Clinical trial NCT02436135
Conditions: Myelofibrosis
Sponsor: Gilead Sciences
Start date: 2015-06-05; Completion date: 2017-11-20
Enrollment: 10 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objective of this study is to evaluate the safety, tolerability, and pharmacokinetics of idelalisib in adults receiving ruxolitinib as therapy for intermediate to high-risk primary myelofibrosis (PMF), post-polycythemia vera, or post-essential thrombocythemia myelofibrosis (post-PV MF or post-ET MF) with progressive or relapsed disease.

This is a dose-escalation study. There will be 4 cohorts (A, B, C, D). Participants will receive an escalating dose or dose frequency of idelalisib based on the safety data of available cohort(s).

Detailed description:

Arms: arm 1: Idelalisib 50 mg once daily in participants receiving ruxolitinib. arm 2: Idelalisib 50 mg twice daily in participants receiving ruxolitinib. arm 3: Idelalisib 150 mg once daily in participants receiving ruxolitinib. arm 4: Idelalisib 150 mg twice daily in participants receiving ruxolitinib.
Interventions: intervention 1: Idelalisib intervention 2: Ruxolitinib
Intervention descriptions: intervention 1: Idelalisib tablets administered orally for 24 weeks intervention 2: Ruxolitinib will be administered per standard of care according to package insert

Protocol documents:
Prot_000.pdf: 
St u d y Title: 
S p o ns o r: 
I N D N u m ber: 
Cli ni c al T ri als. g o v 
I de ntifier: 
I n di c ati o n: 
P r ot o c ol I D: 
Gil e a d Cli ni c al 
P r o g r a m M a n a g e r: 
Gil e a d M e di c al M o nit or: 
P r ot o c ol V e rsi o n/ D at e: 
(r J GI L E A U 
C LI NI C A L S T U D Y P R O T O C O L 
A P h as e l b O p e n- L a b el St u d y t o E v al u at e t he S af et y, T ol er a bilit y, 
a n d P h a n n a c o ki n eti cs ofl d el alisi b i n S u bj e cts R e c ei vi n g 
R u x oliti. ni b as T h er a p y f or Pri m ar y, P ost- P ol y c yt h e mi a V er a, or 
P ost- Ess e nti al T hr o m b o c yt h e mi a M y el ofi br osis wit h Pr o gr essi v e 
or R el a ps e d Dis e as e 
Gil e a d S ci e n c es, I nc. 
3 3 3 L a k esi d e Dri v e 
F ost er Cit y, C A 9 4 4 0 4 
1 0 1 2 5 4 
N C T 0 2 4 3 6 1 3 5 
M y el ofi br osis 
G S- U S- 3 9 7- 1 2 4 5 ( Pr e vi o usl y G S- U S- 3 1 3- 1 2 4 5) 
Na me: 
[ PP D 
T el e p h o n e: 
l P. P D 
Na me: 
[ PP D 
T el e p h o n e: 
[ PP D 
M o bile: 
[ PP D 
E- mail: 
[ P. Pl) 
Ori gi nal: 
2 3 M a y 2 0 1 4 
A m e n d m e nt 1: 
0 8 O ct o b er 2 0 1 4 
A m e n d m e nt 2: 
1 4 N o v e m b er 2 0 1 4 
A m e n d m e nt 3: 
2 9 M ar c h 2 0 1 6 
A m e n d m e nt 4: 
1 3 S e pt e m b er 2 0 1 6 
A m e n d m e nt 5: 
2 6 O ct o b er 2 0 1 6 
C O N FI D E N TI A LI T Y S T A T E M E N T 
T h e i nf or m ati o n c o nt ai n e d i n t his d o c u m e nt, p arti c ul arl y u n p u blis h e d d at a, is t he pr o p ert y or 
u n d er c o ntr ol of Gil e a d S ci e n c es, I nc., a n d is pr o vi d e d t o y o u i n c o nfi d e n c e as a n i n v esti g at or, 
p ot e nti al i n v esti g at or, or c o ns ult a nt, f or r e vi e w b y y o u, y o ur st aff, a n d a n a p pli c a bl e 
I nstit uti o n al R e vi e w B o ar d or I n d e p e n d e nt Et hics C o m mitt e e. T h e i nf or m ati o n is o nl y t o b e us e d 
b y y o u i n c o n n e cti o n wit h a ut h ori z e d cli ni c al st u di es of t h e i n v esti g ati o n al dr u g d es cri b e d i n t h e 
pr ot oc ol. Y o u will n ot dis cl os e a n y of t h e i nf or m ati o n t o ot hers wit h o ut writt e n a ut h ori z ati o n 
fr o m Gil e a d S ci e n c es, I n c., e x c e pt t o t he e xt e nt n e c ess ar y t o o bt ai n i nf or m e d c o ns e nt fr o m t h os e 
p ers o ns t o w h o m t h e dr u g m a y b e a d mi nist er e d. 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 2
2 6 Oct o ber 2 0 1 6
T A B L E O F C O N T E N T S
C CI
T A B L E O F C O N T E N T S ..............................................................................................................................................2
LI S T O F I N -T E X T T A B L E S ........................................................................................................................................5
LI S T O F I N -T E X T FI G U R E S ......................................................................................................................................5
P R O T O C O L S Y N O P SI S ..............................................................................................................................................6
G L O S S A R Y O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S ....................................................................1 8
1.
I N T R O D U C TI O N ..............................................................................................................................................2 1
1. 1.
Bac k gr o u n d ............................................................................................................................................2 1
1. 1. 1.
Bac k gr o u n d o n M yel ofi br osis ..............................................................................................2 1
1. 1. 2.
Rati o nale f or I n hi biti o n of PI 3 K/ A K T Pat h w a y i n M yel ofi br osis.......................................2 2
1. 2.
I delalisi b.................................................................................................................................................2 3
1. 2. 1.
Ge neral I nf or mati o n .............................................................................................................2 3
1. 2. 2.
Precli nical P har mac ol o g y a n d T o xic ol o g y ...........................................................................2 5
1. 2. 3.
Cli nical Trials of I delalisi b ...................................................................................................2 6
1. 3.
I nf or mati o n a b o ut C o m pa ni o n Dr u g ......................................................................................................2 8
1. 3. 1.
R u x oliti ni b ............................................................................................................................2 8
1. 4.
Rati o nale f or t his St u d y..........................................................................................................................2 9
1. 5.
C o m plia nce ............................................................................................................................................3 0
2.
O BJ E C TI V E S .....................................................................................................................................................3 1
3.
S T U D Y D E SI G N ................................................................................................................................................3 2
3. 1.
E n d p oi nts ...............................................................................................................................................3 2
3. 2.
St u d y Desi g n ..........................................................................................................................................3 2
3. 3.
St u d y Treat me nts ...................................................................................................................................3 6
3. 4.
D urati o n of Treat me nt ............................................................................................................................3 6
3. 5.
Disc o nti n uati o n Criteria f or C o h orts ......................................................................................................3 6
3. 6.
S o urce Data ............................................................................................................................................3 6
4.
S U BJ E C T P O P U L A TI O N ..................................................................................................................................3 8
4. 1.
N u m ber of S u bjects a n d S u bject Selecti o n ............................................................................................3 8
4. 2.
I ncl usi o n Criteria....................................................................................................................................3 8
4. 3.
E xcl usi o n Criteria ...................................................................................................................................4 0
5.
I N V E S TI G A TI O N A L M E DICI N A L P R O D U C T S ........................................................................................... 4 2
5. 1.
Descri pti o n a n d Ha n dli n g of I delalisi b a n d R u x oliti ni b .........................................................................4 2
5. 1. 1.
F or m ulati o n ..........................................................................................................................4 2
5. 1. 2.
Pac ka gi n g a n d La beli n g .......................................................................................................4 2
5. 1. 3.
St ora ge a n d Ha n dli n g ...........................................................................................................4 2
5. 2.
D osa ge a n d A d mi nistrati o n of I delalisi b ................................................................................................4 3
5. 2. 1.
D osi n g I nstr ucti o ns ..............................................................................................................4 3
5. 2. 2.
D ose Le vels ..........................................................................................................................4 3
5. 3.
D ose A dj ust me nts ..................................................................................................................................4 4
5. 4.
Pri or a n d C o nc o mita nt Me dicati o ns .......................................................................................................4 8
5. 4. 1.
A ntica ncer or E x peri me ntal T hera pies Ot her t ha n I delalisi b ...............................................4 9
5. 4. 2.
A ntie metics ..........................................................................................................................4 9
5. 4. 3.
Gra n ul oc yte C ol o n y -Sti m ulati n g Fact ors a n d Er yt hr o p oieti n ..............................................4 9
5. 4. 4.
Dr u gs t hat U n der g o C Y P 3 A -De pe n de nt Meta b olis m ..........................................................4 9
5. 4. 5.
Dr u gs t hat I n hi bit/I n d uce C Y P 3 A -De pe n de nt Meta b olis m ..................................................4 9


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 3
2 6 Oct o ber 2 0 1 6
5. 4. 6.
I m m u nizati o n .......................................................................................................................5 0
5. 4. 7.
H y dr o x y urea .........................................................................................................................5 0
5. 4. 8.
S ur ger y .................................................................................................................................5 0
5. 4. 9.
Diet .......................................................................................................................................5 0
5. 5.
Acc o u nta bilit y f or I delalisi b ...................................................................................................................5 0
5. 5. 1.
I n vesti gati o nal Me dici nal Pr o d uct Ret ur n or Dis p osal.........................................................5 1
6.
S T U D Y P R O C E D U R E S ....................................................................................................................................5 2
6. 1.
S u bject E nr oll me nt a n d Treat me nt Assi g n me nt .....................................................................................5 2
6. 2.
St u d y Pr oce d ure Descri pti o ns ................................................................................................................5 2
6. 2. 1.
I nf or me d C o nse nt .................................................................................................................5 2
6. 2. 2.
Me dical a n d Me dicati o n Hist or y ..........................................................................................5 2
6. 2. 3.
D y na mic I nter nati o nal Pr o g n ostic Sc ori n g S yst e m ( DI P S S) f or 
Pri mar y M yel ofi br osis
.........................................................................................................5 2
6. 2. 4.
Vital Si g ns ............................................................................................................................5 2
6. 2. 5.
P h y sical E xa mi nati o n ...........................................................................................................5 3
6. 2. 6.
E C O G Perf or ma nce Stat us ...................................................................................................5 3
6. 2. 7.
Patie nt -re p orte d O utc o mes ( P R O) Assess me nts ..................................................................5 3
6. 2. 8.
Electr ocar di o gra m ................................................................................................................5 4
6. 2. 9.
La b orat or y Assess me nts .......................................................................................................5 4
6. 2. 1 0.
I m mu ne M o nit ori n g .............................................................................................................5 5
6. 2. 1 1.
Pre g na nc y Test .....................................................................................................................5 5
6. 2. 1 2.
P har m ac o ki netics ( P K) .........................................................................................................5 5
6. 2. 1 3.
P ne u m oc ystis Jir o veci P ne u m o nia (PJ P) Pr o p h yla xis ..........................................................5 5
6. 2. 1 4.
Bi o mar kers ...........................................................................................................................5 5
6. 2. 1 5.
B o ne Marr o w  Bi o ps y a n d As pirate......................................................................................5 6
6. 2. 1 6.
Ma g netic Res o na nce I ma gi n g ( M RI) ...................................................................................5 6
6. 2. 1 7.
A d verse E ve nts a n d C o nc o mita nt Me dicati o ns ....................................................................5 6
6. 2. 1 8.
Assess me nt of Diarr hea/ C olitis ............................................................................................5 6
6. 2. 1 9.
E val uati o n f or Gastr oi ntesti nal E ve nts/ C olitis .....................................................................5 6
6. 2. 2 0.
Differe ntiati o n Bet wee n S mall -B o w el a n d Lar ge -B o w el Diarr hea ......................................5 7
6. 3.
Pretreat me nt Assess me nts ......................................................................................................................5 7
6. 3. 1.
Scree ni n g Visit .....................................................................................................................5 7
6. 3. 2.
Baseli ne Assess me nts ...........................................................................................................5 7
6. 4.
Treat me nt Peri o d ....................................................................................................................................5 8
6. 5.
E xte nsi o n Peri o d ....................................................................................................................................5 8
6. 6.
P ost -treat me nt Assess me nts...................................................................................................................5 8
6. 6. 1.
E n d of St u d y .........................................................................................................................5 8
6. 6. 2.
Safet y F oll o w -u p Visit .........................................................................................................5 8
6. 6. 3.
L o n g -ter m F oll o w U p...........................................................................................................5 8
6. 7.
U nsc he d ule d Visits .................................................................................................................................5 9
6. 8.
Assess me nts f or Pre mat ure Disc o nti n uati o n fr o m St u d y .......................................................................5 9
6. 9.
Criteria f or Disc o nti n uati o n of St u d y Treat me nt ....................................................................................5 9
6. 1 0.
Criteria f or Disc o nti n uati o n fr o m St u d y ................................................................................................5 9
7.
A D V E R S E E V E N T S A N D T O XI CI T Y M A N A G E M E N T ...............................................................................6 1
7. 1.
Defi niti o ns of A d verse E ve nts, A d verse Reacti o ns, a n d Seri o us A d verse E ve nts ....................................6 1
7. 1. 1.
A d verse E ve nts .....................................................................................................................6 1
7. 1. 2.
Seri o us A d verse E ve nts ........................................................................................................6 1
7. 1. 3.
Cli nical La b orat or y A b n or malities a n d Ot her A b n or mal Assess me nt s as 
A d verse E ve nts or Seri o us A d verse E ve nts .........................................................................6 2
7. 2.
Assess me nt of A d verse E ve nts a n d Seri o us A d verse E ve nts .................................................................6 3
7. 2. 1.
Assess me nt of Ca usalit y f or St u d y Dr u gs a n d Pr oce d ures ...................................................6 3
7. 2. 2.
Assess me nt of Se verit y ........................................................................................................6 3


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 4
2 6 Oct o ber 2 0 1 6
C CI
7. 3.
I n vesti gat or Re q uire me nts a n d I nstr ucti o ns f or Re p orti n g A d verse E ve nts a n d Seri o us 
A d verse E ve nts t o Gilea d .......................................................................................................................6 4
7. 4.
Gilea d Re p orti n g Re q uire me nts .............................................................................................................6 6
7. 5.
Cli nical La b orat or y A b n or malities a n d Ot her A b n or mal Assess me nt s as A d verse E ve nts or 
Seri o us A d verse E ve nts ..........................................................................................................................6 6
7. 6.
Rec o m me n dati o ns f or E val uati o n, I nter ve nti o n, a n d Dr u g Disc o nti n uati o n f or S pecific 
A d verse E ve nts or C o n diti o ns ................................................................................................................6 7
7. 6. 1.
Der m at ol o gical E ve nts .........................................................................................................6 7
7. 6. 2.
Gastr oi ntesti nal E ve nts .........................................................................................................6 7
7. 6. 3.
He patic E ve nts ......................................................................................................................6 9
7. 6. 4.
H e m at ol o gical a n d I m m u n ol o gical E ve nts ...........................................................................6 9
7. 6. 5.
I nfecti o us E ve nts ..................................................................................................................6 9
7. 6. 6.
P ul m o nar y E ve nts ................................................................................................................7 0
7. 6. 7.
Sec o n dar y Mali g na ncies .......................................................................................................7 1
7. 6. 8.
T u m or L ysis S y n dr o me ........................................................................................................7 1
7. 6. 9.
Pre g na nc y, Lactati o n, a n d Re pr o d ucti o n ..............................................................................7 1
7. 6. 1 0.
Ultra vi olet E x p os ure ............................................................................................................7 2
7. 6. 1 1.
F urt her Safet y I nf or mati o n ...................................................................................................7 3
7. 7.
S pecial Sit uati o ns Re p orts ......................................................................................................................7 3
7. 7. 1.
Defi niti o ns of S pecial Sit uati o ns ..........................................................................................7 3
7. 7. 2.
I nstr ucti o ns f or Re p orti n g S pecial Sit uati o ns.......................................................................7 4
8.
S T A TI S TI C A L C O N SI D E R A T I O N S................................................................................................................7 6
8. 1.
A nal ysis O bjecti ves a n d E n d p oi nts ........................................................................................................7 6
8. 1. 1.
A nal ysis O bjecti ves ..............................................................................................................7 6
8. 1. 2.
Pri mar y E n d p oi nt .................................................................................................................7 6
8. 1. 3.
Sec o n dar y E n d p oi nt .............................................................................................................7 6
8. 2.
A nal ysis C o n ve nti o ns .............................................................................................................................7 7
8. 2. 1.
A nal ysis Sets ........................................................................................................................7 7
8. 3.
Data Ha n dli n g C o n ve nti o ns ...................................................................................................................7 8
8. 4.
D e m o gra p hic Data a n d Baseli ne C haracteristics ...................................................................................7 8
8. 5.
Safet y A nal ysis .......................................................................................................................................7 8
8. 5. 1.
E xte nt of E x p os ure ...............................................................................................................7 9
8. 5. 2.
A d verse E ve nts .....................................................................................................................7 9
8. 5. 3.
La b orat or y E val uati o ns ........................................................................................................8 0
8. 6.
P har m ac o ki netic A nal ysis ......................................................................................................................8 0
8. 7.
Efficac y A nal ysis ...................................................................................................................................8 0
8. 8.
Sa m ple Size ............................................................................................................................................8 1
9.
R E S P O N SI BI LI TI E S ..........................................................................................................................................8 2
9. 1.
I n vesti gat or Res p o nsi bilities ..................................................................................................................8 2
9. 1. 1.
G o o d Cli nical Practice ..........................................................................................................8 2
9. 1. 2.
I nstit uti o nal Re vie w B oar d (I R B) Re vie w a n d A p pr o val.....................................................8 2
9. 1. 3.
I nf or me d C o nse nt .................................................................................................................8 2
9. 1. 4.
C o nfi de ntialit y ......................................................................................................................8 3
9. 1. 5.
St u d y Files a n d Rete nti o n of Rec or ds ..................................................................................8 3
9. 1. 6.
Case Re p ort F or ms ...............................................................................................................8 4
9. 1. 7.
I n vesti gati o nal Me dici nal Pr o d uct Acc o u nta bilit y a n d Ret ur n.............................................8 5
9. 1. 8.
I ns pecti o ns............................................................................................................................8 5
9. 1. 9.
Pr ot oc ol C o m plia nce ............................................................................................................8 5
9. 2.
S p o ns or Res p o nsi bilities ........................................................................................................................8 5
9. 2. 1.
Pr ot oc ol M o dificati o ns .........................................................................................................8 5
9. 2. 2.
St u d y Re p ort a n d P u blicati o ns .............................................................................................8 5
-


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 5
2 6 Oct o ber 2 0 1 6
9. 3.
J oi nt I n vesti gat or/ S p o ns or Res p o nsi bilities ...........................................................................................8 6
9. 3. 1.
Access t o I nf or mati o n f or M o nit ori n g ..................................................................................8 6
9. 3. 2.
Access t o I nf or mati o n f or A u diti n g or I ns pecti o ns ..............................................................8 6
9. 3. 3.
St u d y Disc o nti n uati o n ..........................................................................................................8 6
1 0.
R E F E R E N C E S ...................................................................................................................................................8 7
1 1.
A P P E N DI C E S ....................................................................................................................................................9 1
A p pe n di x 1.
I n vesti gat or Si g nat ure Pa ge ....................................................................................................9 2
A p pe n di x 2.
St u d y Pr oce d ures Ta ble ..........................................................................................................9 3
A p pe n di x 3.
Dia g n ostic Criteria a n d Pr o g n ostic Sc ori n g S yste m f or M yel ofi br osis ..................................9 8
A p pe n di x 4.
D y na mic I nter nati o nal Pr o g n ostic Sc ori n g S yste m ( DI P S S) f or Pri mar y 
M y el ofi br osis ........................................................................................................................1 0 0
A p pe n di x 5.
D y na mic I nter nati o nal Pr o g n ostic Sc ori n g S yste m Pl us ( DI P S S Pl u s) ................................1 0 1
A p pe n di x 6.
Re vise d I nter nati o nal W or ki n g Gr o u p f or M yel o pr oliferati ve Ne o p las ms Researc h 
a n d Treat me nt (I W G -M R T) a n d E ur o pea n
Le u ke mia Net ( E L N) Res p o nse Criteria 
f or M yel ofi br osis ..................................................................................................................1 0 2
A p pe n di x 7.
E C O G Perf or ma nce Stat us Sc ori n g S yste m .........................................................................1 0 4
A p pe n di x 8.
M P N S y m pt o m Assess me nt F or m ( M P N -S A F) ...................................................................1 0 5
A p pe n di x 9.
M o difie d M yel o pr oliferati ve Ne o plas m S y m pt o m Assess me nt F or m T o tal 
S y m pt o m Sc ore ....................................................................................................................1 0 7
A p pe n di x 1 0.
Pre g na nc y Preca uti o ns, Defi niti o n f or Fe male of C hil d beari n g P o te ntial, a n d 
C o ntrace pti ve Rec o m me n dati o ns .........................................................................................1 0 8
A p pe n di x 1 1.
C T C A E versi o n 4. 0 3 ............................................................................................................1 1 1
LI S T O F I N -T E X T T A B L E S
Ta ble 5- 1.
I delalisi b D ose Re d ucti o n Al g orit h m .....................................................................................4 4
Ta ble 5- 2.
I delalisi b D ose A dj ust me nt G ui deli nes ..................................................................................4 5
Ta ble 5- 3.
K n o w n P ote nt I n d ucers of C Y P 3 A ........................................................................................5 0
Ta ble 6- 1.
A nal ytes ..................................................................................................................................5 4
Ta ble 7- 1.
Gra di n g of A d verse E ve nt Se verit y ........................................................................................6 4
LI S T O F I N -T E X T FI G U R E S
Fi g ure 3- 1.
St u d y Sc he ma .........................................................................................................................3 5
Fi g ure 7- 1.
Ka pla n -Meier Ti me t o Diarr hea or C olitis
.............................................................................6 8


I d elalisi b 
Pr ot o c o l G S -U S- 3 9 7 -1 2 4 5 
Gil e a d S c ie n c es, I nc. 
P R O T O C O L S Y N O P SI S 
Gil e a d S ci e n c e s, I nc. 
3 3 3 L a k e si d e D ri v e 
F o st e r C it y, C A 9 4 4 0 4 
Fi n al 
A m e n d m e nt 5 
S t u dy Title: 
A P h ase l b O p e n- L a b el St u d y t o E v al u at e t he S af et y , Tol er a bilit y , 
a n d P h a n n a c o ki n et ics ofl d el a lisi b i n S u bj e cts R e c ei vi ng 
R u x o liti nib as T h er a p y f or Pr i mai y, P ost - Pol y c yt h e mi a V er a, or 
P ost- Ess e n ti al T hr om b o c yt h e mi a M y el o fibr osis wit h P r o gress iv e or 
R el a ps e d Di s e as e 
I N D Nu m b e r: 
1 0 1 2 5 4 
C li ni c al T ri al s. g ov 
I de ntifier: 
N C T 0 2 4 3 6 1 3 5 
S t u dy C e nt e r s Pl a n n e d: 
T w o c e nt ers i n t h e U ni t e d St at es 
O bj e cti v es: 
T h e pri ma 1 y o b je cti v es of t his stu d y ai·e as f ollo ws: 
C O N FI D E N TI A L 
• 
T o e v alu at e t h e s af et y a n d t ol er a bilit y of id el alisi b t hr ou g h 
2 8 d a ys i n s ubj e cts re c ei vi n g m x o liti ni b as t h er a p y f or 
i nt e1m e di at e t o hi g h ris k pri ma 1 y m ye lofi br osis ( PM F) , 
p ost -p o ly c yth e mi a v er a , or p ost -ess enti al 
t hr o m b o c yth e mi a m y e lofi br os is ( p ost- P V M F or p ost - ET M F) 
wit h pr o gressi ve or r el a ps e d di s e as e 
• 
T o d et e n n i ne t h e p h a n n a c o ki n eti cs ( P K) of i d el alisi b a n d 
m x o litini b, i n s ubj e cts r e c ei vi ng m x olit i ni b wit h P M F , p ost -P V 
M F, or p ost - E T M F wit h pr o gr essi v e or r el a ps e d dis e as e 
T h e s e c on d ai y o bj e ct iv es of t his st u d y ai·e as f oll o ws: 
• 
T o e v alu at e t h e s af et y a n d t ol er a bilit y of c on ti n u ous d ai l y 
a d ministr ati o n of i d el alisi b b e y o n d 2 8 da ys i n s u bjects r e c ei vi n g 
m x olit i ni b wit h  P M F, p ost - PV M F , or p ost -E T M F 
• 
T o e v alu at e t h e effi c a c y of id el alisi b i n s u bj e cts re c ei vi n g 
m x olit i ni b wit h  P M F, p ost - PV M F , or p ost -E T M F b y 
2 0 1 3 R e vis e d I nt er nati o nal W o rki n g Gr o u p f or 
M y el o pr olif er ati v e N e o p las ms R eseai·ch a n d Tr e at m e nt 
(I W G-M R T) a n d E ur o p e a n  Le u k emi a N et (E L N) res p on s e 
cr it eri a 
P a g e 6 
2 6 O c to b er 2 0 1 6 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 7
2 6 Oct o ber 2 0 1 6
St u d y Desi g n:
T his is a P hase 1 b, o pe n -la bel, d ose escalati o n st u d y. T he pla n ne d 
n u m ber of s u bjects i n eac h c o h ort is 6. T here will be 4 c o h orts 
(A, B, C, a n d D ), w hic h will be e nr olle d se q ue ntiall y. C o h ort A will 
be e nr olle d first.
Idelalisi b will be a d mi nistere d i n s u bjects recei vi n g r u x oliti ni b as 
t hera py f or P M F, p ost -P V M F, or p ost -E T M F a n d ha ve bee n 
mai ntai ne d o n a sta ble d ose of r u x oliti ni b f or at least 4 wee ks pri or 
t o st u d y e ntr y. O n Da y 1, s u bjects will ha ve a P K sa m ple dra w n 
a n d t he n re d uce t he r u x oliti ni b d ose as f oll o ws:

S u bjects o n a sta ble r u x oliti ni b d ose of greater t ha n or e q ual t o 
1 0 m g t wice dail y , will ha ve t heir r u x oliti ni b d ose re d uce d b y 
5 0 % (r o u n de d u p t o t he cl osest a vaila ble ta blet stre n gt h) .

S u bjects o n a sta ble r u x oliti ni b d ose of 5 m g t wice dail y  will 
ha ve t heir r u x oliti ni b d ose re d uce d t o 5 m g o nce dail y .
Idelalisi b will be a d mi nistere d starti n g o n Da y  5.
P K sa m ples will be o btai ne d o n Da y s 1, 4, a n d 1 0 as s h o w n i n t he 
sc he ma bel o w:
T he starti n g d oses of i delalisi b i n C o h orts A, B, C, a n d D, are 
5 0 m g o nce dail y, 5 0 m g t wice dail y, 1 5 0 m g o nce dail y , a n d 
1 5 0 m g t wice dail y , res pecti vely . E nr oll me nt i nt o t he st u d y  will be 
o n h ol d w hile t he safety re vie w tea m ( S R T ) e val uates t he data pri or 
t o c o h ort e x pa nsi o n a n d d ose escalati o n.
T he first 3 s u bj ects will be e nr olle d i n C o h ort A at 5 0 m g o nce 
dail y i delalisi b. After t he t hir d s u bject has c o m plete d Da y 2 8 
( 4 wee ks), t he S R T will re vie w t he safet y data. E nr oll me nt will be 
o n h ol d u ntil t he S R T deter mi nes t he c o h ort ca n be e x p a n de d t o 
e nr oll a n a d diti o nal 3 s u bjects. After t he si xt h s u bject i n C o h ort A 
c o m pletes Da y 5 6 ( 8 wee ks) , t he S R T will re vie w t he c u m ulati ve
safety a n d P K data fr o m all s u bjects i n C o h ort A. E nr oll me nt will 
be o n h ol d u ntil t he S R T deter mi nes C o h ort B ca n be o pe n t o 
e nr oll me nt. If t he S R T dee ms t he c o m bi nati o n of i delalisib wit h 
r u x oliti ni b safe a n d t olera ble at t he 5 0 m g  o nce dail y d ose, 
C o h ort B will be o pe n t o e nr oll me nt.
S c h e m a 
I S cr e e ni n,;i I 
S u bj e ct s ar e 
e ligi bl e f or t h e 
s t u ct y aft er 
m a int ai ni n g a 
st a bl er u x oli li ni b 
d o s e f or at l e a st 
4  w e e k s pri ort o 
st u ct y e nt r y 
O bt a i n 
r u xoli li ni b P K 
s a m pl e t h e n 
r e du c e 
r u x olit i ni b 
d o s e 
O bt ai nr u x o lib n i b 
P K s a m p le s • 
l nili atei d el al isi b 
d o s i n g 
i 
O bt ai n r u x oli b nib & 
i d el alisi b P K s a m pl e s 
S u bj e ct c o nti n u e s o n 
st u d y 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 8
2 6 Oct o ber 2 0 1 6
E nr oll me nt a n d safet y assess me nt b y t he S R T i n C o h ort B at 5 0 m g 
t wice daily i delalisi b will pr ocee d as f oll o ws: T he first 3 s u bjects 
will be e nr olle d. After t he t hir d s u bject has c o m plete d Da y 2 8 
( 4 wee ks), t he S R T will re vie w t he c u m ulati v e safet y data f or 
C o h orts A a n d B. E nr oll me nt will be o n h ol d u ntil t he S R T 
deter mi nes C o h ort B ca n be e x p a n de d t o e nr oll a n a d diti o nal 
3 s ubjects. After t he si xt h s u bject i n C o h ort B c o m pletes Da y 2 8 
( 4 wee ks), t he S R T will re vie w t he c u m ulati ve safet y  data fr o m all 
s u bjects i n C o h orts A a n d B, a n d t he c u m ulati ve P K data f or 
C o h ort B. E nr oll me nt will be o n h ol d u ntil t he S R T deter mi nes 
C o h ort C ca n be o pe n t o e nr oll me nt. If t he S R T dee ms t he 
c o m bi nati o n of i delalisi b wit h r u x oliti ni b safe a n d t olera ble at t he 
5 0 m g t wice dail y d ose, C o h ort C will be o pe n t o e nr oll me nt.
E nr oll me nt a n d safet y assess me nt b y t he S R T i n C o h ort C at 
1 5 0 m g o nce dail y i delalisi b will pr ocee d as f oll o ws : T he fi rst 
3 s u bjects will be e nr olle d. After t he t hir d s u bject has c o m plete d 
D a y 2 8 ( 4 wee ks) , t he S R T will re vie w t he c u m ulati ve safety data
f or C o h orts A, B, a n d C. E nr oll me nt will be o n h ol d u ntil t he S R T 
deter mi nes C o h ort C ca n be e x p a n de d t o e nr oll a n a d diti o nal 
3 s u bjects. After t he si xt h s u bject i n C o h ort C c o m pletes Da y 2 8 
( 4 wee ks) , t he S R T will re vie w t he c u m ulati ve safet y  data fr o m all 
s u bjects i n C o h orts, A, B, a n d C a n d t he c u m ulati v e P K data f or 
C o h ort C. E nr oll me nt will be o n h ol d u ntil t he S R T deter mi nes 
C o h ort D ca n be o pe n t o e nr oll me nt. If t he S R T dee ms t he 
c o m bi nati o n of i delalisi b wit h r u x oliti ni b safe a n d t olera ble at t he 
1 5 0 m g o nce dail y d ose , C o h ort D will be o pe n t o e nr ol l me nt.
E nr oll me nt a n d safet y assess me nt b y t he S R T i n C o h ort D at 
1 5 0 m g t wice dail y  i delalisi b will pr ocee d as f oll o w s: T he first 
3 s u bjects will be e nr olle d. After t he t hir d s u bject has co m plete d 
D a y 2 8 ( 4 wee ks), t he S R T will re vie w t he c u m ulati ve safety data
f or C o h orts A, B, C, a n d D. E nr oll me nt will be o n h ol d u ntil t he 
S R T deter mi nes C o h ort D ca n be e x p a n de d t o e nr oll a n a d diti o nal 
3 s u bjects. After t he si xt h s u bject i n Co h ort D c o m pletes Da y 2 8 
( 4 wee ks) , t he S R T will re vie w t he c u m ulati ve safe t y data fr o m all 
s u bjects i n C o h orts A, B, C, a n d D, a n d t he c u m ulati ve P K data f or 
C o h ort D.
A d diti o nal c o h orts are n ot pla n ne d after e nr oll me nt i n C o h ort D is 
c o m plete. S u bjects w h o d o n ot recei ve ≥ 1 d ose of i delalisi b will be 
dee me d u ne val ua ble a n d re p lace d.
I n s u bjects wit h o ut de m o nstra ble cli nical be nefit, d ose escalati o n 
(t o a hi g her d ose c o h ort) ma y  be per mitte d b y t he S R T after 
C o h ort C ( i delalisi b 1 5 0 m g o nce dail y) has bee n f ull y e nr olle d a n d 
t he last s u bject has bee n o n st u d y dr u g f or at least 28 da y s. 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 9
2 6 Oct o ber 2 0 1 6
T he S R T will c o nsi der t he f oll o wi n g −t he s u bject’s c o m plia nce 
wit h t hera p y, t olera bilit y of t he c o m bi nati o n of i delalisi b a n d 
r u x oliti ni b, o verall i nci de nce a n d se verity of a d verse e ve nts ( A Es)
relate d t o i delalisi b or r u x oliti ni b, d ose re d ucti o n f or se vere t o xicit y 
a n d d ose m o dificati o ns. A d diti o nall y , s u bjects m ust s h o w a lac k of 
res p o nse by v ol u metric i ma gi n g (t hree di me nsi o nal [ 3 D] 
ma g netic res o na nce i ma gi n g [ M RI] or c o m p ute d t o m o gra p h y [ C T], 
if M RI is n ot feasi ble), or b y pal pati o n of t he li ver a n d/or s plee n,
after at least 1 2 wee ks o n st u d y.
T he S R T will c o nsist of at least o ne i n vesti gat or a n d t he f oll o wi n g 
Gilea d Scie nces, I nc. ( Gilea d) st u d y tea m me m bers: 
t he m e dical m o nit or, re prese ntati ves fr o m Dr u g Safet y  a n d 
P u blic Healt h ( D S P H ), Cli nical O perati o ns , a n d Bi ostatistics. 
Ot her s m a y  be i n vite d t o partici pate as me m bers of t he S R T if 
a d diti o nal e x pertise is desire d. T he me dical m o nit or ser ves as t he 
c hair of t he S R T .
N u m ber of S u bjects
Pla n ne d:
A p pr o xi matel y  2 4
Tar get P o p ulati o n:
S u bjects c urre ntl y recei vi n g r u x oliti ni b f or treat me nt of P M F, 
p ost -P V M F,
or p ost -E T M F a n d meet 2 0 1 3 Re vise d I WG- M R T 
a n d E L N res p o nse criteria f or pr o gressi ve or rela pse d disease.
D urati o n of Treat me nt:
T he d urati o n of treat me nt is 2 4 wee ks. S u bjects w h o c o m plete t he 
2 4- wee k treat me nt peri o d o n i delalisi b, a n d i n t he o pi ni o n of t he 
i n vesti gat or are deri vi n g cli nical be nefit , ca n re mai n o n t he st u d y
f or t he e xte nsi o n peri o d u ntil disease pr o gressi o n . T he o verall 
d urati o n of t he trial is e x pecte d t o be a p pr o xi matel y  3 ye ars.
C o h o n A 
I O E L A 5 0 m g o n c e d all y 
• 
3 s u b Jec:ts 
e nr oll e d 
S af et y d at arll\'l e w a n e, all J s u bj e ct s 
c o m pl et e d a y 2 8 
C o h o n e 
I O E L A 5 0 m g t wi c e d all y 
• 
S af et y d at a r e vi e w aft er all 3 s u b je ct s 
c o m pl e ll d a y 2 8 
C o h o n o 
S 1 1fet y 1 1 n d P K d & 1 1r e vl e w 
1 1 1te,t M la,t 1 ul)/ e c 1l n 
C o h o « C c o m p k 1 1 e. 2 8 d o y, 
(- 4 " "'ff bl, pri oft o d o M 
n c o 1 oli o! 1 
I O E L A 1 5 0 m g t wi c e d all y 
,.. J s u bj e ct s 
e nr oll e d 
'----'---' 
C o h o n C 
I D E L A 1 5 0 m g o n c e d all y 
• 
S af et y d at a r e vi e w aft er a ~ 3 s u b je ct s 
c o m p lete d a y 2 8 
• 
S a fet y d al a r w.'i e w a n er a" 3 s u b J e d S 
c o m pl et e d a y 2 8 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 0
2 6 Oct o ber 2 0 1 6
Dia g n osis a n d 
Eli gi bilit y  Criteria:
I ncl usi o n Criteri a:
S u bjects m ust meet all of t he f oll o wi n g i ncl usi o n criteria t o be 
eli gi ble f or partici pati o n i n t his st u d y:
1)
A ge ≥ 1 8 y ears of a ge
2)
S u bjects m ust ha ve bee n o n a sta ble d ose of r u x oliti ni b f or at 
least 4 wee ks pri or t o st u d y  e ntr y
3)
S u bjects wit h P M F, p ost -P V M F, or p ost -E T M F classifie d as 
hi g h ris k or i nter me diate ris k as defi ne d b y t he 
D y na mic I nter nati o nal Pr o g n ostic Sc ori n g S y ste m (D I PS S) f or 
Pri mar y  Myel ofi br osis (A p pe n di x 4 ) or DI P S S Pl us, if 
c yt o ge netics are a vaila ble (A p pe n di x 5 )
4)
S u bjects wit h P M F, p ost -P V M F,
or p ost -E T M F w h o are 
recei vi n g r u x oliti ni b a n d meet 2 0 1 3 Re vise d I WG- M R T a n d 
E L N res p o nse criteria wit h pr o gress i ve a n d rela pse d disease, 
wit h m o dificati o ns f or pr o gressi ve disease
a)
Pr o gressi ve disease:

A p peara nce of a ne w s ple n o me g al y t hat is pal pa ble at 
least 5 c m bel o w t he left c ostal mar gi n (L C M ), or

A ≥1 0 0 % i ncrease i n pal pa ble dista nce, bel o w L C M, 
f or baseli ne s ple n o me gal y of 5-1 0 c m , or

A 5 0 % i ncrease i n pal pa ble dista nce, bel o w L C M, f or 
baseli ne s ple n o me gal y of > 1 0 c m , or

A n i ncrease i n pal pa ble s ple n o me gal y fr o m best 
r u x oliti ni b res p o nse of > 2 5 % b ut < 5 0 % i n a s u bject 
w h o d oes n ot meet criteria f or c o m plet e re missi o n ( C R), 
partial re missi o n ( P R), or cli nical i m pr o ve me nt ( CI)
b)
Rela pse d disease:

N o l o n ger meeti n g criteria f or at least CI  after ac hie vi n g 
C R, P R, or CI , or

L oss of a ne mia res p o nse persisti n g f or at least 1 m o nt h ,
or

L oss of s plee n res p o nse persis ti n g f or at least 1 m o nt h
5)
Life e x pecta nc y  > 2 4 wee ks i n t he o pi ni o n of t he i n vesti gat or
6)
Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) perf or ma nce 
stat us of ≤2


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 1
2 6 Oct o ber 2 0 1 6
7)
Re q uire d scree ni n g la b orat or y  val ues as s h o w n i n t he f oll o wi n g 
ta ble:
Or g a n S yste m
P ar a meter
Re q uire d V al ue
He patic
Ser u m t otal bilir u bi n
≤1. 5 × U L N
( u nless ele vate d d ue t o 
Gil bert’s s yn dr o me or he m ol y sis)
Ser u m A L T
≤2. 5 × U L N
Ser u m A S T
He mat o p oietic
A N C
≥ 1. 0 × 1 0 9/ L
Peri p heral bl o o d blast or b o ne 
marr o w bl o o d blast c o u nt
< 2 0 %
Platelets
≥ 5 0 × 1 0 9/ L
Re nal
eC Cr
a
≥3 0 m L/ mi n
Pre g na nc y
β- h C G b
Ne gati ve
I nfecti o n
HI V
Ne gati ve HI V a nti b o d y
H B V
Ne gati ve H Bs A g a n d ne gati ve
H Bc a nti b o d y , or p ositi ve 
H B c a nti b o d y a n d ne gati ve f or 
H B V D N A b y  q ua ntitati ve P C R
H C V
Ne gati ve viral R N A
(if H C V a nti b o d y is p ositi ve)
C M V
Ne gati ve C M V P C R or 
p p 6 5 a nti ge n
a
As calc ulate d b y t he C oc kcr oft -Ga ult f or m ula or meas ure d
b
F or w o me n of c hil d beari n g p ote ntial o nl y
A b bre vi ati o ns : H Bc a nti b o d y =a nti -he patitis B c ore a nti b o d y
8)
Fe male s u bjects of c hil d beari n g p ote ntial, willi n g t o use a 
pr ot oc ol -rec o m me n de d met h o d of c o ntrace pti o n d uri n g 
heter ose x ual i nterc o urse fr o m si g ni n g of i nf or me d c o nse nt 
t hr o u g h o ut t he st u dy treat me nt peri o d a n d t o 3 0 da ys fr o m t he 
last d ose of i delalisi b (see A p pe n di x 1 0 f or m ore i nf or mati o n) 
9)
M ale s u bjects ha vi n g i nterc o urse wit h fe males of c hil d beari n g
p ote ntial, willi n g t o use a pr ot oc ol rec o m me n de d met h o d of 
c o ntrace pti o n fr o m Da y 1 t hr o u g h o ut t he st u d y treat me nt peri o d 
a n d f or 9 0 da ys f oll o wi n g t he last d ose of i delalisi b a n d t o 
refrai n fr o m s per m d o nati o n fr o m Da y 1 t hr o u g h o ut t he st u d y 
treat me nt peri o d a n d f or 9 0 da ys f oll o wi n g t he last d ose of 
i delalisi b (see A p pe n di x 1 0 f or m ore i nf or mati o n)
1 0) I n t he j u d g me nt of t he i n vesti gat or, partici pati o n i n t he pr ot oc ol 
offers a n acce pta ble be nefit -t o-ris k rati o w he n c o nsi deri n g 
c urre nt m yel ofi br osis disease stat us, me dical c o n diti o n, t he 
p ote ntial be nefits a n d ris ks of alter nati ve treat me nts f or 
m y el ofi br osis


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 2
2 6 Oct o ber 2 0 1 6
1 1) Willi n g a n d a ble t o c o m pl y  wit h sc he d ule d visits, dr u g 
a d mi nistrati o n p la n, i ma gi n g st u dies, la b orat or y tests, ot her 
st u d y pr oce d ures, a n d st u d y restricti o ns, i ncl u di n g ma n dat or y 
pr o p h y la xis f or P ne u m oc y stis jir o veci p ne u m o nia (PJ P ) 
1 2) A ble t o u n dersta n d a n d willi n g t o si g n t he i nf or me d c o nse nt 
f or m
E xcl usi o n Criteri a:
S u bjects w h o meet a n y of t he f oll o wi n g e xcl usi o n criteria are n ot t o 
be e nr olle d i n t his st u d y .
1)
S u bjects o n a sta ble r u x oliti ni b d ose of 5 m g o nce dail y
2)
Hist or y  of pri or all o ge neic b o ne marr o w pr o ge nit or cell or s oli d 
or ga n tra ns pla ntati o n
3)
O n g oi n g dr u g -i n d uce d li ver i nj ur y, alc o h olic li ver disease, 
n o n- alc o h olic steat o he patitis, pri mar y  biliar y cirr h osis, 
e xtra he patic o bstr ucti o n ca use d b y c h olelit hiasis, cirr h osis of 
t he li ver
4)
O n g oi n g dr u g -i n d uce d p ne u m o nitis
5)
O n g oi n g i nfla m mat or y  b o wel disease
6)
O n g oi n g alc o h ol o r dr u g a d dicti o n
7)
C yt o me gal o vir us (C M V ): O n g oi n g i nfecti o n, treat me nt, or 
pr o p h y la xis wit hi n t he past 2 8 da ys
8)
U nc o ntr olle d i nterc urre nt ill ness i ncl u di n g, b ut n ot li mite d t o, 
acti ve u nc o ntr olle d bacterial, f u n gal, or viral i nfecti o n ( or acti ve 
or c hr o nic bl ee di n g e ve nt wit hi n 4 wee ks pri or t o first d ose of 
i n vesti gati o nal me dici nal pr o d uct (I M P) t hat w o ul d li mit 
c o m plia nce wit h st u d y re q uire me nts as j u d ge d b y t he treati n g 
p h y sicia n
9)
Hist or y  of a c o nc urre nt or sec o n d mali g na nc y e xce pt f or 
a de q uatel y treate d l ocal basal cell or s q ua m o us cell carci n o ma 
of t he s ki n, cer vical carci n o ma i n sit u, s u perficial bla d der 
ca ncer, as y m pt o matic pr ostate ca ncer wit h o ut k n o w n metastatic 
disease a n d wi t h n o re q uire me nt f or t hera py or re q uiri n g o nl y 
h or m o nal t hera p y a n d wit h n or mal pr ostate -s pecific a nti ge n f or 
≥ 1 y ear, a de q uatel y treate d Sta ge 1 or 2 ca ncer c urre ntl y i n 
c o m plete re missi o n, or a n y ot her ca ncer t hat has bee n i n 
c o m plete re missi o n f or ≥5 ye ars


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 3
2 6 Oct o ber 2 0 1 6
1 0) Partici pati o n i n a n o n g oi n g i n vesti gati o nal dr u g or de vice trial 
or use wit hi n 6 wee ks of c he m ot hera p y ( wit h e xcepti o n ma de 
f or hy dr o x y urea, see Secti o n 5. 4. 6 ), i n vesti gati o nal a ge nt, 
i m m u n o m o d ulati n g t hera p y, bi ol o gic t hera p y or ra diati o n 
t hera py . Er yt hr o p oieti n sti m ulati n g a ge nts ( E S A) are all o we d as 
l o n g as a s u bject has bee n o n a sta ble d ose f or a mi ni m u m of 
1 2 wee ks f or t he treat me nt of a ne mia.
1 1) S y m pt o matic c o n gesti v e heart fail ure 
( Ne w Y or k Heart Ass ociati o n Classificati o n > Class II), 
u nsta bl e a n gi na, or u nsta ble car diac arr h yt h mia re q uiri n g 
me dicati o n
1 2) K n o w n h y perse nsiti vit y  t o t he st u d y I M P, t he meta b olites, or 
f or m ulati o n e xci pie nts
1 3) U n willi n g or u na ble t o ta ke oral me dicati o n
1 4) U nres ol ve d n o n -he mat ol o gic t o xicities fr o m pri or t hera pies t hat 
are > C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts 
( C T C A E) Gra de 1 ( wit h t he e xce pti o n of al o pecia 
[ Gra de 1 or 2 per mitte d])
1 5) Pre g na nt or lactati n g fe males
St u d y  Pr oce d ures/
Fre q ue nc y :
Treat me nt
S u bjects will re d uce t heir r u x oliti ni b d ose o n Da y  1 b y 5 0 % as 
descri be d i n St u d y  Desi g n.
Idelalisi b will be a d mi nistere d orall y  ( P O) be gi n ni n g o n Da y 5 at 
5 0 m g o nce dail y ( C o h ort A), 5 0 m g t wice daily ( C o h ort B), 
1 5 0 m g o nce dail y ( C o h ort C), a n d 1 5 0 m g t wice dail y ( C o h ort D). 
T he o nce dail y  d ose will be ta ke n i n t he m or ni n g. I deall y, d oses
ta ke n t wice dail y s h o ul d be at a p pr o xi matel y 1 2-h o ur i nter vals 
(e g, at 7 A M a n d at 7 P M). B ot h r u x oliti ni b a n d i delalisi b s h o ul d be 
ta ke n at t he sa me ti me, a n d i n t he cli nic w he n visits are sc he d ule d.
Visits a n d E val uati o ns
After t he 2 8 -d a y  scree ni n g peri o d, st u d y visits are sc he d ule d o n 
D a y 1 a n d D a y 4 d uri n g Wee k 1, e ver y  wee k fr o m Wee ks 2 t o 4 
a n d e ver y 2 wee ks t hereafter u p t o Wee k 2 4. S u bjects w h o are 
c o nti n ui n g st u d y after Wee k 2 4 will ha ve st u d y visits sc he d ule d 
e ver y 4 wee ks.
O n Da y s 1 t o 4 o n st u d y i nitiati o n, o nl y r u x oliti ni b will be 
a d mi nistere d. Bl o o d sa m ples f or P K will be c ollecte d o n 
D a y s 1 a n d 4 relati ve t o t he m or ni n g d ose of r u x oliti ni b. O n Da y 5, 
i delalisi b a d mi nistrati o n will be i nitiate d a n d i delalisi b a n d r u x oliti ni b 
will be d ose d t o get her. P K bl o o d sa m ples will be c ollecte d o n Da y 1 0 
relati ve t o t he m or ni n g d ose of i delalisi b a n d r u x oliti ni b.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 4
2 6 Oct o ber 2 0 1 6
Safet y  a n d la b orat or y assess me nts will be c o n d ucte d at st u d y visits 
as defi ne d i n Secti o n 6 a n d A p pe n di x 2 . T he M y el o pr oliferati ve 
Ne o plas m S y m pt o m Assess me nt F or m ( M P N-S A F , A p pe n di x 8 )
will be c o m plete d b y s u bjects wee kl y f or t he first 2 4 wee ks t he n 
m o nt hl y  f or s u bjects o n st u d y be yo n d Wee k 2 4.
T hree di me nsi o nal ( 3 D) M RI  ( or C T, if M RI is n ot feasi ble) of t he 
li ver a n d s plee n will be e val uate d at scree ni n g, Wee ks 1 2 a n d 2 4. 
Idelalisi b d osi n g will c o nti n ue i n t he a bse nce of disease pr o gressi o n 
or t o xicit y  warra nti n g disc o nti n uati o n of t hera p y, as l o n g as t here is 
e vi de nce of cli nical be nefit as j u d ge d b y t he i n vesti gat or.
V ol u metric i ma gi n g of t he li ver b y 3 D M RI ( or C T, if M RI  n ot 
feasi ble) perf or me d as sta n dar d of care pri or t o si g ni n g t he I C F, a n d 
wit hi n 8 wee ks of e nr oll me nt, ma y  be use d t o f ulfill t he scree ni n g 
re q uire me nt.
Test Pr o d uct, D ose, a n d 
M o de of A d mi nistr ati o n:
T he d ose of i delalisi b f or t his st u d y will be a d mi nistere d P O at 
5 0 m g o nce dail y ( C o h ort A), 5 0 m g t wice daily ( C o h ort B) ,
1 5 0 m g o nce dail y ( C o h ort C), or 1 5 0 m g t wice dail y ( C o h ort D ).
T he d ose will be decrease d t o D ose Le vel – 1, as defi ne d i n 
Ta ble 5- 1 , if t he s u bject has a t o xicit y re q uiri n g d ose a dj ust me nt.
N o d ose re d ucti o n is per mitte d i n C o h ort A.
I n C o h orts B, C, a n d D t he d ose ma y  be i ncrease d bac k t o t he 
starti n g d ose if t he t o xicit y has res ol ve d t o ≤ Gra de 1 or t he 
s u bject’s baseli ne, at t he discreti o n of t he i n vesti gat or. I n C o h ort A 
t he starti n g d ose ma y be res u me d if t he t o xicit y has res ol ve d t o 
≤Gra de 1 or t he s u bject’s baseli ne, at t he discreti o n of t he 
i n vesti gat or.
Criteri a f or E v al u ati o n:
Pri mar y  E n d p oi nts

O verall safet y pr ofile of i delalisi b a n d r u x oliti ni b after 2 8 d a y s 
of e x p os ure c haracterize d b y  t he ty pe, fre q ue nc y, se verit y, 
ti mi n g, a n d relati o ns hi p t o i delalisi b of a d verse e ve nts ( A E), 
a b n or mal la b orat or y tests, dr u g disc o nti n uati o ns d ue t o A E a n d 
seri o us a d verse e ve nts ( S A E). T o xicit y will be assesse d b y  
gra di n g of A E acc or di n g t o t he C T C A E V 4. 0 3

P har mac o ki netic para meters of r u x oliti ni b (a n d meta b olite[s], 
as a p plica ble) a n d i delalisi b a nd/ or its pri mar y  meta b olite, 
G S -5 6 3 1 1 7 ( C ma x , Tma x , A U C, a n d C tr o u g h)


