
A P hase 3 Si n gle Ar m St u d y E val uati n g t he Efficac y a n d Safet y of Ge ne T hera p y 
i n S u bjects wit h Tra nsf usi o n-de pe n de nt β -T halasse mia, w h o d o n ot ha ve a β 0/ β0 
Ge n ot y pe, b y Tra ns pla ntati o n of A ut ol o g o us C D 3 4 + Ste m Cells Tra ns d uce d E x 
Vi v o wit h a Le nti viral β A- T 8 7 Q -Gl o bi n Vect or i n S u bjects ≤5 0 Years of A ge  
Pr ot oc ol N u m ber:  
H G B -2 0 7  
O bjecti ves:  
Pri m ar y:  e val uate t he efficac y of treat me nt wit h Le nti Gl o bi n B B 3 0 5 Dr u g 
Pr o d uct i n s u bjects ≤5 0 years of a ge wit h tra nsf usi o n -de pe n de nt β -t halasse mia 
( T D T) w h o d o n ot ha ve a β 0/ β0 ge n ot y pe at t he H B B  ge ne  
Sec o n d ar y: e val uate t he safet y of treat me nt wit h Le nti Gl o bi n B B 3 0 5 Dr u g 
Pr o d uct i n s u bjects ≤5 0 years of a ge wit h T D T w h o d o n ot ha ve a β 0/ β0 ge n ot y pe 
at t he H B B  ge ne  
St u d y Desi g n:  
T his is a si n gle -ar m, m ultisite, si n gle -d ose, P hase 3 st u d y wit h 2 c o h orts of 
s u bjects wit h T D T w h o d o n ot ha ve a β 0 m utati o n at b ot h  alleles of t he β-gl o bi n 
(H B B ) ge ne (i.e., n o n-β 0/ β0): C o h ort 1 i ncl u des at least 1 5 s u bjects ≥1 2 a n d ≤5 0 
years of a ge, a n d C o h ort 2 i ncl u des at least 8 s u bjects < 1 2 years of a ge. Patie nts 
tra ns pla nte d at y o u n ger a ges bef ore a d va nce d disease s y m pt o ms of t halasse mia 
are ma nifeste d are h y p ot hesize d t o ha ve differe nt rates of tra ns pla nt -relate d 
c o m plicati o ns, differe nt l o n g -ter m disease o utc o mes, a n d p ote ntiall y differe nt 
efficac y of ge ne tra ns d ucti o n t ha n a d ult patie nts.  
T he st u d y will e val uate t he efficac y a n d safet y of a ut ol o g o us he mat o p oietic ste m 
cell ( H S C) tra ns pla ntati o n ( H S C T) usi n g Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct f or 
t he treat me nt of β-t halasse mia (I N N/ U S A N: beti be gl o ge ne a ut ote mcel), a n 
a ut ol o g o us C D 3 4 + cell -e nric he d p o p ulati o n t hat c o ntai ns he mat o p oie tic ste m 
cells tra ns d uce d wit h B B 3 0 5 le nti viral vect or e nc o di n g t he β A- T 8 7 Q -gl o bi n ge ne, 
s us pe n de d i n cr y o preser vati o n s ol uti o n. 
S u bjects ≥1 2 a n d ≤5 0 years of a ge m ust ha ve T D T wit h a hist or y of tra nsf usi o n of 
at least 1 0 0  m L/ k g/ year of pac ke d re d bl o o d ce lls ( p R B Cs) i n t he 2 years 
prece di n g e nr oll me nt, or be ma na ge d u n der sta n dar d t halasse mia g ui deli nes (e. g., 
T halasse mia I nter nati o nal Fe derati o n, 2 0 1 4; see A p pe n di x  1 0. 4 ) wit h ≥8 
tra nsf usi o ns of p R B Cs per year i n t he 2 years prece di n g e nr oll me nt (s u bjects ≥1 2 
years; Rac h mile witz a n d Giar di n a, 2 0 1 1 ). S u bjects < 1 2 years of a ge m ust ha ve a 
hist or y of tra nsf usi o n of at least 1 0 0  m L/ k g/ year of p R B Cs i n t he 2 years 
prece di n g e nr oll me nt. I n a d diti o n t o ha vi n g a hist or y of tra nsf usi o n of at least 
1 0 0  m L/ k g/ year of p R B Cs i n t he 2 years prece di n g e nr oll me nt, s u bjects < 5 years 
of a ge m ust wei g h a mi ni m u m of 6 k g a n d reas o na bl y be a ntici pate d t o be a ble t o 
pr o vi de at least t he mi ni m u m n u m ber of cells re q uire d t o i nitiate t he 
ma n ufact uri n g pr ocess.  
Treat me nt will pr ocee d i n a sta g gere d fas hi o n. After 2 s u bjects ≥1 2 years of a ge 
ha ve attai ne d ne utr o p hil e n graft me nt after Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct 
i nf usi o n i n C o h ort 1, t he i n de pe n de nt Data M o nit ori n g C o m mittee ( D M C) will 
re vie w t heir safet y data a n d deter mi ne w het her t he st u d y ca n safel y pr ocee d with 
t he treat me nt of s u bjects ≥5 a n d < 1 2 years of a ge. After at least 2 s u bjects ≥5 a n d 
< 1 2 years of a ge ha ve attai ne d ne utr o p hil e n graft me nt after Le nti Gl o bi n B B 3 0 5 
Dr u g Pr o d uct i nf usi o n t he D M C will re vie w t heir safet y data a n d deter mi ne 
w het her t he st u d y ca n safel y pr ocee d wit h t he treat me nt of s u bjects y o u n ger t ha n 
5 years of a ge. S u bjects < 1 2 years of a ge ma y o nl y be e nr olle d at sites wit h 
re g ulat or y a p pr o val f or t he s pecifie d a ge ra n ge. 
T he st u d y has 4 disti nct sta ges, as f oll o ws.  
St a ge 1: Scree ni n g t o deter mi ne eli gi bilit y f or treat me nt   
S u bjects wit h pre vi o usl y k n o w n β 0/ β0 ge n ot y pes s h o ul d n ot e nter Scree ni n g.   
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F or t he p ur p oses of scree ni n g, t he H B B  m utati o n I V S I -1 1 0 ( G A) will be 
c o nsi dere d e q ui vale nt t o a β 0 m utati o n. S u bjects wit h T D T w h o are d oc u m e nte d 
t o ha ve ot her H B B  ge n ot y pes (i.e., n o n -β 0/ β0) ma y e nter Scree ni n g. H B B  ge n ot y pe 
f or all s u bjects will be c o nfir me d d uri n g Scree ni n g al o n g wit h a d diti o nal 
para meters of eli gi bilit y.  
St a ge 2:  A ut ol o g o us C D 3 4 + cell c ollecti o n, Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct 
ma n ufact ure a n d dis p ositi o n  
Eac h s u bject will u n der g o H S C m o bilizati o n wit h a gra n ul oc yte -c ol o n y 
sti m ulati n g fact or ( G-C S F; e. g., fil grasti m, le n o grasti m) a n d pleri xaf or. Peri p heral 
bl o o d m o n o n uclear cells ( P B M Cs) f or dr u g pr o d uct ma n ufact ure will be  c ollecte d 
b y a p heresis. A t otal of 2 m o bilizati o n c ycles ma y be perf or me d if nee de d a n d 
eac h m o bilizati o n c ycle ma y i ncl u de u p t o 3  a p heresis da ys. H o we ver, s u bjects 
w h ose dr u g pr o d uct fails t o meet s pecificati o ns f or a n y reas o n ma y u n der g o 
re peat a p heresis a n d ma n ufact ure of ne w dr u g pr o d uct. A p heresis pr o d ucts ca n 
als o be use d f or resc ue cells; alter nati vel y, a b o ne marr o w har vest is als o all o we d 
t o pr oc ure cells f or resc ue.  
St a ge 3: M yel oa blati ve c o n diti o ni n g ( 4 da ys of c o n diti o ni n g f oll o we d b y at leas t 
4 8 h o urs of was h o ut) a n d i nf usi o n of Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct ( Da y 1)  
After t he tra ns d uce d cells are dis p ositi o ne d f or cli nical use, a n d t he s u bject's  
eli gi bilit y has bee n re-c o nfir me d ( b y cli nical la b orat or y tests, p h ysical 
e xa mi nati o n, perf or ma nce stat us, a d verse e ve nt ( A E) re vie w a n d ot her tests base d 
o n i nstit uti o nal re q uire me nts), t he s u bject will u n der g o m yel oa blati ve 
c o n diti o ni n g wit h b us ulfa n.  
After c o m pleti o n of t he 4 -da y c o urse of b us ulfa n, t here m ust be a mi ni m u m of 
4 8  h o urs of was h o ut bef ore dr u g pr o d uct i nf usi o n.  
O n st u d y Da y 1, t ha we d Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct will be a d mi nistere d 
via i ntra ve n o us (I V) i nf usi o n at a d ose of ≥5. 0 × 1 0 6 C D 3 4 + cells/ k g.  
St a ge 4:  F oll o w -u p, t hr o u g h e n graft me nt a n d u p t o 2 4 m o nt hs after dr u g pr o d uct 
i nf usi o n 
S u bjects will be f oll o we d dail y i n t he tra ns pla nt u nit f or A Es, a n d la b orat or y 
para meters will be f oll o we d t o m o nit or b o ne marr o w e n graft me nt. T he s u bjec t 
will be disc har ge d fr o m t he tra ns pla nt u nit o nce t he s u bject is c o nsi dere d 
me dicall y sta ble.  
T he g oal d uri n g t he f oll o w -u p peri o d is t o mai ntai n he m o gl o bi n ( H b) ≥9 g/ d L. 
Tra nsf usi o ns s h o ul d be a v oi de d f or H b ≥9 g/ d L u nless t he nee d is me dicall y 
j ustifie d (e. g., as a re q uire me nt f or s ur ger y). It is rec o m me n de d t hat s u bjects 
s h o ul d recei ve p R B C tra nsf usi o ns f or H b < 7 g/ d L, a n d f or cli nicall y s y m pt o matic 
a ne mia, irres pecti ve of H b le vel.  
S u bjects will be f oll o we d i n t his pr ot oc ol f or a peri o d of 2 4  m o nt hs after 
Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct i nf usi o n. T hereafter s u bjects will be e x pecte d 
t o e nr oll i n a se parate l o n g-ter m f oll o w-u p pr ot oc ol ( L T F -3 0 3) t hat will assess 
safet y a n d efficac y be y o n d M o nt h 2 4 f or a t otal of 1 5 years after dr u g pr o d uct 
i nf usi o n. 
D at a M o nit ori n g 
C o m mittee:  
A n i n de pe n de nt Data M o nit ori n g C o m mittee ( D M C) c o m prise d of me m bers wit h 
a p pr o priate scie ntific a n d me dical e x pertise t o m o nit or t he st u d y will be 
c o n ve ne d.  
T he D M C will be c har ge d wit h re vie w of all safet y data f or t his s t u d y, i ncl u di n g 
A Es, seri o us a d verse e ve nts ( S A Es) a n d rele va nt la b orat or y val ues. T he D M C 
will ha ve t he ri g ht t o rec o m me n d t hat t he S p o ns or st o p t he st u d y at a n y ti me d ue 
t o c o ncer ns f or t he safet y of t he s u bjects. 
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N u m ber of S u bjects 
Pl a n ne d:  
A p pr o xi matel y 2 3 s u bjects i n t otal will be treate d wit h dr u g pr o d uct, at least 1 5 of 
w h o m m ust be ≥1 2 a n d ≤5 0 years of a ge (at least 5 of w h o m m ust be ≥1 2 a n d 
< 1 8), a n d at least 8 of w h o m m ust be < 1 2 years of a ge. Re place me nt s u bjects ma y 
be a d de d if s u bjects are scree n fail ures or wit h dra w pri or t o dr u g pr o d uct i nf usi o n.  
N o m ore t ha n 7 s u bjects ≥1 2 a n d ≤5 0 years of a ge a n d 4 s u bjects < 1 2 years of a ge 
w h o are treate d ca n ha ve a β E  allele (i.e., a p pr o xi matel y 5 0 % of s u bjects).  
I ncl usi o n Criteri a: 
1.  S u bjects ≤5 0 years of a ge at t he ti me of c o nse nt or asse nt (as a p plica ble), a n d 
a ble t o pr o vi de writte n c o nse nt (a d ults, or le gal g uar dia ns, as a p plica ble) or 
asse nt (a d olesce nts or c hil dre n). Pe diatric s u bjects ( < 1 2 years of a ge) ma y 
o nl y be e nr ol le d at a gi ve n site if a p pr o ve d b y t he rele va nt re g ulat or y 
a ut h orit y. Pr o vi de d t hat t he D M C has a p pr o ve d e nr olli n g s u bjects y o u n ger 
t ha n 5 years of a ge, s u bjects y o u n ger t ha n 5 years of a ge ma y be e nr olle d at 
sites wit h re g ulat or y a p pr o val f or t he s pecifie d a ge ra n ge if t he y wei g h a 
mi ni m u m of 6  k g a n d are reas o na bl y a ntici pate d t o be a ble t o pr o vi de at least 
t he mi ni m u m n u m ber of cells re q uire d t o i nitiate t he ma n ufact uri n g pr ocess.  
2.  Dia g n osis  of T D T wit h a hist or y of at least 1 0 0 m L/ k g/ year of p R B Cs i n t he 
2 years prece di n g e nr oll me nt (all s u bjects), or be ma na ge d u n der sta n dar d 
t halasse mia g ui deli nes (e. g., T halasse mia I nter nati o nal Fe derati o n, 2 0 1 4; see 
A p pe n di x  1 0. 4 ) wit h ≥8 tra nsf usi o ns of p R B Cs per year i n t he 2 years 
prece di n g e nr oll me nt (s u bjects ≥1 2 years; Rac h mile witz a n d Giar di na, 2 0 1 1 ). 
3.  Cli nicall y sta ble, ha ve a Kar n ofs k y perf or ma nce stat us of ≥8 0 f or a d ults 
( ≥1 6 years of a ge) or a La ns k y perf or ma nce stat us of ≥8 0 f or a d olesce n ts or 
c hil dre n ( < 1 6  years of a ge), a n d eli gi ble t o u n der g o H S C T.  
4.  Treate d a n d f oll o we d f or at least t he past 2 years i n a s pecialize d ce nter t hat 
mai ntai ne d detaile d me dical rec or ds o n R B C tra nsf usi o ns (i ncl u di n g v ol u me 
a n d u nits of R B Cs a n d ass ociate d pre -tra nsf usi o n H b val ues, retic ul oc yte 
c o u nts a n d rele va nt bl o o d ba n k details as a vaila ble), i n -patie nt 
h os pitalizati o n, a n d ir o n c helati o n hist or y.  
E xcl usi o n Criteri a:  
1.  Prese nce of a m utati o n c haracterize d as β 0 o n b ot h H B B  alleles. F or t he 
p ur p ose of scree ni n g, I V S I -1 1 0 ( G A) [ H G V S n o me nclat ure: H B B :c. 9 3-
2 1 G > A] will be c o nsi dere d e q ui vale nt t o a β 0 m utati o n.  
2.  P ositi ve f or prese nce of h u ma n i m m u n o deficie nc y vir us t y pe 1 ( HI V -1) or 2 
( HI V-2), he patitis B vir us ( H B V), or he pa titis C vir us ( H C V). S y p hilis (ra pi d 
plas ma rea gi n [ R P R]) testi n g is als o re q uire d a n d a p ositi ve test f or s y p hilis is 
e xcl usi o nar y w here ma n date d b y re gi o nal dr u g pr o d uct ma n ufact uri n g 
practices. N ote t hat s u bjects w h o ha ve bee n vacci nate d a gai nst he patit is B 
( he patitis B s urface a nti b o d y-p ositi ve) w h o are ne gati ve f or ot her mar kers of 
pri or he patitis B i nfecti o n (e. g., ne gati ve f or he patitis B c ore a nti b o d y) are 
eli gi ble. S u bjects wit h past e x p os ure t o H B V ( H Bc A b p ositi ve a n d/ or H Be 
A b p ositi ve) are als o  eli gi ble f or t he st u d y pr o vi de d t he y are ne gati ve b y 
assess me nt f or H B V D N A. Als o n ote t hat s u bjects w h o are p ositi ve f or a nti -
he patitis C a nti b o d y are eli gi ble as l o n g as t he y ha ve a ne gati ve H C V viral 
l oa d. W here cli nicall y a n d/ or re gi o nall y i n dicate d, ot her tests ma y be 
perf or me d, i n w hic h case p ositi ve res ults w o ul d e xcl u de t he s u bject fr o m 
partici pati n g: f or e xa m ple, h u ma n T -l y m p h otr o pic vir us-1 ( H T L V -1) or -2 
( H T L V-2), t u berc ul osis, t o x o plas m osis, Tr y pa n os o ma cr uzi, West Nile 
Vir us, or Zi ka Vir us.  
3.  Cli nicall y si g nifica nt a n d acti ve bacterial, viral, f u n gal, or parasitic i nfecti o n 
as deter mi ne d b y t he cli nical i n vesti gat or.  
4.  A w hite bl o o d cell ( W B C) c o u nt < 3 × 1 0 9/ L, a n d/ or platelet c o u nt < 1 0 0 × 1 09/ L 
n ot relate d t o h y pers ple nis m.  
5.  U nc orrecte d blee di n g dis o r der.  
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6.  A n y pri or or c urre nt mali g na nc y ( wit h t he e xce pti o n of a de q uatel y treate d 
c o ne‑ bi o psie d i n sit u carci n o ma of t he cer vi x uteri a n d basal or s q ua m o us cell 
carci n o ma of t he s ki n) or m yel o pr oliferati ve or si g nifica nt i m m u n o deficie nc y 
dis or der.  
7.  I m me diate fa mil y me m ber (i.e. pare nt or si bli n gs) wit h a k n o w n Fa milial 
Ca ncer S y n dr o me (i ncl u di n g b ut n ot li mite d t o here ditar y breast a n d o varia n 
ca ncer s y n dr o me, here ditar y n o n -p ol y p osis c ol orectal ca ncer s y n dr o me a n d 
fa milial a de n o mat o us p ol y p osis). 
8.  Pri or H S C T.  
9.  A d va nce d li ver disease, defi ne d as:  
a. 
Persiste nt as partate tra nsa mi n ase, ala ni ne tra nsa mi nase, or direct 
bilir u bi n val ue > 3 ×  t he u p per li mit of n or mal ( U L N), or  
b.  Baseli ne pr ot hr o m bi n ti me or partial t hr o m b o plasti n ti me > 1. 5 ×  U L N, 
s us pecte d of arisi n g fr o m li ver disease, or  
c. 
Ma g netic Res o na nce I m a gi n g ( M RI) of t he li ver de m o nstrati n g clear 
e vi de nce of cirr h osis, or  
d.  M RI fi n di n gs s u g gesti ve of acti ve he patitis, si g nifica nt fi br osis, 
i nc o ncl usi ve e vi de nce of cirr h osis, or li ver ir o n c o nce ntrati o n ≥1 5 m g/ g 
re q uire f oll o w-u p li ver bi o ps y i n s u bjects ≥ 1 8 years of a ge. I n s u bjects 
< 1 8 years of a ge, t hese M RI fi n di n gs are e xcl usi o nar y, u nless i n t he 
o pi ni o n of t he i n vesti gat or, a li ver bi o ps y c o ul d pr o vi de a d diti o nal data 
t o c o nfir m eli gi bilit y a n d w o ul d be safe t o perf or m. If a li ver bi o ps y is 
perf or me d base d o n M RI fi n di n gs, a n y e vi de nce of cirr h osis, bri d gi n g 
fi br osis, or si g nifica nt acti ve he patitis will be e xcl usi o nar y.  
1 0.  Baseli ne esti mate d gl o mer ular filtrati o n rate < 7 0 m L/ mi n/ 1. 7 3 m 2, as 
deter mi ne d usi n g t he C hr o nic Ki d ne y Disease E pi de mi ol o g y C olla b orati o n 
creati ni ne e q uati o n f or ≥1 8 years of a ge, a n d Be dsi de Sc h wartz e q uati o n 
calc ulat or f or < 1 8 years of a ge (see 
htt p:// w w w ki d ne y. or g/ pr ofessi o nals/ k d o qi/ gfr _calc ulat or.cf m).  
1 1.  U nc o ntr olle d seiz ure dis or der.  
1 2.  Diff usi o n ca pacit y of car b o n m o n o xi de ( D Lc o) < 5 0 % of pre dicte d (c orrecte d 
f or H b a n d/ or al ve olar v ol u me, as cli nicall y i n dicate d). If D Lc o ca n n ot be 
assesse d d ue t o a ge or c o g niti o n -relate d restricti o ns, t here m ust be a n or mal 
res pirat or y e xa m, c hest ra di o gra p h wit h o ut p ul m o nar y i nfiltrates, a n d o x y ge n 
sat urati o n b y p ulse o xi metr y > 9 2 % o n r o o m air. I n t he prese nce of cli nicall y 
si g nifica nt a b n or mal fi n di n gs o n c hest ra di o gra p h, cli nicall y si g nifica nt 
a b n or mal fi n di n gs o n t he res pirat or y e xa m, or o x y ge n sat urati o n b y p ulse 
o xi metr y ≤9 2 % o n r o o m air, t h e s u bject will be e xcl u de d.  
1 3.  A car diac T 2 * < 1 0 ms b y M RI.  
1 4.  A n y ot her e vi de nce of se vere ir o n o verl oa d t hat, i n t he i n vesti gat or’s o pi ni o n, 
warra nts e xcl usi o n.  
1 5.  Partici pati o n i n a n ot her cli nical st u d y wit h a n i n vesti gati o nal dr u g wit hi n 3 0 
da ys of Scree ni n g.  
1 6.  A n y ot her c o n diti o n t hat w o ul d re n der t he s u bject i neli gi ble f or H S C T, as 
deter mi ne d b y t he atte n di n g tra ns pla nt p h ysicia n or i n vesti gat or.  
1 7.  Pri or recei pt of ge ne t hera p y.  
1 8.  Dia g n osis of si g nifica nt ps yc hiatric dis or der of t he s u bject t hat c o ul d 
seri o usl y i m pe de t he a bilit y t o partici pate i n t he st u d y. 
1 9.  Pre g na nc y or breastfee di n g i n a p ost part u m fe male or a bse nce of a de q uate 
c o ntrace pti o n f or fertile s u bjects. Fe males of c hil d -beari n g p ote ntial a n d 
males are re q uire d t o use t w o differe nt effecti ve met h o ds of c o ntrace pti o n 
fr o m Scree ni n g t hr o u g h at least 6 m o nt hs after dr u g pr o d uct i nf usi o n. If 
s u bjects are tr ul y se x uall y a bsti ne nt ( w here tr ue se x ual a bsti ne nce is defi ne d 
C CI

Pr ot oc ol H G B - 2 0 7 Versi o n 6. 0  
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as bei n g i n li ne wit h t he preferre d a n d us ual lifest yle of t he s u bject), n o 
sec o n d met h o d is re q uire d. 
2 0.  A n assess me nt b y t he i n vesti gat or t hat t he s u bject w o ul d n ot c o m pl y wit h t he 
st u d y pr oce d ures o utli ne d i n t he pr ot oc ol. 
2 1.  A k n o w n a n d a vaila ble h u ma n le u k oc yte a nti ge n ( H L A) -matc he d fa mil y 
d o n or. If re q uire d b y re gi o nal re g ulat or y a ut h orit y, patie nts wit h a k n o w n a n d 
a vaila ble matc he d u nrelate d d o n or will be e xcl u de d fr o m t he st u d y.  
2 2.  A n y c o ntrai n dicati o ns t o t he use of G -C S F a n d pleri xaf or d uri n g t he 
m o bilizati o n of he mat o p oietic ste m cells a n d a n y c o ntrai n dicati o ns t o t he use 
of b us ulfa n a n d a n y ot her me dici nal pr o d ucts use d d uri n g t he m yel oa blati ve 
c o n diti o ni n g, i ncl u di n g h y perse nsiti vit y t o t he acti ve s u bsta nces or t o a n y of 
t he e xci pie nts. 
D ur ati o n of S u bject 
P artici p ati o n:  
Ti me bet wee n Scree ni n g a n d dr u g pr o d uct i nf usi o n will be varia ble a n d is 
esti mate d ge nerall y t o be bet wee n 3 t o 5 m o nt hs (e. g., u p t o 3 m o nt hs bet wee n 
Scree ni n g a n d M o bilizati o n, f oll o we d b y a p pr o xi matel y 2 m o nt hs bef ore dr u g 
pr o d uct i nf usi o n). T hereafter t he s u bject is pla n ne d t o re mai n o n st u d y f or 
a p pr o xi matel y 2 4 m o nt hs. Eli gi ble s u bjects will t he n be e x pecte d t o e nr oll i n a 
se parate l o n g-ter m f oll o w-u p st u d y u ntil a p pr o xi matel y 1 5 years p ost‑ dr u g 
pr o d uct i nf usi o n.  
Test Pr o d uct, D ose a n d 
M o de of A d mi ni str ati o n: 
Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct is a n a ut ol o g o us C D 3 4 + cell -e nric he d 
p o p ulati o n t hat c o ntai ns he mat o p oietic ste m cells tra ns d uce d wit h B B 3 0 5 
le nti viral vect or e nc o di n g t he βA- T 8 7 Q -gl o bi n ge ne, s us pe n de d i n cr y o preser vati o n 
s ol uti o n. All s u bjects are t o recei ve Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct o n Da y 1 
via I V i nf usi o n at a d ose of ≥5. 0 × 1 0 6 C D 3 4 +  cells/ k g. 
Effic ac y e n d p oi nts:  
Pri m ar y E n d p oi nt  
T he pr o p orti o n of s u bjects w h o meet t he defi niti o n of “tra nsf usi o n i n de pe n de nce” 
( TI). TI is defi ne d as a wei g hte d a vera ge H b ≥9 g/ d L wit h o ut a n y p R B C 
tra nsf usi o ns f or a c o nti n u o us peri o d of ≥1 2 m o nt hs at a n y ti me d uri n g t he st u d y 
after dr u g pr o d uct i nf usi o n.  
Sec o n d ar y E n d p oi nts  
•  
C haracterizati o n of s u bjects ac hie vi n g TI:  
− 
Pr o p orti o n of s u bjects w h o meet t he de fi niti o n of TI at 
M o nt h  2 4  
− 
D urati o n of TI  
− 
Ti me fr o m dr u g pr o d uct i nf usi o n t o ac hie ve me nt of TI  
− 
Wei g hte d a vera ge H b d uri n g TI  
•  
C haracterizati o n of tra nsf usi o n re d ucti o n ( T R):  
− 
Pr o p orti o n of s u bjects wit h a re d ucti o n i n t he a n n ualize d m L/ k g 
p R B Cs tra nsf use d f r o m 1 2 m o nt hs p ost -dr u g pr o d uct i nf usi o n 
t hr o u g h M o nt h 2 4 (a p pr o xi matel y a 1 2-m o nt h peri o d) of at least 
5 0 %, 6 0 %, 7 5 %, 9 0 % or 1 0 0 % c o m pare d t o t he a n n ualize d 
m L/ k g p R B C tra nsf usi o n re q uire me nt d uri n g t he 2 years pri or 
t o e nr oll me nt  
− 
A n n ualize d n u m ber a n d v ol u me of p R B C tra nsf usi o ns fr o m 
1 2  m o nt hs p ost -dr u g pr o d uct i nf usi o n t hr o u g h M o nt h 2 4 
c o m pare d t o t he a n n ualize d n u m ber a n d v ol u me of tra nsf usi o ns 
d uri n g t he 2  years pri or t o e nr oll me nt  
− 
Ti me fr o m dr u g pr o d uct i nf usi o n t o last p R B C t ra nsf usi o n 
− 
Ti me fr o m last p R B C tra nsf usi o n t o M o nt h 2 4  
C CI

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•  
Wei g hte d a vera ge na dir H b d uri n g t he 2 years pri or t o e nr oll me nt 
c o m pare d t o wei g hte d a vera ge na dir H b fr o m 1 2 m o nt hs p ost -dr u g 
pr o d uct i nf usi o n t hr o u g h M o nt h 2 4  
•  
U ns u p p orte d t otal H b le vels o ver ti me, i ncl u di n g M o nt h 6, M o nt h 9, 
M o nt h 1 2, M o nt h 1 8, a n d M o nt h 2 4  
•  
U ns u p p orte d t otal H b le vels ≥1 0  g/ d L, ≥1 1  g/ d L, ≥1 2  g/ d L, 
≥1 3  g/ d L, ≥1 4  g/ d L o ver ti me, i ncl u di n g M o nt h 6, M o nt h 9, M o nt h 
1 2, M o nt h 1 8, a n d M o nt h 2 4  
•  
C haracterizati o n of use of ir o n c helati o n a n d/ or t hera pe utic 
p hle b ot o m y a m o n g all s u bjects:  
− 
Pr o p orti o n of s u bjects w h o ha ve n ot recei ve d ir o n c helati o n 
t hera p y f or at least 6 m o nt hs f oll o wi n g dr u g pr o d uct i nf usi o n 
− 
Ti me fr o m last ir o n c helati o n use t o last f oll o w -u p  
− 
Pr o p orti o n of s u bjects usi n g t hera pe utic p hle b ot o m y a n d 
a n n ualize d fre q ue nc y of p hle b ot o m y use per s u bject f oll o wi n g 
dr u g pr o d uct i nf usi o n  
•  
E val uati o n of t he c ha n ge i n ir o n b ur de n o ver ti me, as meas ure d b y:  
− 
C ha n ge i n li ver ir o n c o nte nt b y M RI at baseli ne t o M o nt h 1 2 
a n d M o nt h 2 4 
− 
C ha n ge i n car diac T 2 * o n M RI at baseli ne t o M o nt h 1 2 a n d 
M o nt h  2 4  
− 
C ha n ge i n ser u m ferriti n at baseli ne t o M o nt h  1 2 a n d M o nt h 2 4  
•  
E val uati o n of healt h -relate d q ualit y of life ( H R Q o L) o ver ti me 
i ncl u di n g M o nt h 1 2 a n d M o nt h 2 4 as c o m pare d t o baseli ne, usi n g 
t he f oll o wi n g vali date d t o ols:  
− 
Pe diatrics: Pe diatric Q ualit y of Life I n ve nt or y ( Pe ds Q L; pare nt 
ge neral c ore a n d ge neral c ore)  
− 
A d olesce nts: Pe ds Q L ( pare nt ge neral c ore a n d ge neral c ore) a n d 
E ur o Q ol -5 D ( Y o ut h versi o n) ( E Q -5 D -Y)  
− 
A d ults: E ur o Q ol -5 D ( E Q -5 D) F u ncti o nal Asses s me nt of Ca ncer 
T hera p y -B o ne Marr o w Tra ns pla nt ( F A C T -B M T), a n d 
S h ort  F or m‑ 3 6 ( S F -3 6) v 2  
E x pl or at or y E n d p oi nts  
•  
Assess me nt of gr o wt h a n d p u bert y para meters (a ge a p pr o priate), 
b o ne de nsit y, dia betes, e n d ocri ne e val uati o ns, a n d ne ur oc o g niti ve 
de vel o p me nt ( pe d iatric s u bjects < 1 8 years of a ge) 
•  
Assess me nt of c ha n ge i n d yser yt hr o p oiesis  
•  
C orrelati o ns of pre -treat me nt varia bles (e. g., dr u g pr o d uct vect or 
c o p y n u m ber [ V C N]) wit h res p o nse (e. g., peri p heral bl o o d V C N, 
H b A T 8 7 Q ) 
•  
Meas ures of healt h res o urce utilizati o n (i ncl u di n g c o m pari n g 
a n n ualize d n u m ber of tra nsf usi o ns, n u m ber of h os pitalizati o ns, a n d 
n u m ber of da ys h os pitalize d, fr o m 1 2  m o nt hs p ost -dr u g pr o d uct 
i nf usi o n t hr o u g h M o nt h 2 4 wit h t he a n n ualize d c orres p o n di n g 
para meters d uri n g t he 2 years pri o r t o e nr oll me nt) 
•  
Le n gt h of i n -patie nt h os pital sta y fr o m i nitiati o n of c o n diti o ni n g t o 
disc har ge  
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Pr ot oc ol H G B - 2 0 7 Versi o n 6. 0  
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S afet y e n d p oi nts:  
Sec o n d ar y E n d p oi nts  
•  
S uccess a n d ki netics of H S C e n graft me nt  
•  
I nci de nce of tra ns pla nt-relate d m ortalit y t hr o u g h 1 0 0 da ys a n d 
t hr o u g h 3 6 5 da ys p ost-dr u g pr o d uct i nf usi o n  
•  
O verall s ur vi val ( O S)  
•  
Detecti o n of vect or -deri ve d re plicati o n c o m pete nt le nti vir us ( R C L) 
i n a n y s u bject 
•  
M o nit ori n g of la b orat or y para meters  
•  
Fre q ue nc y a n d se verit y of cli nical A Es  
•  
I nci de nce of ac ute a n d/ or c hr o nic graft-vers u s-h ost disease ( G V H D)  
•  
T he n u m ber of s u bjects wit h i nserti o nal o nc o ge nesis 
( m yel o d ys plasia, le u ke mia, l y m p h o ma, etc.)  
E x pl or at or y E n d p oi nt  
•  
T he n u m ber of s u bjects wit h cl o nal pre d o mi na nce  
P h ar m ac o d y n a mic 
e n d p oi nts:  
Sec o n d ar y E n d p oi nts  
•  
β A‑ T 8 7 Q ‑ gl o bi n e x pressi o n o ver ti me i ncl u di n g M o nt h 6, M o nt h 9, 
M o nt h 1 2, M o nt h 1 8, a n d M o nt h 2 4, as meas ure d b y assessi n g t he 
rati o of βA‑ T 8 7 Q ‑ gl o bi n t o all β-li ke-gl o bi ns, a n d α‑ gl o bi n t o all 
β‑li ke‑ gl o bi ns, i n w h ole bl o o d  
− 
C orrelati o n of β A- T 8 7 Q -gl o bi n e x pressi o n at earl y ti me p oi nts 
p ost‑ dr u g pr o d uct i nf usi o n t o β A- T 8 7 Q -gl o bi n e x pressi o n at later 
ti me p oi nts, as well as cli nical o utc o mes. 
•  
V C N i n peri p heral bl o o d o ver ti me, i ncl u di n g M o nt h 6, M o nt h 9, 
M o nt h 1 2, M o nt h 1 8, a n d M o nt h 2 4  
E x pl or at or y E n d p oi nt  
•  
Relati o ns hi p bet wee n meas ures of m yel oa blati o n a n d 
p har mac o d y na mic a n d cli nical o utc o mes  
A d diti o nall y, e x pl orat or y met h o ds ma y be use d t o e val uate p har mac o d y na mic 
e n d p oi nts.  
St atistic al Met h o ds:  
S a m ple size esti m ati o n:  
N o f or mal sa m ple size calc ulati o ns were perf or me d.  
A p pr o xi matel y 2 3 s u bjects i n t otal will be treate d wit h Le nti Gl o bi n B B 3 0 5 Dr u g 
Pr o d uct, at least 1 5 of w h o m m ust be ≥1 2 a n d ≤5 0 years of a ge ( C o h ort 1), a n d at 
least 8 of w h o m m ust be < 1 2 years of a ge ( C o h ort 2). T he pr o p ose d sa m ple size i n 
C o h ort 1 is base d o n t he pre mise t hat e xcl u di n g a treat me nt effect of < 3 0 % wit h a 
hi g h pr o ba bilit y is of val ue ( de m o nstrati n g wit h 9 7. 5 % c o nfi de nce t hat ≥3 0 % of 
s u bjects bec o me TI) a n d a p oi nt esti mate of t he pr o p orti o n of patie nts w h o bec o me 
TI of at least 6 0 % is c o nsi dere d cli nicall y mea ni n gf ul. A m o n g t he pr o p ose d sa m ple 
size of 1 5 treate d s u bjects ≥1 2 a n d ≤5 0 years of a ge i n C o h ort 1, a p oi nt esti mate 
f or s uccess of 6 0 % ( 9 o ut of 1 5 s u bjects), w o ul d yiel d a l o wer 1-si de d 9 7. 5 % e xact 
c o nfi de nce b o u n d of 3 2. 3 %, e xcee di n g t he 3 0 % mi ni mal criteri o n. A m o n g t he 
pr o p ose d sa m ple size of 8 treate d s u bjects < 1 2 years of a ge i n C o h ort 2, a p oi nt 
esti mate f or s uccess of 6 2. 5 % ( 5 o ut of 8 s u bjects) w o ul d yiel d a l o wer 1 -si de d 
9 7. 5 % e xact c o nfi de nce b o u n d  of 2 4. 5 %.  
P o p ul ati o ns f or a n al ysis:  
• 
I nte nt-t o-Treat  (I T T)  p o p ulati o n:  All  s u bjects  w h o  i nitiat e  a n y  st u d y  
pr oce d ures,  be gi n ni n g  wit h  m o bilizati o n  b y  gra n ul oc yte  c ol o n y  
sti m ulati n g fact or ( G-C S F) a n d/ or pleri xaf or  
C CI