I d el alisi b 
Pr ot o c ol G S -U S- 3 9 7 -1 2 4 5 
Gil e a d S ci e n c es , I n c. 
C O N FI D E N TI A L 
S e c o n da 1 y E n d p o i nts 
Fi n al 
A m e n d m e nt 5 
• 
O v er a ll s af et y pr ofil e of id el alisi b a n d r nx olit i ni b c on ti n u o us 
d ail y a dmi ni str ati o n b e y o n d 2 8 d a ys of e x p osm e c h ar a ct eri z e d 
b y t h e t y p e, freq u e n c y, s e v erit y, ti mi n g, a nd r el ati ons hi p t o 
i d elalisi b of a n y A E, a b n o 1 mal la b orat o 1 y t ests, dr n g 
dis c o n ti n u ati ons d u e t o A E a n d S A E. T o xi c it y wi ll b e ass ess e d 
b y gr a di n g of A E a c c or di ng t o t h e C T C A E V 4. 0 3 
•  
Rat e of o v er a ll res p on s e as d efi n e d b y 2 0 1 3 R e vis e d I W G-M R T 
a n d E L N r es p o ns e cr it eri a (A p p e n di x 6 ), ie, C R , P R, or CI 
(th e a ch i e v e m ent of a n ei ni a, s ple e n , or s y m pt o ms r es p on s e 
wit h o ut pr o gr essi v e dis e as e or i ncr e as e i n s e v erit y of a n ei ni a, 
t hr o m b o c yt o p e ni a, or n e u tr o p eni a) 
P a g e 1 5 
2 6 O c to b er 2 0 1 6 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 6
2 6 Oct o ber 2 0 1 6
P har mac o ki netics:
Plas ma c o nce ntrati o n o f ru x oliti ni b (a n d meta b olite[s], 
as a p plica ble ) a n d i delalisi b a nd/ or its pri mar y  meta b olite, 
G S - 5 6 3 1 1 7, will be meas ure d. Bl o o d sa m ples f or assessi n g 
ru x oliti ni b P K will be c ollecte d relati ve t o t he m or ni n g d ose of 
r u x oliti ni b, o n Da y  1 pre d ose, a n d Da y 4 pre d ose , 0. 5, 1, 1. 5, 2, 3, 
4, 6, 8, a n d 1 2 h o urs p ost d ose after t hese s u bjects are e nr olle d i nt o 
t he st u d y pri or t o t he i nitiati o n of i delalisi b treat me nt. O n Da y 5, 
i delalisi b a d mi nistrati o n will be i nitiate d , a n d i delalisi b a n d 
r u x oliti ni b will be d ose d t o get her. Bl o o d sa m ples will be c ollecte d
o n D a y 1 0, relati ve t o t he m or ni n g d ose of i delalisi b a n d 
r u x oliti ni b, pre d ose , 0. 5, 1, 1. 5, 2, 3, 4, 6, 8, a n d 1 2 h o urs p ost d ose 
t o assess ru x oliti ni b , i delalisi b a n d c orres p o n di n g meta b olite P K.
Be gi n ni n g Da y 1 5 a n d t hr o u g h o ut t he st u dy as o utli ne d i n Secti o n 6
a n d A p pe n di x 2 , P K sa m ples will c o nti n ue t o be c ollecte d pre d ose
a n d 1. 5 h o urs p ost d ose .
St atistic al Met h o ds:
A nal y sis Met h o ds
T he i nte nt -t o-treat (I T T) a nalys is set c o nsists of all s u bjects w h o 
recei ve ≥1 d ose of i delalisi b. It will be use d i n t he a nalys es of 
s u bject c haracteristics, st u d y dr u g (i delalisi b) treat me nt 
a d mi nistrati o n, safet y a n d efficac y e n d p oi nts.
S u bject c haracteristics a n d st u d y res ults will be desc ri be d a n d 
s u m marize d. Descri pti ve s u m maries will be pre pare d t o s h o w 
sa m ple size, mea n, sta n dar d de viati o n ( St D), 
9 5 % c o nfi de nce i nter vals ( CIs) o n t he mea n, me dia n, mi ni m u m, 
a n d ma xi m u m f or c o nti n u o us varia bles a n d c o u nts, perce nta ges a n d 
9 5 % CI s o n t he perce nta ge f or cate g orical varia bles. I nteri m safet y 
s u m maries f or S R T will be s h o w n by eac h c o h ort a n d all c o h orts 
t o get her.
Res p o nse rates will be prese nte d wit h c orres p o n di n g e xact 
9 5 % CI s. S u bjects w h o ha ve missi n g baseli ne or o n-st u d y res p o nse 
assess ment wil l be c o u nte d as n o n-res p o n ders.
P F S a n d d urati o n of res p o nse ( D O R ) will be descri be d i n t he 
a p pr o priate a nal ys is set usi n g Ka pla n-Meier met h o ds. T he s ur vi val 
f u ncti o ns will be pl otte d a n d me dia n s ur vi val ti mes will be 
prese nte d wit h c orres p o n di n g 9 5 % CI s.
Perce nt c ha n ge fr o m baseli ne at Wee ks 1 2 a n d 2 4 a n d best c ha n ge 
fr o m baseli ne f or s plee n, li ver, a n d T S S will be prese nte d wit h 
c orres p o n di n g me dia n, sta n dar d d e viati o n, mi ni m u m, a n d 
ma xi m u m.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 7
2 6 Oct o ber 2 0 1 6
Sa m ple Size
As t his is a P hase 1 b st u d y  wit h a pri mar y o bjecti ve of assessi n g 
safety, t he sa m ple size is n ot base d o n f or mal p o wer calc ulati o ns. 
T he sa m ple size of a p pr o xi matel y  6 s u bjects per d ose c o h ort i n 
C o h orts A, B, C, a n d D is c o nsi dere d a de q uate f or a n i nitial
assess me nt of safet y a n d t olera bilit y f or s u bse q ue nt e val uati o ns.
T his st u d y  will be c o n d ucte d i n acc or da nce wit h t he g ui deli nes of G o o d Cli nical Practice ( G C P) 
i ncl u di n g arc hi vi n g of esse ntial d oc u me nts.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 8
2 6 Oct o ber 2 0 1 6
G L O S S A R Y O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F  T E R M S
3 D
T hree Di me nsi o nal
A E
A d verse E ve nt
A L T
Ala ni ne Tra nsa mi nase
A N C
A bs ol ute Ne utr o p hil C o u nt
A S T
As partate Tra nsa mi nase
A T P
A de n osi ne Tri p h os p hate
A U C
Area U n der t he Ser u m C o nce ntrati o n O ver Ti me C ur ve
β -h C G
Beta H u ma n C h ori o nic G o na d otr o pi n
B A T
B e st A vaila ble T hera p y
B C R P
Breast Ca ncer R esista nce P r otei n
BI D
T w ice Dail y
C F R
C o de of Fe deral Re g ulati o ns
CI
Cli nical I m pr o ve me nt
CIs
C o nfi de nce I nter vals
C L L
C hr o nic L y m p h oc ytic Le u ke mia
C M V
C yt o me gal o vir us
C ma x
Ma xi m u m Dr u g C o nce ntrati o n
C tr o u g h
Tr o u g h plas ma c o nce ntrati o n
C R
C o m plete Re missi o n
C T
C o m p ute d T o m o gra p h y
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
C Y P
C y t oc hr o me P 4 5 0 E nz y me
DI P S S
D y na mic I nter nati o nal W or ki n g Gr o u p Pr o g n ostic Sc ori n g S yste m
D N A
De o x yri b o n ucleic Aci d
D O R
D urati o n of Res p o nse
D S P H
Dr u g Safet y a n d P u blic Healt h
E C 9 0
Dr u g c o nce ntrati o n at 9 0 % of ma xi mal effect
E C G
Electr ocar di o gra m
e C cr
Esti mate d Creati ni ne Cleara nce
e C R F
Electr o nic Case Re p ort F or m
E C O G
Easter n C o o perati ve O nc ol o g y Gr o u p
E L N
E ur o pea n Le u ke mia Net
E O S
E n d of St u d y
E S A
Er yt hr o p oieti n Sti m ulati n g A ge nts
E S R
Er yt hr oc yte Se di me ntati o n R ate
E T
Esse ntial T hr o m b oc yt he mia
E U
E ur o pea n U ni o n
F L
F ollic ular L y m p h o ma


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 9
2 6 Oct o ber 2 0 1 6
F D A
F o o d a n d Dr u g A d mi nistrati o n
G C P
G o o d Cli nical Practice
G- C S F
Gra n ul oc yte C ol o n y -Sti m ulati n g Fact or
G G T
Ga m ma - Gl uta m yltra nsferase
G L P
G o o d La b orat or y Practice
G M -C S F
Gra n ul oc yte -Macr o p ha ge
C ol o n y - Sti m ulati n g Fact or
H Bc
H e patitis B C ore
H Bs A g
He patitis B S urface A nti ge n
H B V
He patitis B Vir us
H C V
He patitis C Vir us
H D
H o d g ki n Disease
HI V
H u ma n I m m u n o deficie nc y Vir us
H L
H o d g ki n L y m p h o ma
I B
I n vesti gat or’s Br oc h ure
I C5 0
C o nce ntrati o n t hat res ults i n 5 0 % i n hi biti o n
I C F
I nf or me d C o nse nt F or m
I C H
I nter nati o nal C o nfere nce o n Har m o nisati o n
I E C
I n de pe n de nt Et hics C o m mittee
I g A
I m m u n o gl o b uli n A
I g G
I m m u n o gl o b uli n G
I g M
I m m u n o gl o b uli n M
I L- 6
I nterle u ki n 6
I M P
I n vesti gati o nal Me dici nal Pr o d uct
i N H L
I n d ole nt n o n-H o d g ki n L y m p h o ma
I U D
Intra uteri ne D e vice
I R B
I nstit uti o nal Re vie w B oar d
I T T
I nte nt T o Treat
I W G-M R T
I nter nati o nal W or ki n g Gr o u p f or M yel ofi br osis Researc h a n d Treat me nt
J A K 2
Ja n us Ki nase 2
L C M
Left C ostal Mar gi n
M D R 1
H u ma n P -gl yc o pr otei n
M F
M y el ofi br osis
M P N
M y el o pr oliferati ve Ne o plas m
M P N -S A F
M y el o pr oliferati ve Ne o plas m S y m pt o m Assess me nt F or
M RI
Ma g netic Res o na nce I ma gi n g
p A kt
P h os p h or ylate d A K T
P B M C
Peri p heral B l o o d M o n o n uclear C ells
P C R
P ol y merase C hai n Reacti o n
P D
Pr o gressi ve Disease
P E
P h y sical E xa mi nati o n


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 2 0
2 6 Oct o ber 2 0 1 6
P F S
Pr o gressi o n Free S ur vi val
PI 3 K
P h os p h oti d yli n osit ol - 3-ki nase
PI P 3
P h os p hati d yli n osit ol ( 3, 4, 5) -tris p h os p hate
PJ P
P ne u m oc ystis jir o veci p ne u m o nia
P K
P har m ac o ki netics
P M F
Pri mar y M yel ofi br osis
P O
Oral A d mi nistrati o n
P ost -E T M F
P ost -Esse ntial T hr o m b oc yt he mia M yel ofi br osis
P ost -P V M F
P ost -P ol yc yt he mi a Vera M y el ofi br osis
P R
Partial R e missi o n
P R O
Patie nt -re p orte d O utc o mes
P T
Preferre d Ter m
P V
P ol yc yt he mia Vera
Q T
Electr ocar di o gra p hic i nter val bet wee n t he be gi n ni n g of t he Q wa ve a n d ter mi nati o n of t he 
T w a ve re prese nti n g t he ti me f or b ot h ve ntric ular de p olarizati o n a n d re p olarizati o n t o occ ur
R B C
Re d Bl o o d Cell C o u nt
R N A
Ri b o n ucleic Aci d
S A E
Seri o us A d verse E ve nt
S D
Sta ble D isease
S O C
S y st e m Or ga n Class
S O P
Sta n dar d O perati n g Pr oce d ure
S R T
Safet y Re vie w Tea m
St D
Sta n dar d De viati o n
S U S A R
S us pecte d U ne x p ecte d Seri o us A d verse Reacti o n
T ma x
T he ti me ( o bser ve d ti me p oi nt) of C ma x
T S S
T otal S y m pt o m Sc ore
T T R
Ti m e T o Res p o nse
U L N
U p per Li mit of N or mal
U S
U nite d States
W B C
W hite Bl o o d C o u nt


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 2 1
2 6 Oct o ber 2 0 1 6
1.
I N T R O D U C TI O N
1. 1.
B ac k gr o u n d
1. 1. 1. 
B ac k gr o u n d o n M yel ofi br osis
T he c hr o nic m yel o pr oliferati ve ne o plas ms ( M P Ns) —
p ol y c yt he mia vera ( P V), 
esse ntial t hr o m b oc yt he mia ( E T), a n d pri mar y mye l ofi br osis ( P M F)—
are ac q uire d marr o w 
dis or ders c haracterize d b y e xcessi ve pr o d ucti o n of mat ure m yel oi d cell s. Maj or m or bi dit y fr o m 
t hese c o n diti o ns res ult fr o m t hr o m b o-he m orr ha gic c o m plicati o ns (arterial a n d ve n o us t hr o m b osis, 
maj or blee di n g) a n d tra nsf or mati o n t o ac ute le u ke mia.
M y el ofi br osis ori gi nates fr o m ac q uire d m utati o ns t hat alter t he he mat o p oietic ste m cell a n d 
pr o d uce alterati o ns i n t he ki nase -me diate d si g nali n g pr ocesses, res ulti n g i n cl o nal 
m y el o pr oliferati o n, b o ne marr o w fi br osis, a n d a b n or mal c y t o ki ne e x pressi o n { Tefferi et al 
2 0 1 1 }. Pri mar y  myel ofi br osis is a rare disease wit h a n i nci de nce of 0. 4 t o 1. 3 per 1 0 0, 0 0 0 pe o ple 
i n Eur o pe, A ustralia, a n d t he U. S. M y el ofi br osis ca n als o occ ur i n patie nts wit h P V 
( 1 0- 2 0 % of s u bjects after 1 0- 2 0 ye ars) a n d E T ( 2 -3 % of s u bjects), i n w hic h case it is calle d 
p ost -p ol y c yt he mia vera ( p ost -P V M F ) or p ost -esse ntial t hr o m b oc yt he mia m yel ofi br osis 
(p ost -E T M F ). T he pri mar y pat h o ge nic mec ha nis m i n P M F is t he u nc hec ke d pr oliferati o n of a 
he mat o p oietic ste m ce ll cl o ne t hat lea ds t o i neffecti ve er yt hr o p oiesis, aty pical me ga kar y oc ytic 
h y per plasia, a n d a n i ncrease i n t he rati o of i m mat ure gra n ul oc y tes t o t otal gra n ul oc ytes. T his 
cl o nal m yel o pr oliferati o n is c haracteristicall y acc o m pa nie d b y b o ne marr o w fi br osis a n d 
e xtra me d ullar y he mat o p oiesis i n t he s plee n, li ver, a n d ot her or ga ns. C haracteristic feat ures of 
e xtra me d ullar y he mat o p oiesis o n a bl o o d s mear i ncl u de tear dr o p-s ha pe d re d cells, 
n ucleate d re d cells, a n d m yel oi d i m mat urit y. T ypical cli nical feat ures i ncl u d e mar ke d 
s ple n o me gal y, pr o gressi ve a ne mia, a n d c o nstit uti o nal s ym pt o ms.
U nf ort u natel y, c urre nt treat me nts f or M F are palliati ve a n d d o n ot alter t he nat ural disease
c o urse. T he o nl y p ote ntial c ure f or M F is all o ge neic ste m cell tra ns pla nt, t he a vaila bilit y of 
w hic h is li mite d b y a ge a n d d o n or restricti o ns. I n 2 0 0 5, a m utati o n i n t he 
J A K 2 c yt o plas mic t yr osi ne ki nase ( J A K 2V 6 1 7 F) was i de ntifie d t hat lea ds t o c o nstit uti ve 
acti vati o n of J A K 2 a n d u na bate d J A K - S T A T si g nali n g, res ulti n g i n t he u nrestrai ne d cell ular
pr oliferati o n c haracteristics of M P Ns. T his pr o m pte d t he de vel o p me nt of J A K 2 i n hi bit ors f or 
m y el ofi br osis, t he m ost c halle n gi n g of t he M P Ns .
Alt h o u g h ver y  effecti ve i n re d uci n g s plee n size a n d miti gati n g sy m pt o ms, J A K i n hi bit ors ha ve 
t h us far n ot s h o w n t he a bilit y t o i m pr o ve le u ke mia-free s ur vi val, re verse disease-defi ni n g 
feat ures s uc h as b o ne marr o w fi br osis, n or s u bsta ntiall y re d uce J A K 2V 6 1 7 F m utati o n b ur de n. 
T he bi ol o gic basis f or t hese s u b o pti mal res p o nses has n ot bee n esta blis he d b ut is li kel y  
attri b uta ble t o J A K 2 de pe n de nt a n d i n de pe n de nt mec ha nis ms. T o date, resista nce m utati o ns 
wit hi n J A K 2 ha ve n ot bee n i de ntifie d as a basis f or ac q uire d resista nce t o J A K i n hi bit ors i n t he 
cli nical setti n g. H o we ver, persiste nt J A K - S T A T si g nali n g me diate d by t he heter o di merizati o n 
bet wee n J A K 2 wit h t he relate d ki nases J A K 1 or T Y K 2 was rece ntl y descr i be d as a mec ha nis m of 
" disease persiste nce" i n prese nce of c hr o nic i nacti vati o n of J A K 2 { K o p pi kar et al 2 0 1 2 } . 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 2 2
2 6 Oct o ber 2 0 1 6
T his p he n o me n o n of persiste nce of t he J A K -S T A T acti vit y  was o bser ve d i n vi v o i n M P N m uri ne 
m o dels, a n d i n pri mar y  sa m ples of patie nts treate d wit h t he J AK 2 i n hi bit or r u x oliti ni b, rece ntl y 
a p pr o ve d b y t he F o o d a n d Dr u g A d mi nistrati o n ( F D A ) i n N o ve m ber 2 0 1 1 f or t he treat me nt of
M F .
1. 1. 2.
R ati o n ale f or I n hi biti o n of PI 3 K/ A K T P at h w a y i n M yel ofi br osis
P h os p hati d y li n osit ol 3-Ki nase ( PI 3 K)/ A K T is a si g nali n g pat h wa y  t hat pla ys a cr ucial r ole i n cell 
gr o wt h, pr oliferati o n, a n d s ur vi val, a n d t here has bee n i ncre asi n g e vi de nce t hat a b n or mal 
u p- re g ulati o n of PI 3 K/ A K T is rele va nt t o M P N pat h o p h ysi ol o g y.
Beca use t he PI 3 K/ A K T pat h wa y is pr o mi ne ntl y acti vate d i n J A K 2V 6 1 7 a n d M P L W 5 1 5 L  
i n d uce d M P Ns, K ha n a n d c ollea g ues e val uate d t he acti v it y of M K-2 2 0 6 a selecti ve 
A K T i n hi bit or i n J A K 2V 6 1 7 F e x pressi n g cell li nes { Ka h n et al 2 0 1 3 , K ha n et al 2 0 1 1 } . T hese 
i n vesti gat ors f o u n d t hat i n hi biti o n of A K T p ote ntl y  s u p presse d gr o wt h of t hese cells b y i n d uci n g 
cell c ycle arrest a n d a p o pt osis. E x p os ure of J A K 2 V 6 1 7 F C D 3 4 + peri p her al cells fr o m M F 
patie nts t o M K -2 2 0 6 s u p presse d c ol o n y f or mati o n fr o m t hese pr o ge nit or cells. T he e x pa nsi o n of 
me ga kar y o c y tes ( C F U- M Ks) fr o m m uri ne b o ne marr o w cells tra ns d uce d wit h M P L W 5 1 5 L was 
a br o gate d i n t he prese nce of t he A K T i n hi bit or M K-2 2 0 6 s u g gesti n g a re q uire me nt f or t he 
PI 3 K / A K T pat h wa y i n a berra nt me ga kar yo c y te e x pa nsi o n, a feat ure of M F.
S y ner gistic i n hi biti o n of pr oliferati o n, i n d ucti o n of a p o pt osis a n d i n hi biti o n of c ol o n y  f or mati o n 
fr o m M P N he mat o p oietic pr o ge nit ors were rece ntl y de m o nstrate d i n m ulti ple p u blicati o ns usin g 
J A K i n hi bit ors c o m bi ne d wit h PI 3K i n hi bit ors, m T O R i n hi bit ors , a ki nase d o w nstrea m of PI 3 K, 
or a d ual PI 3 K -m T O R i n hi bit or { B o ga ni et al 2 0 1 3 , C h o o n g et al 2 0 1 2 , Fi s k us et al 2 0 1 3} . 
C h o o n g a n d c ollea g ues e xte nsi vel y  e x pl ore d t he c o m bi nati o n of t w o J A K i n hi bit ors 
(r ux oliti ni b a n d S A R 3 0 2 5 0 3) wit h a pa nel of 1 5 i n hi bit ors tar geti n g a d diti o nal si g nali n g 
pat h wa y s i n cell li nes e n gi neere d t o o vere x press W T J A K 2, J A K 2V 6 1 7 F , T P O R W 5 1 5 L a n d W T 
T P O R. A m o n g t he 1 5 i n hi bit ors teste d, o nl y  t he PI 3 K i n hi bit ors ( Z S T K 4 7 4, G D C 0 9 4 1 a nd 
B E Z 2 3 5) s y n er gize d t o i n hi bit t he cell pr oliferati o n a n d s ur vi val of t he cells e n gi neere d t o mi mic 
t he ge netic lesi o ns o bser ve d i n M P N. C o m bi nati o n of r u x oliti ni b a n d G D C 0 9 4 1 was f urt her 
s h o w n t o re d uce C F U-E a n d B F U -E c ol o n y  f or mati o n fr o m he mat o p oietic pr o ge nit ors is olate d 
fr o m a m o use m o del of M P N a n d fr o m t w o P V patie nts. B E Z 2 3 5, a d ual PI 3 K m T O R i n hi bit or 
i n d uce d cell c ycle arrest a n d a p o pt osis i n J A K 2V 6 1 7 F e x pressi n g h u ma n cell li nes a n d i n cells 
deri ve d fr o m M P N patie nt { Fis k us et al 2 0 1 3 } . C o m bi nati o n of B E Z 2 3 5 wit h S A R 3 0 2 5 0 3 a 
J A K i n hi bit or, s yner gisticall y decrease d via bilit y  i n J A K 2V 6 1 7 F e x pressi n g cell li nes a n d C D 3 4 +
pr o ge nit or cells fr o m M F patie nts. N or mal C D 3 4 + pr o ge nit or cells a p peare d less se nsiti ve t o t he 
c o m bi ne d i n hi biti o n of t he J A K 2 a n d t he PI 3 K pat h wa y. The ge nerati o n of 
er yt hr o p oieti n -de pe n de nt c ol o nies fr o m P V patie nts was als o s y ner gisticall y  i n hi bite d b y t he 
c o m bi nati o n of m T O R i n hi bit ors wit h t he J A K i n hi bit ors r u x oliti ni b a n d A Z D 1 4 8 0 { B o ga ni et al 
2 0 1 3 }. T hese i n vitr o data i n dicate t hat i n hi biti o n of PI 3 K or of t he d o w nstrea m effect or ki nases 
A K T or m T O R are acti ve a gai nst M P N cells a n d t heir c o m bi nati o n wit h J A K i n hi bit ors 
pr o d uce d s y ner gis m . T he PI 3 K i n hi bit ors G D C 0 9 4 1 a n d B E Z 2 3 5 i n hi bit all Class I PI 3 K 
is of or ms. T he C lass I PI 3K is c o m p ose d of a re g ulat or y s u b u nit a n d a catal ytic s u b u nit 
(desi g nate d p 1 1 0 α, p 1 1 0 β, p 1 1 0 δ , or p 1 1 0γ) e n d o we d wit h ki nase acti vit y. T he catalyt ic s u b u nit 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 2 3
2 6 Oct o ber 2 0 1 6
of t he heter o di mer defi nes t he 4 Class I PI 3 K is of or ms: PI 3 K α, PI K β, PI 3 δ , a n d PI 3 Kγ. 
I delalisi b is a n oral selecti ve s mall m olec ule a de n osi ne tri p h os p hate (A T P ) c o m petiti ve i n hi bit or 
of t he PI 3 K δ is of or m w h ose e x pressi o n is restricte d t o he mat o p oietic cells. T he PI 3 K δ is of or m 
was i de ntifie d as t he pre d o mi na nt is of or m e x presse d i n C D 3 4 + cells fr o m M F patie nts ( Gilea d, 
data o n file) . Idelalisi b i n hi bite d t he PI3 K/ A K T pat h wa y , wit h a d ose-de pe n de nt decreas e of 
p- A K T a n d p -S 6 ri b os o mal pr otei n, d o w nstrea m p har mac o dy n a mic mar kers of t his pat h wa y.
I n hi biti o n was o bser ve d i n C D 3 4 + peri p heral cells fr o m b ot h r u x oliti ni b-naï ve a n d c hr o nic 
r u x oliti ni b-treate d patie nts. Idelalisi b al o ne a n d i n c o m bi nati o n wit h r u x oliti ni b i n hi bite d t he 
s ur vi val a n d i n d uce d a p o pt osis as assesse d by A n ne xi n V stai ni n g i n M F -deri ve d pr o ge nit or cells
{ Mea d o ws et al 2 0 1 3 }. Base d o n PI 3 K/ A K T i n v ol ve me nt i n M F, t he e x pressi o n of PI3 K δ 
is of or m i n M F pr o ge nit or cells, t he p ote nt an d selecti ve i n hi biti o n of t he PI 3 K δ is of or m ac hie ve d 
b y  i delalisi b, a n d t he a bilit y of i delalisi b t o i n hi bit AK T si g nali n g a n d s ur vi val of M F C D 3 4 +
pr o ge nit or cells { Mea d o ws et al 2 0 1 3 } ( Gilea d data o n file), we pr o p ose a P hase 1 b trial of 
i delalisi b i n c o m bi nati o n wit h r u x oliti ni b i n s u bjects wit h P M F , p ost -P V M F or p ost -E T M F a n d 
w h o meet t he criteria of pr o gressi ve or rela pse d disease as defi ne d i n t he i ncl usi o n criteria , a n d
base d o n t he 2 0 1 3 Re vise d I nter nati o nal W or ki n g Gr o u p f or M yel o pr oliferati ve Ne o plas ms 
Researc h a n d Treat me nt (I WG -M R T ) a n d E ur o pea n Le u ke mia Net (E L N ) res p o nse criteria 
partic ularl y gi ve n t he lac k of usef ul, disease- m o dif y i n g a ge nts i n t hese r u x oliti ni b treate d 
patie nts { Cer va ntes et al 2 0 0 9 }.
1. 2.
I del alisi b
1. 2. 1.
Ge ner al I nf or m ati o n
I delalisi b was a p pr o ve d i n t he U S o n J ul y 2 3, 2 0 1 4 a n d i n t he E ur o pea n U ni o n ( E U) o n 
Se pte m ber 1 8, 2 0 1 4. Refer t o l ocal la beli n g f or t he a p pr o ve d i n dicati o n state me nts a n d d osi n g 
rec o m me n dati o ns.
I delalisi b is a p ote nt c o m petiti ve i n hi bit or of t he A T P bi n di n g site of t he PI 3 K p 1 1 0 δ 
catal yt ic d o mai n, w hic h has bee n s h o w n t o be pr o mi ne ntl y  e x presse d i n cells of he mat o p oietic 
ori gi n { La n n utti et al 2 0 1 1 , O k ke n ha u g et al 2 0 0 3a , Va n haese br oec k et al 2 0 0 5 } . In hi biti o n of 
PI 3 K δ has bee n s h o w n t o m o d ulate cell ular f u ncti o ns i ncl u di n g m otilit y , pr oliferati o n, s ur vi val, 
a n d recr uit me nt of a d diti o nal i ntracell ular si g nali n g e nzy m es t hr o u g h t he B -cell rece pt or ( BC R) , 
c yt o ki ne, c he m o ki ne a n d i nte gri n rece pt ors.
1. 2. 1. 1.
R ole of P h os p hati d y li n osit ol 3-Ki nases i n T u m or Pat h o ge nesis
Class I  PI 3 Ks are a fa mil y of i ntracell ular si g nali n g pr otei ns t hat are esse ntial c o m p o ne nts of 
mi grat or y , pr oliferati ve, s ur vi val, a n d differe ntiati o n pat h wa ys i n ma n y cell t ypes, i ncl u di n g 
t h ose of he mat o p oietic ori gi n { O k ke n ha u g et al 2 0 0 2 , O k ke n ha u g et al 2 0 0 3a , O k ke n ha u g et al 
2 0 0 3 b } . T hese e nz y m es c o nsist of a re g ulat or y s u b u nit ( desi g nate d p 5 0, p 5 5, p 8 5, or p 1 0 1) a n d a 
catal yt ic s u b u nit ( desi g nate d p 1 1 0 α, p 1 1 0 β, p 1 1 0γ , or p 1 1 0δ ). U p o n PI 3 K acti vati o n, p 1 1 0 
ge nerates t he ke y li pi d sec o n d messe n ger p h os p hati d y li n osit ol ( 3, 4, 5)-tris p h os p hate ( PIP 3) 
t hr o u g h p h os p h or ylati o n of t he 3 p ositi o n of t he i n osit ol hea d gr o u p of p h os p h oli pi ds prese nt i n 
t he cell me m bra ne. PIP 3 acts as a bi n di n g site f or recr uit me nt a n d acti vati o n of n u m er o us 
i ntracell ular si g nali n g e nz ymes. T he m ost i m p orta nt of t hese is t he seri ne/t hre o ni ne ki nase, A K T, 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 2 4
2 6 Oct o ber 2 0 1 6
w hic h me diates a p ositi ve ple otr o pic effect o n cell s ur vi val, pr oliferati o n, gr o wt h, a n d 
meta b olis m { E n gel ma n et al 2 0 0 6 } acti n g t hr o u g h m T O R si g nali n g { Ha y  2 0 0 5 , Osa ki et al 
2 0 0 4 } . T he acti vit y of PI 3 K is o p p ose d b y li pi d p h os p hatases t hat i ncl u de p h os p hatase a n d 
te nsi n h o m ol o g ( P T E N), a k n o w n t u m or s u p press or t hat is e x presse d i n all cells a n d i n osit ol 
p ol y p h os p hate 5 -p h os p hatase ( S HI P 1 a n d S HI P 2 ), e nz yme s t hat are e x presse d i n he mat o p oietic 
cells.
PI 3 K δ s h o ws a n e x pressi o n patter n t hat is lar gel y restricte d t o cells of he mat o p oietic ori gi n 
{ Va n haese br oec k et al 2 0 0 5 }. Mice deficie nt i n PI 3 K δ ha ve n o gr oss a b n or malities, 
re pr o d uce, a n d li ve a n or mal life s pa n wit h o ut a n i ncrease d s usce pti bilit y  t o i nfecti o ns 
{ O k ke n ha u g et al 2 0 0 2 , O k ke n ha u g et al 2 0 0 3a , O k ke n ha u g et al 2 0 0 3 b } . H o we ver, effects o n 
i ntracell ular si g nali n g, pr oliferati o n, mi grati o n, a n d differe ntiati o n ha ve bee n o bser ve d i n cells of 
m y el oi d a n d l y m p h oi d li nea ges { S uj o bert et al 2 0 0 5 }.
T he i m p orta nce of t he PI 3 K/ A K T si g nali n g pat h wa y  has bee n s h o w n i n a n u m ber of 
he mat o p oietic mali g na ncies i ncl u di n g n o n- H o d g ki n l ym p h o ma, ma ntle cell l y m p h o ma, c hr o nic 
l ym p h oc y tic le u ke mia, a n d H o d g ki n disease ( H D). PI 3 K δ is critical f or m ulti ple si g nali n g
pat h wa y s t hat are h yperacti ve i n B -cell mali g na ncies a n d c o nfer s ur vi val, pr oliferati o n a n d 
h o mi n g t o mali g na nt B cells . A s ur ve y  of m ulti ple l ym p h o ma cell li nes s h o we d u nif or m 
e x pressi o n of PI3 K a n d i n ma n y cases c o nstit uti ve acti vati o n of t he PI 3 K pat hwa y  as i n dicate d 
b y  e x pressi o n of p h os p h or ylate d A K T ( p A kt) { La n n utti et al 2 0 1 1 } . In hi biti o n of PI 3 K δ b y 
i delalisi b re d uce d t he via bilit y of cell li nes-deri ve d fr o m N H L. I n H o d g ki n’s disease, t he 
i m p orta nce of t he PI 3 K/ A kt/ m T O R pat h wa y has bee n de m o nstrate d { Castellares et al 2 0 0 8 , 
Ge or ga kis et al 2 0 0 5 , Mea d o ws et al 2 0 1 0 } . I n a n e val uati o n of R S cells i n pri mar y l ym p h n o de 
secti o ns fr o m patie nts wit h H o d g ki n L y m p h o ma (H L ), 2 7 of 4 2 ( 6 4. 3 %) de m o nstrate d p A kt, 
i n dicati n g t hat c o nstit uti ve PI3 K acti vit y  is a feat ure of t hese cells. F urt her st u dies i n H L-deri ve d 
cells li nes c o nfir me d o vere x pressi o n of p A kt, s h o wi n g t hat p A kt e x pressi o n ca n be i n d uce d 
t hr o u g h PI 3 K by e xter nal sti m uli s uc h as c oc ult ure wit h str o mal cells a n d t hat t his effect was 
bl oc ke d b y i delalisi b. Idelalisi b s h o we d d ose- a nd ti me -de pe n de nt a nti pr oliferati ve effects a n d 
e n ha nce d a p o pt osis i n cell li nes deri ve d fr o m patie nts wit h H D { Mea d o ws et al 2 0 1 0 , Mea d o ws 
et al 2 0 1 2}.
1. 2. 1. 2.
Dr u g S u bsta nce a n d F or m ulati o n
Idelalisi b is a n orally bi oa vaila ble, n o vel c he mical e ntit y wit h a m olec ular wei g ht of 
~ 4 1 5 dalt o ns. F or t o xic ol o gical a n d cli nical testi n g, i delalisi b has bee n ma n ufact ure d a n d 
f or m ulate d acc or di n g t o c urre nt G o o d Ma n ufact uri n g Practices.
F or f urt her i nf or mati o n refer t o i delalisi b I nvesti gat or’s B r oc h ure (I B).


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 2 5
2 6 Oct o ber 2 0 1 6
1. 2. 2.
Precli nic al P h ar m ac ol o g y a n d T o xic ol o g y
1. 2. 2. 1.
N o ncli nical P har mac ol o g y
Idelalisi b e x hi bits hi g h selecti vit y a n d p ote nc y. T he c o nce ntrati o n of i delalisi b i n d uci n g 
5 0 % i n hi biti o n ( I C5 0) of PI3 K δ is 1 9 n M, w hereas t he I C 5 0 val ues f or PI 3 K α, PI 3 K β, a n d PI 3 Kγ 
were 8 6 0 0, 4 0 0 0, a n d 2 1 0 0 n M, res pecti vel y. I n a d diti o n, i delalisi b at 1 0 μ M di d n ot 
si g nifica ntly i nteract wit h a n y of 4 0 2 ki nases teste d ot her t ha n t he PI 3 K is of or ms. Ra di oli ga n d 
dis place me nt assa y s t hat meas ure f u nctio nal bi n di n g i nteracti o ns de m o nstrate d t hat i delalisi b
( 1 0 μ M) di d n ot si g nifica ntl y  i n hi bit bi n di n g of a n y of t he 6 8 ra di o-li ga n ds teste d.
T he effects of i delalisi b o n si g nali n g a n d a p o pt osis i n mali g na nt B cells were assesse d t hr o u g h a 
series of i n vitr o e x peri me nts i n cell li nes a n d sa m ples fr o m a d ult s u bjects wit h 
f ollic ular l ym p h o ma ( F L), diff use lar ge B -cell l y m p h o ma ( D L B C L), ma ntle cell l ym p h o ma 
( M C L), a n d C L L . T hese st u dies de m o nstrate d t hat i delalisi b ca uses a d ose -de pe n de nt re d ucti o n 
of A kt p h os p h or y lati o n at cli nicall y ac hie va ble e x p osure. I n sa m ples deri ve d fr o m F L patie nt 
fi ne nee dle bi o psies, treat me nt wit h 0. 1 μ M i delalisi b le d t o 5 0 % t o 9 0 % i n hi biti o n of 
A kt p h os p h or y lati o n. C o nce ntrati o ns i n d uci n g a 5 0 % re d ucti o n of A kt p h os p h or ylati o n a n d 
g r o wt h i n hi biti o n ( E C5 0) were i n t he ra n ge of 0. 1 t o 0. 5 μ M i n 2 i n d ole nt n o n- H o d g ki n 
l ym p h o ma (i N H L) cell li nes ( W S U -N H L n o d ular histi oc y tic l ym p h o ma a n d W S U -F S C C L , 
l o w-gra de f ollic ular s mall clea ve d cell l y m p h o ma). I n t hese 2 cell li nes, i delalisi b at 0. 5 μ M 
res ulte d i n a 3- t o 5-f ol d i ncrease i n t he po p ulati o n of a p o pt otic ( A n ne xi n V- p ositi ve) cells as 
assesse d b y fl o w c y t o metr y. T his a n d ot her testi n g i n n o ncli nical m o dels of l ym p h oi d ne o plasia 
c o nfir m t he i m p orta nce of t he PI 3 K δ pat h wa y  i n i N H L a n d d oc ume nt i delalisi b acti vit y i n 
s u p pressi n g t he gr o wt h a n d s ur vi val of t hese mali g na nt cell t ypes.
I n vitr o a n d i n vi v o safet y p har mac ol o g y st u dies wit h i delalisi b ha ve de m o nstrate d a fa v ora b le 
n o n- cli nical safet y pr ofile (Gilea d data o n file ). T hese st u dies i n dicate t hat t he dr u g ma y 
mi ni mall y  sl o w b o ne marr o w pr o ge nit or pr oliferati o n a n d differe ntiati o n a n d t hat it has e x pecte d 
i n hi bit or y effects o n B-cell res p o nse t o a nti ge n c halle n ge. H o we ver, t he data i n dicate t hat 
i delalisi b is u nli kel y to ca use seri o us off -tar get effects or a d verse effects o n critical or ga n 
s yste ms. Idelalisi b has n o mea ni n gf ul effect o n t he h u ma n et her -à-g o -g o -relate d ge ne ( h E R G) 
c ha n nel, i n dicati n g t hat i delalisi b w o ul d n ot be e x pecte d t o i n d uce cli nical Q T pr ol o n gati o n .
Idelalisi b has als o pr o ve d t o be well t olerate d i n sta n dar d i n vi v o G o o d La b orat or y Practice 
( G LP) st u dies of p har mac ol o gical safet y . A f u ncti o nal o bser vati o n batter y i n rats re veale d n o 
a d verse effects o n be ha vi or or o n a ut o n o mic, ne ur o m usc ular, or se ns ori m ot or f u ncti o n. I n a 
car di o p ul m o nar y f u ncti o n st u d y i n a wa ke, tele meterize d male bea gle d o gs, si n gle d oses of 
i delalisi b i n d uce d n o mea ni n gf ul a b n or malities i n p ul m o nar y, car di o vasc ular, arterial bl o od gas, 
or E C G (i ncl u di n g Q T i nter val) para meters. I n a n assess me nt of bacterial c halle n ge i n rats, 
i delalisi b e n ha nce d, rat her t ha n i m paire d, t he p ha g oc y tic h ost cleara nce of sta p h yl oc occal 
bacteria.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 2 6
2 6 Oct o ber 2 0 1 6
1. 2. 2. 2.
N o ncli nical Meta b olis m a n d P har mac o ki netics
C o nsiste nt wit h t he m o derate t o hi g h bi oa vaila bilit y see n i n n o nc li nical s pecies, i delalisi b s h o ws 
hi g h per mea bilit y  acr oss h u ma n Cac o-2 cell m o n ola y ers. At l o wer c o nce ntrati o ns, t he re verse 
per mea bilit y  at l o w c o nce ntrati o n e xcee ds f or war d per mea bilit y, i n dicati n g effl u x dri ve n b y 
tra ns p orters [e g, h u ma n P-gl yc o pr otei n ( M D R 1) a n d breast ca ncer resista nce pr otei n ( B C R P)]; 
i delalisi b is a s u bstrate f or t he effl u x tra ns p orters M D R 1 a n d B C R P; h o we ver, t he per mea bilit y 
i ncreases i n a c o nce ntrati o n- de pe n de nt ma n ner, res ulti n g i n a l o wer effl u x rati o at hi g her, 
cli nicall y releva nt c o nce ntrati o ns of i delalisi b.
F urt her details ca n be f o u n d i n t he i delalisi b I B.
1. 2. 2. 3.
T o xic ol o g y
T he t o x ic ol o gical pr ofile of i delalisi b was well c haracterize d t hr o u g h t he c o n d uct of si n gle d ose, 
re peat d ose, de vel o p me ntal a n d re pr o d ucti ve, ge netic t o xic ol o g y a n d l ocal t olera nce st u dies. T he 
pri mar y  tar get or ga n t o xicities f oll o wi n g re peate d d osi n g i ncl u de t he ly m p h oi d, he patic, male 
re pr o d ucti ve sys te ms i n rats a n d d o gs, a n d gastr oi ntesti nal s yste m i n d o gs. A d verse effects i n t he 
l ym p h oi d s y ste m were pri maril y t he res ult of o n tar get p har mac ol o g y res ulti n g i n decrease d 
l ym p h oc y tes i n m ulti ple l ym p h oi d or ga ns, pri maril y  i n v ol vi n g ty pical B -cell re gi o ns. 
Li ver effects were tra nsie nt a n d re versi ble wit h c o nti n ue d d osi n g a n d di d n ot res ult i n 
c hr o nic li ver i nj ur y. Re d ucti o n i n s per m n u m bers i n males were re versi ble a n d di d n ot i m pact 
fertilit y or re pr o d ucti ve perf or ma nce. Gastr oi ntesti nal effects i n d o gs were mi n or, s u perficial, 
a n d c o nsi dere d sec o n dar y t o effects o n l y m p h oc y tes i n Pe yer’s Patc hes. Idelal isi b was s h o w n t o 
be terat o ge nic a n d ass ociate d wit h e m br y o- fetal let halit y. Effects o n t he re pr o d ucti ve sys te m 
ha ve bee n re p orte d f or i n hi bit ors w hic h tar get ot her is of or ms of PI 3 K. T he d ose -de pe n de nce a n d 
p ote ntial of i delalisi b t o selecti vely i n hi bit a d diti o nal PI 3 K is of or ms ma y  be res p o nsi ble f or t his 
off -tar get t o xicit y. A d diti o nall y, t he dr u g ma y ha ve t he p ote ntial t o pr o d uce p h ot ot o xic reacti o ns 
i n h u ma ns. T hese fi n di n gs re prese nt t o xicities t hat ca n be m o nit ore d, are c o nsi dere d cli nically 
ma na gea ble , or are c o nsi dere d acce pta ble ris ks i n t he i nte n de d patie nt p o p ulati o n.
F urt her details ca n be f o u n d i n t he i delalisi b I B.
1. 2. 3.
Cli nic al Tri als of I del alisi b
1. 2. 3. 1. 
Cli nical E x perie nce wit h I delalisi b
F or a d diti o nal or u p date d i nf or mati o n, please refer t o t he c urre nt versi o n of t he i delalisi b I B.
1. 2. 3. 2. 
P hase 1 St u dies i n Healt h y S u bjects a n d i n Patie nts wit h Aller gic R hi nitis 
( St u dies 1 0 1- 0 1, 1 0 1- 0 4, a n d 1 0 1 - 0 5)
T hree st u dies i n healt h y  s u bjects ( St u dies 1 0 1- 0 1, 1 0 1-0 4, a n d 1 0 1 -0 5) ha ve pr o vi de d 
i nf or mati o n re gar di n g dr u g safety, p har mac o ki netics, f o o d effects, a n d t he p ote ntial f or dr u g 
i nteracti o ns wit h C Y P 3 A 4 i n hi bit ors{ We b b et al 2 0 1 0 } . O ne of t hese trials als o i ncl u de d a 
preli mi nar y  e val uati o n of a bs or pti o n, meta b olis m a n d e xcreti o n i n healt h y v ol u nteers; i n t his 
trial, u nla bele d i delalisi b was c o -a d mi nistere d wit h a trace a m o u nt of [ 1 4C] i delalisi bgi ve n eit her 
orall y  or i ntra ve n o usly a n d bi ol o gical sa m ples were assesse d b y accelerat or mass s pectr o metr y.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 2 7
2 6 Oct o ber 2 0 1 6
Safet y  res ults fr o m t hese st u dies i n dicate d t hat i delalisi b was well t olerate d w he n a d mi nistere d t o 
healt h y  s u bjects at si n gle d oses t hr o u g h 4 0 0 m g (t he hi g hest d ose le vel teste d) a n d was als o 
ge nera ll y well t olerate d w he n a d mi nistere d t o healt h y s u bjects o ver 7 da ys at d ose le vels t hr o u g h 
2 0 0 m g/ d ose t wice dail y (t he hi g hest d ose le vel teste d). D osi n g wit h 2 0 0 m g/ d ose t wice daily f or 
7 da y s res ulte d i n a s ki n ras h i n 3 o ut of 6 s u bjects; hist ol o gical fi n di n gs were c o nsiste nt wit h a 
dela y e d-t ype h y p erse nsiti vit y mac ul o pa p ular e xa nt he ma. Ras hes ha ve s o meti mes occ urre d i n 
patie nts wit h he mat ol o gical mali g na ncies recei vi n g i delalisi b, b ut ha ve n ot t y picall y pr o ve d 
d ose - or treat me nt -li miti n g. I n place b o co ntr olle d si n gle -d ose a n d m ulti ple -d ose trials, re peate d 
electr ocar di o gra m ( E C G ) e val uati o ns perf or me d i n ta n de m wit h p har mac o ki netic m o nit ori n g 
s h o we d n o e vi de nce of dr u g-, d ose-, or e x p os ure-de pe n de nt effects o n car diac r h yt h m or 
car diac i nter vals (e g, Q T i nter val).
P har mac o ki netic res ults i n dicate d t hat i delalisi b a p peare d ra pi dly i n plas ma wit h a me dia n T ma x
of 1 t o 1. 5 h o urs. C ma x a n d A U C i ncrease d i n a less -t ha n-d ose -pr o p orti o nal ma n ner a n d mea n 
t1/ 2 val ues acr oss t he d ose ra n ge were 6. 5 t o 9. 8 h o urs.
Idelalisi b d osi n g after a hi g h -fat, hi g h-cal orie meal dela y e d me dia n time of ma xi m u m 
c o nce ntrati o n ( T ma x ) fr o m 0. 7 5 t o 3 h o urs; mea n Cma x was u naffecte d a n d mea n A U C was 
~ 4 0 % hi g her. T hese c ha n ges i n i delalisi b e x p os ures are c o nsi dere d m o dest/cli nicall y  
n o n -rele va nt; t h us, i delalisi b ma y  be gi ve n wit h or wit h o ut f o o d.
Idelalisi b is meta b olize d i n h u ma ns pri maril y b y al de h yde o xi dase, wit h s o me i n v ol ve me nt of 
C Y P 3 A 4 a n d U G T 1 A 4. Acc or di n gl y, w he n i delalisi b was a d mi nistere d f oll o wi n g 4 d a y s of dail y 
d osi n g wit h ket oc o naz ole (a p ote nt i n hi bit or of C Y P 3 A 4), m o dest/ m o derate i ncreases i n mea n 
i delalisi b C ma x a n d A U C val ues of ~ 3 0 % a n d ~ 8 0 % hi g her, res pecti vel y, w hic h is n ot 
c o nsi dere d t o be cli nicall y rele va nt a n d s u g gesti n g t hat i delalisi b is a wea k C Y P 3 A s u bstrate. 
G S - 5 6 3 1 1 7 is f or me d fr o m i delalisi b pri maril y  via al de h yde o xi dase.
T he 1 4C- la bele d i delalisi b h u ma n mass bala nce res ults s h o we d t hat t he dr u g has m o derate t o hi g h 
oral bi oa vaila bilit y . Idelalisi b is eli mi nate d mai nl y via he patic meta b olis m a n d bilia r y e xcreti o n 
i n t he feces ( ~ 7 8 % of d ose); rec o ver y  i n uri ne was < 1 5 %. G S -5 6 3 1 1 7 was t he o nl y  circ ulati n g 
meta b olite o bser ve d i n h u ma n plas ma, a n d was al s o o bser ve d i n uri ne a n d feces.
Res ults fr o m t he St u d y  G S-U S - 3 1 3-0 1 3 0 i n dicate t ha t i delalisi b d oes n ot affect t he 
p har mac o ki netics of s u bstrates of P g p, B C R P, O A T P 1 B 1, or O A T P 1 B 3 tra ns p orters. i delalisi b is 
n ot e x pecte d t o affect t he e x p os ures of c oa d mi nistere d a ge nts via tra ns p orter me diate d 
i nteracti o ns. As s uc h, c oa d mi nistrati o n of p ote nt i n d ucers of C Y P 3 A s uc h as rifa m pi n, 
car ba maze pi ne, p he n yt oi n, a n d St. J o h n’s W ort wit h i delalisi b s h o ul d be a v oi de d.
T he e x p os ures ( A U C) of pr o be C Y P 3 A s u bstrate, mi daz ola m, were ~ 5- f ol d u p o n 
c oa d mi nistrati o n wit h i delalisi b vers us mi daz ola m al o ne , dri ve n b y c o m petiti ve a n d 
ti me-de pe n de nt C Y P 3 A i n hi biti o n b y  G S-5 6 3 1 1 7, t he o nl y  circ ulati n g meta b olite of i delalisi b. 
C oa d mi nistrati o n of t he hi g hl y p ote nt C Y P 3 A i n d ucer rifa m pi n res ulte d i n a ~ 7 5 % re d ucti o n i n 
i delalisi b s yste mic e x p os ures, li kel y dri ve n b y  a hi g her relati ve c o ntri b uti o n t o C Y P 3 A t o o verall 
i delalisi b cleara nce u n der t he i n d uce d state.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 2 8
2 6 Oct o ber 2 0 1 6
P har mac o d y na mic res ults s h o we d t hat a n i delalisi b d ose of 2 0 0 m g i n hi bite d e x vi v o bas o p hil 
acti vati o n via t he PI 3 K δ-s pecific, hi g h-affi nit y I gE rece pt or (a nti F Cε R 1) i n bas o p hils c ollecte d 
fr o m healt hy v ol u nteers. T he fi n di n gs were c o nfir me d w he n t he dr u g was assesse d o ver 7 d a y s i n 
a P hase 1 b st u d y  i n s u bjects wit h aller gic r hi nitis. I n t his st u d y, i delalisi b at a d ose le vel of 
1 0 0 m g/ d ose t wice dail y s h o we d cli nical a n d p har mac o dy na mi c acti vit y (atte n uati n g a d verse 
res p o nses t o aller ge nic c halle n ge a n d decreasi n g mar kers of i nfla m mati o n) a n d was well 
t olerate d.
1. 2. 3. 2. 1.
Cli nical St u dies i n Patie nts wit h He mat ol o gic Mali g na ncies
Idelalisi b as m o n ot hera p y or i n co m bi nati o n wit h ot he r a ge nts (s uc h as be n da m usti ne, 
c hl ora m b ucil) a n d i m m u n ot hera p y (rit u xi ma b, ofat u m u ma b) has bee n s h o w n t o be t olera ble a n d 
de m o nstrate d cli nical efficac y  i n cli nical trials i n patie nts wit h i N H L, C L L a n d ot her he mat ol o gical 
mali g na ncies .
1. 3.
I nf or m ati o n a b o ut C o m p a ni o n Dr u g
1. 3. 1.
R u x oliti ni b
R u x oliti ni b p h os p hate is a ki nase i n hi bit or mar kete d f or t he treat me nt of i nter me diate or
h i g h-ris k myel ofi br osis, p ost -p ol y c yt he mia vera m yel ofi br osis, a n d p ost -esse ntial
t hr o m b oc yt he mia myel ofi br osis. T h e a p pr o val of r u x oliti ni b is base d o n t he res ults of t he
C O M F O R T - 1 st u d y w hic h de m o nstrate d t hat ru x oliti ni b, as c o m pare d wit h place b o, pr o vi de d 
si g nifica nt cli nical be nefits i n patie nts wit h m yel ofi br osis b y re d uci n g s plee n size, a meli orati n g 
de bilitati n g m yel ofi br osis -relate d sy m pt o ms, a n d i m pr o vi n g o verall s ur vi val. T hese be nefits 
ca me at t he c ost of m ore fre q ue nt a ne mia a n d t hr o m b oc y t o pe nia i n t he earl y part of t he treat me nt 
peri o d { Verst o vse k et al 2 0 1 2 }. I n t his st u d y 4 1. 9 % of patie nts o n r u x oliti ni b ac hie ve d a s plee n 
res p o nse defi ne d as at least 3 5 % re d ucti o n i n s plee n v ol u me fr o m baseli ne t o Wee k
2 4, vers us 
0. 7 % of patie nts o n place b o ( p < 0. 0 0 1). I n a d diti o n, 4 5. 9 % of pa tie nts o n r u x oliti ni b ac hie ve d 
i m pr o ve me nt i n m yel ofi br osis relate d sy m pt o ms c o m pare d t o 5. 3 % of patie nts i n t he place b o 
ar m ( p < 0. 0 0 1) { Verst o vse k et al 2 0 1 2 }. I n t he C O M F O R T - 2 st u d y w here patie nts wit h 
i nter me diate-2 or hi g h ris k m y el ofi br osis recei ve d eit her r u x oliti ni b or best a vaila ble t hera p y  
( B A T), 2 8 % of patie nts i n t he r u x oliti ni b ar m ac hie ve d a s plee n res p o nse defi ne d as at least a 
3 5 % re d ucti o n i n s plee n v ol u m e fr o m baseli ne at Wee k
4 8, vers us 0 % of patie nts o n best 
a vaila ble t hera p y ( p < 0. 0 0 1 ) { Harris o n et al 2 0 1 2 } . T he be nefits of r u x oliti ni b are n ot li mite d t o 
o nl y  t h ose wit h m utate d J A K 2V 6 1 7 F { Cer va ntes et al 2 0 1 3 } .
D osi n g of r u x oliti ni b at i nitiati o n of treat me nt is pre dicate d u p o n a patie nt’s platelet c o u nt, wit h 
d ose re d ucti o n i n dicate d f or vari o us de grees of t hr o m b oc yt o pe nia. F or patie nts wit h platelet 
c o u nt a b o ve 2 0 0 x 1 0 9/ L pri or t o starti n g treat me nt, t he rec o m me n de d starti n g d ose of 
r u x oliti ni b is 2 0 m g orall y t wice dail y, w hile f or t h ose wit h platelet c o u nt bet wee n 
1 0 0 x 1 0 9/ L a n d 2 0 0 x 1 0 9/ L, rec o m me n de d starti n g d ose is 1 5 m g orall y t wice daily. F or t h ose 
wit h platelet c o u nt bet wee n 5 0 x 1 0 9/ L a n d less t ha n 1 0 0 x 1 09/ L, t he rec o m me n de d starti n g d ose 
g oes d o w n t o 5 m g orall y t wice dail y ( r u x oliti ni b pac ka ge i nsert). A ne mi a a n d t hr o m b oc yt o pe nia 
were t he m ost c o m m o n he mat ol o gic a d verse e ve nts ( A E ) f or s u bjects o n t he r u x oliti ni b ar m i n 
t he C O M F O R T -1 st u d y , wit h a p pr o xi matel y half of all Gra de 3 or 4 a ne mia e ve n ts occ urri n g 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 2 9
2 6 Oct o ber 2 0 1 6
d uri n g t he first 8 wee ks of treat me nt, f oll o we d b y attai n me nt of a ne w stea d y state of 
he m o gl o bi n le vel t hat was a p pr o xi matel y  1. 0 g/ d L bel o w baseli ne by Wee k
2 4. F or t h ose 
s u bjects o n t he r u x oliti ni b ar m w h o de vel o pe d Gra de 3 or 4 t hr o m b oc yt o pe nia, a p pr o xi matel y  
half of t he t hr o m b oc y t o pe nia e ve nts als o occ urre d d uri n g t he first 8 wee ks of treat me nt a n d 
res ulte d i n r u x oliti ni b d ose a dj ust me nts or d ose i nterr u pti o ns o n st u d y {Verst o vse k et al 2 0 1 2 }. 
I n t he C O M F O R T-2 st u d y, t hr o m b oc yt o pe nia a n d a ne mia were als o t he m ost c o m m o n 
he mat ol o gic A E , c o nsiste nt wit h t he mec ha nis m of r u x oliti ni b. T hr o m b oc yt o pe nia was t he m ost 
c o m m o n reas o n f or d ose a dj ust me nt of r u x oliti ni b i n t he C O M F O R T - 2 st u d y ( 4 1 %), c o m pare d 
t o t he B A T ar m ( 1 %). There were als o m ore patie nts w h o re q uire d at least o ne tra nsf usi o n of 
pac ke d re d bl o o d cells o n t he r u x oliti ni b ar m ( 5 1 %), c o m pare d t o t h ose o n t he B A T ar m ( 3 8 %) 
{ Verst o vse k et al 2 0 1 2 } .
R u x oliti ni b is pre d o mi na ntl y  meta b olize d b y C Y P 3 A 4. T he Cma x a n d A U C of r u x oliti ni b 
i ncrease d 3 3 % a n d 9 1 %, res pecti vely, f oll o wi n g c oa d mi nistrati o n wit h str o n g C Y P 3 A 4 i n hi bit or 
ket oc o naz ole 2 0 0 m g t wice dail y f or 4 da ys, c o m pare d t o r u x oliti ni b d ose d al o ne. T here was a n 
8 % a n d 2 7 % i ncrease i n t he C ma x a n d A U C of r u x oliti ni b, res pecti vel y , f oll o wi n g 
c oa d mi nistrati o n wit h er yt hr o m yci n, a m o derate C Y P 3 A 4 i n hi bit or, at 5 0 0 m g t wice dail y  f or 
4 da y s, c o m pare d t o r u x oliti ni b d ose d al o ne.
F or c urre nt i nf or mati o n a b o ut r u x oliti ni b, refer t o t he pac ka ge i nsert.
1. 4.
R ati o n ale f or t his S t u d y
Gilea d is c o n d ucti n g t his P hase 1 b st u d y t o e val uate t he safet y, t olera bilit y a n d P K of i delalisi b
i n s u bjects recei vi n g r u x oliti ni b as t hera p y f or P M F , p ost -P V M F , or p ost -E T M F w h o are 
mai ntai ne d o n a sta ble d ose of r u x oliti ni b f or at least 4 wee ks pri or t o i nitiati n g t hera p y wit h
i delalisi b. T h o u g h r u x oliti ni b has de m o nstrate d efficac y  i n patie nts wit h M F, t he res p o nses 
pri maril y  relate t o miti gati o n of s ple n o me gal y a n d c o nstit uti o nal s ym pt o ms. I n m ost patie nts, 
re versi o n of marr o w fi br osis a n d re d ucti o n of J A K 2V 6 1 7 F alle le b ur de n are n ot o bser ve d. 
T w o t o t hree ye ar i m pr o ve me nt i n s ur vi val has bee n o bser ve d i n r u x oliti ni b -treate d patie nts vs 
t h ose i nitiall y ra n d o mize d t o place b o ( C O M F O R T-I) or best a vaila ble t hera p y  ( C O M F O R T-II), 
w hic h ma y  be relate d t o i m pr o ve me nt of t he meta b olic pr ofile of patie nts. S u b o pti mal res p o nses 
ma y  i n part relate t o re-acti vati o n of J A K acti vit y t hr o u g h its heter o di merizati o n wit h 
J A K famil y  me m bers, a n d persiste nt acti vit y/ u pre g ulat o n of si g nali n g pat h wa ys, s uc h as 
PI 3 K/ A K T.
Precli nical data i n dicate t hat PI 3 K a n d/ or m T O R i n hi bit ors are acti ve a gai nst M P N cells a n d 
t heir c o m bi nati o n wit h J A K 1/ 2 i n hi bit ors pr o d uce d s yner gis m. T h us, c o nc ur re nt tar geti n g of 
PI 3 K a n d J A K/ S T A T pat h wa y s m a y  re prese nt a ne w t hera pe utic strate g y t o o pti mize efficac y 
a n d re d uce t o xicit y i n patie nts wit h M P N.
Idelalisi b at 5 0 m g o nce dail y , 5 0 m g t wice dail y, 1 5 0 m g o nce dail y , a n d 1 5 0 m g t wice dail y 
will be teste d i n t his st u d y. Gi ve n t he E C 9 0 f or PI3 K of a p pr o xi matel y 3 0 1 n M ( ~ 1 2 5 m g/ m L), 
t he me dia n tr o u g h c o nce ntrati o n f oll o wi n g 1 5 0 m g t wice daily was a b o ve t he E C 9 0 a n d t he 
me dia n tr o u g h c o nce ntrati o n f oll o wi n g 1 5 0 m g  o nce daily was bel o w t he E C 9 0. T o get her wit h 
5 0 m g o nce dail y , t he pr o p ose d d ose re gi me ns will facilitate t he e val uati o n of t he e x p os ure-
res p o nse relati o ns hi p i n t he st u d y p o p ulati o n o ver a wi de ra n ge of i delalisi b e x p os ures.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 3 0
2 6 Oct o ber 2 0 1 6
T he d oses of i delalisi b selecte d f or t his st u d y are i nf or me d by t he meta b olis m of i delalisi ba n d 
r u x oliti ni b a n d t he p ote ntial f or dr u g-dr u g i nteracti o n. T here are c urre ntl y  n o cli nical data o n 
m o n ot hera p y f or i delalisi b i n M F or t he c o m bi nati o n of i delalisi b a n d r u x oliti ni b. T he ref ore, t o 
mi ni mize t he e x p os ure of s u bjects t o t o xicities c o h ort e x pa nsi o n will occ ur se q ue ntiall y .
1. 5.
C o m pli a nce
T his st u d y  will be c o n d ucte d i n c o m plia nce wit h t his pr ot oc ol, G o o d Cli nical Practice ( G C P), 
a n d all a p plica ble re g ulat or y re q uire me nts.


I d elalisi b 
Pr o to c o l G S -U S- 3 9 7 -1 2 4 5 
Gi l e a d S c ie n c es, I n c. 
2. 
O B J E C TI V E S 
T h e pr i m a1y o bj e ct iv es of t his st u d y are as f oll o ws: 
Fi n al 
A m e n d m e nt 5 
• 
T o e v al uate t h e s af et y a n d t ol er a bilit y of id el alisi b t hr o u gh 2 8 da ys i n s ubj e cts re c ei vi n g 
r n x olitini b as t h er a p y f or i nte 1 me diate t o hi g h r is k P M F, p ost -P V M F , or p ost -E T M F wit h 
pr o gr essi v e or rela ps e d dis e as e 
• 
T o d et e n n i ne t h e P K of i d el alisi b a n d r nx oliti n i b, i n s ubj e cts r e c ei vi ng r nx olit i ni b wit h P M F , 
p ost -P V M F, or p ost- E T M F wit h pr o gr essi v e or r el a ps e d dis e as e 
T h e s e c o n d ai y o bj e cti v es of t his st u d y are as f oll o ws: 
• 
T o e v al uate t h e s af et y a n d t ol er a bilit y of c o nti nu o us d ail y a d mi nistr ati on of i d el alisi b b e y o n d 
2 8 d a ys i n s ubj e cts re c ei vi n g r n x oliti ni b wit h P M F, p ost -P V M F, or p ost- E T M F 
• 
T o e v al uate t h e effi c a c y of id el alisi b i n s u bjects recei vi ng r n x oliti ni b wit h PM F, 
p ost -P V M F, or p ost- E T M F b y 2 0 1 3 R e v is e d I W G- M R T a n d E L N r es p on s e crit eri a 
I 
C O N FI D E N TI A L 
P a g e 3 1 
2 6 O c to b er 2 0 1 6 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 3 2
2 6 Oct o ber 2 0 1 6
3.
S T U D Y  D E SI G N
3. 1.
E n d p oi nts
T he e n d p oi nts f or t his st u d y  are descri be d i n Secti o n 8 .
3. 2.
St u d y Desi g n
T his is a P hase 1 b, o pe n -la bel, d ose escalati o n st u d y. T he pla n ne d n u m ber of s u bjects i n eac h 
c o h ort is 6. T here will be 4 c o h orts ( A, B, C a n d D), w hic h will b e e nr olle d se q u e ntiall y. 
C o h ort A will be e nr olle d first.
Idelalisi b will be a d mi nistere d i n s u bjects recei vi n g r u x ol iti ni b as t hera p y f or P M F, p ost-P V M F,
or p ost -E T M F a n d w h o ha ve bee n mai ntai ne d o n a sta ble d ose of r u x oliti ni b f or at least 4
wee ks 
pri or t o st u d y  e ntr y. O n Da y  1 s u bjects will ha ve a P K sa m ple dra w n a n d t he n re d uce t he 
r u x oliti ni b d ose as f oll o ws:

S u bjects o n a sta ble r u x oliti ni b d ose of greater t ha n or e q ual t o 1 0 m g t wice dail y , will ha ve 
t heir r u x oliti ni b d ose re d uce d by 5 0 % (r o u n de d u p t o t he cl osest a vaila ble ta blet stre n gt h).

S u bjects o n a sta ble r u x oliti ni b d ose of 5 m g t wice dail y , will ha ve t heir r u x oliti ni b d ose 
re d uce d t o 5 m g  o nce dail y.
I delalisi b will be a d mi nistere d starti n g o n D a y 5.
P K sa m ples will be o btai ne d o n D a y s 1, 4 a n d 1 0 as s h o w n i n t he sc he ma bel o w:
T he sta rti n g d oses of I i delalisi b i n C o h orts A, B, C, a n d D are 5 0 m g o nce dail y, 5 0 m g  
t wice dail y, 1 5 0 m g o nce dail y , a n d 1 5 0 m g t wice dail y, res pecti vely. E nr oll me nt i nt o t he st u d y  
will be o n h ol d w hile t he safety re vie w tea m ( S R T ) e val uates t he data pri or t o c o h ort e x pa nsi o n 
a n d d ose escalati o n .
T he first 3 s u bjects will be e nr olle d i n C o h or t A at 5 0 m g o nce daily i delalisi b. After t he 
t hir d su bject has c o m plete d Da y  2 8 ( 4 wee ks), t he S R T will re vie w t he safet y data. E nr oll me nt 
will be o n h ol d u ntil t he S R T deter mi nes t he c o h ort ca n be e x pa n de d t o e nr oll a n a d diti o nal 
S c h e m a 
I S c re e ni n g 
S u bj e ct s ar e 
e ligi bl e f or t he 
s t ud y a fter 
m a i nta i ni ng a 
st a b l e r ux o lili nib 
d o s e f or at le a s t 
4 w e e k s p ri or t o 
s t ud y e nt r y 
D a y 1 
O b t ai n 
r ux o liti nib P K 
s a m p l e t he n 
re d u c e 
r ux o lili nib 
d o s e 
i 
O bt a i n r ux o liti nib 
P K s a m pl e s 
II 
I nitiat e i d el a lisi b 
d o s i n g 
D a y 1 0 
i 
O bt ai n r ux o liti nib & 
i d el alisi b P K s a m p le s 
S u b j ect c o nti n u e s o n 
s t ud y 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 3 3
2 6 Oct o ber 2 0 1 6
3 s u bjects. After t he si xt h s u bject i n C o h ort A c o m pletes Da y  5 6 ( 8 wee ks), the S R T will re vie w 
t he c u m ulati ve safet y a n d P K data fr o m all s u bjects i n C o h ort A. E nr oll me nt will be o n h ol d u ntil 
t he S R T deter mi nes C o h ort B ca n be o pe n t o e nr oll me nt. If t he S R T dee ms t he c o m bi nati o n of 
i delalisi b wit h r u x oliti ni b safe a n d t olera ble a t t he 5 0 m g o nce daily d ose, C o h or t B will be o pe n 
t o e nr oll me nt.
E nr oll me nt a n d safet y assess me nt b y t he S R T i n C o h ort B at 5 0 m g t wice dail y i delalisi b will 
pr ocee d as f oll o ws : T he first 3 s u bjects will be e nr olle d. After t he t hir d s u bject has c o m plete d
D a y 2 8 ( 4 wee ks), t he S R T will re vie w t he c u m ulati v e safet y data f or C o h orts A a n d B. 
E nr oll me nt will be o n h ol d u ntil t he S R T deter mi nes C o h ort B ca n be e x pa n de d t o e nr oll a n 
a d diti o nal 3 s u bjects. After t he si xt h s u bject i n C o h ort B c o m pletes Da y 2 8 ( 4 w ee ks), t he S R T 
will re vie w t he c u m ulati ve safet y data fr o m all s u bjects i n C o h orts A a n d B, a n d t he c u m ulati v e 
P K data f or C o h ort B. E nr oll me nt will be o n h ol d u ntil t he S R T deter mi nes C o h o rt C ca n be 
o pe n t o e nr oll me nt. If t he S R T dee ms t he c o m bi nati o n of i delalisi b wit h r u x oliti n i b safe a n d 
t olera ble at t he 5 0 m g  t wice daily d ose, C o h ort C will be o pe n t o e nr oll me nt.
E nr oll me nt a n d safet y assess me nt b y t he S R T i n C o h ort C at 1 5 0 m g o nce dail y i delalisi b will 
pr ocee d as f oll o ws: T he first 3 s u bjects will be e nr olle d. After t he t hir d s u bject has c o m plete d 
D a y 2 8 ( 4 wee ks), t he S R T will re vie w t he c u m ulati ve safet y data f or C o h orts A, B a n d C. 
E nr oll me nt will be o n h ol d u ntil t he S R T deter mi nes C o h ort C ca n be e x p a n de d t o enr oll a n 
a d diti o nal 3 s u bjects. After t he si xt h s u bject i n C o h ort B c o m pletes Da y 2 8 ( 4 wee ks), t he S R T 
will re vie w t he c u m ulati ve safet y data fr o m all s u bjects i n C o h orts A, B a n d C , a n d t he 
c u m ulati ve P K data f or C o h ort C. E nr oll me nt will be o n h ol d u nti l t he S R T deter mi nes C o h ort D
ca n be o pe n t o e nr oll me nt. If t he S R T dee ms t he c o m bi nati o n of i delalisi b wit h r u x oliti ni b safe 
a n d t olera ble at t he 1 5 0 m g o nce dail y d ose, C o h or t C will be o pe n t o e nr oll me nt.
E nr oll me nt a n d safet y assess me nt b y t he S R T i n Co h ort D at 1 5 0 m g t wice dail y i delalisi b will 
pr ocee d as f oll o ws : T he first 3 s u bjects will be e nr olle d. After t h e t hir d s u bject has c o m plete d 
D a y 2 8 ( 4 wee ks), t he S R T will re vie w t he c u m ulati ve safet y data f or C o h orts A, B, C a n d D. 
E nr oll me nt will be o n h ol d u ntil t he S R T deter mi nes C o h ort D ca n be e x pa n de d t o e nr oll a n 
a d diti o nal 3 s u bjects. After t he si xt h s u bject i n C o h ort C c o m pletes Da y 2 8 ( 4 wee ks), t he S R T 
will re vie w t he c u m ulati ve safet y data fr o m all s u bjects i n C o h orts A, B, C , a n d D , a n d t he 
c u m ulati ve P K data f or C o h ort D.
A d diti o nal c o h orts are n ot pla n ne d after e nr oll me nt i n C o h ort D is c o m plete. S u bjects w h o d o 
n ot recei ve ≥1 d ose of i delalisi b will be dee me d u ne val ua ble a n d re place d.
I n s u bjects wit h o ut de m o nstra ble cli nical be nefit, d ose escalati o n (t o a hi g her d ose c o h ort) ma y be 
per mitte d b y  t he S R T after C o h ort C (i delalisi b 1 5 0 m g o nce dail y ) has bee n f ull y e nr olle d a n d t he 
last s u bject has bee n o n st u d y dr u g f or at least 2 8 da ys. T he S R T will c o nsi der t he f oll o wi n g −t he 
s u bject’s c o m plia nce wit h t hera p y, t olera bilit y of t he c o m bi nati o n of i delalisi ba n d r u x oliti ni b, 
o verall i nci de nce a n d se verit y of A Es (relate d t o i delalisi b or r u x oliti ni b), d ose re d ucti o n f or 
se vere t o xicit y a n d d ose m o dificati o ns. A d diti o nall y , s u bjects m ust s h o w a lac k of res p o nse b y 
v ol u metric i ma gi n g (t hree di me nsi o nal [ 3 D] mag netic res o na nce i ma gi n g [ M RI] or c o m p ute d 
t o m o gra p h y [ C T], if M RI is n ot feasi ble), or b y pal pati o n of t he li ver a n d/ or s plee n after at least 
1 2 wee ks o n st u d y .


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal 
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 3 4
2 6 Oct o ber 2 0 1 6
T he S R T will c o nsist of at least o ne i n vesti gat or a n d t he f oll o wi n g Gilea d st u d y  tea m me m bers: 
t he me dical m o nit or, re prese ntati ves fr o m Dr u g Safet y  a n d P u blic Healt h (D S P H ), 
Cli nical O perati o ns, a n d Bi ostatistics. Ot hers ma y be i n vite d t o partici pate as m e m bers of t he 
S R T if a d diti o nal e x pertise is desire d. T he me dical m o nit or ser ves as t he c hair of t he S R T.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 3 5
2 6 Oct o ber 2 0 1 6
Fi g ure 3- 1.
St u d y Sc he m a
C o h ort A: 
ID E L A 5 0 m g o n c e d ail y 
3 S U b J e d s 
e nr oll e d 
I 3 S U b J e d s 
' 
e nr oll e d 
S af et y d at a , r e-.t e w art er all 3 s u b j,e <:t s 
c o m pl et e d a y 2 8 
C o h ort B: 
I D E L A 5 0 m g t wi c e d ail y 
3 s u D J e ct s 
e nr oll e d ' 
3 S U D J e ct s 
e nr oll e d 
S af el)' d at a r e vi e w all er all 3 s utii e ct s 
co m111e e d a y 2 8 
C o h ort O:  
I 
5 nf et y 1 > n d P K d alil r e vi e w 
aft er t h e, la:st , u bje ct • ~ 
C o h Ott C c o m p ! i 
2 8 d• yi 
w e e b), pri or 'O O il < >0 < > 
i 4: I tiO il 
I D E L A 1 5 0 m g t wi c e d ail y 
,.. J s u b J, e d s 
e nr oll e d 
3 s u b J e cl s 
e nr olt e d 
C o h ort C: 
l D E L A 1 5 0 m g o n c e cl arl y 
3 S U D Je d s 
e nr olle d 
3 sut >Jects 
e nr o n e o 
S af e 
d at a r e•Jf e w a!\ er all 3 s utl J e dt s 
C(l m pt et e c a y 2 8 
' 
S. af e · Oi!l a r e , e w afl er atl 3 s vt 1 J e d s 
c o m pl et e d a y 2 8 


I d elalisi b 
Pr ot o c o l G S -U S- 3 9 7 -1 2 4 5 
Gil e a d S c ie n c es, I n c. 
3. 3. 
S t u dy T r e at m e nt s 
Fi na l 
A m e n d m e nt 5 
T h e d os e of id el alisi b wi ll b e 5 0 m g o n c e d ail y ( C oh o 1t A), 5 0 m g t wic e d a il y ( C oh o 1t B), 
1 5 0 m g o n c e d ai l y ( C o h o 1t C) , a n d 15 0 m g t wic e d a il y ( C o h o 1t D) a d mi nist ere d or all y 
c on ti n u o usl y. T h e tr e at m ent p e ri o d f or i n divi d u al s u bje cts is e x p e ct e d t o b e 2 4 w e e ks i n 
d ur ati o n. S u bj e cts wi ll re c ei v e t h e first d os e of i d el alisi b o n D a y 5. 
T h e stu d y d m g, i d el alisi b, wi ll b e s up pli e d b y Gil e a d . T h e f o1 m u l ati o n, p a c k a g i ng, a n d d os i ng 
r e gi m en ar e d es c ri b e d i n S e ct i o n 5. 
T h e c o m p an i o n di u g , m x o litini b , will b e a c quir e d b y t h e i nv est ig at ors t hr o u g h c o m m erci all y 
a v aila bl e m e a n s. R u x olit i ni b wi ll b e a d mi nist er ed p e r stan d ar d of c ar e d uri n g s cre eni n g. 
O n D a y 1, t h e m x o liti ni b d os e wi ll b e re du c e d b y 5 0 % as d es cri b e d i n St u d y D esi g n 
( S e cti o n 3. 2 ). S u bj e cts wi ll c ont i n ue r u x olit i ni b d osi n g d ur i ng s cre eni n g a n d thr ou g h o ut t h e 
st u d y tre at m ent p er io d. 
3. 4. 
D u r ati o n of T r e at m e nt 
T h e d ur ati on of tr e at m ent f or i ndi vi d u al s ubj e cts is e x p e ct e d t o b e 2 4 w e e ks. 
T h e s cre eni n g p e ri o d is 2 8 d a ys, tr e at m ent p e ri o d is 2 4 w e e ks, a nd t h e s af et y f ollo w -u p p e ri o d is 
3 0 d a ys aft er th e e n d of st u d y ( EO S) visi t. S u bj e cts w h o ar e o n i d el alisi b b e y o n d w e e k 2 4 , a n d i n 
t h e o pi n i o n of t h e i nv esti g at o r ar e d e ri vi ng clini c al b e n efit, c a n r em a i n o n t h e stu d y a n d r e c ei v e 
b oth m x olit ini b a nd i d el a lisi b tr e at m ent f or t h e e xt en si on p er io d u n til dis e as e pr o gr essi o n. 
3. 5. 
Di sc o nti n u ati o n C rit e ri a f o r C o h o rt s 
T h e 4 c oh o 1ts ( A, B, C, a n d D) pl a n n e d f or thi s st u d y wi ll b e enr o lle d s e qu e nti a lly. C o h ort A wi ll 
b e t h e first c oh ort o p e n t o e nr o llm e n t. T h e S R T wi ll n ot o p e n C o h or ts B, C, or D t o enr oll m e nt if 
t h e c u mu l ati v e d at a r e v e als u n e x p e ct e d tre at m e nt -rel at e d A E t o i d el alisi b i n t h e pre c e di ng 
c oh o 1ts. 
3 . 6. 
S o u r c e D at a 
P ati e nt re p ort e d o u t c o m es d at a c o lle ct e d o n p a p e r will b e c on si d er e d s o ur c e data. 
C O N FI D E N TI A L 
P a g e 3 6 
2 6 O c to b er 2 0 1 6 


I d elalisi b 
Pr ot o c ol G S -U S- 3 9 7 -1 2 4 5 
Gil e a d S c i e nc es, I nc. 
C O N FI D E N TI A L 
P a g e 3 7 
Fi n al 
A m e n d m e nt 5 
2 6 O c to b er 2 0 1 6 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 3 8
2 6 Oct o ber 2 0 1 6
4.
S U B J E C T P O P U L A TI O N
4. 1.  
N u m ber of S u bjects a n d S u bject Selecti o n
A p p r o xi matel y 2 4 s u bjects w h o meet t he eli gi bilit y criteria will be e nr olle d.
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 i ncl usi o n criteria t o be eli gi ble f or partici pati o n i n t his 
st u d y:
1)
A ge ≥ 1 8 y ears of a ge
2)
S u bjects m ust ha ve bee n o n a sta ble d ose of r u x oliti ni b f or at least 4 wee ks pri or t o st u d y  
e ntr y
3)
S u bjects wit h P M F, p ost -P V M F,
or p ost -E T M F classifie d as hi g h ris k or i nter me diate ris k 
as defi ne d b y t he D y na mic I nter nati o nal Pr o g n ostic Sc ori n g S yste m ( DI PS S ) f or 
P M F (A p pe n di x 4 ) or DI P S S Pl us , if c yt o ge netics are a vaila ble (A p pe n di x 5 )
4)
S u bjects wit h P M F, p ost -P V M F,
or p ost - E T M F w h o are recei vi n g r u x oliti ni b a n d meet 
2 0 1 3 Re vise d I WG- M R T a n d E L N res p o nse criteria wit h pr o gressi ve a n d rela pse d disease, 
wi t h m o dificati o ns f or pr o gressi ve disease
a)
Pr o gressi ve disease:

A p peara nce of a ne w s ple n o me gal y t hat is pal pa ble at least 5 c m bel o w t he 
left c ostal mar gi n (L C M ), or

A ≥1 0 0 % i ncrease i n pal pa ble dista nce, bel o w L C M, f or baseli ne s ple n o me galy of 
5- 1 0 c m, or

A 5 0 % i ncrease i n pal pa ble dista nce, bel o w L C M, f or baseli ne s ple n o me gal y  of > 1 0 c m, 
or

A n i ncrease i n pal pa ble s ple n o me gal y fr o m best r u x oliti ni b res p o nse of > 2 5 % b ut < 5 0 % 
i n a s u bject w h o d oes n ot meet criteria f or co m plete re missi o n ( C R), partial remissi o n 
( P R), or cli nical i m pr o ve me nt ( CI)
b)
Rela pse d disease:

N o l o n ger meeti n g criteria f or at least CI  after ac hie vi n g C R, P R, or CI, or

L oss of a ne mia res p o nse persisti n g f or at least 1 m o nt h , or

L oss of s plee n res p o nse persisti n g f or at least 1 m o nt h


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 3 9
2 6 Oct o ber 2 0 1 6
5)
Life e x pecta nc y  > 2 4 wee ks i n t he o pi ni o n of t he i n vesti gat or
6)
E ur o pea n C o o perati ve O nc ol o g y  Gr o u p (E C O G) perf or ma nce stat us of ≤ 2
7)
Re q uire d scree ni n g la b orat or y val ues as s h o w n i n t he ta ble bel o w:
Or g a n S yste m
P a r a m eter
Re q uire d V al ue
He patic
Ser u m t otal bilir u bi n
≤1. 5 × U L N
( u nless ele vate d d ue t o Gil bert’s s y n dr o me or he m ol ysis)
Ser u m A L T
≤2. 5 × U L N
Ser u m A S T
H e m at o p oietic
A N C
≥ 1. 0 × 1 0 9/ L
Peri p heral bl o o d blast or
b o ne marr o w  bl o o d blast c o u nt
< 2 0 %
Platelets
≥ 5 0 × 1 0 9/ L
Re nal
eC Cr
a
≥3 0 m L / mi n
Pre g na nc y
β- h C G b
Ne gati ve
I nfecti o n
HI V
Ne gati ve HI V a nti b o d y
H B V
Ne gati ve H Bs A g a n d ne gati ve H Bc a nti b o d y , or p ositi ve 
H Bc a nti b o d y a n d ne gati ve H B V D N A b y q ua ntitati ve P C R
H C V
Ne gati ve viral R N A (if H C V a nti b o d y is p ositi ve)
C M V
Ne gati ve C M V P C R or p p 6 5 a nti ge n
a
As calc ulate d b y t he C oc kcr oft -Ga ult f or m ula or meas ure d
b
F or w o me n of c hil d beari n g p ote ntial o nl y
A b bre vi ati o ns: H Bc a nti b o d y =a nti -he patitis B c ore a nti b o d y
8)
F e male s u bjects of c hil d beari n g p ote ntial, willi n g t o use a pr ot oc ol -rec o m me n de d met h o d of 
c o ntrace pti o n d uri n g heter ose x ual i nterc o urse fr o m si g ni n g of i nf or me d c o nse nt t hr o u g h o ut 
t he st u d y treat me nt peri o d a n d t o 3 0 da y s fr o m t he last d ose of i delalisi b
(see A p pe n di x 1 0 f or m ore i nf or mati o n)
9)
M ale s u bjects ha vi n g i nterc o urse wit h fe males of c hil d beari n g p ote ntial, willi n g t o use a 
pr ot oc ol rec o m me n de d met h o d of c o ntrace pti o n fr o m Da y 1 t hr o u g h o ut t he st u d y  treat me nt 
peri o d a n d f or 9 0 da y s f oll o wi n g t he last d ose of i delalisi b a n d t o refrai n fr o m s per m 
d o nati o n fr o m D a y 1 t hr o u g h o ut t he st u d y  treat me nt peri o d a n d f or 9 0 d a y s f oll o wi n g t he last 
d ose of i delalisi b (see A p pe n di x 1 0 f or m ore i nf or mati o n)
1 0) I n t he j u d g me nt of t he i n vesti gat or, partici pati o n i n t he pr ot ocol offers a n acce pta ble 
be nefit -t o-ris k rati o w he n c o nsi deri n g c urre nt mye l ofi br osis disease stat us, me dical 
c o n diti o n, t he p ote ntial be nefits a n d ris ks of alter nati ve treat me nts f or m y el ofi br osis


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 4 0
2 6 Oct o ber 2 0 1 6
1 1) Willi n g a n d a ble t o c o m pl y  wit h sc he d ule d visits, dr u g a d mi nistrati o n pla n, i ma gi n g st u dies, 
la b orat or y tests, ot her st u d y  pr oce d ures, a n d st u d y restricti o ns , i ncl u di n g ma n dat or y 
pr o p h y la xis f or PJ P  
1 2) A ble t o u n dersta n d a n d willi n g t o si g n t he i nf or me d c o nse nt f or m
4. 3. 
E xcl usi o n Criteri a
S u bjects w h o meet a n y of t he f oll o wi n g e xcl usi o n criteria are n ot t o be e nr olle d i n t his st u d y .
1)
S u bjects o n a sta ble r u x oliti ni b d ose of 5 m g o nce dail y
2)
Hist or y  of pri or all o ge neic b o ne marr o w pr o ge nit or cell or s oli d or ga n tra ns pla ntati o n
3)
O n g oi n g dr u g -i n d uce d li ver i nj ur y, alc o h olic li ver disease, n o n-alc o h olic steat o he patitis, 
pri mar y biliar y  cirr h osis, e xtra he patic o bstr ucti o n ca use d b y ch olelit hiasis, cirr h osis of 
t he li ver
4)
O n g oi n g dr u g -i n d uce d p ne u m o nitis
5)
O n g oi n g i nfla m mat or y  b o wel disease
6)
O n g oi n g alc o h ol or dr u g a d dicti o n
7)
C M V: O n g oi n g i nfecti o n, treat me nt, or pr o p h yl a xis wit hi n t h e past 2 8 da ys 
8)
U nc o ntr olle d i nterc urre nt ill ness i ncl u di n g, b ut n ot li mite d t o, acti ve u nc o ntr olle d bacterial, 
f u n gal, or viral i nfecti o n, or acti ve or c hr o nic blee di n g e ve nt wit hi n 4 wee ks pri or t o first 
d ose of i n vesti gati o nal me dici nal pr o d uct (I M P) t h at w o ul d li mit c o m plia nce wit h st u d y  
re q uire me nts as j u d ge d b y t he treati n g p h ysicia n
9)
Hist or y  of a c o nc urre nt or sec o n d mali g na nc y e xce pt f or a de q uately treate d l ocal basal cell or 
s q ua m o us cell carci n o ma of t he s ki n, cer vical carci n o ma i n sit u, s u perficial bla d der ca ncer, 
as ym pt o matic pr ostate ca ncer wit h o ut k n o w n metastatic disease a n d wit h n o re q uire me nt f or 
t hera py or re q uiri n g o nl y h or m o nal t hera p y a n d wit h n or mal pr ostate -s pecific a nti ge n f or 
≥1 ye ar, a de q uatel y treate d Sta ge 1 or 2 ca ncer c urre ntl y i n c o m plete re missi o n, or a n y ot her 
ca ncer t hat has been i n c o m plete re missi o n f or ≥ 5 ye ars
1 0) Partici pati o n i n a n o n g oi n g i n vesti gati o nal dr u g or de vice trial or use wit hi n 6 wee ks of 
c he m ot hera p y ( wit h e xce pti o n ma de f or h ydr o x y u rea, see Secti o n 5. 4. 6 ),
i n vesti gati o nal a ge nt, i m m u n o m o d ulati n g t hera py, bi ol o gic t hera p y or ra diati o n t hera py . 
E r yt hr o p oieti n sti m ulati n g a ge nts ( E S A) are all o we d as l o n g as a s u bject has bee n o n a sta ble 
d ose f or a mi ni m u m of 1 2 wee ks f or t he treat me nt of a ne mia.
1 1) S y m pt o matic c o n gesti ve heart fail ure 
( Ne w Y or k H eart Ass ociati o n Classificati o n > Class II), u nsta ble a n gi na, or u nsta ble car diac 
arr h yt h mia re q uiri n g me dicati o n


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 4 1
2 6 Oct o ber 2 0 1 6
1 2) K n o w n h y perse nsiti vit y  t o t he st u d y I M P, t he meta b olites, or f or m ulati o n e xci pie nts
1 3) U n willi n g or u na ble t o ta ke oral me dicati o n
1 4) U nres ol ve d n o n -he mat ol o gic t o xicities fr o m pri or t hera pies t hat are 
> C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts (C T C A E ) Gra de 1 ( wit h t he e xce pti o n 
of al o pecia [Gra de 1 or 2 per mitte d] )
1 5) Pre g na nt or lactati n g fe males


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 4 2
2 6 Oct o ber 2 0 1 6
5.
I N V E S TI G ATI O N A L  M E DICI N A L  P R O D U C T S
5. 1.
Descri pti o n a n d H a n dli n g of Idel alisi b a n d R u x oliti ni b
5. 1. 1.
F o r m ul ati o n
Idelalisi b will be pr o vi de d i n ta blet f or m i nte n de d f or oral a d mi nistrati o n. Eac h ta blet c o ntai ns 
5 0 m g, 1 0 0 m g, or 1 5 0 m g  of acti ve i delalisi b. T he 5 0 m g a n d 1 5 0 m g ta blets will be use d f or 
i nitial t herap y ; t he 1 0 0 m g  ta blets are pr o vi de d f or use b y t h ose s u bjects w h o re q uire a d ose 
re d ucti o n (see Ta ble 5- 1 ).
T he 5 0 m g a n d 1 5 0 m g ta blets are pi n k; t he 1 0 0 m g ta blets ar e ora n ge. B ot h ta blets are 
fil m-c oate d, a n d i ncl u de t he f oll o wi n g i nacti ve e xci pie nts: micr ocr y stalli ne cell ul ose, 
h y dr o x y p r o pyl  cell ul ose, cr oscar mell ose s o di u m, s o di u m starc h glyc ol ate, ma g nesi u m stearate, 
re d ir o n o xi de ( 5 0 m g a n d 1 5 0 m g ta blets o nl y), F D & C Yell o w # 6/ S u nset Yell o w F C F
Al u mi n u m La ke ( 1 0 0 m g ta blets o nl y ), p olyet h yl e ne gl yc ol, talc, p ol y vi n y l alc o h ol ( P V A), a n d 
tita ni u m di o xi de.
Refer t o t he r u x oliti ni b pac ka ge i nsert f or t he r u x oliti ni b f or m ulati o n.
5. 1. 2.
P a c k a gi n g a n d L a beli n g
Idelalisi b ta blets are pac ka ge d i n w hite, hi g h de nsit y p olyet h yl e ne ( H D P E) b ottles. Eac h b ottle 
c o ntai ns 6 0 ta blets of o ne of t he rele va nt d ose stre n gt hs (5 0 m g, 1 0 0 m g, or 1 5 0 m g ) a nd 
p ol y ester pac ki n g material. Eac h b ottle is e ncl ose d wit h a w hite, c o nti n u o us -t hrea d, 
c hil d-resista nt, p ol y pr o p y le ne scre w ca p wit h a n i n d ucti o n -seale d a n d al u mi n u m face d li ner.
St u d y  dr u g (i delalisi b) t o be distri b ute d t o ce nters i n t he U S will be la bele d t o meet a p plica ble 
re q uire me nts of t he U nite d States F o o d a n d Dr u g A d mi nistrati o n ( F D A) a n d/ or ot her l ocal 
re g ulati o ns.
Refer t o t he r u x oliti ni b pac ka ge i nsert f or r u x oliti ni b pac ka gi n g a n d la beli n g.
5. 1. 3.
St or a ge a n d H a n dli n g
Idelalisi b s h o ul d be st ore d at c o ntr olle d r o o m te m perat ure of 2 5° C ( 7 7° F); e xc ursi o ns are 
per mitte d bet wee n 1 5° C a n d 3 0° C ( 5 9° F a n d 8 6 ° F). St ora ge c o n diti o ns are s pecifie d o n t he la bel. 
U ntil dis pe nse d t o t he s u bjects, all b ottles of st u d y  dr u gs s h o ul d be st ore d i n a sec urel y l oc ke d 
area, accessi ble o nl y t o a ut h orize d site pers o n nel. T o e ns ure t he sta bilit y a n d pr o per 
i de ntificati o n, st u d y dr u g(s) s h o ul d n ot be st ore d i n a c o ntai ner ot her t ha n t he c o ntai ner i n w hic h 
t he y were s u p plie d.
Refer t o t he r u x oliti ni b pac ka ge i nsert f or r u x oliti ni b st ora ge a n d ha n dli n g.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 4 3
2 6 Oct o ber 2 0 1 6
5. 2.
D os a ge a n d A d mi nistr ati o n of I del alisi b
T he cli nic p har macist or a n alter nati ve q ualifie d pers o n will be res p o nsi ble f or dis pe nsi n g
i delalisi b. Ta blets s h o ul d be ke pt i n t he ori gi nal b ottles pr o vi de d.
5. 2. 1.
D osi n g I nstr ucti o ns
T he prescri be d d ose of idelalisi b will be ta ke n orall y . At eac h d ose a d mi nistrati o n, i delalisi b is t o 
be s wall o we d w h ole wit h 1 2 0 t o 2 4 0 m L  (a p pr o xi matel y 4 t o 8 o u nces) of water. I n case of 
brea ka ge of t he ta blets i n t he oral ca vit y, a d diti o nal wa ter s h o ul d be ta ke n as a ri nse.
Idelalisi b ma y  be ta ke n wit h or wit h o ut f o o d. T here are n o k n o w n dietar y restricti o ns relate d t o 
st u d y dr u g use. W he n i delalisi b is d ose d o nce dail y , it will be ta ke n i n t he m or ni n g. W he n 
i delalisi b is d ose d t wice dail y  it s h o ul d be ta ke n at a p pr o xi matel y t he sa me ti mes eac h d a y .
I deall y, d oses s h o ul d be ta ke n at a p pr o xi mat el y 1 2 h o ur i nter vals (e g, at 7 A M a n d at 7 P M).
At s pecifie d cli nic visits, i delalisi b a n d/ or r u x oliti ni b will be a d mi nistere d i n t he cli nic at t he 
sa me ti me wit h d osi n g a p pr o priatel y ti me d relati ve t o bl o o d sa m pli n g f or p har mac o ki netics. 
C li nic staff will rec or d i delalisi b a n d r u x oliti ni b a d mi nistrati o n i nf or mati o n, i ncl u di n g t he e xact 
cl oc k ti me of eac h d ose, f or d oses a d mi nistere d i n t he cli nic or h os pital. Pri or t o t hese visits, 
s u bjects will be re mi n de d n ot t o ta ke t heir m or ni n g d ose of i delalisi b a n d/ or r u x oliti ni b bef ore 
c o mi n g i nt o t he cli nic. S u bjects will als o be re mi n de d t o bri n g i delalisi b a n d r u x oliti ni b wit h 
t he m t o cli nic f or d osi n g. T hereafter, s u bjects will be gi ve n a n a de q uate s u p pl y  of ta blets t o ta ke 
at h o me.
S u bjects w h o ha ve a dela y  i n a d mi nistrati o n of i delalisi b of < 6 h o urs s h o ul d ta ke t he pla n ne d 
d ose as s o o n as p ossi ble after t he i nte n de d ti me of a d mi nistrati o n. F or s u bjects w h o ha ve a dela y  
i n a d mi nistrati o n of i delalisi b of 6 h o urs, t he d ose s h o ul d n ot be ta ke n. Idelalisi b
a d mi nistrati o n ma y c o nti n ue b ut t he misse d d ose s h o ul d n ot be ma de u p a n d t he pla n ne d ti mi n g 
of s u bse q ue nt st u d y  dr u g d osi n g s h o ul d n ot be altere d. V o mite d d oses ma y be reta ke n, b ut o nl y  
if t he ta blet is visi ble i n t he v o mit us.
S u bjects will c o nti n ue o n t he sa me sc he d ule of a d mi nistrati o n of r u x oli ti ni b pri or t o i nitiati o n of
i delalisi b. Refer t o t he r u x oliti ni b pac ka ge i nsert f or a d diti o nal i nf or mati o n o n r u x oliti ni b d osa ge 
a n d a d mi nistrati o n.
5. 2. 2.
D ose Le vels
I delalisi b d ose le vels a n d ta blet n u m bers f or all t he c o h orts are pr o vi de d i n Ta ble 5- 1 . T he l o wer 
d ose le vel ( D ose Le vel −1) is pr o vi de d i n case a s u bject re q uires i delalisi b d ose m o dificati o n. 
D ose m o dificati o ns ma y  be ma de i n res p o nse t o t o xicit y as descri b ed bel o w
(Ta ble 5- 1 a n d Ta ble 5 - 2).


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 4 4
2 6 Oct o ber 2 0 1 6
T a ble 5- 1.
I del alisi b D ose Re d ucti o n Al g orit h m
C o h ort A
D ose Le vel
D osi n g Re gi me n
T a blet Stre n gt h
T a blet N u m ber Per D ose
Starti n g d ose
5 0 m g/ d ose o nce dail y
5 0 m g
1
−1
N o d ose re d ucti o n per mitte d
N ot a p plica ble
N ot a p plica ble
C o h ort B
D ose Le vel
D osi n g Re gi me n
T a blet Stre n gt h
T a blet N u m ber Per D ose
Starti n g d ose
5 0 m g/ d ose BI D
5 0 m g
1
−1
5 0 m g/ d ose o nce dail y
5 0 m g
1
C o h ort C
D ose Le vel
D osi n g Re gi me n
T a blet Stre n gt h
T a blet N u m ber Per D ose
Starti n g d ose
1 5 0 m g/ d ose o nce dail y 
1 5 0 m g
1
−1
1 0 0 m g/ d ose o nce dail y 
1 0 0 m g
1
C o h ort D
D ose Le vel
D osi n g Re gi me n
T a blet Stre n gt h
T a blet N u m ber Per D ose
Starti n g d ose
1 5 0 m g/ d ose BI D
1 5 0 m g
1
−1
1 0 0 m g/ d ose BI D
1 0 0 m g
1
If a s u bject e x perie nces a n A E t hat is s us pecte d t o be relate d t o i delalisi b d uri n g t he c o urse of 
st u d y, t he n i delalisi b a d mi nistrati o n will be ma na ge d as i n Ta ble 5- 2 .
After a n i delalisi b d ose re d ucti o n, t he d ose nee d n ot be re -escalate d, e ve n if t here is mi ni mal or 
n o t o xicit y  wit h t he re d uce d d ose. H o we ver, if t he s u bject t olerates t he l o wer d ose le vel of 
i delalisi b f or ≥4 wee ks, t he n t he d ose ma y be i ncrease d t o t he starti n g d ose, at t h e discreti o n of 
t he i n vesti gat or. S uc h a re-escalati o n ma y be partic ularl y warra nte d if f urt her e val uati o n re veals 
t hat t he A E t hat le d t o t he d ose re d ucti o n was n ot relate d t o i delalisi b.
5. 3.
D ose A dj ust me nts
T he d ose a dj ust me nt rec o m me n dati o ns i n Ta ble 5- 2 are base d o n t he C T C A E v 4. 0 3
(A p pe n di x 1 1 ). H o we ver, e xce pti o ns are e x pecte d f or s u bjects w h o i nitiate st u d y treat me nt wit h 
l o w bl o o d c o u nts. Cli nical j u d g me nt s h o ul d a p ply, a n d i n cases of u ncertai nt y , t he st u d y me dical 
m o nit or s h o ul d be c o ntacte d.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 4 5
2 6 Oct o ber 2 0 1 6
T he d o se m o dificati o n i nstr ucti o ns f oc us o n t he t y pes of e ve nts m ost c o m m o nl y attri b ute d t o
i delalisi b. T he ma na ge me nt f or i delalisi b attri b ute d a d verse e ve nts is pr o vi de d i n Ta ble 5- 2 a n d 
c o m prises re q uire d a n d rec o m me n de d acti o ns. V ariati o ns ma y be warra nte d base d o n a n 
i n vesti gat or’s i n di vi d ual j u d g me nt i n c o nsi deri n g p ote ntial ris ks, be nefits, a n d t hera pe utic 
alter nati ves a vaila ble t o eac h s u bject ; variati o n fr o m t he g ui deli nes o utli ne d i n Ta ble 5- 2 re q uires
writte n a p pr o val fr o m t he Gilea d me dical m o nit or .
If i delalisi b or r u x oliti ni b is wit h hel d f or m ore t ha n 4 c o nsec uti ve wee ks d ue t o treat me nt-relate d 
t o xicit y, it will be per ma ne ntl y disc o nti n ue d.
If i delalisi b or r u x oliti ni b is wit h hel d f or reas o ns ot her t ha n treat me nt- relate d t o xicit y f or m ore 
tha n 4 c onsec uti ve wee ks eit her dr u g ma y  be restarte d wit h ap pr o val fr o m t he 
Gilea d me dical m o nit or.
T a ble 5 - 2.
I del alisi b D ose A dj ust me nt G ui deli nes
N CI C T C A E v 4. 0 3 Gr a de
Re q uire d Acti o n
Rec o m me n de d Acti o n
H E M A T O L O GI C A L A D V E R S E E V E N T S:
Ne utr o pe ni a
a
Gra de ≤ 2 ne utr o pe nia
Mai ntai n c urre nt d ose le vel a n d sc he d ule.
Gra de 3 ne utr o pe nia  
Mai ntai n c urre nt d ose le vel a n d sc he d ule. 
M o nit or C B C
at least wee kl y u ntil
ne utr o pe nia has rec o vere d t o Gra de 2 .
Gra de 4 ne utr o pe nia
( or occ urre nce of ne utr o pe nic 
fe ver or i nfecti o n)
I nterr u pt i delalisi b d osi n g.
M o nit or C B C wee kl y u ntil ne utr o pe nia 
has i m pr o ve d t o ≤Gra de 2. 
Idelalisi b d osi n g ma y be res u me d at a 
l o wer d ose le vel w he n A N C gra de is 
≤Gra de 3.
T hr o m b oc yt o pe ni a
a
Gra de ≤ 3
Mai ntai n c urre nt d ose le vel a n d sc he d ule.
Gra de 4
Wit h h ol d f or br uisi n g or blee di n g relate d 
t o i delalisib al o n g wit h a de q uate rec o ver y 
of t hr o m b oc yt o pe nia ( Gra de ≤3 ).
Ma y res u me i delalisi b at i nitial or
l o wer 
d ose le vel at i n vesti gat or discreti o n.
N O N -H E M A T O L O GI C A L A D V E R S E E V E N T S:
Der m at ol o gic al
R as h
Gra de ≤ 2
Mai ntai n c urre nt d ose le vel a n d sc he d ule.
Gra de ≥ 3
Wit h h ol d i delalisi b a n d m o nit or at least 
o nce w ee kl y u ntil ras h  Gra de ≤ 1
M a y  res u me at l o wer d ose le vel 
( C o h orts B, C, a n d D) or disc o nti n ue 
i delalisi b at i n vesti gat or discreti o n.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 4 6
2 6 Oct o ber 2 0 1 6
N CI C T C A E v 4. 0 3 Gr a de
Re q uire d Acti o n
Rec o m me n de d Acti o n
Ste ve ns -J o h ns o n S y n dr o me ( S J S) / T o xic E pi derm a l Necr ol ysis ( T E N)
A n y Gra de 
1.
Disc o nti n ue i delalisi b.
2.
I nterr u pt c oa d mi nistere d 
me dicati o ns p ote ntiall y ass ociate d 
wit h SJ S or T E N. 
3.
I nstit ute treat me nt per i nstit uti o nal 
sta n dar ds
Di arr he a or c olitis
A n y Gra de
1.
O btai n hist or y of o nset a n d d urati o n 
of diarr hea, i ncl u di n g descri pti o n of 
n u m ber of st o ols a n d st o ol 
c o m p ositi o n (e g, water y, bl o o d y, 
n oct ur nal), tra vel hist or y, dietar y 
c ha n ges a n d a me dicati o n re vie w t o 
i de ntif y p ossi ble diarr he o ge nic 
a ge nts.
2.
Perf or m p h ysical e xa mi nati o n 
i ncl u di n g assess me nt f or fe ver, 
dizzi ness, a b d o mi nal pai n/cra m pi n g, 
a n d wea k ness ( e. g., e val uate f or 
se psis, b o wel o bstr ucti o n, 
de h y drati o n) .
1.
Pr o vi de a nti -diarr heal a n d mai ntai n 
c urre nt i delalisi b d ose le vel a n d 
sc he d ule.
2.
Differe ntiate bet wee n s mall -b o w el 
a n d lar ge -b o wel diarr hea o n a 
cli nical basis.  If u nclear, c o nsi der 
u p per a n d l o w er tract e n d osc o p y 
wit h bi o ps y.
-S mall b o wel diarr hea is 
c haracterize d b y lar ge v ol u me 
diarr hea ( m ore t ha n o ne per da y), 
p ossi ble ass ociate d de h y drati o n, 
wei g ht l oss a n d para u m bilical pai n.   
C o nsi der a n e n d osc o pic s mall -
b o w el bi o ps y a n d e val uate ot her 
eti ol o gies s uc h as celiac disease.
-Lar ge -b o w el diarr hea ma y prese nt 
wit h l o wer pel vic pai n, te nes m us, 
a n d ge nerall y s maller st o ol 
v ol u mes wit h gr oss bl o o d 
fre q ue ntl y f o u n d i n t he st o ol. 
C o nsi der  a c ol o n osc o pic 
e val uati o n a n d bi o ps y.
3.
E ns ure g o o d h y drati o n stat us
Gra de ≥ 2 diarr hea or c olitis 
( u nless cli nical dia g n osis is 
esta blis he d fr o m me dical 
hist or y a n d p h ysical 
e xa mi nati o n)
1.
St o ol c ult ure f or r o uti ne pat h o ge ns 
( Sal m o nella, S hi gella, 
Ca m p yl o bacter s pecies), testi n g f or 
Cl ostri di u m difficile t o xi n, 
R ota vir us, C yt o me gal o vir us ( C M V), 
a n d A de n o vir us 
2.
St o ol f or O va a n d Parasites 
( Cr y pt os p ori di u m par v u m, Is os p ora 
belli, E nter oc yt oz o o n bie ne usi, 
Se ptata i ntesti nalis, Str o n g yl oi des, 
Micr os p ori dia, E nta m oe ba 
hist ol ytica, C ycl os p ora), Giar dia 
a nti ge n