Pr ot oc ol H G B - 2 0 7 Versi o n 6. 0  
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• 
Tra ns pla nt P o p ulati o n ( T P): All s u bjects w h o recei ve Le nti Gl o bi n B B 3 0 5 
Dr u g Pr o d uct  
• 
S uccessf ul  E n graft me nt  P o p ulati o n  ( S E P):  All  s u bjects  w h o  ha ve  
s uccessf ul ne utr o p hil e n graft me nt after Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct 
i nf usi o n 
T he pri mar y p o p ulati o n f or a nal ysis of safet y will be t he I T T p o p ulati o n. T he 
pri mar y p o p ulati o n f or t he a nal ysis of efficac y, p har mac o d y na mic, a n d tra ns pla nt -
relate d e n d p oi nts will be t he T P. T he S E P will be use d t o pr o vi de s u p p orti ve data 
f or s u bjects w h o e n graft. 
A n al ysis of pri m ar y effic ac y e n d p oi nt:  
S uccess criteria f o r t his st u d y are tar gete d at ac hie ve me nt of TI i n 9 o ut of 1 5 
s u bjects ≥1 2 years of a ge a n d 5 o ut of 8 s u bjects < 1 2 years of a ge. A p oi nt-
esti mate of t he pr o p orti o n of s u bjects ac hie vi n g TI, wit h a 2 -si de d 9 5 % CI 
calc ulate d usi n g t he Cl o p per -Pears o n e xact bi n o mial met h o d will be e m pl o ye d.  
A n al ysis of s afet y:  
All A Es will be c ollecte d fr o m si g ni n g of i nf or me d c o nse nt/asse nt t hr o u g h M o nt h 
2 4 Visit f or t he I T T p o p ulati o n, irres pecti ve of se verit y gra de or relati o ns hi p t o 
Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct. All A Es  will be liste d a n d descri pti ve statistics 
f or A Es will be s u m marize d f or t he f oll o wi n g ti me peri o ds: 1) fr o m i nf or me d 
c o nse nt/asse nt u p t o t he start of m o bilizati o n; 2) fr o m start of m o bilizati o n u p t o 
start of c o n diti o ni n g; 3) fr o m start of c o n diti o ni n g t hr o u g h ne utr o p hil 
e n graft me nt; 4)  fr o m ne utr o p hil e n graft me nt t hr o u g h M o nt h 2 4 Visit; 5) fr o m 
dr u g pr o d uct i nf usi o n t hr o u g h M o nt h 2 4 Visit; a n d 6) fr o m i nf or me d 
c o nse nt/asse nt t hr o u g h M o nt h 2 4 Visit.  
A d diti o nall y, s ur vi val stat us, la b orat or y res ults a n d i nserti o nal o nc o ge nesis 
(i nserti o nal m uta ge nesis res ulti n g i n o nc o ge nesis) e ve nts will be s u m marize d. 
T he pla n ne d statistical met h o d ol o g y details will be prese nte d i n t he Statistical 
A nal ysis Pla n ( S A P).  
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Pr ot oc ol H G B - 2 0 7 Versi o n 6. 0  
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LI S T O F A B B R E VI A TI O N S  
A b bre vi ati o n  
Defi niti o n  
A b  
A nti b o d y  
A D L  
Acti vities of dail y li vi n g  
A E  
A d verse e ve nt  
All o -H S C T  
All o ge neic he mat o p oietic ste m cell tra ns pla nt(ati o n)  
A N C  
A bs ol ute ne utr o p hil c o u nt  
A U C  
Area u n der t he c ur ve  
B F U -E  
B urst -f or mi n g u nits-er yt hr oi d 
C B C  
C o m plete bl o o d c o u nt 
c/ d g 
C o pies per di pl oi d ge n o me  
C M V  
C yt o me gal o vir us  
C R F  
Case re p ort f or m  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  
D Lc o  
Diff usi o n ca pacit y of car b o n m o n o xi de  
D M C  
Data M o nit ori n g C o m mittee  
D N A  
De o x yri b o n ucleic aci d  
E B V  
E pstei n -Barr vir us  
E C  
Et hics C o m mittee  
E C G  
Electr ocar di o gra m  
e C R F  
Electr o nic case re p ort f or m  
E D C  
Electr o nic data ca pt ure  
E P O  
E Q -5 D  
E Q -5 D -Y  
F A C T -B M T  
Er yt hr o p oieti n  
E ur o Q o L -5 D  
E ur o Q ol -5 D ( Y o ut h versi o n)  
F u ncti o nal Assess me nt of Ca ncer T hera p y -B o ne Marr o w Tra ns pla nt  
F E V 1 
F orce d e x pirat or y v ol u me i n 1 sec o n d  
F S H  
F ollicle sti m ulati n g h or m o ne  
F V C  
F orce d vital ca pacit y  
G -C S F  
Gra n ul oc yte c ol o n y sti m ulati n g fact or  
G C P  
G o o d Cli nical Practice  
G F R  
Gl o mer ular filtrati o n rate  
G M P  
G o o d Ma n ufact uri n g Practice  
G V H D  
Graft -vers us -h ost disease  
H b  
He m o gl o bi n  
H b A  
H b E  
He m o gl o bi n A  
He m o gl o bi n E  
H B B  
β‑ gl o bi n ge ne  
H Bs A b  
He patitis B s urface a nti b o d y  
H B V  
He patitis B vir us  
Hct  
He mat ocrit  
H C V  
H G V S  
He patitis C vir us  
H u ma n Ge n o me Variati o n S ociet y  
HI V -1  
H u ma n i m m u n o deficie nc y vir us t y pe 1  
HI V -2  
H u ma n i m m u n o deficie nc y vir us t y pe 2  
H L A  
H O M A  
H u ma n le u k oc yte a nti ge n  
H o me ostatic m o del assess me nt  
C CI

Protocol HGB-207 Version 6.0  
10 June 2021 
Page 22 
Confidential 
Abbreviation 
Definition 
HPLC 
High pressure liquid chromatography 
HRQoL 
Health-related quality of life 
HSC 
Hematopoietic stem cell 
HSCT 
Hematopoietic stem cell transplant(ation) 
HSV 
Herpes simplex virus 
HTLV-1 
Human T-lymphotropic virus type 1 
HTLV-2 
IBC 
Human T-lymphotropic virus type 2 
Institutional Biosafety Committee 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IgA 
Immunoglobulin A 
IGF-1 
Insulin-like growth factor 1 
IGFBP-3 
Insulin-like growth factor-binding protein 3 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IRB 
Institutional Review Board 
IS 
Integration site 
ISA 
Integration site analysis 
ITT 
Intent-to-treat population 
IV 
Intravenous 
KM 
Kaplan-Meier 
LCR 
Locus control region 
LH 
Luteinizing hormone 
LIC 
Liver iron concentration 
LVEF 
Left ventricular ejection fraction 
MCH 
Mean corpuscular hemoglobin  
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MRI 
Magnetic resonance imaging 
NK 
Natural killer 
OS 
Overall survival 
PBL 
Peripheral blood leukocyte 
PBMC 
Peripheral blood mononuclear cell 
PedsQL 
PFTs 
Pediatric Quality of Life Inventory 
Pulmonary function tests 
PK 
Pharmacokinetic 
PTH 
Parathyroid hormone 
pRBC 
Packed red blood cell(s) 
q6h 
Every 6 hours 
qPCR 
Quantitative polymerase chain reaction 
RBC 
Red blood cell(s) 
RCL 
Replication competent lentivirus 
RNA 
Ribonucleic acid 
RPR 
Rapid plasma reagin 
RV 
Respiratory volume 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 

Pr ot oc ol H G B - 2 0 7 Versi o n 6. 0  
1 0 J u ne 2 0 2 1  
Pa ge 2 3 
A b bre vi ati o n  
Defi niti o n  
S D  
Sta n dar d de viati o n  
S E P  
S uccessf ul e n graft me nt p o p ulati o n  
S F -3 6  
SI N  
S N P  
S h ort F or m -3 6  
Self -i nacti vati n g 
Si n gle n ucle oti de p ol y m or p his m  
S O E  
Sc he d ule of E ve nts  
S O M  
St u d y O perati o ns Ma n ual  
S U S A R  
S us pecte d, u ne x pecte d seri o us a d verse dr u g reacti o ns  
T 4  
T D T  
T h yr o xi ne  
Tra nsf usi o n -de pe n de nt β -t halasse mia 
TI  
Tra nsf usi o n i n de pe n de nce 
T N C  
T otal n ucleate d cells  
T R  
Tra nsf usi o n re d ucti o n  
T P  
Tra ns pla nt p o p ulati o n  
T S H  
T h yr oi d sti m ulati n g h or m o ne  
U L N  
U p per li mit of n or mal  
U S  
U nite d States  
V C N  
Vect or c o p y n u m ber  
V S V -G  
Vesic ular st o matitis vir us gl yc o pr otei n  
V Z V  
Varicella z oster vir us  
W B C  
W hite bl o o d cell  
 
C CI

Pr ot oc ol H G B - 2 0 7 Versi o n 6. 0  
1 0 J u ne 2 0 2 1  
Pa ge 2 4 
T A B L E O F C O N T E N T S  
M E DI C A L O F FI C E R C O N T A C T I N F O R M A TI O N  ..................................................................... 2 
S U M M A R Y O F C H A N G E S  ........................................................................................................... 3 
C LI NI C A L S T U D Y P R O T O C O L S Y N O P SI S ............................................................................. 1 3 
LI S T O F A B B R E VI A TI O N S  ........................................................................................................ 2 1 
T A B L E O F C O N T E N T S  ............................................................................................................... 2 4 
LI S T O F T A B L E S  ......................................................................................................................... 2 8 
LI S T O F FI G U R E S  ....................................................................................................................... 2 8 
1.  
I N T R O D U C TI O N ...................................................................................................... 2 9 
2.  
S T U D Y O BJ E C TI V E S A N D E N D P OI N T S  .............................................................. 3 0 
2. 1.  
St u d y O bjecti ves ......................................................................................................... 3 0  
2. 2.  
St u d y E n d p oi nts .......................................................................................................... 3 1  
2. 2. 1.  
Effic ac y E n d p oi nts ...................................................................................................... 3 1  
2. 2. 2.  
Safet y E n d p oi nts ......................................................................................................... 3 2  
2. 2. 3.  
P har mac o d y na mic E n d p oi nts ..................................................................................... 3 3  
3.  
I N V E S TI G A TI O N A L P L A N ..................................................................................... 3 4 
3. 1.  
O vera ll Desi g n a n d Pla n of t he St u d y ......................................................................... 3 4 
3. 2.  
Data M o nit ori n g C o m mittee  ....................................................................................... 3 5 
3. 3.  
Rati o nale f or t he St u d y Desi g n ................................................................................... 3 6  
3. 4.  
Rati o nale f or D ose of St u d y Dr u g .............................................................................. 3 7  
3. 5.  
Treat me nt Disc o nti n uati o n a n d E nr oll me nt S us pe nsi o n Criteria ............................... 3 8  
3. 5. 1.  
St o p pi n g R ules f or B us ulfa n ....................................................................................... 3 8  
3. 5. 2.  
E nr oll me nt S us pe nsi o n Criteria .................................................................................. 3 8  
4.  
S T U D Y P O P U L A TI O N  ............................................................................................. 4 0 
4. 1.  
N u m ber of S u bjects .................................................................................................... 4 0  
4. 2.  
I n cl usi o n Criteria ........................................................................................................ 4 0 
4. 3.  
E xcl usi o n Criteria  ....................................................................................................... 4 0 
4. 4.  
S u bject I d e ntificati o n a n d Re gistrati o n  ...................................................................... 4 2 
4. 5.  
S u bject Wit h dra wal fr o m t he St u d y ........................................................................... 4 3  
5.  
S T U D Y T R E A T M E N T S ............................................................................................ 4 5 
5. 1.  
Descri pti o n of Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct ...................................................... 4 5  
5. 2.  
S u m mar y of Treat me nts t o be Perf or me d or A d mi nistere d  ........................................ 4 5 
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Pr ot oc ol H G B - 2 0 7 Versi o n 6. 0  
1 0 J u ne 2 0 2 1  
Pa ge 2 5 
 
5. 2. 1.  
M o bilizati o n a n d A p heresis Pr oce d ure ....................................................................... 4 5  
5. 2. 1. 1.  
M o bilizati o n  ................................................................................................................ 4 6 
5. 2. 1. 2.  
A p heresis  .................................................................................................................... 4 8 
5. 2. 2.  
B o ne Ma rr o w H ar v est Pr oce d ure ............................................................................... 4 8 
5. 2. 3.  
C o n diti o ni n g ............................................................................................................... 4 8  
5. 2. 3. 1.  
Ge ner al C o nsi derati o ns ............................................................................................... 4 8  
5. 2. 3. 2.  
P har mac o ki netics f or B us ulfa n D ose A dj ust me nts .................................................... 4 9  
5. 2. 4.  
I nf usi o n Pr oce d ur es, D os e, a n d A d mi nistrati o n ......................................................... 5 0 
5. 3.  
St ora ge a n d Sta bilit y of Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct ....................................... 5 0  
5. 4.  
Pr o d uct Acc o u nta bilit y ............................................................................................... 5 0  
5. 5.  
Met h o d of Assi g ni n g S u bjects t o Treat me nt .............................................................. 5 1  
5. 6.  
Bli n di n g, Pac ka gi n g, a n d La beli n g ............................................................................. 5 1  
5. 6. 1.  
Bli n di n g a n d Brea ki n g t he Bli n d ................................................................................ 5 1  
5. 6. 2.  
Pac ka gi n g a n d La b eli n g .............................................................................................. 5 1  
5. 7.  
D urati o n of S u bject Parti ci pati o n ............................................................................... 5 1  
5. 8.  
Assess me nt of Treat me nt C o m plia nce  ....................................................................... 5 2 
5. 9.  
Pri or a n d C o nc o mita nt Me dicati o ns ........................................................................... 5 2  
5. 9. 1.  
Pri or Me dicati o ns ........................................................................................................ 5 2  
5. 9. 2.  
C o nc o mita nt Me dicati o ns a n d T hera pi es: Ge neral ..................................................... 5 2  
5. 9. 3.  
C o nc o mita nt Me dicati o ns a n d T hera pi es: Tra nsf usi o ns ............................................. 5 3  
5. 9. 4.  
C o nc o mita nt Me dicati o ns a n d T hera pi es: Ir o n C h elati o n .......................................... 5 4  
5. 9. 5.  
C o nc o mita nt Me dicati o ns: I nfecti o n S ur veilla nce a n d Pr o p h yla xis .......................... 5 4  
6.  
S T U D Y A S S E S S M E N T S  .......................................................................................... 5 5 
6. 1.  
Sc he d ule of E ve nts ..................................................................................................... 5 5  
6. 2.  
Assess me nts  ................................................................................................................ 6 3 
6. 2. 1.  
De m o gra p hics a n d Me di cal Hist or y ........................................................................... 6 3  
6. 2. 1. 1.  
Ge n ot y pe ..................................................................................................................... 6 3  
6. 2. 2.  
Cli nical/ P h ysical E xa mi nati o n  .................................................................................... 6 4 
6. 2. 3.  
Vital Si g ns  .................................................................................................................. 6 4 
6. 2. 4.  
Electr ocar di o gra m  ....................................................................................................... 6 4 
6. 2. 5.  
I ma gi n g ....................................................................................................................... 6 4 
6. 2. 6.  
P ul m o nar y F u ncti o n Tests .......................................................................................... 6 5  
6. 2. 7.  
Tra nsf usi o ns ................................................................................................................ 6 5  
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Pr ot oc ol H G B - 2 0 7 Versi o n 6. 0  
1 0 J u ne 2 0 2 1  
Pa ge 2 6 
 
6. 2. 8.  
I n-patie nt H os pitalizati o ns  .......................................................................................... 6 5 
6. 2. 9.  
He m o gl o bi n o pat h y Mar k ers i n Bl o o d ........................................................................ 6 5  
6. 2. 1 0.  
B o ne Marr o w a n d Bl o o d f or D yser yt hr o p oiesis St u dies ............................................ 6 5  
6. 2. 1 1.  
Testi n g f or Vect or C o p y N u m ber, I nte grati o n Site A nal ysis, a n d Re plicati o n 
C o m pete nt Le nti vir us ................................................................................................. 6 6  
6. 2. 1 2.  
B us ulfa n P har mac o ki neti cs ........................................................................................ 6 6  
6. 2. 1 3.  
Sa m ples f or St ora ge a n d P ote ntial Bi o mar ker A nal ysis ............................................. 6 6  
6. 2. 1 4.  
Fertilit y Preser v ati o n  .................................................................................................. 6 7 
6. 2. 1 5.  
Healt h -Relate d Q ualit y of Life Assess me nt  ............................................................... 6 7 
6. 2. 1 6.  
Cli nical La b orat or y Tests  ........................................................................................... 6 7 
6. 2. 1 6. 1.  
He mat ol o g y a n d Cli nical C he mistr y  .......................................................................... 6 8 
6. 2. 1 6. 2.  
D yser yt hr o p oiesis St u dies .......................................................................................... 6 8  
6. 2. 1 6. 3.  
Uri nal ysis  .................................................................................................................... 6 8 
6. 2. 1 6. 4.  
Pre g na nc y T esti n g ...................................................................................................... 6 9  
6. 2. 1 6. 5.  
Ser ol o g y ...................................................................................................................... 6 9  
6. 2. 1 6. 6.  
H or m o nal Testi n g ....................................................................................................... 6 9  
6. 2. 1 6. 7.  
Cli nical W or k - u p f or U n e x pecte d Bl o o d Test Res ults ............................................... 6 9 
6. 2. 1 7.  
I m m u n ol o gical T esti n g ............................................................................................... 6 9 
6. 2. 1 8.  
Assess me nt of Cl o nal Pre d o mi na nce a n d/ or S us pici o n of Mali g na nc y ..................... 7 0  
6. 2. 1 8. 1.  
Assess me nt of Cl o nal Pre d o mi na nce .......................................................................... 7 0  
6. 2. 1 8. 2.  
Cli nical W or k - u p f or P ot e ntial Mali g na nc y ............................................................... 7 2 
6. 2. 1 9.  
A d verse E v e nts  ........................................................................................................... 7 2 
6. 2. 1 9. 1.  
Assess me nts D uri n g t he St u d y ................................................................................... 7 2  
6. 2. 1 9. 2.  
A d verse E v e nts Defi niti o ns ........................................................................................ 7 3  
6. 2. 1 9. 3.  
A d verse E v e nt Assess me nt of Se verit y a n d Relati o ns hi p .......................................... 7 4  
6. 2. 1 9. 4.  
Pr oce d ures f or A E a n d S A E C ollecti o n a n d Re p orti n g .............................................. 7 5  
6. 2. 1 9. 5.  
I m me diat e Re p orti n g of S A Es .................................................................................... 7 5 
6. 2. 1 9. 6.  
Safet y Re p orti n g t o Re g ulat or y A ut h orities, Et hics C o m mittees, a n d 
I n v esti gat ors ................................................................................................................ 7 6 
6. 2. 1 9. 7.  
Pre g na nc y a n d C o ntrace pti o n ..................................................................................... 7 6  
6. 2. 2 0.  
U nsc he d ule d Visits ..................................................................................................... 7 7  
6. 2. 2 1.  
L o n g- ter m F oll o w- U p Pr ot oc ol .................................................................................. 7 7  
7.  
S T A TI S TI C A L P R O C E D U R E S  ................................................................................ 7 8 
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Pr ot oc ol H G B - 2 0 7 Versi o n 6. 0  
1 0 J u ne 2 0 2 1  
Pa ge 2 7 
 
7. 1.  
Sa m ple Size Esti mati o n  .............................................................................................. 7 8 
7. 2.  
P o p ulati o ns f or A nal ysis ............................................................................................. 7 8  
7. 3.  
Pla n ne d A nal yses ........................................................................................................ 7 9  
7. 3. 1.  
I nteri m A nal yses ......................................................................................................... 7 9 
7. 3. 2.  
Fi n al A nal yses  ............................................................................................................ 7 9 
7. 3. 3.  
A d diti o nal Data Re vie w  ............................................................................................. 7 9 
7. 3. 4.  
I m pact of t he C O VI D- 1 9 Pa n de mic ........................................................................... 7 9 
7. 4.  
Statistical Met h o ds  ...................................................................................................... 7 9 
7. 4. 1.  
Ge ner al Met h o ds  ......................................................................................................... 7 9 
7. 4. 2.  
Baseli ne Defi niti o ns  .................................................................................................... 7 9 
7. 4. 3.  
Dis p ositi o n of S u bjects ............................................................................................... 8 0  
7. 4. 4.  
De m o gra p hic a n d Baseli ne C haracteristics  ................................................................ 8 0 
7. 4. 5.  
Efficac y A nal ysis  ........................................................................................................ 8 0 
7. 4. 5. 1.  
A nal ysis of Pri mar y Effi cac y E n d p oi nt ...................................................................... 8 0  
7. 4. 5. 2.  
A nal ysis of Sec o n dar y Efficac y E n d p oi nts ................................................................ 8 1  
7. 4. 6.  
Safet y A nal ysis  ........................................................................................................... 8 2 
7. 4. 7.  
P har mac o d y na mic A n al yses  ....................................................................................... 8 3 
8.  
A D MI NI S T R A TI V E R E Q UI R E M E N T S  .................................................................. 8 4 
8. 1.  
G o o d Cli nical Practice  ................................................................................................ 8 4 
8. 2.  
Et hical C o nsi derati o ns ................................................................................................ 8 4  
8. 3.  
S u bject I nf or mati o n a n d I nf or me d C o nse nt ............................................................... 8 4  
8. 4.  
S u bject C o nfi de ntialit y  ............................................................................................... 8 4 
8. 5.  
Pr ot oc ol C o m plia nce .................................................................................................. 8 5  
8. 6.  
Direct Access t o S o urce Data  ..................................................................................... 8 5 
8. 7.  
Electr o nic Case Re p ort F or m C o m pleti o n  .................................................................. 8 5 
8. 8.  
Rec or d Rete nti o n  ........................................................................................................ 8 6 
8. 9.  
Lia bilit y a n d I ns ur a nce ............................................................................................... 8 6  
8. 1 0.  
P u blicati o n a n d Prese ntati o n of St u d y Fi n di n gs a n d Use of I nf or mati o n .................. 8 6  
9.  
R E F E R E N C E S  ........................................................................................................... 8 7 
1 0.  
A P P E N DI C E S  ............................................................................................................ 9 0 
1 0. 1.  
Gl o mer ular Filtrati o n Rate Calc ulati o n  ...................................................................... 9 0 
1 0. 2.  
Kar n ofs k y Perf or ma n ce Stat us Scale  .......................................................................... 9 1 
1 0. 3.  
La ns k y Perf or m a nce Stat us Scale  ............................................................................... 9 1 
C CI

Pr ot oc ol H G B - 2 0 7 Versi o n 6. 0  
1 0 J u ne 2 0 2 1  
Pa ge 2 8 
 
1 0. 4.  
G ui deli nes f or Tr a nsf usi o n V ol u me ........................................................................... 9 2  
I N V E S TI G A T O R S T A T E M E N T ................................................................................................. 9 3 
 
LI S T O F T A B L E S  
Ta ble  1: 
D ose of Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct or Bac k- u p Cells .................................... 3 8  
Ta ble  2: 
M o bilizati o n f or S u bjects w h o ha ve a n I ntact S plee n ................................................ 4 7  
Ta ble  3: 
M o bilizati o n f or S u bjects w h o d o n ot ha ve a n I ntact S plee n ..................................... 4 7  
Ta ble  4: 
Sc he d ule of E ve nts: Scr ee ni n g a n d C D 3 4 + Cell H ar vest ........................................... 5 6  
Ta ble  5: 
Sc he d ule of E ve nts: C o n diti o ni n g a n d Dr u g Pr o d uct I nf usi o n .................................. 5 8  
Ta ble  6: 
Sc he d ule of E ve nts: F oll o w- u p ................................................................................... 6 0  
Ta ble  7: 
A ge -a p pr o priate Vali date d H R Q o L T o ols .................................................................. 6 7 
Ta ble  8: 
He mat ol o g y, Ir o n St u dies, Ser u m C he mistr y, a n d Li ver F u n cti o n ............................ 6 8  
 
LI S T O F FI G U R E S  
 
C CI
C CI

Pr ot oc ol H G B - 2 0 7 Versi o n 6. 0  
1 0 J u ne 2 0 2 1  
Pa ge 2 9 
 
1.  
I N T R O D U C TI O N 
β -T halasse mia is a r are h ere ditar y bl o o d dis or der prese nt gl o ball y, i ncl u di n g i n t he U S  a n d E ur o pe, 
t hat is f o u n d m ost c o m m o nl y i n pers o ns of Me diterra nea n, Mi d dle East er n, I n dia n, a n d S o ut h 
Asia n desce nt (C ola h et al., 2 0 1 0 ). It is ca use d b y t he a bse n ce or re d u ce d pr o d ucti o n of t he β-
c hai ns of he m o gl o bi n ( H b) A ( H b A), a heter otetra mer c o m prise d of 2 β -gl o bi n a n d 2 α - gl o bi n 
c hai ns ( α 2β 2) t hat acc o u nts f or > 9 5 % of t he H b i n t he bl o o d of a d ults. O ver 2 0 0 m utati o ns i n t he 
ge ne  t hat  e nc o d es  β -gl o bi n ( H B B ) ha ve b ee n i d e ntifie d; t here are t w o H B B  alleles per di pl oi d 
ge n o me.  M utati o ns  t hat  res ult  i n  c o m plet e  a br o gati o n  of  pr o d ucti o n  of  β -gl o bi n  pr ot ei n  
(e. g., n o nse nse m utati o ns) are c ollecti vel y referre d t o as β 0 m utati o ns ( Ca o a n d Gala nell o, 2 0 1 0). 
M utati o ns t hat res ult i n re d ucti o n, b ut n ot c o m plete a bse n ce, of pr o d ucti o n of β -gl o bi n pr otei n 
(e. g., affecti n g s plici n g) are c ollecti vel y referre d t o as β +  m utati o ns. T here are s o m e β +  m utati o ns 
w hic h  pr o d uce  mi ni mal  β -gl o bi n;  i n  partic ular  t he  I V S  I -1 1 0  G A  m utati o n  ( H G V S  
n o me nclat ure: 
H B B :c. 9 3-2 1 G > A)  c o nsiste ntl y  res ults  i n  dra maticall y  re d uce d  β - gl o bi n 
pr o d ucti o n, a n d is  c o m m o nl y gr o u pe d cli nicall y wit h β 0 m utati o ns (B or g na- Pi g natti a n d Gala nell o, 
2 0 0 9 ).  βE  is a s p ecific H B B  m utati o n i n t he c o di n g re gi o n of t h e ge n e t hat res ults i n re d u ce d 
pr o d ucti o n  of  β -gl o bi n  beca use  of  alter n ate s plici n g,  as  w ell  as  a si n gle a mi n o  aci d  c h a n ge  
( misse nse m utati o n, gl uta mic aci d t o l ysi ne at  c o d o n 2 6), res ulti n g i n a n electr o p h oreticall y  
disti n g uis ha ble  heter otetra mer,  h e m o gl o bi n  E  ( H b E).  T he  β E m utati o n is c o m m o n i n S o ut heast 
Asia ( 1 5 % t o 3 0 % pr e val e nce of m utati o n i n t he t otal p o p ulati o n) ( Be nz,  2 0 1 5).  
A bs e nce or re d ucti o n i n β -gl o bi n pr o d ucti o n res ults i n a n acc u m ulati o n of e xcess u nc o m ple x e d α -
gl o bi n c hai ns i n er yt hr o blasts, w hic h preci pitate, lea di n g t o pre mat ure d eat h of t he cells a n d  
i neffecti ve er yt hr o p oiesis t hat ca uses t he a ne mi a c haracteristic of patie nts  wit h  β -t halasse mia 
(Gala nell o a n d Ori g a, 2 0 1 0 ).  T he  cli nical  i m plicati o ns  of  t he  α‑ gl o bi n/ β‑ gl o bi n  i m bala nce  are 
t w of ol d: 1) p atie nts lac k s ufficie nt r e d bl o o d cells ( R B Cs) a n d H b t o effecti vel y tra ns p ort o x y ge n 
t hr o u g h o ut t he b o d y; a n d 2) ele vate d he m ol ysis ca n lea d t o m or bi dities via s ple n o me gal y, marr o w 
e x pa nsi o n, c o nc o mita nt b o ne def or mities, a n d ir o n o verl oa d. Patie nts w h o are h o m oz y g o us f or 
m utati o ns t hat are β 0 (i.e., β 0/ β0 ge n ot y pe) pr o d uce n o β -gl o bi n, a n d he nce us uall y cli nicall y prese nt 
wit h  se vere  tr a nsf usi o n -de pe n de nt  β -t halass e mia  ( T D T),  als o  calle d  β-t halasse mia  maj or.  I n  
c o ntrast, patients w h o are h o m oz y g o us f or β + allel es, or are c o m p o u n d heter oz y g o us f or β 0, β+ , or 
β E (i.e., β0/ β+ , β0/ βE , β+ / βE ge n ot y pes) ge n erall y pr o d uce s o me e n d o ge n o us β -gl o bi n, a n d ma y h a ve 
a s pectr u m of cli nical se v erit y, ra n gi n g fr o m se v ere T D T t o mil der f or ms of t halasse mia.  
C hr o nic bl o o d tra nsf usi o n re gi me ns are hi g hl y effecti ve at pre v e nti n g t he hall mar k s y m pt o ms of 
disease, b ut i ntr o d u ce a l ar ge ir o n o verl oa d (Ca o et al., 1 9 9 6 ) t hat o v er ti m e ca n lea d t o m ortalit y 
t hr o u g h ir o n ass o ciate d h eart a n d li ver t o xicit y ( Vic hi ns k y et al., 2 0 0 5a; Vi c hi ns k y et al., 2 0 0 5 b) 
a n d m ust be ma na ge d usi n g ir o n c helati o n re gi m e ns ( Ca p pelli ni et al., 2 0 0 6 ). P o or c o m plia nce 
wit h c helati o n re gi me ns r e mai ns a ke y c halle n ge, a n d e ve n wit h c urre nt t hera pies, o verall s ur vi v al 
u ntil t he a ge of 3 0 y ears is o nl y 5 5 % f or patie nts wit h se vere T D T ( M o d ell et al. 2 0 0 0; Delea et 
al. 2 0 0 7).  
All o ge neic he m at o p oieti c ste m cell tra ns pla nt (all o -H S C T) is c urre ntl y t he o nl y a vaila ble c urati ve 
treat me nt f or patie nts wit h T D T. H o we ver, beca use of t he si g nifica nt ris k of tra ns pla nt-relat e d 
m ortalit y, graft - vers us-h ost disease ( G V H D), a n d graft rejecti o n wit h all o‑ H S C T, tra ns pla nts are 
i nfre q ue ntl y perf or me d, a n d are offere d pri maril y t o patie nts wit h a vaila ble h u ma n le u k oc yte 
a nti ge n ( H L A)- matc h e d si bli n g d o n ors ( < 2 5 % of cases).  
C CI

Pr ot oc ol H G B - 2 0 7 Versi o n 6. 0  
1 0 J u ne 2 0 2 1  
Pa ge 3  
 
T he a bs e nce of s uita ble d o n ors, t he si g nifica nt ris ks of tra ns pl a ntati o n, a n d t he re q u ire me nt f or 
p ost- tra ns pla nt i m m u n os u p pressi o n t hera p y t o pre ve nt G V H D i n dicate u n m et me dical nee ds, e ve n 
wit h all o - H S C T, f or patie nts wit h T D T. 
I n or d er t o a d dress t his u n met me dical nee d, bl ue bir d bi o is i n vesti gati n g t he use of Le nti Gl o bi n 
B B 3 0 5 Dr u g Pr o d uct f or t he treat me nt of β -t halasse mia (I N N/U S A N: beti be gl o ge ne a ut ote mcel ) 
i n s u bjects wit h T D T. 
T he B B 3 0 5 le nti viral vect or e nc o des a si n gle a mi n o aci d varia nt of β -gl o bi n, β A‑ T 8 7 Q ‑ gl o bi n, w hic h 
c o nser ves t he pr otei n’s f u ncti o n w hile all o wi n g f or q ua ntificati o n relati ve t o ot her gl o bi n s pecies. 
E x pressi o n of β A‑ T 8 7 Q ‑ gl o bi n is dri ve n b y t h e er yt hr oi d li nea ge s p ecific gl o bi n l oc us c o ntr ol re gi o n 
( L C R) t o c orrect t he β-gl o bi n/ α - gl o bi n i m bala nce i n er yt hr oc ytes. Treat me nt of t he s u bject’s o w n 
H S Cs wit h t he B B 3 0 5 le nti viral vect or t hr o u g h tra ns d ucti o n s h o ul d eli mi nate t he ris k of G V H D 
a n d graft r ejecti o n a n d a v oi d t he nee d f or l o n g ter m i m m u n os u p pressi o n.  
As of 0 3 Mar c h 2 0 2 0, 2 3 s u bjects ha ve b ee n treate d i n St u d y H G B- 2 0 7. Ei g ht s u bje cts were < 1 2 
years of a ge, 6 s u bjects w ere ≥ 1 2 t o <  1 8 y ears of a ge, a n d 9 s u bjects were ≥ 1 8 years of a ge. D ata 
f or t he s u bj ects e nr olle d i n t his st u d y are pr o vi de d i n t he I n v esti gat or's Br oc h ure f or L e nti Gl o bi n 
B B 3 0 5 Dr u g Pr o d uct.  
T he  safet y  pr ofile  o f  Le nti Gl o bi n  B B 3 0 5  Dr u g  Pr o d uct  is  c o nsiste nt  wit h  m yel oa blati ve  
c o n diti o ni n g use d f or a ut ol o g o us tra ns pla ntati o n (see I n vesti gat or’s Br oc h ure).  
Ta ke n t o get her, t hese dat a de m o nstrate t he p ot e ntial of treat me nt wit h Le nti Gl o bi n B B 3 0 5 Dr u g 
Pr o d uct t o re d u ce or eli mi nate t he re q uire me nt f or R B C tra nsf usi o ns f or patie nts wit h T D T.  
2.  
S T U D Y O B J E C TI V E S A N D E N D P OI N T S   
2. 1.  
St u d y O bjecti ves  
Pri m ar y:  e val u ate t he efficac y of treat me nt wit h Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct i n s u bjects 
≤5 0 years of a ge wit h T D T w h o d o n ot ha ve a β 0/ β0 ge n ot y pe at t he H B B  ge ne 
C
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Sec o n d ar y: e val uate t h e safet y of treat me nt wit h Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct i n s u bjects 
≤5 0 years of a ge wit h T D T w h o d o n ot ha ve a β 0/ β0 ge n ot y pe at t he H B B  ge ne.  
2. 2.  
St u d y E n d p oi nts  
2. 2. 1.  
Effic ac y E n d p oi nts  
Pri m ar y E n d p oi nt  
T he pr o p orti o n of s u bj ects w h o meet t he defi niti o n of “tra nsf usi o n i n d e pe n de nce” ( TI). TI is 
defi ne d as a wei g hte d a v era ge H b ≥9  g/ d L wit h o ut a n y p R B C tra nsf usi o ns f or a c o nti n u o us peri o d 
of ≥1 2 m o nt hs at a n y ti me d uri n g t he st u d y after dr u g pr o d uct i nf usi o n.  
Sec o n d ar y E n d p oi nts  
•  C haracterizati o n of s u bjects ac hie vi n g TI:  
− Pr o p orti o n of s u bjects w h o meet t he defi niti o n of TI at M o nt h 2 4 
− D urati o n of TI 
− Ti me fr o m dr u g pr o d uct i nf usi o n t o ac hie ve me nt of TI 
− Wei g hte d a v era g e H b d uri n g TI  
•  C haracterizati o n of tr a nsf usi o n re d ucti o n ( T R): 
− Pr o p orti o n of s u bjects wit h a re d u cti o n i n t he a n n u alize d m L/ k g p R B Cs tra nsf use d 
fr o m 1 2 m o nt hs p ost -dr u g pr o d uct i nf usi o n t hr o u g h M o nt h 2 4 (a p pr o xi matel y a 1 2 -
m o nt h peri o d) of at least 5 0 %, 6 0 %, 7 5 %, 9 0 % or 1 0 0 % c o m pare d t o t he a n n ualize d 
m L/ k g p R B C tra nsf usi o n re q uire me nt d uri n g t he 2 years pri or t o e nr oll me nt 
− A n n ualize d n u m ber a n d v ol u me of p R B C tra nsf usi o ns fr o m 1 2  m o nt hs p ost - dr u g 
pr o d uct  i nf usi o n  t hr o u g h  M o nt h  2 4  c o m pare d  t o  t he  a n n ualize d  n u m b er  a n d  
v ol u me of tra nsf usi o ns d uri n g t he 2 years pri or t o e nr oll me nt 
− Ti me fr o m dr u g pr o d uct i nf usi o n t o last p R B C tra nsf usi o n 
− Ti me fr o m last p R B C tra nsf usi o n t o M o nt h 2 4  
•  Wei g hte d  a v era g e  na dir  H b  d uri n g  t he  2  years  pri or  t o  e nr oll me nt  c o m pare d  t o  
wei g hte d  a vera ge  n a dir  H b  fr o m  1 2  m o nt hs  p ost -dr u g  pr o d uct  i nf usi o n  t hr o u g h  
M o nt h 2 4 
•  U ns u p p orte d t otal H b le v els o ver ti me, i ncl u di n g M o nt h 6, M o nt h 9, M o nt h 1 2, M o nt h 
1 8, a n d M o nt h 2 4 
•  U ns u p p orte d t otal H b le vels ≥1 0  g/ d L, ≥1 1  g/ d L, ≥1 2  g/ d L, ≥1 3  g/ d L, ≥1 4  g/ d L o ver 
ti me, i ncl u di n g M o nt h 6, M o nt h 9, M o nt h 1 2, M o nt h 1 8, a n d M o nt h 2 4 
•  C haracterizati o n of use of ir o n c h elati o n a n d/ or t hera pe utic p hle b ot o m y a m o n g all 
s u bjects: 
− Pr o p orti o n of s u bjects w h o ha ve n ot recei ve d ir o n c helati o n t hera p y f or at least 6 
m o nt hs f oll o wi n g dr u g pr o d uct i nf usi o n 
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− Ti me fr o m last ir o n c helati o n use t o last f oll o w - u p 
− Pr o p orti o n of s u bjects usi n g t hera pe utic p hle b ot o m y a n d a n n ualize d fre q u e nc y of 
p hle b ot o m y use per s u bject f oll o wi n g dr u g pr o d u ct i nf usi o n 
•  E val uati o n of t he c h a n ge i n ir o n b ur de n o ver ti me, as meas ure d b y:  
− C ha n ge i n li ver ir o n c o nt e n t b y ma g netic res o na n ce i ma gi n g ( M RI) at b as eli ne t o 
M o nt h 1 2 a n d M o nt h 2 4 
− C ha n ge i n car di ac T 2 * o n M RI at b aseli ne t o M o nt h 1 2 a n d M o nt h 2 4 
− C ha n ge i n ser u m ferriti n at baseli ne t o M o nt h 1 2 a n d M o nt h 2 4 
•  E val uati o n of h ealt h -r elat e d q ualit y of life ( H R Q o L) o ver ti me i ncl u di n g M o nt h 1 2 a n d 
M o nt h 2 4 as c o m pare d t o baseli ne, usi n g t he f oll o wi n g vali date d t o ols: 
− Pe diatrics: Pe diatric Q ualit y of Life I n ve nt or y ( P e ds Q L; pare nt ge neral c ore a n d 
ge neral c ore)  
− A d olesce nts:  Pe ds Q L  ( p are nt  ge n eral  c ore  a n d  ge neral  c or e)  a n d  E ur o Q ol -5 D 
( Y o ut h versi o n) ( E Q- 5 D-Y)  
− A d ults: E ur o Q ol -5 D ( E Q -5 D), F u ncti o nal Ass ess me nt of Ca ncer T hera p y - B o ne 
Marr o w Tra ns pla nt ( F A C T- B M T), a n d S h ort F or m- 3 6 ( S F- 3 6) v 2  
2. 2. 2.  
S afet y E n d p oi nts  
Sec o n d ar y E n d p oi nts  
•  S uccess a n d ki netics of H S C e n graft me nt  
•  I n ci de nce  of  tra ns pla nt-relate d  m ortalit y  t hr o u g h  1 0 0  da ys  a n d  t hr o u g h  3 6 5  da ys  
p ost- dr u g pr o d uct i nf usi o n 
•  O verall s ur vi val ( O S) 
•  Detecti o n of vect or- d eri v e d re plicati o n c o m p ete nt le nti vir us ( R C L) i n a n y s u bject 
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•  M o nit ori n g of la b orat or y para mete rs 
•  Fre q u e nc y a n d se verit y of cli nical A Es  
•  I n ci de nce of ac ute a n d/ or c hr o nic graft- vers us-h ost disease ( G V H D)  
•  T he  n u m ber  of  s u bjects  wit h  i nserti o nal  o nc o ge nesis  ( m yel o d ys plasia,  le u ke mia,  
l y m p h o ma, etc.)  
E x pl or at or y E n d p oi nt 
•  T he n u m ber of s u bjects wit h cl o nal pre d o mi na nce (see Secti o n  6. 2. 1 8  f or descri pti o n 
of criteria f or cl o n al pre d o mi na nce a n d cli nical w or k - u p of mali gna nc y)  
2. 2. 3.  
P h ar m ac o d y n a mic E n d p oi nts 
Sec o n d ar y E n d p oi nts  
•  β A‑ T 8 7 Q ‑ gl o bi n e x pressi o n o ver ti me, i ncl u di n g M o nt h 6, M o nt h 9, M o nt h 1 2, M o nt h 1 8, 
a n d M o nt h 2 4, as meas ure d b y assessi n g t he rati o of β A‑ T 8 7 Q ‑ gl o bi n t o all β-li ke- gl o bi ns, 
a n d α‑ gl o bi n t o all β‑li ke‑ g l o bi ns, i n w h ole bl o o d 
− C orrelati o n  of  β A- T 8 7 Q -gl o bi n e x pressi o n at earl y ti me p oi nts p ost -dr u g pr o d uct 
i nf usi o n  t o  βA- T 8 7 Q -gl o bi n  e x pressi o n  at  later  ti me  p oi nts,  as  well  as  cli nical  
o utc o mes. 
•  V C N i n peri p h eral bl o o d o ver ti me, i ncl u di n g M o nt h 6, M o nt h 9, M o nt h 1 2, M o nt h  1 8, 
a n d M o nt h 2 4 
E x pl or at or y E n d p oi nt 
•  Relati o ns hi p bet wee n meas ures of m yel oa bl ati o n a n d p har mac o d y na mics a n d cli nical 
o utc o mes 
A d diti o nall y, e x pl orat or y met h o ds ma y be use d t o e val uate p h ar mac o d y n a mic e n d p oi nts. 
 