I d el alisi b 
Pr ot o c ol G S -U S - 3 9 7-1 2 4 5 
Gil e a d S ci e n c e s, I n c. 
N C I C T C A E v 4 . 0 3 G r a d e 
R e q ui r e d A c tio n 
Gr a d e ~ 3 diaI T hea or c olitis 
or p er sist e nt Gr a d e 2 
dir u T hea or c olitis with o ut 
cl e ar eti ol o g y 
B o w e l P e l "f or atio n 
1. 
Wit h h ol d i d el alisi b. 
2. 
C o nsi d er a nti-dir u T heal 
(e g, l o p er a mi d e) a n d/ or a d diti o n of 
a nti-i nfl a m m at or y a g e nt 
( e g, sulf a sal a zi n e , b u d e so ni d e ). 
I Di sc o nti n u e i d el alisi b. 
R e c o m m e n d e d A c tio n 
Fi n al 
A m e n d m e nt 5 
1. 
E n d o sc o p y w it h bi o p s y is str o n gl y 
r e c o m m e n d e d t o a sses b y 
i m m u n o hist o c h e misti y (I H C) a n d 
P C R f or C M V , A d e n o v ir us. 
I 
3. 
At Gr a d e ~ l , m a y r esu m e 
i d el alisi b at l ow er d os e or 
di sc o nti n u e at i nv esti g at or 
di screti o n. 
H E P A TI C A D V E R S E E V E N T S ( EL E V A TI O N S I N A L T , A S T, O R BI LI R U BI N) : 
Gra de'.', 2 
M o nit or A L T , A S T , A L P , a n d bilir n bi n 
(A L T /A S T > 3- 5 x U L N) 
at least w e e kly u ntil all ab n or m ali ties 
( Bilir n bi n > l. 5- ~ 3 x U L N) 
ar e Gr a d e ~ l . T h er e aft er , m ai nt ai n 
c w Te nt d os e l ev el. 
Gr a d e 3 
1. 
Wit h h ol d i d el alisi b. 
(A L T /A S T > 5- 2 0 x U L N) 
2. 
M o nit or A L T , A S T, A L P , a n d 
( Bilir n bi n > 3- l 0 x U L N) 
bilir n bi n at least we e kly u n til all 
a b n or m aliti es ar e Gr a d e ~ l . 
3. 
If bilir n bi n a b n or m alit y w as 
Gr a d e < 3, r esu m e i d el ali si b at 
sa m e d o se l ev el. If bilir n bi n 
a b n or m alit y w as Gr a d e ~ 3 , resu m e 
i d el alisi b at l ow er d o se l ev el 
(C o h or ts B, C, a n d D) or r e-
c h all e n g e at s a m e d o se l ev el 
(C o h ort A). 
Gr a d e 4 
1. 
Wit h h ol d i d el alisi b. 
If bilir n bi n a b n or m alit y w as Gr a d e < 4, 
(A L T / A S T > 2 0 xU L N) 
2. 
M o nit or A L T , A S T, A L P , a n d 
r esu m e i d el alisi b at l ow er d o se l ev el 
( Bilir n bi n >  l 0 x U L N) 
bilir n bi n at least we e kly u n til all 
(C o h or ts B, C, a n d D), r e- c h all e n g e at 
a b n or m aliti es ar e Gr a d e 
1. 
sa m e d o se l ev el (C o h ort A). 
3. 
If bilir n bi n a b n or m alit y w as Gr a d e 4, 
di sc o nti n u e i d el alisi b 
P n e u m o niti s ( wit h ne w o n s et o r w o rs eni n g of b as e li ne dys p n e a , co u g h, 0 1· h y p o xi a wit h o ut o b vi o us i nf e cti o us 
c a u s e) 
Gr a d e 1 (asy m pt o m ati c ) 
Gr a d e ~ 2 
C O N FI D E N TI A L 
Wit h h ol d i d el alisi b u n til resol uti o n t o 
b a seli ne. M a y r esu m e at l ow er d o se l ev el 
or di sc o nti n u e at i nve sti g ator di scr eti o n. 
Di sc o nti n u e i d el alisi b p er m a n e ntl y i n 
su bj e ct s wit h a ny s e v erit y of 
s ym pt o m ati c p n e u m o niti s a n d i nstit ut e 
tlrera p y as cli ni c ally a p pr o pri ate. 
P a g e 4 7 
2 6 O c to b er 2 0 1 6 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 4 8
2 6 Oct o ber 2 0 1 6
N CI C T C A E v 4. 0 3 Gr a de
Re q uire d Acti o n
Rec o m me n de d Acti o n
P ne u m oc ystis p ne u m o ni a
A n y Gra d e
Disc o nti n ue i delalisi b
C M V i nfecti o n b / Re acti v ati o n
A n y Gra de
1.
I nterr u pt i delalisi b u p o n u ne q ui v ocal 
cli nical or la b orat or y e vi de nce of 
C M V i nfecti o n.
2.
Treat acc or di n g t o esta blis he d 
cli nical g ui deli nes.
3.
If t he be nefits of res u mi n g i delalisi b  
are j u d ge d t o o ut wei g h t he ris ks, 
c o nsi derati o n s h o ul d be gi ve n t o 
a d mi nisteri n g pre -e m pti ve C M V 
t hera p y
O T H E R N O N -H E M A T O L O GI C A L A D V E R S E E V E N T S:
Gra de ≤2
Mai ntai n c urre nt d ose le vel a n d sc he d ule
a n d mo nit or at least w ee kl y u ntil res ol ve d.
Gra de ≥3
If felt t o be relate d t o i delalisi b, wit h h ol d i delalisi b u ntil Gra de ≤ 1. Ma y res u me 
i delalisi b at sa me or l o w er d ose le vel or disc o nti n ue i delalisi b at i n vesti gat or 
discreti o n.
a
Refer t o A p pe n di x 1 1 f or C T C A E 4. 0 3 gra di n g
b
C M V s h o ul d be dia g n ose d usi n g cli nical or la b orat or y criteria per esta blis he d i nstit uti o nal sta n dar d .
T here will be n o d ose re d ucti o ns f or s u bjects i n C o h ort A at 5 0 m g o nce dail y idelalisi b . 
M o dificati o ns t o r u x oliti ni b d osi n g will be base d o n its pac ka ge i nsert .
5. 4. 
Pri or a n d C o nc o mit a nt Me dic ati o ns
T o t he e xte nt p ossi ble, a d mi nistrati o n of a n y prescri pti o n or o ver -t he-c o u nter dr u g pr o d ucts ot her 
t ha n st u d y me dicati o n s h o ul d be mi nimize d d uri n g t he st u d y peri o d. S u bjects s h o ul d be 
disc o ura ge d fr o m use of street dr u gs, her bal re me dies, self- prescri be d dr u gs, t o bacc o pr o d ucts, or 
e xcessi ve alc o h ol at a n y t i me d uri n g t he cli nical st u d y of idelalisi b .
If c o nsi dere d necessar y f or t he s u bject’s well- bei n g, dr u gs f or c o nc o mita nt me dical c o n diti o ns or 
f or sy m pt o m ma na ge me nt ma y  be gi ve n at t he discreti o n of t he i n vesti gat or. T he decisi o n t o 
a ut h orize t he use of a n y dr u g ot her t ha n idelalisi b or r u x oliti ni b s h o ul d ta ke i nt o acc o u nt s u bject
safety, t he me dical nee d, t he p ote ntial f or dr u g i nteracti o ns, t he p ossi bilit y f or mas ki n g 
s ym pt o ms of a m ore s i gnifica nt u n derl yi n g e ve nt, a n d w het her use of t he dr u g will c o m pr o mise 
t he o utc o me or i nte grity of t he st u d y .
S u bjects s h o ul d be i nstr ucte d a b o ut t he i m p orta nce of t he nee d t o i nf or m t he cli nic staff of t he 
use of a n y dr u gs or re me dies ( w het her prescri be d, o ver -t he-c o u nter, or illicit) bef ore a n d d uri n g 
t he c o urse of t he st u d y. A n y  c o nc o mita nt dr u gs ta ke n b y a s u bject d ur i n g t he c o urse of t he st u d y 
a n d t he reas o n f or use will be rec or de d o n t he electr o nic case re p ort f or ms (e C R Fs).


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 4 9
2 6 Oct o ber 2 0 1 6
I nf or mati o n re gar di n g use or restricti o ns o n s pecific c o nc o mita nt me dicati o ns, dietar y meas ures, 
or ot her i nter ve nti o ns is pr o vi de d bel o w.
5. 4. 1.
A nti c a ncer or E x peri me nt al T her a pies Ot her t h a n I del alisi b
N o ot her a ntica ncer t hera pies (i ncl u di n g c he m ot hera py, ra diati o n, a nti b o d y t hera p y, 
i m m u n ot hera p y, or ot her e x peri me ntal t hera pies) of a n y ki n d are per mitte d w hile t he s u bject is 
o n st u d y e xce pt as i n d icate d i n Secti o n 5. 4. 6 . S u bjects are n ot all o we d t o partici pate c o nc urre ntl y 
i n a n y ot her t hera pe utic cli nical st u d y.
5. 4. 2.
A ntie metics
Na usea a n d/ or v o miti n g ha ve n ot bee n c o m m o nl y o bser ve d wit h idelalisi b i n pri or st u dies. 
H o we ver, s u bjects w h o e x perie nce na usea or v o miti n g w hile o n st u d y will be ma na ge d base d o n 
t he j u d g me nt of t he treati n g p hys icia n a n d l ocal i nstit uti o nal practices.
5. 4. 3.  
Gr a n ul oc yte C ol o n y- Sti m ul ati n g F act ors a n d Er yt hr o p oieti n
Gra n ul oc y te-macr o p ha ge c ol o n y -sti m ulati n g fact ors ( G M- C S F) s h o ul d n ot be a d mi nistere d 
gi ve n t he p ote ntial f or G M- C S F -relate d i nfla m mat or y sy m pt o ms. T he use of Gra n ul oc y te 
c ol o n y-sti m ulati n g fact or ( G-C S F) is per mitte d i n c o m plia nce wit h re gi o nal prescri bi n g 
i nf or mati o n. T he i n dicati o n, use, d ose a n d d urati o n of G- C S F will be d oc u me nte d i n t he eC R F .
T he use of er y t hr o p oietic sti m ulati n g a ge nts w hile o n st u d y  is n ot per mitte d if t he s u bject has n ot 
bee n o n E S As f or at least 1 2 wee ks pri or t o st u d y e ntr y.
5. 4. 4.
Dr u gs t h at U n der g o C Y P 3 A -De pe n de nt Met a b olis m
T he maj or meta b olite of i delalisi b , G S- 5 6 3 1 1 7, is a re versi ble a n d ti me de pe n de nt i n hi bit or of 
C Y P 3 A; acc or di n gl y c oa d mi nistrati o n of idelalisi b wit h mi daz ola m, a pr o be C Y P 3 A s u bstrate, 
res ulte d i n a n a p pr o xi matel y 5-f ol d i ncrease i n mi daz ola m s yste mic e x p os ure ( A U C), i n dicati n g 
t hat i delalisi b is a str o n g i n hi bit or of C Y P 3 A . C oa d mi nistrati o n of C Y P 3 A s u bstrates wit h 
idelalisi b ma y  res ult i n a n i ncrease i n t heir sys te mic e x p os ures (e g, certai n a ntiarr h yt h mics, 
calci u m c ha n nel bl oc kers, be nz o diaze pi nes, H M G - C o A re d uctase i n hi bit ors, 
p h os p h o diesteras e- 5 [ P D E 5] i n hi bit ors, warfari n). A v oi d c oa d mi nistrati o n of narr o w t hera pe utic 
i n de x C Y P 3 A s u bstrates (e g, alfe nta nil, c ycl os p ori ne, sir oli m us, tacr oli m us, cisa pri de, pi m ozi de, 
fe ntan y l, q ui ni di ne, er g ota mi ne, di h ydr oer g ota mi ne, aste miz ole, terfe na di ne ) wit h i delalisi b.
5. 4. 5.
Dr u gs t h at I n hi bit/In d uce C Y P 3 A -De pe n de nt Met a b olis m
R u x oliti ni b is pri maril y  meta b olize d b y C Y P 3 A 4. T he C ma x a n d AU C of r u x oliti ni b i ncrease d 
3 3 % a n d 9 1 %, res pecti vel y, f oll o wi n g c oa d mi nistrati o n wit h str o n g C Y P 3 A 4 i n hi bit or 
ket oc o naz ole 2 0 0 m g t wice dail y f or 4 da ys, c o m pare d t o r u x oliti ni b d ose d al o ne. W he n 
a d mi nisteri n g r u x oliti ni b wit h str o n g C Y P 3 A 4 i n hi bit ors a d ose re d ucti o n is rec o m me n de d.
Idelalisi b is meta b olize d pri maril y via al de h yde o xi dase a n d i n part b y  C Y P 3 A. A cli nical 
dr u g -dr u g i nteracti o n st u d y  (st u d y 1 0 1-0 5) i n dicate d t hat a d mi nistrati o n of a p ote nt C Y P 3 A 
i n hi bit or t o get her wit h idelalisi b res ulte d i n a n a p pr o xi matel y 8 0 % i ncrease i n idelalisi b plas ma 
e x p os ures ( A U C), w hic h is n ot c o nsi dere d t o be cli nicall y  rele va nt a n d s u g gesti n g t hat idelalisi b


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 5 0
2 6 Oct o ber 2 0 1 6
is a wea k C Y P 3 A s u bstrate. Res ults fr o m a cli nical dr u g- dr u g i nteracti o n st u d y  
( G S-U S - 3 1 3- 0 1 3 0) i n dicate t hat w he n c o- a d mi nistere d wit h rifa m pi n, a hi g hl y  p ote nt i n d ucer of 
C Y P 3 A, idelalisi b e x p os ures are a p pr o xi matel y 7 5 % l o wer. C oa d mi nistrati o n of p ote nt i n d ucers 
of C Y P 3 A wit h idelalisi b s h o ul d be a v oi de d; a list of p ote nt i n d ucers is pr o vi de d i n Ta ble 5- 3
bel o w:
T a ble 5- 3.
K n o w n P ote nt I n d ucers of C Y P 3 A
Effect o n C Y P 3 A
Dr u g Cl ass
Me dic ati o ns
P ote nt C Y P 3 A I n d ucers
A nti m yc o bacterial s
Rifa m pi n
A ntic o n v ulsa nts
car ba maze pi ne, p he n yt oi n
F o o ds/ her bs
St. J o h n’s w ort
A b bre vi ati o n: C Y P =c yt oc hr o me P 4 5 0 e nz y me
5. 4. 6.
I m m u niz ati o n
Beca use of its acti o ns t o i n hi bit PI 3 K δ -de pe n de nt B -cell f u ncti o n, hi g h d oses of idelalisi b ca n 
i m pair pri mar y or sec o n dar y res p o nses t o i m m u nizati o n i n a ni mals. S u bjects w h o are at 
s u bsta ntial ris k of a n i nfecti o n (e g, i nfl ue nza) t hat mi g ht be pre ve nte d b y i m m u nizati o n, 
c o nsi derati o n s h o ul d be gi ve n t o pr o vi di n g t he vacci ne pri or t o i nitiati o n of idelalisi b . Of n ote, 
t he safety of i m m u nizati o n wit h li ve viral vacci nes f oll o wi n g idelalisi b t hera p y has n ot bee n 
st u die d a n d vacci nati o n wit h li ve vir us vacci nes d uri n g st u d y is n ot rec o m me n de d.
5. 4. 7.
H y dr o x y ure a
T he use of h y dr o x y u rea is per missi ble t o c o ntr ol bl o o d c o u nts w he n dee me d re q uire d i n t he 
me dical j u d g me nt of t he i n vesti gat or. T he d ose, d urati o n , a n d i n dicati o n f or h ydr o x y urea will be 
d oc u me nte d a n d ca pt ure d i n t he e C R F.
5. 4. 8.
S ur ger y
T here are n o k n o w n effects of i delalisi b o n c oa g ulati o n or w o u n d heali n g. T he r u x oliti ni b 
pr o d uct i nsert s h o ul d be c o ns ulte d f or i nf or mati o n o n c oa g ulati o n, w o u n d heali n g, or s ur ger y .
5. 4. 9.
Diet
T here are n o s pecific dietar y  restricti o ns i n t he st u d y. Idelalisi b ma y  be ta ke n wit h or wit h o ut 
f o o d. R u x oliti ni b ca n be ta ke n wit h or wit h o ut f o o d.
5. 5.
Acc o u nt a bilit y f or I del alisi b
T he i n vesti gat or is res p o nsi ble f or e ns uri n g a de q uate acc o u nta bilit y  of all use d a n d u n use d
idelal isi b. T his i ncl u des ac k n o wle d ge me nt of recei pt of eac h s hi p me nt of idelalisi b
( q ua ntit y a n d c o n diti o n). All use d a n d u n use d idelalisi b dis pe nse d t o s u bjects m ust be ret ur ne d t o 
t he site.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 5 1
2 6 Oct o ber 2 0 1 6
Idelalisi b acc o u nta bilit y rec or ds will be pr o vi de d t o eac h st u dy site t o:

Rec or d t he date recei ve d a n d q ua ntit y  of idelalisi b

Rec or d t he date, s u bject n u m ber, a n d t he idelalisi b kit n u m ber dis pe nse d

Rec or d t he date, q ua ntit y of use d a n d u n use d idelalisi b ret ur ne d, al o n g wit h t he i nitials of t he 
pers o n rec or di n g t he i nf or ma ti o n
5. 5. 1. 
I n vesti g ati o n al M e dici n al Pr o d uct Ret ur n or Dis p os al
Idelalisi b s h o ul d be retrie ve d fr o m eac h s u bject at t he e n d of eac h dis pe nsi n g i nter val. T he 
q ua ntit y  of st u d y dr u g a n d t he date ret ur ne d by t he s u bject will be rec or de d i n t he st u d y  dr u g 
acc o u nta bilit y rec or ds. All st u d y dr u g ret ur ne d b y t he s u bject will be retai ne d f or re vie w b y t he 
st u d y site m o nit or pri or t o ret ur n t o Gilea d or destr ucti o n o n- site.


I d el alisi b 
Pr o to c o l G S -U S- 3 9 7 -1 2 4 5 
Gil e a d S c ie n c es, I nc. 
6. 
S T U D Y P R O C E D U R E S 
Fi na l 
A m e n d m e nt 5 
T h e stu d y p r o c e dur es t o b e c on d u ct e d f or e a ch s u bj e ct e m olle d i n th e stu d y ar e pr ese n t e d i n 
tab ul ar f on n i n A p p e n di x 2 a n d d es cri b e d i n t h e te xt t hat f ollo ws. T h e i nv es tig a t or m u st 
d o c llllle nt a ny d e v iat i o n fro m p r oto c ol p r o c e dur es a n d n o tif y t he s p on s or. 
6. 1. 
S u bj e ct E n r oll m e nt a n d T r e at m e nt As si g n m e nt 
A ll su bj e cts or l e g ally a c c ep ta bl e re p res en t ati v es m u st p e rs on a lly si g n , dat e a nd r e c e iv e a c op y 
of th e i nf o1 m e d c o n s ent f o1 m (IC F) b ef or e a ny s t ud y s pe cifi c s cr e eni n g pr o c e d ur es ar e 
p e ifo n n e d. S u bj e cts w ill b e ass ig n e d a u ni q u e s cree ni n g nlllll b er at t he ti me of c o n s en t. 
It is t h e resp o nsi bili t y of t h e i nv est ig at o r t o e ns ur e t hat s u bje cts ar e eligi bl e f or t he s t u dy pri or t o 
e m ol l ment. O n ce e lig i bilit y is c onf m n e d a s u bj e ct wi ll b e assig n e d a n o t her u ni q u e s u bj e ct 
nlllll b er. T hi s nlllll b er wi ll b e u s e d t o id e nti f y t he s u bj e c t thr ou g h o ut t he s t ud y a nd m u st r e m ai n 
th e s am e. T h is is a n o p e n l ab el stu d y . 
6. 2. 
6. 2. 1. 
6. 2. 2. 
S t u dy P r o c e d u r e D e sc ri pti o n s 
I nf o r m e d C o ns e nt 
M e di c al a n d M e di c ati o n Hi st o ry 
A c o m p l et e m e di c al, sur gi c al a n d c on c omi t a nt m e dic ati on hi st o 1y  will b e o b t ai ne d d uri n g 
s cre eni n g a n d r e c o rd e d o n t he e C R F . T hi s i nclu d es t he J A K 2 V 6 1 7 F m ut at i o n status if k n o w n. 
A h ist o 1y  of m edi c ati ons t a ke n withi n 3 m o nth s p rior t o s creeni n g, a nd d uri n g t he s cree ni n g 
p e rio d (e g, r nx o liti nib d ose) w ill b e o bt a i ne d a n d r e c ord e d i n t h e e C R F . 
T h e t r ans f usi o n hi st o 1y wit hi n 3 m o nt hs of s cree ni n g a n d tr ans f usi o n e v ent s t hr o u g h out t h e stu d y 
i ncl u di ng s cree ni n g wi ll b e r e c ord e d a n d r e p o rt e d i n t h e e C R F . 
6. 2. 3. 
D y n a mi c I nt e r n ati o n al P r o g n o sti c S c o ri n g S ys t e m ( DI P SS) f o r 
P ri m a r y M y el ofi b r o sis 
T h e DI P S S w ill b e c om pl et e d f or all s u bj e cts at s creeni n g. If c yt o g e n eti cs is av a ila ble f or t he 
s ubj e c t, t h e DI P S S Pl u s s h o ul d b e c om pl et e d i nst e a d of t h e D I PS S . 
6. 2. 4. 
Vit al Si g n s 
Vit al si g ns, i nclu d i ng bl o o d pr ess ur e, h e aii r ate, r esp ir ato 1y r at e, a nd or al t em p er atur e, wi ll b e 
m eas ur e d b y th e i nv esti g at o r or q u a lifie d d esi g n ee at e v e1y visit as liste d i n t he s t u dy p r o c ed ur es 
(A p p e n di x 2 ). 
C O N FI D E N TI A L 
P a g e 5 2 
2 6 O c to b er 2 0 1 6 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 5 3
2 6 Oct o ber 2 0 1 6
6. 2. 5. 
P h ysic al E x a mi n ati o n
T he p h y sical e xa mi nati o n ( P E), i ncl u di n g pal pati o n of t he li ver a n d s plee n, ma y  be perf or me d b y 
a p h ysicia n, p h ysicia n’s assista nt or n urse practiti o ner q ualifie d t o perf or m t he assess me nt at t he 
ti me p oi nts liste d i n t he st u d y pr oce d ures (A p pe n di x 2 ).
At Scree ni n g, a c o m plete P E will be perf or me d i ncl u di n g hei g ht, b o d y wei g ht, a n d cli n ical si g ns, 
a n d s ym pt o ms. Hei g ht will be meas ure d at scree ni n g o nl y. B o d y wei g ht assess me nts will be 
perf or me d t hr o u g h o ut t he st u d y per i nstit uti o nal practice . Breast, ge nital, a n d rectal e xa mi nati o ns 
are n ot re q uire d at a n y st u d y visit u nless warra nte d i n t he o pi ni o n of t he i n vesti gat or. P hys ical 
e xa mi nati o n fi n di n gs d uri n g t he scree ni n g peri o d will eit her be re p orte d as me dical hist or y or 
a d verse e ve nts base d o n t he re q uire me nts i n Secti o n 7. 1. 1 .
At s u bse q ue nt st u d y  visits, t he P E will be a n i nteri m e xa mi nati o n t o m o nit or a n y c ha n ges a n d 
will i ncl u de a n assess me nt of disease -relate d cli nical si g ns a n d sy m pt o ms. P h y sical e xa ms will 
be sc he d ule d e ver y  4 wee ks d uri n g t he e xte nsi o n peri o d u ntil a s u bject has bee n o n st u d y f or 
1 ye ar, w h e n it will be sc he d ule d e ver y 1 2 wee ks .
M ore fre q ue nt e xa mi nati o ns ma y be perf or me d at t he i n vesti gat or’s discreti o n, if cli nicall y  
i n dicate d.
6. 2. 6.
E C O G Perf or m a nce St at us
Perf or ma nce stat us will be assesse d at Scree ni n g a n d at e ver y visit a p h ysical e xa m is sc he d ule d 
as o utli ne d i n t he st u d y pr oce d ures (A p pe n di x 2 ).
6. 2. 7.
P atie nt -re p orte d O utc o mes ( P R O) Assess me nts
P R O assess me nts perf or me d at st u d y visits s h o ul d be c o m plete d pri or t o a n y ot her visit 
assess me nts.
6. 2. 7. 1.
M y el o pr oliferati ve Ne o pla s m S ym pt o m Assess me nt F or m ( M P N -S A F)
T he f ull M P N -S A F (A p pe n di x 8 ) is a 2 7-ite m q uesti o n naire t hat c o nsists of t he 9 -q uesti o n 
Brief Fati g ue I n ve nt or y a n d e x pa n ds o n t he assess me nt c ollecte d usi n g t he m o difie d 
M y el o pr oliferati ve Ne o plas m S ym pt o m Assess me nt F or m T otal S y m pt o m Sc or e 
(M P N S A F
T S S , A p pe n di x 9 ). T his will be c o m plete d wee kl y  f or t he first 2 4 wee ks, t he n 
m o nt hl y  f or t he s u bjects o n st u d y be yo n d Wee k 2 4 , a n d at E O S. W he ne ver st u d y  visits are 
sc he d ule d t he q uesti o n naire s h o ul d be c o m plete d i n t he cli nic. S u bjects will recei ve a c o p y of t he 
q uesti o n naire t o c o m plete at h o me bet wee n cli nic visits be gi n ni n g Wee k 4.
T h e M P N-S A F is self -a d mi nistere d. I n t he e ve nt a tra nslate d versi o n of t he q uesti o n naire is n ot 
a vaila ble i n t he pri mar y la n g ua ge i n w hic h t he s ubject rea ds or c o n verses, P R O data will n ot be 
c ollecte d.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 5 4
2 6 Oct o ber 2 0 1 6
6. 2. 8.
Electr oc ar di o gr a m
A sta n dar d 1 2- lea d E C G re p orti n g will be perf or me d at t he Scree ni n g visit per i nstit uti o nal 
practice a n d w he ne ver cli nicall y  i n dicate d at t he discreti o n of t he i n vesti gat or. T he i nvesti gat or
or q ualifie d desi g nee will re vie w all E C Gs. T he ori gi nal E C G traci n gs will be mai ntai ne d i n t he 
s o urce d oc u me ntati o n of eac h s u bject a n d t he a p pr o priate data re p orte d o n t he e C R F .
6. 2. 9.
L a b or at or y Assess me nts
Bl o o d sa m ples f or l ocal la b orat or y  testi n g will be c ollecte d acc or di n g t o t he st u d y pr oce d ures i n 
A p pe n di x 2 . A d diti o nal safety la b orat or y  assess me nts ma y be perf or me d if cli nicall y i n dicate d.
T a ble 6- 1.
A n al ytes
C he mistr y
H e m at ol o g y
Uri n al ysis c
Ot her
Al b u mi n
Al kali ne p h os p hatase
A L T / S G P T
A S T / S G O T
Bicar b o nate
B U N
Calci u m
C hl ori de
Creati ni ne a
G G T
Gl uc ose
Ir o nb
L D H
Ma g nesi u m
P h os p h or us
P otassi u m
S o di u m
T otal bilir u bi n
Direct bilir u bi n
T otal pr otei n
Uric aci d
A N C
R B C
H e m o gl o bi n
H e m at ocrit
Platelets
Retic ul oc ytes ( %)
W B C
Differe ntia l
Ne utr o p hils
Ba n ds
E osi n o p hils
Bas o p hils
L y m p h oc ytes
M o n oc ytes
Blasts
Pr o m y el o c ytes
M y el oc ytes
Meta m yel oc ytes
N ucleate d Re d Bl o o d Cells
S pecific gra vit y
p H
Occ ult bl o o d
Pr otei n
Gl uc ose
Micr osc o pic
c
R B C casts
W B C casts
Ser u m β- h C G or uri ne pre g na nc y test d
HI V a nti b o d y
He patitis B s urface a nti ge n
He patitis B c ore a nti b o d y e
He patitis C a nti b o d y
He patitis C viral R N A f
E S R
C M V ( q ua ntitati ve P C R or 
p p 6 5 a nti ge n)
I m m u ne m o nit ori n g:

L y m p h oc yte s u bset pa nel usi n g 
fl o w c yt o metr y 
(i m m u n o p he n ot y pi n g) 

Q ua ntitati ve i m m u n o gl o b uli ns: 
I g G, I g M, I g A

Ser u m C H 5 0 le vel
C o a g ul ati o n
P T /I N R
aP T T / P T T
B o ne M arr o w
B last ( %)
A b bre vi ati o ns: E S R =er yt hr oc yte se di me ntati o n rate; G G T = ga m ma -gl uta m yltra nsferase;
N ote: A d diti o nal c o m p o ne nts, a b n or mal, a n d/ or at y pical cells will als o be re p orte d if prese nt .
a 
Esti mate d creati ni ne cleara nce/ gl o mer ular filtrati o n rate will be calc ulate d base d o n t he C oc kr oft- Ga ult f or m ula
b
T his i ncl u des se r u m ir o n, tra nsferri n, tra nsferri n sat urati o n a n d ferriti n.
c  
Di pstic k will be use d f or uri nal ysis ; micr osc o pic will be perf or me d o nl y if di pstic k res ults are a b n or mal.
d
Fe males of c hil d beari n g p ote ntial
e
O nl y if h e patitis B s urface a nti ge n is p ositi ve
f
O nl y if he patitis C a nti b o d y is p ositi ve


I d elalisi b 
Pr o to c o l G S -U S- 3 9 7 -1 2 4 5 
Gi l e a d S c ie n c es, I nc. 
6. 2. 1 0. 
I m m u n e M o nit o ri n g 
Fi na l 
A m e n d m e nt 5 
L a b or at o 1y s am pl es f or i mm u n e m o n it ori ng wi ll b e c oll e ct e d at S c re en i n g, W e e k 4, 1 2 , 2 4 a n d 
e v er y 1 2 w e e ks t h er e aft er a n d E O S visit: 
• 
L y m p h o c yt e s ubs et p a n el us i ng fl o w c yt o m eti y (i m mu n o p h e n ot y p i ng) 
•  
Q ua ntit ati v e i m mu n o gl o b u li ns: lg G , l g M, l g A 
• 
S er n m C H 5 0 le v e l 
6. 2. 1 1. 
P r e g n a n c y T e st 
F e m al es of chi l db e ari n g p ot e nti al wi ll h a v e a pr e g n a n c y t est d ur i n g S cr e e n i n g (s er nm) a n d 
m o nt hl y t h r ou g h o ut t h e st u d y (ur i n e) as o ut li ne d i n t h e st u d y pr o c e dur es i n A p p e n di x 2. 
6. 2 . 12. 
P h a r m a c o ki n e ti cs ( PK) 
Bl o o d s a m pl es f or P K a n al ys is wi ll b e c oll e ct e d t hr ou g h o ut t h e st u d y as o ut li ne d i n t h e stu d y 
pr o c e dur es A p p e n di x 2. S a m pl es f or r nx olit i ni b P K wi ll b e c oll e ct e d rel ati v e t o r nx olit i ni b 
d osi n g o n D a y 1 pr e d os e a n d D a y 4 at pr e d os e , 0. 5 , 1, 1. 5 , 2, 3, 4, 6, 8, a n d 1 2 h o ur s p ost d os e. 
S a m pl es f or i d el alisi b a n d r n x oliti ni b P K wi ll b e c oll e ct e d b e gi n n i ng D a y 1 0 r el ativ e t o id el alisi b 
a n d r nx olit ini b d osi n g at pr e d os e , 0. 5 , 1, 1. 5 , 2, 3, 4, 6, 8, a n d 1 2 h o ur s p ost d os e. F o r t h e 
1 2 h o ur p ost d os e P K ti m e p o i nt o n D a y 4 a n d D a y 1 0 , t h e bl o o d s a m pl e f or P K wi ll b e c oll e ct e d 
pr i or t o r nx oliti n i b a nd/ or id el alisi b d osi n g. 
O n D a ys 1 5, 3 6, 7 8, a n d 1 6 2 bl o o d s a m pl es wi ll b e c o lle ct e d pr e d os e a n d 1. 5 h o ur s p ost d os e. If 
t h e E O S visit c o i nci d es wit h W e e k 2 4 ( Da y 1 6 2) , e v e1y eff o 1i s h o ul d b e m a d e t o c oll e ct t h e 
pr e d os e bl o o d s am pl e f or i d el alisi b a n d r n x oliti ni b P K. A ± 5 m i n ute wi n d o w wi ll b e allo w e d f or 
all P K s a m pl e c o lle cti on ti m e p o i nts. 
6. 2 . 13. 
P n e u m o c ys tis Ji r o v e ci P n e u m o ni a (P J P ) P r o p h y l axis 
S u bj e cts m ust r e c eiv e ti·im et h o p ri m-s ulf a m eth o x a z o l e or ot h e r est a b lis he d pr o p h yl a xis f or PJ P 
t hr ou g h o ut t h e c our s e of i d el alisi b ti·eat men t. 
Pr o p h yl a xis wi ll c ont i n ue f or a p e ri o d of 2 t o 6 m o nt hs aft er id el alisi b di s c on ti n u ati o n. T h e 
d ur ati o n of pr o p h yl a x is s h o ul d b e b as e d o n clini c al j u d g m ent a n d m a y t a k e i nt o a c c o u nt ris k 
f a ct ors s u c h as c o nc 0 1 nitant c o1ii c ost er oi d ti·eat m e nt a n d pr ol o n g e d n e u ti· o pe nia aft er i d el alisi b 
ti·eat m e nt e n ds . 
- -
C O N FI D E N TI A L 
P a g e 5 5 
2 6 O c to b er 2 0 1 6 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 5 6
2 6 Oct o ber 2 0 1 6
6. 2. 1 5.
B o ne M arr o w Bi o ps y a n d As pir ate
B o ne marr o w bi o ps y a n d as pirate wit h c yt o ge netics, c ore bi o psy, tric hr o me stai n f or retic uli n, 
a n d ir o n stai n will be perf or me d as o utli ne d i n t he st u d y pr oce d ures (A p pe n di x 2 ). It will be 
o btai ne d at scree ni n g if o ne has n ot bee n d o ne i n t he past 3 m o nt hs or if t he res ults are n ot 
a vaila ble, Da ys 7 8, 1 6 2, a n d e ver y 2 4 wee ks d uri n g t he e xte nsi o n peri o d. At t he E O S , a b o ne 
marr o w bi o ps y a n d as pirate will be o btai ne d if o ne has n ot bee n d o ne i n t he past 2 4 wee ks.
6. 2. 1 6.
M a g netic Res o n a nce I m a gi n g ( M RI )
A 3 D M RI ( or C T, if M RI n ot feasi ble) f or t he li ver a n d s plee n size b y v ol u metric i ma gi n g will 
be perf or me d at Scree ni n g, Wee ks 1 2, 2 4 , e ver y 1 2 wee ks d uri n g t he e xte nsi o n peri o d, a n d at t he 
E O S visit if o ne has n ot bee n d o ne wit hi n t he past 1 2 wee ks (see A p pe n di x 2 ).
V ol u metric i ma gi n g of t he li ver b y 3 D M RI ( or C T, if M RI  n ot feasi ble) perf or me d as sta n dar d 
of care pri or t o si g ni n g t he IC F, a n d wit hi n 8 wee ks of e nr oll me nt, ma y be use d t o f ulfill t he 
scree ni n g re q uire me nt.
6. 2. 1 7.
A d verse E ve nts a n d C o nc o mit a nt Me dic ati o ns
S u bjects will be assesse d f or a d verse e ve nts a n d c o nc o mita nt me dicati o ns d uri n g eac h visit . A ny 
A E or c o nc o mita nt me dicati o n use re p orte d t hr o u g h o ut t he st u d y  will be rec or de d i n t he eC R F
wit h a p pr o priate s o urce d oc u me ntati o n
6. 2. 1 8.
Assess me nt of Di arr he a/ C olitis

O btai n hist or y  of o nset a n d d urati o n of diarr hea, i ncl u di n g descri pti o n of n u m ber of st o ols 
a n d st o ol c o m p ositi o n (e g, water y, bl o o d y, n oct ur nal), tra vel hist or y, dietar y c ha n ges a n d a 
me dicati o n re vie w t o i de ntif y  p ossi ble diarr he o ge nic a ge nts

Perf or m p h ys ical e xa mi nati o n i ncl u di n g assess me nt f or fe ver, dizzi ness, a b d o mi nal 
pai n/cra m pi n g, a n d wea k nes s (ie, e val uate f or se psis, b o wel o bstr ucti o n, de h ydrati o n)
6. 2. 1 9.
E v al u ati o n f or G astr oi ntesti n al E ve nts/ C olitis
F or Gra de 2 c olitis a n d diarr hea ( u nless cli nical dia g n osis is esta blis he d fr o m me dical hist or y  a n d 
p h y sical e xa mi nati o n), t he f oll o wi n g testi n g is re q uire d:

St o ol c ult ure f or r o uti ne pat h o ge ns ( Sal m o nella, S hi gella, Ca m p yl o bacter s pecies, 
Cl ostri di u m difficile t o xi n, R ota vir us, C y t o me gal o vir us, A de n o vir us)

St o ol f or O va a n d Parasites ( Cr y pt os p ori di u m par v u m, I s os p ora belli, E nter oc yt oz o o n 
bie ne usi, S e ptata i ntesti nalis, Str o n g yl oi des, Micr os p ori dia, E nta m oe ba hist ol ytica, 
C y cl os p ora), Giar dia a nti ge n


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 5 7
2 6 Oct o ber 2 0 1 6
F or gra de ≥ 3 or persist e nt gra de 2 c olitis or diarr hea wit h o ut clear eti ol o g y  (e g, cl ostri di u m 
difficile e nter oc olitis) , e n d osc o p y wit h bi o ps y is re q uire d. All bi o ps y sa m ples s h o ul d i ncl u de 
i m m u n o hist oc he mistr y (I H C) a n d P C R f or C M V, A de n o vir us.  
6. 2. 2 0.
Differe nti ati o n Bet wee n S m all -B o w el a n d L ar ge -B o wel Di arr he a
Differe ntiati o n bet wee n s mall- b o wel a n d lar ge -b o wel diarr hea: ma y be p ossi ble o n a cli nical 
basis. If u nclear, c o nsi der u p per a n d l o wer tract e n d osc o p y wit h bi o ps y.

S mall b o wel diarr hea is c haracterize d b y lar ge v ol u me diarr hea ( m ore t ha n o ne per da y), 
p ossi ble ass ociate d de h y drati o n wei g ht l oss a n d para u m bilical pai n. C o nsi der a n e n d osc o pic 
s mall-b o wel bi o ps y  a n d e val uate ot her eti ol o gies s uc h as celiac disease.

Lar ge -b o wel diarr hea ma y  prese nt wit h l o wer pel vic pai n, te nes m us, ge nerall y s maller st o ol 
v ol u me wit h gr oss b l o o d fre q ue ntly f o u n d i n t he st o ol; C o nsi der a c ol o n osc o pic e val uati o n 
a n d bi o ps y.
6. 3.
Pretre at me nt Assess me nts
6. 3. 1. 
Scree ni n g Visit
T he scree ni n g date is defi ne d as t he date t he s u bject si g ns t he i nf or me d c o nse nt f or m. T he 
scree ni n g peri o d be gi ns o nce a s u bject has pr o vi de d writte n i nf or me d c o nse nt t o partici pate i n 
t he st u d y a n d e n ds o n t he first da y of t he treat me nt peri o d. S u bjects will be scree ne d wit hi n 
2 8 da y s t o deter mi ne eli gi bilit y f or partici pati o n i n t he st u d y. Assess me nts f or t his visit are 
o utli ne d i n st u d y pr oce d ures A p pe n di x 2 . M RI  ( or C T, if M RI is n ot feasi ble) s h o ul d be t he last 
scree ni n g assess me nt sc he d ule d after all ot her eli gi bilit y re q uire me nts ha ve bee n met. Wit h t he 
e xce pti o n of i ma gi n g a n d pal pati o n of t he li ver a n d/ or s plee n, s ta n dar d of care pr oce d ures 
c o n d ucte d pri or t o a s u bject’s partici pati o n i n t he st u d y b ut are wit hi n t he 2 8 da y  scree ni n g 
wi n d o w ma y  be use d t o deter mi ne eli gi bilit y, at t he discreti o n of t he i n vesti gat or.
Fr o m t he ti me of o btai ni n g i nf or me d c o nse nt t hr o u g h t he first a d mi nistrati o n of I M P, rec or d all 
seri o us a d verse e ve nts (S A E ), as well as a ny n o n -seri o us A E relate d t o pr ot oc ol-ma n date d 
pr oce d ures o n t he A E eC R F . All ot her u nt o war d me dical occ urre nces o bser ve d d uri n g t he 
scree ni n g peri o d, i ncl u di n g e xacer bati o n or c ha n ges i n me dical hist or y are t o be ca pt ure d o n t he 
me dical hist or y  eC R F . See S ecti o n 7 A d verse E ve nts a n d T o xicit y  Ma na ge me nt f or a d diti o nal 
details.
6. 3. 2.
B aseli ne Assess me nts
T he baseli ne assess me nts (see A p pe n di x 2
C CI
) will be c o n d ucte d o n Da y  1 after s u bject eli gi bilit y 
has bee n esta blis he d wit hi n t he 2 8 da y  scree ni n g peri o d. T he st u d y pr oce d ures i n t he cli nic are 
sc he d ule d relati ve t o t he m or ni n g d ose of r u x oliti ni b. Pri or t o t he sc he d ule d visit, s u bjects s h o ul d 
be re mi n de d n ot t o ta ke t heir m or ni n g d ose bef ore c o mi n g t o t he cli nic.


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6. 4.
Tre at me nt Peri o d
T he treat me nt peri o d is Wee ks 1 t o 2 4, w hic h i ncl u des t he baseli ne assess me nts ( Secti o n 6. 3. 2 ) 
a n d t he visit sc he d ule is o utli ne d i n A p pe n di x 2 . T he st u d y  pr oce d ures i n t he cli nic are sc he d ule d 
relati ve t o t he m or ni n g d ose of r u x oliti ni b a n d/ or idelalisi b . Pri or t o t he sc he d ule d visits, s u bjects 
s h o ul d be i nstr ucte d t o h ol d t heir m or ni n g d ose bef ore c o mi n g t o t he cli nic o n da y s w here P K la b 
dra ws will be ta ke n ( Da y 1 a n d 4 f or r u x oliti ni b, a n d Da y  1 0, 1 5, 3 6, 7 8, 1 6 2 f or b ot h i delalisi b 
a n d r u x oliti ni b P K).
6. 5.
E xte nsi o n Peri o d
T he e xte nsi o n peri o d be gi ns after Wee k 2 4 a n d t he visit sc he d ule is o utli ne d i n A p pe n di x 2 . 
P h y sical e xa ms will be sc he d ule d e ver y 4 wee ks u ntil a s u bject has bee n o n st u d y f or 1 ye ar,
w he n it will be sc he d ule d e ver y 1 2 wee ks . Assess me nts sc he d ule d e ver y  1 2 a n d 2 4 wee ks will 
o verla p assess me nts sc he d ule d e ver y 4 wee ks. T he st u d y  pr oce d ures i n t he cli nic are sc he d ule d 
relati ve t o t he m or ni n g d ose of r u x oliti ni b a n d/ or idelalisi b . Pri or to t he sc he d ule d visits, s u bjects 
s h o ul d be re mi n de d n ot t o ta ke t heir m or ni n g d ose bef ore c o mi n g t o t he cli nic.
6. 6.
P ost -tre at me nt Assess me nts
T he E O S a n d Safet y  F oll o w- u p visits ma y  be perf or me d o n t he sa me da y, if t he s u bject will be 
disc o nti n ui n g st u d y  treat me nt a n d disc o nti n ui n g t he st u d y at t he sa me ti me 
(e g, wit h dra wal of c o nse nt). After disc o nti n ui n g treat me nt, s u bjects will c o m plete t he f oll o wi n g 
visit a n d disc o nti n ue st u d y partici pati o n.
6. 6. 1.
E n d of St u d y
E n d of St u d y  assess me nts (see A p pe n di x 2 ) will b e c o m plete d o nce it has bee n deter mi ne d t hat 
t he s u bject will disc o nti n ue all st u d y assess me nts. As state d i n Secti o n 6. 8 , e ve n if a s u bject 
per ma ne ntl y disc o nti n ues idelalisi b d osi n g, e ver y  atte m pt s h o ul d be ma de t o kee p t he s u bject i n 
t he st u d y a n d c o ntin ue t o perf or m t he re q uire d st u d y -relate d f oll o w- u p a n d pr oce d ures.
If a bo ne marr o w bi o ps y a n d as pirate has n ot bee n d o ne wit hi n t he past 2 4 wee ks it will be 
sc he d ule d at t he E O S visit. A 3 D M RI ( or C T, if M RI n ot feasi ble) f or t he li ver a n d s plee n size 
b y  v ol u metric i ma gi n g will als o be sc he d ule d if o ne has n ot bee n d o ne wit hi n t he past 1 2 wee ks .
If t he E O S visit c oi nci des wit h Wee k
2 4 ( Da y 1 6 2 ), e ver y eff ort s h o ul d be ma de t o c ollect t he 
pre d ose bl o o d sa m ple f or idelalisi b a n d r u x oliti ni b P K.
6. 6. 2.
S afet y F oll o w -u p Visit
T he safety f oll o w-u p visit will be sc he d ule d 3 0 da y s after t he s u bject’s E O S visit , wit hi n a 
wi n d o w of ± 7 d a y s as o utli ne d i n st u d y pr oce d ures ( A p pe n di x 2 ).
6. 6. 3.
L o n g -ter m F oll o w U p
N o l o n g -ter m f oll o w u p is pla n ne d f or t his st u d y.


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6. 7.
U nsc he d ule d Visits
U nsc he d ule d visits ma y  occ ur at a n y ti me w hile t he s u bject is e nr olle d o n st u d y . Vital si g ns, 
la b orat or y assess me nts, E C G, a n d p h ysical e xa mi nati o n ma y be c o n d ucte d at t hese visits. Data 
ge nerate d d uri n g a n u nsc he d ule d visit will be c ollecte d o n t he eC R F .
6. 8.
Assess me nts f or Pre m at ure Disc o nti n u ati o n fr o m St u d y
If a s u bject disc o nti n ues st u d y d osi n g (f or e xa m ple, as a res ult of a n A E), e ver y  atte m pt s h o ul d 
be ma de t o kee p t he s u bject i n t he st u d y  a n d c o nti n ue t o perf or m t he re q uire d st u d y-relate d 
f oll o w-u p a n d pr oce d ures u ntil disease pr o gressi o n (see Secti o n 6. 6. 1 a n d 6. 6. 2 ). If t his is n ot 
p ossi ble or acce pta ble t o t he s u bject or i n vesti gat or, t he s u bject ma y  be wit h dra w n fr o m t he 
st u d y.
6. 9.
Criteri a f or Disc o nti n u ati o n of St u d y Tre at me nt
All st u d y  partici pa nts will be e nc o ura ge d t o recei ve idelalisi b f or 2 4 wee ks a n d will recei ve 
r u x oliti ni b f or t he sa me peri o d of ti me (e xcl u di n g t he prece di n g 4 wee k peri o d pri or t o 
i nitiati n g idelalisi b ). S u bjects w h o are o n idelalisi b be y o n d Wee k 2 4, a n d i n t he o pi ni o n of t he 
i n vesti gat or are deri vi n g cli nical be nefit, ca n re mai n o n t he st u d y f or t he e xte nsi o n peri o d u ntil 
disease pr o gressi o n. S u bjects will be e nc o ura ge d t o c o m plete idelalisi b a n d/ or r u x oliti ni b e ve n if 
o ne of t he i n di vi d ual a ge nts m ust be disc o nti n ue d d ue t o a ge nt -s pecific t o xicit y.
St u d y  dr u g (idelalisi b ) m a y  be disc o nti n ue d i n t he f oll o wi n g i nsta nces, i n c o ns ultati o n wit h t he 
Gilea d Me dical
M o nit or:

U nacce pta ble t o xicit y , or t o xicit y t hat, i n t he j u d g me nt of t he i n vesti gat or, c o mpr o mises t he 
a bilit y t o c o nti n ue st u d y-s pecific pr oce d ures or is c o nsi dere d n ot t o be i n t he s u bject’s best 
i nterest

O bjecti ve e vi de nce of defi niti ve disease pr o gressi o n ( base d o n 2 0 1 3 Re vise d I WG- M R T a n d 
E L N res p o nse criteria, A p pe n di x 6 )

S u bject re q uest t o disc o nti n ue f or a n y reas o n

S u bject n o nc o m plia nce

Pre g na nc y  or breastfee di n g d uri n g t he st u d y
If per ma ne nt disc o nti n uati o n of idelalisi b occ urs pri or t o defi niti ve pr o gressi o n s u bjects s hall 
re mai n o n st u d y u ntil defi niti ve pr o gressi o n or criteria f or stu d y  disc o nti n uati o n are met.
6. 1 0.  
Criteri a f or Disc o nti n u ati o n fr o m St u d y
S u bject st u d y  partici pati o n ma y be e n de d d ue t o a n y of t he f oll o wi n g reas o ns:

I nitiati o n of ne w or i n vesti gati o nal t hera py i n t he a bse nce of pr o gressi o n

Disease pr o gressi o n ( base d o n 2 0 13 Re vise d I WG- M R T a n d E L N criteria , A p pe n di x 6 )


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
Wit h dra wal of c o nse nt

Si g nifica nt s u bject n o nc o m plia nce wit h st u d y  dr u g a d mi nistrati o n, st u d y pr oce d ures, or
st u d y re q uire me nts

I n vesti gat or’s decisi o n t o re m o ve t he s u bject fr o m t he st u d y, i n c o ns ultati o n wit h t he 
Gilea d m e dical m o nit or

Pre g na nc y or breastfee di n g

Deat h

Disc o nti n uati o n of st u d y  b y t he s p o ns or, a re g ulat or y a ge nc y, or a n I RB


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7.
A D V E R S E E V E N T S A N D T O XI CI T Y  M A N A G E M E N T
7. 1.
Defi niti o ns of A d verse E ve nts, A d verse Re acti o ns, a n d Seri o us A d verse E ve nts
7. 1. 1.
A d verse E ve nts
A n a d verse e ve nt ( A E) is a n y  u nt o war d me dical occ urre nce i n a cli nical st u d y s u bject 
a d mi nistere d a p har mace utical pr o d uct , w hic h d oes n ot necessaril y ha ve a ca usal relati o ns hi p 
wit h t h e treat me nt. A n A E ca n t heref ore be a ny u nfa v ora ble a n d / or u ni nte n de d si g n, sy m pt o m, 
or disease te m p orall y  ass ociate d wit h t he use of a me dici nal pr o d uct, w het her or n ot c o nsi dere d 
relate d t o t he me dici nal pr o d uct. A E m a y  als o i ncl u de pre- or p ost -treat me nt c o m plicati o ns 
t hat occ ur as a res ult of pr ot oc ol s peci fie d pr oce d ures, lac k of efficac y, o ver d ose, 
dr u g a b use/mis use re p orts, or occ u pati o nal e x p os ure. Pree xisti n g e ve nts t hat i ncrease i n se verity 
or c ha n ge i n nat ure d uri n g or as a c o nse q ue nce of partici pati o n i n t he cli nical st u d y  will als o be 
c o nsi dere d A E .
A n A E d oes n ot i ncl u de t he f oll o wi n g:

La b orat or y  a b n or malities n ot re q uiri n g cli nical i nter ve nti o n or f urt her i n vesti gati o n. S uc h 
a b n or malities will be ca pt ure d as part of o verall la b orat or y  m o nit ori n g.

Me dical or s ur gical pr oce d ures s uc h as s ur ger y, e n d osc o p y, t o ot h e xtracti o n, a n d tra nsf usi o n.
T he c o n diti o n t hat le d t o t he pr oce d ure m a y  be a n A E a n d m ust be re p orte d.

Pre -e xisti n g diseases , c o n diti o ns , or la b orat or y  a b n or malities prese nt or detecte d bef ore t he 
scree ni n g visit t hat d o n ot w orse n

Sit uati o ns w here a n u nt o war d me dical occ urre nce has n ot occ urre d ( e g, h os pitalizati o n f or 
electi ve s ur ger y, s ocial a n d/ or c o n ve nie nce a d missi o ns)

O ver d ose wit h o ut cli nical se q uelae (see Secti o n 7. 7. 1 )

A n y  me dical c o n diti o n or cli nicall y si g nifica nt la b orat or y a b n or malit y wit h a n o nset date 
bef ore t he c o nse nt f or m is si g ne d a n d n ot relate d t o a pr ot oc ol -ass ociate d pr oce d ure is n ot a n 
A E. I t is c o nsi dere d t o be pre-e xisti n g a n d will be d oc u me nte d o n t he m e dical hist or y eC R F .
7. 1. 2.
Seri o us A d verse E ve nts
A n S A E or seri o us a d verse dr u g reacti o n ( S A D R) is defi ne d as a n e ve nt t hat, at a n y d ose, res ults 
i n t he f oll o wi n g:

Deat h

Life -t hreate ni n g ( N ote: T he ter m “life-t hreate ni n g” i n t he defi niti o n of “seri o us” refers to a n 
e ve nt i n w hic h t he s u bject was at ris k of deat h at t he ti me of t he e ve nt; it d oes n ot refer t o a n 
e ve nt t hat h y p ot heticall y mi g ht ha ve ca use d deat h if it were m ore se vere.)

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


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
Persist e nt or si g nifica nt disa bilit y/i nca pacity

A c o n ge nital a n o mal y/ birt h defect

A me dicall y i m p orta nt e ve nt or reacti o n: s uc h e ve nts ma y n ot be i m me diatel y 
life-t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize t he s u bject or ma y 
re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her o utc o mes c o nstit uti n g S A E . Me dical a n d 
scie ntific j u d g me nt m ust be e xercise d t o deter mi ne w het her s uc h a n e ve nt is a re p orta ble 
u n der e x pe dite d re p orti n g r ules. E xa m ples of me dicall y i m p orta nt e ve nts i ncl u de i nte nsi ve 
treat me nt i n a n e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m; bl o o d d yscrasias or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n; a n d de vel o p me nt of dr u g de pe n de nc y  or 
dr u g a b use. F or t he a v oi da nce of d o u bt, i nfecti o ns res ulti n g fr o m c o nta mi nate d me dici nal 
pr o d uct will be c o nsi dere d a me dicall y i m p orta nt e ve nt a n d s u bject t o e x pe dite d re p orti n g 
re q uire me nts.
7. 1. 2. 1.
Pr ot oc ol -S pecific Seri o us A d verse E ve nt I nstr ucti o ns
T o mai ntai n t he i nte grit y of t he st u d y , t he f oll o wi n g e ve nts t hat are assesse d as u nrelate d t o I M P 
will n ot be c o nsi dere d S A E s:

P r o gressi o n of m yel ofi br osis

D eat h relate d to pr o gressi o n of m y el ofi br osis
H o we ver, e ve nts of pr o gressi o n of m y el ofi br osis a n d deat h relate d t o pr o gressi o n of 
m y el ofi br osis t hat are assesse d b y t he i n vesti gat or as relate d t o I M P will be c o nsi dere d S A E s a n d 
will be re p orte d t o re g ulat or y  a ge ncies i n a n e x pe dite d fas hi o n b y Gilea d.
All e ve nts of pr o gressi o n of m y el ofi br osis a n d deat h relate d t o pr o gressi o n of m y el ofi br osis, 
re gar dless of i n vesti gat or assess me nt of relatio ns hi p t o I M P, will be re p orte d i n t he eC R Fs a n d, 
as a p pr o priate, i n t he fi nal cli nical st u d y  re p ort a n d i n a n y rele va nt a g gre gate safety re p orts.
7. 1. 3.
Cli nic al L a b or at or y A b n or m alities a n d Ot her A b n or m al Assess me nts as 
A d verse E ve nts or Seri o us A d verse E ve nts
La b orat or y  a b n or malities wit h o ut cli nical si g nifica nce are n ot rec or de d as A E s or S A E s. 
H o we ver, la b orat or y  a b n or malities (e g, cli nical c he mistr y, he mat ol o g y, a n d uri nal ysis) t hat 
re q uire me dical or s ur gical i nter ve nti o n or lea d t o I M P i nterr u pti o n, m o dificati o n, or 
disc o nti n uati o n m ust be rec or de d as a n A E, as well as a n S A E, if a p plica ble. I n a d diti o n, 
la b orat or y or ot her a b n or mal assess me nts (e g, electr ocar di o gra m, x-ra ys, vital si g ns) t hat are 
ass ociate d wit h si g ns a n d/ or s y m pt o ms m ust be rec or de d as a n A E or S A E if t he y  meet t he 
defi niti o n of a n A E or S A E as descri be d i n Secti o ns 7. 1. 1 a n d 7. 1. 2 , res pecti vel y. If t he 
la b orat or y a b n or malit y is part of a sy n dr o me, rec or d t he s yn dr o me or dia g n osis (e g, a ne mia), n ot 
t he la b orat or y res ult (ie, decrease d he m ogl o bi n).
F or s pecific i nf or mati o n o n ha n dli n g of cli nical la b orat or y  a b n or malities i n t his st u d y, please 
refer t o Secti o n 7. 5 .


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7. 2.  
Assess me nt of A d verse E ve nts a n d Seri o us A d verse E ve nts
T he i n vesti gat or or q ualifie d s u bi n vesti gat or is res p o nsi ble f or assessi n g A E s a n d S A E s f or 
ca usalit y a n d se verit y, a n d f or fi nal re vie w a n d c o nfir mati o n of acc urac y of e ve nt i nf or mati o n 
a n d assess me nts.
7. 2. 1.
Assess me nt of C a us alit y f or St u d y Dr u gs a n d Pr oce d ur es
T he i n vesti gat or or q ualifie d s u bi n vesti gat or is res p o nsi ble f or as sessi n g t he relati o ns hi p t o 
I M P t hera p y usi n g cli nical j u d g me nt a n d t he f oll o wi n g c o nsi derati o ns:

N o : E vi de nce e xists t hat t he A E has a n eti ol o g y  ot her t ha n t he I M P. F or a n S A E , a n 
alter nati ve ca usalit y m ust be pr o vi de d (e g, pre -e xisti n g c o n diti o n, u n derlyi n g disease, 
i nterc urre nt ill ness, or c o nc o mita nt me dicati o n).

Yes : T here is reas o na ble p ossi bilit y  t hat t he e ve nt ma y ha ve bee n ca use d b y t he I MP.
It s h o ul d be e m p hasize d t hat i neffecti ve treat me nt s h o ul d n ot be c o nsi dere d as ca usally relate d i n 
t he c o nte xt of A E re p orti n g.
T he relati o ns hi p t o st u d y  pr oce d ures (e g, i n vasi ve pr oce d ures s uc h as ve ni p u nct ure or bi o psy) 
s h o ul d be assesse d usi n g t he f oll o wi n g c o nsi derati o ns:

N o: E vi de nce e xists t hat t he A E has a n eti ol o g y  ot her t ha n t he st u d y pr oce d ure.

Yes: T he A E occ urre d as a res ult of pr ot oc ol pr oce d ures, (e g, ve ni p u n ct ure )
7. 2. 2.
Assess me nt of Se verit y
T he se verit y of a n A E will be gra de d usi n g t he C T C A E, Versi o n 4. 0 3 (A p pe n di x 1 1 ). F or eac h 
e pis o de, t he hi g hest se verit y  gra de attai ne d s h o ul d be re p orte d .
If a C T C A E criteri o n d oes n ot e xist, t he i n vesti gat or s h o ul d use t he gra de or a djecti ves:
Gra de 1 ( mil d), Gra de 2 ( m o derate), Gra de 3 (se vere), Gra de 4 (life-t hreate ni n g), or 
Gra de 5 (fatal) t o descri be t he ma xi m u m i nte nsit y of t he A E . F or p ur p oses of c o nsiste nc y wit h 
t he C T C A E, t hese i nte nsit y gra des are defi ne d i n Ta ble 7- 1 .


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T a ble 7- 1.
Gr a di n g of A d verse E ve nt Se verit y
Gr a de
A djecti ve
Descri pti o n
Gra de 1 
Mil d
Si g n or s y m pt o m is prese nt, b ut it is easil y t olerate d, is n ot e x pecte d t o ha ve a 
cli nicall y si g nifica nt effect o n t he s u bject’s o verall healt h a n d well -bei n g, d oes 
n ot i nterfere wit h t he s u bject’s us ual f u ncti o n, a n d is n ot li kel y t o re q uire 
me dical atte nti o n.
Gra de 2 
M o derate
Si g n or s y m pt o m ca uses i nterfere nce wit h us ual acti vit y or affect cli nical stat us, 
a n d ma y re q uire me dical i nter ve nti o n.
Gra de 3 
Se vere
Si g n or s y m pt o m is i nca pacitati n g or si g nifica ntl y affects cli nical stat us a n d 
li kel y re q uires me dical i nter ve nti o n a n d/ or cl ose f oll o w- u p.
Gra de 4 
Life -t hreate ni n g
Si g n or s y m pt o m res ults i n a p ote ntial t hreat t o life.
Gra de 5 
Fatal
Si g n or s y m pt o m res ults i n deat h.
T he disti ncti o n bet wee n t he seri o us ness a n d t he se verit y  of a n A E s h o ul d be n ote d. Se vere is a 
meas ure of i nte nsit y;  t h us, a se vere reacti o n is n ot necessaril y a seri o us reacti o n. F or e xa m ple, a 
hea dac he ma y  be se vere i n i nte nsit y, b ut w o ul d n ot be classifie d as seri o us u nless it met o ne of 
t he criteria f or seri o us e ve nts liste d i n Secti o n 7. 1 ab o ve.
7. 3. 
I n vesti g at or Re q uire me nts a n d I nstr ucti o ns f or Re p orti n g A d verse E ve nts 
a n d Seri o us A d verse E ve nts t o Gile a d
All S A E s, re gar dless of ca use or relati o ns hi p, t hat occ ur after t he s u bject first c o nse nts t o 
partici pate i n t he st u d y (ie, si g ni n g t he i nf or me d c o nse nt) a n d t hr o u g h o ut t he d urati o n of t he 
st u d y, i ncl u di n g t he pr ot oc ol-re q uire d p ost treat me nt f oll o w-u p peri o d, m us t be re p orte d t o t he 
e C R F data base a n d Gilea d D S P H as i nstr ucte d. T his als o i ncl u des a n y  S A E res ulti n g fr o m 
pr ot oc ol -ass ociate d pr oce d ures perf or me d fr o m scree ni n g o n war ds.
All A E s, re gar dless of ca use or relati o ns hi p, t hat occ ur fr o m i nitiati o n of st u d y me dicati o n u ntil 
4 wee ks after last a d mi nistrati o n of st u d y  IM P m ust be re p orte d t o t he e C R F data base as 
i nstr ucte d.
All s pecial sit uati o ns i ncl u di n g pre g na nc y , re gar dless of ca use or relati o ns hi p, u ntil 3 0 da y s f or 
fe males or 9 0 da ys f or males after last a d mi nistrati o n of st u d y dr u g(s) m ust be re p orte d t o t he 
e C R F data base as i nstr ucte d.
A n y  S A E a n d deat hs t hat occ ur a fter t he p ost treat me nt f oll o w-u p visit b ut wit hi n 3 0 da y s of t he 
last d ose of st u d y IM P, re gar dless of ca us alit y, s h o ul d als o be re p orte d.
All A E s s h o ul d be f oll o we d u p u ntil res ol uti o n if p ossi ble. If by t he last da y o n st u d y  
(i ncl u di n g t he off-st u d y me dicati o n f oll o w- u p peri o d) t he A E has n ot res ol ve d, t he n t he A E will 
be f oll o we d u p u ntil t he i n vesti gat or a n d/ or Gilea d deter mi ne t hat t he s u bject's c o n diti o n is 
sta ble. H o we ver, Gilea d ma y re q uest t hat certai n A E s be f oll o we d u ntil res ol uti o n.


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I n vesti gat ors are n ot o bli gate d t o acti vely see k S A E after t he 3 0 da y peri o d . H o we ver, if t he 
i n vesti gat or lear ns of a ny S A E t hat occ urs after st u d y partici pati o n has c o ncl u de d a n d t he e ve nt 
is dee me d rele va nt t o t he use of I M P, he/s he s h o ul d pr o m ptl y d oc u me nt a n d re p ort t he e ve nt t o 
Gilea d D S P H.

All A E s a n d S A E s will be rec or de d i n t he e C R F data base wit hi n t he ti meli nes o utli ne d i n t he 
e C R F c o m pleti o n g ui deli ne.
At t he ti me of st u d y  start, S A E s will be re p orte d usi n g a pa per seri o us A E re p orti n g f or m.
Electr o n ic Seri o us A d verse E ve nt (e S A E) Re p orti n g Pr ocess

Site pers o n nel rec or d all S A E data i n t he e C R F data base a n d fr o m t here tra ns mit t he S A E 
i nf or mati o n t o Gilea d D S P H wit hi n 2 4 h o urs of t he i n vesti gat or’s k n o wle d ge of t he e ve nt. 
Detaile d i nstr ucti o ns ca n be f o u n d i n t he e C R F c o m pleti o n g ui deli nes.

If f or a ny reas o n it is n ot p ossi ble t o rec or d t he S A E i nf or mati o n electr o nicall y , ie, t he e C R F 
data base is n ot f u ncti o ni n g, rec or d t he S A E o n t he pa per seri o us A E re p orti n g f or m a n d 
s u b mit wit hi n 2 4 h o urs as describe d a b o ve.

As s o o n as it is p ossi ble t o d o s o, a n y S A E re p orte d via pa per m ust be tra nscri be d i nt o t he 
e C R F Data base acc or di n g t o i nstr ucti o ns i n t he e C R F c o m pleti o n g ui deli nes.

If a n S A E has bee n re p orte d via a pa per f or m beca use t he e C R F data base has been l oc ke d, n o 
f urt her acti o n is necessar y.

All A E s a n d S A E s will be rec or de d i n t he e C R F data base wit hi n t he ti meli nes o utli ne d i n t he 
e C R F c o m pleti o n g ui deli ne. 

Site pers o n nel rec or d all S A E data i n t he e C R F data base a n d fr o m t here tra ns mit t he S A E 
i nf or mati o n t o Gilea d D S P H wit hi n 2 4 h o urs of t he i n vesti gat or’s k n o wle d ge of t he e ve nt. 
Detaile d i nstr ucti o ns ca n be f o u n d i n t he e C R F co m pleti o n g ui deli nes.

If f or a ny reas o n it is n ot p ossi ble t o rec or d t he S A E i nf or mati o n electr o nicall y , ie, t he e C R F 
data bas e is n ot f u ncti o ni n g, rec or d t he S A E o n t he pa per S A E re p orti n g f or m a n d s u b mit 
wit hi n 2 4 h o urs as descri be d a b o ve.

As s o o n as it is p ossi ble t o d o s o, a n y  S A E re p orte d via pa per m ust be tra nscri be d i nt o t he 
e C R F data base acc or di n g t o i nstr ucti o ns i n t he e C R F c o m pleti o n g ui deli nes.

If a n S A E has bee n re p orte d via a pa per f or m beca use t he e C R F data base has bee n l oc ke d, n o 
f urt her acti o n is necessar y.


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
F or fatal or life -t hreate ni n g e ve nts, c o pies of h os pital case re p orts, a ut o psy re p orts, a n d ot her 
d oc u me nts a re als o t o be s u b mitte d b y e-mail or fa x w he n re q ueste d a n d a p plica ble. 
Tra ns missi o n of s uc h d oc u me nts s h o ul d occ ur wit h o ut pers o nal s u bject i de ntificati o n, 
mai ntai ni n g t he tracea bilit y  of a d oc u me nt t o t he s u bject i de ntifiers.

A d diti o nal i nf or mati o n ma y  be re q ueste d t o e ns ure t he ti mel y  c o m pleti o n of acc urate safety 
re p orts.
A n y  me dicati o ns necessar y f or treat me nt of t he S A E m ust be rec or de d o nt o t he c o nc o mita nt 
me dicati o n secti o n of t he s u bject’s e C R F a n d t he e ve nt descri pti o n secti o n of t he S A E f or m.
Ser i o us A d verse E ve nt Pa per Re p orti n g Pr ocess

All S A E s will be rec or de d o n t he S A E re p ort f or m a n d s u b mitte d b y fa xi n g t he re p ort f or m 
wit hi n 2 4 h o urs of t he i n vesti gat or’s k n o wle d ge of t he e ve nt t o t he atte nti o n of Gilea d D S P H.

As s o o n as it is p ossi ble t o d o s o, a n y  S A E re p orte d via pa per m ust be tra nscri be d i nt o t he 
e C R F data base acc or di n g t o i nstr ucti o ns i n t he e C R F c o m pleti o n g ui deli nes.
If a n S A E has bee n re p orte d via a pa per f or m beca use t he e C R F data base has bee n l oc ke d, n o 
f urt her acti o n is necessar y.
7. 4.
Gile a d Re p orti n g Re q uire me nts
De pe n di n g o n rele va nt l ocal le gislati o n or re g ulati o ns, i ncl u di n g t he a p plica ble U S F D A 
C o de of Fe deral Re g u lati o ns, t he E ur o pea n U ni o n ( E U ) Cli nical Trials Directi ve ( 2 0 0 1/ 2 0/ E C) 
a n d rele va nt u p dates, a n d ot her c o u ntr y -s pecific le gislati o n or re g ulati o ns, Gilea d ma y be 
re q uire d t o e x pe dite t o w orl d wi de re g ulat or y a ge ncies re p orts of S A E s, S A D Rs, or s us pecte d 
u ne x pecte d seri o us a d verse reacti o ns ( S U S A Rs). I n acc or da nce wit h t he E U Cli nical Trials
Directi ve ( 2 0 0 1/ 2 0/ E C), Gilea d or a s pecifie d desi g nee will n otif y  w orl d wi de re g ulat or y 
a ge ncies a n d t he rele va nt IE C i n c o ncer ne d Me m ber States of a p plica ble S U S A Rs as o utli ne d i n 
c urre nt re g ulati o ns.
Assess me nt of e x pecte d ness f or S A E s will be deter mi ne d b y  Gilea d usi n g refere nce safet y 
i nf or mati o n s pecifie d i n t he i n vesti gat or’s br oc h ure or rele va nt l ocal la bel as a p plica ble.
All i n vesti gat ors will recei ve a safet y letter n otif yi n g t he m of rele va nt sus pecte d u ne x pecte d 
seri o us a d verse reacti o n (S U S A R ) re p orts. T he i n vesti gat or s h o ul d n otif y t he IR B of 
S U S A R re p orts as s o o n as is practical, w here t his is re q uire d by l ocal re g ulat or y a ge ncies, a n d i n 
acc or da nce wit h t he l ocal i nstit uti o nal p olic y.
7. 5.
Cli ni c al L a b or at or y A b n or m alities a n d Ot her A b n or m al Assess me nts as 
A d verse E ve nts or Seri o us A d verse E ve nts
La b orat or y  a b n or malities wit h o ut cli nical si g nifica nce are n ot rec or de d as A E or S A E . H o we ver, 
la b orat or y a b n or malities (e g, cli nical c he mistr y, he mat ol o g y , a n d uri nalys is) t hat re q uire me dical 
or s ur gical i nter ve nti o n or lea d t o I M P i nterr u pti o n, m o dificati o n, or disc o nti n uati o n m ust be 
rec or de d as a n A E, as well as a n S A E, if a p plica ble. I n a d diti o n, la b orat or y or ot her a b n or mal 


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assess me nts (e g, electr ocar di o gra m, x -ra ys, vital si g ns) t hat are ass ociate d wit h si g ns a n d/ or 
s ym pt o ms m ust be rec or de d as a n A E or S A E if t he y  meet t he defi niti o n of a n A E or S A E as 
descri be d i n Secti o n 7. 1. 1 a n d Secti o n 7. 1. 2 . If t he la b orat or y a b n or malit y is part of a s yn dr o me, 
rec or d t he s yn dr o me or dia g n osis (e g, a ne mia), n ot t he la b orat or y res ult 
(ie, decrease d he m o gl o bi n).
7. 6.
Rec o m me n d ati o ns f or E v al u ati o n, I nter ve nti o n, a n d Dr u g Disc o nti n u ati o n 
f or S pecific A d verse E ve nts or C o n diti o ns
7. 6. 1.
Der m at ol o gic al E ve nts
S u bjects r ecei vi n g i delalisi b wit h ≥Gra de 3 ras h ha ve ge nerall y prese nte d wit h a mac ul o pa p ular 
ras h o n t he tr u n k a n d e xtre mities t hat is occasi o nall y ass ociate d wit h fe ver a n d/ or pr urit us a n d 
res p o n de d t o treat me nt wit h di p he n h ydra mi ne a n d/ or t o pical or oral c ortico ster oi ds. 
F or s u bjects w h o de vel o p a se vere ras h f or w hic h a n u n derl yi n g eti ol o g y  ca n n ot be i de ntifie d 
(e. g., i nfecti o n, c o-s us pect dr u g), st u d y dr u g s h o ul d be i nterr u pte d. Res u m pti o n of st u d y  dr u g 
s h o ul d be c o nsi dere d o nce ras h res ol ves.
Se vere c uta ne o us reacti o ns, i ncl u di n g fatal e ve nts of Ste ve ns -Jo h ns o n s y n dr o me ( SJ S) a n d 
t o xic e pi der mal necr ol ys is ( T E N), ha ve bee n re p orte d i n s u bjects recei vi n g i delalis b. Assess me nt 
of p ote ntial ca usal ass ociati o n bet wee n i delalisi b a n d t he occ urre nce of SJ S or T E N has bee n 
c o nf o u n de d b y t he c oa d mi nistrati o n of a nti ne o plastic a ge nts (e . g., be n da m usti ne, rit u xi ma b) 
a n d/ or ot her c o nc o mita nt me dicati o ns k n o w n t o be ass ociate d wit h SJ S or T E N 
(e.g., all o p uri n ol). If SJ S or T E N is s us pecte d, i delalisi b a n d all c oa d mi nistere d me dicati o ns 
ass ociate d wit h SJ S or T E N s h o ul d be i nterr u pte d a n d t he s u bject treate d acc or di n gl y per 
i nstit uti o nal sta n dar ds. 
S u bjects s h o ul d be m o nit ore d f or t he de vel o p me nt of SJ S, T E N, or ot her se vere c uta ne o us 
reacti o ns a n d i delalisi b treat me nt s ho ul d be disc o nti n ue d if s uc h e ve nts occ ur.
7. 6. 2.
G astr oi ntesti n al E ve nts
Is olate d cases of gastr oi ntesti nal i nfla m mati o n (e g, st o matitis, c olitis, cecitis) ha ve bee n n ote d i n 
s u bjects recei vi n g i delalisi b. Rare cases of gastr oi ntesti nal perf orati o n ha ve occ urre d , ge nerally 
i n t he setti n g of occ ult carci n o ma, mese nteric e mb ol us or di vertic ular disease. St u d y  treat me nt 
(i delalisi b) s h o ul d be disc o nti n ue d i n s u bjects w h o e x perie nce b o wel perf orati o n.
C h ola n gitis ma nifest as h y per bilir u bi ne mia o ut of pr o p orti o n t o se r u m tra nsa mi nase ele vati o ns 
has bee n o bser ve d. W hile
disease -relate d fact ors, ne utr o pe nia, t o xicit y fr o m pri or t hera pies, 
effects of o n g oi n g s u p p orti ve care, or pre -e xisti n g c h olelit hiasis ma y ha ve i nitiate d s uc h e ve nts, 
it is p ossi ble t hat i delalisi b pla y e d a c o ntri b ut or y r ole. I n s uc h s u bjects, rec halle n ge wit h 
i delalisi b has bee n p ossi ble a n d has n ot bee n ass ociate d wit h ot her se vere a d verse e ve nts. 
S u bjects w h o ha ve de vel o pe d e vi de nce of e nteritis d uri n g i delalisi b t hera p y have bee n 
s uccessf ully treate d wit h a nti diarr heals (e g, l o pera mi de) a n d wit h e nteric ster oi dal 
(e g, b u des o ni de) or n o n- ster oi dal (e g s ulfasalazi ne [Az ulfi di ne ® ]) a nti-i nfla m mat or y a ge nts a n d 
ha ve bee n a ble t o c o nti n ue or res u me i delalisi b.


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F or st u d y s u bjects w h o de vel o p se vere a b d o mi na l pai n t he p ossi bilit y of a b o wel o bstr ucti o n or 
perf orati o n s h o ul d be c o nsi dere d. A p pr o priate cli nical a n d ra di o gra p hic e xa mi nati o n s h o ul d be 
perf or me d a n d s u p p orti ve care or s ur gical i nter ve nti o n s h o ul d be c o nsi dere d. 
F or s u bjects w h o de vel o p persiste nt diarr hea, ca uses relate d t o c o nc o mita nt me dicati o ns or 
gastr oi ntesti nal i nfecti o n s s uc h as Cl ostri di u m difficile ( partic ularly f or patie nts rece ntl y treate d 
wit h br oa d s pectr u m a nti bi otics), S hi gella, Ca m p yl o bacter, Yersi nia a n d C M V s h o ul d be 
c o nsi dere d an d treate d if a p pr o priate . De pe n di n g u p o n t he cli nical circ u msta nces, e n d osc o p y a n d 
bi o ps y , wit h bacterial a n d viral I H C stai ni n g s h o ul d be c o nsi dere d. I n t he e ve nt t hat a n i nfecti o us 
ca use is n ot i de ntifie d, a n a nti m otilit y  a ge nt (e g, l o pera mi de) m a y  lesse n s y m pt o ms a n d 
i nter ve nti o n wit h e nteric ster oi dal (e g, b u des o ni de) or n o n-ster oi dal (e g, s ulfasalazi ne) 
a nti-i nfla m mat or y a ge nts s h o ul d be c o nsi dere d. I n s uc h s u bjects, rec halle n ge wit h i delalisi b at a 
l o wer d ose le vel has res ulte d i n rec urre nce of sy m pt o ms i n s o me b ut n ot all s u bjects a n d has n ot 
bee n ass ociate d wit h ot her se vere a d verse e ve nts. Wit h h ol d i delalisi b f or s u bjects wit h
Gra de 3 
di arr hea a n d m o nit or at least wee kl y u ntil res ol ve d, t he n ma y res u me i delalisi b at sa me d ose if i n 
C o h ort A, or at pre vi o us d ose le vel if i n C o h orts B t hr o u g h D. Disc o nti n ue i delalisi b 
per ma ne ntl y f or Gra de 4 diarr hea.
7. 6. 2. 1.
I n vesti gati o n f or I delalisi b Late O nset or Se vere Diarr hea/ C olitis
See C T C A E Versi o n 4. 0 3 (A p pe n di x 1 1 ) f or defi niti o n s of c olitis a n d diarr hea .
A m o n g i delalisi b-treate d patie nts w h o re p orte d diarr hea or c olitis, t he me dia n ti me t o o nset of 
a n y gra de diarr hea or c olitis was 1. 9 m o nt hs (ra n ge, 0. 0– 2 9. 8), of gra de 1 or 2 was 1. 5 m o nt hs 
(ra n ge, 0. 0– 1 5. 2) a n d of gra de 3 or 4 was 7. 1 m o nt hs (ra n ge, 0. 5 – 2 9. 8). Ka pla n – Meier c ur ves of 
ti me t o onset of diarr hea or c olitis are s h o w n f or all i delalisi b - treate d patie nts i n Fi g ure 7- 1
{ C o utre et al 2 0 1 5 } .
Fi g ure 7- 1.
K a pl a n -Meie r Ti me t o Di arr he a or C olitis
I delalisi b-ass ociate d se vere diarr hea res p o n ds p o orl y  t o a nti m otilit y a ge nts h o we ver, me dia n 
ti me t o res ol uti o n ra n ge d bet wee n 1 wee k a n d 1 m o nt h acr oss trials f oll o wi n g i nterr u pti o n of 
i delalisi b treat me nt a n d, i n s o me i nsta nces, i nitiati o n of c ortic oster oi d treat me nt
{ Gilea d Scie nces I nc 2 0 1 4 } .
1 0 0 
8 0 
6 0 
4 0 
2 0 
K a pl a n- M ei er Ti m e t o D i arr h e a or C oliti s 
A n y  G r a d e 
• - o-
Gr a d e ~ 3 
.,.,. _____ -·-· 
0  
4  
8 
1 2 
1 6 
2 0 
2 4 
2 8 
3 2  3 6 
4 0 
4 4 
4 8 
5 2 
T i m e Si n c e F i r st D o s e ( M o nt h s) 
- · -
.... ,. , ...,.,.., ,,.,,,.,,,.,,:, .. , ..,.,,..,, • .,..,., .. """' .. "'"" "' '""'' " "" " 
• < > < »> 
,,...,, 
> t > < »J 
" " "' ' 
- d 
- •• > 0 1 > < > 0) 
, ... _ 
, 
...,.,.,.., 
1 M I N > , .. .-, ""'°" .. , .. ., , _,,,,.., ,.,, ... , 0 < 1 C NI ) 
> <- > 
> 1- 1 
"
'""' 
V erti c al d ot li n e re pr- e s e nt s m e di a n ti m e t o o n s et c al c ul at e d b a s e d o n all s u bj e ct s wit h a n e v e n t 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 6 9
2 6 Oct o ber 2 0 1 6
7. 6. 3.
He p atic E ve nts
7. 6. 3. 1.
Tra nsa mi nase Ele vati o ns
C o nsiste nt wit h o bser vati o ns i n a d o g t o xic ol o g y  stu d y , re versi ble asy m pt o matic A L T/ A S T 
i ncreases were als o o bser ve d early i n t he i delalisi b pr o gra m i n p h ase 1 st u dies 
( 1 0 1- 0 2 a n d 1 0 1 - 0 7) i n s u bjects wit h he mat ol o gic mali g na ncies. Tra nsa mi nase ele vati o ns 
ge nerall y occ urre d wit hi n 4 t o 1 2 wee ks of dr u g i nit iati o n, a n d res ol ve d s p o nta ne o usl y o ver a 
peri o d of 2 t o 4 wee ks wit h dr u g bei n g c o nti n ue d f or Gra de 1 a n d 2 ele vati o ns a n d dr u g wit h hel d 
f or Gra de 3 or 4 ele vati o ns u ntil res ol uti o n. T hese early o bser vati o ns ha ve bee n c o nsiste nt wit h 
t he o n g oi n g e x perie nce wit h i delalisi b treat me nt a n d tra nsa mi nase ele vati o ns are n o w well 
c haracterize d as m ost fre q ue ntl y asy m pt o matic, tra nsie nt a n d occ ur ri n g wit hi n t he first 3 m o nt hs 
of treat me nt.
Gra de 1 or 2 ele vati o ns c o m m o nl y  res ol ve des pite c o nti n ue d i delalisi b treat m e nt a n d 
Gra de 3 or 4 ele vati o ns ca n be ma na ge d b y te m p oraril y wit h h ol di n g i delalisi b. S uccessf ul 
rec halle n ge after res ol uti o n at eit her t he sa me or l o wer d ose le vel of i delalisi b has bee n ac hie ve d 
i n t he maj orit y of s u bjects. T here has bee n n o e vi de nce of i m paire d sy nt hetic f u ncti o n. Cl ose 
m o nit ori n g of he patic la b orat or y  tests d uri n g t hera p y is i m p orta nt t o all o w f or a p pr o priate 
i delalisi b i nterr u pti o n a n d rei nstit uti o n s o t hat s u bjects ma y  c o nti n ue wit h st u d y dr u g treat me nt.
7. 6. 4.
He m at ol o gic al a n d I m m u n ol o gic al E ve nts
I n t he P hase 1 e x perie nce wit h i delalisi b i n patie nts wit h N H L  a n d C L L, s u bjects wit h Gra de ≥3 
ne utr o pe nia, a ne mia, a n d/ or t hr o m b oc y t o pe nia were e nr olle d t o cli nical trials. Decrease d le vels 
of ne utr o p hil c o u nts, he m o gl o bi n, or platelet c o u nts d uri n g i delalisi b a d mi nistrati o n were lar gel y 
d ue t o mi n or fl uct uati o ns i n t hese para meters a m o n g s u bjects wit h pre -e xisti n g he mat ol o gical 
a b n or malities d ue t o disease or pri or t hera p y. T h us, i delalisi b di d n ot a p pear t o i n d uce o vert 
m y el os u p pres si o n. O b vi o us patter ns of dr u g- me diate d re d ucti o ns i n circ ulati n g C D 4 + 
l ym p h oc y te c o u nts or s u p pressi o n of ser u m I g G le vels were als o n ot o bser ve d.
Treat me nt - e mer ge nt Gra de 3 or 4 ne utr o pe nia e ve nts, i ncl u di n g fe brile ne utr o pe nia, ha ve 
occ urre d i n s u bjects treate d wit h i delalisi b. All s u bjects are re q uire d t o ha ve t heir bl o o d c o u nts 
m o nit ore d at least e ver y 2 wee ks d uri n g t he first 2 4 wee ks of i delalisi b d osi n g. F or s u bjects w h o 
de vel o p A N C 0. 5 t o < 1. 0 x 1 0 9/ L ( Gra de 3), bl o o d c o u nts s h o ul d be m o nit ore d at least wee kly
u ntil A N C ≤Gra de 2. F or s u bjects w h o de vel o p A N C < 0. 5 x 1 0 9/ L ( Gra de 4), i delalisi b s h o ul d 
be i nterr u pte d a n d bl o o d c o u nts m o nit ore d at least wee kl y u ntil A N C is ≥1. 0 x 1 0 9/ L ( Gra de 2), 
at w hic h p oi nt, i delalisi b d osi n g ma y  be res u me d at sa me or l o wer d ose le vel at i n vesti gat or 
discreti o n. Ne utr o pe nia s h o ul d be ma na ge d acc or di n g t o esta blis he d cli nical g ui deli nes. N o 
m o dificati o n of a n y dr u g f or c ha n ges i n circ ulati n g C D 4 + c o u nts or I g le vels is pla n ne d.
7. 6. 5.
I nfecti o us E ve nts
Patie nts wit h l ym p h oi d ca ncers recei vi n g i delalisi b ha ve de vel o pe d seri o us a n d fatal i nfecti o ns 
d uri n g t hera p y. O p p ort u nistic i nfecti o ns, m ost n ota bl y  P ne u m ocystis jir oveci p ne u m o nia ( PJ P) 
a n d C M V i nfecti o n, ha ve m ost fre q ue ntl y occ urre d wit hi n t he first 6 m o nt hs of treat m e nt wit h 
i delalisi b a n d are i ncrease d i n t he c o nte xt of c o nc urre nt myel os u p pressi ve t hera p y s uc h as 
be n da m usti ne.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 7 0
2 6 Oct o ber 2 0 1 6
S u bjects m ust recei ve tri met h o pri m- s ulfa met h o xaz ole or ot her esta blis he d pr o p h yla xis f or PJ P
t hr o u g h o ut t he co urse of i delalisi b treat me nt. Pr o p h y la xis will c o nti n ue f or a peri o d of 2 t o 
6 m o nt hs after i delalisi b disc o nti n uati o n.  T he d urati o n of pr o p h yl a xis s h o ul d be base d o n 
cli nical j u d g me nt a n d ma y ta ke i nt o acc o u nt ris k fact ors s uc h as c o nc o mita nt c ortic oster oi d 
treat me nt a n d pr ol o n ge d ne utr o pe nia after i delalisi b treat me nt e n ds. S u bjects m ust per ma ne ntl y  
disc o nti n ue i delalisi b u p o n dia g n osis of PJ P.
C M V s ur veilla nce f or acti ve disease ( q ua ntitati ve P C R or p p 6 5 a nti ge n) m ust be c o n d ucte d 
a p pr o xi matel y e ver y 4 wee ks t hr o u g h o ut t he c o urse of i delalisi b treat me nt. C M V viral l oa d 
testi n g s h o ul d be perf or me d fr o m t he sa me s peci me n t ype w he ne ver p ossi ble a n d ca uti o n s h o ul d 
be e xercise d w he n c o m pari n g C M V viral l oa d res ults acr oss differe nt testi n g ce nters. If 
u ne q ui v ocal cli nical or la b orat or y  e vi de nce of C M V i nfecti o n is prese nt, t he s u bject m ust 
per ma ne ntl y disc o nti n ue i delalisi b treat me nt a n d u n der g o effecti ve a nti viral treat me nt acc or di n g 
t o esta blis he d cli nical g ui deli nes.
I n hi g h-ris k s u bjects ( hist or y of rec urre nt i nfecti o n, all o ge neic tra ns pla nt, treat me nt wit h 
ale mt uz u ma b, h yp o ga m ma gl o b uli ne mia) ot her i nfecti o n pr o p h yl a xis s h o ul d be c o nsi dere d per 
c o nse ns us g ui deli nes. A d mi nistrati o n of i ntra ve n o us i m m u n o gl o b uli n is per mitte d per sta n dar d 
i nstit uti o nal practice { Raa na ni et al 2 0 0 9 }. F or s u bjects w h o de vel o p a n i nfecti o n, a p pr o priate 
me dical t hera p y s h o ul d be i nstit ute d i n a ti mel y ma n ner.
7. 6. 6.
P ul m o n ar y E ve nts
D oc u me nte d bacterial, f u n gal, viral, a n d p ne u m oc ystis p ne u m o nias ha ve bee n o bser ve d i n 
patie nts recei vi n g i delalisi b, pri maril y i n patie nts wit h C L L. S o me st u d y s u bjects recei vi n g 
i delalisi b al o ne or i n c o m bi nati o n ha ve de vel o pe d e vi de nce of p ne u m o nitis wi t h o ut d oc u me nte d 
p ul m o nar y i nfecti o n. 
Gi ve n t he p ote ntial f or i nfecti o us or dr u g -relate d p ul m o nar y  a d verse e ve nts, cli nicia ns s h o ul d 
be partic ularl y  o bser va nt f or e vi de nce of res pirat or y e ve nts i n s u bjects partici pati n g i n t his 
trial. S u bjects w h o descri b e p ul m o nar y sy m pt o ms (e g, d y s p nea on e xerti o n, c o u g h, 
s h ort ness of breat h); ma nifest a decli ne fr o m baseli ne of ≥ 5 % i n o x y ge n sat urati o n, or 
de m o nstrate e vi de nce of p ul m o nar y  i nfla m mati o n (e g, f ocal or diff use i nterstitial patter n or 
gr o u n d -glass o pacities o n c hest C T) s h o ul d be e val uate d. P ote ntial bacterial, f u n gal, or viral 
eti ol o gies s h o ul d be assesse d . N o ni nfecti o us eti ol o gies s uc h as p ul m o nar y  e de ma or 
t hr o m b oe m b olis m s h o ul d als o be c o nsi dere d.
As a p pr o priate f or t he cli nical sit uati o n a n d c u lt ure res ults, s u bjects s h o ul d be treate d e m pirically 
or gi ve n s pecific a nti bi otics, a ntif u n gals, or a nti viral a ge nts f or a c ult ure d or ga nis m. S u p p orti ve 
care, i ncl u di n g o x y ge n or mec ha nical ve ntilati o n, s h o ul d be pr o vi de d as necessar y .
F or s u bjects wit h s us pecte d Gra de 1 p ne u m o nitis, wit h h ol d i delalisi b u ntil res ol uti o n t o baseli ne. 
U p o n res ol uti o n t o baseli ne, i delalisi b ma y be res u me d at l o wer d ose le vel or disc o nti n ue d at 
i n vesti gat or discreti o n. F or s u bjects wit h s us pecte d Gra de ≥2 p ne u m o niti s (e g, new o nset or 
w orse ni n g of baseli ne c o u g h, d y s p nea, h yp o xia a n d/ or a diff use i nterstitial patter n or gr o u n d -
glass o pacities o n c hest i ma gi n g wit h o ut o b vi o us i nfecti o us eti ol o g y ), i delalisi b m ust be 
disc o nti n ue d per ma ne ntl y  a n d t hera p y i nitiate d as cli nicall y a p pr o priate.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 7 1
2 6 Oct o ber 2 0 1 6
7. 6. 7.
Sec o n d ar y M ali g n a ncies
S u bjects recei vi n g i delalisi b f or C L L or i N H L ha ve de vel o pe d pre -mali g na nt a n d sec o n dar y  
mali g na nt diseases, s uc h as basal cell carci n o ma, m y el o d ys plastic s y n dr o me, m yel o pr oliferati ve 
dis or ders, a n d m ore a g gressi ve l y m p h oi d mali g na ncies (e g, ha ve ha d Ric hter tra nsf or mati o n). 
Ge nerall y  t his has occ urre d i n s u bjects w h o ha ve recei ve d m ulti ple pre vi o us li nes of t hera p y a n d 
w he n i delalisi b is c o m bi ne d wit h ot her t hera pies s uc h as rit u xi ma b or be n da m usti ne. T he s pecific 
ass ociati o n of t he t hera pe utic a ge nts wit h t hese t y p es of e ve nts has n ot bee n deter mi ne d.
T here are re p orts of pre - mali g na nt a n d mali g na nt diseases t hat ha ve de vel o pe d i n s u bjects w h o 
ha ve bee n treate d wit h be n da m usti ne, i ncl u di n g m y el o d ys plastic sy n dr o me, m y elo pr oliferati ve 
dis or ders, ac ute m y el oi d le u ke mia, a n d br o nchial carci n o ma. T he s pecific ass ociati o n of t he 
t hera pe utic a ge nts wit h t hese t ypes of e ve nts has n ot bee n deter mi ne d.
7. 6. 8.
T u m or L ysis S y n dr o me
T u m or l y sis s yn dr o me has n ot bee n o bser ve d wit h neit her idelalisi b n or r u x oliti ni b m o n ot hera p y .
7. 6. 9.
Pre g n a nc y, L act ati o n, a n d Re pr o d ucti o n
I delalisi b has i n d uce d e m br yo let halit y  a n d terat o ge nicit y w he n a d mi nistere d t o pre g na nt fe male 
rats at mater nall y t o xic d oses. H o we ver, defi niti ve re pr o d ucti ve t o xic ol o g y st u dies i n a ni mals 
ha ve n ot yet bee n perf or me d a n d t he s pecific effects of i delalisi b o n h u ma n e m br y o ge nesis or 
fetal de vel o p me nt are u n k n o w n. W het her i delalisi b is e xcrete d i n h u ma n breast mil k is u n k n o w n. 
Ge neral t o xic ol o g y st u dies of i delalisi b i n rats a n d d o gs i n dicate d d ose -de pe n de nt re d ucti o ns i n 
testic ular wei g hts, wit h persiste nt mi ni mal t o mil d de ge nerati o n of t he se mi nifer o us t u b ules a n d 
decrease d s per mat oz oa i n rats a n d h y p os per mat o ge nesis i n d o gs. T he i m plicati o ns of t hese 
testic ular c ha n ges f or a ni mal or h u ma n fertilit y are u n k n o w n.
Gi ve n t he p ote ntial t he ris ks t o a fet us or i nfa nt as a res ult of e x p os ure t o i delalisi b, w o me n of 
re pr o d ucti ve p ote ntial e nteri n g t his st u d y m ust ha ve a ne gati ve ser u m pre g na nc y test at baseli ne 
a n d m ust n ot be breastfee di n g. Males a n d fe males of c hil d beari n g p ote ntial s h o ul d a bstai n fr o m 
se x ual i nterc o urse or use a n effecti ve f or m of c o ntrace pti o n (see A p pe n di x 1 0 ). If a fe male st u dy 
partici pa nt bec o mes pre g na nt or deci des t o breastfee d d uri n g t he c o urse of t he st u d y , all st u d y 
t hera py ( i delalisi b/) m ust be disc o nti n ue d.
7. 6. 9. 1.
PJ P Pr o p h y la xis
Tri met h o pri m s ulfa met h o xaz ole is rate d a Pre g na nc y cate gor y  C a ge nt. I n rats, oral d oses of 
5 3 3 m g/ k g or 2 0 0 m g/ k g pr o d uce d terat ol o gic effects ma nifeste d mai nl y as cleft palates. 
O ne s ur ve y f o u n d n o c o n ge nital a b n or malities i n 3 5 c hil dre n w h ose m ot hers ha d recei ve d oral 
s ulfa met h o xaz ole a n d tri met h o pri m at t he ti me of c o nce pti o n or s h ortly t hereafter. Beca use 
s ulfa met h o xaz ole a n d tri met h o pri m ma y i nterfere wit h f olic aci d meta b olis m it s h o ul d be use d 
d uri n g pre g na nc y  o nl y if t he p ote ntial be nefit j ustifies t he p ote ntial ris k t o t he fet us.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 7 2
2 6 Oct o ber 2 0 1 6
Da ps o ne is rate d a Preg na nc y  Cate g or y C a ge nt . E xte nsi ve, b ut u nc o ntr olle d e x perie nce a n d t w o 
p u blis he d s ur ve y s o n t he use of Da ps o ne i n pre g na nt w o me n ha ve n ot s h o w n t hat Da ps o ne 
i ncreases t he ris k of fetal a b n or malities if a d mi nistere d d uri n g all tri mesters of pre g na nc y or can 
affect re pr o d ucti o n ca pacit y . Beca use of t he lac k of a ni mal st u dies or c o ntr olle d h u ma n 
e x perie nce, Da ps o ne s h o ul d be gi ve n t o a pre g na nt w o ma n o nl y  if clearly nee de d. Da ps o ne is 
e xcrete d i n breast mil k i n s u bsta ntial a m o u nts. He m ol y tic reacti o ns ca n occur i n ne o nates. 
Beca use of t he p ote ntial f or t u m or ge nicit y s h o w n f or Da ps o ne i n a ni mal st u dies a decisi o n 
s h o ul d be ma de w het her t o disc o nti n ue n ursi n g or disc o nti n ue t he dr u g ta ki n g i nt o acc o u nt t he 
i m p orta nce of dr u g t o t he m ot her.
At o va q u o ne is rate d a Pre g na nc y  Cate g or y C a ge nt . At o va q u o ne is terat o ge nic a n d di d n ot ca use 
re pr o d ucti ve t o xicit y i n rats at plas ma c o nce ntrati o ns u p t o 2 t o 3 ti mes t he esti mate d h u ma n 
e x p os ure. At o va q u o ne ca n ca use mater nal t o xicit y  i n ra b bits at plas ma c o nce ntrati o ns t hat were 
a p pr o xi matel y o ne half t he esti mate d h u ma n e x p os ure. Mea n fetal b o dy le n gt hs a n d wei g hts 
were decrease d a n d t here were hi g her n u m bers of earl y res or pti o n a n d p ost -i m pla ntati o n l oss per 
da m. I t is n ot clear w het her t hese effects are ca use d b y at o va q u o ne directl y or are sec o n dar y t o 
mater nal t o xicit y . C o nce ntrati o ns of at o va q u o ne i n ra b bit fet uses a vera ge d 3 0 % of t he c o nc urre nt 
m ater nal plas ma c o nce ntrati o ns. T here are n o a de q uate a n d well -c o ntr olle d st u dies i n pre g na nt 
w o me n. At o va q u o ne s h o ul d be use d d uri n g pre g na nc y  o nly if t he p ote ntial be nefit j ustifies t he 
p ote ntial ris k t o t he fet us. It is n ot k n o w n w het her at o va q u o ne is e xcrete d i nt o h u ma n mil k. 
Beca use ma n y dr u gs are e xcrete d i nt o h u ma n mil k, ca uti o n s h o ul d be e xercise d w he n 
At o va q u o ne is a d mi nis tere d t o a n ursi n g w o ma n. I n a rat st u dy, at o va q u o ne c o nce ntrati o ns i n t he 
mil k were 3 0 % of t he c o nc urre nt at o va q u o ne c o nce ntrati o ns i n t he mater nal plas ma.
Aer os olize d Pe nta mi di ne ( Ne b u Pe nt) is a Pre g na nc y  Cate g or y C a ge nt. T here are n o a de q uate 
a n d well c o ntr olle d st u dies of Ne b u Pe nt i n pre g na nt w o me n. O ne literat ure re p ort i n dicate d t hat 
i ntra ve n o usl y a d mi nistere d pe nta mi di ne i n pre g na nt rats at 4 m g/ k g/ da y was e m br yolet hal; 
terat o ge nicity was n ot o bser ve d i n t his st u d y. It is u n k n o w n w het her pe nta mi di ne a d mi nistere d 
via t he aer os olize d r o ute cr osses t he place nta at cli nicall y  si g nifica nt c o nce ntrati o ns. It is n ot 
k n o w n w het her Ne b u Pe nt ca n ca use fetal har m w he n a d mi nistere d t o a pre g na nt w o ma n. 
Ne b u Pe nt s h o ul d be gi ve n t o a pre g na nt w o ma n o nl y  if clearly nee de d. It is n ot k n o w n w het her 
Ne b u P e nt is e xcrete d i n h u ma n mil k. Ne b u Pe nt s h o ul d n ot be gi ve n t o a n ursi n g m ot her u nless 
t he p ote ntial be nefits are j u d ge d t o o ut wei g h t he u n k n o w n ris ks.
7. 6. 1 0.
Ultr a vi olet E x p os ure
I n vitr o st u dies i n dicate e n ha nce d c yt ot o xicit y w he n e m br yo nic m uri ne fi br o blasts treate d wit h 
G S - 5 6 3 1 1 7 (t he maj or meta b olite of i delalisi b) are si m ulta ne o usl y e x p ose d t o ultra vi olet li g ht. 
W hile n o ncli nical fi n di n gs s u g gest t he h y p ot hetical p ote ntial f or p h ot ot o xicit y i n h u ma ns, 
a vaila ble cli nical data d o n ot re veal a p h ot osafet y c o ncer n. Alt h o u g h s pecific cli nical c orrelates 
f or t hese n o ncli nical data are n ot a vaila ble, i n vesti gat ors a n d st ud y  s u bjects s h o ul d be 
o bser va nt f or t he p ossi bilit y t hat st u d y partici pa nts ma y ha ve e xa g gerate d s u n b ur n reacti o ns 
(e g, b ur ni n g, er yt he ma, e x u dati o n, vesicles, blisteri n g, e de ma) i n v ol vi n g areas of s ki n e x p ose d t o 
ultra vi olet li g ht.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 7 3
2 6 Oct o ber 2 0 1 6
7. 6. 1 1. 
F urt her S afet y I nf or m ati o n
F urt her safet y i nf or mati o n re gar di n g t he st u d y dr u g ma y be f o u n d i n t he i n vesti gat or br oc h ure 
f or i delalisi b.
F urt her safet y i nf or mati o n re gar di n g r u x oliti ni b is pr o vi de d i n t he c urre nt pr o d uct la beli n g.
7. 7.
S peci al Sit u ati o ns Re p orts
7. 7. 1.
Defi niti o ns of S peci al Sit u ati o ns
S pecial sit uati o n re p orts i ncl u de all re p orts of me dicati o n err or, a b use, mis use, o ver d ose, lac k of 
effect re p orts, a n d pre g na nc y re p orts re gar dless of a n ass ociate d A E. Als o i ncl u des re p orts of
a d verse reacti o ns i n i nfa nts f oll o wi n g e x p os ure fr o m breastfee di n g , a n d re p orts of a d verse 
reacti o ns ass ociate d wit h pr o d uct c o m plai nts a n d re p orts arisi n g fr o m occ u pati o nal e x p os ure.
A pre g na nc y  re p ort is use d t o re p ort a ny pre g na nc y f oll o wi n g mater nal or pater nal e x p os ure t o 
t he me dici nal pr o d uct.
Me dicati o n err or is a n y u ni nte nti o nal err or i n t he prescri bi n g, dis pe nsi n g, or a d mi nistrati o n of a 
me dici nal pr o d uct w hile i n t he c o ntr ol of t he healt h care pr o vi der, s u bject, or c o ns u mer.
A b use is defi ne d as persiste nt or s p ora dic i nte nti o nal e xcessi ve use of a me dici nal pr o d uct b y  a 
s u bject.
Mis use is defi ne d as a n y i nte nti o nal or i na p pr o priate use of a me dici nal pr o d uct t hat is n ot i n 
acc or da nce wit h t he pr ot oc ol i nstr ucti o ns or t he l ocal prescri bi n g i nf or mati o n.
A n o ver d ose is defi ne d as a n acci de ntal or i nte nti o nal a d mi nistrati o n of a q ua ntit y  of a me dici nal 
pr o d uct gi ve n per a d mi nistrati o n or c u m ul ati vel y w hic h is a b o ve t he ma xi m u m rec o m me n de d 
d ose as per pr ot oc ol or i n t he pr o d uct la belli n g (as it a p plies t o t he dail y  d ose of t he s u bject 
i n q uesti o n). I n cases of a discre pa nc y i n dr u g acc o u nta bilit y, o ver d ose will be esta blis he d o nly 
w he n it is clear t hat t he s u bject has ta ke n t he e xcess d ose(s). O ver d ose ca n n ot be esta blis he d 
w he n t he s u bject ca n n ot acc o u nt f or t he discre pa nc y  e xce pt i n cases i n w hic h t he i n vesti gat or has 
reas o n t o s us pect t hat t he s u bject has ta ke n t he a d diti o nal d ose(s).
Lac k of effect is defi ne d as a sit uati o n w here t here is a p pare nt fail ure of t he me dici nal pr o d uct or 
me dical tec h n ol o g y  t o bri n g a b o ut t he i nte n de d be neficial effect o n t he i n di vi d ual i n a defi ne d 
p o p ulati o n wit h a gi ve n me dical pr o ble m, u n der i deal c o n diti o ns of use.
Pr o d uct c o m plai nt is defi ne d as c o m plai nts arisi n g fr o m p ote ntial de viati o ns i n t he ma n ufact ure, 
pac ka gi n g, or distri b uti o n of t he me dici nal pr o d uct.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 7 4
2 6 Oct o ber 2 0 1 6
7. 7. 2.
I nstr ucti o ns f or Re p orti n g S peci al Sit u ati o ns
7. 7. 2. 1.
I nstr ucti o ns f or Re p orti n g Pre g na ncies
T he i n vesti gat or s h o ul d re p ort all pre g na ncies t hat are i de ntifie d after t he s u bject first c o nse nts t o 
partici pate i n t he st u d y (ie, si g ns t he i nf or me d c o nse nt) a n d t hr o u g h o ut t he st u d y, i ncl u di n g t he 
p ost st u d y dr u g f oll o w -u p peri o d, t o t he Gilea d D S P H usi n g t he pre g na nc y re p ort f or m wit hi n 
2 4 h o urs of bec o mi n g a ware of t he pre g na nc y . Refer t o S ecti o n 7. 3 a n d t he e C R F c o m pleti o n 
g ui deli nes f or f ull i nstr ucti o ns o n t he mec ha nis m of pre g na nc y  re p orti n g.
T he pre g na nc y  itself is n ot c o nsi dere d a n A E n or is a n i n d uce d electi ve a b orti o n t o ter mi nate a 
pre g na nc y  wit h o ut me dical reas o ns.
A n y  pre mat ure ter mi nati o n of pre g na nc y (e g, a s p o nta ne o us a b orti o n, a n i n d uce d t hera pe utic 
a b orti o n d ue t o c o m plicati o ns or ot her me dical reas o ns) m ust be re p orte d wit hi n 2 4 h o urs as a n 
S A E . T he un derl yi n g me dical reas o n f or t his pr oce d ure s h o ul d be rec or de d as t he A E ter m.
A s p o nta ne o us a b orti o n is al wa y s c o nsi dere d t o be a n S A E a n d will be re p orte d as descri be d i n 
S ecti o ns 7. 1. 1 a n d 7. 1. 2 . F urt her m ore, a ny S A E occ urri n g as a n a d verse pre g na nc y  o utc o me p ost 
st u d y m ust be re p orte d t o Gilea d D S P H.
T he s u bject s h o ul d recei ve a p pr o priate m o nit ori n g a n d care u ntil t he c o ncl usi o n of t he 
pre g na nc y . T he o utc o me s h o ul d be re p orte d t o Gilea d D S P H usi n g t he pre g na nc y o utc o me re p ort 
f or m. If t he e n d of t he preg na nc y  occ urs after t he st u d y has bee n c o m plete d, t he o utc o me s h o ul d 
be re p orte d directl y t o Gilea d D S P H. Gilea d D S P H c o ntact i n f or mati o n is as f oll o ws: 
E mail:
 a n d Fa x: 
Pre g na ncies of fe male part ners of male st u d y s u bjects e x p ose d t o Gilea d or ot her st u d y  dr u gs 
m ust als o be re p orte d a n d rele va nt i nf or mati o n s h o ul d be s u b mitte d t o Gilea d D S P H usi n g t he 
pre g na nc y  a n d pre g na nc y o utc o me f or ms wit hi n 2 4 h o urs. M o nit ori n g of t he s u bject s h o ul d 
c o nti n ue u ntil t he c o ncl usi o n of t he pre g na nc y. If t he e n d of t he pre g na nc y  occ urs after t he st u d y 
has bee n c o m plete d, t he o utc o me s h o ul d be re p orte d directl y t o Gilea d D S P H, 
fa x n u m ber
 or e mail 
 
Refer t o A p pe n di x 1 0
P P D
f or Pre g na nc y Preca uti o ns, Definiti o n f or Fe male of C hil d beari n g 
P ote ntial, a n d C o ntrace pti ve Rec o m me n dati o ns.
7. 7. 2. 2.
Re p orti n g Ot her S pecial Sit uati o ns
All ot her s pecial sit uati o n re p orts m ust be re p orte d o n t he s pecial sit uati o ns re p ort f or m a n d 
f or war de d t o Gilea d D S P H wit hi n 2 4 h o urs of t he i n vesti gat or bec o mi n g a ware of t he sit uati o n. 
T hese re p orts m ust c o nsist of sit uati o ns t hat i n v ol ve st u d y  IM P
as well as a n y Gilea d pr o d uct 
ta ke n as a c o nc o mita nt me dicati o n, w het her or n ot ass ociate d wit h a n a d verse e ve nt . T his 
re p orti n g re q uire me nt d oes n ot a p pl y  t o n o n- Gilea d c o nc o mita nt me dicati o ns. E xce pt f or 
sit uati o ns t hat res ult i n A E , s pecial sit uati o ns i n v ol vi n g n o n -Gilea d c o nc o mita nt me dicati o ns will 
n ot be re p orte d. A n y i na p pr o priate use of me dicati o ns pr o hi bite d b y t his p r ot oc ol s h o ul d n ot be 
re p orte d as “ mis use,” b ut ma y be m ore a p pr o priatel y d oc u me nte d as a pr ot oc ol de viati o n.
P P D
P P D
P P D


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 7 5
2 6 Oct o ber 2 0 1 6
Refer t o S ecti o n 7. 3 a n d t he e C R F c o m pleti o n g ui deli nes f or f ull i nstr ucti o ns o n t he mec ha nis m 
of s pecial sit uati o ns re p orti n g.
All cli nical se q ue lae i n relati o n t o t hese s pecial sit uati o n re p orts will be re p orte d as A E s or S A E s
at t he sa me ti me usi n g t he A E e C R F a n d/ or t he S A E re p ort f or m. Details of t he s y m pt o ms a n d 
si g ns, cli nical ma na ge me nt, a n d o utc o me will be re p orte d, w he n a vaila ble.