 
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3.  
I N V E S TI G A TI O N A L P L A N 
3. 1.  
O ver all Desi g n a n d Pl a n of t he St u d y  
T his is a si n gle -ar m, m ultisite, si n gle -d ose, P hase 3 st u d y wit h 2 c o h orts of s u bjects wit h T D T 
w h o d o n ot ha ve a β 0 m utati o n at b ot h alleles of t he β - gl o bi n (H B B ) ge ne (i.e., n o n-β 0/ β0): C o h ort 1 
i ncl u des at least 1 5 s u bjects ≥1 2 a n d ≤5 0 years of a ge, a n d C o h ort 2 i ncl u des at least 8 s u bjects 
< 1 2 years of a g e.  
T he st u d y will e val uate t he efficac y a n d safet y of a ut ol o g o us he mat o p oietic ste m cell ( H S C) 
tra ns pla ntati o n  ( H S C T)  usi n g  Le nti Gl o bi n  B B 3 0 5  Dr u g  Pr o d uct,  a n  a ut ol o g o us  C D 3 4 +  
cell‑e nri c he d p o p ulati o n t hat c o ntai ns he mat o p oietic ste m cells tra ns d uce d wit h B B 3 0 5 le nti viral 
vect or e n c o di n g t he β A- T 8 7 Q - gl o bi n ge ne, s us pe n de d i n cr y o preser vati o n s ol uti o n. 
S u bjects  ≥1 2  a n d  ≤5 0  years  of  a ge m ust ha ve T D T wit h a hist or y of tra nsf usi o n of at least 
1 0 0 m L/ k g/ year of p R B Cs i n t he 2 y ears prece di n g e nr oll me nt, or  be m a na ge d u n der sta n dar d 
t halasse mia g ui deli nes (e. g., T halasse mia I nter nati o nal Fe derati o n, 2 0 1 4; see A p pe n di x 1 0. 4 ) wit h 
≥8  tra nsf usi o ns  of  p R B Cs  per  year  i n  t he  2  years  prece di n g  e nr oll me nt  (s u bjects  ≥1 2  years; 
Rac h mile witz a n d Giar di n a, 2 0 1 1). S u bjects < 1 2 years of a ge m ust ha ve a hist or y of tra nsf usi o n 
of at least 1 0 0  m L/ k g/ year of p R B Cs i n t he 2 years prece di n g e nr oll me nt. I n a d diti o n t o ha vi n g a 
hist or y of tra nsf usi o n of at least 1 0 0  m L/ k g/ year of p R B Cs i n t he 2 years prece di n g e nr oll me nt, 
s u bjects < 5 years of a ge m ust wei g h a mi ni m u m of 6 k g a n d reas o n a bl y be a ntici pate d t o be a ble 
t o pr o vi de at least t he mi ni m u m n u m ber of cells re q uire d t o i nitiate t he ma n ufact uri n g pr o cess.  
Treat me nt will pr ocee d i n a sta g g ere d fas hi o n. After 2 s u bjects ≥1 2 y ears of  a ge h a ve  attai ne d 
ne utr o p hil  e n gr aft me nt  after  Le nti Gl o bi n  B B 3 0 5  Dr u g  Pr o d u ct  i nf usi o n  i n  C o h ort  1,  t he  
i n de pe n de nt Data M o nit ori n g C o m mittee ( D M C) will re vie w t heir safet y data a n d deter mi ne 
w het her t he st u d y ca n saf el y pr ocee d wit h t he treat me nt of s u bjects ≥5 a n d < 1 2 years of a g e. After 
at least 2 s u bjects ≥5 a n d < 1 2 years of a ge h a ve att ai ne d ne utr o p hil e n graft me nt after Le nti Gl o bi n 
B B 3 0 5 Dr u g Pr o d uct i nf usi o n t he D M C will re vie w t heir safet y data a n d deter mi ne w het her t he 
st u d y ca n safel y pr o cee d wit h t he treat me nt of s u bjects y o u n ger t h a n 5 years of a ge. S u bjects < 1 2 
years of a ge ma y o nl y be e nr olle d at sites wit h re g ulat or y a p pr o val f or t he s pecifie d a g e ra n ge. 
T he st u d y has 4 disti nct sta ges, as f oll o ws.  
St a ge 1: Scree ni n g t o deter mi ne eli gi bilit y f or treat me nt  
S u bjects wit h pre vi o usl y k n o w n β 0/ β0 ge n ot y pes s h o ul d n ot e nter Scree ni n g.   
F or t he p ur p oses of s cree ni n g, t he H B B  m utati o n I V S I -1 1 0 ( G A) will be c o nsi dere d e q ui v ale nt 
t o a β0 m utati o n. S u bjects wit h T D T w h o are d oc u me nte d t o ha ve ot her H B B  ge n ot y pes (i.e., 
n o n- β 0/ β0) ma y e nter Scree ni n g. T h e H B B  g e n ot y pe f or all s u bj ects will be c o nfir me d d uri n g 
Scree ni n g al o n g wit h a d diti o nal para meters of eli gi bilit y.  
St a ge 2:  A ut ol o g o us C D 3 4 + cell c ollecti o n, Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct ma n ufact ure a n d 
dis p ositi o n  
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Eac h s u bject will u n der g o H S C m o bilizati o n wit h a gra n ul oc yte -c ol o n y sti m ulati n g fact or ( G -C S F; 
e. g., fil grasti m, le n o grasti m) a n d pleri xaf or. Peri p heral bl o o d m o n o n uclear cells ( P B M Cs) will be 
c ollecte d b y a p her esis.  A t otal of 2 m o bilizati o n c ycles ma y be perf or me d if nee de d a n d eac h 
m o bilizati o n c ycle ma y i ncl u de u p t o 3 a p heresis da ys. H o we ver, s u bjects w h ose dr u g pr o d uct 
fails t o meet s pecificati o ns f or a n y reas o n ma y u n der g o re peat a p heresis a n d ma n ufact ure of n ew 
dr u g pr o d uct. A p h eresis pr o d ucts ca n als o be use d f or res c ue cells; alter nati vel y, a b o ne marr o w 
har vest is als o all o we d t o pr oc ure cells f or resc u e.  
St a ge 3: M yel oa blati ve c o n diti o ni n g ( 4 da ys of c o n diti o ni n g f oll o we d b y at least 4 8 h o urs of 
was h o ut) a n d i nf usi o n of Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct ( Da y 1)  
After t he tra ns d uce d cells are dis p ositi o ne d f or cli nical use, a n d t he s u bject's eli gi bilit y has bee n 
re-c o nfir me d ( b y cli nical la b orat or y tests, p h ysical e xa mi nati o n, perf or ma nce stat us, A E re vie w 
a n d ot her  tests  base d  o n  i nstit uti o nal  re q uire me nts),  t he  s u bject  will  u n der g o  m yel oa bl ati ve  
c o n diti o ni n g wit h b us ulfa n.  
After c o m pleti o n of t he 4 -da y c o urse of b us ulfa n, t here m ust be a mi ni m u m of 4 8 h o urs of was h o ut 
bef ore dr u g pr o d uct i nf usi o n.  
O n st u d y Da y 1, t ha we d Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct will be a d mi nistere d via i ntra ve n o us 
(I V) i nf usi o n at a d ose of ≥5. 0 × 1 06 C D 3 4 + cells/ k g.  
St a ge 4:  F oll o w- u p, t hr o u g h e n graft me nt a n d u p t o 2 4 m o nt hs after dr u g pr o d uct i nf usi o n 
S u bjects will be f oll o we d dail y i n  t he tra ns pla nt u nit f or A Es, a n d la b orat or y para met ers will be 
f oll o we d t o m o nit or b o ne marr o w e n graft me nt. T h e s u bject will be disc h ar g e d fr o m t he tra ns pla nt 
u nit o nce t he s u bject is c o nsi dere d me dicall y sta ble. 
T he g oal d uri n g t he f oll o w -u p peri o d is t o  mai ntai n H b ≥9 g/ d L. Tra nsf usi o ns s h o ul d be a v oi d e d 
f or H b ≥9 g/ d L u nless t he nee d is me dicall y j ustifie d (e. g., as a pre-re q uire me nt f or s ur ger y). It is 
rec o m me n de d t hat s u bjects s h o ul d recei ve R B C tra nsf usi o ns f or H b < 7 g/ d L, a n d f or cli nicall y 
s y m pt o matic a ne mia, irres pecti ve of H b le v el. 
S u bjects will be f oll o we d i n t his pr ot oc ol f or a peri o d of 2 4  m o nt hs after L e nti Gl o bi n B B 3 0 5 Dr u g 
Pr o d uct i nf usi o n. T her eafter s u bjects will be e x pecte d t o e nr oll i n a se parat e l o n g‑ter m f oll o w‑ u p 
pr ot oc ol ( L T F -3 0 3) t hat will assess safet y a n d efficac y be y o n d M o nt h 2 4 f or a t otal of 1 5  years 
after dr u g pr o d uct i nf usi o n. T he e n d of St u d y H G B -2 0 7 will be d efi ne d as t h e last visit f or t he last 
s u bject. 
3. 2.  
D at a M o nit ori n g C o m mittee  
A n i n de pe n de nt Data M o nit ori n g C o m mittee ( D M C) c o m prise d of me m bers wit h a p pr o priate 
scie ntific a n d me di cal e x pertise t o m o nit or t he st u d y will be c o n ve n e d bef ore t he first patie nt is 
m o bilize d. A c harter d escri bi n g t he c o m p ositi o n a n d c o n d uct of t h e D M C will be iss ue d a n d a gree d 
t o b y all D M C me m bers pri or t o t he D M C’s i nitial safet y re vie w meeti n g.  
T he D M C will b e c h ar g e d wit h r e vie w of all safet y data f or t his st u d y, i ncl u di n g A Es, seri o us 
a d verse e v e nts ( S A Es) a n d rele v a nt la b orat or y v al ues. I n a d diti o n, t he D M C will be c har g e d wit h 
re vie w of saf et y data t o d eter mi ne w h et her t he st u d y ca n safel y pr ocee d wit h treat me nt of s u bjects 
< 1 2 years a n d < 5 y ears of a ge (ref er t o Secti o n  3. 1 ). 
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T he D M C will ha ve t he ri g ht t o rec o m me n d halti n g t he st u d y at a n y ti me d ue t o c o ncer ns f or t he 
safet y of t he s u bjects ( R efer t o Secti o n 3. 5. 2  for t he e nr oll me nt s us pe nsi o n criteria), h o w e ver all 
fi nal decisi o ns re g ar di n g st u d y c o n d uct re mai n wit h t he S p o ns or. 
3. 3.  
R ati o n ale f or t he St u d y Desi g n  
T D T re q uires lifel o n g treat me nt wit h c hr o nic bl o o d tra nsf usi o ns a n d d oes n ot s p o nta ne o usl y 
res ol ve. S uccessful treat me nt i n c hil d h o o d has t h e p ote ntial t o pre ve nt m or bi dities ge nerall y s ee n 
later i n life. T he dia g n osis of T D T is fre q u e ntl y ma de i n t he first year of life w he n i nfa nts b ec o me 
s y m pt o matic, b ut re gar dl ess of w h e n t he dia g n osis is ma de, eac h s u bject s h o ul d e nter t his st u d y 
wit h a sta ble pr ofile of tra nsf usi o n de p e n de nc y. F oll o wi n g treat me nt wit h Le nti Gl o bi n B B 3 0 5 
Dr u g Pr o d uct, it is a ntici pate d t hat t here will be a n i ncrease i n t he a m o u nt of e n d o ge n o us H b 
pr o d uce d, l ea di n g t o a c orres p o n di n g re d ucti o n or eli mi nati o n of tra nsf usi o n nee d t hat ca n be 
rea dil y  q ua ntifie d  a n d  c o m pare d  a g ai nst  t he  s u bject’s  o w n  pre-treat me nt  tra nsf usi o n  pr ofile.  
T heref ore,  bec o mi n g  tra nsf usi o n  i n de pe n de nt  ( pri mar y  efficac y  e n d p oi nt),  or  e x perie nci n g  a  
si g nifica nt re d u cti o n i n t he v ol u me of tra nsf usi o ns (sec o n d ar y effi cac y e n d p oi nt), is e x pecte d t o 
re pres e nt t he m ost cli nicall y mea ni n gf ul e ve nt i n patie nts wit h T D T. B ot h TI a n d si g nifica nt T R 
are li kel y t o res ult i n m ulti ple cli nical be nefits f or patie nts, i ncl u di n g m ost salie nt l y, l o n g-ter m 
re d ucti o n of ir o n b ur de n, as well as r e d uce d e x p os ure t o p ote ntial c o m plicati o ns of tra nsf usi o n 
t hera p y ( e. g. tra nsf usi o n reacti o ns, all o-i m m u nizati o n, i nfecti o n wit h bl o o d b or ne pat h o ge ns). 
Data fr o m P hase 1/ 2 St u dies H G B -2 0 4 a n d H G B -2 0 5 s u g geste d t hat s u bjects wit h T D T w h o  were 
n ot h o m oz y g o us f or β 0 alleles (i.e., h a d n o n -β 0/ β0 ge n ot y pes) w ere m ost li kel y t o ac hi e ve TI  aft er 
e n graft me nt. T h us, t he c urre nt pr ot oc ol, w hic h h as a pri mar y e n d p oi nt of TI, will o nl y e nr oll 
s u bjects w h o d o n ot h a v e a β 0/ β0 ge n ot y pe. T his ma y i ncl u de s u bjects wit h ge n ot y pes of β 0/ β+ , 
β 0/ βE , β+ / β+ , a n d β+ / βE . Fr o m a p h ysi ol o gic pers pecti ve, s u bjects wit h at least o ne β+  or β E  allele 
pr o d uce s o me e n d o ge n o us β -gl o bi n, w hic h alt h o u g h b y itself is i ns ufficie nt t o s ustai n life, w he n 
s u p ple me nte d b y tra ns d uce d 
 ma y be s ufficie nt t o ac hi e ve TI. I n c o ntrast, tra ns d uce d 
 le vels  ac hie ve d  i n  St u dies  H G B-2 0 4  a n d  H G B -2 0 5  w ere  pre dicte d  t o  re d u ce  t he  
re q uire me nt  f or tra nsf us e d bl o o d i n patie nts w h o d o n ot  pr o d uce a n y of  t heir  o w n  β- gl o bi n 
(i.e., β 0/ β0), b ut ma y n ot s ustai n TI. Si milar t o β0 alleles, t he β + allele I V S -I- 1 1 0 ( GA) is wi del y 
rec o g nize d as pr o d uci n g little t o n o β- gl o bi n (B or g na- Pi g natti a n d Gala nell o, 2 0 0 9 ), t h us s u bjects 
wit h  β 0/I V S-I-1 1 0 or I V S -I- 1 1 0/I V S-I-1 1 0  ge n ot y pes  were  gr o u p e d  wit h  t he  β 0/ β0 s u bjects i n 
St u d y H G B- 2 1 2.  
H B B  m utati o ns ha ve bee n st u die d f or e x pressi o n of β -gl o bi n a n d t heir cate g oriz ati o n i nt o β 0 or 
β + m utati o ns ha ve bee n catal o g ue d i n m ulti ple c orr o b orati ve s o urces, s uc h as: 
•  A Syll a b us of H u m a n He m o gl o bi n V ari a nts  (H uis ma n et al., 1 9 9 6 ) 
•  A Syll a b us of T h al asse mi a M ut ati o ns  (H uis ma n et al., 1 9 9 7 ) 
•  Cre ati n g a n I nter net -B ase d D at a b ase of Bet a T h al asse mi a M ut ati o ns , Sa n J ose State 
U ni versit y Master’s T h esis, Sc h olar W or ks. ( G e or ge, 2 0 0 8 ) 
T he  o n -li ne  catal o g u e  w hic h  will  be  utilize d  f or  t his  st u d y  is  t he  gl o bi n  ge ne  s er ver  
htt p:// gl o bi n. b x. ps u.e d u/  (Har dis o n et al., 2 0 0 1 ). 
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Beca use eac h s u bj ect’s p retreat me nt sta ble tra nsf usi o n pr ofile is t he m ost s uita ble c o m parat or f or 
cli nical i m pr o ve me nt after treat me nt, a n d beca us e meas uri n g 
 i n peri p heral bl o o d all o ws 
direc t  e val u ati o n  of  pr otei n  e x pressi o n  a n d  p ot e ntial  c orrel ati o n  wit h  cli nical  o utc o me,  n o  
u ntreate d c o ntr ol gr o u p is i ncl u de d i n t his st u d y. F urt her m ore, beca use of t he p ote ntial t o xicit y of 
b us ulfa n, it w o ul d n ot be et hical t o i ncl u de a c o ntr ol gr o u p t hat d oes n ot recei ve Le nti Gl o bi n 
B B 3 0 5 Dr u g Pr o d uct treat me nt i n t his P hase 3 o pe n- la bel st u d y. 
S u bjects  wit h  H L A -matc he d  fa mil y  d o n ors  are  e xcl u de d  fr o m  t his  st u d y,  as  t hese  s u bjects  
ge nerall y h a ve b etter o ut c o mes i n all o -H S C T t ha n d o s u bjects wit h o ut H L A -matc he d relate d H S C 
d o n ors.  
T his st u d y was e x pa n d e d t o i ncl u de s u bjects y o u n g er t ha n 1 2 y ears of a g e base d o n pre vi o us res ults 
t hat t his treat me nt was w ell-t olerate d i n a d olesce nts. As of 2 6 A u g ust 2 0 1 6, a t otal of 2 2 s u bjects 
wit h T D T a g e d bet w ee n 1 2 a n d 3 5 y ears (i ncl u di n g 5 a d oles ce nts of 1 2, 1 6, 1 6, 1 6,  a n d 1 7 years 
of a ge) ha ve bee n i nf use d wit h Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct. D uri n g a varia ble f oll o w - u p 
peri o d of 6 m o nt hs t o al m ost 3 years, n o ne of t he s u bjects ha ve e x perie nce d seri o us dr u g - pr o d uct 
relate d a d v erse e v e nts ( A Es), or dr u g pr o d uct-relat e d A Es greater t ha n Gra d e 1. All s u bjects ha ve 
e n graft e d a n d e x pr ess 
 wit h varia ble re d u cti o n i n tra nsf usi o n-re q uireme nts a n d/ or TI. I n 
a d diti o n, it is i m p orta nt t o st u d y pe diatric s u bjects beca use p atie nts tra ns pla nte d at y o u n ger a g es 
bef ore  a d va n ce d  disease  s y m pt o ms  of  t halasse mia  are  ma nifeste d  are  h y p ot hesize d  t o  ha v e  
differe nt  rat es  of  tra ns pla nt -relate d  c o m plicati o ns,  differe nt  l o n g-ter m  disease  o utc o m es,  a n d  
p ote ntiall y differe nt efficac y of ge n e tra ns d u cti o n t ha n a d ult patie nts. 
I n St u d y H G B-2 0 7, tr eat me nt of s u bjects y o u n ger t ha n 1 2 will be perf or m e d i n a sta g gere d fas hi o n 
wit h safet y m o nit ori n g.  
T he s h ort -ter m ris ks ass ociate d wit h m yel oa blati o n are li kel y of a lesser ma g nit u de i n pe diatric 
s u bjects as o p p ose d t o a d ults d ue t o t heir b etter or ga n f u ncti o ns a n d l o wer ir o n o verl oa d, a n d are 
als o  li kel y  t o  be  of  a  lesser  ma g nit u de  t ha n  t he  o verall  ris ks  ass o ciate d  wit h  all o ge n eic  
tra ns pla ntati o n, w hic h is re g ularl y offere d t o c hil dre n wit h T D T i n t his a ge gr o u p ( < 1 2 years of 
a ge) wit h a n H L A - matc h e d si bli n g d o n or. All o ge neic b o ne marr o w tra ns pla nt ( B M T) is c urre ntl y 
rec o m me n de d i n y o u n g c hil dre n bef ore t he de vel o p me nt of ir o n o verl oa d a n d ir o n relate d tiss ue 
da ma ge (A n gel u cci  a n d  Bar o ncia ni, 2 0 0 8 ).  Tra ns pla nt  relate d m ortalit y ass ociate d wit h b ot h 
all o ge neic  a n d  a ut ol o g o us  B M T  is  l o wer  i n  y o u n ger  patie nts  d ue  t o  better  t olera nce  of  
m yel oa blati ve treat me nts (Ca h n et al., 1 9 9 5; Keati n g et al., 1 9 9 6 ).  
3. 4.  
R ati o n ale f or D ose of St u d y Dr u g  
Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct is a n a ut ol o g o us C D 3 4 + cell -e nric h e d p o p ulati o n t hat c o ntai ns 
he mat o p oietic  ste m  cells  tra ns d uce d  wit h  B B 3 0 5  le nti viral  vect or  e nc o di n g  t he  β A‑ T 8 7 Q - gl o bi n 
ge ne, s us pe n de d i n cr y o preser v ati o n s ol uti o n. Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct is a d mi nistere d 
via I V i nf usi o n.  
T he  d ose  of  C D 3 4 +  cells  t o  be  a d mi nistere d  is  base d  o n  acce pte d  safe  practice  t o  ac hie v e  
he mat o p oietic  r ec o nstit uti o n  wit h  l o n g‑ter m  e n graft me nt  after  a ut ol o g o us  tra ns pla ntati o n.  T h e 
mi ni m u m C D 3 4 + d ose ass ociate d wit h fa v ora ble e n graft me nt ki netics is a p pr o xi matel y 1. 5 × 1 0
6 t o 
3. 0 × 1 0 6 cells/ k g ( Be n der et al., 1 9 9 2; Jillella a n d Ust u n, 2 0 0 4; Mi ya m ot o et al., 2 0 0 4; Perez- Si m o n 
et al., 1 9 9 8). Cli nical data fr o m o n g oi n g trials utilizi n g Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct s u g gest 
t hat i m pr o ve me nt i n e n graft me nt s pecificall y of vect or-tra ns d uce d cells ma y be ac hie ve d wit h 
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sli g htl y hi g her cell d oses, i.e., ≥ 5. 0 × 1 0 6 C D 3 4 + cells/ k g.  It is als o n ota ble t hat i n ge neral t he 
har vest of C D 3 4 + cells fr o m a p her esis yiel ds m uc h hi g her n u m bers ( u p t o 2 1 -f ol d hi g her) of 
C D 3 4 + cells t ha n are o bt ai ne d fr o m a b o ne m arr o w pr oce d ure ( Be y er et al., 1 9 9 5; Mi ya m ot o et 
al., 2 0 0 4; Perez- Si m o n et al., 1 9 9 8; T o et al., 1 9 9 2 ). Gi ve n t hes e data, Ta bl e  1 o utli nes t he s o urce 
of s u bject cells, usa g e, a n d mi ni mal d ose t o be a d mi nistere d.  
T a ble 1:  
D ose of Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct or B ac k- u p Cells  
Us a g e 
D ose a 
Dr u g Pr o d uct ( o btai ne d b y a p heresis)   
≥5. 0 × 1 0 6 C D 3 4 +  cells/ k g a 
Bac k -u p Cells ( o btai ne d b y a p heresis; f or resc ue)  
≥1. 5 × 1 0 6 C D 3 4 +  cells/ k g 
Bac k -u p Cells ( o btai ne d b y b o ne marr o w har vest; f or 
resc ue)  
> 1. 0 × 1 0 8 T N C/ k g  
T N C, t otal n ucleate d cells 
a   N ote t hat t his d ose re prese nts t he cell c o u nt after tra ns d ucti o n. If m ore t ha n 1 tra ns d ucti o n is perf or me d, t he t otal 
d ose of t he res ulti n g m ulti ple dr u g pr o d uct l ots m ust meet t his criteri o n.  
3. 5.  
Tre at me nt Disc o nti n u ati o n a n d E nr oll me nt S us pe nsi o n C riteri a 
See Secti o n 4. 5  f or “s u bj ect wit h dra w al fr o m t he st u d y”. 
3. 5. 1.  
St o p pi n g R ules f or B us ulf a n  
O nce m yel oa blati o n wit h b us ulfa n has be g u n, t here are n o st o p pi n g r ules f or b us ulfa n. I n t he 
a ntici pate d ver y r are e v e nt of c o nse nt wit h dra wal d uri n g c o n diti o ni n g or t he de vel o p me nt of a ne w 
me dical  c o n diti o n t hat, i n t he i n vesti gat or’s o pi ni o n, p uts t he s u bject  at  ris k wit h c o nti n ue d  
b us ulfa n treat me nt, t he Me dical M o nit or s h o ul d be c o ntacte d i m me diatel y. I n s uc h sit uati o ns i n 
w hic h b us ulfa n c o n diti o ni n g has n ot bee n c o m plete d per pr ot oc ol, L e nti Gl o bi n B B 3 0 5 Dr u g 
Pr o d uct s h o ul d n ot be gi ve n, a n d it is li kel y t hat resc ue t hera p y will be re q uire d. 
3. 5. 2.  
E nr oll m e nt S us pe nsi o n Criteri a  
E nr oll me nt i n t his st u d y ma y be st o p p e d at a n y ti me f or safet y reas o ns. It will be t he res p o nsi bilit y 
of t he D M C t o deter mi ne if t here is reas o na ble ca use f or s us pe n di n g e nr oll me nt. T he S p o ns or or 
S p o ns or’s desi g nee will pr o m ptl y i nf or m t he re g ulat or y a ut h orities, i n vesti gat ors, I nstit uti o nal 
Re vie w B oar ds (I R Bs) / Et hics C o m mittees ( E Cs), a n d ot her a p pr o priate i nstit uti o nal re g ulat or y 
b o dies if a decisi o n t o s us pe n d e nr oll me nt is ma de. I n t he e ve nt e nr oll me nt is s us pe n de d, n o ne w 
m o bilizati o n/c o n diti o ni n g/ or dr u g pr o d uct i nf usi o n of s u bjects will be i nitiate d, b ut s u bjects w h o 
ha ve alrea d y bee n treate d wit h Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d u ct will c o nti n ue i n t he st u d y. If 
m o bilizati o n has bee n i nitiate d, cell c ollecti o n will be c o m plete d at i n vesti gat or’s discreti o n. 
Li ke wise, if t h e st u d y is halte d w hile a s u bject is u n der g oi n g c o n diti o ni n g, c o n diti o ni n g will be 
c o m plete d at i n vesti gat or’s discreti o n, a n d e v er y eff ort will be ta ke n t o restart t he st u d y pri or t o 
t heir sc he d ule d i nf usi o n. H o we ver, a s u bject ma y be i nf use d wit h t heir resc ue cells f oll o wi n g 
c o n diti o ni n g if t he st u d y ca n n ot be r estarte d i n ti me.  
E nr oll me nt a n d treat me nt wit h dr u g pr o d uct will be te m p oraril y s us pe n de d f or a n y of t he f oll o wi n g 
reas o ns, a n d will res u m e after re vie w a n d rec o m me n dati o ns fr o m t he D M C a n d (as re q uire d) 
a p pr o val fr o m t he rele v a nt re g ulat or y a g e nc y(ies): 
•  Deat h, u ntil t he ca use of t he deat h is deter mi ne d *  
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•  Detecti o n of le u k e mia/l y m p h o ma d ue t o vect or- m e diate d i nserti o nal o nc o g e nesis * * 
•  Detecti o n of vect or- d eri v e d R C L i n a n y s u bject (c o nfir me d o n c o- c ult ure assa y)  
•  Fail ure t o ac hie ve rec o nstit uti o n wit h tra ns d uce d cells i n > 1 s u bj ect, re q uiri n g use of 
bac k u p cells 
•  Deter mi nati o n of u n e x p ecte d, cli nicall y si g nifica nt, or u nacce pt a ble ris k t o  s u bjects 
(e. g., de vel o p me nt of dr u g pr o d uct -relate d, Gra de 3 or 4 t o xicities i n at least 3 s u bjects) 
•  If a n y criteria f or cl o n al pre d o mi na nce or tri g gers f or cli nical w or k-u p f or mali g na nc y 
is  satisfie d  (refer  t o  Secti o n  6. 2. 1 8 ),  treat me nt  of  a n y  e nr olle d  s u bjects  will  be  
te m p oraril y s us pe n de d u ntil f urt her re vie w b y t he D M C. 
* A n y deat h of a s u bject wit h T D T i n a n y st u d y after recei vi n g Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct will res ult i n a h ol d 
of f urt her e nr oll me nt a n d treat me nt wit h dr u g pr o d uct u ntil a n i n vesti gati o n i nt o t he ca use of deat h is perf or me d. If 
it is deter mi ne d t hat t he deat h was n ot relate d t o t he dr u g pr o d uct, t he n e nr oll me nt/treat me nt wit h dr u g pr o d uct ma y 
restart. If t he relati o ns hi p bet wee n t he deat h a n d t he dr u g pr o d uct is n ot clear, or it a p pears t hat t he deat h ma y be 
relate d t o t he st u d y dr u g, e nr oll me nt will be hel d u ntil t he D M C assess me nt a n d rec o m me n dati o ns as descri be d 
a b o ve.  I n  cases  i n  w hic h  t he  ca use  of  deat h  is  still  u n der  i n vesti gati o n,  s u bjects  t hat  ha ve  alrea d y  recei ve d  
c o n diti o ni n g ma y recei ve eit her bac k -u p cells or Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct o n a case -b y -case basis i n 
c o ns ultati o n wit h t he D M C.  
* *If a s u bject is dia g n ose d wit h le u ke mia or l y m p h o ma after recei vi n g Le nti Gl o bi n B B 3 0 5 i n a n y cli nical st u d y, 
e nr oll me nt will be hel d u ntil deter mi nati o n is ma de as t o w het her t he mali g na nc y was relate d t o a vect or -me diate d 
i nserti o n. O nce t his assess me nt occ urs, if t he mali g na nc y is n ot relate d t o a vect or -me diate d i nserti o n, e nr oll me nt 
ma y res u me. If t he relati o ns hi p bet wee n t he mali g na nc y a n d a n i nserti o n is n ot clear or it a p pears t he y ma y be 
relate d, e nr oll me nt will be hel d u ntil t he D M C assess me nt a n d rec o m me n dati o ns as descri be d a b o ve. 
 
 
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4.  
S T U D Y P O P U L A TI O N  
4. 1.  
N u m ber of S u bjects  
A p pr o xi matel y 2 3 s u bjects i n t otal will be treate d wit h dr u g pr o d uct, at least 1 5 of w h o m m ust be 
≥1 2 a n d ≤5 0 years of a g e (at l east 5 of w h o m m ust be ≥1 2 a n d < 1 8), a n d at least 8 of w h o m m ust 
be < 1 2 year s of a ge. Re pl ace me nt s u bjects ma y be a d de d if s u bjects are s cree n fail ures or wit h dra w 
pri or t o dr u g pr o d uct i nf usi o n. 
N o m ore t ha n 7 s u bjects ≥1 2 a n d ≤5 0 y ears of a ge a n d 4 s u bjects < 1 2 y ears of a ge w h o are treat e d 
ca n ha v e a β E  allele (i. e., a p pr o xi mate l y 5 0 % of s u bjects). 
4. 2.  
I ncl usi o n Criteri a 
S u bjects m ust meet all of t he f oll o wi n g criteri a t o be c o nsi dere d eli gi ble f or e nr oll me nt i n t he 
st u d y. 
1.  S u bjects  ≤5 0  years  of  a ge  at  t he  ti me  of  c o nse nt  or  asse nt  (as  a p plica bl e),  a n d  a ble  t o 
pr o vi de writte n c o nse nt ( a d ults, or le gal g uar dia ns, as a p plica ble) or asse nt (a d olesce nts or 
c hil dre n). Pe diatric s u bj ects ( < 1 2 y ears of a ge) ma y o nl y be e nr olle d at a gi ve n site if 
a p pr o ve d  b y  t he  rele va nt  re g ulat or y  a ut h orit y.  Pr o vi de d  t hat  t he  D M C  has  a p pr o ve d  
e nr olli n g s u bjects y o u n ger t ha n 5 years of a g e, s u bjects y o u n ger t ha n 5 years of a ge ma y 
be e nr olle d at sites wit h re g ulat or y a p pr o v al f or t he s pecifie d a g e ra n g e if t he y wei g h a 
mi ni m u m of 6 k g a n d are reas o na bl y a ntici pate d t o be a ble t o pr o vi de at least t he mi ni m u m 
n u m ber of cells re q uire d t o i nitiate t he ma n ufact uri n g pr ocess. 
2.  Dia g n osis of T D T wit h a hist or y of at least 1 0 0 m L/ k g/ year of p R B Cs i n t he 2 years 
prece di n g e nr oll me nt (all s u bjects), or be ma na ge d u n der sta n dar d t halasse mia g ui deli nes 
(e. g., T halass e mia I nter n ati o nal Fe d erati o n, 2 0 1 4; see A p pe n di x 1 0. 4 ) wit h ≥8 tra nsf usi o ns 
of p R B Cs per year i n t he 2 years prece di n g e nr oll me nt (s u bjects ≥1 2  years; Rac h mile witz 
a n d Giar di na, 2 0 1 1 ). 
3.  Cli nicall y sta ble, ha ve a Kar n ofs k y  p erf or ma nce stat us of ≥8 0 f or a d ults ( ≥1 6 years of a g e) 
or a L a ns k y perf or ma n ce stat us of ≥8 0 f or a d olesce nts or c hil dre n ( < 1 6 years of a g e), a n d 
eli gi ble t o u n der g o H S C T. 
4.  Treate d a n d f oll o we d f or at least t he past 2 years i n a s pecialize d ce nter t h at mai ntai ne d 
detaile d me dical r ec or ds o n R B C tra nsf usi o ns (i ncl u di n g v ol u me a n d u nits of R B Cs a n d 
ass ociate d pr e -tra nsf usi o n H b val ues, retic ul oc yte c o u nts a n d rele va nt bl o o d ba n k details 
as a vaila ble), i n - patie nt h os pitalizati o n, a n d ir o n c helati o n hist or y.  
4. 3.  
E xcl usi o n Criteri a  
S u bjects meeti n g a n y of t he f oll o wi n g criteria will be e xcl u de d fr o m t he st u d y. 
1.  Prese nce  of  a  m utati o n  c har acterize d  as  β 0 o n  b ot h  H B B  alleles.  F or  t he  p ur p ose  of  
scree ni n g, t he H B B  m utati o n I V S I -1 1 0 ( G A) [ H G V S n o me nclat ure: H B B :c. 9 3- 2 1G > A] 
will be c o nsi dere d e q ui vale nt t o a β 0 m utati o n.  
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2.  P ositi ve f or prese n ce of h u ma n i m m u n o deficie n c y vir us t y pe 1 ( HI V -1) or 2 ( HI V -2), 
he patitis B vir us ( H B V), or he patitis C vir us ( H C V). S y p hilis (ra pi d plas ma rea gi n  [ R P R]) 
testi n g is als o re q uire d a n d a p ositi ve test f or s y p hilis is e xcl usi o nar y w here ma n date d b y 
re gi o nal  dr u g  pr o d uct  ma n ufact uri n g  practices.  N ote  t hat  s u bjects  w h o  ha ve  bee n  
vacci nat e d a gai nst he patitis B ( he patitis B s urface a nti b o d y - p ositi ve) w h o are ne gati ve f or 
ot her mar kers of pri or h e patitis B i nfecti o n [e. g., ne gati ve f or h e patitis B c ore a nti b o d y] 
are  eli gi ble.  S u bjects  wit h  past  e x p os ure  t o  H B V  ( H Bc  A b  p ositi ve  a n d/ or  H Be  A b  
p ositi ve) are als o eli gi ble f or t he st u d y pr o vi de d t h e y are ne gati ve b y assess me nt f or H B V 
D N A. Als o n ote t hat s u bjects w h o are p ositi ve f or a nti- he patitis C a nti b o d y are eli gi ble as 
l o n g as t he y ha ve a ne gati ve H C V viral l oa d. W h ere cli nicall y a n d/ or re gi o nall y i n dicate d, 
ot her tests ma y be perf or me d, i n w hic h case p ositi ve res ults w o ul d e xcl u de t he s u bject fr o m 
partici pati n g: f or e x a m ple, h u ma n T -l y m p h otr o pic  vir us‑ 1  ( H T L V-1) or -2 ( H T L V - 2), 
t u berc ul osis, t o x o plas m osis, Tr y pa n os o ma cr u zi, West Nile Vir us, or Zi ka Vir us. 
3.  Cli nicall y si g nifica nt a n d acti ve bacterial, viral, f u n gal, or parasitic i nfecti o n as deter mi ne d 
b y t he cli nical i n vesti gat or.  
4.  A w hite bl o o d cell ( W B C) c o u nt < 3 × 1 0 9/ L, a n d/ or platelet c o u nt < 1 0 0 × 1 09/ L n ot relate d 
t o h y pers ple nis m. 
5.  U nc orr ecte d blee di n g dis or der.  
6.  A n y pri or or c urre nt mali g na nc y ( wit h t he e xce pti o n of a de q uatel y treate d c o ne - bi o psie d 
i n sit u carci n o ma of t he cer vi x uteri a n d basal or s q ua m o us cell carci n o ma of t he s ki n) or 
m yel o pr oliferati ve or si g nifica nt i m m u n o deficie n c y dis or der. 
7.  I m me diat e fa mil y me m ber (i.e. pare nt or si bli n gs) wit h a k n o w n Fa milial Ca ncer S y n dr o me 
(i ncl u di n g b ut n ot li mite d t o here ditar y breast a n d o varia n ca ncer s y n dr o me, here ditar y 
n o n- p ol y p osis c ol orectal ca ncer s y n dr o me a n d fa milial a de n o mat o us p ol y p osis). 
8.  Pri or H S C T.  
9.  A d va nce d li ver disease, defi ne d as: 
a. Persiste nt  as partat e  tr a nsa mi nase,  al a ni ne  tra ns a mi nase,  or  direct  bilir u bi n  val ue  
> 3  ×  t he u p per li mit of n or mal ( U L N), o r  
b.  Baseli ne  pr ot hr o m bi n  ti me  or  partial  t hr o m b o plasti n  ti me  > 1. 5 ×  U L N, s us pecte d of 
arisi n g fr o m li ver diseas e, or  
c. M RI of t he li ver de m o nstrati n g clear e vi de nce of cirr h osis, or  
d.  M RI fi n di n gs s u g gesti ve of acti ve h e patitis, si g nifica nt fi br osis, i nc o ncl usi v e e vi de n ce 
of  cirr h osis,  or  li ver  ir o n  c o nce ntrati o n  ≥1 5  m g/ g  re q uire  f oll o w -u p li ver bi o ps y i n 
s u bjects  ≥  1 8  years  of  a ge.  I n  s u bjects  <  1 8  years  of a ge, t hese M RI fi n di n gs are 
e xcl usi o nar y, u nless i n t he o pi ni o n of t he i n vesti gat or, a li ver bi o ps y c o ul d pr o vi de 
a d diti o nal data t o c o nfir m eli gi bilit y a n d w o ul d be safe t o perf or m. If a li ver bi o ps y is 
perf or me d base d o n M RI fi n di n gs, a n y e vi d e n ce of cirr h osis, bri d gi n g fi br osis, or 
si g nifica nt acti ve he p atitis will be e xcl usi o nar y. 
1 0.  Baseli ne esti mate d gl o mer ular filtrati o n rate < 7 0 m L/ mi n/ 1. 7 3 m 2, as deter mi ne d usi n g t he 
C hr o nic Ki d ne y Disease E pi de mi ol o g y C olla b orati o n creati ni ne e q uati o n f or ≥1 8  years o f 
a ge,
 a n d
 Be dsi de
 Sc h wartz
 e q uati o n
 calc ulat or
 f or
 < 1 8
 y ears
 of
 a g e
 