I d el alisi b 
Pr ot o c ol G S -U S- 3 9 7 -1 2 4 5 
Gi le a d S ci e n c es , I n c. 
8. 
S T A TI S TI C A L C O N SI D E R A TI O N S 
8. 1. 
A n al ysis O bj e cti v es a n d E n d p oi nts 
8. 1. 1. 
A n al ysis O bj e cti v es 
T h e pri ma 1y o b je ctiv es of thi s st u dy are as f ollo ws : 
Fi n al 
A m e n d m e nt 5 
•  
T o e v al uat e t he s af et y a nd t oler abili t y of i dela lisi b t hr ou g h 2 8 da ys i n su bj e cts re c e i vi ng 
r nx o liti nib as t her ap y f or i nt en n e diat e t o hi g h ris k P M F , post - PV M F , or p os t-E T M F with 
pr o g ressi v e or r el a p s e d di s e as e 
•  
T o d e t er mi ne t he P K of i del alisi b a n d r nx o liti ni b, i n su bj e cts re c e i vi ng r nx o liti nib w it h P M F, 
p os t- PV M F, or p ost - E T M F w it h pr o g ress iv e or r ela p s e d di s e as e 
T h e s e c on d ai y o bj e c tiv es of thi s st ud y ai·e as f ollo ws : 
•  
T o e v al uat e t he s af et y a nd t oler abili t y of c o nt i n uo us d a ily a d mi ni str ati o n of i del alisi b be y on d 
2 8 d a ys i n su bj e cts re c e i vi ng r nx o liti ni b wit h P M F, p ost - PV M F , or post - E T M F 
•  
T o e v al uat e t h e effi c a c y of i d e lalisi b i n s u bj e cts re c e i vi ng r nx o liti ni b w it h P M F , 
p os t- PV M F, or p ost - E T M F b y 2 0 1 3 R e vis e d I WG- M R T a nd E L N resp o n s e crit eria 
I 
8. 1. 2. 
P ri m a r y E n d p oi nt 
T h e pri ma 1y  e n d p o i nts are: 
•  
Ov er a ll s af et y pr ofile of i del alisi b a nd r nx o liti nib aft er 2 8 da ys of e x p os ur e c h ai·act eriz e d b y 
th e t y p e, freq u e n c y, s e v erit y, ti mi ng, a nd r el ati o nshi p t o i d e l alisi b of A E , ab n o n n al 
l a b or at o1y  t ests , di u g di s c ont i n uati o ns d u e t o A Es a nd S A E s. T o x icit y w ill b e ass ess e d b y 
gr a d i ng of A Es a c c or di ng t o t he C T C A E V 4. 0 3 (A p p e n di x 1 1 ). 
• 
P h aim a c o ki netic pai·am et ers of r nx o liti nib ( an d m et ab o lite[s], as a p p lic abl e) a n d i del alisi b 
a n d/ o r its pri m a1y  m et a b o lite, G S- 5 6 3 1 1 7 ( C ma x, T max , A U C, a nd Ctr o u g h) 
8. 1. 3. 
S e c o n d a r y E n d p oi nt 
T h e s e c on d ai y en d p o i nts ar e: 
•  
Ov er a ll s af et y pr ofile of i d e lalisi b a nd r nx o liti nib c ont i n uo us d a ily a d mi ni str ati o n be y on d 
2 8 d a ys of e xp os ur e c h ai·act erize d b y t he t y p e, fre q u en c y, s e v erit y, ti mi ng, a n d r elat i o nshi p 
t o ide l alisi b of a ny A E , ab n o 1 m al l a b or at o1y  t ests , di u g di s c ont i n uati o ns d u e t o A Es a nd 
S A E s. T o xi c it y w ill b e ass ess e d b y gr a d i ng of A E s a c c o r di ng t o t he C T CA E V 4. 0 3 
C O N FI D E N TI A L 
P a g e 7 6 
2 6 O c to b er 2 0 1 6 


I d elalisi b 
Pr o to c o l G S -U S- 3 9 7 -1 2 4 5 
Gi l e a d S c ie n c es, I n c. 
Fi na l 
A m e n d m e nt 5 
• 
R at e of o v e r all res p on s e as de fi ne d b y 2 0 1 3 R e v is e d I W G-M R T a n d E L N r es p on s e cr it eri a 
(A p p e n di x 6), ie, C R , PR, or CI (t h e a chi e v e m e nt of a n e mi a, s pl e en, or s y m pt oms r es p on s e 
wit h o ut pr o g ressi v e di s e as e or i n cre as e i n s e v erit y of a n e mi a, thr o m b o c yt o p eni a, 
or n e u tr o p e ni a). C li ni c al i mpr o v e m e nt wi ll b e m e as ur e d as a n y of th e f ollo w i ng: 
- 
Best s ple e n or liv er r esp o n s e (f or s pl e ne ct o miz e d s u bj e cts) r at e b y p a lp at i o n 
-
B est a n e mi a r es p on s e r at e 
-
B est s y m pt oms r es p on s e 
-
I 
I 
I 
I 
I 
I 
I 
8. 2. 
8. 2. 1. 
8. 2. 1. 1. 
A n al ys is Co n v e nti o n s 
A n al ys is Sets 
I nt ent- t o-Tr e at (IT T) A n al ysis S et 
T h e I T T a n al ysis s et c on sists of all s ubj e cts w h o r e c eiv e ~ 1 d os e ofi d e l alisib. T hi s a n alysis s et 
wi ll b e us e d i n t h e a n alys es of s ubj e ct c h ar a ct eristi cs, st ud y dr ng ti·eat ment a d mi nisti·ati o n, s af et y 
a n d effi c a c y e n d p oi nts . 
C O N FI D E N TI A L 
P a g e 7 7 
2 6 O c to b er 2 0 1 6 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 7 8
2 6 Oct o ber 2 0 1 6
8. 2. 1. 2.
P har mac o ki netic A nal y sis Sets
T he P K a nal ys is sets c o nsist of all s u bjects i n t he I T T set w h o ha ve t h e necessar y baseli ne a n d 
o n- st u d y meas ure me nts t o pr o vi de i nter preta ble res ults f or t he s pecific para meters of i nterest.
8. 3.
D at a H a n dli n g C o n ve nti o ns
B y -s u bject listi n gs will be create d f or i m p orta nt varia bles fr o m eac h e C R F m o d ule. S u m mar y 
ta bles f or c o nti n uo us varia bles will c o ntai n t he f oll o wi n g statisti cs: N ( n u m ber i n p o p ulati o n), 
n ( n u m ber wit h data), mea n, me dia n, sta n dar d de viati o n, mi ni m u m, a n d ma xi m u m. S u m mar y 
ta bles f or cate g orical varia bles will i ncl u de: N, n, perce nta ge, a n d 9 5 % c o nfi de nce i nter vals (CI s)
o n t he perce nta ge , w here a p pr o priate. U nless ot her wise i n dicate d, 9 5 % CIs f or bi nar y  varia bles 
will be calc ulate d usi n g t he bi n o mial distri b uti o n . Data will be descri be d a n d s u m marize d f or all 
s u bjects a n d by a nal ys is set a n d ti me p oi nt. As a p pr o priate, c ha n ges fr o m baseli ne t o eac h 
s u bse q ue nt ti me p oi nt will be descri be d a n d s u m marize d. Si milarl y , as a p pr o priate, t he best 
c ha n ge fr o m baseli ne d uri n g t he st u d y will als o be descri be d a n d s u m marize d. Gra p hical 
tec h ni q ues (e g, waterf all pl ots, Ka pla n -Meier
c ur ves, li ne pl ots) ma y be use d w he n s uc h met h o ds 
are a p pr o priate a n d i nf or mati ve.
T he baseli ne val ue use d i n eac h a nal ys is will be t he last ( m ost rece nt) pre-treat me nt val ue. Data 
fr o m all sites will be p o ole d f or all a nal yses. A nal yses will be base d u p o n t he o bser ve d data 
u nless met h o ds f or ha n dli n g missi n g data are s pecifie d. If t here is a si g nifica nt de gree of 
n o n- n or malit y , a nalys es ma y be perf or me d o n l o g-tra nsf or me d data or n o n para metric tests ma y 
be a p plie d, as a p pr o priate.
T he f oll o wi n g ce ns ori n g c o n ve nti o ns will be a p plie d f or ti me -t o-e ve nt e n d p oi nts:

D urati o n of res p o nse ( D O R ) a n d P F S: Data fr o m s ur vi vi n g, n o n -pr o gressi n g s u bjects will be 
ce ns ore d at t he last a de q uate res p o nse assess me nt date p ri or t o t he i nitiati o n of 
P V o r E T treat me nt ( w hic he ver is a p plica ble) ot her t ha n t he st u dy treat me nt or t he last ti me 
t hat lac k of defi niti ve pr o gressi o n was o bjecti vel y d oc u me nte d.   
8. 4.  
De m o gr a p hic D at a a n d B aseli ne C h ar acteristics
A listi n g of I T T a nalys is set s u bjects will be ge nerate d t o descri be site, s u bject n u m ber, first 
scree ni n g date, first treat me nt date, mali g na nc y, sta ge, t he l o n gest d urati o n of st u d y dr u g 
(i delalisi b) treat me nt, a n d t he reas o n f or disc o nti n ui n g st u dy treat me nt. A vaila ble i nf or mati o n o n 
s u bjects w h o were screene d or re gistere d b ut n ot treate d ma y  be liste d se paratel y. A ta ble will be 
create d s u m marizi n g t hese cate g ories i n ter ms of n u m ber a n d perce nt f or t he I T T a nal ysis set.
S u bject baseli ne c haracteristics will be liste d a n d s u m marize d f or t he I T T a nal ysis set.
8. 5.
S afet y A n al ysis
All safet y data c ollecte d o n or after t he date t hat st u d y dr u g was first dis pe nse d u p t o t he date of 
last d ose of st u d y dr u g pl us 3 0 da y s will be s u m marize d. Data f or t he pretreat me nt will be 
i ncl u de d i n data listi n gs. I nteri m safety s u m maries f or S R T will be s h o w n b y c o h ort a n d 
c o m bi ni n g all c o h orts.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 7 9
2 6 Oct o ber 2 0 1 6
8. 5. 1.
E xte nt of E x p os ure
Descri pti ve i nf or mati o n will be pr o vi de d re gar di n g t he n u m ber of d oses of st u d y dr u g
prescri be d, t he t otal n u m ber of d oses ta ke n, t he perce nt of e x pecte d d oses ta ke n, t h e n u m ber of 
da y s of st u d y dr u g, a n d t he n u m ber a n d ti mi n g of prescri be d d ose m o dificati o n a n d i nterr u pti o ns.
C o m plia nce will be descri be d i n ter ms of t he pr o p orti o n of st u d y dr u g act uall y ta ke n base d o n 
ret ur ne d pill c o u nt relati ve t o t he a m o u nt t hat was dis pe nse d (ta ki n g i nt o acc o u nt 
p h y sicia n-prescri be d m o dificati o n a n d i nterr u pti o ns).
8. 5. 2.
A d verse E ve nts
All A E will be liste d. T he f oc us of A E s u m marizati o n will be o n treat me nt -e mer ge nt A E . 
A treat me nt-e mer ge nt A E is defi ne d as a n A E t hat occ urs or w orse ns i n t he peri o d fr o m t he first 
d ose of st u d y  dr u g (i delalisi b) t o 3 0 da ys after t he last d ose ofi delalisi b.
A E will be classifie d usi n g Me dical Dicti o nar y  f or Re g ulat or y Acti vities ( Me d D R A) 
( htt p:// w w w. me d dra mss o.c o m) wit h descri pti o ns b y Sys tem Or ga n Class ( S O C), Hi g h -Le vel 
Gr o u p Ter m ( H L G T), Hi g h -Le vel Ter m ( H L T), Prefe rre d Ter m ( P T), a n d L o wer-Le vel Ter m 
( L L T). T he se verit y of A E will be gra de d b y t he i n ves ti gat or acc or di n g t o t he C T C A E, 
Versi o n 4. 0 3, w he ne ver p ossi ble. I f a C T C A E criteri o n d oes n ot e xist f or a s pecific t y pe of A E, 
t he gra de c orres p o n di n g t o t he a p pr o priate a djecti ve will be use d by t he i n vesti gat or t o descri be 
t he ma xi m u m i nte nsit y of t he A E: Gra de 1 ( mil d), Gra de 2 ( m o derate), Gra de 3 (se vere), 
Gra de 4 (life t hreate ni n g), or Gra de 5 (fatal). T he relati o ns hi p of t he A E t o t he I M P will be 
cate g orize d as relate d or u nrelate d.
Treat me nt -e mer ge nt A E will be s u m marize d. S u m mar y  ta bles will be prese nte d t o s h o w t he 
n u m ber of s u bjects re p orti n g treat me nt -e mer ge nt A E b y  se verity gra de a n d c orres p o n di n g 
perce nta ges. A s u bject w h o re p orts m ulti ple treat me nt -e mer ge nt A E wi t hi n t he 
sa me P T ( or S O C ) is c o u nte d o nl y o nce f or t hat P T ( or SO C ) usi n g t he w orst se verity gra de. A E 
descri pti o ns will be prese nte d b y  decreasi n g fre q ue nc y f or a gi ve n S O C a n d P T . Se parate listi n gs 
a n d s u m maries will be pre pare d f or t he f oll o wi n g t y pes of treat me nt e mer ge nt A E s:

St u d y -dr u g -relate d A E

A E t hat are Gra de ≥ 3 i n se verit y

A E lea di n g t o i delalisi b or r u x oliti ni b i nterr u pti o n a n d/ or d ose m o dificati o n

A E lea di n g t o i delalisi b or r u x oliti ni b disc o nti n uati o n

S A E


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
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8. 5. 3.
L a b or at or y E v al u ati o ns
All la b orat or y  data will be liste d. S u m maries of la b orat or y data will be base d o n o bser ve d data.
T he f oc us of la b orat or y  data s u mmarizati o n will be o n treat me nt -e mer ge nt la b orat or y 
a b n or malities. A treat me nt -e mer ge nt la b orat or y a b n or malit y is defi ne d as a n a b n or mality t hat, 
c o m pare d t o baseli ne, w orse ns b y ≥1 gra de i n t he peri o d fr o m t he first d ose of st u d y dr u g 
(i delalisi b) t o 3 0 da y s after t he last d ose of st u d y dr u g. If baseli ne data are missi n g, t he n a ny 
gra de d a b n or malit y  (ie, a n a b n or malit y t hat is Gra de ≥1 i n se verit y) will be c o nsi dere d treat me nt 
e mer ge nt.
He mat ol o gical, ser u m bi oc he mistr y , a n d uri ne data will be pr o gra m maticall y gra de d acc or di n g 
t o CT C A E se verit y  gra de, w he n a p plica ble. F or para meters f or w hic h a C T C A E scale d oes n ot 
e xist, refere nce ra n ges fr o m t he ce ntral la b orat or y will be use d t o deter mi ne pr o gra m maticall y  if 
a la b orat or y para meter is bel o w, wit hi n, or a b o ve t he n or mal ra n ge f or the s u bject’s a ge, se x, etc.
He mat ol o gical a n d ser u m bi oc he mistr y  a n d t heir c ha n ges fr o m baseli ne will be s u m marize d, b y 
visit. S u m mar y  ta bles will be prese nte d f or eac h rele va nt assa y t o s h o w t he n u m ber of s u bjects 
b y  C T C A E se verit y gra de wit h c orres p o n di ng perce nta ges. F or para meters f or w hic h a C T C A E 
scale d oes n ot e xist, t he fre q ue nc y of s u bjects wit h val ues bel o w, wit hi n, a n d a b o ve t he n or mal 
ra n ges will be s u m marize d. S u bjects will be c haracterize d o nl y o nce f or a gi ve n assa y, base d o n 
t heir w orst se verit y gra de o bser ve d d uri n g a peri o d of i nterest (e g, d uri n g t he st u d y  or fr o m 
baseli ne t o a partic ular visit).
S hift ta bles f or he mat ol o g y  a n d ser u m bi oc he mistr y will als o be prese nte d b y s h o wi n g c ha n ge i n 
C T C A E se verit y gra de fr o m baseli ne t o t he w orst gra de p ost -baseli ne . F or para meters f or w hic h 
a C T C A E scale d oes n ot e xist, s hift ta bles will be prese nte d s h o wi n g c ha n ge i n res ults fr o m 
baseli ne t o t he w orst gra de p ost baseli ne. Se parate listi n gs a n d s u m maries will be pre pare d f or 
la b orat or y a b n or malities t hat are Gra de ≥3 i n se verit y.
8. 6. 
P h ar m ac o ki netic A n al ysis
Plas ma c o nce ntrati o ns of i delalisi b a n d meta b olite (if a p pr o priate) will be liste d a n d 
s u m marize d usi n g descri pti ve statistics ( e g, sa m ple size, arit h metic mea n, ge o metric mea n, 
% c oefficie nt of variati o n, sta n dar d de viati o n, me dia n, mi ni m u m, a n d ma xi m u m). Plas ma 
c o nce ntrati o ns of i delalisi b a n d meta b olite (if a p pr o priate) o ver ti me will be pl otte d i n 
se mi l o garit h mic a n d li near f or mats as mea n ± sta n dar d de viati o n. R ele va nt P K para meters will 
be calc ulate d a n d s u m marize d .
8. 7.
Effic ac y A n al ysis
T he sec o n dar y e n d p oi nt is t he rate of o verall res p o nse as defi ne d b y 2 0 1 3 Re vise d I WG- M R T
a n d E L N res p o nse criteria (A p pe n di x 6 ) ie, C R, P R, or CI (t he ac hie ve me nt of a ne mia, s plee n, or 
s ym pt o ms res p o nse wit h o ut pr o gressi ve disease or i ncrease i n se verit y  of a ne mia, 
t hr o m b oc yt o pe nia, or ne utr o pe nia ). Res p o nse rates will be prese nte d wit h c orres p o n di n g e xact 
9 5 % CI s. S u bjects w h o ha ve missi n g baseli ne or o n -st u d y res p o nse assess me nt will be c o u nte d 
as n o n-res p o n ders.


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P F S a n d D O R will be descri be d i n t he a p pr o priate a nal ys is set usi n g Ka pla n-Meier met h o ds. T he 
s ur vi val f u ncti o ns will be pl otte d a n d me dia n s ur vi val ti mes will be prese nte d wit h 
c orres p o n di n g 9 5 % CI s.
Cate g orical e n d p oi nts will be descri be d. S u bjects w h o d o n ot ha ve s ufficie nt baseli ne or o n st u d y 
assess me nt s t o c haracterize res p o nse, will be c o u nte d as n o n -res p o n ders. Res p o nse rates will be 
prese nte d wit h c orres p o n di n g e xact 9 5 % CI s.
Perce n t c ha n ge fr o m baseli ne at Wee ks 1 2 a n d 2 4 a n d best c ha n ge fr o m baseli ne f or s plee n, li ver 
a n d T S S will be prese nte d wit h c orres p o n di n g me dia n, sta n dar d de viati o n, mi ni m u m, a n d 
ma xi m u m.
8. 8.
S a m ple Size
As t his is a P hase 1 b st u d y  wit h a pri mar y o bjecti ve of assessi n g safety, t he sa m ple size is n ot 
base d o n f or mal p o wer calc ulati o ns. T he sa m ple size of a p pr o xi matel y  6 s u bjects per d ose c o h ort
i n C o h ort A, B, C, a n d D is c o nsi dere d a de q uate f or a n i nitial assess me nt of safet y a n d 
t olera bilit y f or s u bse q ue nt e val uati o ns.


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9.
R E S P O N SI BI LI TI E S
9. 1.
I n vesti g at or Res p o nsi bilities
9. 1. 1.  
G o o d Cli nic al Pr actice
T he i n vesti gat or will e ns ure t hat t his st u d y  is c o n d ucte d i n acc or da nce wit h t he pri nci ples of t he 
Declarati o n of Helsi n ki (as a me n de d i n E di n b ur g h, T o k y o, Ve nice, H o n g K o n g , a n d 
S o ut h Africa), I nter nati o nal C o nfere nce o n Har m o nisati o n (I C H) g ui deli nes, or wit h t he la ws a n d 
re g ulati o ns of t he c o u ntr y i n w hic h t he researc h is c o n d ucte d, w hic he ver aff or ds t he greater 
pr otecti o n t o t he st u d y  s u bject.
T he i n vesti gat or will e ns ure a d here nce t o t he basic pri nci ples of G o o d Cli nical Practice, as 
o utli ne d i n 2 1 C F R 3 1 2, s u b part D, “ Res p o nsi bilities of S p o ns ors a n d I n vesti gat ors,” 
2 1 C F R, part 5 0, 1 9 9 8, a n d 2 1 C F R, part 5 6, 1 9 9 8 .
T he i n vesti gat or a n d all a p plica ble s u bi n vesti gat ors wil l c o m pl y wit h 2 1 C F R, Part 5 4, 1 9 9 8, 
pr o vi di n g d oc u me ntati o n of t heir fi na ncial i nterest or arra n ge me nts wit h Gilea d, or pr o prietar y  
i nterests i n t he i n vesti gati o nal dr u g u n der st u dy. T his d oc u me ntati o n m ust be pr o vi de d pri or t o 
t he i n vesti gat or’s (a n d a n y s u bi n vesti gat or’s) partici pati o n i n t he st u d y. T he i n vesti gat or a n d 
s u bi n vesti gat or a gree t o n otif y Gilea d of a ny c ha n ge i n re p orta ble i nter ests d uri n g t he st u d y a n d 
f or 1 year f oll o wi n g c o m pleti o n of t he st u d y. St u d y c o m pleti o n is defi ne d as t he date w he n t he 
last s u bject c o m pletes t he pr ot oc ol-defi ne d acti vities.
9. 1. 2. 
I nstit uti o n al Re vie w B o ar d (I R B) Re vie w a n d A p pr o v al
T he i n vesti gat or ( or s p o ns or as a p pr o priate acc or di n g t o l ocal re g ulati o ns) will s u b mit t his 
pr ot oc ol, i nf or me d c o nse nt f or m, a n d a n y acc o m pa n y i n g material t o be pr o vi de d t o t he s u bject 
(s uc h as a d vertise me nts, s u bject i nf or mati o n s heets, or descri pti o ns of t he st u d y use d t o o btai n 
i nf or me d c o nse nt) t o a n I R B. T he i n vesti gat or will n ot be gi n a ny st u d y s u bject acti vities u ntil 
a p pr o val fr o m t he I RB has bee n d oc u me nte d a n d pr o vi de d as a letter t o t he i n vesti gat or.
Bef ore i m ple me ntati o n, t he i n vesti gat or will s u b mit t o a n d recei ve d oc u me nte d a p pr o val fr o m 
t he I RB a n y  m o dificati o ns ma de t o t he pr ot oc ol or a n y acc o m pa n yi n g material t o be pr o vi de d t o 
t he s u bject after i nitial I RB a p pr o val, wit h t he e xce pti o n of t h ose necessar y t o re d uce i m me diate 
ris k t o st u d y s u bjects.
9. 1. 3.
I nf or me d C o nse nt
T he i n vesti gat or is res p o nsi ble f or o btai ni n g writte n i nf or me d c o nse nt fr o m eac h i n di vi d ual 
partici pati n g i n t his st u d y after a de q uate e x pla nati o n of t he ai ms, met h o ds, o bjecti ves, a n d 
p ote ntial hazar ds of t he st u d y  a n d bef ore u n derta ki n g a ny st u d y-relate d pr oce d ures. T he 
i n vesti gat or m ust use t he m ost c urre nt I R B-a p pr o ve d c o nse nt f or m f or d oc u me nti n g writte n 
i nf or me d c onse nt. Eac h i nf or me d c o nse nt ( or asse nt as a p plica ble) will be a p pr o priatel y si g ne d 
a n d date d b y t he s u bject or t he s u bject’s le gall y a ut h orize d re prese ntati ve a n d t he pers o n 
c o n d ucti n g t he c o nse nt disc ussi o n, a n d als o b y  a n i m partial wit ness if re q uire d by I R B or l ocal 
re q uire me nts.


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9. 1. 4.
C o nfi de nti alit y
T he i n vesti gat or m ust ass ure t hat s u bjects’ a n o n y mit y  will be strictl y mai ntai ne d a n d t hat t heir 
i de ntities are pr otecte d fr o m u na ut h orize d parties. O nl y s u bject i nitials, date of birt h, a n ot her 
u ni q ue i de ntifie r (as all o we d by l ocal la w) a n d a n i de ntificati o n c o de will be rec or de d o n a n y 
f or m or bi ol o gical sa m ple s u b mitte d t o t he S p o ns or, I RB, or la b orat or y . La b orat or y  s peci me ns 
m ust be la bele d i n s uc h a w a y  as t o pr otect s u bject i de ntit y w hile all o wi n g t he res ults t o be 
rec or de d t o t he pr o per s u bject. Refer t o s pecific la b orat or y i nstr ucti o ns N O T E : T he i n vesti gat or 
m ust kee p a scree ni n g l o g s h o wi n g c o des, na mes, a n d a d dresses f or all s u bjects scree ne d a n d f or 
all s u bjects e nr olle d i n t he trial. S u bject data will be pr ocesse d i n acc or da nce w it h all a p plica ble 
re g ulati o ns.
T he i n vesti gat or a grees t hat all i nf or mati o n recei ve d fr o m Gilea d, i ncl u di n g b ut n ot li mite d t o t he
I B, t his pr ot oc ol, e C R F, t he I M P, a n d a n y ot her st u d y i nf or mati o n, re mai n t he s ole a n d e xcl usi ve 
pr o pert y of Gilea d d uri n g t he c o n d uct of t he st u d y a n d t hereafter. T his i nf or mati o n is n ot t o be 
discl ose d t o a n y  t hir d part y (e xce pt e m pl oye es or a ge nts directl y i n v ol ve d i n t he c o n d uct of t he 
stu d y  or as re q uire d b y la w) wit h o ut pri or writte n c o nse nt fr o m Gilea d. T he i n vesti gat or f urt her 
a grees t o ta ke all reas o na ble preca uti o ns t o pre ve nt t he discl os ure b y  a n y e m pl o yee or a ge nt of 
t he st u d y site t o a ny t hir d part y or ot her wise i nt o t he p u blic d o mai n.
9. 1. 5. 
St u d y Files a n d Rete nti o n of Rec or ds
T he i n vesti gat or m ust mai ntai n a de q uate a n d acc urate rec or ds t o e na ble t he c o n d uct of t he st u d y 
t o be f ull y d oc u me nte d a n d t he st u d y data t o be s u bse q ue ntl y verifie d. T hese d oc u me nts s h o ul d 
be classifie d i nt o at least t he f oll o wi n g t w o cate g ories: ( 1) i n vesti gat or’s st u d y file, a n d 
( 2) s u bject cli nical s o urce d oc u me nts.
T he i n vesti gat or’s st u d y file will c o ntai n t he pr ot oc ol/a me n d me nts, q uer y f or ms, I RB a n d 
g o ver n me ntal a p pr o val wit h c orres p o n de nce, i nf or me d c o nse nt, dr u g rec or ds, staff 
c urric ul u m vitae a n d a ut h orizati o n f or ms, a n d ot her a p pr o priate d oc u me nts a n d c orres p o n de nce.
T he re q uire d s o urce data s h o ul d i ncl u de se q ue ntial n otes c o ntai ni n g at least t he f oll o wi n g 
i nf or mati o n f or eac h s u bject:

S u bject i de ntificati o n ( na me, date of birt h, ge n der);

D oc u me ntati o n t hat s u bject meets eli gi bilit y criteria, ie, hist or y, p h ysical e xa mi nati o n, a n d 
c o nfir mati o n of dia g n osis (t o s u p p ort i ncl usi o n a n d e xcl usi o n criteria);

D oc u me ntati o n of t he reas o n(s) a c o nse nte d s u bject i s n ot e nr olle d;

Partici pati o n i n st u d y (i ncl u di n g st u d y n u m ber);

St u d y  disc usse d a n d date of i nf or me d c o nse nt;

Dates of all visits;


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
D oc u me ntati o n t hat pr ot oc ol s pecific pr oce d ures were perf or me d;

Res ults of efficac y  para meters, as re q uire d by t he pr ot oc ol;

Start a n d e n d date (i ncl u di n g d ose re gi me n) of I M P, i ncl u di n g dates of dis pe nsi n g a n d ret ur n;

Rec or d of all a d verse e ve nts a n d ot her safet y  para meters (start a n d e n d date, a n d i ncl u di n g 
ca usalit y a n d se verit y);

C o nc o mita nt me dicati o n (i ncl u di n g start a n d e n d date, d ose if rele va nt; d ose c ha n ges);

Date of st u d y c o m pleti o n a n d reas o n f or early disc o nti n uati o n, if it occ urs.
All cli nical st u d y  d oc u me nts m ust be retai ne d by t he i n vesti gat or u ntil at least 2 ye ars or 
acc or di n g t o l ocal la ws, w hic he ver is l o n ger , after t he last a p pr o val of a mar keti n g a p plicati o n i n 
a n IC H re gi o n (ie, U nite d States, E ur o pe, or Ja pa n) a n d u ntil t here are n o pe n di n g or pla n ne d 
mar keti n g a p plicati o ns i n a n I C H re gi o n; or, if n o a p plicati o n is file d or if t he a p plicati o n is n ot 
a p pr ove d f or s uc h i n dicati o n, u ntil 2 years after t he i n vesti gati o n is disc o nti n ue d a n d re g ulat or y 
a ut h orities ha ve bee n n otifie d. I n vesti gat ors ma y  be re q uire d t o retai n d oc u me nts l o n ger if 
s pecifie d b y  re g ulat or y re q uire me nts, b y l ocal re g ulati o ns, or b y a n a gree me nt wit h Gilea d. T he 
i n vesti gat or m ust n otif y Gilea d bef ore destr oyi n g a n y  cli nical st u d y rec or ds.
S h o ul d t he i n vesti gat or wis h t o assi g n t he st u d y rec or ds t o a n ot her part y or m o ve t he m t o a n ot her 
l ocati o n, Gilea d m ust be n otifie d i n a d va nce.
If t he i n vesti gat or ca n n ot pr o vi de f or t his arc hi vi n g re q uire me nt at t he st u d y site f or a n y or all of 
t he d oc u me nts, s pecial arra n ge me nts m ust be ma de bet wee n t he i n vesti gat or a n d Gilea d t o st ore 
t hese rec or ds sec urely a wa y fr o m t he site s o t hat t he y ca n be ret urne d seale d t o t he i n vesti gat or 
i n case of an i ns pecti o n. W he n s o urce d oc u me nts are re q uire d f or t he c o nti n ue d care of t he 
s u bject, a p pr o priate c o pies s h o ul d be ma de f or st ora ge a wa y fr o m t he site.
9. 1. 6.
C ase Re p ort F or ms
F or eac h s u bject c o nse nte d, a n e C R F will be c o m plete d b y  a n a ut h orize d st u d y staff me m ber 
w h ose trai ni n g f or t his f u ncti o n is d oc u me nte d acc or di n g t o st u d y  pr oce d ures. e C R F s h o ul d be 
c o m plete d o n t he da y of t he s u bject visit t o e na ble t he s p o ns or t o perf or m ce ntral m o nit ori n g of 
safety data. S u bs e q ue nt t o data e ntr y, a st u dy m o nit or will perf or m s o urce data verificati o n 
wit hi n t he E D C s y ste m. Ori gi nal e ntries as well as a n y  c ha n ges t o data fiel ds will be st ore d i n t he 
a u dit trail of t he s yste m. Pri or t o data base l oc k ( or a n y i nteri m ti me p oi nts as descri be d i n t he 
cli nical data ma na ge me nt pla n), t he i n vesti gat or will use his/ her l o g i n cre de ntials t o c o nfir m t hat 
t he f or ms ha ve bee n re vie we d, a n d t hat t he e ntries acc urately reflect t he i nf or mati o n i n t he 
s o urce d oc u me nts. T he e C R F ca pt ure t he data re q uire d per t he pr ot oc ol sc he d ule of e ve nts a n d 
pr oce d ures. S y ste m-ge nerate d or ma n ual q ueries will be iss ue d t o t he i n vesti gati ve site staff as 
data discre pa ncies are i de ntifie d b y  t he m o nit or or i nter nal Gilea d staff, w h o r o uti nel y re vie w t he 
data f or c o m plete ness, c orrect ness, a n d c o nsiste nc y. T he site c o or di nat or is res p o nsi ble f or 
res p o n di n g t o t he q ueries i n a ti mel y ma n ner, wit hi n t he s yste m, eit her by c o nfir mi n g t he data as 


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c orrect or u p dati n g t he ori gi nal e ntr y , a n d pr o vi di n g t he reas o n f or t he u pdate 
(e g, data e ntr y err or). At t he c o ncl usi o n of t he trial, Gilea d will pr o vi de t he site wit h a rea d - o nly 
arc hi ve c o p y of t he data e ntere d b y t hat site. T his arc hi ve m ust be st ore d i n acc or da nce wit h t he 
rec or ds rete nti o n re q uire me nts o utli ne d i n Secti o n 9. 1. 5 .
9. 1. 7.
I n vesti g ati o n al Me dici n al Pr o d uct Acc o u nt a bilit y a n d Ret ur n 
Gilea d rec o m me n ds t hat use d a n d u n use d I M P s u p plies be ret ur ne d t o t he s hi p pi n g facilit y  fr o m 
w hic h it ca me f or e ve nt ual destr ucti o n. T he st u d y m o nit or will pr o vi de i nstr ucti o ns f or ret ur n . If 
ret ur n is n ot p ossi ble, t he st u d y m o nit or will e val uate eac h st u d y ce nter’s I M P dis p osal 
pr oce d ures a n d pr o vi de a p pr o priate i nstr ucti o n f or destr ucti o n of u n use d I M P s u p plies. I f t he site 
has a n a p pr o priate sta n dar d o perati n g pr oce d ure ( S O P) f or dr u g destr ucti o n as deter mi ne d b y  
Gilea d Q A, t he site ma y  destr o y use d (e m pty or partiall y e m pt y) a n d u n use d I M P s u p plies i n 
acc or da nce wit h t hat site’s a p pr o ve d S O P. A c o p y of t he site’s a p pr o ve d S O P will be o btai ne d 
f or ce ntral files.
If I M P is destr oye d o n s ite, t he i n vesti gat or m ust mai ntai n acc urate rec or ds f or all I M P 
destr o y e d. Rec or ds m ust s h o w t he i de ntificati o n a n d q ua ntit y  of eac h u nit destr o ye d, t he met h o d 
of destr ucti o n, a n d t he pers o n w h o dis p ose d of t he I M P. U p o n st u d y  c o m pleti o n, c o pies of t he 
I MP acc o u nta bilit y  rec or ds m ust be file d at t he site. A n ot her c o p y will be ret ur ne d t o Gilea d.
T he st u d y  m o nit or will re vie w I M P s u p plies a n d ass ociate d rec or ds at peri o dic i nter vals.
9. 1. 8.
I ns pecti o ns
T he i n vesti gat or will ma ke a vaila ble all s o urce d oc u me nts a n d ot her rec or ds f or t his trial t o 
Gilea d ’s a p p oi nte d st u dy m o nit ors , t o I RB , or t o re g ulat or y a ut h ority i ns pect ors.
9. 1. 9.
Pr ot oc ol C o m pli a nce
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t he st u d y  is c o n d ucte d i n acc or da nce wit h t he 
pr oce d ures a n d e val uati o ns descri be d i n t his pr ot oc ol.
9. 2. 
S p o ns or Res p o nsi bilities
9. 2. 1. 
Pr ot oc ol M o dific ati o ns
Pr ot oc ol m o dificati o ns, e xce pt t h ose i nte n de d t o re d uce i m me diate ris k t o st u d y  s u bjects, ma y be 
ma de o nl y  b y Gilea d. T he i n vesti gat or m ust s u b mit all pr ot oc ol m o dificati o ns t o t he I RB i n 
acc or da nce wit h l ocal re q uire me nts a n d recei ve d oc u me nte d I R B a p pr o val bef ore m o dificati o ns 
ca n be i m ple me nte d.
9. 2. 2.
St u d y Re p ort a n d P u blic ati o ns
A cli nical st u d y  re p ort ( C S R) will be pre pare d a n d pr o vi de d t o t he re g ulat or y a ge nc y . Gilea d will 
e ns ure that t he re p ort meets t he sta n dar ds set o ut i n t he I C H G ui deli ne f or Str uct ure a n d C o nte nt 
of Cli nical St u d y  Re p orts (IC H E 3). N ote t hat a n a b bre viate d re p ort ma y  be pre pare d i n certai n 
cases.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 8 6
2 6 Oct o ber 2 0 1 6
In vesti gat ors i n t his st u d y  m a y c o m m u nicate, orall y prese nt, or p u blis h i n scie ntific j o ur nals or 
ot her sc h olarl y me dia o nl y after t he f oll o wi n g c o n diti o ns ha ve bee n met:

T he res ults of t he st u d y i n t heir e ntiret y ha ve bee n p u blicl y discl ose d b y or wit h t he c o nse nt 
of Gilea d i n a n a bstract, ma n uscri pt, or prese ntati o n f or m or t he st u dy has bee n c o m plete d at 
all st u d y sites f or at least 2 years

T he i n vesti gat or will s u b mit t o Gilea d a n y  pr o p ose d p u blicati o n or prese ntati o n al o n g wit h 
t he res pecti ve scie ntific j o ur nal or prese ntati o n f or u m at least 3 0 da ys bef ore s u b missio n of 
t he p u blicati o n or prese ntati o n. 

N o s uc h c o m m u nicati o n, prese ntati o n, or p u blicati o n will i ncl u de Gilea d’s c o nfi de ntial
i nf or mati o n (see Secti o n 9. 1. 4 ).

T he i n vesti gat or will c o m pl y  wit h Gilea d’s re q uest t o delete refere nces t o its 
c o nfi de ntial i nf or mati o n ( ot her t ha n t he st u d y res ults) i n a n y pa per or prese ntati o n a n d a grees 
t o wit h h ol d p u blicati o n or prese ntati o n f or a n a d diti o nal 6 0 da ys i n or der t o o btai n pate nt 
pr otecti o n if dee me d necessar y .
9. 3.
J oi nt I n vesti g at or/ S p o ns or Res p o nsi bilities
9. 3. 1.
Acces s t o I nf or m ati o n f or M o nit ori n g
I n acc or da nce wit h re g ulati o ns a n d g ui deli nes, t he st u d y  m o nit or m ust ha ve direct access t o t he 
i n vesti gat or’s s o urce d oc u me ntati o n i n or der t o verif y t he acc urac y of t he data rec or de d i n t he 
e C R F.
T he m o nit or is res p o nsi ble f or r o uti ne re vie w of t he e C R F at re g ular i nter vals t hr o u g h o ut t he 
st u d y t o verif y a d here nce t o t he pr ot oc ol a n d t he c o m plete ness, c o nsiste nc y, a n d acc urac y of t he 
data bei n g e ntere d o n t he m. T he m o nit or s h o ul d ha ve access t o a n y s u bject rec or ds nee de d t o
verif y  t he e ntries o n t he e C R F. T he i n vesti gat or a grees t o c o o perate wit h t he m o nit or t o e ns ure 
t hat a n y pr o ble ms detecte d t hr o u g h a ny t y pe of m o nit ori n g (ce ntral, o n site) are res ol ve d.
9. 3. 2.
Access t o I nf or m ati o n f or A u diti n g or I ns pecti o ns
Re prese ntati ves of re g ulat or y a ut h orities or of Gilea d ma y c o n d uct i ns pecti o ns or a u dits of t he 
cli nical st u d y. If t he i n vesti gat or is n otifie d of a n i ns pecti o n b y a re g ulat or y a ut h orit y t he 
i n vesti gat or a grees t o n otif y t he Gilea d me dical m o nit or i m me diatel y. T he i n vesti gat or a grees t o 
pr o vi de t o re prese ntati ves of a re g ulat or y  a ge nc y or Gilea d access t o rec or ds, facilities, a n d 
pers o n nel f or t he effecti ve c o n d uct of a n y i ns pecti o n or a u dit.
9. 3. 3.
St u d y Disc o nti n u ati o n
B ot h t he s p o ns or a n d t he i n vesti gat or reser ve t he ri g ht t o te r mi nate t he st u dy at a n y ti me. S h o ul d 
t his be necessar y, b ot h parties will arra n ge disc o nti n uati o n pr oce d ures a n d n otif y t he a p pr o priate 
re g ulat or y a ut h ority(i es) a n d I RBs. I n ter mi nati n g t he st u d y , Gilea d a n d t he i n vesti gat or will 
ass ure t hat a de q uate c o n si derati o n is gi ve n t o t he pr otecti o n of t he s u bjects’ i nterests.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 8 7
2 6 Oct o ber 2 0 1 6
1 0.
R E F E R E N C E S
Bar osi G, Mesa R A, T hiele J, Cer va ntes F, Ca m p bell PJ, Verst o vse k S, et al. Pr o p ose d criteria 
f or t he dia g n osis of p ost-p ol y c yt he mia vera a n d p ost-esse ntial t hr o m b oc yt he mia 
m y el ofi br osis: a c o nse ns us state me nt fr o m t he I nter nati o nal W or ki n g Gr o u p f or 
M y el ofi br osis Researc h a n d Treat me nt. Le u ke mia 2 0 0 8; 2 2 ( 2): 4 3 7 - 8.
B o ga ni C, Bartal ucci N, Marti nelli S, T ozzi L , G u gliel melli P, B osi A, et al. m T O R i n hi bit ors 
alo ne a n d i n c o m bi nati o n wit h J A K 2 i n hi bit ors effecti vel y i n hi bit cells of 
m y el o pr oliferati ve ne o plas ms. P Lo S O N E 2 0 1 3; 8 ( 1):e 5 4 8 2 6.
Castellares C, Barreir o P, Marti n -Car b o ner o L, La bar ga P, Vis p o M E, Casa d o R, et al. L i ver 
cirr h osis i n HI V-i nfecte d patie nts: pre vale nce, aeti ol o g y a n d cli nical o utc o me. J 
Viral He pat 2 0 0 8; 1 5 ( 3): 1 6 5 - 7 2.
Cer va ntes F, D u priez B, Pereira A, Passa m o nti F, Reill y  J T, M orra E, et al. Ne w pr o g n ostic 
sc ori n g sys te m f or pri mar y myel ofi br osis base d o n a st u d y of t he I nter nati o nal 
W or ki n g Gr o u p f or M yel ofi br osis Researc h a n d Treat me nt. Bl o o d 2 0 0 9; 1 1 3 
( 1 3): 2 8 9 5- 9 0 1.
Cer va ntes F, Va n n ucc hi A M, Kila djia n JJ, Al -Ali H K, Sir ul ni k A, Stal b o vs ka ya V, et al. T hree -
ye ar efficac y, safety, a n d s ur vi val fi n di n gs fr o m C O M F O R T -II, a p hase 3 st u d y 
c o m pari n g r u x oliti ni b wit h best a vaila ble t hera p y f or m yel ofi br osis. Bl o o d 2 0 1 3.
C h o o n g M L, Pec q uet C, Tai SJ, Y o n g J, Pe n d har kar V, Wa n g S, et al. C o m bi nati o n Treat me nt 
wit h J A K 2 a n d PI 3 K I n hi bit ors i n M y el o pr oliferati ve Ne o plas ms[ A bstract 1 8 0]. 
2 0 1 2; 1 2 0.
C o ut re S E, Barrie nt os J C, Br o w n J R, de V os S, F ur ma n R R, Keati n g MJ, et al. Ma na ge me nt of 
a d verse e ve nts ass ociate d wit h i delalisi b treat me nt - e x pert pa nel o pi ni o n. Le u k 
L y m p h o ma 2 0 1 5: 1- 2 0.
E n gel ma n J A, L u o J, Ca ntle y  LC. T he e v ol uti o n of p h os p hati d y li n osit ol 3- ki nases as re g ulat ors 
of gr o wt h a n d meta b olis m. Nat ure re vie ws. Ge netics 2 0 0 6; 7 ( 8): 6 0 6 -1 9.
Fis k us W, Verst o vse k S, Ma ns h o uri T, S mit h J E, Pet h K, A b h y a n kar S, et al. D ual 
PI 3 K/ A K T/ m T O R i n hi bit or B E Z 2 3 5 s y ner gisticall y e n ha nces t he acti vit y of 
J A K 2 i n hibit or a gai nst c ult ure d a n d pri mar y h u ma n m yel o pr oliferati ve ne o plas m 
cells. M ol Ca ncer T her 2 0 1 3; 1 2 ( 5): 5 7 7- 8 8.
Ga n gat N, Cara mazza D, Vai d y a R, Ge or ge G, Be g na K, Sc h wa ger S, et al. DI P S S pl us: a 
refi ne d D yna mic I nter nati o nal Pr o g n ostic Sc ori n g S y ste m f or pri mar y  
m y el ofi br osis t hat i nc or p orates pr o g n ostic i nf or mati o n fr o m kar y ot y pe, platelet 
c o u nt, a n d tra nsf usi o n stat us. J Cli n O nc ol 2 0 1 1; 2 9 ( 4): 3 9 2 - 7.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 8 8
2 6 Oct o ber 2 0 1 6
Ge or ga kis G V, Li  Y, Rassi da kis G Z, Me deir os LJ, Mills G B, Y o u nes A. I n hi biti o n of t he 
p h os p hati d y li n ositol- 3 ki nase/ A kt pr o m otes G 1 cell c ycle arrest a n d a p o pt osis i n 
H o d g ki n l y m p h o ma. Br J Hae mat ol 2 0 0 5; 1 3 2: 5 0 3 - 1 1.
Gilea d Scie nces I nc. Z Y D E LI G ® (i delalisi b) ta blets, f or oral use. U. S. Prescri bi n g I nf or mati o n. 
F oster Cit y , C A. J ul y 2 0 1 4:
Harris o n C, Kila djia n JJ, Al -Ali H K, Gissli n ger H, Waltz ma n R, Stal b o vs ka y a V, et al. J A K 
i n hi biti o n wit h r u x oliti ni b vers us best a vaila ble t hera py f or m yel ofi br osis. N E n gl 
J Me d 2 0 1 2; 3 6 6 ( 9): 7 8 7- 9 8.
H a y  N. T he A kt- m T O R ta n g o a n d its rele va nce t o ca ncer. Ca ncer cell 2 0 0 5; 8 (3): 1 7 9 - 8 3.
Ka h n I, H ua n g Z, We n Q, Sta n kie wicz MJ, Gilles L, G ol de ns o n B, et al. A K T is a t hera pe utic 
tar get i n m yel o pr oliferati ve ne o plas ms. Le u ke mia 2 0 1 3: 1 - 2 6.
K ha n I, H ua n g Z, We n Q, K o p pi kar P, Le vi ne R, Tefferi A, et al. I n hi biti o n of A K T Si g nali n g 
P o te ntl y In hi bits t he Gr o wt h of J A K a n d M P L -M uta nt Cells i n t he 
M y el o pr olifererati ve Ne o plas ms In Vitr o a n d I n Vi v o [ A bstract 3 8 6 2]. 2 0 1 1; 1 1 8.
K o p pi kar P, B ha g wat N, Kil pi vaara O, Ma ns h o uri T, A dli M, Hrici k T, et al. Heter o di meric 
J A K– S T A Tacti vati o n as a me c ha nis m of persiste nce t o J A K 2 i n hi bit or t hera p y . 
Nat ure 2 0 1 2; 0 0 0: 1 -6.
La n n utti BJ, Mea d o ws S A, Her ma n S E, Kas his hia n A, Stei ner B, J o h ns o n AJ, et al. C A L -1 0 1, a 
p 1 1 0 delta- selecti ve p h os p hati d yli n osit ol- 3-ki nase ( PI 3 K) i n hi bit or f or t he 
treat me nt of B-cell mali g na ncies, i n hi bits PI 3 K si g nali n g a n d cell ular via bilit y . 
Bl o o d 2 0 1 1; 1 1 7 ( 2): 5 9 1 - 4.
Mea d o ws S, N g u ye n M H, Q ue va C, La n n utti B, Kas his hia n A, J u n SJ, et al. PI 3 K δ I n hi bit or 
I delalisi b In hi bits A K T Si g nali n g i n M y el ofi br osis Patie nts o n C hr o nic J A K 
I n hibit or T hera p y [ A bstract 4 0 6 5]. 2 0 1 3.
Mea d o ws S A, Kas his hia n A, J o h ns o n D, Die hl V, L a n n utti BJ. C A L- 1 0 1, a p ote nt selecti ve 
i n hi bit or of t he p 1 1 0 delta is of or m of p h os p hati d yli n osit ol- 3-ki nase, atte n uates 
pat h wa y  si g nali n g, i n d uces a p o pt osis, a n d o verc o mes si g nals fr o m t he 
micr oe n vir o n me nt i n cell ular m o dels of H o d g ki n l y m p h o ma [ A bstract 3 9 2 6]. 
Bl o o d ( A S H A n n ual Meeti n g A bstracts) 2 0 1 0; 1 1 6.
Mea d o ws S A, Ve ga F, Kas his hia n A, J o h ns o n D, Die hl V, Miller L L, et al. PI 3 K delta i n hi bit or, 
G S -1 1 0 1 ( C A L -1 0 1), atte n uates pat h wa y si g nali n g, i n d uces a p o pt osis, a n d 
o verc o mes si g nals fr o m t he micr oe n vir o n me nt i n cell ular m o dels of H o d g ki n 
l ym p h o ma. Bl o o d 2 0 1 2; 1 1 9 ( 8): 1 8 9 7 - 9 0 0.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 8 9
2 6 Oct o ber 2 0 1 6
O k ke n ha u g K, Bila nci o A, Farj ot G, Pri d dle H, Sa nc h o S, Pes kett E, et al. I m paire d B a n d T cell 
a nti ge n rece pt or si g nali n g i n p 1 1 0 delta PI 3 -ki nase m uta nt mice. Scie nce 
2 0 0 2; 2 9 7 ( 5 5 8 3): 1 0 3 1 - 4.
O k ke n ha u g K, Va n haese br oec k B. PI 3 K -si g nalli n g i n B- a n d T -cells: i nsi g hts fr o m ge ne-
tar gete d mice. Bi oc he mical S ociety tra nsacti o ns 2 0 0 3a; 3 1 ( Pt 1): 2 7 0 - 4.
O k ke n ha u g K, Va n haese br oec k B. PI 3 K i n l y m p h oc y te de vel o p me nt, differe ntiati o n a n d 
acti vati o n. Nat ure re vie ws 2 0 0 3 b; 3 ( 4): 3 1 7 - 3 0.
Osa ki M, Os hi m ura M, It o H. PI 3 K- A kt pat h wa y : its f u ncti o ns a n d alterati o ns i n h u ma n ca ncer. 
A p o pt osis 2 0 0 4; 9 ( 6): 6 6 7 - 7 6.
Passa m o nti F, Cer va ntes F, Va n n ucc hi A M, M orra E, R u mi E, Pereira A, et al. A d y na mic 
pr o g n ostic m o del t o pre dict s ur vi val i n pri mar y  m yel ofi br osis: a st u d y b y t he 
I W G-M R T (I nter nati o nal W or ki n g Gr o u p f or M ye l o pr oliferati ve Ne o plas ms 
Researc h a n d Treat me nt) . Bl o o d 2 0 1 0; 1 1 5 ( 9): 1 7 0 3- 8.
Raa na ni P, Gafter -G vili A, Pa ul M, Be n -Bassat I, L ei b o vici L, S h pil ber g O. Im m u n o gl o b uli n 
pr o p h y la xis i n c hr o nic l y m p h oc ytic le u ke mia a n d m ulti ple m yel o ma: s yste matic 
re vie w a n d meta-a nal ys is. Le u k L y m p h o ma 2 0 0 9; 5 0 ( 5): 7 6 4 - 7 2.
S uj o bert P, Bar det V, C or nillet- Lefe b vre P, Ha yflic k J S, Prie N, Ver dier F, et al. Esse ntial r ole 
f or t he p 1 1 0 delta is of or m i n p h os p h oi n ositi de 3-ki nase acti vati o n a n d cell 
pr oliferati o n i n ac ute m yel oi d le u ke mia. Bl o o d 2 0 0 5; 1 0 6 ( 3): 1 0 6 3 - 6.
Tefferi A, Cer v a ntes F, Mesa R, Passa m o nti F, Verst o vse k S, Va n n ucc hi A M, et al. Re vise d 
res p o nse criteria f or m yel ofi br osis: Inter nati o nal W or ki n g Gr o u p -
M y el o pr oliferati ve Ne o plas ms Researc h a n d Treat me nt (I W G -M R T) a n d 
E ur o pea n Le u ke mia Net ( E L N) c o nse ns us re p ort. Bl o o d 2 0 1 3; 1 2 2 ( 8): 1 3 9 5 - 8.
Tefferi A, T hiele J, Orazi A, K vas nic ka H M, Bar b ui T, Ha ns o n C A, et al. Pr o p osals a n d 
rati o nale f or re visi o n of t he W orl d Healt h Or ga nizati o n dia g n ostic criteria f or 
p ol y c yt he mia vera, esse ntial t hr o m b oc yt he mia, a n d pri mar y m y el ofi br osis: 
rec o m me n dati o ns fr o m a n a d h oc i nter nati o nal e x pert pa nel. Bl o o d 2 0 0 7; 1 1 0 
( 4): 1 0 9 2- 7.
Tefferi A, Vai nc he n ker W. M y el o pr oliferati ve ne o plas ms: m olec ular pat h o p h y si ol o g y, esse ntial 
cli nical u n dersta n di n g, a n d treat me nt strate gies. J Cli n O nc ol 2 0 1 1; 2 9 ( 5): 5 7 3 - 8 2.
T hiele J, K vas nic ka H M, Facc hetti F, Fra nc o V, va n der Walt J, Orazi A. E ur o pea n c o nse ns us o n 
gra di n g b o ne marr o w fi br osis a n d assess me nt of cell ularit y . Hae mat ol o gica 
2 0 0 5; 9 0 ( 8): 1 1 2 8 - 3 2.
Va n haese br oec k B, Ali K, Bila nci o A, Geeri n g B , F o u kas L C. Si g nalli n g b y PI 3 K is of or ms: 
i nsi g hts fr o m ge ne-tar gete d mice. Tre n ds Bi oc he m Sci 2 0 0 5; 3 0 ( 4): 1 9 4- 2 0 4.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 9 0
2 6 Oct o ber 2 0 1 6
Verst o vse k S, Mesa R A, G otli b J, L e v y R S, G u pta V, Di Persi o J F, et al. A d o u ble -bli n d, 
place b o -c o ntr olle d trial of r u x oliti ni b f or m yel ofi brosis. N E n gl J Me d 2 0 1 2; 3 6 6 
( 9): 7 9 9- 8 0 7.
We b b H, C he n H, Y u A, Peter ma n S, H oles L, La n n utti B, et al. Cli nical P har mac o ki netics of 
C A L -1 0 1, a p 1 1 0 8 Is of or m -selecti ve PI 3 K I n hi bit or, F oll o wi n g Si n gle- a n d 
M ulti ple -D ose A d mi nistrati o n i n Healt h y  V ol u nteers a n d Patie nts wit h 
He mat ol o gical Mali g na ncies [ A bstract 1 7 7 4]. A S H A n n ual Meeti n g A bsracts  
2 0 1 0. 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 9 1
2 6 Oct o ber 2 0 1 6
1 1.
A P P E N DI C E S
A p pe n di x 1.
I n vesti gat or Si g nat ure Pa ge
A p pe n di x 2.
St u d y Pr oce d ures Ta ble
A p pe n di x 3.
Dia g n ostic Criteria a n d Pr o g n ostic Sc ori n g S yste m f or M yel ofi br osis
A p pe n di x 4.
D y na mic I nter nati o nal Pr o g n ostic Sc ori n g S yste m ( DI P S S) f or Pri mar y 
M y el ofi br osis
A p pe n di x 5.
D y na mic I nter nati o nal Pr o g n ostic Sc ori n g S yste m Pl us ( DI P S S Pl u s)
A p pe n di x 6.
Re vise d I nter nati o nal W or ki n g Gr o u p f or M yel o pr oliferati ve Ne o p las ms Researc h 
a n d Treat me nt (I W G -M R T) a n d E ur o pea n
Le u ke mia Net ( E L N) Res p o nse Criteria 
f or M yel ofi br osis
A p pe n di x 7.
E C O G Perf or ma nce Stat us Sc ori n g S yste m
A p pe n di x 8.
M P N S y m pt o m Assess me nt F or m ( M P N -S A F)
A p pe n di x 9.
M o difie d M yel o pr oliferati ve Ne o plas m S y m pt o m Assess me nt F or m T o tal 
S y m pt o m Sc ore
A p pe n di x 1 0.
Pre g na nc y Preca uti o ns, Defi niti o n f or Fe male of C hil d beari n g P o te ntial, a n d 
C o ntrace pt i ve Rec o m me n dati o ns
A p pe n di x 1 1.
C T C A E versi o n 4. 0 3