(see htt p:// w w w. ki d ne y. or g/ pr ofessi o nals/ k d o qi/ gfr _calc ulat or.cf m ) 
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1 1.  U nc o ntr olle d seiz ur e dis or der. 
1 2.  Diff usi o n ca pacit y of car b o n m o n o xi de ( D Lc o) < 5 0 % of pre dict e d (c orrecte d f or H b  a n d/ or 
al ve olar  v ol u me,  as  cli nicall y  i n dicate d).  If  D Lc o  ca n n ot  be  ass esse d  d ue  t o  a ge  or  
c o g niti o n-relate d r estricti o ns, t here m ust be a n or mal res pirat or y e x a m, c hest ra di o gra p h 
wit h o u t p ul m o nar y i nfiltrates, a n d o x y g e n sat urati o n b y p ulse o xi metr y > 9 2 % o n r o o m air. 
I n t he pres e nce of cli nicall y si g nifica nt a b n or mal fi n di n gs o n c hest ra di o gra p h, cli nicall y 
si g nifica nt  a b n or mal  fi n di n gs  o n t he res pirat or y e xa m, or o x y ge n sat urati o n b y p u lse 
o xi metr y ≤9 2 % o n r o o m air, t he s u bject will be e x cl u de d.  
1 3.  A car diac T 2 * < 1 0 ms b y M RI.  
1 4.  A n y ot her e vi de nce of s e vere ir o n o v erl oa d t hat, i n t he i n vesti gat or’s o pi ni o n, warra nts 
e xcl usi o n. 
1 5.  Partici pati o n i n a n ot her cli nical  st u d y wit h a n i n vesti gati o nal  dr u g wit hi n 3 0 da ys of 
Scree ni n g.  
1 6.  A n y ot her c o n diti o n t hat w o ul d re n der t he s u bject i neli gi ble f or H S C T, as deter mi ne d b y 
t he atte n di n g tra ns pla nt p h ysicia n or i n vesti gat or. 
1 7.  Pri or recei pt of g e ne t her a p y. 
1 8.  Dia g n osis of si g nifica nt ps yc hiatric dis or der of t h e s u bject t hat c o ul d s eri o usl y i m pe de t he 
a bilit y t o partici pate i n t he st u d y.  
1 9.  Pre g na nc y or breastf ee di n g i n a p ost part u m fe mal e or a bse n ce of a de q uat e c o ntrace pti o n 
f or fertile s u bjects. Fe males of c hil d-beari n g p ote ntial a n d males are re q uire d t o use t w o 
differe nt eff ecti ve met h o ds of c o ntrace pti o n fr o m Scree ni n g t hr o u g h at least 6 m o nt hs after 
dr u g pr o d uct i nf usi o n. If s u bjects are tr ul y se x uall y a bsti ne nt ( w here tr u e se x ual a bsti ne nce 
is defi ne d as bei n g i n li ne wit h t he preferre d a n d us ual lifest yle of t he s u bject), n o sec o n d 
met h o d is re q uire d. ( See Secti o n 6. 2. 1 9. 7  f or m ore details). 
2 0.  A n assess me nt  b y  t he i n vesti gat or t hat  t he  s u bject  w o ul d n ot  c o m pl y wit h t he st u d y 
pr oce d ur es o utli ne d i n t he pr ot oc ol. 
2 1.  A k n o w n a n d a vaila ble H L A -matc h e d fa mil y d o n or. If re q uire d b y re gi o nal re g ulat or y 
a ut h orit y, patie nts wit h a k n o w n a n d a v aila ble matc he d u nrelat e d d o n or will be e xcl u de d 
fr o m t he st u d y. 
2 2.  A n y c o ntrai n dicati o ns t o t he use of G -C S F a n d pleri xaf or d uri n g t he m o bilizati o n of 
he mat o p oietic ste m cells a n d a n y c o ntrai n dicati o ns t o t he use of b us ulfa n a n d a n y ot her 
me dici nal  pr o d ucts  re q uire d  d uri n g  t he  m yel oa blati ve  c o n diti o ni n g,  i ncl u di n g  
h y perse nsiti vit y t o t he acti ve s u bsta nces or t o a n y of t he e xci pie nts. 
4. 4.  
S u bject I de ntific ati o n a n d Re gistr ati o n  
If t he s u bject is willi n g t o partici pate i n t he st u d y, t he n t he site will be gi n t he c o nse nt a n d ass e nt 
(as  a p plica ble)  pr ocess  as  per  i nstit uti o nal  practices,  acc or di n g  t o  G o o d  Cli nical  Practice  
(I C H-G C P). Writte n i nf or me d c o nse nt a n d ass e nt (as a p plica ble) m ust be o btai ne d b ef ore t he 
c o n d uct of a n y Scree ni n g tests n ot perf or me d r o uti nel y i n t he treat me nt of t he s u bject.  
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U p o n o btai ni n g t he si g ne d i nf or me d c o nse nt a n d asse nt (as a p plica ble), t he p ote ntial s u bject will 
be re gister e d a n d assi g ne d a u ni q ue s u bject n u m ber. O nce a s u bject n u m ber has bee n assi g ne d t o 
a s pecific s u bject, it ca n n ot be reassi g ne d t o a ne w s u bject. T he s u bject n u m ber will sta y wit h t he 
sa me s u bject e v e n if a s u bject is rescr ee n e d. 
S u bjects w h o fail s cree ni n g ma y n ot be re -s cree ne d with o ut pri or disc ussi o n wit h t he bl ue bir d bi o 
Me dical M o nit or. I n g e neral, s u bjects w h o fail scree ni n g f or p ote ntiall y re versi ble c o n diti o ns, s uc h 
as ir o n o v erl oa d, s h o ul d n ot be r e -scree n e d u ntil stri n ge nt ma na ge m e nt of t he c o n diti o n, s uc h as 
a g gressi ve ir o n c hel ati o n, has bee n i n place f or at least 3 m o nt hs fr o m t he ti me of scree n fail ure, 
a n d t he faile d i ncl usi o n/e xcl usi o n criteria has b ee n c o nfir me d t o ha v e bee n re me die d. 
4. 5.  
S u bject Wit h dr a w al fr o m t he St u d y  
S u bjects ha ve t he ri g ht t o wit h dra w fr o m t he st u d y  at a n y ti me f or a n y reas o n. After gi vi n g 
i nf or me d c o nse nt a n d ass e nt (as a p plica ble), s u bjects ma y wit h dra w or be wit h dra w n fr o m st u d y 
relate d pr oce d ur es a n d treat me nts (e. g., a p h eresis, b us ulfa n c o n diti o ni n g) u n der t he f oll o wi n g 
c o n diti o ns: 
•  wit h dra wal of c o nse nt or asse nt, 
•  t he s u bject is u na ble t o c o m pl y wit h pr ot oc ol-defi ne d visits or ot her re q uire me nts of 
t he pr ot oc ol,  
•  a n y me dical c o n diti o n w hic h, i n t he o pi ni o n of t he i n vesti gat ors, w o ul d p ut t he s u bject 
at ris k f or c o nti n ui n g treat me nt or f oll o w- u p st u dies, or 
•  a de q uate cells are n ot c ollecte d d uri n g har vests, or fail ure of tra ns d uce d cells t o be 
dis p ositi o ne d f or cli nical use.  
Alt h o u g h s u bjects ha ve t he ri g ht t o wit h dra w fr o m t he st u d y at a n y ti me, wit h dra wal aft er t he start 
of c o n diti o ni n g a n d bef or e a d mi nistrati o n of Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct b y i nf usi o n will be 
str o n gl y disc o ura ge d, beca use t his w o ul d be c o nsi dere d delet eri o us t o t he s u bject. I n s uc h cas es, 
t he s u bject’s st ore d bac k- u p cells (rat her t ha n tra ns d uce d cells) will be i nf use d.  
F or  s u bjects w h o wit h dra w c o nse nt or asse nt (if rele va nt), n o f urt her data will be c ollecte d o n t he 
s u bject. 
F or s u bjects w h o wit h dr a w f or r eas o ns ot her t ha n wit h dra wal of c o nse nt, a n y S A Es o p e n at t he 
ti me of disc o nti n uati o n s h o ul d be f oll o we d-u p u ntil res ol uti o n or are deter mi ne d t o be a sta ble or 
c hr o nic c o n diti o n. See als o Secti o n  6. 2. 1 9. 1  f or A Es m o nit ori n g of s u bjects w h o wit h dra w fr o m 
t he st u d y. 
•  If wit h dra wal is bef ore dr u g pr o d uct i nf usi o n, s u bjects s h o ul d re mai n o n st u d y f or at 
least 3 0 da ys aft er a n y i n v asi ve st u d y pr oce d ure (e. g., m o bilizati o n, li ver bi o ps y) bef ore 
wit h dra wal a n d o n g oi n g A Es s h o ul d be f oll o we d f or t he 3 0 -d a y d urati o n. I n t h e ra re 
case  a  s u bject  u n der g o es  m yel oa blati o n  a n d  recei ves  bac k -u p  cells  i nstea d  of  
Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct, s u bject s h o ul d re mai n o n t he st u d y f or at l east 
3 m o nt hs p ost m yel oa blati o n a n d A Es s h o ul d be f oll o we d f or t he 3- m o nt h d urati o n.  
•  If wit h dra wal is after dr u g pr o d uct i nf usi o n, s u bjects will be as ke d t o c o m plete t he sa me 
assess me nts  as  s p ecifi e d  i n  t he  Sc h e d ule  of  E ve nts  ( S O E)  f or  M o nt h  2 4  
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( Earl y Ter mi nati o n Visit assess me nts) a n d will be e x pecte d t o e nr oll i n t he l o n g -ter m 
f oll o w-u p St u d y L T F‑ 3 0 3.  
S u bjects wit h dra w n fr o m t he st u d y pri or t o dr u g pr o d uct i nf usi o n will be re place d. 
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5.  
S T U D Y T R E A T M E N T S  
5. 1.  
Descri pti o n of Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct  
B B 3 0 5 Le nti vir al Vect or:  B B 3 0 5 le nti viral vect or is a re plicati o n d efecti ve, self-i n acti vati n g 
( SI N), t hir d ge nerati o n HI V-1 base d le nti viral v ect or pse u d ot y pe d wit h t he vesic ular st o matitis 
vir us gl yc o pr otei n  ( V S V-G)  e n vel o pe  pr otei n,  carr yi n g  t he  h u ma n  β‑ gl o bi n  ge ne  wit h  a  si n gle 
m o dificati o n at c o d o n 8 7 ( β A 8 7  T hr: Gl n [ β A‑ T 8 7 Q ]). B B 3 0 5 le nti viral vect or is n ot a d mi nistere d t o 
s u bjects; rat her, it is use d f or e x-vi v o tra ns d u cti o n of a ut ol o g o us C D 3 4 + h e mat o p oietic ste m cells.  
Le nti Gl o bi n  B B 3 0 5  Dr u g  Pr o d uct :  Le nti Gl o bi n  B B 3 0 5  Dr u g  Pr o d uct  is  a n  a ut ol o g o us  
C D 3 4 + cell-e nric he d p o p ulati o n t hat c o ntai ns he mat o p oietic ste m cells tra ns d uce d wit h B B 3 0 5 
le nti viral vect or e n c o di n g t he βA- T 8 7 Q - gl o bi n ge ne, s us pe n de d i n cr y o preser vati o n s ol uti o n. 
5. 2.  
S u m m ar y of Tre at me nts t o be Perf or me d or A d mi nistere d  
After  c o nfir mati o n  of  eli gi bilit y,  H S Cs  m ust  be  c ollecte d  fr o m  t he  s u bject  f or  2  p ur p os es: 
1) tra ns d ucti o n  f or  Le nti Gl o bi n  B B 3 0 5  Dr u g  Pr o d uct  a n d  2)  f or  resc u e  cells  (t o  be  us e d  if  
t he s u bject  fails  t o e n gr aft  wit h tra ns d uce d cells or is u na ble t o recei ve Le nti Gl o bi n B B 3 0 5 
Dr u g  Pr o d uct aft er c o n diti o ni n g has c o m me nce d). 
A d diti o nal details are pr o vi de d i n t he f oll o wi n g s u bsecti o ns. 
5. 2. 1.  
M o biliz ati o n a n d A p heresis Pr oce d ure  
H b  f or  t he  s u bject  is  rec o m me n d e d  t o  b e  ≥1 1  g/ d L  d uri n g  m o bilizati o n  a n d  a p h eresis 
(see Secti o n  5. 9. 3  f or  d etails).  Eac h  s u bject  will  u n der g o  H S C  m o bilizati o n  wit h  a  G-C S F 
(e. g., fil grasti m, le n o gr asti m) a n d pleri xaf or. Peri p heral bl o o d m o n o n uclear cells ( P B M Cs) will be 
c ollecte d b y a p her esis. A se par ate ma n u al o n a p heresis re q uire me nts a n d rec o m me n d ati o ns will 
be pr o vi de d. 
A t otal of 2 m o bilizati o n c ycles ma y be perf or me d if nee de d. H o w e ver, s u bjects w h ose dr u g 
pr o d uct f ails t o meet s pecificati o ns f or a n y reas o n ma y u n d er g o re peat a p h eresis a n d ma n ufact ure 
of  ne w  dr u g  pr o d u ct.  A d diti o nal  m o bilizati o n  c ycles  will  o nl y  be  p erf or me d  if  t he  i nitial  
m o bilizati o n c ycle was t olerate d, a n d i n t he o pi ni o n of t he st u d y p h ysicia n, w o ul d n ot je o par dize 
t he s u bject’s me dical c o n diti o n.  
Eac h m o bilizati o n c ycle ma y i ncl u de u p t o 3 a p heresis pr oce d ure da ys, a n d m o bilizati o n re gi me n 
after  2  da ys  of  a p her esis  s h o ul d  be  disc usse d  wit h  t he  Me di cal  M o nit or.  N o  m ore  t ha n  
2 c o nsec uti ve a p her esis pr oce d ur e pr o d u cts ma y be se nt f or eac h tra ns d u cti o n; eac h tra n s d u cti o n 
pr o d uces a n i n di vi d ual dr u g pr o d uct l ot. A p h eresis pr oce d ure pr o d u cts are als o t o be us e d f or 
resc ue cells a n d ma y c o me fr o m eit her a f ull or partial da y of c ollecti o n. N ote t hat a p heresis 
c ollecti o ns i nte n de d f or dr u g pr o d uct ma n ufact ure o n a gi v e n da y ma y be s plit t o re m o ve cells f or 
resc ue (≥1. 5 × 1 0 6 C D 3 4 + cells/ k g b ut <4. 0 × 1 0 6 C D 3 4 + cells/ k g) o nl y if ≥2 5 × 1 0 6 C D 3 4 + cells/ k g 
are pr oc ure d o n t he first da y of a p heresis, or a n a g gre gate of ≥1 6 × 1 0 6 C D 3 4 + cells/ k g are c ollecte d 
t hr o u g h s u bse q ue nt da ys of a p heresis. See t he a p heresis ma n ual f or f urt her details. N ote als o t hat 
ali q u ots of cells i nte n de d f or resc ue s h o ul d be fr o ze n a n d st ore d at t he e n d of eac h c ollecti o n da y 
(i.e., s h o ul d n ot be hel d o ver ni g ht t o be p o ole d wit h t he ne xt da y’s c ollecti o n, e ve n if nee d t o 
c ollect a d diti o nal cells f or c o m plete r esc u e d ose). M o bilizati o n c ycles m ust be se parate d b y at least 
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2 wee ks (i.e., fr o m last da y of cell c ollecti o n i n C ycle 1 t o first da y of G- C S F i n C ycle 2). A b o ne 
marr o w har vest is als o all o we d, b ut o nl y t o pr oc ure cells f or resc u e cells.  
If 2 m o bilizati o n c y cles are n ee de d t o c ollect e n o u g h H S Cs t o meet t he re q uire me nt of a t otal d ose 
of ≥5. 0 × 1 0 6 C D 3 4 + cells/ k g, t he n 2 tra ns d u cti o ns will be perf or me d, o ne o n t he cells c ollecte d 
d uri n g M o bilizati o n C ycl e 1 a n d a n ot her o n t he cells c ollecte d d uri n g M o bilizati o n C ycle 2. Eac h 
tra ns d uce d pr o d uct fr o m eac h m o bilizati o n c ycle is a n i n de p e n de nt dr u g pr o d uct l ot. T h us, s u bjects 
w h o re q uir e 2 m o bilizati o n c ycles t o pr o d uce t he mi ni m u m cell d ose will be treat e d wit h 2 dr u g 
pr o d uct l ots i n t otal. 
T he har v este d cells t o be use d f or tra ns d ucti o n will be selecte d f or t he C D 3 4 + mar k er t o e nric h f or 
H S Cs, tra ns d uce d wit h B B 3 0 5 le nti viral vect or a n d st ore d i n t he va p or p hase of li q ui d nitr o ge n 
w hile rele as e testi n g is o n g oi n g. 
P ote ntial  ris ks  relate d  t o  G -C S F  (e. g.,  fil grasti m,  le n o grasti m),  pleri xaf or,  a n d  a p heresis  are  
i ncl u de d i n t he I nf or m e d C o nse nt f or ms a n d i n t he res pecti ve pr o d uct la b els (e. g., U S PI, S m P Cs). 
G- C S F will be use d wit hi n t he mar keti n g  a ut h orizati o n a n d f oll o wi n g t he prescri bi n g i nf or mati o n.  
5. 2. 1. 1.  
M o biliz ati o n  
Rece nt  p u blis he d  data  i n dicate  t hat  t he  use  of  pleri xaf or  i n  p e diatric  patie nts  is  safe  a n d  
effecti ve f or  t he  m o bilizati o n  of  p eri p heral  bl o o d  ste m  cells  f or  a ut ol o g o us  tra ns pla ntati o n  
(Te usi n k et al., 2 0 1 6 ). T he a d diti o n of pl eri xaf or t o G-C S F i n pe diatri c patie nts u n der g oi n g 
ste m cell m o bilizati o n pri or t o tra ns pla ntati o n as part of treat me nt of m ali g na nt t u m ors has als o 
bee n s h o w n t o res ult i n s u ccessf ul m o bilizati o n of t he vast maj orit y of p atie nts w h o fail t o m o bilize 
wit h si n gle a ge nt G -C S F, as well as t o pr o d uce lar ger yiel ds of C D 3 4 + cells (Masc ha n  et al., 2 0 1 5). 
T o xicities o bser ve d i n t he st u d y  were Gra d e 1 or 2, a n d i ncl u de d diarr hea, na usea, ossal gia, a n d 
urticaria. Pleri xaf or is t h us e x pecte d t o i nc ur mi ni mal a d diti o nal safet y ris ks be y o n d t he use of 
si n gle a ge nt G-C S F a n d t o ha ve a l o wer rate of faile d m o bilizati o n, res ulti n g i n re d uce d ris k  of 
re peat e x p os ures t o G-C S F a n d re p eat a p h eresis atte m pts.  
T he c o m bi nati o n of pleri xaf or a n d a G -C S F s uc h as fil grasti m or le n o grasti m ma y be t he m ost 
a p pr o priate m o bilizati o n strate g y f or s u bjects wit h β -t halasse mia (Ya n n a ki et al., 2 0 1 3; Y a n na ki  et 
al., 2 0 1 2). T he m o bilizati o n a p pr oac h bel o w (Ta bl e  2, Ta b le 3) f oll o ws t his rece nt data, a n d uses 
fil grasti m as a n e xa m ple of t he G-C S F. M o dificati o ns t o t his a p pr oac h are all o w e d o nl y after 
c o ns ultati o n wit h t he Me dical M o nit or. 
 
 
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T a ble 2: 
M o biliz ati o n f or S u bjects w h o h a ve a n I nt act S plee n  
M o biliz ati o n 
d a y  
Fil gr asti m 
d ose a 
Pleri x af or d ose 
(e ve ni n g) 
C o m plete 
Bl o o d 
C o u nt 
( C B C) 
Peri p her al 
C D 3 4 + c o u nt  
A p heresis  
1  
1 0 µ g/ k g  
 
X  c 
 
 
2  
1 0 µ g/ k g  
 
X  c 
 
 
3  
1 0 µ g/ k g  
 
X c 
 
 
4  
1 0 µ g/ k g  
0. 2 4  m g/ k g  
X  
X d 
 
5  
1 0 µ g/ k g  
0. 2 4  m g/ k g  
X  
X d  
X  
6 (if nee de d)  b 
1 0 µ g/ k g  
b 
X  
X d 
X  
7 (if nee de d)  b 
 
 
 
X d 
X  
a D osa ge of fil grasti m s h o ul d be decrease d if W B C > 1 0 0  ×  1 0 9/ L pri or t o t he da y of a p heresis u nless disc usse d wit h 
Me dical M o nit or; H b is rec o m me n de d t o be mai ntai ne d ≥1 1 g/ d L d uri n g t he m o bilizati o n a n d a p heresis p hase.  
b M o bilizati o n re gi me n after 2 da ys of a p heresis s h o ul d be disc usse d wit h t he Me dical M o nit or.  
c Rec o m me n de d b ut ca n be deferre d i n case of diffic ult y i n o btai ni n g C B C (e. g., wee ke n d) at t he discreti o n of t he site 
i n vesti gat or.  
d C D 3 4 + c o u nt is d o ne b ot h o n t he da y pri or t o a p heresis, as well as o n t he da y of a p heresis  
T a ble 3: 
M o biliz ati o n f or S u bjects w h o d o n ot h a ve a n I nt act S plee n  
M o biliz ati o n 
d a y  
Fil gr asti m 
d ose a 
Pleri x af or 
d ose 
(e ve ni n g) 
C o m plete 
Bl o o d C o u nt 
( CB C)  
Peri p her al 
C D 3 4 + c o u nt  
A p heresis  
1  
5 µ g/ k g  
 
X  c 
 
 
2  
5 µ g/ k g  
 
X  c 
 
 
3  
5 µ g/ k g  
 
X c 
 
 
4  
5 µ g/ k g  
0. 2 4  m g/ k g  
X  
X d 
 
5  
5 µ g/ k g  
0. 2 4  m g/ k g  
X  
X d 
X  
6 (if nee de d)  b 
5 µ g/ k g  
b 
X  
X d 
X   
7 (if nee de d) b 
 
 
 
X d 
X  
a D osa ge of fil grasti m s h o ul d be decrease d if W B C > 1 0 0  ×  1 0 9/ L pri or t o t he da y of a p heresis u nless disc usse d wit h 
Me dical M o nit or; H b is rec o m me n de d be mai ntai ne d ≥1 1 g/ d L d uri n g t he m o bilizati o n a n d a p heresis p hase.  
b M o bilizati o n re gi me n after 2 da ys of a p heresis s h o ul d be disc usse d wit h t he Me dical M o nit or.  
c Rec o m me n de d b ut ca n be deferre d i n case of diffic ult y i n o btai ni n g C B C (e. g., wee ke n d) at t he discreti o n of t he site 
i n vesti gat or. 
d C D 3 4 + c o u nt is d o ne b ot h o n t he da y pri or t o a p heresis, as well as o n t he da y of a p heresis  
 
After c o m pleti o n of M o bilizat i o n a n d A p h eresis C ycle 1, if a d diti o nal H S Cs are nee de d eit her f or 
dr u g pr o d uct ma n ufact ur e, or f or res c ue cells (i.e., if < 1. 5 × 1 0 6 C D 3 4 + cells/ k g ha ve bee n c ollecte d 
a n d st ore d at t he site f or r esc ue cells), t he s u bject s h o ul d be gi n M o bilizati o n a n d A p he resis C ycle 2 
n o s o o ner t ha n 2 w ee ks after t he c o m pleti o n of M o bilizati o n a n d A p heresis C ycle 1. M o bilizati o n 
a n d A p heresis C ycle 2 s h o ul d f oll o w t he sa me pr o ce d ures as M o bilizati o n a n d A p heresis C ycle 1, 
alt h o u g h t he d ose of pleri xaf or a n d G -C S F a n d t he a p h eresis s c he d ule m a y be m o difie d base d o n 
t he  s u bject’s  e x p erie n ce  fr o m  M o bilizati o n  a n d  A p heresis  C ycle  1.  At least  1. 5 × 1 06  C D 3 4 + 
cells/ k g s h o ul d be st ore d f or res c ue cells at eac h p artici pati n g site’s la b orat or y. 
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5. 2. 1. 2.  
A p heresis  
As  descri be d  a b o ve,  t y picall y  a  s u bject’s  first  a p heresis  will  occ ur  o n  M o bilizati o n  Da y  5.  
H o we ver, after disc ussi o n wit h t he Me dical M o nit or, it ma y occ ur o n M o bilizati o n Da y 4 or 6, if 
t he s u bject has a partic ularl y r o b ust or sl u g gis h res p o nse, res pecti vel y, t o m o bilizati o n. O n eac h 
da y of a p her esis, t he s u bj ect s h o ul d ha v e a c o m plete p h ysical e x a mi nati o n (i ncl u di n g wei g ht) a n d 
vital si g ns perf or me d pri or t o be gi n ni n g a p heresis, a n d a n a b bre vi ate d p h ysical e x a mi nati o n a n d 
vital si g ns a gai n after c o m pleti o n of a p heresis.  
5. 2. 2.  
B o ne M arr o w H ar v est Pr oce d ure  
If s ufficie nt cells f or res c ue ar e n ot pr oc ure d aft er 2 M o bilizati o n C ycles, t he i n vesti gat or ca n 
pr ocee d  wit h  a  b o ne  marr o w  har vest.  B o ne  marr o w  har v est  will  be  perf or me d  acc or di n g  t o  
i nstit uti o nal g ui deli nes at t he cli nical site.  
5. 2. 3.  
C o n diti o ni n g  
5. 2. 3. 1.  
Ge ner al C o nsi der ati o ns  
M yel oa blati ve c o n diti o ni n g of t he s u bject will be perf or me d usi n g b us ulfa n.  
C o n diti o ni n g will o nl y be gi n after t h e f oll o wi n g criteria are met:  
1.  All Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct t o be use d f or a partic ular s u bject has bee n r elease 
teste d, dis p ositi o ne d f or cli nical use, a n d is st ore d at t he cli nical site.  
2.  It is rec o m me n de d t hat s u bjects mai ntai n a h y pertra nsf usi o n re gi me n at least 3 0 da ys pri or 
t o c o n diti o ni n g t o mai ntai n a pre-tra nsf usi o n H b of ≥1 1 g/ d L. Ir o n c helati o n will li kel y 
nee d t o be a dj uste d t o c o m pe nsate f or t h e i ncrease d ir o n l oa d, u ntil re q uire d disc o nti n uati o n 
per pr ot oc ol. See Secti o n  5. 9. 3  f or details. 
3.  T h e  s u bject  has  u n der g o ne  A E  a n d  c o nc o mita nt  me dicati o ns  assess me nts,  p h ysical  
e xa mi nati o n, vital si g ns, a n d la b orat or y tests as per t he S O E a n d c o nti n ues t o meet t he 
eli gi bilit y criteria base d o n t hese res ults.  
4.  Ir o n c hel ati o n t hera p y has bee n st o p pe d at least 7 da ys pri or t o start of t he c o n diti o ni n g. 
D ue t o dr u g -dr u g i nter acti o ns (S weiss et al., 2 0 1 2 ), disc o nti n uati o n of deferasir o x, a n d 
i nstit uti o n of a n alter nati ve ir o n c hel ati o n a ge nt, at least 2 5 da ys bef ore i nitiati n g b us ulfa n 
treat me nt ma y be c o nsi dere d; if t his is d o ne, t he alter nati ve c hel ati o n a ge nt s h o ul d be 
st o p pe d at least 7 da ys pri or t o starti n g b us ulfa n. 
5.  B us ulfa n will be a d mi nistere d via I V i nf usi o n f or 4  c o nsec uti ve da ys o n D a ys ‑ 6  t hr o u g h -
3, at a st arti n g d ose of 3. 2 m g/ k g as a 3 -h o ur i nf usi o n o nce dail y f or a t otal  of 4 d oses or 
0. 8 m g/ k g as a 2 -h o ur i nf usi o n e ver y 6 h o urs f or a t otal of 1 6  d os es. Please refer t o t h e 
b us ulfa n prescri bi n g i nf or mati o n f or details o n a p pr o priate met h o d f or  d eter mi nati o n of 
patie nt wei g ht. It is rec o m me n de d t hat b us ulfa n is a d mi nistere d at  0. 8 m g/ k g e ver y 6 h o urs 
i n  c hil dre n  a n d  a d olesce nts  t o  a v oi d  hi g her  pea k  c o nce ntrati o ns w hile  still  pr o vi di n g  
e q ui vale nt dail y e x p os ur e. A n y m o dificati o ns t o t he b us ulfa n re gi me n s h o ul d be re vie w e d 
a n d a p pr o v e d b y t he Me dical M o nit or pri or  t o a d mi nistrati o n. Please n ote t hat t he ti mi n g 
of b us ulfa n p har mac o ki n etic ( P K)  s a m ple c ollecti o n is base d o n w h et her a 2 -h o ur or 3 -
h o ur  i nf usi o n  is  use d.  T he  d ose of  b us ulfa n  will  be  a dj uste d  base d  o n  first  d ose  
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p har mac o ki netics ( a n d if a vaila ble, t hir d da y d ose p har mac o ki n etics) i n or der t o attai n 
tar gete d c o nce ntrati o n ( area u n der t he c ur v e [ A U C]; see n e xt Secti o n  5. 2. 3. 2  f or tar gete d 
A U Cs). If nee d e d, t he Da y 4 b us ulfa n d os e ma y be dela ye d b y u p t o 1 2 h o urs t o all o w f or 
t he recei pt of t he Da y 3 b us ulfa n P K res ults a n d a p pr o priate d ose m o dificati o n. 
Cli nical s ites t hat all o w f or a test d os e of b us ulfa n se v eral da ys b ef ore m yel oa blati o n t o pre-
deter mi ne t he b us ulfa n d ose ma y als o d o s o i n t his pr ot oc ol. A d diti o nal m o dificati o ns t o t he 
b us ulfa n c o n diti o ni n g re gi me n (e. g., s plitti n g d oses) ma y be c o nsi dere d  after disc ussi o n a n d 
a gree m e nt wit h t he Me di cal M o nit or.  
U nless  t he y  ha v e  a  c o ntrai n dicati o n,  all  s u bjects  are  t o  recei ve  pr o p h yla xis  f or  h e patic  
ve n o‑ occl usi ve  disease  ( V O D)/si n us oi dal  o bstr u cti o n  s y n dr o me  ( S O S)  pri or  t o  i nitiati o n  of 
c o n diti o ni n g, a n d t his s h o ul d be rec or de d i n t h e e C R F; urs o de o x yc h oli c aci d is preferre d a n d 
s h o ul d be a d mi nistere d per i nstit uti o nal g ui deli nes. If t here are n o i nstit uti o nal sta n dar ds f or 
a d mi nistrati o n of urs o de o x yc h olic aci d, t he n t h e f oll o wi n g re gi me n s h o ul d be use d: 1 2 m g/ k g dail y 
di vi de d  i n  2  d oses,  st arti n g  at  least  5  da ys  pri or  t o  i nitiati o n  of  b us ulfa n  c o n diti o ni n g  a n d  
c o nti n ui n g f or t he first 3 m o nt hs after c o m pleti o n of b us ulfa n c o n diti o ni n g ( R u ut u et al. 2 0 0 2, 
2 0 1 4) . A nti-seiz ur e pr o ph yla xis s h o ul d be gi n at least 1 2 h o urs bef ore i nitiati n g b us ulfa n a n d 
s h o ul d c o nti n ue f or at least 2 4 h o urs after c o m pleti o n of t he f o ur d a ys of b us ulfa n a d mi nistrati o n. 
All dr u gs ot her t ha n p he n yt oi n are all o we d f or a nti -seiz ure pr o p h yla xis. A d diti o nal s up p orti ve 
me dicati o ns are p er mitte d as per site sta n dar d practices.  
5. 2. 3. 2.  
P h ar m ac o ki netics f or B us ulf a n D ose A dj ust me nts  
Tar get first d ose P K will be perf or me d i n all s u bjects re gar dless of b us ulfa n d osi n g sc he d ule. Dail y 
d osi n g will tar get a n A U C 0- 2 4 h of 4 2 0 0 (ra n ge 3 8 0 0 t o 4 5 0 0) µ M * mi n. E ver y 6- h o ur ( q 6 h) d osi n g 
will tar get a n A U C 0- 6 h of 1 0 5 0 (ra n ge 9 5 0 t o 1 1 2 5) µ M * mi n. 
Sa m ples f or P K a nal ysis of b us ulfa n d ose will als o be dra w n o n t he t hir d da y of d osi n g (after 
c o m pleti o n of 3r d da y of o nce dail y d osi n g or after first d ose o n t hir d da y w h e n usi n g q 6 h re gi me n) 
usi n g g ui deli nes bel o w.  
Rec o m m e n d ati o ns f or o nce d aily d osi n g : Sa m ples f or b us ulfa n P K a nal ysis s h o ul d be c ollecte d at 
t he e n d of t he first 3 h o ur i nf usi o n ( 3 h o ur ti m e p oi nt), t he n at 3 h o urs 1 5 mi n utes, 3  h o urs 
3 0 mi n utes, 4 h o urs, 5 h o urs, 6 h o urs, a n d 8 h o urs ( +/ − 5 mi n ute wi n d o w u p t o a n d i ncl u di n g t he 
3 h o ur 3 0 mi n utes ti me p oi nt; +/ − 1 5 mi n ute wi n d o w f or all s u bse q ue nt c ollecti o ns ti mes) after t he 
start of t he first i nf usi o n. Sa m ples f or P K a nal ysis s h o ul d als o be dra w n o n t h e t hir d da y of b us ulfa n 
d osi n g, usi n g t he sa me sc he d ule.  
Rec o m m e n d ati o ns f or d osi n g every 6 h o urs ( q 6 h):  Sa m ples f or b us ulfa n P K a nal ysis s h o ul d be 
c ollecte d at t he e n d of t he first 2 h o ur i nf usi o n ( 2 h o ur ti me p oi nt), t he n at 2 h o urs 1 5 mi n utes, 
2 h o urs  3 0  mi n utes,  3  h o urs,  4  h o urs,  5  h o urs,  a n d  6  h o urs  ( +/ −  5  mi n ute  wi n d o w  u p  t o  a n d 
i ncl u di n g t he 2 h o ur 3 0 mi n utes ti me p oi nt; +/ − 1 5 mi n ute wi n d o w f or all s u bse q ue nt c ollecti o ns 
ti mes) after t he start of t he first i nf usi o n. Sa m ples f or P K a nal ysis s h o ul d als o be dra w n o n t he 
t hir d da y of b us ulfa n d osi n g, usi n g t he sa me sc he d ule. 
N ote: Sa m ples s h o ul d n ot be dra w n fr o m t he l u me n use d t o i nf use b us ulfa n. 
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Cli nical sites m ust eit her be a ble t o meas ure first a n d t hir d da y b us ulfa n P K, or alter nati vel y 
e m pl o y a test d ose of b us ulfa n se v eral d a ys b ef ore b e gi n ni n g m yel oa blati o n t o pre -d eter mi ne 
b us ulfa n d ose a n d r e -c o nfir m P K o n t he first da y of d osi n g. Base d o n  b us ulfa n P K res ults f or da y  1 
a n d (if test d ose met h o d is n ot use d) da y 3 of d osi n g, b us ulfa n d ose a dj ust me nts s h o ul d be ma de 
f or s u bse q ue nt d osi n g as p ossi ble. Sites t hat r o uti nel y perf or m dail y b us ulfa n m o nit ori n g, wit h 
s u bse q ue nt d ose a dj ust m e nts, ma y d o s o as part of t his pr ot oc ol. S pecific det ails re gar di n g b us ulfa n 
d osi n g, p har mac o ki netics a n d a dj ust me nts will be ca pt ure d i n t he case re p ort f or m ( C R F).  
After c o m pleti o n of t he 4 -da y c o urse of b us ulfa n, t here m ust b e a mi ni m u m of 4 8  h o urs b ef ore 
Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct a d mi nistrati o n. B us ulfa n le vels will be meas ure d 4 8 h o urs after 
fi nal d ose of b us ulfa n f or retr os pecti ve c o nfir mati o n of a de q uat e was h- o ut. 
5. 2. 4.  
I nf usi o n Pr oce d ures, D ose, a n d A d mi nistr ati o n 
Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct is t o be gi ve n after a mi ni m u m of 4 8  h o urs after c o m pleti o n of 
t he b us ulfa n c o n diti o ni n g re gi me n i n or der t o ac hi e ve c o m plete was h o ut of b us ulfa n.  
Pre -h y drati o n a n d pre -m e dicati o n of t he s u bject are n ot re q uire d b ut sites s h o ul d f oll o w l ocal 
pr oce d ur es f or H S C i nf usi o n.  
Pri or t o a d mi nistrati o n, t he dr u g pr o d uct(s) m ust be t ha we d at a p pr o xi matel y 3 7° C a n d t he i nf usi o n 
of t he dr u g pr o d uct s h o ul d be c o m plete d i m me diatel y aft er t ha wi n g a n d wit hi n a ma xi m u m of 4 
h o urs of its t ha wi n g.  
Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct will be  a d mi nistere d o n Da y  1 via I V i nf usi o n at t he cli nical 
site.  T he  d ose  t o  be  a d mi nistere d  is  ≥5. 0 × 1 0 6 C D 3 4 +  cells/ k g.  S u bjects  w h o  u n der g o  
2 m o bilizati o n c ycles (a n d s u bse q ue nt tra ns d ucti o n of t h ose cells) t o ac hie ve a t otal d ose of 
≥5. 0 × 1 0 6 C D 3 4 +  cells/ k g  will  ha ve  2  Le nti Gl o bi n  B B 3 0 5  Dr u g  Pr o d uct  l ots,  w hic h  will  be  
a d mi nistere d i n se q ue nce, wit h t he sec o n d a d mi nistere d i m me diatel y aft er t he first.  
Vital si g n m o nit ori n g i ncl u di n g E C G, p ulse o xi metr y, a n d bl o o d press ure meas ure me nts, s h o ul d 
be e m pl o ye d d uri n g dr u g -pr o d uct i nf usi o n.  A d diti o nall y, vital si g ns (e xcl u di n g E C G) s h o ul d be 
meas ure d f or t w o h o urs after i nf usi o n (e. g. e v er y 3 0 t o 6 0 mi n utes). I nf usi o n reacti o ns, i ncl u di n g 
a na p h yla xis, will be m a n a ge d acc or di n g t o t he me dical j u d g me nt of t he p h ysicia n o vers eei n g t he 
i nf usi o n. Refer t o t he St u d y O perati o ns Ma n u al ( S O M) f or a d diti o nal det ail re gar di n g i nf usi o n. 
5. 3.  
St or a ge a n d St a bilit y of Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct  
All cell ma ni p ulati o n pr oce d ures will be perf or m e d i n tra ns d ucti o n facilities i n acc or da n ce wit h 
c urre nt G o o d Ma n ufact uri n g Practice ( G M P) f oll o wi n g pr ocess -s pecific pr o ce d ures. T h e s u bject’s 
C D 3 4 + cell -e nric he d p o p ulati o n c o ntai ni n g cells tra ns d uce d wit h B B 3 0 5 le nti viral vect or are 
fr oze n  a n d  st ore d  i n  cr y o preser v ati o n  s ol uti o n  i n  t he  va p or  p hase  of  li q ui d  nitr o ge n  at  t he  
tra ns d ucti o n facilit y u ntil releas e testi n g a n d dis p ositi o ni n g f or cli nical use. Le nti Gl o bi n B B 3 0 5 
Dr u g Pr o d uct will be st ore d i n t h e v a p or p h ase of li q ui d nitr o ge n at t he cli nical site u ntil t ha w e d 
f or cli nical use. 
5. 4.  
Pr o d uct  Acc o u nt a bilit y  
Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct acc o u nta bilit y a n d tracea bilit y are ulti matel y t he res p o nsi bilit y 
of t he Pri nci pal I n vesti g at or a n d S p o ns or. H o we ver, t his res p o nsi bilit y ma y be dele gat e d t o a 
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s uita bl y q ualifie d i n vesti gat or w h o has ha d a p pr o priate st u d y-s pecifi c trai ni n g a n d w h ose na me 
has bee n a p pr o priatel y liste d o n t he Dele gati o n of Res p o nsi bilit y L o g f or t his tas k. 
Detaile d r ec or ds will be mai ntai ne d t o all o w f or acc urate acc o u nta bilit y a n d tracea bilit y of t he 
Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct as per a p plica ble S p o ns or a n d cli nical site pr oce d ures. Refer t o 
t he S O M f or f urt her details. 
All material c o ntai ni n g Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct will be treat e d a n d dis p ose d of as 
hazar d o us waste i n acc or da nce wit h g o ver ni n g re g ulati o ns a n d cli nical site pr oce d ures. 
5. 5.  
Met h o d of Assi g ni n g S u bjects t o Tre at me nt  
All s u bjects e nter e d i nt o t he st u d y will be assi g ne d t o t he si n gle treat me nt gr o u p i n t his o pe n -la b el 
st u d y. 
5. 6.  
Bli n di n g, P ac k a gi n g, a n d L a beli n g  
5. 6. 1.  
Bli n di n g a n d Bre a ki n g t he Bli n d  
T his is a n u n bli n de d, o pe n- la bel st u dy. 
5. 6. 2.  
P ac k a gi n g a n d L a beli n g  
Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct is a n a ut ol o g o us C D 3 4 + cell -e nric h e d p o p ulati o n t hat c o ntai ns 
he mat o p oietic  ste m  cells  tra ns d uce d  wit h  B B 3 0 5  le nti viral  vect or  e nc o di n g  t he  β A‑ T 8 7 Q - gl o bi n 
ge ne, s us pe n de d i n cr y o preser v ati o n s ol uti o n. 
Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct will be la b ele d b y t he tra ns d u cti o n facilit y wit h f ull patie nt 
tracea bilit y acc or di n g t o G o o d Ma n ufact uri n g Practices.  
5. 7.  
D ur ati o n of S u bject P artici p ati o n  
Ti me bet wee n Scree ni n g a n d dr u g pr o d u ct i nf usi o n will be varia ble a n d  is esti mate d ge nerall y t o 
be bet wee n 3 t o 5 m o nt hs (e. g., u p t o 3 m o nt hs bet wee n Scree ni n g a n d M o bilizati o n, f oll o we d b y 
ar o u n d 2 m o nt hs bef or e dr u g pr o d uct i nf usi o n). T hereafter s u bject is pla n n e d t o re mai n o n st u d y 
f or a p pr o xi matel y 2 4 m o nt hs. Eli gi ble s u bjects will t he n be e x pecte d t o e nr oll i n a se parate 
l o n g‑ter m f oll o w- u p st u d y u ntil a p pr o xi matel y 1 5 years p ost‑ dr u g pr o d uct i nf usi o n.  
If t he s u bject is u na ble t o u n der g o m o bilizati o n wit hi n a p pr o xi matel y 3 m o nt hs of t he i nitiati o n of 
scree ni n g, s o me assess me nts ma y nee d t o be re peate d t o c o nfir m c o nti n ui n g eli gi bilit y or t o 
pr o vi de a relia ble b aseli ne pri or t o st u d y pr o ce d ures. I n p artic ular, p h ysical e x a m,  vital si g ns, 
perf or ma n ce  stat us,  H R Q o L,  electr o car di o gra m  ( E C G),  c o m plete  bl o o d  c o u nt,  c h e mistr y,  
uri nal ysis, a n d li ver f u ncti o n tests, a n d f or w o me n of c hil d -beari n g p ote ntial, tests f or  pre g n a nc y, 
m ust be perf or me d wit hi n 3 m o nt hs of  pr ocee di n g t o e val uati o n f or m o bilizati o n. F or s u bjects wit h 
e x p os ure ris ks f or HI V, H B V a n d H C V, t hese tests s h o ul d als o be re peat e d.  
S o me of t hese assess me nts ma y be perf or me d i m me diatel y pri or t o m o bilizati o n, as s pecifie d i n 
t he sc he d ule of e ve nts. W here cli nicall y a n d/ or re gi o nall y i n dicate d, ot h er tests f or i nfecti o us 
pat h o ge ns ma y be p erf or me d, as re q uir e d b y re gi o nal re g ulati o ns or at p h ysicia n discreti o n. Ot her 
bl o o d tests, i ncl u di n g t h ose f or i m m u ne s u bsets, h or m o nal or d ys er yt hr o p oiesis testi n g  o nl y nee d 
t o be re p eate d if m ore t h a n 6 m o nt hs ha ve tra ns pire d, u nless t here is cli nical c o n cer n d ue t o a n 
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i nitial scree ni n g test (e. g. b or derli ne t h yr oi d f u ncti o n). Car diac M RI (if i nitial val ue ≥ 1 5 ms, a n d 
n o cli nicall y si g nifica nt a b n or malit y o n E C G) a n d li ver M RI (if n o e vi de nce of fi br osis a n d LI C ≤ 
1 0 m g/ g o n i nitial M RI, a n d if n o ne w cli nicall y si g nifica nt li ver f u ncti o n a b n or malities) d o n ot 
nee d t o be re peate d if p erf or me d wit hi n t he p ast 1 year, a n d if ir o n c helati o n has bee n a d here d t o 
i n t he i nter v e ni n g ti me; if t hese sti p ulati o ns are n ot met, t he n t hese tests s h o ul d be re peate d if m ore 
t ha n 3 m o nt hs ha ve tra ns pire d. T he n ee d f or li ver bi o ps y s h o ul d be g ui d e d b y M RI fi n di n gs, as 
descri be d i n t he pr ot oc ol, u nless a bi o ps y perf or m e d wit hi n o ne year of m o bilizati o n e x hi bite d n o 
e vi de nce of fi br osis or he patitis. P ul m o nar y f u ncti o n tests a n d ec h ocar di o gra p h y (if n o b or derli ne 
val ues o n i nitial testi n g of eit her test) als o d o n ot nee d t o be re peate d u nless m ore t ha n 1 year has 
tra ns pire d. T hal asse mia  ge n ot y pi n g,  baseli ne  V C N,  baseli ne  R C L  a n d  b aseli ne  β A- T 8 7 Q - gl o bi n, 
o nce perf or me d, d o n ot h a ve t o be r e peat e d.  
5. 8.  
Assess me nt of Tre at me nt C o m pli a nce  
Eli gi ble s u bjects will recei ve Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct b y I V a d mi nistrati o n o n a si n gle 
da y as i n - patie nts a n d t h us will be m o nit ore d b y h os pital pers o n nel. 
5. 9.  
Pri or a n d C o nc o mit a nt Me dic ati o ns  
5. 9. 1.  
Pri or Me dic ati o ns  
All me dicati o ns ta ke n wit hi n 3 0 da ys pri or t o t he Scree ni n g Visit f or eli gi ble s u bjects are t o b e 
rec or d e d i n t he C R F, wit h t he e xce pti o n of p R B C tra nsf usi o ns a n d ir o n c h elat ors, w hic h are t o be 
ca pt ure d f or t he 2 years pri or t o st u d y e nr oll me nt (si g ni n g of t he i nf or me d c o nse nt f or m [I C F]), as 
n ote d bel o w a n d i n Secti o n 6. 2. 1  Me dical Hist or y.  
5. 9. 2.  
C o nc o mit a nt Me dic ati o ns a n d T her a pies: Ge ner al  
All c o nc o mita nt treat me nts, i ncl u di n g tra nsf usi o ns, will be d oc u me nte d. 
T he use of er yt hr o p oieti n -li ke sti m ulati n g a ge nts, h y dr o x y urea, a n d electi ve s ple necto m y (f or 
s u bjects wit h i ntact s plee ns) will be pr o hi bite d fr o m Scree ni n g t hr o u g h e n d of st u d y. I n a d diti o n, 
use of a n y p ote ntiall y dis ease m o dif yi n g t hera p y (e. g., l us paterce pt) s h o ul d n ot be i nitiate d wit h o ut 
disc ussi o n wit h a n d e x plicit a p pr o val of t he S p o ns or’s Me dical M o nit or. 
Per mitte d c o nc o mita nt treat me nts ma y i ncl u de:  
•  H y drati o n, be gi n ni n g 1 2 h o urs b ef ore i nitiati n g c o n diti o ni n g a n d c o nti n ui n g t hr o u g h 
2 4 h o urs t hereafter 
•  Pre ve nti o n or treat me nt of na usea a n d v o miti n g b y pr o p h ylactic a d mi nistrati o n of a nti -
na usea me dicati o ns  
•  Seiz ure  pr o p h yla xis.  All  dr u gs  ot her  t ha n  p h e n y t oi n  are  all o we d  f or  a nti-seiz ure 
pr o p h yla xis d uri n g c o n diti o ni n g.   
•  Urs o de o x yc h olic  aci d  s h o ul d  be  a d mi nistere d  pr o p h ylacticall y  f or  pre ve nti o n  of  
he patic ve n o -o ccl usi ve disease ( V O D)/si n us oi dal o bstr ucti o n s y n dr o me ( S O S), u nless 
t he s u bject has a c o ntrain dicati o n t o use of urs o de o x yc h olic aci d. Defi br oti de ma y be 
use d i n lie u of urs o de o x yc h olic aci d as pr o p h yla xis a n d s h o ul d be a d mi nistere d per 
i nstit uti o nal sta n dar ds f or pre ve nti o n a n d/ or treat me nt of V O D/ S O S. If t here are n o 
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i nstit uti o nal sta n dar ds f or a d mi nistrati o n of urs o d e o x yc h olic aci d, t he n t he f oll o wi n g 
re gi me n s h o ul d be use d: 1 2 m g/ k g dail y di vi de d i n 2 d oses, starti n g at least 5 da ys pri or 
t o  i nitiati o n  of  b us ulfa n  c o n diti o ni n g  a n d  c o nti n ui n g  f or  t he  first  3  m o nt hs  after  
c o m pleti o n of b us ulfa n c o n diti o ni n g ( R u ut u et al. 2 0 0 2, 2 0 1 4). 
•  Tra nsf usi o ns s h o ul d be gi ve n acc or di n g t o H b a n d platelet c o u nts base d o n i nstit uti o nal 
g ui deli nes d uri n g t he h os pitalizati o n t o s u p p ort e n graft me nt. All bl o o d pr o d ucts will 
be filt ere d a n d irra diat e d.  
•  G- C S F s h o ul d n ot be use d pri or t o Da y 2 1 wit h o ut e x plicit a p pr o val fr o m t he bl ue bir d 
bi o Me dical M o nit or. After Da y 2 1, G -C S F ma y be use d acc or di n g t o i nstit uti o nal 
g ui deli nes.  
•  S u bjects will be is olate d a n d a p pr o priate preca uti o ns will be ta ke n if t he p ol y n uclear 
le u k oc yte  c o u nt  is  < 0. 5 ×  1 09/ L.  Br oa d-s pectr u m  a nti bi otic  treat me nt  will  be  
a d mi nistere d  acc or di n g  t o  sta n dar d  pr oce d ures  f or  t he  ma na ge me nt  of  fe brile  
ne utr o pe nia. 
F or t h e p ur p os es of t his st u d y, vacci n es (e. g., C O VI D -1 9 vac ci nes) are c o nsi dere d c o nc o mita nt 
me dicati o ns. Alt h o u g h i nteracti o ns bet w ee n a vacci ne a n d L e nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct are 
n ot
 e x pecte d,  t he  pr ot oc ol
 i ncl u des
 use  of  i m m u n o m o d ulat or y  ( pleri xaf or)  a n d
 
i m m u n os u p pressi ve  me dicati o n  ( b us ulfa n).  L ocal  g ui deli nes  s h o ul d  be  f oll o we d  re gar di n g  a  
mi ni m u m  ti me  peri o d  bet wee n  a n y  me dicati o n  t o  be  pr o vi de d  as  part  of  treat me nt  wit h  
Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct a n d a n y vacci ne; it is rec o m me n de d t hat vacci nes are n ot 
a d mi nistere d t o s u bjects wit hi n 1 m o nt h of i nitiati n g m o bilizati o n f or ste m cell c ollecti o n, wit hi n 
1  wee k  after  r ecei vi n g  m o bilizati o n  a ge nts,  wit hi n  1  m o nt h  of  i nitiati n g  m yel oa blati ve  
c o n diti o ni n g, or wit hi n 6 m o nt hs after dr u g pr o d uct i nf usi o n. Re vacci nati o n p ost -dr u g pr o d uct 
i nf usi o n s h o ul d be c o nsi dere d p er I n v esti gat or's discreti o n d ue t o p ote ntial l oss of i m m u nit y after 
m yel oa blati ve c o n diti o ni n g a n d ma y be a d mi nistere d f oll o wi n g l ocal g ui deli nes. 
T he pr escri bi n g i nf or mati o n of t he v acci n e a d mi nistere d s h o ul d be  referre d t o  f or  t he lat est  
i n dicati o n,  c o ntrai n dicati o ns  a n d  safet y  i nf or m ati o n  as  well  as  t he  l atest  ge neral  cli nical  
rec o m me n dati o ns o n vacci ne a d mi nistrati o n i n t he c o u ntr y or re gi o n. 
All vacci nati o ns d uri n g t he st u d y peri o d s h o ul d be d oc u me nte d i n t he C R F. 
See ne xt secti o ns f or tra nsf u si o ns ( Secti o n 5. 9. 3 ), ir o n c helati o n ( Secti o n 5. 9. 4 ), a n d i nfecti o n 
pr o p h yla xis ( Secti o n  5. 9. 5 ) rec o m me n d ati o ns. 
5. 9. 3.  
C o nc o mit a nt Me dic ati o ns a n d T her a pies: Tr a nsf usi o ns  
Tra nsf usi o ns f or t he 2 y ears pri or t o scree ni n g t hr o u g h e n d of st u d y will be d oc u me nte d. 
Rec o m me n dati o ns f or tra nsf usi o ns are ma d e f or 4 se parat e peri o ds d uri n g treat me nt:  
1.  Pri or t o a p heresis: tra nsf usi o ns are rec o m me n de d t o o btai n H b ≥1 1 g/ d L.  
2.  It is rec o m me n de d t hat, if p ossi ble, pre-tra nsf usi o n H b ≥1 1 g/ d L be mai ntai ne d f or at least 
o ne  m o nt h  pri or  t o  i nitiati o n  of  c o n diti o ni n g.  Ir o n  c helati o n  s h o ul d  be  a dj uste d  
a p pr o priatel y t o mi ni mize t he effects of t h e a d diti o nal ir o n l oa d.  
3.  D uri n g  c o n diti o ni n g  a n d  h os pitalizati o n  s u p p orti n g  e n graft me nt:  f oll o w  i nstit uti o nal  
g ui deli nes.  
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4.  D uri n g p ost -disc har ge f oll o w -u p: It is rec o m me n de d t hat s u bjects s h o ul d recei v e R B C 
tra nsf usi o ns f or a n y H b < 7 g/ d L, a n d f or cli nicall y s y m pt o matic a ne mia, irres pecti ve of H b 
le vel.  Decisi o ns  re g ar di n g  tra nsf usi o n  i n  as y m pt o matic  s u bjects  ( wit h o ut  cli nicall y  
s y m pt o matic a ne mia) s h o ul d be base d o n ce ntral la b orat or y H b val ues a n d n ot l ocall y 
dra w n H b. Tra nsf usi o ns s h o ul d be a v oi de d f or H b ≥9  g/ d L, u nless t he nee d is me dicall y 
j ustifie d (e. g., as a pre-re q uire me nt f or s ur ger y), or if t he s u bject h as a n ac q uire d c o n diti o n 
re q uiri n g hi g her bas eli ne H b (e. g. pre g na nc y).  
5. 9. 4.  
C o nc o mit a nt Me dic ati o ns a n d T her a pies: Ir o n C hel ati o n 
Ir o n c hel at ors f or t he 2 y ears pri or t o s cree ni n g t hr o u g h e n d of st u d y will be d oc u me nte d. 
C helati o n m ust st o p at least 7 da ys pri or t o starti n g b us ulfa n. D ue t o dr u g -dr u g i nteracti o ns (S weiss 
et al., 2 0 1 2), disc o nti n uati o n of deferasir o x a n d i nstit uti o n of a n alter nati ve ir o n c helati o n age nt at 
least 2 5 da ys bef ore i nitiati n g b us ulfa n treat me nt m a y be c o nsi d ere d; if t his is d o ne, t he alter nati ve 
c helati o n a g e nt s h o ul d b e st o p pe d at least 7 da ys pri or t o starti n g b us ulfa n. Ir o n c h elati o n t hera p y 
usi n g deferasir o x or d ef er o xa mi ne s h o ul d be restarte d n o s o o ner t ha n aft er disc h ar ge fr o m t he 
h os pital p ost-tra ns pla nt. Deferi pr o ne ma y be us e d n o s o o ner t ha n 6 m o nt hs after tra ns pla nt d u e t o 
t he  p ote ntial  ris k  of  m yel os u p pressi o n  (as  per  prescri bi n g  i nf or mati o n  f or  Deferi pr o n e),  a n d  
alter nati ve c h elati o n re gi me ns s h o ul d be e m pl o ye d i n t he i nteri m. Starti n g d ose of c helat or is 
rec o m me n de d b ase d o n i nstit uti o nal pr ot oc ols. D oses ma y nee d t o be a dj uste d c o nti n u o usl y base d 
o n ser u m ferriti n le vels t o pre ve nt t o xicit y. 
P hle b ot o m y ca n be use d i n lie u of c helati o n i n s u bjects w h o ha ve H b c o nsiste ntl y ≥1 1 g/ d L a n d 
w h o  are  n o  l o n ger  recei vi n g  re g ular  tra nsf usi o ns.  T o  a v oi d  t o xicit y,  o nce  ser u m  ferriti n  is  
≤1 0 0 0  n g/ m L,  d o w n war d  a dj ust me nt  of  d ose  of  c helat or  a n d  d ecreasi n g  t he  fre q u e nc y  of  
p hle b ot o m y is a d vise d, as per i nstit uti o nal pr ot oc ols. C helati o n s h o ul d be disc o nti n ue d if s u bjects 
bec o me TI, LI C is < 5 m g/ g, a n d ser u m ferriti n is < 5 0 0 n g/ m L. S u bjects w h o are n ot ta ki n g c helat ors 
s h o ul d be c o nti n uall y r eassesse d f or c hel ati o n nee ds p ost-H S C T base d o n t he S O E of t h e rele va nt 
pr ot oc ol. 
5. 9. 5.  
C o nc o mit a nt Me dic ati o ns: I nfecti o n S ur veill a nce a n d Pr o p h yl a xis 
T he Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct is a C D 3 4 + cell -e nric he d p o p ulati o n a n d is f u ncti o nall y 
T cell-de plete d.  T h us,  o p p ort u nistic  i nfecti o n  s ur veilla nce  a n d  pr o p h yla x is  is  rec o m me n de d.  
Bel o w is a s u g geste d a p pr oac h t o i nfecti o n s ur veilla nce a n d pr o p h yla xis. Alter nati ves t hat f oll o w 
i nstit uti o nal practices ma y be e m pl o ye d. 
•  I n s u bjects wit h past e x p os ure t o H B V, re g ular m o nit ori n g of H B V de o x yri b o n ucleic 
aci d ( D N A) f or u p t o 3 m o nt hs after dr u g pr o d uct i nf usi o n is a d vise d, wit h pre -e m pti ve 
la vi m u di ne rec o m me n d e d f or a n y i ncreas e i n H B V D N A titer ( H B V reacti vati o n). 
Si milarl y, s u bjects wit h past e x p os ure t o H C V will u n der g o re g ular m o nit ori n g of H C V 
D N A f or u p t o 3 m o nt hs after dr u g pr o d uct i nf usi o n. 
•  Her pes si m ple x vir us ( H S V) pr o p h yla xis: Ac ycl o vir pr o p h yla xis is rec o m me n de d f or 
at least 3 m o nt hs after dr u g pr o d uct i nf usi o n f or p atie nts w h o are s er o -p ositi v e f or H S V 
or varicella z oster vir us ( V Z V).  
•  P ne u m oc ystis  p ne u m o nia  pr o p h yla xis:   Tri met h o pri m -s ulfa met h o xaz ole  or  a n  
e q ui vale nt dr u g is rec o m me n de d f or at least 3 m o nt hs after dr u g pr o d uct i nf usi o n.  
C CI

Pr ot oc ol H G B - 2 0 7 Versi o n 6. 0  
1 0 J u ne 2 0 2 1  
Pa ge 5 5 
 
•  F u n gal  pr o p h yla xis:  A nti -f u n gal  pr o p h yla xis is rec o m me n de d wit h a ge nts s uc h as 
fl uc o naz ole f or at least 3 m o nt hs after dr u g pr o d u ct i nf usi o n.  
•  I ntr a ve n o us i m m u n o gl o b uli n (I g G) ma y be a d mi nistere d f or 3 m o nt hs t o mai ntai n I g G 
le vels per i nstit uti o nal g ui deli nes. 
•  F oll o w i nstit uti o nal p ost -tra ns pla ntati o n g ui deli nes f or re-i m m u nizati o n of s u bjects. 
•  S u bjects s h o ul d n ot use me dicati o ns wit h a nti -retr o viral acti vit y (s uc h as t h ose use d f or 
HI V pr e -e x p os ure pr o p h yla xis) fr o m at least o ne m o nt h pri or t o m o bilizati o n u ntil at 
least 7 da ys after dr u g pr o d uct i nf usi o n. 
6.  
S T U D Y A S S E S S M E N T S  
6. 1.  
Sc he d ule of E ve nts  
T he st u d y has 4 disti nct sta ges, as f oll o ws. 
•  Sta ge 1:  
Scree ni n g  
•  Sta ge 2:  
A ut ol o g o us C D 3 4 + cell c ollecti o n a n d L e nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct 
ma n ufact ur e a n d dis p ositi o n 
•  Sta ge 3:  
M yel oa blati ve c o n diti o ni n g (a p pr o xi matel y Da y -6 t hr o u g h Da y   -3) a n d 
i nf usi o n of Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct ( D a y 1) 
•  Sta ge 4:   
F oll o w- u p t hr o u g h M o nt h 2 4 
T he S O E t o be p erf or me d is o utli ne d i n Ta ble  4 f or Sta ges 1 a n d 2, i n Ta ble  5 f or Sta ge 3, a n d i n 
Ta ble  6 f or Sta ge 4.  
Detaile d descri pti o ns of t he efficac y, p h ar mac o d y na mics, a n d safet y pr oce d ures t o be c o n d uct e d 
d uri n g t his st u d y are pr o vi de d i n t he f oll o wi n g s u bsecti o ns. I n  partic ular, certai n la b orat or y tests 
re q uire d f or g o o d cli nical practices ma y be dra w n c o nc urre ntl y f or a nal ysis b y b ot h ce ntral a n d 
l ocal la borat ories; t hese will be s pecifie d i n t he S O M. It will be at t he I n v esti gat or's discreti o n t o 
dra w l ocal la b or at or y ass a ys base d o n t he ur ge nc y nee de d f or t he res ults. Assa ys re q uire d d uri n g 
h os pitalizati o n peri o ds (i.e., m o bilizati o n/a p heresis, c o n diti o ni n g t hr o u g h tra ns pla nt, a n d p ost -
tra ns pla nt) will n ot be perf or me d ce ntrall y u nless i n dicate d b y t he Me dical M o nit or. 
S u bjects will be as ke d t o c o m pl y wit h t he pr ot oc ol s pecifie d assess me nts acc or di n g t o t he ti me 
peri o ds e n u merat e d i n t he S O E. If t he ti mi n g of assess me nts is s hifte d d ue t o sc he d uli n g c o nflicts 
(e. g.,  li mite d  be d  a v aila bilit y  at  t he  h os pital,  dela ys  i n  scree ni n g  assess me nts,  re p eate d  
m o bilizati o ns, dela ys i n sc he d uli n g c o n diti o ni n g a n d Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct i nf usi o n), 
t hese will n ot be c o nsi der e d pr ot oc ol de viati o ns.  
E val uati o ns a n d pr oce d ures i de ntifie d i n t he S O E ma y be perf or me d at u nsc he d ule d visits, as 
cli nicall y i n dicate d, at t he i n vesti gat or’s discreti o n i n c o ns ultati o n wit h t he S p o ns or as a p pr o pri ate.  
If a s u bject is n ot a ble t o visit t he st u d y site d ue t o f orce of nat ure (e. g., C O VI D-1 9 p a n de mic), 
t he n a tele healt h visit s h o ul d be c o nsi dere d t o e ns ure a p pr o priate o versi g ht a n d safet y m o nit ori n g. 
I n a d diti o n t o t his, if t he s u bject is a ble t o visit a l ocal d oct or a n d/ or la b orat or y, t he n pre- defi ne d 
assess me nts ma y b e p erf or me d at a l o cal la b orat or y or d oct or’s offi ce, p er I n v esti gat or discreti o n.  
C CI

Pr ot oc ol H G B - 2 0 7 Versi o n 6. 0  
1 0 J u ne 2 0 2 1  
Pa ge 5 6 
 
T a ble 4: 
Sc he d ule of E ve nts: Scree ni n g a n d C D 3 4 + Cell H ar vest 
Pr oce d ure  
Scree ni n g  
( U p t o 9 0 d a ys bef ore m o biliz ati o n) M o biliz ati o n
1 
D a ys 
of 
h ar vest  
Si g ni n g of i nf or me d c o nse nt f or m (I C F)/asse nt  
X  
 
 
De m o gra p hics a n d me dical hist or y 2 
X  
 
 
P h ysical e xa mi nati o n  
X 3 
X 3 
X 3 
Vital si g ns  
X  
X 4 
X 4 
Bl o o d f or cli nical la b orat or y tests  
X 5 
X 6 
X 6 
Esti mate d Gl o mer ular Filtrati o n Rate ( G F R)  
X  
 
 
Uri nal ysis  
X  
 
 
Bl o o d f or ser ol o g y  
X 7 
 
 
Bl o o d f or i m m u n ol o gical testi n g  
X 8 
 
 
Bl o o d f or ser u m β -h u ma n c h ori o nic g o na d otr o pi n  f or w o me n of 
c hil d‑ beari n g p ote ntial (ser u m pre g na nc y test)   
X 
X 9 
 
Bl o o d f or h or m o nal a n d d yser yt hr o p oiesis testi n g  
X 1 0 
 
 
Bl o o d f or re plicati o n c o m pete nt le nti vir us ( R C L) 1 1, vect or c o p y n u m ber 
( V C N), gl o bi n H P L C, a n d gl o bi n i n a ut ol o g o us cells 
X 
 
 
Bl o o d f or t halasse mia ge n ot y pi n g 1 2 
X  
 
 
Bl o o d f or st ora ge: p ote ntial bi o mar ker a nal ysis ( o pti o nal)  
X  
 
 
Peri p heral bl o o d C D 3 4 + cell c o u nt  
 
 
X 1 3 
S per m / testic ular tiss ue or o oc yte ba n ki n g, if re q ueste d  
X 1 4 
 
 
Li ver bi o ps y (if re q uire d)  
X  
 
 
B o ne marr o w ( m or p h ol o g y st u dies)  
X 1 5 
 
 
1 2 -lea d E C G 
X  
 
 
I ma gi n g: C hest X-ra y, car diac D o p pler ec h ocar di ol o g y (i ncl. L V E F), 
car diac a n d li ver T 2 * M RI, S O C li ver a n d s plee n M RI, b o ne i ma gi n g 
( X ra y a n d/ or D E X A sca n)1 6 
X 
 
 
P ul m o nar y f u ncti o n tests  
X 1 7 
 
 
Tra nsf usi o n re gi me n  
 
X 1 8 
 
Healt h -relate d Q ualit y of Life ( H R Q o L) Assess me nt 
X  
 
 
A d verse e ve nt c ollecti o n  
C o nti n u o us fr o m I C F si g ni n g  
Pri or a n d c o nc o mita nt me dicati o ns (i ncl. ir o n c helat ors f or t he pri or 2 
years)  
C o nti n u o us fr o m I C F si g ni n g 
1 U p  t o  2  c ycles  of  m o bilizati o n  are  per mitte d.  See  als o  Secti o n  5. 2. 1. 1  f or  rec o m me n dati o ns  o n  d osi n g  f or  
m o bilizati o n.  
2 I ncl u des rec or ds f or t he pri or 2 years tra nsf usi o n hist or y (see Secti o n  6. 2. 1  f or details re q uire d) a n d i n-patie nt 
h os pitalizati o n; i ncl u des ge n ot y pe ( m utati o ns at H B B  ge ne).  
3 I ncl u des wei g ht, hei g ht, ne ur oc o g niti ve de vel o p me nt e val uati o n (f or s u bjects < 1 8 years of a ge), perf or ma nce stat us 
a n d Ta n ner sta gi n g (if rele va nt) at Scree ni n g. A c o m plete p h ysical e xa mi nati o n (i ncl u di n g wei g ht) s h o ul d be 
perf or me d wit hi n 5 da ys pri or t o or o n t he first da y of e ver y m o bilizati o n c ycle, a n d o n e ver y da y of a p heresis pri or 
t o a p heresis. A n a b bre viate d p h ysical e xa mi nati o n is re q uire d e ver y da y after c o m pleti o n of a p heresis. 
4 Vital si g ns s h o ul d be perf or me d o n t he first da y of e ver y m o bilizati o n c ycle, a n d o n eac h a p heresis da y, pri or t o t he 
a p heresis pr oce d ure t he n a gai n after t he a p heresis pr oce d ure is c o m plete d. If t he s u bject u n der g oes a b o ne marr o w 
har vest, vital si g ns s h o ul d be perf or me d o n t he da y of t he b o ne marr o w har vest pri or t o t he har vest a n d t he n a gai n 
pri or t o disc har ge.  
C CI

Pr ot oc ol H G B - 2 0 7 Versi o n 6. 0  
1 0 J u ne 2 0 2 1  
Pa ge 5 7 
 
5 I ncl u des he mat ol o g y ( C B C, platelets, retic ul oc ytes, n ucleate d R B Cs), ir o n st u dies (ir o n, ferriti n, tra nsferri n, ser u m 
tra nsferri n rece pt or), ser u m c he mistr y (i ncl u di n g fasti n g gl uc ose/i ns uli n a n d H o me ostasis M o del Assess me nt i n de x), 
li ver f u ncti o n tests, pr ot hr o m bi n a n d partial t hr o m b o plasti n ti me. Oral gl uc ose t olera nce test is re q uire d f or a n y 
a b n or mal fasti n g gl uc ose.  
6 C B C s h o ul d be  perf or me d d uri n g m o bilizati o n a n d e ver y da y of a p heresis.  
7 I ncl u di n g testi n g f or prese nce of HI V-1, HI V -2, H B V, H C V, a n d R P R. Bl o o d ma y als o be dra w n f or a d diti o nal 
ser ol o g y testi n g if s u bject has ris k fact ors or cli nical e vi de nce of i nfecti o n wit h ot her c o m m u nica ble disease a ge nts 
or disease. Tests s h o ul d be d o ne acc or di n g t o c o u ntr y -s pecific a n d i nstit uti o nal g ui deli nes 
8 T cell s u b sets ( C D 4, C D 8), B cells ( C D 1 9), nat ural killer cells ( C D 1 6 a n d/ or C D 5 6); i m m u n o gl o b uli ns (I g G, I g M, 
a n d I g A)   
9 S h o ul d be c o nfir me d ne gati ve pri or t o m o bilizati o n  
1 0 H or m o nal testi n g i ncl u des t h yr oi d f u ncti o n (free T 4, T S H), P T H. F or s u bjects after p u bert y, als o i ncl u des L H, F S H 
a n d estra di ol (fe males o nl y); test oster o ne ( males o nl y). F or s u bjects < 1 8 years of a ge, i ncl u des gr o wt h h or m o ne 
(I G F-1 a n d I G F B P -3). 
 