l delalisi b 
Pr ot oc ol G S- U S- 3 9 7- 1 2 4 5 
Fi nal 
Gilea d Scie nces, I nc. 
A me n d me nt 5 
A p pe n di x 1. 
I n vesti g at or Si g n at ure P a ge 
GI L E A D S CI E N C E S, I N C. 
3 3 3 L A K E SI D E D RI V E 
F O S T E R CI T Y, C A 9 4 4 0 4 
S T U D Y A C K N O W L E D G E M E N T 
A P hase 1 b O p e n- L a b el St u d y t o E val uate t he Safet y, T olera bilit y, a n d P har mac o ki netics of 
I delalisi b i n S u bjects Recei vi n g R u x oliti ni b as T hera p y f or Pri m ar y, P ost- P ol y c yt h e mi a V er a , or 
P ost- Ess e nti al T hr o m b oc yt he mia M y el ofi br osis wit h Pr o gr essi v e or 
Rela pse d Disease 
G S- U S- 3 9 7- 1 2 4 5, A me n d me nt 5, 2 6 Oct o ber 2 0 1 6 
T his pr ot oc ol h as bee n a p pro ve d b y Gilea d Scie nces, I nc. T he f oll o wi n g si g nat ure d oc u me nts 
---'-'t h=i .:..s ..;..a p p,;.;:;r o...:..v_a....::l _. ----------..... 
P P D 
Si g nat ure 
Date 
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 t he pr ot oc ol, i ncl u di n g all a p p e n di c es, a n d I a gree t h at it c o ntai ns all necessar y 
d et ails f or m e a n d m y st aff t o c o n d uct t his st u d y as descri be d. I will c o n d uct t his st u d y as 
o utli ne d herei n a n d will ma ke a reas o na ble eff ort t o c o m plete t he st u d y wit hi n t he ti me 
desi g nate d. 
I will pr o vi de all st u d y pers o n nel u n der m y s u per visi o n c o pies of t he pr ot oc ol a n d access t o all 
i nf or mati o n pr o vi de d b y Gilea d Scie nces, I nc. I will disc uss t his material wit h t he m t o e ns ure 
t h at t h e y ar e f ull y i nf or m e d a b o ut t h e dr u gs a n d t h e st u d y. 
Pri nci pal I n vesti gat or Na me ( Pri nte d) 
Si g n at ur e 
Date 
Site N u m ber 
C O N FI D E N TI A L 
Pa ge 9 2 
2 6 Oct o ber 2 0 1 6 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 9 3
2 6 Oct o ber 2 0 1 6
A p pe n di x 2.
St u d y Pr oce d ures T a ble
Wee ks 1 t o
4
Peri o d
Scree ni n g
Tre at me nt
Wee k
1
2
3 
4
St u d y D a y
-2 8 t o - 1 
1
4
1 0
1 5 
2 2
H o urs rel ati ve t o 
d osi n g
Pre d ose
0
0. 5
1
1. 5
2 
3 
4 
6 
8
1 2
Pre d ose
0
0. 5
1
1. 5
2 
3 
4 
6 
8
1 2
I nf or me d c o nse nt
X
M P N -S A F a
X
X
X  
X
Me dical & 
me dicati o n hist or y b
X
Vital si g ns c
X  
X  
X
X
X  
X
P h ysical e xa m d
X  
X
X
X  
X
E C O G
X  
X
X
X  
X
DI P S S e
X
1 2 -lea d E C G
X
He mat ol o g y f
X  
X
X
X  
X
C he mistr y g
X  
X
X
X  
X
Uri nal ysis
X
E S R
X
C oa g ulati o n
X
Pre g na nc y test h
X  
X
HI V scree n 
X
P ne u m oc ystis 
jir o veci p ne u m o nia
(PJ P)  Pr o p h yla xis s
X
X
X  
X
C M V Testi n g r
X
X


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 9 4
2 6 Oct o ber 2 0 1 6
Peri o d
Scree ni n g
Tre at me nt
Wee k
1
2
3 
4
St u d y D a y
-2 8 t o - 1 
1
4
1 0
1 5 
2 2
H o urs rel ati ve t o 
d osi n g
Pre d ose
0
0. 5
1
1. 5
2 
3 
4 
6 
8
1 2
Pre d ose
0
0. 5
1
1. 5
2 
3 
4 
6 
8
1 2
I m m u ne 
M o nit ori n g
X
X
He patitis ser ol o g y
X
R u x oliti ni b P K i
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Idelalisi b & 
R u x oliti ni b P K j
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
B o ne marr o w 
bi o ps y a n d as pirate l
X
R u x oliti ni b d osi n g m
X
X
X
X
X  
X  
X  
X
Idelalisi b d osi n g n
X
X  
X  
X  
X
Idelalisi b
dis pe nsi n g, 
acc o u nta bilit y o
X
X
X  
X  
X
A E, C o n me ds p
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
M RI
q
X
a
T he M P N -S A F will be c o m plete d wee kl y fr o m Wee k 1 t o 2 4 t he n m o nt hl y after Wee k 2 4 a n d at E O S . W he n visits are sc he d ule d, it s h o ul d be c o m plete d at t he cli nic.
S u bjects will recei ve a c o p y of  t he q uesti o n naire t o c o m plete at h o me bet wee n cli nic visits be gi n ni n g Wee k 4.
b
T he me dical a n d me dicati o n hist or y will i ncl u de t he J A K 2V 6 1 7 F m utati o n stat us if k n o w n, r u x oliti ni b d ose a n d tra nsf usi o n hist or y wit hi n 3 m o nt hs of scree ni n g.
c
Vital si g ns i nc l u de bl o o d press ure, heart rate, res pirat or y rate, a n d oral te m perat ure.
d
B o d y wei g ht , pal pati o n of t he s plee n a n d li ver will be perf or me d at eac h P E. H ei g ht will be perf or me d at scree ni n g o nl y. 
e
DI P S S Pl us s h o ul d be c o m plete d f or s u bjects w h o ha ve c yt o ge netics i nf or mati o n.
f
He mat ol o g y: C B C wit h differe ntial, retic ul oc yte c o u nt . A N C m o nit ore d at least e ver y 2 wee ks f or t he first 2 4 wee ks of i delalisi b treat me nt . F or s u bjects w h o de vel o p
ne utr o pe nia of A N C 0. 5 t o < 1. 0 x 1 0 9/ L ( Gra de 3), A N C s h o ul d be m o nit ore d at least wee kl y u ntil A N C≤ Gra de 2  . F or s u bjects w h o de vel o p A N C < 0. 5 x 1 0 9/ L ( Gra de 
4), i delalisi b s h o ul d be i nterr u pte d a n d A N C s h o ul d be m o nit ore d at least wee kl y u ntil A N C is ≥ 1. 0 x 1 0 9/ L 0. 5 x 1 0 9
C CI
/ L ( Gra de 2).
g 
C he mistr y: C o m pre he nsi ve meta b olic pa nel wit h A L T, A S T, G G T, ir o n, L D H, ma g nesi u m, p h os p h or us t otal bilir u bi n, direct bilir u bi n , uric aci d.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 9 5
2 6 Oct o ber 2 0 1 6
h 
F or fe males of c hil d beari n g p ote ntial o nl y. Ser u m pre g na nc y test will b e perf or me d d uri n g scree ni n g o nl y . A uri ne pre g na nc y test will be o btai ne d t hr o u g h o ut t he rest of t he 
st u d y.
i
T he r u x oliti ni b Da y 1 P K sa m ple will be dra w n pre d ose. T he 1 2 h o ur p ost d ose P K ti me p oi nt o n Da y 4 will be perf or me d pri or t o t he sec o n d r u x oliti ni b d osi n g.
j
Bl o o d sa mples will be c ollecte d f or r u x oliti ni b, i delalisi b a n d/ or meta b olite P K be gi n ni n g Da y 1 0. T he 1 2 h o ur p ost d ose P K ti me p oi nt o n Da y 1 0 will be perf or me d pri or t o 
i delalisi b a n d r u x oliti ni b d osi n g. Be gi n ni n g Da y 1 5 P K sa m ples will be c ollecte d pre d ose a n d 1. 5 h o urs p ost d ose .
l
B o ne marr o w bi o ps y a n d as pirate will be c ollecte d at S cree ni n g if o ne has n ot bee n d o ne i n t he past 3 m o nt hs or res ults are n ot a vaila ble, Da y s 7 8, 1 6 2 a n d e ver y 2 4 wee ks 
d uri n g t he e xte nsi o n peri o d . It will als o be c ollecte d at E O S , if o ne has n ot bee n d o ne i n t he past 2 4 wee ks . B o ne marr o w st u dies i ncl u de c yt o ge netics, c ore bi o ps y, tric hr o me 
stai n f or retic uli n, a n d ir o n stai n.
m
R u x oliti ni b d osi n g will be i n cli nic w he n visits are sc he d ule d. Pri or t o t he sc he d ule d visits, s u bjects s h o ul d be i nstr ucte d t o h ol d t heir m or ni n g d ose bef ore c o mi n g t o t he cli nic 
o n da ys w here P K la b dra ws will be ta ke n ( Da y 1 a n d 4 f or r u x oliti ni b, a n d Da y 1 0, 1 5, 3 6, 7 8, 1 6 2 f or b ot h i delalisi b a n d r u x oliti ni b P K).
n 
I delalisi b d osi n g will be i n t he cli nic w he n visits are sc he d ule d. Pri or t o t he sc he d ule d visits, s u bjects s h o ul d be i nstr ucte d t o h ol d t heir m or ni n g d ose bef ore c o mi n g t o t he 
cli nic o n da ys w here P K la b dra w s will be ta ke n ( Da y 1 a n d 4 f or r u x oliti ni b, a n d Da y 1 0, 1 5, 3 6, 7 8, 1 6 2 f or b ot h i delalisi b a n d r u x oliti ni b P K).
o 
I delalisi b will be dis pe nse d i n cli nic o n Da y 4 f or t he s u bject t o self -a d mi nister be gi n ni n g Da y 5. Idelalisi b acc o u nta bilit y s h o ul d be d o ne at e ver y cli nic visit.
p  
A d verse e ve nts a n d c o nc o mita nt me dicati o ns will be assesse d a n d d oc u me nte d t hr o u g h o ut t he st u d y. F or assess me nt of Diarr hea/ C olitis see Secti o n 6. 2. 1 8
C CI
.
q
T hree di me nsi o nal M RI ( or C T , if M RI n ot feasi ble) f or t he li ver a n d s plee n size b y v ol u metric i ma gi n g . A n M RI s h o ul d be d o ne at t he E O S visit o nl y if it has n ot bee n d o ne 
wit hi n 1 2 wee ks of t he visit.
r
C M V testi n g will be perf or me d e ver y 4 wee ks starti n g at Scree ni n g a n d c o nti n ui n g t hr o u g h E O S.
s 
S u bjects m ust recei ve tri met h o pri m-s ulfamet h o xaz ole or ot her esta blis he d pr o p h yla xis f or PJ P t hr o u g h o ut t he c o urse of i delalisi b treat me nt.  Pr o p h yla xis will c o nti n u e f or a 
peri o d of 2 t o 6 m o nt hs after i delalisi b disc o nti n uati o n.  T he d urati o n of pr o p h yla xis s h o ul d be base d o n cli nical j u d g me nt a n d ma y ta ke i nt o acc o u nt ris k fact ors s uc h as 
c o nc o mita nt c ortic oster oi d treat me nt a n d pr ol o n ge d ne utr o pe nia after i delalisi b treat me nt e n ds.
I 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 9 6
2 6 Oct o ber 2 0 1 6
Wee k s 6 t o 2 4
Peri o d
Tre at m e nt
E xte nsi o n peri o d o
E O S q
F oll o w U p r
Wee k
6 
8
1 0 
1 2 
1 4 
1 6 
1 8 
2 0 
2 2 
2 4
Q 4 W
Q 1 2 W p
Q 2 4 W p
3 0 ± 7 d a ys
after E O S
St u d y D a y
3 6 
5 0 
6 4 
7 8 
9 2 
1 0 6 
1 2 0 
1 3 4 
1 4 8 
1 6 2
Visit Wi n d o w ( D a ys)
± 3 
± 3 
± 3 
± 3 
± 3
± 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
M P N -S A F a
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
Vital si g ns b
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X  
X
P h y sical e xa mc
X  
X  
X  
X  
X  
X  
X  
X
X  
X
E C O G
X  
X  
X  
X  
X  
X  
X  
X
X  
X
H e m at ol o g y d
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X  
X
C he mistr y e
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X  
X
P ne u m oc ystis jir o veci p ne u m o nia
(PJ P) Pr o p h yla xis t
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
C M V Testi n g s
X  
X  
X  
X  
X  
X  
X  
X  
X
I m m u ne M o nit ori n g
X
X
X  
X  
X
Pre g na nc y test f
X
X  
X  
X  
X  
X
X  
X
Idelalisi b & R u x oliti ni b P K g
X
X
X
B o ne marr o w  bi o ps y a n d as pirate i
X
X
X  
X
R u x oliti ni b d osi n g j
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Idelalisi b d osi n g k
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Idelalisi b dis pe nsi n g, 
acc o u nta bilit y l
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
A E, C o n me ds m
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X  
X
M RI
n
X
X
X
X
C CI
a
T he M P N -S A F will be c o m plete d wee kl y fr o m Wee k 1 t o 2 4 t he n m o nt hl y after Wee k 2 4 a n d at E O S . W he n visits are sc he d ule d, it s h o ul d be c o m plete d at t he cli nic.
S u bjects will recei ve a c o p y of t he q uesti o n naire t o c o m plete at h o me bet wee n cli nic visits be gi n ni n g Wee k 4.
b
Vital si g ns i ncl u de bl o o d press ure, heart rate, res pira t or y rate a n d oral te m perat ure.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 9 7
2 6 Oct o ber 2 0 1 6
c
B o d y wei g ht , pal pati o n of t he s plee n a n d li ver will be p erf or me d at eac h P E. Hei g ht will be perf or me d at scree ni n g o nl y. P h ysical e xa ms will be sc he d ule d e ver y 4 wee ks 
d uri n g t he e xte nsi o n peri o d e xce pt after a s u bject has bee n o n st u d y f or 1 year, w he n it will be sc he d ule d e ver y 1 2 wee ks.
d
He mat ol o g y: C B C wit h differe ntial, retic ul oc yte c o u nt . A N C m o nit ore d at least e ver y t w o wee ks f or t he first 2 4 wee ks of i delalisi b treat me nt. F or s u bjects w h o de vel o p 
ne utr o pe nia of A N C 0. 5 t o < 1. 0 x 1 0 9/ L ( Gra de 3), m o nit or A N C at least wee kl y u ntil A N C≤ Gra de 2  . F or s u bjects w h o de vel o p A N C < 0. 5 x 1 0 9/ L ( Gra de 4), i delalisi b 
s h o ul d be i nterr u pte d a n d m o nit or A N S C at least wee kl y u ntil A N C is ≥ 1. 0 x 1 0 9/ L 0. 5 x 1 09/ L( Gra de 2)
e
C he mistr y: C o m pre he nsi ve meta b olic pa nel wit h A L T, A S T, G G T, ir o n, L D H, ma g nesi u m, t otal bilir u bi n, p h os p h or us , uric aci d.
f 
F or fe males of c hil d beari n g p ote ntial o nl y. Ser u m pre g na nc y test will be perf or me d d uri n g scree ni n g o nl y . A uri ne pre g na nc y test will be o btai ne d t hr o u g h o ut t he rest of t he 
st u d y.
g
Bl o o d sa m ples will be c ollecte d f or r u x oliti ni b, i delalisi b a n d/ or meta b olite P K be gi n ni n g Da y 1 0. Be gi n ni n g Da y 1 5 P K sa m ples will be c ollecte d pre d ose a n d 1. 5 h o urs 
p ost d ose .
i
B o ne marr o w bi o ps y a n d as pirate will be o btai ne d at scree ni n g if o ne has n ot bee n d o ne i n t he past 3 m o nt hs or res ults are n ot a vaila ble , Da y s 7 8, 1 6 2 a n d e ver y 2 4 wee ks 
d uri n g t he e xte nsi o n peri o d . It will als o be o btai ne d at E O S if o ne has n ot bee n d o ne i n t he past 2 4 wee ks . B o ne marr o w st u dies i ncl u de c yt o ge netics, c ore bi o ps y, tric hr o me 
stai n f or retic uli n, a n d ir o n stai n.
j
R u x oliti ni b d osi n g will be i n cli nic w he n visits are sc he d ule d.
k
Idelalisi b d osi n g will be i n t he cli nic w he n visits are sc he d ule d.
l 
Idelalisi b will be dis pe nse d i n cli nic o n Da y 4 f or t he s u bject t o self -a d mi nister be gi n ni n g Da y 5. Idelalisi b acc o u nta bilit y s h o ul d be d o ne at e ver y cli nic visit.
m  
A d verse e ve nts a n d c o nc o mita nt me dicati o ns will be assesse d a n d d oc u me nte d t hr o u g h o ut t he st u d y. F or assess me nt of Diarr hea/ C olitis please see Secti o n 6. 2. 1 8
C CI
.
n
T hree di me nsi o nal M RI ( or C T , if M RI n ot feasi ble) f or t he li ver a n d splee n size b y v ol u metric i ma gi n g . A n M RI s h o ul d be d o ne at t he E O S visit o nl y if it has n ot bee n d o ne 
wit hi n 1 2 wee ks of t he visit.
o
If s u bjects are deri vi n g cli nical be nefit (as deter mi ne d b y t he i n vesti gat or) a n d c o m plete Wee k 2 4 , s u bjects ca n e nter e xte nsi o n p eri o d u ntil t he y de m o nstrate pr o gressi ve 
disease a n d/ or ha ve u nacce pta ble t o xicit y, as defi ne d b y t he pr ot oc ol. P h ysical e xa ms will be sc he d ule d e ver y 4 wee ks d uri n g t he e xte nsi o n peri o d e xce pt after a s u bject has 
bee n o n st u d y f or 1 year, w he n it will be sc he d ule d e ver y 1 2 wee ks.
p
Q 1 2 W a n d Q 2 4 W assess me nts will o verla p wit h Q 4 W assess me nts a n d will be sc he d ule d at t he sa me visit.
q
If t he E O S visit c oi nci des wit h Wee k
2 4 (Da y 1 6 2 ), t he pre d ose bl o o d sa m ple f or P K m ust be c ollecte d.
r
T he safet y f oll o w u p visit is w it hi n 3 0 da ys of E O S.
s 
C M V testi n g will be perf or me d e ver y 4 wee ks starti n g at Scree ni n g a n d c o nti n ui n g t hr o u g h E O S.
t 
S u bjects m ust recei ve tri met h o pri m-s ulfa met h o xaz ole or ot her esta blis he d pr o p h yla xis f or PJ P t hr o u g h o ut t he c o urse of i delal isi b treat me nt.  Pr o p h yla xis will c o nti n ue f or a 
peri o d of 2 t o 6 m o nt hs after i delalisi b disc o nti n uati o n.  T he d urati o n of pr o p h yla xis s h o ul d be base d o n cli nical j u d g me nt a n d ma y ta ke i nt o acc o u nt ris k fact ors s uc h as 
c o nc o mita nt c ortic oster oi d treat me nt a n d pr ol o n ge d ne utr o pe nia after i delalisi b treat me nt e n ds.
I 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 9 8
2 6 Oct o ber 2 0 1 6
A p pe n di x 3.
Di a g n ostic Criteri a a n d Pr o g n ostic Sc ori n g S yste m f or M yel ofi br osis
2 0 0 8 W H O Di a g n ostic Criteri a f or P M F 5
(Dia g n osis re q uires meeti n g all 3 maj o r criteria a n d 2 mi n or criteria.)
M aj or Criteri a
1.
Prese nce of me ga kar y oc yte pr oliferati o n a n d at y pia a, us uall y acc o m pa nie d b y eit her retic uli n or
c olla ge n fi br osis; or i n t he a bse nce of si g nifica nt retic uli n fi br osis, t he me ga kar y oc yte c ha n ges m ust be
acc o m pa nie d b y a n i ncrease d b o ne marr o w  cell ularit y c haracterize d b y gra n ul oc ytic pr oliferati o n a n d ofte n 
decrease d er yt hr o p oiesis (ie, prefi br otic cell ular -p hase disease)
2.
N ot meeti n g W H O criteria f or P V b, B C R -A B L 1 + C M L c, M D S
d or ot her m yel oi d ne o plas m s
3.
D e m o nstrati o n of J A K 2 V 6 1 7 F or ot her cl o nal mar ker (e g, M P L W 5 1 5 L/ K); or i n t he a bse nce of a
cl o nal mar ker, 
n o e vi de nce t hat t he b o ne marr o w  fi br osis is sec o n dar y t o i nfecti o n, a ut oi m m u ne dis or der or ot her 
c hr o nic i nfla m mat or y c o n diti o n; hair y cell le uke mia or ot her l y m p h oi d ne o plas m; m etastatic mali g na nc y; or 
t o xic (c hr o nic) m yel o pat hiese
Mi n or Criteri a
f
1.
Le u k oer yt hr o blast osis
2.
I ncrease i n ser u m lactate de h y dr o ge nase le vel
3.
A ne mia
4.
Pal pa ble s ple n o me gal y
W H O = W orl d Healt h Or ga nizati o n; P M F = pri mar y m yel o fi br osis; P V = p ol yc yt he mia vera; B C R- A B L = brea k p oi nt cl uster
re gi o n-a bels o n le u ke mia vir us pr otei n; C M L =c hr o nic m yel o ge n o us le u ke mia; M D S = m yel o d ys plastic s y n dr o me; 
J A K =Ja n us ki nase; M P L =t hr o m b o p oieti n rece pt or.
a
S mall t o lar ge me ga kar y oc ytes wi t h a n a berra nt n uclear/c yt o plas mic rati o a n d h y perc hr o matic, b ul b o us or irre g ularl y f ol de d 
n uclei a n d de nse cl usteri n g.
b 
Re q uires t he fail ure of ir o n re place me nt t hera p y t o i ncrease he m o gl o bi n ( H b) le vel t o t he P V ra n ge i n t he prese nce of 
decrease d ser u m ferriti n. E xcl usi o n of P V is base d o n H b a n d he mat ocrit le vels; re d cell mass meas ure me nt is n ot re q uire d.
c
Re q uires t he a bse nce of B C R -A B L 1.
d 
Re q uires t he a bse nce of d yser yt hr o p oiesis a n d d ys gra n ul o p oiesis.
e
Patie nts wit h c o n diti o ns ass ociate d wit h reacti ve m yel ofi br osis are n ot i m m u ne t o P M F, a n d t he dia g n osis s h o ul d be 
c o nsi dere d i n s uc h cases if ot her criteria are met.
f
De gree of a b n or malit y c o ul d be b or derli ne or mar ke d.
{ Tefferi et al 2 0 0 7 }


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 9 9
2 6 Oct o ber 2 0 1 6
2 0 0 8 I W G -M R T Di a g n osis Criteri a
f or P ost P V- M F a n d P ost -E T M F
Di a g n ostic Criteri a f or P ost -P V M F
Di a g n ostic Criteri a f or P ost -E T M F
Re q uire d Criteri a 6
1.
D oc u me ntati o n of a pre vi o us dia g n osis of E T or P V as defi ne d b y t he W H O criteria
2.
B o ne marr o w  fi br osis Gra de 2- 3 ( o n a 0 -3 scale) or Gra de 3- 4 ( o n a 0 -4 scale) a
A d diti o n al criteri a ( 2 are re q uire d)
A d diti o n al criteri a ( 2 are re q uire d)
1.
A ne mia b or s ustai ne d l oss of re q uire me nt f or eit her 
p hle b ot o m y (i n t he a bse nce of
c yt ore d ucti ve t hera p y) or f or c yt ore d ucti ve
treat me nt f or er yt hr oc yt osis
1.
A ne mia b a n d a ≥2 m l/ m L−1 decrease fr o m baseli ne 
he m o gl o bi n le vel
2.
A le u k oer yt hr o blastic peri p heral bl o o d pict ure
2.
A le u k oer yt hr o blastic peri p heral bl o o d pict ure a
3.
I ncreasi n g s ple n o me gal y of ≥5 c m ( dista nce of t he 
ti p of t he s plee n fr o m t he left c ostal mar gi n) or t he 
a p peara nce of a ne wl y pal pa ble s ple n o me gal y
3.
I ncreasi n g s ple n o me gal y of ≥5 c m  ( dista nce of t he 
ti p of t he s plee n fr o m t he left c ostal mar gi n) or t he 
a p peara nce of a ne wl y pal pa ble s ple n o me gal y
4.
I ncrease d lactate de h y dr o ge nase 
(a b o ve refere nce le vel)
4.
De vel o p me nt of ≥ of 3 c o nstit uti o nal s y m pt o ms:
> 1 0 % w ei g ht l oss i n 6 m o nt hs, ni g ht s weats,
u ne x plai ne d fe ver ( > 3 7. 5 °C)
5.
De vel o p me nt of ≥1 of 3 c o nstit uti o nal s y m pt o ms: 
> 1 0 % w ei g ht l oss i n 6 m o nt hs, ni g ht s weats, 
u ne x plai ne d fe ver ( > 3 7. 5 °C)
I W G-M R T =I nter nati o nal W or ki n g Gr o u p f or M yel ofi br osis Researc h a n d Treat me nt; P V = p ol yc yt he mia vera; 
M F = m yel ofi br osis; E T =esse ntial t hr o m b oc yt he mia; W H O = W orl d Healt h Or ga nizati o n
a
Gra de 2 -3 acc or di n g t o t he E ur o pea n classificati o n: diff use, ofte n c oarse fi ber net w or k wit h n o e vi de nce of c olla ge nizati o n 
( ne gati ve tric hr o me stai n) or diff use, c oarse fi ber net w or k wit h areas of c olla ge nizati o n ( p ositi ve tric hr o me stai n). Gra de 3- 4 
acc or di n g t o t he sta n dar d classificati o n: diff use a n d de nse i ncrease i n retic uli n wit h e xte nsi ve i ntersecti o ns, occasi o nall y 
wit h o nl y f ocal b u n dles of c olla ge d a n d/ or f ocal oste oscler osis or diff use a n d de nse i ncrease i n retic uli n wit h e xte nsi ve 
i ntersecti o ns wit h c oarse b u n dles of c olla ge n, ofte n ass ociate d wit h si g nifica nt oste o p orisis.
b
Bel o w t he refere nce ra n ge f or a p pr o priate a ge, se x, ge n der a n d altit u de c o nsi derati o ns.
{ Bar osi et al 2 0 0 8 }


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 0 0
2 6 Oct o ber 2 0 1 6
A p pe n di x 4.
D y n a mic I nter n ati o n al Pr o g n ostic Sc ori n g S yste m (D I PS S) f or 
Pri m ar y M yel ofi br osis
Pr o g n ostic v ari a ble
V al ue
0
1
2
A ge
≤ 6 5
> 6 5
W B C
≤ 2 5
> 2 5
H g b
≥ 1 0
< 1 0
Peri p heral Blast
< 1
≥ 1
C o nstit uti o nal s y m pt o ms
N o
Yes
T he ris k cate g or y is o btai ne d b y a d di n g u p t he val ues of eac h pr o g n ostic varia ble.
Ris k Le vel
D I P S S Sc ore
L o w
0
I nter me diate- 1
1 or 2
I nter me diate- 2
3 or 4
Hi g h
> 4
{ Passa m o nti et al 2 0 1 0 }


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 0 1
2 6 Oct o ber 2 0 1 6
A p pe n di x 5.
D y n a mic I nter n ati o n al Pr o g n ostic Sc ori n g S yste m Pl us (DI P S S P l us)
Pr o g n ostic v ari a ble
V al ue
0
1
2
A ge
≤ 6 5
> 6 5
W B C
≤ 2 5
> 2 5
H g b
≥ 1 0
< 1 0
Peri p heral Blast
< 1
≥ 1
C o nstit uti o nal s y m pt o ms
N o
Yes
Platelet c o u nt
> 1 0 0 × 1 0 9/l
< 1 0 0 × 1 0 9/l
R B C tra nsf usi o n ( o n g oi n g nee d)
N o
Yes
P o or ris k B M c yt o ge netics
( + 8,-7/ 7 q -, i( 1 7 q), i n v( 3), -5/ 5 q, 1 2 p -, 
or 1 1 q 2 3 rearra n ge me nts).
N o ne
≥1
T he ris k cate g or y is o btai ne d b y a d di n g u p t he val ue s of eac h pr o g n ostic varia ble.
Ris k cate g ories are defi ne d as:

L o w : 0 a d verse p oi nts

I nter me di ate- 1: 1 a d verse p oi nt

I nter me di ate- 2: 2-3 a d verse p oi nts

Hi g h : ≥4 a d verse p oi nts
{ Ga n gat et al 2 0 1 1 }


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 0 2
2 6 Oct o ber 2 0 1 6
A p pe n di x 6.  
Re vise d I nter n ati o n al W or ki n g Gr o u p f or M yel o pr olifer ati ve 
Ne o pl as ms Rese arc h a n d T re at me nt (I W G-M R T) a n d 
E ur o pe a n Le u ke mi a Net ( E L N) Res p o nse Criteri a f or M yel ofi br osis
C o m plete re missi o n ( C R)
B o ne marr o w : a ge-a dj uste d n or m ocell ularit y; < 5 % blasts; ≤Gra de 1 m yel ofi br osis,
A N D
Peri p heral bl o o d: he m o gl o bi n ≥ 1 0 g/ d L a n d < U L N;
ne utr o p hil c o u nt ≥1 × 1 0 9/ L a n d < U L N; platelet c o u nt ≥ 1 0 0 × 1 0 9/ L a n d < U L N, 
< 2 % i m mat ure m yel oi d cells,
A N D
Cli nical: res ol uti o n of disease s y m pt o ms; s plee n a n d li ver n ot pal pa ble; n o e vi de nce of 
e xtra me d ullar y he mat o p oiesis
Partial re missi o n ( P R)
Peri p heral bl o o d: he m o gl o bi n ≥ 1 0 g/ d L a n d < U L N;
ne utr o p hil c o u nt ≥1 × 1 0 9/ L a n d < U L N; platelet c o u nt ≥ 1 0 0 × 1 0 9/ L a n d < U L N, 
< 2 % i m mat ure m yel oi d cells,
A N D
Cli nical: res ol uti o n of disease s y m pt o ms; s plee n a n d li ver n ot pal pa ble; n o e vi de nce of 
e xtra me d ullar y he mat o p oiesis
O R
B o ne marr o w : a ge-a dj uste d n or m oce ll ularit y; < 5 % blasts; ≤Gra de 1 m yel ofi br osis, 
A N D
Peri p heral bl o o d: he m o gl o bi n ≥ 8. 5 b ut < 1 0 g / d L a n d < U L N;
ne utr o p hil c o u nt ≥ 1 × 1 0 9/ L a n d < U L N;
platelet c o u nt ≥ 5 0 b ut < 1 0 0 x 1 0 9/ L a n d < U L N; < 2 % i m mat ure m yel oi d cells,
A N D
Cli nical: res ol uti o n of disease s y m pt o ms; s plee n a n d li ver n ot pal pa ble, n o e vi de nce of 
e xtra me d ullar y he mat o p oiesis
Cli nical i m pr o ve me nt 
T he ac hie ve me nt of a ne mia, s plee n or s y m pt o ms res p o nse wit h o ut pr o gressi ve disease 
or i ncrease i n s e verit y of a ne mia, t hr o m b oc yt o pe nia or ne utr o pe nia
A ne mia res p o nse
Tra nsf usi o n -i n de pe n de nt patie nts: a ≥ 2 g/ d L  i ncrease i n he m o gl o bi n le vel
(a p plica ble o nl y t o patie nts wit h baseli ne he m o gl o bi n < 1 0 g/ d L)
Tra nsf usi o n -de pe n de nt patie nts: bec o mi n g tra nsf usi o n-i n de pe n de nt
S plee n res p o nse
A baseli ne s ple n o me gal y t hat is pal pa ble at 5 -1 0 c m, bel o w  t he left c ostal mar gi n, 
bec o mes n ot pal pa ble,
O R
A baseli ne s ple n o me gal y t hat is pal pa ble at > 1 0 c m, bel o w  t he left c ostal mar gi n, 
decreases b y ≥ 5 0 %
A baseli ne s ple n o me gal y t hat is pal pa ble at < 5 c m, bel o w  t he left c ostal mar gi n, is n ot 
eli gi ble f or s plee n res p o nse
S y m pt o ms res p o nse
A ≥ 5 0 % re d ucti o n i n t he M yel o pr oliferati ve Ne o plas m S y m pt o m Assess me nt F or m 
t otal s y m pt o m sc ore ( M P N S A F T S S)


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 0 3
2 6 Oct o ber 2 0 1 6
Pr o gressi ve disease
A p peara nce of a ne w s ple n o me gal y t hat is pal pa ble at least 5 c m bel o w t he left c ostal 
mar g i n,
O R
A ≥1 0 0 % i ncrease i n pal pa ble dista nce, bel o w  left c ostal mar gi n, f or baseli ne 
s ple n o me gal y of 5-1 0 c m ,
O R
A 5 0 % i ncrease i n pal pa ble dista nce, bel o w left c ostal mar gi n, f or ba seli ne 
s ple n o me gal y of > 1 0 c m,
O R
Le u ke mic tra nsf or mati o n c o nfir me d b y a b o ne marr o w  blast c o u nt of ≥2 0 %,
O R
A peri p heral bl o o d blast c o nt e nt of ≥ 2 0 % ass ociate d wit h a n a bs ol ute blast c o u nt of 
≥1 × 1 0 9/ L t hat lasts f or at least 2 wee ks
Sta ble disease ( S D)
Bel o n gi n g t o n o ne of t he a b o ve liste d res p o nse cate g ories
Rela pse 
N o l o n ger meeti n g criteria f or at least cli nical i mpr o ve me nt after ac hie vi n g C R, P R, or 
cli nical i m pr o ve me nt,
O R
L oss of a ne mia res p o nse persiste nt f or at least 1 m o nt h,
O R
L oss of s plee n res p o nse persisti n g f or at least 1 m o nt h
a
Baseli ne a n d p ost -treat me nt b o ne marr o w sli des are t o be stai ne d at t he sa me ti me a n d i nter prete d at o ne sitti n g b y a ce ntral 
re vie w pr ocess. C y t o ge netic a n d m olec ular res p o nses are n ot re q uire d f or C R assi g n me nt.
b
Gra di n g of m yel ofi br osis is acc or di n g t o t he E ur o pea n classificati o n { T hiele et al 2 0 0 5 } . It is u n dersc ore d t hat t he c o nse ns us 
defi niti o n of “a c o m plete re missi o n b o ne marr o w” is t o be use d o nl y i n t h ose patie nts w here all ot her criteria, i ncl u di n g 
res ol uti o n of le u k oer yt hr o blast osis, are met.
c 
I m mat ure m yel oi d cells c o nstit ute blasts + pr o m yel oc ytes + m yel oc ytes + meta m yel oc yte s + n ucleate d re d bl o o d cells. 
I n s ple nect o mize d patie nts, < 5 % i m mat ure m yel oi d cells is all o we d.
d 
I ncrease i n se verit y of a ne mia c o nstit utes t he occ urre nce of ne w tra nsf usi o n de pe n de nc y or a ≥ 2 g/ d L decrease i n 
he m o gl o bi n le vel fr o m pre -treat me nt baseli ne t hat lasts f or at least 1 2 wee ks. I ncrease i n se verit y of t hr o m b oc yt o pe nia or 
ne utr o pe nia is defi ne d as a 2 -gra de decli ne, fr o m pre -treat me nt baseli ne, i n platelet c o u nt or a bs ol ute ne utr o p hil c o u nt, 
acc or di n g t o C o m m o n Ter mi n ol o g y Criter ia f or A d verse E ve nts ( C T C A E). I n a d diti o n, assi g n ment t o CI re q uires a 
mi ni m u m platelet c o u nt of ≥2 5, 0 0 0 × 1 0 9/ L a n d a bs ol ute ne utr o p hil c o u nt of ≥ 0. 5 × 1 0 9/ L.
e
I n s ple nect o mize d patie nts, pal pa ble he pat o me gal y is s u bstit ute d wit h t he sa me meas ure me nt strate g y.
f
S plee n or li ver res p o nses m ust be c o nfir me d b y  i ma gi n g st u dies w here a ≥ 3 5 % re d ucti o n i n s plee n v ol u me, as assesse d b y 
M RI or C T, is re q uire d. F urt her m ore, a ≥ 3 5 % v ol u me re d ucti o n i n t he s plee n or li ver, b y M RI or C T, c o nstit utes a res p o nse 
re gar dless of w hat is re p orte d wit h p h ysical e xa mi nati o n.
g
Pr o gressi ve disease assi g n me nt f or s ple n o me gal y re q uires c o nfir mati o n b y M RI or C T s h o wi n g a ≥ 2 5 % i ncrease i n s plee n 
v ol u me fr o m baseli ne. Baseli ne val ues f or b ot h p h ysical e xa mi nati o n a n d i ma gi n g st u dies refer t o pre- treat me nt baseli ne a n d 
n ot t o p ost -treat me nt meas ure me nts.
{ Tefferi et al 2 0 1 3 }


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 0 4
2 6 Oct o ber 2 0 1 6
A p pe n di x 7.
E C O G Perf or m a nce St at us Sc ori n g S yste m
Gr a de
E C O G
0
F ull y acti ve, a ble t o carr y o n all pre -disease perf or ma nce wit h o ut restricti o n
1
Restricte d i n p h ysicall y stre n u o us acti vit y b ut a m b ula t or y a n d a ble t o carr y o ut 
w or k of a li g ht or se de ntar y nat ure, e g , li g ht h o use wor k, office w or k
2
A m b ulat or y a n d ca pa ble of all self -care b ut u na ble t o carr y o ut a n y w or k acti vities. U p a n d a b o ut 
m o re t ha n 5 0 % of wa ki n g h o urs
3
Ca pa ble of o nl y li mite d self -care, c o nfi ne d t o be d or c hair m ore t ha n 5 0 % of w a ki n g h o urs
4
C o m pletel y disa ble d. Ca n n ot carr y o n a n y self -care. T otall y c o nfi ne d t o be d or c hair
5
Dea d


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 0 5
2 6 Oct o ber 2 0 1 6
A p pe n di x 8.
M P N S y m pt o m Assess me nt F or m ( M P N -S A F)
I nstr ucti o ns: Please fill o ut all q uesti o ns, as best a ble, reflecti n g h o w t hese s y m pt o ms affecte d 
y o u o ver t he L A S T W E E K u nless directe d ot her wise. C o m plete f or ms u ntil t he S T O P 
i nstr ucti on t o war d t he e n d of t he pac ket.
S y m pt o m
1 t o 1 0 ( 0 if a bse nt) r a n ki n g *
1 is m ost fa v ora ble a n d 1 0 least fa v ora ble
Please rate y o ur fati g ue
( weari ness, tire d ness) b y circli n g t he 
o ne n u m ber t h at best descri bes y o ur 
fati g ue ri g ht N O W
( N o Fati g ue)  0  1  2  3  4  5  6  7  8  9  1 0 ( W orst I ma gi na ble)
Please rate y o ur fati g ue
( weari ness, tire d ness) b y circli n g t he 
o ne n u m ber t hat best descri bes y o ur 
U S U A L L e vel of fati g ue d uri n g 
past 2 4 h o urs
( N o Fati g ue)  0   1  2  3  4  5  6  7  8  9  1 0 ( W orst I ma gi na ble)
Please rate y o ur fati g ue
( weari ness, tire d ness) b y circli n g t he 
o ne n u m ber t hat best descri bes y o ur 
W O R S T le vel of fati g ue d uri n g 
past 2 4 h o urs
( N o Fati g ue) 0  1  2  3  4  5  6  7  8  9  1 0 ( W orst I ma gi na ble)
Circle t he o ne n u m ber t h at descri bes h o w, d uri n g t he p ast 2 4 h o urs, f ati g ue h as i nterfere d wit h y o ur

Ge neral Acti vit y
( D oes n ot I nterfere) 0 1 2 3 4 5 6 7 8 9 1 0 ( C o m pletel y I nterferes)

M o o d
( D oes n ot I nterfere)  0 1 2 3 4 5 6 7 8 9 1 0 ( C o m pletel y I nterferes)

Wal ki n g a bilit y
( D oes n ot I nterfere)  0   1   2   3   4   5   6   7   8   9   1 0   ( C o m pletel y I nterferes)

N or mal W or k (i ncl u des w o r k b ot h 
o utsi de t he h o m e a n d dail y c h ores)
( D oes n ot I nterfere)   0   1   2   3   4   5   6   7   8   9   1 0   ( C o m pletel y I nterferes)

Relati o ns wit h ot her pe o ple
( D oes n ot I nterfere)  0   1   2   3   4   5   6   7   8   9 1 0   ( C o m pletel y I nterferes)

E nj o y me nt of life
( D oes n ot I nterfere)  0  1   2   3   4   5   6   7   8   9  1 0   ( C o m pletel y I nterferes)
Circle t he o ne n u m ber t h at desc ri bes h o w, d uri n g t he p ast Wee k
h o w m uc h diffic ult y y o u h a ve h a d wit h e ac h of t he f oll o wi n g s y m pt o ms

Filli n g u p q uic kl y w he n y o u eat
( Earl y Satiet y)
( A bse nt)  0   1   2   3   4   5   6   7   8   9   1 0   ( W orst I ma gi na ble)

A b d o mi nal pai n 
( A bse nt)  0   1   2   3   4   5   6   7   8   9   1 0   ( W orst I ma gi na ble)

A b d o mi nal disc o mf ort
( A bse nt)  0   1   2   3   4   5   6   7   8   9   1 0   ( W orst I ma gi na ble)

I nacti vit y
( A bse nt)  0   1   2   3   4   5   6   7   8   9   1 0   ( W orst I ma gi na ble)

Pr o ble ms wit h Hea dac hes 
( A bse nt)  0   1   2   3   4   5   6   7   8   9   1 0   ( W orst I ma gi na ble)

Pr o ble ms wit h C o nce ntrati o n −
C o m pare d t o pri or t o m y M P D
( A bse nt)  0   1   2   3   4   5   6   7   8   9   1 0   ( W orst I ma gi na ble)


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 0 6
2 6 Oct o ber 2 0 1 6
Circle t he o ne n u m ber t h at desc ri bes h o w, d uri n g t he p ast Wee k
h o w m uc h diffic ult y y o u h a ve h a d wit h e ac h of t he f oll o wi n g s y m pt o ms (c o nti n ue d)

Dizzi ness /Verti g o / Li g ht hea de d ness
( A bse nt)  0   1   2   3   4   5   6   7   8   9   1 0   ( W orst I ma gi na ble)

N u m b ness/ Ti n gli n g (i n m y ha n ds 
a n d feet)
( A bse nt)  0   1   2   3   4   5   6   7   8   9   1 0   ( W orst I ma gi na ble)

Diffic ult y slee pi n g
( A bse nt)  0   1   2   3   4   5   6   7   8   9   1 0   ( W orst I ma gi na ble)

De pressi o n or sa d m o o d
( A bse nt)  0   1   2   3   4   5   6   7   8   9   1 0   ( W orst I ma gi na ble)

Pr o ble ms wit h Se x ual Desire or 
F u ncti o n 
( A bse nt)  0   1   2   3   4   5   6   7   8   9   1 0   ( W orst I ma gi na ble)

C o u g h
( A bse nt)  0   1   2   3   4   5   6   7   8   9   1 0   ( W orst I ma gi na ble)

Ni g ht S weats
( A bse nt)  0   1   2   3   4   5   6   7   8   9   1 0   ( W orst I ma gi na ble)

Itc hi n g ( pr urit us)
( A bse nt)  0   1   2   3   4   5   6   7   8   9   1 0   ( W orst I ma gi na ble)

B o ne Pai n ( diff use n ot j oi nt pai n 
or art hritis)
( A bse nt)  0   1   2   3   4   5   6   7   8   9   1 0   ( W orst I ma gi na ble)

Fe ver ( > 1 0 0 °F)
( A bse nt)  0   1   2   3   4   5   6   7   8   9   1 0   ( Dail y)

U ni nte nti o nal wei g ht l oss last 
6 m o nt hs
( A bse nt)  0   1   2   3   4   5   6   7   8   9   1 0   ( W orst I ma gi na ble)
W hat is y o ur O verall Q ualit y of Life?
( As g o o d as it ca n be)  0 1  2  3  4  5  6  7  8  9 1 0 ( As Ba d as it ca n be)


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 0 7
2 6 Oct o ber 2 0 1 6
A p pe n di x 9.
M o difie d M yel o pr olifer ati ve Ne o pl as m S y m pt o m Assess me nt F or m 
T ot al S y m pt o m Sc ore
1)
R ate y o ur w orst i nci de nce of tire d ness i n t he p ast 2 4 h o urs.
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0
A bse nt
W orst
I ma gi na ble
2)
R ate y o ur w orst i nci de nce of filli n g u p q uic kl y w he n y o u e at (e arl y s atiet y) i n t he p ast 
2 4 h o urs.
0
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0
A bse nt
W orst
I ma gi na ble
3)
R ate y o ur w orst i nci de nce of a b d o mi n al disc o mf ort i n t he p ast 2 4 h o urs.
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0
A bse nt
W orst
I ma gi na ble
4)
R ate y o ur w orst i nci de nce of ni g ht s we ats i n t he p ast 2 4 h o urs.
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0
A bse nt
W orst
I ma gi na ble
5)
R ate y o ur w orst i nci de nce of itc hi n g ( pr urit us) i n t he p ast 2 4 h o urs.
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0
A bse nt
W orst
I ma gi na ble
6)
R ate y o ur w orst i nci de nce of b o ne p ai n ( diff use n ot j oi nt p ai n or art hritis) i n t he p ast 
2 4 h o urs.
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0
A bse nt
W orst
I ma gi na ble
7)
R ate y o ur w orst i nci de nce of p ai n u n der ri bs o n t he left si de i n t he p ast 2 4 h o urs.
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0
A bse nt
W orst
I ma gi na ble
8)
R ate y o ur w orst i nci de nce of i n acti vit y i n t he p ast 2 4 h o urs.
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0
A bse nt
W orst
I ma gi na ble


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 0 8
2 6 Oct o ber 2 0 1 6
A p pe n di x 1 0. 
Pre g n a nc y Prec a uti o ns, Defi niti o n f or Fe m ale of C hil d be ari n g 
P ote nti al, a n d C o ntr ace pti ve Rec o m me n d ati o ns
1)
Pre g n a nc y a n d C o ntr ace pti o n Re q uire me nts f or M ales a n d Fe m ales of C hil d be ari n g 
P ote nti al
Idelalisi b is c o ntrai n dicate d i n pre g na nc y as a ni mal st u dies i n rats a n d ra b bits ha ve s h o w n t hat 
st u d y dr u g is terat o ge nic. Pre g na nc y m ust be e xcl u de d bef ore t he start of treat me nt wit h st u d y 
dr u g a n d pre ve nte d t hereafter b y relia ble c o ntrace pti ve met h o ds. Pre g na nc y tests will be 
perf or me d re g ularl y  (refer t o A p pe n di x 2 ) t hr o u g h o ut t his st u d y. Please refer t o t he latest versi o n
of t he i n ves ti gat or’s br oc h ure f or a d diti o nal i nf or mati o n
2)
Defi niti o n of Fe m ale of C hil d be ari n g P ote nti al
F or t he p ur p oses of t his st u d y , a fe male s u bject of c hil d beari n g p ote ntial is a n o n me n o pa usal 
fe male w h o has n ot ha d a h ysterect o my, bilateral o o p h orect o m y, or me d icall y d oc u me nte d 
o varia n fail ure. T his defi niti o n i ncl u des a p u bertal fe male w h o has n ot y et starte d me nstr uati n g. 
A w o ma n w h o has ha d a t u bal sterilizati o n is c o nsi dere d t o be of c hil d beari n g p ote ntial.
A fe male s u bject ma y  be c o nsi dere d me n o pa usal i n eit her of t he f oll o wi n g c o n diti o ns:

S ur gical me n o pa use: A p pr o priate me dical d oc u me ntati o n of pri or c o m plete bilateral 
o o p h orect o m y (ie, s ur gical re m o val of t he o varies a n d occ urri n g at t he a ge at w hic h t he 
pr oce d ure was perf or me d)

S p o nta ne o us me n o pa use: Per ma ne nt cessati o n of pre vi o usl y occ urri n g me nses as a res ult of 
o varia n fail ure wit h d oc u me ntati o n of h or m o nal deficie nc y  b y a certifie d healt h care 
pr o vi der. T he w orl d wi de mea n a ge of s p o nta ne o us me n o pa use is 4 9. 2 4 ( St D 1. 7 3) years
A h or m o nal deficie nc y s h o ul d be pr o perly d oc u me nte d i n t he case of s us pecte d s p o nta ne o us 
me n o pa use as f oll o ws:

If a ge ≥5 4 y ears a n d wit h t he a bse nce of n or mal me nses: ser u m f ollicle sti m ulati n g h or m o ne 
( F S H) le vel ele vate d t o wit hi n t he p ost me n o pa usal ra n ge base d o n t he la b orat or y refere nce 
ra n ge w here t he h or m o nal assa y is perf or me d

If a ge < 5 4 ye ars a n d wit h t he a bse nce of n or mal me nses : ne gati ve ser u m or uri ne 
h u ma n c h ori o nic g o na d otr o pi n ( h C G) wit h c o nc urre ntl y  ele vate d ser u m F S H le vel i n t he 
p ost me n o pa usal ra n ge, de presse d estra di ol ( E 2) le vel i n t he p ost me n o pa usal ra n ge, a n d 
a bse nt ser u m pr o gester o ne le vel, base d o n t he la b orat or y  refere nce ra n ges w here t he 
h or m o nal assa y s are perf or me d
3)
C o ntr ace pti ve Re q uire me nts
Male s u bjects a n d fe male s u bjects of c hil d beari n g p ote ntial w h o e n ga ge i n i nterc o urse m ust 
a gree t o utilize pr ot oc ol s pecifie d met h o ds of c o ntrace pti o n fr o m t he scree ni n g/e nr oll me nt visit 
t hr o u g h o ut t he st u dy peri o d a n d f or 9 0 da ys fr o m t he last d ose of st u d y dr u g ( i delalisi b) f or male 
s u bjects a n d f or 3 0 da ys f oll owi n g t he last d ose of st u d y  dr u g (i delalisi b) f or fe male s u bjects of 
c hil d beari n g p ote ntial. 