1 1 T w o sa m ples re q uire d t o be arc hi ve d f or p ote ntial R C L testi n g: o ne f or t he R C L scree ni n g test, a n ot her f or R C L 
P B L c oc ult ure test  
1 3 Peri p heral bl o o d C D 3 4 + c o u nt s h o ul d be perf or me d o n t he da y pri or t o a p heresis, as well as o n t he da y of a p heresis.  
1 4 Ma y occ ur a n y ti me bef ore c o n diti o ni n g; h or m o nal treat me nt, if a p plica ble as part of ba n ki n g, s h o ul d st o p at least 7 
da ys pri or t o c o n diti o ni n g.  
1 5 B o ne marr o w c ollecti o n f or m or p h ol o g y, cell ularit y, cell c o u nt a n d ir o n stai ns. F or s u bjects u n der g oi n g re -scree ni n g, 
b o ne marr o w c ollecti o n d oes n ot nee d t o be perf or me d. If s ufficie nt sa m ple is a vaila ble, sa m ple ma y be arc hi ve d 
a n d/ or ot her researc h tests (e. g., ge netic testi n g) ma y be perf or me d.  
1 6 A ge a p pr o priate  b o ne i ma gi n g ( b o ne a ge/ mi neral de nsit y) t o be d o ne base d o n i n vesti gat or’s j u d g me nt.  
1 7 I ncl u di n g o x y ge n sat urati o n; c orrecte d % pre dicte d F V C, % pre dicte d F E V 1; % pre dicte d R V; a n d % pre dicte d 
D Lc o (c orrecte d f or H b a n d/ or al ve olar v ol u me, as cli nicall y i n dicate d). If s u bject ca n n ot perf or m t hese p ul m o nar y 
f u ncti o n tests d ue  t o  a ge  or  c o g niti o n-relate d  restricti o ns, t he n  res pirat or y  e xa m,  c hest ra di o gra p h,  a n d  p ulse 
o xi metr y will s u bstit ute f or  t hese assess me nts. 
1 8 T o mai ntai n H b ≥1 1 g/ d L pri or t o m o bilizati o n  
C CI
C CI
C CI

Pr ot oc ol H G B - 2 0 7 Versi o n 6. 0  
1 0 J u ne 2 0 2 1  
Pa ge 5 8 
 
T a ble 5: 
Sc he d ule of E ve nts: C o n diti o ni n g a n d Dr u g Pr o d uct I nf usi o n 
 
Prec o n diti o ni n g  
C o n diti o ni n g  
I nf usi o n 
P ost -i nf usi o n 
u ntil 
e n gr aft me nt 
A p pr o xi m atel y 3 0 
d a ys bef ore b us ulf a n  
U p t o 7 
d a ys 
bef ore 
b us ulf a n  
D a y - 6 t o - 3 
i ncl usi ve1 
D a y 1  
D a y 1 u ntil 
disc h ar ge  
P h ysical e xa mi nati o n  
 
X 2 
X  
X 3 
X 4 
Vital Si g ns  
 
X  
X  
X 5 
X 6 
St o p ir o n c helati o n  
 
X 7 
 
 
 
H y pertra nsf usi o n t o pre -tra nsf usi o n H b 
≥1 1 g/ d L  
X 8 
 
 
 
 
Bl o o d f or cli nical la b orat or y tests 9 
 
X  
X  
X  
X 4 1 0 
Bl o o d f or ser u m β -h u ma n c h ori o nic 
g o na d otr o pi n  f or fe male s u bjects of c hil d-
beari n g p ote ntial (ser u m pre g na nc y test)  
 
X  
 
 
 
Bl o o d f or ser u m tra nsferri n rece pt or 
 
X  
 
X  
X 1 1 
Bl o o d f or retic ul oc yte c o u nt  
 
X  
 
X  
X 1 1 
Re -c o nfir mati o n of eli gi bilit y 
 
X 1 2 
 
 
 
A nti -seiz ure a n d V O D/ S O S pr o p h yla xis 
 
 
X 1 3 
 
 
B us ulfa n c he m ot hera p y  
 
 
X  
 
 
Bl o o d f or b us ulfa n p har mac o ki netics 1 4 
 
X  
X  
 
 
I nf usi o n of Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct 
 
 
 
X  
 
A d verse e ve nt c ollecti o n  
 
C o nti n u o us fr o m I C F si g ni n g  
C o nc o mita nt me dicati o n c ollecti o n  
 
C o nti n u o us fr o m I C F si g ni n g  
1 Pla n ne d Da ys relati ve t o Da y 1, b ut ma y var y de pe n di n g o n le n gt h of was h -o ut ( 4 8 h o ur mi ni m u m) bef ore dr u g pr o d uct i nf usi o n  
2 I ncl u des perf or ma nce stat us at prec o n diti o ni n g visit  
3 T o be perf or me d o n Da y 1 bef ore dr u g pr o d uct a d mi nistrati o n  
4 At least t wice a wee k d uri n g h os pitalizati o n  
5 Vital si g n m o nit ori n g i ncl u di n g E C G, p ulse o xi metr y, a n d bl o o d press ure meas ure me nts s h o ul d be e m pl o ye d d uri n g dr u g -pr o d uct i nf usi o n.  A d diti o nall y, vital 
si g ns (e xcl u di n g E C G) s h o ul d be meas ure d f or t w o h o urs after i nf usi o n (e. g. e ver y 3 0 t o 6 0 mi n utes)  
6 T o be perf or me d dail y u ntil disc har ge  
C CI

Pr ot oc ol H G B - 2 0 7 Versi o n 6. 0  
1 0 J u ne 2 0 2 1  
Pa ge 5 9 
 
7 Ir o n c helati o n m ust be st o p pe d at least 7 da ys bef ore i nitiati n g c o n diti o ni n g. See Secti o n  5. 9. 4  f or disc o nti n uati o n of deferasir o x 
8 Pre -c o n diti o ni n g h y pertra nsf usi o n is rec o m me n de d, b ut n ot re q uire d. Ir o n c helati o n s h o ul d be ma na ge d a p pr o priatel y t o mi ni mize a d diti o nal ir o n o verl oa d.  
Pre‑tra nsf usi o n he m o gl o bi n, a n d if a vaila ble, ser u m ferriti n a n d ser u m tra nsferri n rece pt or s h o ul d be rec or de d as u nsc he d ule d la bs.  
9 C B C; ser u m c he mistr y; li ver f u ncti o n tests; a n d a n y ot her tests t hat are cli nicall y i n dicate d or re q uire d b y i nstit uti o nal g ui deli nes, i ncl u di n g f or e xa m ple testi n g 
f or c yt o me gal o vir us ( C M V), E pstei n Barr vir us ( E B V), H S V a n d V Z V I g G. O n Da y 1 la bs are t o be c ollecte d pri or t o i nf usi o n. Cli nical la b orat or y tests s h o ul d 
be o btai ne d o n a m ore fre q ue nt basis if cli nicall y i n dicate d (e. g. m o nit ori n g & e val uati o n of A Es).  
1 0 C B Cs are perf or me d dail y d uri n g h os pitalizati o n u ntil A N C e n graft me nt is de m o nstrate d  
1 1 Retic ul oc ytes a n d ser u m tra nsferri n rece pt or s h o ul d be m o nit ore d dail y fr o m Da y 1 t hr o u g h Da y + 7  
1 2 Re vie w C B C, ser u m c he mistr y, li ver f u ncti o n tests, p h ysical e xa mi nati o n, perf or ma nce stat us, a n d  A E hist or y; ser u m β -h u ma n c h ori o nic g o na d otr o pi n f or w o me n 
of c hil d -beari n g p ote ntial (ser u m pre g na nc y test); verificati o n t hat Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct has bee n cli nicall y dis p ositi o ne d,  is a vaila ble o n site a n d 
t hat resc ue cells are a vaila ble. N ote t hat if Scree ni n g Visit a n d Prec o n diti o ni n g Visits are > 1 year a part, t he f oll o wi n g tests m ust be re peate d: P F Ts, esti mate d  
G F R, a n d car diac D o p pler ec h ocar di ol o g y (i ncl. L V E F).  
1 3 A nti -seiz ure pr o p h yla xis t o start at least 1 2 h o urs bef ore i nitiati n g b us ulfa n a n d t o c o nti n ue at least 2 4 h o urs after c o m pleti o n of 4 da y  b us ulfa n c o urse; V O D/ S O S 
pr o p h yla xis as ma n date d i n Secti o n  5. 9. 2 . 
1 4 A test d ose of b us ulfa n se veral da ys bef ore be gi n ni n g m yel oa blati o n t o pre -deter mi ne b us ulfa n d ose is als o per mitte d. P K a nal ysis of first d ose of  b us ulfa n o n 
first a n d t hir d da y of d osi n g is re q uire d. 
C CI

Pr ot oc ol H G B - 2 0 7 Versi o n 6. 0  
1 0 J u ne 2 0 2 1  
Pa ge 6 0 
 
T a ble 6: 
Sc he d ule of E ve nts: F oll o w -u p  
Pr oce d ure  
F oll o w -U p: D a y ( D), M o nt h ( M)  ( Visit Wi n d o w, d a ys) P ost-Dr u g Pr o d uct I nf usi o n  
D 3 0  
D 6 0  
D 9 0  D 1 2
0 
D 1 5 0  D 1 8
0 
D 2 1 0  D 2 4
0 
D 2 7 0  D 3 0 0  D 3 3 0  D 3 6 0  D 4 2 0  D 4 5 0  D 4 8
0 
D 5 4 0  D 6 0 0  D 6 6 0  D 7 2 0  
M 1  
( ± 7) 
M 2  
( ± 7) 
M 3  
( ± 7) 
M 4  
( ± 1 4
) 
M 5  
( ± 1 4) 
M 6  
( ± 1 4) 
M 7  
( ± 1 4) 
M 8  
( ± 1 4
) 
M 9  
( ± 1 4) 
M 1 0  
( ± 1 4) 
M 1 1  
( ± 1 4) 
M 1 2  
( ± 3 0) 
M 1 4  
( ± 3 0) 
M 1 5  
( ± 3 0) 
M 1 6  
( ± 3 0
) 
M 1 8  
( ± 3 0) 
M 2 0  
( ± 3 0) 
M 2 2  
( ± 3 0) 
M 2 4  
( ± 3 0) 
P h ysical e xa mi nati o n 1 
X  
X  
X  
X  
X  
X  
 
 
X  
 
 
X  
 
X  
 
X  
 
 
X  
Vital si g ns  
X  
X  
X  
X  
X  
X  
 
 
X  
 
 
X  
 
X  
 
X  
 
 
X  
Bl o o d f or ser u m β -h u ma n 
c h ori o nic
 g o na d otr o pi n  
f or  w o me n  of  c hil d-
beari n g  p ote ntial  (ser u m  
pre g na nc y test) 2 
 
 
X  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Bl o o d
 f or
 cli nical
 
la b orat or y tests3 
X  
X  
X  
X  
X  
X  
 
 
X  
 
 
X  
 
X  
 
X  
 
 
X  
Bl o o d f or C B C o nl y  
 
 
 
 
 
 
X  
X  
 
X  
X  
 
X  
 
X  
 
X  
X  
X  
Bl o o d
 f or
 fasti n g
 
Gl uc ose/I ns uli n le vels 4 
 
 
 
 
 
X  
 
 
 
 
 
X  
 
 
 
X  
 
 
X  
Esti mate d G F R  
 
 
X  
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
 
X  
Bl o o d f or ir o n st u dies 5 
 
 
X  
 
 
X  
 
 
 
 
 
X  
 
X  
 
X  
 
 
X  
Bl o o d f or i m m u n ol o g y 6 
 
 
X  
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
 
X  
Bl o o d  f or  h or m o nal  a n d 
 
testi n g7  
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
Bl o o d
 f or
 gl o bi n  i n  
a ut ol o g o us cells  
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
Bl o o d  f or  gl o bi n  H P L C  
& V C N  
  
X  
X  
 
 
X  
 
 
X  
 
 
X  
 
 
 
X  
 
 
X  
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T a ble 6: 
Sc he d ule of E ve nts: F oll o w -u p  
Pr oce d ure  
F oll o w -U p: D a y ( D), M o nt h ( M)  ( Visit Wi n d o w, d a ys) P ost-Dr u g Pr o d uct I nf usi o n  
D 3 0  
D 6 0  
D 9 0  D 1 2
0 
D 1 5 0  D 1 8
0 
D 2 1 0  D 2 4
0 
D 2 7 0  D 3 0 0  D 3 3 0  D 3 6 0  D 4 2 0  D 4 5 0  D 4 8
0 
D 5 4 0  D 6 0 0  D 6 6 0  D 7 2 0  
M 1  
( ± 7) 
M 2  
( ± 7) 
M 3  
( ± 7) 
M 4  
( ± 1 4
) 
M 5  
( ± 1 4) 
M 6  
( ± 1 4) 
M 7  
( ± 1 4) 
M 8  
( ± 1 4
) 
M 9  
( ± 1 4) 
M 1 0  
( ± 1 4) 
M 1 1  
( ± 1 4) 
M 1 2  
( ± 3 0) 
M 1 4  
( ± 3 0) 
M 1 5  
( ± 3 0) 
M 1 6  
( ± 3 0
) 
M 1 8  
( ± 3 0) 
M 2 0  
( ± 3 0) 
M 2 2  
( ± 3 0) 
M 2 4  
( ± 3 0) 
Bl o o d f or R C L  a nal yses 8 
 
 
X  
 
 
X  
 
 
 
 
 
X  
 
 
 
 
 
 
X 9 
Bl o o d f or I S A  
 
 
 
 
 
X  
 
 
 
 
 
X  
 
 
 
X  
 
 
X  
B o ne marr o w 1 0 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
Li ver  a n d  s plee n  S O C  
M RI  
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
P ul m o nar y
 f u ncti o n
 
tests1 1  
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
Car diac
 a n d
 li ver
 
T 2 * M RI
 &
 
ec h ocar di ol o g y 1 2 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
1 2 -lea d E C G 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
B o ne
 i ma gi n g  ( X -ra y 
a n d/ or De xa Sca n) 1 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
H R Q o L Assess me nt  
 
 
X 1 4 
 
 
X  
 
 
 
 
 
X  
 
 
 
X  
 
 
X  
Rec or d tra nsf usi o ns  
C o nti n u o us fr o m I C F si g ni n g  
Rec or d h os pitalizati o ns  
C o nti n u o us fr o m p ost -dr u g pr o d uct i nf usi o n disc har ge  
A d verse e ve nt c ollecti o n  
C o nti n u o us fr o m I C F si g ni n g  
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T a ble 6: 
Sc he d ule of E ve nts: F oll o w -u p  
Pr oce d ure  
F oll o w -U p: D a y ( D), M o nt h ( M)  ( Visit Wi n d o w, d a ys) P ost-Dr u g Pr o d uct I nf usi o n  
D 3 0  
D 6 0  
D 9 0  D 1 2
0 
D 1 5 0  D 1 8
0 
D 2 1 0  D 2 4
0 
D 2 7 0  D 3 0 0  D 3 3 0  D 3 6 0  D 4 2 0  D 4 5 0  D 4 8
0 
D 5 4 0  D 6 0 0  D 6 6 0  D 7 2 0  
M 1  
( ± 7) 
M 2  
( ± 7) 
M 3  
( ± 7) 
M 4  
( ± 1 4
) 
M 5  
( ± 1 4) 
M 6  
( ± 1 4) 
M 7  
( ± 1 4) 
M 8  
( ± 1 4
) 
M 9  
( ± 1 4) 
M 1 0  
( ± 1 4) 
M 1 1  
( ± 1 4) 
M 1 2  
( ± 3 0) 
M 1 4  
( ± 3 0) 
M 1 5  
( ± 3 0) 
M 1 6  
( ± 3 0
) 
M 1 8  
( ± 3 0) 
M 2 0  
( ± 3 0) 
M 2 2  
( ± 3 0) 
M 2 4  
( ± 3 0) 
C o nc o mita nt  me dicati o n  
(i ncl.  ir o n  c helat ors  &  
p hle b ot o m y)  
C o nti n u o us fr o m I C F si g ni n g  
1 I ncl u des wei g ht at e ver y visit, hei g ht a n d perf or ma nce stat us e ver y 6 m o nt hs after dr u g pr o d uct i nf usi o n. Ta n ner sta gi n g s h o ul d be perf or me d e ver y 6 m o nt hs 
d uri n g p u bert y, if rele va nt. F or s u bjects < 1 8 years of a ge, 
will be e val uate d e ver y 6 m o nt hs.  
2 S h o ul d be c o nfir me d pri or t o m o bilizati o n  
3 He mat ol o g y ( C B C, platelets, retic ul oc ytes, n ucleate d R B Cs); ser u m c he mistr y a n d li ver f u ncti o n tests, a n d a d diti o nal cli nical la b orat or y tests as cli nicall y 
i n dicate d. Cli nical la b orat or y tests s h o ul d be o btai ne d o n a m ore fre q ue nt basis if cli nicall y i n dicate d (e. g. m o nit ori n g & eval uati o n of A Es). If t he res ults fr o m 
bl o o d tests are n ot as e x pecte d, a d diti o nal testi n g ma y nee d t o be perf or me d a n d ma y i ncl u de a p h ysical e xa m, bl o o d tests, i ma gi n g tests, or a b o ne marr o w bi o ps y 
t o all o w f or f urt her i n vesti gati o n of ste m cells. 
4 Fasti n g gl uc ose a n d i ns uli n le vels ( H O M A i n de x) at least e ver y 6 m o nt hs. A n oral gl uc ose t olera nce test s h o ul d be perf or me d f or a n a b n or mal fasti n g gl uc ose.  
5 Ir o n st u dies (ir o n, ferriti n, ser u m tra nsferri n rece pt or, tra nsferri n) s h o ul d als o be perf or me d pri or t o restarti n g ir o n c helati o n/ p hle b ot o m y. 
6 T cell s u bsets [ C D 4, C D 8], B cells ( C D 1 9), a n d nat ural killer cells ( C D 1 6 a n d/ or C D 5 6); i m m u n o gl o b uli ns (I g G, I g M, a n d I g A)   
7 H or m o nal testi n g i ncl u des t h yr oi d f u ncti o n (free T 4, T S H); P T H. F or s u bjects after p u bert y, als o i ncl u des L H, F S H a n d estra di ol (fe males o nl y); test oster o ne 
( males o nl y). F or s u bjects < 1 8 years of a ge, i ncl u des gr o wt h h or m o ne (I G F-1 a n d I G F B P -3). 
   
8 T w o sa m ples re q uire d, o ne f or R C L scree ni n g  test, a n ot her f or p ote ntial c oc ult ure of P B Ls if R C L scree ni n g test is p ositi ve 
9 If a s u bject’s pre vi o us R C L tests were all ne gati ve, t he 2 4 M o nt h sa m ple will be arc hi ve d. 
1 0 B o ne marr o w f or 
 st u dies (retic ul oc ytes, n ucleate d R B C, ser u m tra nsferri n rece pt or, he pci di n, a n d er yt hr o p oieti n), as well as m or p h ol o g y, 
cell ularit y, cell c o u nt, a n d ir o n c o nte nt; if s ufficie nt s a m ple is a vaila ble, sa m ple ma y be arc hi ve d a n d/ or ot her researc h tests (e. g., V C N, I S A, H P L C, ge netic 
testi n g) ma y be perf or me d.  
1 1 I ncl u di n g o x y ge n sat urati o n; c orrecte d % pre dicte d F V C, % pre dicte d F E V 1; % pre dicte d R V; a n d % pre dicte d D Lc o (c orrecte d f or H b a n d/ or al ve olar v ol u me, 
as cli nicall y i n dicate d). If s u bject ca n n ot perf or m t hese p ul m o nar y f u ncti o n tests d ue t o a ge or c o g niti o n -relate d restricti o ns, t he n res pirat or y e xa m, c hest 
ra di o gra p h, a n d p ulse o xi metr y will s u bstit ute f or t hese assess me nts. If s u bject bec o mes a ble t o perf or m s pir o metr y a n d l u n g diff usi o n ca pacit y test, t hese 
p ul m o nar y f u ncti o n tests s h o ul d be perf or me d per S O E a n d/ or at a n u nsc he d ule d ti me p oi nt.  
1 2 A n n ual ec h ocar di o gra p h y is o nl y re q uire d if cli nicall y si g nifica nt a b n or malit y is o bser ve d o n t he Scree ni n g ec h ocar di o gra m, or a n y s u bse q ue nt ec h ocar di o gra m, 
or if t here is e vi de nce of ir o n o verl oa d (car diac T 2 * ≤2 0 ms) or ot her cli nicall y si g nifica nt a b n or malit y o n car diac T 2 * M RI  
1 3 A ge a p pr o priate b o ne i ma gi n g ( b o ne a ge/ mi neral de nsit y) t o be d o ne base d o n i n vesti gat or j u d g me nt.  
1 4 At t he Da y 9 0 Visit, o nl y t he E Q -5 D a n d F A C T -B M T t o ols are t o be c o m plete d.  
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6. 2.  
Assess me nts  
6. 2. 1.  
De m o gr a p hics a n d Me dic al Hist or y  
S u bject de m o gra p hic dat a s uc h as se x, a ge, race, et h nicit y, a n d c o u ntr y of birt h will be o btai n e d 
d uri n g Scree ni n g. A c o m plete me dical hist or y als o will be o btai ne d d uri n g Scree ni n g,  i ncl u di n g 
s ple nect o m y hist or y. T h e me dical hist or y is t o i ncl u de all pri or a n d c urre nt me dical hist or y, 
i ncl u di n g t he c o nfir me d t halasse mia ge n ot y pe, a g e at dia g n osis, a ge w he n ir o n c helati o n t hera p y 
be ga n, a ge of first tra nsf usi o n, a n d a g e w he n fre q ue nc y of tra nsf usi o ns was esta blis he d (i.e., a ge 
at w hic h tra nsf usi o n nee ds t o be sta bilize d t o a p pr o xi matel y bet wee n o n ce e ver y 3 -8 wee ks). 
Tra nsf usi o n hist or y (i ncl u di n g date, a m o u nt tra nsf use d, n u m ber of u nits, a vera ge v ol u me of u nits 
a n d a ver a ge c o n ce ntr ati o n of he mat ocrit [ Hct] of R B Cs tra nsf use d), al o n g wit h t he ass ociate d 
retic ul oc yte a n d H b val u es ta ke n pri or t o t he tra nsf usi o n w here a vaila ble, s h o ul d als o be c ollect e d 
f or t he 2 years pri or t o st u d y e nr oll me nt. 
All i n -patie nt h os pitalizati o ns ( da ys) f or t he 2 years pri or t o st u d y e nr oll me nt are t o be d oc u me nte d, 
w here i n -p ati e nt h os pitalizati o n is defi ne d as d urati o n of h os pitalizati o n f or at least 2 4 h o urs. 
Ir o n c helati o n hist or y (c h elati o n a ge nt, d ose/ u nit, r o ute, fre q ue n c y, dates a n d reas o n f or st o p pi n g) 
f or t he 2 y ears pri or t o t he st u d y e nr oll me nt s h o ul d als o be c ollect e d. I n a d diti o n, all a v aila ble 
ser u m ferriti n val ues s h o ul d be c ollecte d fr o m t his 2-year pre -e nr oll me nt peri o d. 
If t he s u bject was ma n a ge d wit h s pecific tra nsf usi o n g oals (i.e., H b a n d/ or s y m pt o m tri g ger f or 
tra nsf usi o n) w hic h wer e a d here d t o f or a mi ni m u m of 1 2 m o nt hs pri or t o st u d y e ntr y, t hese s h o ul d 
be rec or de d.  
6. 2. 1. 1.  
Ge n ot y pe  
Ge n ot y pe will  b e r ec or de d fr o m  t he s u bject’s me dical  rec or ds  a n d us e d t o det er mi ne i nitial  
eli gi bilit y t o e nter Scree ni n g. I n a d diti o n, m utati o n at eac h allele of t he β -gl o bi n l oc us ( H B B  ge ne) 
as deter mi ne d b y se q ue n ci n g a n d n otate d acc or di n g t o t he precise ge netic m utati o n i de ntifie d per 
rec o m me n dati o n of t he H u ma n Ge n o me Variati o n S ociet y (w w w. H G V S. or g ) will be assesse d b y 
a  ce ntr alize d  la b orat or y  pri or  t o  s u bjects  be gi n ni n g  m o bilizati o n  a n d  a p heresis  t o  c o nfir m  
eli gi bilit y.  M utati o ns  will  be  classifie d  as  β + ,  β0 or  β E  base d  o n  t h e  gl o bi n  ge ne  s er ver  
( htt p:// gl o bi n. b x. ps u.e d u/),  a n  a n n otate d  o nli ne  c o m pre he nsi ve  d ata  bas e  of  H B B  m utati o ns. 
S u bjects w h ose g e n ot y pi n g d oes n ot c o nfir m t he m as eli gi ble will be dis c o nti n ue d fr o m t his st u d y 
pri or t o be gi n ni n g m o bilizati o n a n d a p h eresis. 
A n a d diti o nal bl o o d sa m ple ta ke n at t he Scree ni n g Visit will be arc hi ve d f or p ote ntial a n al yses of 
ge nes i m p orta nt i n T D T at a ce ntr al la b orat or y, w hic h ma y i ncl u de:  
•  Al p ha- gl o bi n ge ne c o p y n u m ber 
•  H G B 2  S N Ps  
•  H B S 1 L- M Y B  S N Ps  
•  B C L 1 1 A  S N Ps  
A n a d diti o nal bl o o d sa m ple will als o be ta ke n at Scree ni n g Visit f or arc hi vi n g t o be use d f or f ut ure 
vali dati o n of a ge n ot y pi n g test t hat ma y be re q uire d f or re g ulat or y a p pr o v al of t his dr u g pr o d uct. 
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6. 2. 2.  
Cli nic al/ P h ysic al E x a mi n ati o n  
A  c o m plete  p h ysical  e xa mi nati o n  ( ge neral  a p peara n ce;  hea d  e y es,  ears,  n ose,  a n d  t hr o at;  
car di o vas c ular; der mat ol o gic, a b d o mi nal; ge nit o uri nar y; l y m p h n o des; he patic; m usc ul os keletal; 
res pirat or y; ne ur ol o gical) is t o be c o n d ucte d as per t he S O E.  I n a d diti o n, at scree ni n g, a n d e ver y 
6 m o nt hs after dr u g pr o d uct i nf usi o n, 
 will be assesse d f or s u bjects 
< 1 8 years of a g e.  
T he s u bject’s wei g ht is t o be meas ure d at e ver y visit t hat i ncl u des a c o m plete p h ysical e xa mi nati o n.  
A n  a b bre vi ate d  p h ysical  e xa mi nati o n  i ncl u des  ge neral  a p peara n ce  a n d  e xa mi nati o n  of  
s y m pt o matic or ga n s yste ms a n d d oes n ot i ncl u de wei g ht. 
T he s u bject’s hei g ht is t o be meas ur e d at t he Scree ni n g Visit a n d at e ver y 6 m o nt hs after dr u g 
pr o d uct i nf usi o n.  
T he s u bject’s perf or ma nce stat us is t o be m eas ure d at t he Scree ni n g Visit, at t he Pre -c o n diti o ni n g 
Visit, a n d at e ver y 6 m o nt hs after dr u g pr o d uct i nf usi o n. See Sec ti o ns 1 0. 2   a n d 1 0. 3  f or m ore 
i nf or mati on o n K ar n ofs k y a n d L a ns k y perf or m a n ce stat us. T est t o b e use d is base d o n a g e at 
i nf or me d c o nse nt. 
A d diti o nall y, Ta n ner st a gi n g s h o ul d be perf or me d at scree ni n g a n d e ver y 6 m o nt hs after i nf usi o n 
d uri n g p u bert y, if rel e va nt. 
6. 2. 3.  
Vit al Si g ns  
Vital si g ns t o be meas ure d i ncl u de s yst olic/ diast olic bl o o d press ure, p ulse, res pirati o n rate, a n d 
te m perat ur e, a n d will be perf or me d i n acc or da n ce wit h i nstit uti o nal sta n dar ds, as per t he S O E .  
6. 2. 4.  
Electr oc a r di o gr a m  
A 1 2 -lea d el ectr o car di o gra m ( E C G) will be o btai n e d as per t h e S O E.  
6. 2. 5.  
I m a gi n g 
Sta n dar d cli nical practice g ui deli nes will be use d t o perf or m t he f oll o wi n g i ma gi n g assess me nt at 
t he ti me p oi nts s pecifie d i n t he S O E: 
•  A c hest X -ra y will be o bt ai ne d at Scree ni n g. 
•  B o ne i ma gi n g ( X -ra y a n d/ or 
 [ D E X A] sca n) s h o ul d als o be d o ne base d o n 
s u bject’s a ge, as per S O E. 
•  Car diac  D o p pler  ec h o car di o gra p h y,  i ncl u di n g  t he  assess me nt  of  left  ve ntric ular  
ejecti o n fr acti o n ( L V E F) will be perf or me d as per S O E.  
•  Li ver a n d s plee n i ma gi n g b y M RI. 
•  Car diac M RI a n d li ver M RI f or deter mi nati o n of T 2 * a n d LI C, res pecti v el y, will be 
perf or me d as defi ne d b y t he i ma gi n g c ore la b orat or y at t he ti mes s pecifie d i n t he S O E.  
A  Bli n de d  I n d e pe n d e nt  Ce ntral  Re vie w  C o m mittee  ( BI C R)  will  e v al uate  M RI  i ma ges  f or  
deter mi nati o n of LI C a n d car di ac a n d li ver T 2 * i n acc or d a nce wit h a n i ma gi n g c hart er. Dr y wei g ht 
of LI C will be meas ur e d. T he M RI i ma ges will be ac q uire d at t he cli nical site i n acc or d a nce wit h 
t he i ma ge ac q uisiti o n g ui deli nes. Li ver a n d s plee n v ol u mes as well as i nci de ntal cli nical fi n di ngs 
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will als o be assesse d b y t he BI C R c o m mittee fr o m t he M RI sta n dar d of care i ma gi n g st u dies. Li ver 
bi o ps y will be perf or me d i n a d ult s u bjects ( ≥ 1 8 years of a ge) if M RI of t he li ver s u g gests acti ve 
he patitis, si g nifica nt fi br osis, i nc o ncl usi ve e vi de nce of  cirr h osis, or LI C is ≥1 5 m g/ g. Li ver bi o ps y 
is c urre ntl y t he preferre d met h o d f or e val uati o n of t he e xte nt of fi br osis  (C a p pelli ni et al., 2 0 1 4 ). 
Li ver bi o ps y will o nl y be perf or me d i n a d ol esce nt a n d pe diatric s u bj ects ( < 1 8 years of a ge), if 
a d diti o nal data be y o n d t h e M RI is f elt t o be a bs ol utel y necessar y b y t he i n v esti gat or t o c o nfir m or 
ref ute M RI data, a n d if t he pr oce d ure is c o nsi dere d t o be safe t o perf or m. Li ver bi o ps y s h o ul d n ot 
be perf or me d o n t hr o m b oc yt o pe nic patie nts if i nc o nsiste nt wit h i nstit uti o nal g ui deli nes. 
6. 2. 6.  
P ul m o n ar y F u ncti o n Tests  
P ul m o nar y f u ncti o n testi n g will be perf or me d as per t he S O E. Para m eters t o be meas ure d i ncl u d e 
o x y ge n  sat urati o n  meas ure d  b y  p ulse  o xi metr y,  %  pre dicte d  f orce d  vital  ca pacit y  ( F V C),  
% pre dicte d f or ce d e x pir at or y v ol u me i n 1 s ec o n d ( F E V 1), % pre dicte d res pirat or y v ol u me ( R V), 
a n d % pr e dicte d D Lc o ( c orrect e d f or H b a n d/ or al ve olar v ol u me, as cli nicall y i n dicate d). If  s u bject 
ca n n ot perf or m t hese p ul m o nar y f u ncti o n tests d ue t o a ge or c o g niti o n -rel ate d restricti o ns, t he n 
res pirat or y e xa m, c h est r a di o gra p h, a n d p ulse o xi metr y will s u bstit ute f or t hese assess me nts. If 
s u bject bec o m es a ble t o perf or m s pir o metr y a n d l u n g diff usi o n ca pacit y test, t hese p ul m o nar y 
f u ncti o n tests s h o ul d be perf or me d p er S O E a n d/ or at a n u nsc he d ule d ti me p oi nt. 
6. 2. 7.  
Tr a nsf usi o ns  
I nter val tra nsf usi o ns re q uire d ar e t o be d oc u me nt e d as per t he S O E. 
6. 2. 8.  
I n- p atie nt H os pit aliz ati o ns 
All i n -patie nt h os pitalizati o ns are t o be d oc u me nte d, w here i n -p atie nt h os pitalizati o n is defi ne d as 
d urati o n of h os pitalizati o n f or at least 2 4 h o urs. 
6. 2. 9.  
He m o gl o bi n o p at h y M ar kers i n Bl o o d 
Bl o o d  sa m ples  are  t o  be  c ollecte d  f or  gl o bi n  pr otei n  a nal yses  b y  hi g h -press ure  li q ui d  
c hr o mat o gra p h y ( H P L C) per t he S O E f or deter mi nati o n of t he rati o of β A- T 8 7 Q -gl o bi n t o all β -li ke-
gl o bi ns a n d t he rati o of α -gl o bi n t o all β -li ke- gl o bi ns. 
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a nal yses of plas ma, cells, pr otei ns, D N A, R N A a n d ot her m olec ules t o st u d y t halasse mia a n d/ or 
ge ne t her a p y, ar e o pti o nal. 
C ollecti o n a n d st ora ge of t he sa m ples des cri be d a b o ve will be s u bject t o discreti o nar y a p pr o val 
fr o m eac h ce nter’s I R B/ E C a n d t he s u bject’s s p ecific writte n c o nse nt. Sa m pl es will be la bele d wit h 
a u ni q ue i de ntificati o n n u m ber t hat i ncl u des n o s u bject i de ntif yi n g i nf or mati o n. 
6. 2. 1 4.  
Fertilit y Preser v ati o n  
Fertilit y preser vati o n ( e. g., s per m  or t estic ular tiss ue ba n ki n g f or m ales  or o oc yte  as pirati o n 
f oll o wi n g o varia n sti m ulati o n a n d cr y o preser vati o n f or fe males) will be d o ne as a p pr o priate at t he 
discreti o n of t he s u bject, t heir le gal g uar dia n (as a p plica ble) a n d t he I n vesti gat or. 
6. 2. 1 5.  
He alt h -Rel ate d Q u alit y of Life Assess me nt  
E val uati o n of healt h -relat e d q ualit y of life ( H R Q o L) o ver ti me usi n g t he f oll o wi n g vali date d t o ols* 
(as s h o w n i n Ta ble  7, acc or di n g t o t he S O E): 
*W her e vali date d tr a nslati o ns of H R Q o L i nstr u me nts are a v aila ble  
•  Pe diatrics: Pe ds Q L ( par e nt ge neral c ore a n d ge nera l c ore)  
•  A d olesce nts: Pe ds Q L ( p are nt ge neral c ore a n d g e n eral c ore) a n d E Q - 5 D-Y  
•  A d ults: E Q -5 D, F A C T - B M T, a n d S F- 3 6 v 2  
T a ble 7: 
A ge - a p pr o pri ate V ali d ate d H R Q o L T o ols 
A ge  
Pe ds Q L  
Ge ner al C ore  
Pe ds Q L P are nt  
Ge ner al C ore  
E Q -5 D -Y  
( y o ut h) 
E Q - 5 D 
S F - 3 6 v 2 
F A C T -B M T  
0 -4  
5 - 1 1 
1 2 -1 7  
 
X 
X  
X  
X 
X  
 
X ( 1 1 o nl y) 
X  
 
 
 
1 8 -5 0   
 
 
X  
X  
X  
Recall  Past m o nt h  
Past m o nt h  
T o da y  
T o da y  
Past 4 wee ks  Past 7 da ys  
S u bjects s h o ul d c o nti n ue usi n g t he sa me H R Q o L  t o ol t hat t he y starte d usi n g o n e nr oll me nt u ntil 
c o m pleti o n of t heir M o nt h 2 4 Visit, e ve n if t he y w o ul d als o be eli gi ble t o c ha n ge t o a hi g her a ge d 
t o ol d uri n g t he st u d y. 
6. 2. 1 6.  
Cli nic al L a b or at or y Tests 
Cli nical  la b orat or y  tests  will  be  perf or m e d  as  s pecifie d  b el o w,  a n d  i n  t he  S O E.  A d diti o nal  
la b orat or y tests s h o ul d b e perf or me d as cli nicall y i n dicate d (e. g. o n g oi n g m o nit ori n g of A Es). A n y 
a d diti o nal la b orat or y par a meters t hat are perf or m e d w hile a s u bject is o n st u d y s h o ul d be e ntere d 
as s uc h i nt o t he cli nical st u d y data base. 
Cli nical la b orat or y tests are t o be perf or m e d a n d re vie we d b y t he i n vesti gat or or q ualifie d desi g nee 
(e. g.,  p h ysicia n’s  assista nt,  n urse  practiti o ner).  All  la b orat or y  assess me nts  will  be  a nal yze d  
ce ntrall y u nless ot her wise n ote d i n t he S O E or S O M.  
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6. 2. 1 6. 1.  He m at ol o g y a n d Cli nic al C he mistr y 
Bl o o d sa m ples f or all he mat ol o g y para meters, a n d cli nical c h e mistries, are t o be c ollecte d as p er 
t he S O E.  
T he f oll o wi n g cli nical la b orat or y par a meters ( Ta ble  8) are t o be deter mi ne d: 
T a ble 8:  
He m at ol o g y, Ir o n St u dies, Ser u m C he mistr y, a n d Li ver F u ncti o n 
He m at ol o g y   
Ir o n St u dies 
C o m plete bl o o d c o u nt ( C B C) wit h differe ntial a 
Ir o n 
Platelet c o u nt  
Ferriti n  
Retic ul oc yte c o u nt  
Ser u m tra nsferri n rece pt or  
N ucleate d R B Cs  
Tra nsferri n  
Ser u m C he mistr y a n d Li ver F u ncti o n  
 
S o di u m  
Bl o o d urea nitr o ge n  
P otassi u m  
Creati ni ne  
C hl ori de  
Gl uc ose b 
Bicar b o nate  
Calci u m  
Al b u mi n  
P h os p hate  
T otal pr otei n  
Bilir u bi n (t otal a n d direct)  
Ala ni ne tra nsa mi nase  
Al kali ne p h os p hatase  
As partate tra nsa mi nase  
Lactic de h y dr o ge nase  
Ga m ma gl uta m yl tra nsferase  
 
a C B C  R B C  e val uati o n  s h o ul d  i ncl u de  R B C  c o u nt,  H b,  he mat ocrit,  mea n  c or p usc ular  v ol u me  ( M C V),  mea n  
c or p usc ular H b ( M C H), a n d mea n c or p usc ular H b c o nce ntrati o n ( M C H C).  
b Fasti n g gl uc ose/i ns uli n a n d H o me ostasis M o del Assess me nt i n de x testi n g s h o ul d be d o ne at  least e ver y 6 m o nt hs. 
Oral gl uc ose t olera nce test is re q uire d f or a n y a b n or mal fasti n g gl uc ose.  
I n a d diti o n, t he G F R will be esti mate d as per t he S O E. See Secti o n 1 0. 1  f or t he f or m ula f or 
calc ulati o n of G F R.  
Pr ot hr o m bi n ti me (re p orte d as t he i nter nati o nal n or malize d rati o [I N R]) a n d partial t hr o m b o plasti n 
ti me will als o be deter mi ne d at t he Scree ni n g Visit as per t he S O E . 
6. 2. 1 6. 3.  Uri n al ysis  
A uri nal ysis will be perf or me d at Scree ni n g.  
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6. 2. 1 6. 4.  Pre g n a nc y Testi n g  
F or f e male s u bj ects of c hil d -beari n g p ote ntial o nl y, ser u m pre g n a nc y t ests ( β -h u ma n c h ori o nic 
g o na d otr o pi n) will be o btai ne d as per t he S O E. 
6. 2. 1 6. 5.  Ser ol o g y 
Scree ni n g ser ol o g y will be e val uate d usi n g sta n d ar d met h o ds as per t he S O E, testi n g f or prese n ce 
of HI V -1, HI V -2, H B V, or H C V. S y p hilis (ra pi d plas ma rea gi n [ R P R]) testi n g is als o re q uire d, 
a n d s u bjects testi n g p ositi ve will be e xcl u de d ( u nless n o l o n ger ma n d ate d b y ce ntral dr u g pr o d uct 
ma n ufact uri n g  practices).  W here  cli nicall y  a n d/ or  re gi o nall y  i n dicat e d,  ot her  tests  ma y  be  
perf or me d,  i n  w hic h  case  p ositi ve  res ults  w o ul d  e xcl u de  t he  s u bject  fr o m  partici pati n g:  f or  
e xa m ple, H T L V -1 or H T L V -2, t o x o plas m osis, Tr y pa n os o ma cr uzi, West Nile Vir us, or Zi ka 
Vir us. I n certai n cir c u msta nces, a d diti o nal testi n g ma y be re q uire d d e pe n di n g o n t he s u bject ’s 
hist or y a n d/ or t he c haract eristics of t he s u bject’s cells (e. g., malaria). 
See als o i nfecti o n s ur v eilla nce ( Secti o n 5. 9. 5 ). 
6. 2. 1 6. 6.  H or m o n al Testi n g 
H or m o nal testi n g, i ncl u di n g t h yr oi d f u ncti o n (free t h yr o xi ne [ T 4], t h yr oi d sti m ulati n g h or m o ne 
[ T S H]) a n d p ar at h yr oi d h or m o ne ( P T H), f or all s u bjects is t o be perf or m e d as per t he S O E. I n 
a d diti o n  f or  s u bjects  aft er  p u bert y,  l utei nizi n g  h or m o ne  ( L H,  fe m ale  s u b jects  o nl y),  f ollicle  
sti m ulati n g h or m o ne ( F S H, fe male s u bjects o nl y), estra di ol (fe male s u bjects o nl y), test oster o ne 
( male s u bjects o nl y), s h o ul d be perf or me d acc or di n g t o t he S O E.  Gr o wt h h or m o ne (I ns uli n-li ke 
gr o wt h fact or 1[I G F -1] a n d I ns uli n -li ke gr o wt h fact or-bi n di n g pr otei n 3 [I G F B P -3]) s h o ul d b e 
assesse d i n a d oles ce nts.  
6. 2. 1 6. 7.  Cli nic al W or k -u p f or U ne x pecte d Bl o o d Test Res ults  
If t he r es ults fr o m bl o o d tests are n ot as e x pect e d, a d diti o nal testi n g ma y nee d t o be perf or me d t o 
all o w f or f urt h er i n vesti g ati o n  of ste m cells a n d m a y i ncl u de:  
•  P h ysical e xa m  
•  Bl o o d tests 
•  I ma gi n g tests 
•  B o ne marr o w bi o ps y a n d/ or as pirati o n ( ma y als o b e arc hi ve d f or a d diti o nal a nal ysis i n 
t he f ut ure, see Secti o n  6. 2. 1 0 ) 
6. 2. 1 7.  
I m m u n ol o gic al Testi n g 
I m m u n ol o gical testi n g, i ncl u di n g T cell s u bsets ( C D 4, C D 8), B cells ( C D 1 9), a n d nat ural killer 
( N K) cells ( C D 1 6 a n d/ or C D 5 6), will be perf or me d as per t he S O E. 
Q ua ntitati o n of i m m u n o gl o b uli ns (I g G, I g M, a n d I g A) is t o be perf or me d as per t he S O E. 
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6. 2. 1 8. 2.  Cli nic al W or k - u p f or P ote nti al M ali g n a nc y 
I n t he e ve nt of cl o nal pr e d o mi na nce, p ersiste nt cl o nal pre d o mi na n ce, or a n y cli nical s us pici o n of 
m yel o d ys plasia, le u ke mi a, or l y m p h o ma, t he Me dical M o nit or will be n otifie d a n d a w or k -u p will 
be perf or me d t hat ma y  o cc ur i n sta ges a n d ma y i n cl u de s o me of t he f oll o wi n g at eac h sta g e:  
•  P h ysical e xa m  
•  C B C wit h differe ntial  
•  L y m p h oc yte s u bsets 
•  St u dies t o r ule o ut i nfecti o us ca use 
•  St u dies t o r ule o ut a ut oi m m u ne disease 
•  I ma gi n g st u dies 
•  B o ne marr o w a nal ysis 
•  C yt o ge netic a n d m olec ul ar a nal ys es  
If t he cli nical w or k-u p i n dicates n o e vi de nce of m yel o d ys plasia, le u ke mia, or l y m p h o ma, t he 
s u bject will c o nti n ue t o be m o nit ore d as p er t he pr ot oc ol-defi n e d S O E, or m ore fre q u e ntl y at 
discreti o n  of  t he  I n v esti gat or  a n d  S p o ns or.  If  t he  c li nical  w or k-u p  i n dicates  a  dia g n osis  of  
m yel o d ys plasia,  le u ke mia,  or  l y m p h o ma,  t he  S p o ns or  will  c o n ve ne  a n  ur ge nt  safet y  re vi e w  
meeti n g. F urt her a n al yses will be deter mi ne d b y t he S p o ns or, i n c o ns ultati o n wit h t he D M C. It 
s h o ul d be n ote d t hat it ma y n ot be p ossi ble t o disti n g uis h t he s o urce of mali g na nc y (e. g., arisi n g 
fr o m u n derl yi n g p at h o p h ysi ol o g y of t he diseas e, tra ns pla nt-relate d me di cati o ns or pr oce d ures, or 
fr o m e x pa nsi o n of ge n e-m o difie d cells d ue t o i ns erti o nal o nc o ge n esis), a n d all eff orts s h o ul d  be 
ma de t o c o nfir m t he s o ur ce of mali g na n c y.  
F or cli nical w or k -u p after i de ntificati o n of a persiste nt pre d o mi na nt cl o ne a n d c o nfir me d pres e nce 
of a b n or mal C B C, b o ne marr o w a n al ysis is rec o m me n de d if n ot pre vi o usl y perf or me d as p art of 
t he cli nical w or k- u p. 
6. 2. 1 9.  
A d verse E ve nts  
6. 2. 1 9. 1.  Assess m e nts D uri n g t he St u d y  
M o nit ori n g of A Es will be c o n d u cte d fr o m t he si g ni n g of i nf or me d c o ns e nt. A Es f or all s u bjects 
(e xcl u di n g scr ee n fail ur es) will be rec or d e d i n t he C R Fs starti n g fr o m t he ti me i nf or me d c o nse nt 
is si g ne d t hr o u g h t he M o nt h 2 4 Visit. All S A Es (i ncl u di n g scree n fail ures) will be re p ort e d fr o m 
t he si g ni n g of i nf or me d c o nse nt/asse nt o n t he S A E re p ort f or m. 
All A Es s h o ul d be m o nit ore d u ntil t he y are res ol ve d or are clearl y deter mi ne d t o be d ue t o a 
s u bject’s sta ble or c hr o nic c o n diti o n or i nter -c urre nt ill ness(es). F or s u bjects w h o wit h dra w f or 
reas o ns ot her t ha n wit h dr a wal of c o ns e nt, a n y S A Es o pe n at t he ti me of disc o nti n uati o n s h o ul d be 
f oll o we d- u p u ntil res ol uti o n or are d eter mi ne d t o b e a sta ble or c hr o nic c o n diti o n.  
If wit h dra wal is bef or e dr u g pr o d uct i nf usi o n, s u bjects s h o ul d re mai n o n st u d y f or at least 3 0 da ys 
after a n y i n vasi ve st u d y pr oce d ur e ( e. g., m o bilizati o n, li ver bi o ps y) bef ore wit h dra wal a n d o n g oi n g 
A Es  s h o ul d  be  m o nit ore d  f or  t he  3 0 -da y  d urati o n.  I n t he  rare  case  a  s u bject  u n der g oes  
m yel oa blati o n a n d r ecei ves bac k -u p cells i nstea d of Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct, s u bject 
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s h o ul d re mai n o n t he st u d y f or at least 3 m o nt hs p ost m yel oa blati o n a n d A Es s h o ul d be f oll o we d 
f or t he 3- m o nt h d urati o n. 
If  wit h dr a wal  is  after  dr u g  pr o d uct  i nf usi o n,  s u bjects  will  be  as ke d  t o  c o m plete  t h e  sa m e  
assess me nts as s pecifie d i n t he S O E f or M o nt h 2 4 ( Earl y Ter mi nati o n Visit assess me nts) a n d will 
be e x pecte d t o e nr oll i n t he l o n g- ter m f oll o w- u p St u d y L T F‑ 3 0 3.  
N ote t hat at t he c o m pleti o n of St u d y H G B -2 0 7, s u bjects will be e x pecte d t o e nr oll i nt o a l o n g -ter m 
f oll o w-u p st u d y ( L T F -3 0 3), t hat will m o nit or t he s afet y of s u bjects (i ncl u di n g dr u g pr o d uct -relat e d 
A Es) t hr o u g h a t otal of 1 5 years after Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct i nf usi o n. If t here is a ga p 
of ti me bet wee n t he fi nal visit i n St u d y H G B - 2 0 7 (e. g., M o nt h 2 4 st u d y visit) a n d partici p ati o n i n 
t he L T F-3 0 3 st u d y (i. e. si g nat ure o n I C F), all S A Es t hat start d uri n g t hat ga p s h o ul d be re p orte d 
o n t he St u d y H G B- 2 0 7 S A E re p ort f or m a n d s u b mitte d acc or di n g t o Secti o n  6. 2. 1 9. 5 . 
6. 2. 1 9. 2.  A d verse E ve nts Defi niti o ns  
6. 2. 1 9. 2. 1.  A d verse E ve nts  
A n A E is a n y u nt o war d me dical occ urre n ce ass o ciate d wit h t he use of a dr u g i n s u bjects, w het her 
or n ot c o nsi dere d dr u g relate d.  A n A E ma y i ncl u de a c ha n ge i n p h ysical si g ns, s y m pt o ms, a n d/ or 
cli nicall y si g nifica nt la b orat or y c ha n g e occ urri n g i n a n y p hase of a cli nical st u d y. T his defi niti o n 
i ncl u des i nterc urre nt ill nesses or i nj uries, a n d e x acer b ati o n of pre-e xisti n g c o n diti o ns. A pre -
e xisti n g c o n diti o n is a cli nical c o n diti o n (i ncl u di n g a c o n diti o n bei n g treate d) t hat is dia g n ose d 
bef ore t he s u bject si g ns t he i nf or me d c o nse nt f or m a n d is d oc u m e nte d as part of t he s u bj ect’s 
me dical hist or y.  
F or t he p ur p oses of t his st u d y, e n graft me nt fail ure is defi ne d  as a n S A E a n d is t o be re p orte d as 
s uc h. ( F or t his pr ot oc ol, e n graft me nt f ail ure is defi ne d as fail ure t o ac hie ve a n A N C ≥5 0 0 cells/ µ L 
f or 3 c o nsec uti ve da ys b y Da y 4 3 or recei vi n g bac k-u p cells at a n y ti me d uri n g t he ne utr o p e nic 
p hase).  
6. 2. 1 9. 2. 2.  U ne x pecte d A d verse E v e nts  
A n A E is c o nsi dere d u n e x pecte d wit h Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct if it is n ot c o nsiste nt i n 
nat ure or se v erit y wit h t he Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct refere nce safet y i nf or mati o n w hic h 
is c o ntai ne d i n t he c urr e nt I n vesti gat or’s Br oc h ure.  
6. 2. 1 9. 2. 3.  C o n d iti o ni n g-rel ate d A d verse E ve nts  
B us ulfa n I V is a c yt ot o xic dr u g t hat ca us es pr of o u n d m yel os u p pressi o n. Acc or di n gl y, s u bjects will 
e x perie n ce  i nte n de d  he mat ol o gic  e ve nts  (e. g.,  ne utr o pe nia,  t hr o m b oc yt o pe nia,  a ne mia)  a n d  
e x pecte d n o n- he mat ol o gi c e ve nts ( e. g., m uc ositis, na usea, v o miti n g, al o peci a, p yre xia) as a res ult 
of recei vi n g b us ulfa n I V. F or t he p ur p oses of t his pr ot oc ol, t hese e ve nts, w hic h are fa miliar t o 
tra ns pla nt p h ysicia ns a n d are descri be d i n t he b us ulfa n pres cri bi n g i nf or mati o n, are c o nsi dere d 
c o n diti o ni n g-relate d e v e nts ( C R Es).  
T he i nte n de d pr of o u n d m yel os u p pressi o n ( ma nifeste d b y ne utr o pe nia, t hr o m b oc yt o pe nia, a n d/ or 
a ne mia)  a n d  e x pecte d  e ve nts  t hat  occ ur  after  t he  i nitiati o n  of  b us ulfa n  I V  c o n diti o ni n g  are  
c o nsi dere d t o be t he direct c o nse q ue nce of b us ulfa n c o n diti o ni n g a n d are t o be re p orte d as A Es 
b ut s h o ul d be attri b ute d t o c o n diti o ni n g a ge nt o n t he A E e C R F, as a p plica ble. 
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6. 2. 1 9. 2. 4.  Seri o us A d verse E ve nts  
A n S A E  is a n y A E t hat: 
•  Res ults i n deat h. 
•  Is i m me diatel y life-t hr eate ni n g; i.e. t he s u bject was at i m me diate ris k of deat h at t he 
ti me of t he e ve nt. It d o es n ot i ncl u de a n A E t hat, h a d it occ urre d i n a m ore s e vere f or m, 
mi g ht ha ve ca use d d eat h.  
•  Re q uires  i n -patie nt  h os pitalizati o n  or  pr ol o n gati o n  of  e xisti n g  h os pitalizati o n.  
H os pitalizati o n a d missi o ns occ urri n g d uri n g t he st u d y peri o d t hat are f or pr oce d ures 
pl a n ne d pri or t o st u dy e ntry  d o n ot meet t his criteria, u nless t here is a c o m plicati o n 
res ulti n g fr o m pr oce d ure t hat pr ol o n gs h os pitalizati o n. 
•  Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pac it y; or a s u bsta ntial disr u pti o n of a 
s u bject’s a bilit y t o c o n d uct n or mal life f u ncti o ns. 
•  Is a c o n ge nital a n o mal y/ birt h defect. 
•  Is a n i m p orta nt me dical e ve nt. A n i m p orta nt me dical e ve nt is a n A E t hat ma y n ot res ult 
i n deat h, be lif e t hreate ni n g, or re q uire h os pitalizati o n b ut ma y be c o nsi dere d seri o us 
w he n, base d u p o n a p pr o priate me dical j u d g me nt, it ma y je o par dize t he s u bject a n d ma y 
re q uire me di cal or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve. 
•  F or t he p ur p os es of t his st u d y, a n y ne w mali g na nc y or ne w dia g n osis of a n e ur ol o gic, 
r he u mat ol o gic, or he mat ol o gic dis or der t h at, i n t h e i n vesti gat or’s o pi ni o n, is cli nicall y 
si g nifica nt a n d re q uires me dical i nter ve nti o n will be c o nsi dere d me dicall y i m p orta nt 
a n d t heref ore s eri o us. 
6. 2. 1 9. 3.  A d verse E ve nt Assess m e nt of Se verit y a n d Rel ati o ns hi p  
F or all A Es, t he i n vesti gat or m ust deter mi ne b ot h t he se verit y of t he e ve nt a n d t he relati o ns hi p of 
t he e ve nt t o Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct a d mi nistrati o n. 
F or i m me diate r e p orti n g of S A Es, t he I n vesti gat or m ust pr o vi de assess me nts of relati o ns hi p a n d 
seri o us criteria at t he ti me of S A E re p ort s u b missi o n t o t he S p o ns or. 
Se verit y will be assesse d b y t he i n vesti gat or usi n g t he f oll o wi n g criteria per Nati o nal Ca ncer 
I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d v erse E ve nts ( C T C A E), versi o n 4. 0 3, i ncl u di n g f or 
A Es t hat are a res ult of a la b orat or y a b n or malit y:  
•  Gr a de 1 : Mil d, as y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic o bser vati o ns 
o nl y; i nter ve nti o n n ot i n dicate d. 
•  Gr a de 2:  M o derate; mi ni mal, l ocal or n o ni n vasi ve i nter ve nti o n i n dicate d; li miti n g a ge -
a p pr o priate i nstr u me nt al acti vities of dail y li vi n g ( A D L).  
•  Gr a de  3 :  Se vere  or  me dicall y  si g nifica nt  b ut  n ot  i m me diatel y  life-t hreate ni n g; 
h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; li miti n g self -
care A D L.  
•  Gr a de 4:  Life -t hr eate ni n g c o nse q ue nces; ur ge nt i nter ve nti o n i n dicate d. 
•  Gr a de 5:  Deat h r elate d t o A E. 
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If t he Gr a de c h a n ges wit hi n a da y, t he ma xi m u m Gra de s h o ul d be rec or de d.  
Rel ati o ns hi p:  T he  I n v esti gat or  is  re q uire d  t o  pr o vi de  a n  assess me nt  of  t he  relati o ns hi p  of  
Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct t o all A Es. T he f oll o wi n g is a g ui deli ne f or d eter mi ni n g t he 
relati o ns hi p of Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct t o a n A E: 
•  N ot Rel ate d : E x p os ure t o t he st u d y treat me nt di d n ot occ ur, or t he occ urre nce of t he 
A E is n ot reas o na bl y rel ate d i n ti me, or t he A E is c o nsi dere d n ot relate d t o t he st u d y 
treat me nt. 
•  U nli kel y Rel ate d :  T he st u d y treat me nt a n d t he A E were n ot cl osel y relate d i n ti me, 
a n d/ or t he A E c o ul d be e x plai ne d m ore c o nsiste ntl y b y ca uses ot her t ha n e x p os ure t o 
t he st u d y treat me nt pr o d uct. 
•  P ossi bl y Rel ate d :  T he st u d y treat me nt a n d t he A E were reas ona bl y relate d i n ti me, 
a n d t he A E c o ul d be e x plai ne d e q uall y w ell b y ca uses ot her t ha n e x p os ure t o t he st u d y 
treat me nt pr o d uct. 
•  Rel ate d :  T h e st u d y tr eat me nt a n d t he A E w ere reas o na bl y relate d i n ti me, a n d t he A E 
was m ore li kel y e x plai ne d b y e x p os ure t o t he st u d y pr o d uct t ha n b y ot her ca uses, or 
t he st u d y treat me nt was t he m ost li kel y ca use of t he A E. 
F or t he p ur p ose of safet y a nal yses a n d safet y re p orti n g, all A Es t hat are classifie d as p ossi bl y 
relate d or relate d will be c o nsi dere d tr eat me nt-relate d e ve nts. 
6. 2. 1 9. 4.  Pr oce d ures f or A E a n d S A E C ollecti o n a n d Re p orti n g  
Eac h s u bject m ust be caref ull y m o nit ore d f or t he de vel o p me nt of a n y A Es. T his i nf or mati o n s h o ul d 
be o btai ne d i n t he f or m of n o n -lea di n g q uesti o ns (e. g., “ H o w are y o u feeli n g?”) a n d fr o m si g ns 
a n d s y m pt o ms detecte d d uri n g eac h e x a mi nati o n, la b orat or y assess me nts, o bser vati o ns of st u d y 
pers o n nel, a n d s p o nta n e o us re p orts fr o m s u bjects. 
A Es f or all eli gi ble s u bjects (i.e., e x cl u di n g scree n fail ures) will be rec or de d i n t he C R F. A n y 
cli nicall y si g nifica nt la b orat or y a b n or malit y or ot h er cli nicall y si g nifica nt fi n di n g is c o nsi dere d a n 
A E a n d t he A E m ust be r ec or de d o n t he a p pr o priat e pa ges of t he C R F. T he dia g n osis / u n derl yi n g 
eti ol o g y rat her t ha n t he si g ns/s y m pt o ms s h o ul d be re p orte d as t he A E, w he n p ossi ble.  If n o 
dia g n osis is a vaila ble, re p ort o nl y t he si g ns a n d s y m pt o ms t hat met A E criteria as i n di vi d ual A E 
ter ms. 
6. 2. 1 9. 5.  I m m e di ate Re p orti n g of S A Es 
All S A Es f or all s u bjects, i ncl u di n g scree n fail ures, m ust be i m me diatel y re p orte d o n t he S A E 
re p ort f or m t o t he S p o ns or ( or desi g nee) wit hi n 2 4 h o urs of t he I n vesti gat or ( or desi g nee) b ec o mi n g 
a war e of t he S A E. All S A Es m ust be r e p orte d w h et her or n ot t he y are c o nsi dere d ca usall y relate d 
t o Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct. T he S A E re p ort f or m a n d c o m pleti o n g ui deli nes ca n be 
f o u n d i n t he St u d y O per ati o ns Ma n ual ( S O M). All f oll o w-u p i nf or mati o n o n S A Es m ust als o be 
i m me diatel y re p orte d t o t he S p o ns or (i.e. wit hi n 2 4 h o urs). 
C o pies of all S A E re p orts a n d ass ociate d d oc u me ntati o n s u b mitte d t o t he S p o ns or will be ke pt i n 
t he I n v esti gat or's st u d y site file. 
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Please  refer  t o  t he  S A E  re p ort  f or m  a n d  ass o ciate d  g ui deli nes  f or  i nf or mati o n  o n  h o w  t o  
i m me diatel y s u b mit S A E re p orts t o t he S p o ns or. 
6. 2. 1 9. 6.  S afet y Re p orti n g t o Re g ul at or y A ut h orities, Et hics C o m mittees, a n d I n vesti g at ors  
If t here are s us p ecte d, u n e x pecte d s eri o us a d verse reacti o ns ( S U S A Rs) ass o ciate d wit h t he use of 
Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct or pleri xaf or, bl ue bir d bi o, I n c., will n otif y t he a p pr o priate 
re g ulat or y a g e nc y(ies) a n d all partici pati n g i n vesti gat ors o n a n e x p e dited b asis a n d i n acc or da n ce 
wit h a p plica ble re g ul ati o ns.  
T he I n vesti gat or or S p o ns or will n otif y t he I R B/ E C a n d ot her a p pr o pri ate i nstit uti o nal re g ulat or y 
b o dies of a n y S U S A Rs or u na ntici pate d pr o bl e ms, i n acc or d a nce wit h l ocal re q uire me nts. 
Re p orti n g of S U S A Rs t o re g ulat or y a g e ncies will be perf or me d wit hi n 7 or 1 5 da ys as i n dicate d 
b y t he e ve nt a n d i n acc or da nce wit h l ocal re g ulati o ns. A n n ual re p orti n g of safet y i nf or mati o n will 
als o be perf or me d b y bl u e bir d bi o, I nc., as re q uire d b y l ocal re g ulati o n.  
6. 2. 1 9. 7.  Pre g n a nc y a n d C o ntr ace pti o n 
Pre g na nc y is neit her a n A E n or a n S A E, u nless a c o m plicati o n relati n g t o t he pre g na n c y occ urs 
(e. g.,  s p o nta ne o us  a b orti o n,  w hic h  re q uires  re p orti n g  as  a n  S A E).  H o we ver,  all  pre g n a ncies  
occ urri n g d uri n g t his st u d y (i n s u bjects or fe male part ners of male s u bjects) are t o be re p orte d i n 
t he sa me ti me fra me as S A Es usi n g t he Pre g na nc y F or m. S A Es e x perie nce d b y s u bject or fe male 
part ner of m ale s u bject d uri n g t he c o urse of t h e pre g na nc y are re q uire d t o b e i m me diatel y re p orte d 
(i.e. wit hi n 2 4 h o urs) o n t he S A E re p ort f or m. 
T he c o urse of all * pre g n a ncies, i ncl u di n g peri nat al a n d ne o natal o utc o me, re gar dless of w h et her 
t he s u bject has disc o nti n ue d partici pati o n i n t h e st u d y, will be f oll o we d u ntil o utc o me, i ncl u di n g 
f oll o w-u p of t he h ealt h st at us of t he ne w b or n at 6  wee ks of a ge a n d a n n u all y t hereafter f or 2  years. 
S A Es e x perie n ce d b y ne w b or n wit hi n 6 wee ks of a ge are re q uire d t o be i m me diatel y re p ort e d (i.e. 
wit hi n 2 4 h o urs) o n t he S A E re p ort f or m. 
* E xce pti o ns i ncl u de: 
I n cases w h er e t he M A L E was t he st u d y s u bject, pre g na nci es res ulti n g fr o m s per m b a n ki n g pri or 
t o recei pt of dr u g pr o d uct will n ot be f oll o we d. 
I n cases w here t he F E M A L E was t he st u d y s u bject, pre g na n cies res ulti n g fr o m o oc yte ba n ki n g 
pri or t o recei pt of dr u g pr o d uct i n w hic h t he pre g na nc y is carri e d t o ter m b y s urr o gac y will n ot be 
f oll o we d. 
B us ulfa n has bee n s h o w n i n a ni mal st u dies t o be terat o ge nic (see pac ka g e i nsert f or a d diti o nal 
details). T he eff ects of a d mi nistrati o n of Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct  o n t he pre g na nt fe male 
or t he de vel o pi n g fet us are u n k n o w n. Fe mal e s u bjects of c hil d -beari n g p ote ntial a n d males are 
re q uire d  t o  use  t w o  differe nt  effecti ve  met h o ds  of  c o ntrace pti o n  (e. g.,  i m pla nts,  i njecta bles,  
c o m bi ne d oral c o ntr ace pti ves, s o me i ntra uteri ne de vices, barrier m et h o ds of c o ntrace pti o n wit h 
s per mici de, vasect o mise d part ner, f or fe m ales; barrier met h o ds of c o ntrace pti o n wit h s per mici de, 
vasect o m y, f or males) fr o m Scree ni n g t hr o u g h at least 6 m o nt hs after dr u g pr o d uct i nf usi o n. If 
s u bjects are tr ul y se x uall y a bsti ne nt ( w here tr ue s e x ual a bsti ne nce is defi n e d as bei n g i n li ne wit h 
t he pref err e d a n d us u al lifest yle of t he s u bject), n o sec o n d met h o d is re q uire d. ( Peri o dic a bsti ne n ce 
[cale n d ar, s y m pt ot her mal, p ost-o v ulati o n met h o ds], wit h dra w al [c oit us i nt err u pt us], s p er mici des 
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o nl y, a n d lactati o nal a me n orr hea met h o d are n ot acce pta bl e met h o ds of c o ntrace pti o n) . Be y o n d 6 
m o nt hs after dr u g pr o d uct i nf usi o n, s u bjects s h o ul d disc uss wit h t heir p h ysicia n pri or t o res u mi n g 
u n pr otecte d i nter c o urse. 
6. 2. 2 0.  
U nsc he d ule d Visits  
U nsc he d ule d visits ma y be perf or me d at a n y ti me d uri n g t he st u d y w he ne ver necessar y t o assess 
f or or t o f oll o w-u p o n A Es or as dee m e d necessar y b y t he i n vesti gat or. E val u ati o ns a n d pr oce d ures 
t o be perf or me d at u nsc h e d ule d visits will be at t he i n vesti gat or’s discreti o n i n c o ns ultati o n wit h 
t he S p o ns or as a p pr o pri ate a n d m a y be b ase d o n t h ose liste d i n t he S O E. U nsc he d ule d visits, 
i ncl u di n g a n y u nsc he d ul e d assess me nts or pr oce d ures perf or me d at t he visit, s h o ul d be pr o m ptl y 
e ntere d i nt o t he C R F. 
6. 2. 2 1.  
L o n g- ter m F oll o w- U p Pr ot oc ol 
S u bjects will be f oll o we d f or 2 4  m o nt hs after dr u g pr o d uct i nf usi o n u n der t his pr ot oc ol. S u bjects 
are e x p ecte d t o be f oll o we d -u p f or a n a d diti o nal 1 3  years u n der a se parat e l o n g -ter m f oll o w- u p 
pr ot oc ol ( L T F -3 0 3), w hi c h will f oc us o n l o n g -ter m safet y, wit h a n e m p hasis o n I S A, i nserti o nal 
o nc o ge nesis,  a n d  l o n g -ter m  efficac y.  A p pr o priate  c o nse nt  will  be  o bt ai ne d  at  t he  ti me  of  
e nr oll me nt i n t he L T F -3 0 3 st u d y. T his f oll o w -u p i ncl u des rec or di n g of S A Es a n d arc hi vi n g of 
peri p her al b l o o d le u k oc yte cell sa m ples f or R C L a n d cl o nalit y testi n g.  
 
 
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7.  
S T A TI S TI C A L P R O C E D U R E S  
Details of t he statistical a nal ysis will be pr o vi de d i n a se parate d oc u me nt (t he Statistical A nal ysis 
Pla n [ S A P]). T his secti o n pr o vi des a ge n eral o ver vie w of t hese pla ns. 
7. 1.  
S a m ple Size Esti m ati o n  
N o f or mal sa m ple size calc ulati o ns were d o n e.  
C o n versi o n t o TI f or p atie nts wit h T D T is ver y u nli kel y t o ha p pe n s p o nta ne o usl y. T heref ore, t he 
c o n versi o n of a n y s u bject i n t he st u d y t o TI w o ul d be attri b uta ble t o t he t hera p e utic eff ect of 
Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct wit h a ver y hi g h pr o ba bilit y. A n y a p precia ble pr o p orti o n of 
s u bjects w h o bec o me tra nsf usi o n i n de pe n de nt o n t he st u d y w o ul d re prese nt a cli nicall y mea ni n gf ul 
treat me nt effect, t o be assesse d a gai nst t he m or bi dit y of t he pr oce d ure. 
A p pr o xi matel y 2 3 s u bj ects will be tr eate d wit h dr u g pr o d uct, at least 1 5 of w h o m m ust be ≥1 2 a n d 
≤5 0 years of a ge ( C o h ort 1; wit h at least 5 s u bjects ≥1 2 a n d < 1 8 years of a ge), a n d at least 8 of 
w h o m m ust be < 1 2 years of a ge ( C o h ort 2). Re place me nt s u bjects ma y b e a d de d if s u bjects are 
scree n fail ures or wit h dra w pri or t o dr u g pr o d uct i nf usi o n. 
T he pr o p ose d sa m ple size i n C o h ort 1 is base d o n t he pre mise t hat e xcl u di n g a treat me nt effect of 
< 3 0 % wit h a hi g h pr o ba bilit y is of val ue ( de m o nstrati n g  wit h  9 7. 5 %  c o nfi de nce  t hat  ≥3 0 %  of 
s u bjects bec o me TI). M ore o ver, a p oi nt esti mate of t he pr o p orti o n of s u bjects w h o bec o me TI of 
at least 6 0 % is c o nsi der e d cli nicall y mea ni n gf ul. T his p oi nt esti mate was selecte d b ase d o n t h e 
mi ni mal criteri o n t o be met i n t he st u d y a n d was s u p p orte d as t he mi ni mal tar get base d o n 
disc ussi o ns wit h ke y o pi ni o n lea ders wit h e x pertise i n t he treat me nt of β -t halasse mia. T heref ore, 
a m o n g t he pr o p ose d s a m ple size of 1 5 treat e d s u bjects ≥1 2 a n d ≤5 0 years of a ge i n C o h ort 1, a 
s uccess criteri o n of 6 0 % is pr o p ose d ( 9 o ut of 1 5 s u bjects), w hic h w o ul d yiel d a l o wer 1 -si de d 
9 7. 5 % e x act  c o nfi de nce  b o u n d of  3 2. 3 %,  e xcee di n g t he 3 0 % mi ni mal  criteri o n.  A m o n g t he  
pr o p ose d sa m ple size of 8 treate d s u bjects < 1 2 y ears of a ge i n C o h ort 2, a s uc cess criteri o n of 
6 2. 5 % ( 5 o ut of 8 s u bjects) w o ul d yiel d a l o wer 1-si de d 9 7. 5 % e xact c o nfi d e nce b o u n d of 2 4. 5 %. 
T he p oi nt esti mate of C o h ort 2 ( 6 2. 5 %) is si milar t o t he p oi nt esti mate of C o h ort 1 ( 6 0 %), a n d 
b ot h p oi nt esti mates are c o nsi dere d cli nicall y m ea ni n gf ul.  
7. 2.  
P o p ul ati o ns f or A n al ysis  
T he f oll o wi n g s u bject p o p ulati o ns will be e val uat e d a n d us e d f or pres e ntati o n a n d a nal ysis of t he 
data:  
•  I nte nt-t o-Treat  (I T T)  p o p ulati o n:  All  s u bjects  w h o  i nitiate  a n y  st u d y  pr oce d ures,  
be gi n ni n g wit h m o bilizati o n b y G- C S F a n d/ or pleri xaf or. 
•  Tra ns pla nt  P o p ulati o n  ( T P):  All  s u bjects  w h o  recei v e  L e nti Gl o bi n  B B 3 0 5  Dr u g  
Pr o d uct. 
•  S uccessf ul E n gr aft me nt P o p ulati o n ( S E P): All s u bjects w h o ha ve s u ccessf ul ne utr o p hil 
e n graft me nt after L e nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct i nf usi o n. 
T he I T T p o p ulati o n is t he pri mar y p o p ulati o n f or t he a nal ysis of safet y para meters. T h e T P is t h e 
pri mar y  p o p ulati o n  f or  t he  a nal ysis  of  effi cac y,  p har mac o d y na mic,  a n d  tra ns pla nt  para meter  
e n d p oi nts (i.e., s uccess a n d ki netics of e n graft me nt, a n d i nci de nce of tra ns pla nt-relate d m ortalit y 
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t hr o u g h 1 0 0 da ys p ost-dr u g pr o d uct i nf usi o n). T he S E P will be use d t o pr o vi de s u p p orti ve data f or 
s u bjects w h o e n gr aft. 
7. 3.  
Pl a n ne d A n al yses  
7. 3. 1.  
I nteri m A n al yses 
I nteri m a nal yses are pla n ne d i n s u p p ort of re g ulat or y s u b missi o ns. T he ti mi n g of t hese a nal yses 
a n d t he n u m b er of s u bjects i ncl u de d i n eac h a nal ysis will ta ke i nt o acc o u nt i n p ut fr o m re g ulat or y 
a ge ncies a n d a p plica bl e r e g ulat or y g ui da nce. T he rati o nale f or eac h a nal ysis will be d oc u me nte d. 
7. 3. 2.  
Fi n al A n al yses 
A fi nal a nal ysis will be perf or me d w he n all s u bjects treate d wit h Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct 
c o m plete t he st u d y. 
7. 3. 3.  
A d diti o n al D at a Re vie w 
Safet y data are r e vie we d o n a n o n g oi n g basis f or si g nal detecti o n,  D M C meeti n gs, a n d t o s u p p ort 
pre par ati o n of re g ul at or y s u b missi o n d oc u me nts.  
A nal yses of st u d y data ma y als o b e perf or me d f or t he p ur p oses of i nter n al d ata re vie w, re g ulat or y 
a ge nc y i nter acti o ns, a n d u p dati n g t he scie ntific c o m m u nit y. 
7. 3. 4.  
I m p act of t he C O VI D-1 9 P a n de mic  
A re vi e w will b e p erf or me d t o deter mi ne w hi c h assess me nts are li kel y t o ha ve bee n affecte d b y 
t he C O VI D-1 9 pa n de mic, a n d if a p plica ble, a nal yses will be perf or me d t o meas ure t h e effect of 
disr u pti o ns d ue t o t he pa n de mic o n t hese assess m e nts. 
7. 4.  
St atistic al Met h o ds  
7. 4. 1.  
Ge ner al Met h o ds  
Ta b ulati o ns  will  be  pr o d uce d  f or  a p pr o priat e  de m o gra p hic,  bas eli ne,  effi cac y,  a n d  safet y  
para meters. F or cate g ori cal  varia bles, s u m mar y ta b ulati o ns of t he n u m ber a n d perce nta ge of  
s u bjects wit hi n eac h cate g or y of t he para meter will be pres e nte d. F or c o nti n u o us varia bles, t he 
n u m ber of s u bjects, mea n, me dia n, sta n dar d de vi ati o n ( S D), mi ni m u m, a n d ma xi m u m val ues will 
be prese nt e d. Descri pti ve s u m mar y statistics as well as 2 -si de d, 9 0 % or 9 5 % or 1-si de d 9 7. 5 % 
c o nfi de nce i nte r vals, as a p pr o priate, will be prese nte d o n selecte d p ara met ers. 
L o n git u di nal data (c ollecte d seriall y o ver ti me) will be prese nte d b y a p pr o priate ti me i nter vals, 
s uc h as m o nt hl y, q uarterl y a n d s o f ort h, de p e n di n g o n t he nat ure of t h e data. 
7. 4. 2.  
B aseli ne Defi ni ti o ns 
T w o years of retr os p ecti ve pre -tra ns pla nt a n d bi ol o gical data will be c ollecte d f or eac h s u bj ect 
i n t he  st u d y,  s o  t hat  eac h  s u bject  ma y  ser ve  as  his/ her  o w n  c o ntr ol  f or  t he  para meters  of  
p R B C  tra nsf usi o n  re q uire me nts,  wei g hte d  a vera ge  na dir  H b  c o nce ntrati o ns,  a n d  i n-patie nt 
h os pitalizati o n ( n u m ber a n d d urati o n). F or t hes e para meters, w here a p plica ble, baseli ne will be 
a n n ualize d o v er t h e 2 y ears pri or t o st u d y e ntr y ( d ate of  i nf or me d c o nse nt). F or p R B C tra nsf usi o n 
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re q uire me nts, t here will be 1 baseli ne p ara m eter, t he a vera ge p er year. Li k e wise, f or t he n u m ber 
of i n - patie nt h os pitalizati o n da ys, i n a d diti o n t o t he t otal n u m ber of h os pitalizati o ns i n t he 2 years 
pri or t o scree ni n g, t he baseli ne a ver a ge p er year will be calc ulate d.  
F or saf et y para met ers, i ncl u di n g s hifts i n ke y la b orat or y para meters, t he m ost rece nt val ue pri or t o 
m o bilizati o n is use d as t he baseli ne ass ess me nt.  
F or ot her efficac y a n d p h ar mac o d y n a mic para met ers, baseli ne will be defi ne d as t he m ost rece nt 
meas ure me nt pri or t o c o n diti o ni n g. 
7. 4. 3.  
Dis p ositi o n of S u bjects  
A ta b ulati o n of t he dis p ositi o n of s u bjects will be pres e nte d, i ncl u di n g t h e n u m ber w h o i nitiate 
m o bilizati o n ,  t he  n u m ber  w h o  i nitiate  m yel oa blati ve  c o n diti o ni n g,  t he  n u m ber  i nf use d  wit h  
Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct, t he n u m b er wit h a n y p ost -dr u g pr o d uct i nf usi o n data a vaila ble 
f or a nal ysis, a n d t he e xte nt of data a vaila ble. T he n u m ber of s u bjects c o m pleti n g t he st u d y t hr o u g h 
M o nt h 2 4 Visit a n d reas o ns f or st u d y disc o nti n uati o n will be re p orte d. 
7. 4. 4.  
De m o gr a p hic a n d B aseli ne C h ar acter istics 
T he f oll o wi n g de m o gra p hic a n d baseli ne c haracteristic fact ors will be s u m marize d: a ge (at ti me 
of e nr oll me nt, at  dia g n osis, at  ti me of first  tra nsf usi o n, w he n fre q ue n c y  of tra nsf usi o ns was 
esta blis he d, w he n ir o n c h elati o n be ga n, a n d at dr u g pr o d uct i nf usi o n), ge n ot y pe, c o u ntr y of birt h, 
race a n d et h nicit y, hist or y of s ple nect o m y a n d s pl ee n size f or s u bjects wit h a s plee n. 
A d diti o nal scree ni n g res ults t o be s u m marize d will i ncl u de t he f oll o wi n g: ec h ocar di o gra m stat us 
( n or mal, a b n or mal, n ot d o ne), L V E F %, a n d li ver ir o n c o nce ntrati o n ( LI C) ( m g/ g dr y wei g ht). 
I n  a d diti o n,  baseli ne  data  fr o m  t he  2-year  retr os pecti ve  c ollecti o n  will  als o  be  s u m marize d,  
i ncl u di n g p R B C v ol u me ( m L/ k g/ year), n u m b er of p R B C tra nsf usi o ns ( n u m ber per year), a n d i n -
patie nt h os pitalizati o n da ys a n d d urati o n ( per year). 
7. 4. 5.  
Effic ac y A n al ysis 
7. 4. 5. 1.  
A n al ysis of Pri m ar y Effic ac y E n d p oi nt 
T he pri mar y efficac y e n d p oi nt is defi ne d as t he pr o p orti o n of s u bjects w h o meet t he d efi niti o n of 
“tra nsf usi o n i n de pe n de n ce” ( TI). TI is defi ne d as a wei g hte d  a vera g e  H b  ≥9  g/ d L  wit h o ut  a n y 
p R B C tra nsf usi o ns f or a c o nti n u o us peri o d of ≥1 2 m o nt hs at a n y ti me d uri n g t he st u d y after dr u g 
pr o d uct i nf usi o n, w her e: 
•  Calc ulati o n of ti me peri o d  of TI will start w he n s u bjects ac hie v e a H b ≥9 g/ d L wit h n o 
tra nsf usi o ns i n t he prece di n g 6 0 da ys. 
•  T o meet t he i nitial TI criteria, t he wei g hte d H b m ust be ≥9 g/ d L at t he e n d of t he 1 2 -
m o nt h peri o d 
•  T o re mai n i n t he TI stat e be y o n d t he 1 2 -m o nt h peri o d, t he  treate d s u bject nee ds t o 
mai ntai n a w ei g hte d H b of ≥9 g/ d L fr o m t hat p oi nt f or war d, wit h o ut recei vi n g a p R B C 
tra nsf usi o n. 
•  A  p R B C  tra nsf usi o n  f or  a  si n gle  ac ut e  e v e nt  (e. g.,  s ur g er y,  tra u ma,  par v o vir us  
i nfecti o n, or se psis) will n ot be c o u nte d t o war ds t he defi niti o n of TI. F or t he calc ulati o n 
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of t he w ei g hte d H b w he n a n all o w e d tra nsf usi o n has occ urre d, t he H b t h at tri g gere d 
t he tra nsf usi o n w o ul d b e carrie d f or war d f or 6 0 d a ys a n d H b val ues d uri n g t h ose 6 0 
da ys w o ul d be i m p ute d b y t he carrie d -f or w ar d val ue. P ost 6 0 da ys, t he act ual H b dra w n 
w o ul d a gai n be use d i n t he calc ul ati o n of TI. 
T he pri mar y efficac y e n d p oi nt of TI will be a n al yze d as a p oi nt -esti mate of t he pr o p orti o n of 
s u bjects ac hie vi n g TI, wit h a 2-si de d 9 5 % c o nfi de nce i nter v al calc ulate d usi n g t he e xact bi n o mial 
met h o d. T he T P will be use d f or pri mar y c o ncl usi o ns of ge ne -t hera p y effi cac y, wit h s u p p orti ve 
a nal yses perf or me d o n t h e S E P.  
7. 4. 5. 2.  
A n al ysis of Sec o n d ar y Effic ac y E n d p oi nts  
T he f oll o wi n g sec o n dar y efficac y e n d p oi nts will be descri pti vel y a n al yze d i n t he T P. 
•  C haracterizati o n of s u bjects ac hie vi n g TI:  
− Pr o p orti o n of s u bjects w h o meet t he defi niti o n of TI at M o nt h 2 4 
− D urati o n of TI 
− Ti me fr o m dr u g pr o d uct i nf usi o n t o ac hie ve me nt of TI  
− Wei g hte d a v era g e H b d uri n g TI  
•  C haracterizati o n of tr a nsf usi o n re d ucti o n ( T R): 
− Pr o p orti o n of s u bjects wit h a re d u cti o n i n t he a n n u alize d m L/ k g p R B Cs tra nsf use d 
fr o m 1 2 m o nt hs p ost -dr u g pr o d uct i nf usi o n t hr o u g h M o nt h 2 4 (a p pr o xi matel y a 1 2 -
m o nt h peri o d) of at least 5 0 %, 6 0 %, 7 5 %, 9 0 % or 1 0 0 % c o m pare d t o t he a n n ualize d 
m L/ k g p R B C tra nsf usi o n re q uire me nt d uri n g t he 2 years pri or t o e nr oll me nt  
− A n n ualize d n u m ber a n d v ol u me of p R B C tra nsf usi o ns fr o m 1 2  m o nt hs p ost - dr u g 
pr o d uct i nf usi o n t hr o u g h M o nt h 2 4 c o m pare d t o t h e a n n ualize d n u m ber a n d v ol u me 
of tra nsf usi o ns d uri n g t h e 2 years pri or t o e nr oll m e nt 
− Ti me fr o m dr u g pr o d uct i nf usi o n t o last p R B C tra nsf usi o n 
− Ti me fr o m last p R B C tra nsf usi o n t o M o nt h 2 4  
•  Wei g hte d  a v era g e  na dir  H b  d uri n g  t he  2  years  pri or  t o  e nr oll me nt  c o m pare d  t o  
wei g hte d  a vera ge  n a dir  H b  fr o m  1 2  m o nt hs  p ost -dr u g  pr o d uct  i nf usi o n  t hr o u g h  
M o nt h 2 4 
•  U ns u p p orte d t otal H b le v els o ver ti me, i ncl u di n g M o nt h 6, M o nt h 9, M o nt h 1 2, M o nt h 
1 8, a n d M o nt h 2 4 
•  U ns u p p orte d t otal H b le vels ≥1 0  g/ d L, ≥1 1  g/ d L, ≥1 2  g/ d L, ≥1 3  g/ d L, ≥1 4  g/ d L o ver 
ti me, i ncl u di n g M o nt h 6, M o nt h 9, M o nt h 1 2, M o nt h 1 8, a n d M o nt h 2 4 
•  C haracterizati o n of use of ir o n c h elati o n a n d/ or t hera pe utic p hle b ot o m y a m o n g all 
s u bjects: 
− Pr o p orti o n of s u bjects w h o ha ve n ot recei ve d ir o n c helati o n t hera p y f or at least 6 
m o nt hs f oll o wi n g dr u g pr o d uct i nf usi o n 
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− Ti me fr o m last i r o n c helati o n use t o last f oll o w- u p 
− Pr o p orti o n  of  s u bjects  usi n g  t hera pe utic  p hle b ot o m y  f oll o wi n g  dr u g  pr o d uct  
i nf usi o n a n d a n n ualize d fre q ue nc y of p hle b ot o m y use per s u bject 
•  E val uati o n of t he c h a n ge i n ir o n b ur de n o ver ti me, as meas ure d b y:  
− C ha n ge i n li ver ir o n c o nt e nt b y M RI at baseli ne t o M o nt h 1 2 a n d M o nt h 2 4 
− C ha n ge i n car di ac T 2 * o n M RI at b aseli ne t o M o nt h 1 2 a n d M o nt h 2 4 
− C ha n ge i n ser u m ferriti n at baseli ne t o M o nt h 1 2 a n d M o nt h 2 4 
•  E val uati o n of h ealt h- r elat e d q ualit y of life ( H R Q o L) o ver ti me i ncl u di n g M o nt h 1 2 a n d 
M o nt h 2 4 as c o m pare d t o baseli ne, usi n g t he f oll o wi n g vali date d t o ols: 
− Pe diatrics: Pe diatric Q ualit y of Life I n ve nt or y ( P e ds Q L; pare nt ge neral c ore a n d 
ge neral c ore)  
− A d olesce nts:  Pe ds Q L  ( p are nt  ge n eral  c ore  a n d  ge neral  c ore)  a n d  E ur o Q ol -5 D 
( Y o ut h versi o n) ( E Q- 5 D-Y)  
− A d ults: E ur o Q ol -5 D ( E Q -5 D), F u ncti o nal Ass ess me nt of Ca ncer T hera p y - B o ne 
Marr o w Tra ns pla nt ( F A C T- B M T), a n d S h ort F or m- 3 6 ( S F- 3 6) v 2 
A nal yses of 
 will be descri b e d i n t he S A P.  
7. 4. 6.  
S afet y A n al ysis 
T he f oll o wi n g sec o n dar y safet y e n d p oi nts will be e val uate d d escri pti vel y: 
•  S uccess a n d ki netics of H S C e n graft me nt  
•  I n ci de nce  of  tra ns pla nt-relate d  m ortalit y  t hr o u g h  1 0 0  da ys  a n d  t hr o u g h  3 6 5  da ys  
p ost‑ dr u g  pr o d uct i nf usi o n 
•  O verall s ur vi val ( O S) 
•  Detecti o n of vect or- d eri v e d R C L i n a n y s u bject 
•  M o nit ori n g of la b orat or y para meters 
•  Fre q u e nc y a n d se verit y of cli nical A Es  
•  I n ci de nce of ac ute a n d/ or c hr o nic G V H D 
•  T he  n u m ber  of  s u bjects  wit h  i nserti o nal  o nc o ge nesis  ( m yel o d ys plasia,  le u ke mia,  
l y m p h o ma, etc.)  
All s u bjects starti n g m o bilizati o n will be e val uate d f or safet y (I T T p o p ulati o n) . Res ults re p orte d 
as i nci de nce will be a nal yze d as pr o p orti o ns.  
All A Es will be c ollecte d fr o m si g ni n g of i nf or me d c o nse nt/asse nt t hr o u g h M o nt h 2 4 Visit f or 
eli gi ble  s u bjects,  irr es pecti ve  of  s e verit y  gra de  or  rel ati o ns hi p  t o  Le nti Gl o bi n  B B 3 0 5  Dr u g 
Pr o d uct. All A Es will be liste d a n d s u m marize d f or t he f oll o wi n g ti me peri o ds: 1) fr o m i nf or me d 
c o nse nt/asse nt  u p  t o  t he  start  of  m o bilizati o n;  2)  fr o m  start  of  m o bilizati o n  u p  t o  start  of  
c o n diti o ni n g; 3) fr o m start of c o n diti o ni n g t hr o u g h ne utr o p hil e n graft me nt; 4)  fr o m ne utr o p hil 
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e n graft me nt t hr o u g h M o nt h 2 4 Visit; 5) fr o m dr u g pr o d uct i nf usi o n  t hr o u g h M o nt h 2 4 Visit; a n d 
6) fr o m i nf or me d c o nse nt/asse nt t hr o u g h M o nt h 2 4 Visit. 
N ote t hat ne utr o p hil e n graft me nt fail ure is a S A E a n d f or t his pr ot oc ol is defi ne d as fail ure t o 
ac hie ve 3 c o ns ec uti ve a bs ol ute ne utr o p hil c o u nt ( A N C) la b orat or y val u es ≥5 0 0  cells/ µ L o btai ne d 
o n differ e nt da ys b y D a y 4 3, or recei vi n g bac k -u p cells at a n y ti me d uri n g t he ne utr o pe ni c p hase. 
If a s u bject fails t o e n graft wit h tra ns d uce d cells, bac k-u p cells c ollect e d per pr ot oc ol ca n be use d 
(see Secti o n  5. 2 ), a n d if > 1 s u bject fails t o ac hie ve rec o nstit uti o n wit h tra ns d uce d cells a n d recei ves 
bac k -u p cells, e nr oll me nt a n d treat me nt wit h dr u g pr o d uct will be te m p oraril y s us pe n de d a n d will 
res u me after re vie w a n d rec o m me n dati o ns fr o m t he D M C a n d (as re q uire d) a p pr o val fr o m t he 
rele va nt r e g ulat or y a g e nc y(ies) (see Secti o n  3. 5. 2 ). 
Platelet e n graft me nt is defi ne d as 3 c o ns ec uti v e  platelet  c o u nt  la b orat or y  val ues  ≥ 2 0 ×  1 09/ L 
o btai ne d o n differe nt da ys w hile n o platelet tra nsf usi o ns  a d mi nistere d f or se ve n da ys i m me diatel y 
prece di n g a n d d uri n g t he e val uati o n p eri o d. T he d a y of plat elet e n graft me nt is t he first da y of t he 
3 c o nsec uti ve  platelet  meas ure me nts.  La b orat or y  meas ures  will  be  c o m pare d  wit h  t heir  
c orres p o n di n g n or mal r a n ges a n d t he i nci de n ce of a b n or mall y hi g h a n d a b n or mall y l o w la b orat or y 
val ues will be calc ul ate d f or eac h rel e va nt pr ot oc ol -s pecifie d la b orat or y test; c ha n ges i n la b orat or y 
para meters o ver ti me will be s u m marize d wit h des cri pti ve statistics a n d s hift ta bles.  
A d diti o nall y,  s ur vi val  stat us,  la b orat or y  res ults  a n d  i nserti o nal  o nc o ge nesis  (i nserti o nal  
m uta ge nesis res ulti n g i n o nc o ge nesis) e ve nts will be s u m marize d.  
Vital si g ns, La ns k y a n d Kar n ofs k y Perf or m a nce stat us res ults, a n d 
 
will be prese nte d as Listi n gs o nl y. 
Re plicati o n -c o m pete nt le nti vir us testi n g a n d I S A will be perf or me d a n d res ults ta b ulate d.  
A nal yses of 
 will be descri be d i n t he S A P. 
7. 4. 7.  
P h ar m ac o d y n a mic A n al y ses 
A nal yses of p har mac o d y na mic e n d p oi nts will be descri be d i n t he S A P. 
 
 
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8.  
A D MI NI S T R A TI V E R E Q UI R E M E N T S  
8. 1.  
G o o d Cli nic al Pr actice  
T he st u d y will be c o n d ucte d i n acc or d a nce wit h t he I nt er nati o nal C o nfere nce o n Har m o nizati o n 
(I C H) G ui deli ne f or G C P a n d t he a p pr o priate re g ulat or y re q uire me nt(s). T he i n vesti gat or will be 
t h or o u g hl y fa miliar wit h t he a p pr o priat e use of Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct as des cri be d i n 
t he pr ot oc ol  a n d I n vesti gat or’s  Br oc h ure. Esse ntial  cli nical  d oc u me nts will  be mai ntai ne d t o 
de m o nstrate t he v ali dit y of t he st u d y a n d t h e i nte grit y of t he dat a c ollect e d. Master files s h o ul d b e 
esta blis he d at t he be gi n ni n g of t he st u d y, mai ntai ne d f or t he d urati o n of t he st u d y a n d retai ne d 
acc or di n g t o t he a p pr o pri ate re g ulati o ns. 
8. 2.  
Et hic al C o nsi der ati o ns  
T he st u d y will be c o n d u cte d i n acc or d a nce wit h et hical pri nci ples f o u n de d i n t he Declarati o n of 
Helsi n ki. T he I R B / E C  a n d ot he r a p pr o priate i nstit uti o nal re g ulat or y b o dies will re vie w all 
a p pr o priate st u d y d oc u me ntati o n i n or der t o safe g uar d t he ri g hts, safet y, a n d well -bei n g of t he 
s u bjects. T he st u d y will o nl y be c o n d ucte d at sites w here I R B / E C a n d a n y ot her a p pr o priate 
i nstit uti o nal re g ulat or y b o d y a p pr o val has bee n o btai ne d. T he pr ot oc ol, I n vesti gat or’s Br oc h ure, 
i nf or me d  c o nse nt,  a d v ertise me nts  (if  a p plica bl e),  writte n  i nf or m ati o n  gi ve n  t o  t he  s u bjects  
(i ncl u di n g  diar y  car ds),  safet y  u p d ates,  a n n ual  pr o gress  re p orts,  a n d  a n y  re visi o ns  t o  t hes e  
d oc u me nts will be pr o vi de d t o t he I R B / E C, I B C, a n d ot her a p pr o priate i nstit uti o nal re g ulat or y 
b o dies b y t he i n vesti gat or. 
8. 3.  
S u bject I nf or m ati o n a n d I nf or me d C o nse nt  
After t he st u d y has b ee n f ull y e x plai ne d, v ol u ntar y writte n i nf or me d c o nse nt will be o btai ne d fr o m 
eit her t he s u bject a n d/ or his/ her g u ar dia n or l e gal re prese ntati ve pri or t o st u d y partici pati o n, as 
well as asse nt if a p plica ble. T he met h o d of o btai ni n g a n d d oc u me nti n g t he i nf or me d c o nse nt/asse nt 
a n d t he c o nte nts of t he c o nse nt/asse nt will c o m pl y wit h I C H -G C P a n d all a p plica ble re g ulat or y 
re q uire me nt(s). C o nse nt t o t his st u d y i n dicates ac k n o wle d g me nt t hat f oll o w- u p is e x pecte d t o last 
1 5 years, wit h t he first 2 years i n t his St u d y H G B -2 0 7 a n d 1 3 a d diti o nal years i n l o n g -ter m foll o w-
u p St u d y L T F -3 0 3. A brief s u m mar y of e x pecte d st u d y pr oce d ures i n St u d y L T F -3 0 3 will be 
descri be d  i n  t he  St u d y  H G B -2 0 7  c o nse nt  s o  t h at  t he  s u bject  a n d/ or  t h eir  g uar dia n  or  le gal  
re pres e ntati ve are a w are of e x pect ati o ns i n St u d y L T F-3 0 3. C o nse nt f or p artici pati o n i n St u d y 
L T F - 3 0 3 will be o btai ne d at t he ti me of e nr oll me nt i n St u d y L T F- 3 0 3.  
8. 4.  
S u bject C o nfi de nti alit y  
I n  or d er  t o  mai ntai n  s u bject  pri vac y,  all  C R Fs,  acc o u nt a bilit y  rec or ds,  st u d y  re p orts,  a n d  
c o m m u nicati o ns will i de ntif y t he s u bject b y t he a ssi g ne d s u bject n u m ber. T he i n vesti gat or will 
gra nt m o nit or(s) a n d a u dit or(s) fr o m t he S p o ns or or its d esi g nee a n d re g ulat or y a ut h orit y(ies) 
access t o t he s u bject’s ori gi nal me dical rec or ds f or verificati o n of data g at here d o n t he C R Fs a n d 
t o a u dit t he d ata c ollecti o n pr ocess. T he s u bject’s c o nfi de ntialit y will b e mai ntai ne d a n d will n ot 
be ma de p u blicl y a v aila ble t o t he e xte nt per mitte d b y t he a p plica ble la ws a n d re g ulati o ns. 
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8. 5.  
Pr ot oc ol C o m pli a nce  
T he i n vesti gat or will c o n d uct t he st u d y i n c o m plia nce wit h t he pr ot oc ol pr o vi de d b y bl ue bir d bi o 
a n d  gi ve n  a p pr o val/fa v ora ble  o pi ni o n  b y  t he  I R B  /  E C  a n d  ot her  a p pr o priate  i nstit uti o nal  
re g ulat or y b o dies. M o dificati o ns t o t he pr ot o c ol s h o ul d n ot be ma d e wit h o ut a gree me nt of b ot h 
t he i n vesti gat or a n d bl u e bir d bi o. C ha n ges t o t he pr ot oc ol will re q uire writte n I R B / E C a n d ot her 
a p pr o priate  i nstit uti o nal  re g ulat or y  b o d y  a p pr o val/fa v ora bl e  o pi ni o n  pri or  t o  i m ple me ntati o n,  
e xce pt w he n t he m o dificati o n is nee de d t o eli mi nate a n i m me diate hazar d(s) t o s u bjects. T he I R B  / 
E C  ma y  pr o vi de,  if  a p plica ble  re g ulat or y  a ut h orit y(ies)  per mit,  e x pe dite d  re vie w  a n d  
a p pr o val/fa v ora ble  o pi ni o n  f or  mi n or  c ha n ge(s)  i n  o n g oi n g  st u dies  t hat  ha ve  t he  a p pr o val  
/fa v ora ble o pi ni o n of t he I R B / E C a n d ot her a p pr o priate i nstit uti o nal re g ulat or y b o dies. bl ue bir d 
bi o, I n c., will s u b mit all pr ot oc ol m o dificati o ns t o t he re g ulat or y a ut h orit y(ies) i n acc or d a nce wit h 
t he g o ver ni n g re g ul ati o ns.  
W he n de vi ati o n fr o m t he pr ot oc ol is r e q uire d t o eli mi nate a n i m me diate h azar d(s) t o s u bjects, t h e 
i n vesti gat or will c o ntact bl ue bir d bi o, if circ u mst a nces per mit, t o disc uss t he pla n ne d c o urs e of 
acti o n. A n y de p art ures  fr o m  t he pr ot oc ol  m ust  be f ull y d oc u me nte d i n t he C R F a n d s o urce  
d oc u me ntati o n. 
8. 6.  
Direct Access t o S o urce D at a  
M o nit ori n g a n d a u diti n g pr oce d ur es de vel o p e d b y bl ue bir d bi o will be f oll o we d, i n or der t o c o m pl y 
wit h I C H - G C P g ui deli nes. 
T he st u d y will be m o nit ore d b y bl ue bir d bi o or its desi g nee. M o nit ori n g will be d o ne b y pers o nal 
visits fr o m a re prese ntati ve of t he S p o ns or (site m o nit or) a n d will i ncl u de  o n-site re vie w of t he 
C R Fs f or c o m plete ness a n d clarit y, cr oss -c hec ki n g wit h s o urce d oc u me nts, a n d clarificati o n of 
a d mi nistrati ve matters. T he re vie w of me dical rec or ds will be perf or me d i n a ma n ner t o e ns ure 
t hat s u bject c o nfi de ntialit y is mai ntai ne d. 
T he site m o nit or will e ns ure t hat t he i n vesti gati o n is c o n d ucte d acc or di n g t o pr ot oc ol desi g n a n d 
re g ulat or y r e q uire me nts b y fre q ue nt c o m m u nicati o ns (letter, e- m ail, tele p h o ne, a n d fa x). 
Re g ulat or y a ut h orities, t he I R B / E C a n d ot her a p pr o priate i nstit uti o nal re g ulat or y b o dies, a n d/ or 
bl ue bir d bi o’s cli nical q ualit y ass ura nce gr o u p ma y re q uest access t o all s o urce d oc u me nts, C R Fs, 
a n d ot her st u d y d oc u m e ntati o n f or o n -site a u dit or i ns pecti o n. Direct access t o t hese d oc u m e nts 
m ust be g uara ntee d b y t he i n vesti gat or, w h o m ust pr o vi de s u p p ort at all ti mes f or t hese acti vities. 
8. 7.  
Electr o nic C ase Re p ort F or m C o m pleti o n  
Case re p ort f or ms will be c o m plete d usi n g a n electr o nic data ca pt ure ( E D C)  s yste m. T he S p o ns or 
or desi g nee will pr o vi de i nstr ucti o n re gar di n g t he pr o per use of t he E D C s yste m. 
It is t he i n vesti gat or’s res p o nsi bilit y t o e ns ure t he acc urac y, c o m plete n ess, a n d ti meli ness of t he 
data  re p orte d  i n  t he  s u bject’s  electr o nic  cas e  re p ort  f or m  (e C R F).  S o urce  d oc u me ntati o n  
s u p p orti n g t he e C R F data s h o ul d i n dicate t he s u bject’s partici pati o n i n t he st u d y a n d s h o ul d 
d oc u me nt t he dates a n d d etails of st u d y pr oce d ures, A Es, a n d s u bject stat us.  
T he i n vesti gat or or d esi g nate d re prese nt ati ve s h o ul d c o m plete t he e C R F pa ges as s o o n as p ossi ble 
after i nf or mati o n is c oll ecte d, pr ef era bl y o n t he sa me da y t hat a st u d y s u bject is see n f or a n 
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e xa mi nati o n, treat me nt, or a n y ot h er st u d y pr oce d ure. A n y o utsta n di n g e ntri es m ust be c o m plete d 
i m me diatel y after the fi nal e xa mi nati o n. A n e x pla nati o n s h o ul d be gi ve n f or all missi n g data. 
T he i n vesti gat or m ust si g n a n d dat e t he I n vesti gat or’s State me nt wit hi n t he E D C s yste m t o e n d orse 
t he rec or de d dat a.  
8. 8.  
Rec or d Rete nti o n  
T he i n vesti gat or will mai ntai n all st u d y rec or ds acc or di n g t o I C H -G C P a n d a p plica ble re g ulat or y 
re q uire me nt(s). Rec or ds will be retai ne d f or at least 2 years aft er t he last mar keti n g a p plicati o n 
a p pr o val or 2 y ears after f or mal disc o nti n uati o n of t he cli nical d e vel o p me nt of t he i n v esti gati o nal 
pr o d uct or acc or di n g t o a p plica ble r e g ulat or y re q uire me nt(s). If t he i n vesti gat or wit h dra ws fr o m 
t he res p o nsi bilit y of kee pi n g t he st u d y rec or ds, c ust o d y m ust be tra nsferre d t o a pers o n willi n g t o 
acce pt t he r es p o nsi bilit y. bl ue bir d bi o, I nc., m ust b e n otifie d i n  writi n g if a c ust o dial c ha n ge o cc urs.  
T he S p o ns or has f ull ri g hts o ver a n y i n ve nti o n, disc o ver y, or i n n o vati o n, pate nta ble or n ot, t hat 
ma y occ ur w h e n perf or mi n g t he st u d y. 
8. 9.  
Li a bilit y a n d I ns ur a nce  
bl ue bir d bi o, I n c., has s u bscri be d t o a n i ns ura n ce p olic y c o veri n g, i n its ter ms a n d pr o visi o ns, its 
le gal lia bilit y f or i nj uries ca use d t o p artici pati n g pers o ns a n d arisi n g o ut of t his researc h perf or m e d 
strictl y i n acc or da n ce wit h t he scie ntific pr ot oc ol as well as wit h a p plica bl e la w a n d pr ofessi o nal 
sta n dar ds. 
8. 1 0.  
P u blic ati o n  a n d  Prese nt ati o n  of  St u d y  Fi n di n gs  a n d  Use  of  
I nf or m ati o n 
All i nf or mati o n re gar di n g B B 3 0 5 le nti viral vect or a n d Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct s u p plie d 
b y bl ue bir d bi o t o t he i n vesti gat or is pri vile ge d a n d c o nfi de ntial i nf or m ati o n. T he i n vest i gat or 
a grees t o use t his i nf or mati o n t o acc o m plis h t he st u d y a n d will n ot use it f or ot her p ur p oses wit h o ut 
c o nse nt fr o m bl u e bir d bi o. It is u n derst o o d t hat t h ere is a n o bli gati o n t o pr o vi de bl ue bir d bi o wit h 
c o m plete data o btai ne d d uri n g t he st u d y. T he i nf or mati o n o btai ne d fr o m t he cli nical st u d y will be 
use d t o war ds t h e de v el o p me nt of B B 3 0 5 le nti viral vect or a n d L e nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct 
a n d  ma y  be  discl ose d  t o  re g ulat or y  a ut h orit y(ies),  ot her  i n vesti gat ors,  c or p orat e  part ners,  or  
c o ns ulta nts as re q uire d. 
It is a ntici pate d t hat t he res ults of t his st u d y will be prese nte d at scie ntific meeti n gs a n d/ or 
p u blis he d i n a peer re vie we d scie ntific or me dical j o ur nal. A P u blicati o ns C o m mittee c o m prise d 
of i n vesti gat ors partici pati n g i n t he st u d y a n d re prese ntati ves fr o m bl ue bir d bi o, as a p pr o priate, 
will be f or me d t o o vers ee t he p u blicati o n a n d prese ntati o n of t he st u d y res ults, w hic h will refl ect 
t he e x perie n ce of all parti ci pati n g cli nical sites.  
N o  p u blicati o n  or  discl os ure  of  st u d y  res ults  will  be  per mitt e d  e xce pt  u n der  t he  ter ms  a n d  
c o n diti o ns  of  a  se par ate  writte n  a gree me nt  bet wee n  S p o ns or  a n d  t he  i n vesti gat or  a n d/ or  t he  
i n vesti gat or's i nstit uti o n. 
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9.  
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2 0 0 1- 1 2- 0 1 5 9 
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efficaci o us f or m o bilizati o n of peri p heral bl o o d ste m cells i n pe diatric patie nts. Tra nsf usi o n  5 6, 
1 4 0 2- 1 4 0 5. 
T o, L. B., R o berts, M. M., Ha yl oc k, D. N., D ys o n, P. G., Bra nf or d, A. L., T h or p, D., H o, J. Q., D art, 
G. W., H or vat h, N., Da v y, M. L. , et al. ( 1 9 9 2). C o m paris o n of h ae mat ol o gi cal rec o ver y ti mes a n d 
s u p p orti ve car e r e q uire m e nts of a ut ol o g o us rec o ver y p hase p eri p heral bl o o d ste m cell tra ns pla nts, 
a ut ol o g o us  b o ne  marr o w  tra ns pla nts  a n d  all o g e neic  b o ne  m arr o w  tra ns pla nts.  B o ne  Marr o w  
Tra ns pla nt  9, 2 7 7- 2 8 4. 
Vic hi ns k y, E., B ute ns k y, E., F u n g, E., H u d es, M., T heil, E., Ferrell, L., Willia ms, R., L o uie, L., 
Lee, P. D., a n d H ar matz, P. ( 2 0 0 5a). C o m paris o n of or ga n d ysf u ncti o n i n tra nsf use d patie nts wit h  
S C D or beta t halasse mia. A m J He mat ol  8 0, 7 0- 7 4. 
Vic hi ns k y, E. P., Mac Kli n, E. A., Wa ye, J. S., L ore y, F., a n d Oli vieri, N. F. ( 2 0 0 5 b). C ha n ges i n t he 
e pi de mi ol o g y of t halasse mia i n N ort h A merica: a ne w mi n orit y disease. Pe diatrics  1 1 6, e 8 1 8- 8 2 5. 
Ya n na ki, E.,  Kar p o ni, G., Zer v o u, F., C o nsta nti n o u, V., B o ui nta, A., Tac h y n o p o ul o u, V., K otta, 
K., J o nli n, E., Pa pa ya n n o p o ul o u, T., A na g n ost o p o ul os, A. , et al. ( 2 0 1 3). He mat o p oietic ste m cell 
m o bilizati o n f or ge ne t hera p y: s u peri or m o bilizati o n b y t he c o m bi nati o n of g ra n ul oc yte-c ol o n y 
sti m ulati n g fact or pl us pleri xaf or i n patie nts wit h beta-t halasse mia maj or. H u m Ge ne T her 2 4, 8 5 2-
8 6 0. 
Ya n na ki, E., Pa pa ya n n o p o ul o u, T., J o nli n, E., Zer v o u, F., Kar p o ni, G., X a g orari, A., Bec k er, P., 
Psat ha, N., Batsis, I., Kal o ya n ni dis, P. , et al. ( 2 0 1 2). He mat o p oietic ste m cell m o bilizati o n f or ge ne 
t hera p y of a d ult patie nts wit h se vere beta-t h alass e mia: res ults of cli nical trials usi n g G-C S F or 
pleri xaf or i n s ple n ect o mize d a n d n o ns ple n ect o mize d s u bjects. M ol T her  2 0, 2 3 0- 2 3 8. 
 
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Pr ot oc ol H G B - 2 0 7 Versi o n 6. 0  
1 0 J u ne 2 0 2 1  
Pa ge 9 0 
 
1 0.  
A P P E N D I C E S 
1 0. 1.  
Gl o mer ul ar Filtr ati o n R ate C alc ul ati o n  
F or a d ults: 
F or use wit h cre ati ni ne ( Scr) re p orte d i n m g/ d L: 
G F R ( m L/ mi n/ 1. 7 3 m 2) = 1 7 5 × ( Scr)-1. 1 5 4 × ( A ge) -0. 2 0 3 × ( 0. 7 4 2 if fe male) × ( 1. 2 1 2 if 
Africa n A merica n) ( c o n v e nti o nal u nits) 
F or use w he n cre ati ni ne ( Scr) is re p orte d i n µ m ol/ L: 
G F R ( m L/ mi n/ 1. 7 3 m 2) = 1 7 5 × ( Scr/ 8 8. 4)-1. 1 5 4 × ( A ge) -0. 2 0 3 × ( 0. 7 4 2 if fe male) × ( 1. 2 1 2 if 
Africa n A merica n) ( SI u nits)  
F or c hil dre n:  
G F R ( m L/ mi n/ 1. 7 3 m 2) = ( 0. 4 1 × H ei g ht i n c m) / Creati ni ne i n m g/ d L 
G F R ( m L/ mi n/ 1. 7 3 m 2) = ( 3 6. 2 × H ei g ht i n c m) / Creati ni ne i n µ m ol/ L 
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Pr ot oc ol H G B - 2 0 7 Versi o n 6. 0  
1 0 J u ne 2 0 2 1  
Pa ge 9 1 
 
1 0. 2.  
K ar n ofs k y Perf or m a nce St at us Sc ale  
T he f oll o wi n g ta ble pres e nts t he Kar n ofs k y perf or ma nce stat us scale a n d s h o ul d be use d f or 
s u bjects ≥1 6 years of a ge. 
P oi nts  
Descri pti o n  
1 0 0  
N or mal, n o c o m plai nts, n o e vi de nce of disease  
9 0  
A ble t o carr y o n n or mal acti vit y  
8 0  
N or mal acti vit y wit h eff ort; s o me si g ns or s y m pt o ms of disease  
7 0  
Cares f or self; u na ble t o carr y o n n or mal acti vit y or t o d o acti ve w or k  
6 0  
Re q uire d occasi o nal assista nce b ut is a ble t o care f or m ost of his/ her nee ds  
5 0  
Re q uire d c o nsi dera ble assista nce a n d fre q ue nt me dical care  
4 0  
Disa ble d; re q uire d s pecial care a n d assista nce  
3 0  
Se verel y disa ble d; h os pitalizati o n i n dicate d. Deat h n ot i m mi n e nt 
2 0  
Ver y sic k; h os pitalizati o n necessar y; acti ve s u p p ort treat me nt necessar y  
1 0  
M ori b u n d; fatal pr ocess pr o gressi n g ra pi dl y  
0  
Dea d  
S o urce: (M or et al., 1 9 8 4 )   
1 0. 3.  
L a ns k y Perf or m a nce St at us Sc ale  
T he f oll o wi n g ta ble pres e nts t he La ns k y perf or ma nce stat us scale a n d s h o ul d be use d f or s u bjects 
< 1 6 years of a g e.  
P oi nts  
Descri pti o n  
1 0 0  
F ull y acti ve, n or mal  
9 0  
Mi n or restricti o ns i n p h ysicall y stre n u o us acti vit y  
8 0  
Acti ve, b ut tires m ore q uic kl y  
7 0  
B ot h greater restricti o n of, a n d less ti me s pe nt i n, acti ve pla y 
6 0  
U p a n d ar o u n d, b ut mi ni mal acti ve pla y; kee ps b us y wit h q uieter acti vities  
5 0  
Gets dresse d, b ut lies ar o u n d m uc h of t he da y; n o acti ve pla y; a ble t o partici pate i n all 
q uiet pla y a n d acti vities  
4 0  
M ostl y i n be d; partici pates i n q uiet acti vities  
3 0  
I n be d; nee ds assista nce e ve n f or q uiet pla y 
2 0  
Ofte n slee pi n g; pla y e ntirel y li mite d t o ver y passi ve acti vities  
1 0  
N o pla y; d oes n ot get o ut of be d  
0  
U nres p o nsi ve  
S o urce: (La ns k y et al., 1 9 8 7 )  
 
 
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Pr ot oc ol H G B - 2 0 7 Versi o n 6. 0  
1 0 J u ne 2 0 2 1  
Pa ge 9 2 
 
1 0. 4.  
G ui deli nes f or Tr a nsf usi o n V ol u me  
Deter mi nati o n of t he a p pr o priate v ol u me of tra nsf use d bl o o d will be base d o n t he he mat ocrit of 
d o n or R B Cs, as s h o w n i n t he ta ble bel o w. 
 
S o urce: G ui deli nes f or t he Ma na ge me nt of Tra nsf usi o n De pe n de nt T halassae mia ( T D T), 3 r d E diti o n; 
(Ca p pelli ni  et al., 2 0 1 4 ). 
 
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Pr ot oc ol H G B - 2 0 7 Versi o n 6. 0  
1 0 J u ne 2 0 2 1  
Pa ge 9 3 
 
Pr ot oc ol Title:  
A P hase 3 Si n gle Ar m St u d y E val uati n g t he Efficac y a n d Safet y of Ge ne 
T hera p y i n S u bjects wit h Tra nsf usi o n - de p e n de nt β -T halasse mia, w h o d o 
n ot  ha ve  a  β 0/ β0 Ge n ot y pe,  b y  Tra ns pla ntati o n  of  A ut ol o g o us  C D 3 4 +  
Ste m Cells Tra ns d uce d E x Vi v o wit h a Le nti viral β A- T 8 7 Q -Gl o bi n Vect or 
( Le nti Gl o bi n B B 3 0 5 Dr u g Pr o d uct) i n S u bjects ≤5 0 Years of A ge 
Pr ot oc ol N u m ber:  H G B - 2 0 7 Versi o n 6. 0, 1 0 J u ne 2 0 2 1 
I N V E S TI G A T O R S T A T E M E N T 
I ha ve rea d, u n derst o o d, a n d a gree t o a bi de b y all t he c o n diti o ns a n d i nstr ucti o ns c o ntai ne d i n t his pr ot oc ol. 
I u n dersta n d t hat all d oc u me ntati o n pr o vi de d t o me b y bl ue bir d bi o or its desi g nate d re prese ntati ve(s) 
c o ncer ni n g t his st u d y t hat has n ot bee n p u blis he d pre vi o usl y will be ke pt i n t he strictest c o nfi de nce. T his 
d oc u me ntati o n i nc l u des t he st u d y pr ot oc ol, i n vesti gat or br oc h ure, case re p ort f or ms, a n d ot her scie ntific 
data.  
I a gree t o pers o nall y c o n d uct or s u per vise t he descri be d i n vesti gati o n(s). 
I a gree t o i nf or m a n y s u bjects, or a n y pers o ns use d as c o ntr ols, t hat t he Dr u g Pr o d uct is bei n g use d f or 
i n vesti gati o nal p ur p oses a n d I will e ns ure t hat t he re q uire me nts relati n g t o o btai ni n g i nf or me d c o nse nt, as 
per l ocal re g ulati o ns a n d u n der G o o d Cli nical Practice (I C H- G C P), are met.  
I a gree t o re p ort t o t he S p o ns or a d verse e ve nts t hat occ ur i n t he c o urse of t he i n vesti gati o n(s) i n acc or da nce 
wit h t his pr ot oc ol a n d as re q uire d b y l ocal re g ulati o ns a n d u n der I C H- G C P.  
I ha ve rea d a n d u n dersta n d t he i nf or mati o n i n t he I n vesti gat or’s Br oc h ure, i ncl u di n g t he p ote ntial ris ks a n d 
si de effects of t he Dr u g Pr o d uct. 
I a gree t o mai ntai n a de q uate a n d acc urate rec or ds a n d t o ma ke t h ose rec or ds a vaila ble f or i ns pecti o n i n 
acc or da nce wit h l ocal re g ulati o ns a n d u n der I C H -G C P.  
I will e ns ure t hat a n et hics c o m mittee t hat c o m plies wit h all l ocal re g ulati o ns a n d I C H -G C P re q uire me nts 
will be res p o nsi ble f or t he i nitial a n d c o nti n ui n g re vie w a n d a p pr o val of t he cli nical i n vesti gati o n.  
I als o a gree t o pr o m ptl y re p ort t o t he et hics c o m mittee all c ha n ges i n t he researc h acti vit y a n d all u na ntici pate d 
pr o ble ms i n v ol vi n g ris ks t o h u ma n s u bjects or ot hers.  
I a gree t hat t his st u d y will n ot c o m me nce wit h o ut t he pri or a p pr o val of t he a p pr o priate nati o nal healt h 
a ut h orities t o get her wit h a pr o perl y c o nstit ute d et hics c o m mittee. I a gree t hat n o c ha n ges will be ma de t o 
t he st u d y pr ot oc ol wit h o ut t he pri or writte n a p pr o val of bl ue bir d bi o a n d t he af ore me nti o ne d re g ulat or y 
b o dies, as a p plica ble i n t h e rele va nt la ws a n d re g ulati o ns . 
I a gree t o e ns ure t hat all ass ociates, c ollea g ues, a n d e m pl o yees assisti n g i n t he c o n d uct of t he st u d y(ies) are 
i nf or me d a b o ut t heir o bli gati o ns i n meeti n g t he a b o ve c o m mit me nts. 
 
I n vesti gat or Na me 
 
I n vesti gat or Si g nat ure 
 
Date  
 
I n vesti gati o nal site or na me of i nstit uti o n a n d l ocati o n ( pri nte d) 
 
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