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 0 9
2 6 Oct o ber 2 0 1 6
Fe male st u d y s u bjects w h o are n ot heter ose x uall y acti ve m ust pr o vi de peri o dic c o nfir mati o n of 
c o nti n ue d a bsti ne nce fr o m heter ose x ual i nterc o urse a n d re g ular pre g n a nc y testi n g w hile 
ta ki n gi delalisi b. T he i n vesti gat or will c o u nsel s u bjects o n t he pr ot oc ol s pecifie d met h o d(s) f or 
a v oi di n g pre g na nc y i n case t he s u bject c h o oses t o e n ga ge i n heter ose x ual i nterc o urse.
Pr ot oc ol s pecifie d c o ntrace pti ve met h o ds are as f oll o ws: ( 1) a c o m bi nati o n of o ne h or m o nal 
met h o d a n d o ne barrier met h o d; ( 2) t w o barrier met h o ds w here o ne met h od is t he male c o n d o m; 
or ( 3) use of a n i ntra uteri ne de vice (I U D) or t u bal sterilizati o n; see A p pe n di x Ta ble 1 bel o w. 
Acce pta ble h or m o nal met h o d s i ncl u de i njecta ble pr o gester o ne, pr o gester o ne i m pla nts, 
c o m bi nati o n oral c o ntrace pti ves, tra ns der mal c o ntrace pti ve patc h, a n d va gi nal ri n g. Acce pta ble 
barrier met h o ds i ncl u de dia p hra g m wit h s per mici de, cer vical ca p wit h s per mici de, a n d t he male 
c o n d o m. Fe male s u bjects m ust use eit her a h or m o nal met h o d or a barrier met h o d if t he part ner 
has a vasect o m y . If a s u bject has u n der g o ne t u bal sterilizati o n or has had a C o p per T 3 8 0 A I U D 
or L N g 2 0 I U D i nserte d, n o ot her c o ntrace pti o n is nee de d.
If t u bal sterilizati o n is via t he Ess ure pr oce d ure, verificati o n of t u bal bl oc ka ge by 
h y ster osal pi n g o gra m ( H S P) m ust be perf or me d a p pr o xi matel y 3 m o nt hs after micr oi nserti o n. 
Pri or t o verificati o n, Ess ure is n ot c o nsi dere d a relia ble f or m of c o ntrace pti o n a n d t he 
c o ntrace ptio n met h o ds descri be d bel o w m ust be use d. Fe male s u bjects w h o utilize h or m o nal 
c o ntrace pti ves as o ne of t heir birt h c o ntr ol met h o ds m ust ha ve use d t he sa me met h o d f or at least 
3 m o nt hs bef ore st u d y d osi n g.
Fe male s u bjects of c hil d beari n g p ote ntial m ust ha ve a ne gati ve ser u m pre g na nc y test at scree ni n g 
a n d a ne gati ve uri ne pre g na nc y  test at baseli ne ( Da y 1) pri or t o recei vi n g t he first d ose of st u d y 
dr u g ( i delalisi b). Lactati n g fe males m ust disc o nti n ue n ursi n g bef ore I M P a d mi nistrati o n.
A p pe n di x T a ble 1 .
Pr ot oc ol S pecifie d C o ntr ace pti ve Met h o ds
M e t h o ds t o Use b y T he msel ves
C o m bi n ati o n Met h o ds
H o r m o ne Met h o ds
(c h o ose o ne a n d use wit h 
a barrier met h o d)
B arrier Met h o ds
( use b ot h O R c h o ose o ne a n d use wit h 
a h or m o ne met h o d)
I ntr a uteri ne De vices (I U Ds)

C o p per T 3 8 0 A I U D

L N g 2 0 I U D
T u b al Steriliz ati o n
Estr o ge n a n d Pr o gester o ne

Oral c o ntrace pti ves

Tra ns der mal patc h

Va gi nal ri n g
Pr o gester o ne

I njecti o n

I mpla nt

Dia p hra g m wit h s per mici de
O R

Cer vical ca p wit h s per mici de

Male c o n d o m
( wit h or wit h o ut 
s per mici de)
Part ner’s vasect o m y m ust be use d wit h a h or m o ne or barrier met h o d.
T he i n vesti gat or will c o u nsel all s u bjects o n t he m ost effecti ve met h o d(s) f or a v oi di n g pre g na nc y  
d uri n g t he st u d y.


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 1 0
2 6 Oct o ber 2 0 1 6
4)
C o ntr ace pti ve Re q uire me nts f or M ale S u bjects
Male s u bjects m ust a gree t o use c o n d o ms d uri n g heter ose x ual i nterc o urse a n d a v oi d s per m 
d o nati o n w hile e nr olle d i n t he st u d y  a n d f or at least 9 0 da ys after a d mi nistrati o n of t he last d ose 
of st u d y  me dicati o n.
Use of c o n d o ms, wit h or wit h o ut s per mi ci de, has bee n pr o ve n t o decrease t he ris k of 
tra ns missi o n of HI V a n d ot her se x uall y tra ns mitte d diseases. T he use of s per mici de is n ot 
rec o m me n de d if t he s u bject or s u bject’s part ner is i nfecte d wit h HI V.
5)
C o ntr ace pti ve Re q uire me nts f or Fe m ale S u bjects
It is rec o m me n de d t hat fe males of c hil d beari n g p ote ntial d o n ot bec o me pre g na nt d uri n g t his 
st u d y. W o me n w h o are a ble t o bec o me pre g na nt a n d w o me n w h o ha ve n ot ha d s ur ger y t o 
bec o me sterile (eit her a h y sterect o my, vasect o m y, or a bilateral t u bal li gati o n), m u st use 
me dicall y  effecti ve a n d relia ble mea ns t o a v oi d pre g na nc y fr o m t he scree ni n g/e nr oll me nt visit 
t hr o u g h o ut t his st u d y peri o d a n d f or 3 0 da ys f oll o win g t he last d ose of st u d y dr u g.
T he i n vesti gat or or t he s u bject’s healt h care pr o vi der m ust rec o m me n d e ffecti ve mea ns of 
c o ntrace pti o n a n d disc uss t he ris ks a n d be nefits of me dicall y  effecti ve met h o ds wit h t he s u bject.
If a s u bject d oes bec o me pre g na nt or s us pects t hat s he ma y ha ve bec o me pre g na nt w hile i n t his 
st u d y, t he i n vesti gat or, i n c o ns ultati o n wit h t he me dical m o nit or, will deci de w het her t he be nefit 
of c o nti n uati o n of t he st u d y  o ut wei g hs a n y p ote ntial ris k t o t he pre g na nt s u bject or her offs pri n g.
6)
Pr oce d ures t o be F oll o we d i n t he E ve nt of Pre g n a nc y
S u bjects will be i nstr ucte d t o n otif y  t he i n vesti gat or if t he y bec o me pre g na nt at a n y ti me d uri n g 
t he st u d y, or if t he y bec o me pre g na nt wit hi n 3 0 da ys of last st u d y dr u g (i delalisi b) d ose. S u bjects 
w h o bec o me pre g na nt or w h o s us pect t hat t he y  are pre g na nt d uri n g t he st u d y m ust re p ort t he 
i nf or mati o n t o t he i n vesti gat or a n d disc o nti n ue st u d y dr u g (i delalisi b) i m me diatel y. S u bjects 
w h ose part ner has bec o me pre g na nt or s us pects s he is pre g na nt d uri n g t he st u d y  m ust re p ort t he 
i nf or mati o n t o t he i n vesti gat or.
I nstr ucti o ns f or re p orti n g pre g na nc y, part ner pre g na nc y, a n d pre g na nc y o utc o me are o utli ne d i n 
Secti o n 7. 7. 2. 1 .


I delalisi b
Pr ot oc ol G S -U S -3 9 7 -1 2 4 5
Fi nal
Gilea d Scie nces, I nc.
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 1 1
2 6 Oct o ber 2 0 1 6
A p pe n di x 1 1.
C T C A E versi o n 4. 0 3
htt p://e vs. nci. ni h. g o v/ft p 1/ C T C A E/ C T C A E _ 4. 0 3 _ 2 0 1 0 -0 6- 1 4 _ Q uic k Refere nce _ 8. 5 x 1 1. p df

SAP_001.pdf: 
S T A TI S TI C A L A N A L Y SI S P L A N
St u d y Title:
A P hase 1 b O pe n -La bel St u d y  t o E val uate t he Safet y, 
T olera bilit y , a n d P har mac o ki netics of I delalisi b i n S u bjects 
Recei vi n g R u x oliti ni b as T hera p y f or Pri mar y , 
P ost -P ol y c yt he mia Vera, or P ost -Esse ntial T hr o m b oc y t he mia 
M y el ofi br osis wit h Pr o gressi ve or Rela pse d Disease
N a me of Test Dr u g:
I delalisi b
St u d y N u m ber:
G S -U S - 3 9 7- 1 2 4 5
Pr ot oc ol Versi o n ( D ate):
A me n d me nt 5 ( 2 6 Oct o ber 2 0 1 6 )
A n al ysis T y pe:
Fi nal
A n al ysis Pl a n Versi o n:
1. 0
A n al ysis Pl a n D ate:
2 Fe br uar y 2 0 1 8
A n al ysis Pl a n A ut h or(s):
C O N FI D E N TI A L A N D P R O P RI E T A R Y I N F O R M A TI O N
P P D
(fJ GI L E A U 


I delalisi b
G S -U S -3 9 7 -1 2 4 5
Statistical A nal ysis Pla n
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2
2 Fe br uar y 2 0 1 8
T A B L E O F C O N T E N T S
T A B L E O F C O N T E N T S ..............................................................................................................................................2
LI S T O F I N -T E X T T A B L E S ........................................................................................................................................3
LI S T O F I N -T E X T FI G U R E S ......................................................................................................................................3
LI S T O F A B B R E VI A TI O N S ........................................................................................................................................4
1.
I N T R O D U C TI O N ................................................................................................................................................6
1. 1.
St u d y O bjecti ves ......................................................................................................................................6
1. 2.
St u d y Desi g n ............................................................................................................................................6
1. 3.
St u d y D urati o n .........................................................................................................................................8
1. 4.
Sa m ple Size a n d P o w er ............................................................................................................................9
2.
T Y P E O F P L A N N E D A N A L Y SI S ....................................................................................................................1 0
2. 1.
I nteri m A nal yses ....................................................................................................................................1 0
2. 2.
Fi nal A nal ysis ........................................................................................................................................1 0
3.
G E N E R A L C O N SI D E R A TI O N S F O R D A T A A N A L Y S E S ............................................................................1 1
3. 1.
A nal ysis Sets ..........................................................................................................................................1 1
3. 1. 1.
All E nr olle d A nal ysis Set .....................................................................................................1 1
3. 1. 2.
F ull A nal ysis Set ..................................................................................................................1 1
3. 1. 3.
P har m ac o ki netic A nal ysis Set ..............................................................................................1 1
3. 2.
S u bject Gr o u pi n g ...................................................................................................................................1 1
3. 3.
Strata a n d C o variates ..............................................................................................................................1 2
3. 4.
E xa mi nati o n of S u bject S u b gr o u ps ........................................................................................................1 2
3. 5.
M ulti ple C o m paris o ns ............................................................................................................................1 2
3. 6.
Missi n g Data a n d O utliers ......................................................................................................................1 2
3. 6. 1.
Missi n g Data
........................................................................................................................1 2
3. 6. 2.
O utliers .................................................................................................................................1 2
3. 7.
Data Ha n dli n g C o n ve nti o ns a n d Tra nsf or mati o ns .................................................................................1 2
3. 8.
A nal ysis Visit Wi n d o ws .........................................................................................................................1 3
3. 8. 1.
Defi niti o n of St u d y Da y .......................................................................................................1 3
3. 8. 2.
A nal ysis Visit Wi n d o ws .......................................................................................................1 4
3. 8. 3.
Selecti o n of Data i n t he E ve nt of M ulti ple Rec or ds i n a n A nal ysis Visit 
Wi n d o w ................................................................................................................................1 4
4.
S U BJ E C T DI S P O SI TI O N ..................................................................................................................................1 5
4. 1.
S u bject E nr oll me nt a n d Dis p ositi o n .......................................................................................................1 5
4. 2.
E xte nt of St u d y Dr u g E x p os ure a n d A d here nce .....................................................................................1 5
4. 2. 1.
D urati o n of E x p os ure t o St u d y Dr u g ....................................................................................1 5
4. 2. 2.
A d here nce t o St u d y Dr u g .....................................................................................................1 6
4. 3.
Pr ot oc ol De viati o ns ................................................................................................................................1 6
5.
B A S E LI N E C H A R A C T E RI S TI C S ....................................................................................................................1 7
5. 1.
D e m o gra p hics ........................................................................................................................................1 7
5. 2.
Ot her Baseli ne C haracteristics ...............................................................................................................1 7
5. 3.
Me dical Hist or y ......................................................................................................................................1 7
5. 4.
Disease Hist or y ......................................................................................................................................1 7
5. 5.
Pri or A ntica ncer T hera p y a n d Pri or Ra diati o n .......................................................................................1 8
6.
E F FI C A C Y A N A L Y S E S ...................................................................................................................................1 9
7.
S A F E T Y A N A L Y S E S ........................................................................................................................................2 0


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Statistical A nal ysis Pla n
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Pa ge 3
2 Fe br uar y 2 0 1 8
7. 1.
A d verse E ve nts a n d Deat hs ....................................................................................................................2 0
7. 1. 1.
A d verse E ve nt Dicti o nar y ....................................................................................................2 0
7. 1. 2.
A d verse E ve nt Se verit y ........................................................................................................2 0
7. 1. 3.
Relati o ns hi p of A d verse E ve nts t o St u d y Dr u g ....................................................................2 0
7. 1. 4.
Seri o us A d verse E ve nts ........................................................................................................2 0
7. 1. 5.
Treat me nt- E mer ge nt A d verse E ve nts ...................................................................................2 0
7. 1. 6.
S u m maries of A d verse E ve nts a n d Deat hs ...........................................................................2 1
7. 1. 7.
Treat me nt- E mer ge nt A d verse E ve nts of I nterest .................................................................2 2
7. 2.
La b orat or y E val uati o ns ..........................................................................................................................2 4
7. 2. 1.
S u m maries of N u meric La b orat or y Res ults .........................................................................2 4
7. 2. 2.
Gra de d La b orat or y Val ues ...................................................................................................2 4
7. 2. 3.
Li ver -relate d La b orat or y E val uati o ns...................................................................................2 5
7. 2. 4.
S hifts Relati ve t o t he Baseli ne Val ue ...................................................................................2 6
7. 3.
B o d y  Wei g ht a n d Vital Si g ns.................................................................................................................2 6
7. 4.
Pri or a n d C o nc o mita nt Me dicati o ns .......................................................................................................2 6
7. 4. 1.
Pri or Me dicati o ns .................................................................................................................2 6
7. 4. 2.
C o nc o mita nt Me dicati o ns .....................................................................................................2 7
7. 5.
Ot her Safet y Meas ures ...........................................................................................................................2 7
7. 6.
C ha n ges Fr o m Pr ot oc ol -S pecifie d Safet y A nal yses ...............................................................................2 7
8.
P H A R M A C O KI N E TI C A N A L Y S E S ................................................................................................................2 8
9.
S O F T W A R E .......................................................................................................................................................2 9
1 0.
S A P R E VI SI O N ..................................................................................................................................................3 0
1 1.
A P P E N DI C E S ....................................................................................................................................................3 1
A p pe n di x 1.
Sc he d ule of Assess me nts ........................................................................................................3 2
A p pe n di x 2.
Ras h Me dical Searc h Ter m .....................................................................................................3 7
LI S T O F I N -T E X T T A B L E S
Ta ble 1.
Gr o u pe d Ter ms f or A d verse E ve nts of I nterest ......................................................................2 3
LI S T O F I N -T E X T FI G U R E S
Fi g ure 1.
P K Sc he ma ...............................................................................................................................7
Fi g ure 2.
St u d y Sc he ma ...........................................................................................................................8


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Statistical A nal ysis Pla n
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L I S T O F A B B R E VI A TI O N S
A E
a d verse e ve nt
A EI
a d verse e ve nt of i nterest
A L T
ala ni ne a mi n otra nsferase
A L P
al kali ne p h os p hatase
A S T
as partate a mi n otra nsferase
BI D
t wice per d a y
B L Q
bel o w  t he li mit of q ua ntitati o n
CI
c o nfi de nce i nter val
C L L
c hr o nic l y m p h oc ytic le u ke mia
C M V
c yt o me gal o vir us
C S R
cli nical st u d y re p ort
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 M C
data m o nit ori n g 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 L N
E ur o pea n Le u ke mia Net
E O T
e n d of treat me nt
E O S
e n d of st u d y
F A S
F ull A nal ysis Set
H L G T
hi g h le vel gr o u p ter m
H L T
hi g h le vel ter m
i N H L
i n d ole nt n o n-H o d g ki n l y m p h o ma
I W G-M R T
I nter nati o nal W or ki n g Gr o u p f or M y el o pr oliferati ve Ne o plas ms Researc h a n d Treat me nt
L L T
l o wer le vel ter m
L O Q
li mit of q ua ntitati o n
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
P K
p har mac o ki netics
PJ P
P ne u m ocystis jir ovecii p ne u m o nia
P M F
pri mar y m yel ofi br osis
P M L
pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y
p ost -E T M F
P ost -Esse ntial T hr o m b oc yt he mia M yel ofi br osis
p ost -P V M F
P ost -P ol yc yt he mia Vera M yel ofi br osis
P T
pr ef err e d ter m
Q 1, Q 3
first q uartile, t hir d q uartile
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S E
sta n dar d err or
SI ( u nits)
i nter nati o nal s yste m of u nits


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Statistical A nal ysis Pla n
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S O C
s yste m or ga n class
S R T
safety re vie w tea m
St D
sta n dar d de viati o n
T E A E
treat me nt-e mer ge nt a d verse e ve nt
T F Ls
ta bles, fi g ures, a n d listi n gs
U L N
u p per li mit of n or mal
W H O
W orl d Hea lt h Or ga nizati o n


I d el alisi b 
G S -U S -3 9 7- 1 2 4 5 
St atisti c al A n al ysis Pl a n 
1. 
I NT R O D U C TI O N 
V ersi o n 1. 0 
T hi s st atisti c al a n alysis pl a n ( S A P) d es c ri b es t h e st atisti c al a n al ysis m e t ho ds a n d d at a 
pr es e n t ati ons t o b e us e d i n t a bles , fi gur es, a n d listi ngs ( T FL s) i n t h e cli nic al stu d y re p o 1t ( C SR) 
f or St u d y G S- U S -3 9 7- 1 2 4 5 . T h is S A P is b as e d o n Pr ot o c ol G S -U S -3 9 7 - 12 4 5 A m e n d m e nt 5 
d at e d 2 6 O ct o b er 2 0 1 6 a n d t h e el e ctr on i c c as e r ep o 1t f on n (e CR F ). T hi s S A P wi ll b e fin a liz e d 
b ef or e d at a b as e fin a liz ati on. A n y c h a n g es m a d e af t er fin a liz ati o n of t h e S A P wi ll b e d o c u m e n t e d 
i n t h e C S R. 
F o llo w i ng i nt er nal r e vi e w , Gi le ad S c i e nces , I nc. ( Gil e a d) d e c id e d t o c e as e cli nic al d e v el o p m e nt 
of id el alisi b i n n e w i ndi c at i o ns w hi ch i nclu d e d t ermi n ati n g St u d y G S- U S -3 9 7 -1 2 4 5. A t ot al of 
1 0 s ubj e cts h a d b e e n e m o lle d w h e n t h e stu d y w as t ermi n at e d. 
1. 1. 
S t u dy O bj e cti v es 
T h e pr i m a1y o b je ctiv es of t his st u d y are as f oll o ws: 
•  
T o e v al uat e t h e s af et y a n d t ol er a bilit y of i d el alisi b t hr ou g h 2 8 da ys i n s ubj e cts re c ei vi n g 
r n x olitini b as t h er a p y f or i nte 1 me diate- t o hi g h -ris k pri m ai y m y el ofi br osis ( P M F), 
p ost -p ol y c yth e mi a v er a , or p ost -ess en ti al t hr om b o c yt h ei ni a m y e lofi br osis ( p ost-P V M F or 
p ost -E T M F) wi t h pr o gr essi v e or r el a ps e d di s e as e 
•  
T o d et e 1mi n e t h e p h a nn a c o ki n eti cs ( P K) of i d el alisi b a n d r nx o liti ni b i n s ubj e cts re c ei vi n g 
r n x olitini b wit h P M F, p ost -P V M F, or p ost- E T M F wit h pr o gr essi v e or r el a ps e d dis e as e 
T h e s e c o n d ai y o bj e cti v es of t his st u d y ai·e as f oll o ws: 
• 
T o e v al uat e t h e s af et y a n d t ol er a bilit y of c o nti n uo us d ail y a di ni nistr ati on of i d el alisi b b e y o n d 
2 8 d a ys i n s ubj e cts re c ei vi n g r n x olitini b wit h P M F, p ost- P V M F , or p ost- E T M F 
•  
T o e v al uat e t h e effi c a c y of id el alisi b i n s u bje cts r e c ei vi ng r nx o liti ni b wit h P M F, p ost- P V 
M F , or p ost -E T M F b y 2 0 1 3 R e vis e d I nt er nati on al W o rki n g Gr o u p f or M y el o pr o liferativ e 
N e o p las ms R eseai·ch a n d Tr e at m e nt (I W G- M RT) a n d E ur o p e a n L e u k ei ni a N et (E L N) 
r es p o ns e crit eri a 
I 
1. 2. 
S t u dy D e si g n 
T hi s is a P h as e lb, o p e n -la b e l, d os e es c alati o n st u d y. T h e pl a n n e d n u m b er of s ubj e cts i n e a ch 
c oh o 1t is 6. T h e r e wi ll b e 4 c oh o 1ts ( A, B, C, a n d D), w hi c h wi ll b e e m oll e d s e qu e nti a lly 
( Fi g ur e 1 ). C o h o 1t A wi ll b e e m o lle d first. 
C O N FI D E N TI A L 
P a g e 6 
2 F e br n a 1 y 2 0 1 8 


I delalisi b
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Statistical A nal ysis Pla n
Versi o n 1. 0
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I delalisi b will be a d mi nistere d i n s u bjects recei vi n g r u x oliti ni b as t hera p y f or P M F, p ost-P V M F, 
or p ost -E T M F , a n d w h o ha ve bee n mai ntai ne d o n a sta ble d ose of r u x oliti ni b f or at least 
4 wee ks pri or t o st u d y e ntr y. O n Da y 1 s u bjects will ha ve a P K sa m ple dra w n a n d t he n t he 
r u x oliti ni b d ose will be re d uce d as f oll o ws:

S u bjects o n a sta ble r u x oliti ni b d ose of greater t ha n or e q ual t o 1 0 m g t wice dail y , will ha ve 
t heir r u x oliti ni b d ose re d uce d by 5 0 % (r o u n de d u p t o t he cl osest a vaila ble ta blet stre n gt h).

S u bjects o n a sta ble r u x oliti ni b d ose of 5 m g t wice dail y , will ha ve t heir r u x oliti ni b d ose 
re d uce d t o 5 m g o nce dail y.
I delalisi b will be a d mi nistere d starti n g o n Da y  5.
P K sa m ples will be o btai ne d o n Da y s 1, 4 a n d 1 0 as s h o w n i n t he sc he ma bel o w:
Fi g ure 1.
P K Sc he m a
T he st arti n g d os es of i delalisi b i n C o h orts A, B, C, a n d D are 5 0 m g o nce daily, 5 0 m g t wice
dai l y, 1 5 0 m g o nce daily , a n d 1 5 0 m g t wice dail y, res pecti vel y. E nr oll me nt i nt o t he st u d y  will be 
o n h ol d w hile t he safety re vie w tea m (S R T) e val uates t he data pri o r to c o h ort e x pa nsi o n a n d 
d ose escalati o n.
T he first 3 s u bjects will be e nr olle d i n C o h o rt A at 5 0 m g o nce dail y i delalisi b. After t he t hir d 
s u bject has c o m plete d Da y 2 8 ( 4 wee ks), t he S R T will re vie w t he safet y data. E nr oll me nt will be 
o n h ol d u ntil t he S R T deter mi ne s t he c o h ort ca n be ex pa n de d t o e nr oll a n a d diti o nal 3 s u bjects. 
After t he si xt h s u bject i n C o h ort A c o m pletes Da y  5 6 ( 8 wee ks), t he S R T will re vie w t he 
c u m ulati ve safet y a n d P K data fr o m all s u bjects i n C o h ort A. E nr oll me nt will be o n h ol d u ntil t he 
S R T d eter mi nes C o h ort B ca n be o pe n t o e nr oll me nt. If t he S R T dee ms t he c o m bi nati o n of 
i delalisi b wit h r u x oliti ni b safe a n d t olera ble at t he 5 0 m g o nce daily d ose, C o h ort B will be o pe n 
t o e nr oll me nt.
E nr oll me nt a n d safet y assess me nt b y t he S R T i n C o h ort B at 50 m g t wice dail y  i delalisi b will
pr ocee d as f oll o ws: T he first 3 s u bjects will be e nr olle d. After t he t hir d s u bject has c o m plete d
D a y  2 8 ( 4 wee ks), t he S R T will re vie w t he c u m ulati ve safety data f or C o h orts A a n d B.
E nr oll me nt will be o n h ol d u ntil t he S R T deter mi nes C o h ort B ca n be e x pa n de d t o e nr oll a n
a d diti o nal 3 s u bjects. After t he si xt h s u bject i n C o h ort B c o m pletes Da y  2 8 ( 4 wee ks), t he S R T 
S c h e m a 
I S cr e e ni n g 
S u bj e ct s ar e 
e ligi bl e f or t he 
s t ud y a fter 
m a i nta i ni ng a 
st a b l e r ux o liti nib 
d o s e f or at l e a s t 
4 w e e k s p ri or t o 
s t ud y e nt r y 
D a y 1 
O bt a i n 
r ux o liti nib P K 
s a m p l e t he n 
re d u c e 
r ux o liti nib 
d o s e 
i 
O bt a i n r ux o liti nib 
P K s a m p le s -
I nitiat e i d e l alisi b 
d o s i ng 
D a y 1 0 
i 
O bt a i n r ux o liti nib & 
id e l alisi b P K s a m pl e s 
S u bj e ct c o nti n u e s o n 
s t ud y 


I delalisi b
G S -U S -3 9 7 -1 2 4 5
Statistical A nal ysis Pla n
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 8
2 Fe br uar y 2 0 1 8
will re vie w t he c u m ulati ve safet y d ata fr o m all s u bjects i n C o h orts A a n d B, a n d t he c u m ulati ve 
P K data f or C o h ort B. E nr oll me nt will be o n h ol d u ntil t he S R T deter mi nes C o h ort C ca n be 
o pe n t o e nr oll me nt. 
If t he S R T deter mi nes s u bse q ue nt c o h orts ca n be e nr olle d, C o h orts C a n d D will pr ocee d 
se q ue ntiall y i n a si milar ma n ner as C o h ort B wit h a 1 5 0 m g o nce daily or 1 5 0 m g t wice dail y
i delalisi b d ose, res pecti vel y.
A d diti o nal c o h orts are n ot pla n ne d after e nr oll me nt i n C o h ort D is c o m plete. S u bjects w h o d o 
n ot recei ve ≥ 1 d ose of i delalisi b will be dee me d u ne val ua ble a n d re place d.
I n s u bjects wit h o ut de m o nstra ble cli nical be nefit, d ose escalati o n (t o a hi g her d ose c o h ort) ma y  
be per mitte d b y t he S R T after C o h ort C ( i delalisi b 1 5 0 m g o nce dail y) has bee n f ull y e nr olle d 
a n d t he last s u bject has bee n o n st u dy dr u g f or at least 2 8 d a y s. 
Fi g ure 2.
St u d y Sc he m a
1. 3.
St u d y D ur ati o n
As pre vi o usl y  descri be d, Gilea d deci de d t o ter mi nate t his st u d y f oll o wi n g a n i nter nal decisi o n t o 
cease cli nical de vel o p me nt of i delalisi b i n ne w i n dicati o ns . T he o verall d urati o n of t he trial was 
i nitiall y pla n ne d t o be a p pr o xi matel y 3 ye ars, wit h n o l o n g -ter m f oll o w-u p e val uati o ns pla n ne d 
after t hat p oi nt. T he act ua l d urati o n of t he st u dy is a p pr o xi matel y 2. 5 y ears.
S af et y a n d P K d at a r e vi e w 
C o h ort B c o m pl et e s 2 8 d a y s 
( 4 w e e k s) . pri or t o d o s e 
S af et y a n d P K d at a re vi e w 
aft er t h e l a st s u bj e ct i n 
C o h ort B c o m p let e s 2 8 
d a y s ( 4 w e e k s) , pri or t o 
d o s e e s c al ati o n 
C o h ort 0: 
l d el ali si b 1 5 0 m g t wi c e d ail y 
r 
3 s u bj e ct s 
e nr oll e d 
C o h ort C: 
l d el ali si b 1 5 0 m g o n c e d ail y 
------' 
3 s u bj e ct s 
e n r olle d 
aft er t h e la st s u bj e ct i n r 
e s c a lati o n 
.-------, 
S a fet y d at a r e vi e w aft e r all 3 s u bj e c t s 
c o m pl et e d a y 2 8 
C O h ort A c o m pl et e s 5 6 
d a y s ( 8 w e e k s) , pri or t o 
C o h ort 
B: 
l d el ali si b 5 0 m g t wi c e d ail y 
S af et y a n d P K d at a r e vie w r 
aft e r t h e l a st s u b je ct i n 
d o s e e s c al ati o n 
.-------, 
C o h ort A'. 
l d el ali si b 5 0 m g o n c e d ail y 
3 s u bj e ct s 
e n r olle d ' 
3 s u bj e ct s 
e nr oll e d 
S a fet y d a t a r e vi e w aft er a ll 3 s u bj e ct s 
c o m p let e d a y 2 8 
3 s u bj e ct s 
e nr oll e d 
3 s u bj e ct s 
I 
e n r olle d . ~ 
S af et y d at a re v ie w aft e r all 3 s u bj e ct s 
c o m p let e d a y 2 8 
3 s u bj e ct s 
e n r olle d ' 
3 s u bj e ct s 
e n r olle d 
S a fet y d at a r e vie w aft e r all 3 s u b j e ct s 
c o m pl et e d a y 2 8 


I delalisi b
G S -U S -3 9 7 -1 2 4 5
Statistical A nal ysis Pla n
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 9
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1. 4.
S a m ple Size a n d P o wer
A t otal of 1 0 s u bjects ha d bee n e nr olle d w he n t he st u d y was ter mi nate d. 
T he f oll o wi n g descri bes t he ori gi nal sa m ple size a n d p o wer c o nsi derati o n:
As t his is a P hase 1 b st u d y  wit h a pri mar y o bjecti ve of assessi n g safety, t he sa m ple size is n ot 
base d o n f or mal p o wer calc ulati o ns. T he sa m ple size of a p pr o xi matel y  6 s u bjects per d ose c o h ort 
i n C o h orts A, B, C, a n d D is c o nsi dere d a de q uate f or a n i nitial assess me nt of safety a n d 
t olera bilit y f or s u bse q ue nt e val uati o ns.


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Statistical A nal ysis Pla n
Versi o n 1. 0
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2.
T Y P E O F  P L A N N E D A N A L Y SI S
2. 1.
I nteri m A n al yses
T his st u d y  d oes n ot ha ve a D M C . T heref ore, n o a nal yses will be c o n d ucte d f or t he D M C.
T he safet y re vie w tea m will re vie w a n d e val uate t he safety a n d P K data of i delalisi b wit h 
r u x oliti ni b pri or t o c o h ort e x pa nsi o n a n d d ose escalati o n.
2. 2.
Fi n al A n al ysis
After all s u bjects ha ve c o m plete d t he st u d y , o utsta n di n g data q ueries ha ve bee n res ol ve d or 
a dj u dicate d as u nres ol va ble , a n d t he data ha ve bee n clea ne d a n d fi nalize d , the fi nal a nalys is of 
t he data will be perf or me d.


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Versi o n 1. 0
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3.
G E N E R A L  C O N SI D E R ATI O N S F O R D A T A  AN A L Y S E S
A nal y sis res ults will be prese nte d usi n g descri pti ve statistics. F or cate g orical varia bles, t he 
n u m ber a n d perce nta ge of s u bjects i n eac h cate g or y will be prese nte d; f or c o nti n u o us varia bles, 
t he n u m ber of s u bjects (n) , mea n, sta n dar d de viati o n (St D ) or sta n dar d err or (S E ), me dia n, first 
q uartile (Q 1 ), t hir d q uartile (Q 3 ), mi ni m u m, a n d ma xi m u m will be prese nte d.
B y -s u bject listi n gs will be prese nte d f or all s u bjects i n t he All E nr olle d A nal y sis Set a n d s orte d 
b y  s u bject I D n u m ber, visit date, a n d ti me (if a p plica ble). Data c ollecte d o n l o g f or ms, s uc h as 
A Es, will be prese nte d i n c hr o n ol o gical or der wit hi n t he s u bject. A ge, se x at birt h, race, a n d 
et h nicit y will be i ncl u de d i n t he listi n gs, as s pace per mits.
3. 1.
A n al ysis Sets
A nal y sis sets defi ne t he s u bjects t o be i ncl u de d i n a n anal ys is. A nal ys is sets a n d t heir defi niti o ns 
are pr o vi de d i n t his secti o n. T he a nal ys is set will be i de ntifie d a n d i ncl u de d as a s u btitle of eac h 
ta ble, fi g ure, a n d listi n g.
A listi n g of reas o ns f or e xcl usi o n fr o m a nal y sis sets will be pr o vi de d b y s u bject.
3. 1. 1.
All E nr olle d A n al ysis Set
All E nr olle d A nal ys is Set i ncl u des all s u bjects w h o recei ve d a st u dy s u bject i de ntificati o n 
n u m ber i n t he st u d y  after scree ni n g.
3. 1. 2.
F ull A n al ysis Set
T he F ull A nal ys is Set ( F A S) i ncl u des all s u bjects w h o t o o k at least 1 d ose of st u d y  dr u g.
3. 1. 3.
P h ar m ac o ki netic A n al ysis Set
T he P har mac o ki ne tic A nal y sis Set will i ncl u de all e nr olle d s u bjects w h o t o o k at least 1 d ose of 
st u d y dr u g a n d ha ve at least 1 n o n missi n g p ost d ose val ue re p orte d b y t he P K la b orat or y. T his is 
t he pri mar y a nal ysis set f or all P K a nalys es.
3. 2.
S u bject Gr o u p i n g
F or a nal y ses based o n t he F A S , s u bjects will be gr o u pe d acc or di n g t o t he act ual treat me nt 
recei ve d. 
F or t he P K A nal y sis Set, s u bjects will be gr o u pe d acc or di n g t o t he act ual treat me nt t he y 
recei ve d.


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3. 3.
Str at a a n d C o v ari ates
T his st u d y  d oes n ot use a stratifie d ra n d o mizati o n sc he d ule w he n e nr olli n g s u bjects. 
N o c o variates will be i ncl u de d i n safety a nal yses.
3. 4.
E x a mi n ati o n of S u bject S u b gr o u ps
T here are n o pres pecifie d s u bject s u b gr o u pi n gs f or safety a nal yses.
3. 5.
M ulti ple C o m p aris o ns
A dj ust me nts f or m ulti plicit y  will n ot be ma de , beca use n o f or mal statistical testi n g will be 
perf or me d i n t his st u d y .
3. 6.
Missi n g D at a a n d O utliers
3. 6. 1.
Missi n g D at a
I n ge neral, missi n g data will n ot be i m p ute d u nless met h o ds f or ha n dli n g missi n g data are 
s pecifie d.
3. 6. 2.  
O utliers
All data will be i ncl u de d i n t he data a nal ys is.
3. 7.  
D at a H a n dli n g C o n ve nti o ns a n d Tr a nsf or m ati o ns
I n ge neral, a ge (i n years) o n t he date of t he first d ose of st u d y dr u g will be use d f or a nal yses a n d 
prese ntati o n i n listi n gs. If an e nr olle d s u bject was n ot d ose d wit h a n y st u d y dr u g, t he e nr oll me nt
date will be use d i nstea d of t he first d osi n g date of st u d y  dr u g. F or scree n fail ures, t he date t he 
i nf or me d c o nse nt was si g ne d will be use d f or t he a ge calc ulati o n. If o nl y t he birt h y ear is 
c ollecte d o n t he C R F, “ 0 1 J ul y” will be use d f or t he u n k n o w n birt h da y  a n d m o nt h f or t he a ge 
calc ulati o n . If o nly birt h year a n d m o nt h are c ollecte d, “ 0 1” will be use d f or t he u n k n o w n birt h 
da y .
N o n -P K data t hat are c o nti n u o us i n nat ure b ut are less t ha n t he l o wer li mit of q ua ntitati o n ( L O Q)
or a b o ve t he u p per L O Q will be i m p ute d as f oll o ws:

A val ue t hat is 1 u nit less t ha n t he L O Q will be use d t o calc ulate descri pti ve statistics if t he 
dat u m is re p orte d i n t he f or m of “ x” ( w here x is c o nsi dere d t he L O Q ). F or e xa m ple, if t he 
val ues are re p orte d as < 5 0 a n d < 5. 0, val ues of 4 9 a n d 4. 9 , res pecti vely, will be use d t o 
calc ulate s u m mar y statistics. A n e xce pti o n t o t his r ule is a ny val ue re p orte d as < 1 or < 0. 1, 
etc. F or val ues re p orte d as < 1 or < 0. 1, a val ue of 0. 9 or 0. 0 9 , res pecti vel y, will be use d t o 
calc ulate s u m mar y statistics.


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
A val ue t hat is 1 u nit a b o ve t he L O Q will be use d t o calc ulate descri pti ve statistics if t he 
dat u m is re p orte d i n t he f or m of “ > x” ( w here x is c o nsi dere d t he L O Q ). Val ues wi t h deci mal 
p oi nts will f oll o w t he sa me l o gic as a b o ve.

T he L O Q will be use d t o calc ulate descri pti ve statistics if t he dat u m is re p orte d i n t he f or m of 
“≤ x” or “ ≥ x” ( w here x is c o nsi dere d t he L O Q ).
Nat ural l o garit h m tra nsf or mati o n will be use d f or plas ma/ bl o o d c o nce ntrati o ns a n d a nal ys is of 
P K para meters. Plas ma c o nce ntrati o n val ues t hat are bel o w t he li mit of q ua ntitati o n ( B L Q) will 
be prese nte d as “ B L Q” i n t he c o nce ntrati o n data listi n g. Val ues t ha t are B L Q will be treate d as 0 
at pre d ose ti me p oi nts, a n d o ne- half t he val ue of t he L O Q at p ost baseli ne ti me p oi nts.
T he f oll o wi n g c o n ve nti o ns will be use d f or t he prese ntati o n of s u m mar y  a n d or der statistics:

If at least 1 s u bject has a c o nce ntrati o n val ue of B L Q f or t he ti me p oi nt, t he mi ni m u m val ue 
will be dis pla y e d as “ B L Q.”

If m ore t ha n 2 5 % of t he s u bjects ha ve a c o nce ntrati o n data val ue of B L Q f or a gi ve n ti me 
p oi nt, t he mi ni m u m a n d Q 1 val ues will be dis pla ye d as “ B L Q.”

If m ore t ha n 5 0 % of t he s u bjects ha ve a c o nce ntrati o n data val ue of B L Q f or a gi ve n ti me 
p oi nt, t he mi ni m u m, Q 1, a n d me dia n val ues will be dis pla y e d as “ B L Q.”

If m ore t ha n 7 5 % of t he s u bjects ha ve a c o nce ntrati o n data val ue of B L Q f or a gi ve n ti me 
p oi nt, t he mi ni m u m, Q 1, me dia n, a n d Q 3 val ues will be dis pla y e d as “ B L Q.”

If all s u bjects ha ve c o nce ntrati o n data val ues of B L Q f or a gi ve n ti me p oi nt, all or der 
statistics ( mi ni m u m, Q 1, me dia n, Q 3, a n d ma xi m u m) will be dis pla ye d as “ B L Q.”
P K para meters t hat are B L Q will be i m p ute d as o ne - half L O Q bef ore l o g tra nsf or mati o n or 
statistical m o del fitti n g.
3. 8.
A n al ysis Visit Wi n d o ws
3. 8. 1.
Defi niti o n of St u d y D a y
St u d y  d a y will be calc ulate d fr o m t he first d osi n g date of st u d y dr u g a n d deri ve d as f oll o ws:

F o r p ost d ose st u d y da ys: Assess me nt D ate – F irst D osi n g D ate + 1

F or d a y s pri or t o t he first d ose : Assess me nt D ate – F irst D osi n g D ate
T heref ore, st u d y  da y 1 is t he da y of first d ose of st u d y dr u g a d mi nistrati o n.


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3. 8. 2.
A n al ysis Visit Wi n d o ws
F or para meters t hat will be s u m marize d b y  visit, t he n o mi nal visit as rec or de d o n t he e C R F will 
be use d. F or para meters assesse d at t he e n d of st u d y  ( E O S) visit, t he assess me nt res ults will be 
assi g ne d t o t he ne xt sc he d ule d visit w here t he res pecti ve data were sc he d ule d t o be c ollecte d. 
T here will be n o a d diti o nal a nal ys is wi n d o wi n g d o ne base d o n t he assess me nt date. U nsc he d ule d 
visits pri or t o t he first d ose date will be i ncl u de d f or t he calc ulati o n of baseli ne val ues.
3. 8. 3.
Selecti o n of D at a i n t he E ve nt of M ul ti ple Rec or ds i n an A n al ysis Visit 
Wi n d o w
De pe n di n g o n t he statistical a nal ys is met h o d, si n gle val ues ma y be re q uire d f or eac h a nal ysis 
wi n d o w. F or e xa m ple, c ha n ge fr o m baseli ne b y visit us uall y  re q uires a si n gle val ue, w hereas a 
ti me-t o-e ve nt a nal ys is w o ul d n ot re q uire 1 val ue per a nal ys is wi n d o w.
If m ulti ple vali d , n o n missi n g , c o nti n u o us meas ure me nts e xist i n an a nal y sis wi n d o w, rec or ds 
will be c h ose n base d o n t he f oll o wi n g r ules if a si n gle val ue is nee de d:

I n ge neral, t he baseli ne val ue will be t he last n o n missi n g val ue o n or pri or t o t he first d osi n g 
date of st u d y dr u g, u nless s pecifie d differe ntl y. If m ulti ple meas ure me nts occ ur o n t he sa me 
da y , t he last n o n missi n g val ue pri or t o t he ti me of first d osi n g o f st u d y dr u g will be 
c o nsi dere d as t he baseli ne val ue. If t hese m ulti ple meas ure me nts occ ur at t he sa me ti me or 
t he time is n ot a vaila ble, t he a vera ge of t hese meas ure me nts (f or c o nti n u o us data) will be 
c o nsi dere d t he baseli ne val ue.

F or p ost baseli ne val ue s:

T he rec or d cl osest t o t he n o mi nal da y  f or t hat visit will be selecte d.

If t here are 2 rec or ds t hat are e q ui dista nt fr o m t he n o mi nal da y, t he later rec or d will be 
selecte d.

If t here is m ore t ha n 1 rec or d o n t he se lecte d da y, t he a vera ge will be ta ke n, u n less 
ot her wise s pecifie d.


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4.
S U B J E C T DI S P O SI TI O N
4. 1.
S u bject E nr oll me nt a n d Dis p ositi o n
A s u m mar y  of s u bject dis p ositi o n will be pr o vi de d b y d ose le vel c o h ort. T his s u m mar y will 
prese nt t he n u m ber of s u bjects scree ne d, t he n u m ber of s u bjects e nr olle d, a n d t he n u m ber of 
s u bjects i n eac h of t he cate g ories liste d bel o w:

F ull A nal ys is Set 

C o m plete d i delalisi b d osi n g t hr o u g h Wee k 2 4

C o m plete d r u x oliti ni b d osi n g t hr o u g h Wee k 2 4

Disc o nti n ue d i delalisi b wit h reas o ns f or pre mat ure disc o nti n uati o n

Disc o nti n ue d r u x oliti ni b wit h reas o ns f or pre mat ure disc o nti n uati o n

C o m plete d st u d y

Disc o nti n ue d t he st u d y wit h reas o ns f or pre mat ure disc o nti n uati o n of st u d y
F or t he stat us of st u d y dr u g a n d st u d y c o m pleti o n a n d reas o ns f or pre mat ure disc o nti n uati o n, t he 
n u m ber a n d perce nta ge of s u bjects i n eac h cate g or y will be pr o vi de d. T he de n o mi nat or f or t he 
perce nta ge calc ulati o n will be t he t otal n u m ber of s u bjects i n t he F A S c orres p o n di n g t o t hat 
c ol u m n.
T he f oll o wi n g b y- s u bject listi n g will be pr o vi de d b y  s u bject i de ntificati o n (I D) n u m ber i n 
asce n di n g or der t o s u p p ort t he a b o ve s u m mar y  ta bles:

Reas o ns f or pre mat ure st u d y  dr u g or st u d y disc o nti n uati o n
4. 2.
E xte nt of St u d y D ru g E x p os ure a n d A d here nce
4. 2. 1.
D ur ati o n of E x p os ure t o St u d y Dr u g
D urati o n of e x p os ure t o i delalisi b will be defi ne d as (last i delalisi b d osi n g date – first i delalisi b 
d osi n g date + 1), re gar dless of te m p orar y  i nterr u pti o ns i n st u d y dr u g a d mi nistrati o n, a n d will be 
e x presse d i n m o nt hs usi n g u p t o 1 deci mal place (e g, 2. 5 m o nt hs). D urati o n of e x p os ure t o 
i delalisi b will be s u m marize d usi n g descri pti ve statistics a n d as t he n u m ber a n d perce nta ge of 
s u bjects e x p ose d f or at least 1 da y, 2, 4, 6, a n d 1 2 m o nt hs, a n d e ver y 6 m o nt hs t hereafter.
N u m ber a n d per ce nta ge of s u bjects w h o ha d i delalisi b d ose i nterr u pti o n, re d ucti o n, a n d re-
escalati o n will be s u m marize d. Id elalisi b d osi n g rec or ds a n d dr u g acc o u nta bilit y  ( dis pe nse a n d 
ret ur n) rec or ds will be liste d b y s u bject.


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D urati o n of e x p os ure t o r u x oliti ni b will be defi ne d as (last r u x oliti ni b d ose date - first r u x oliti ni b
d ose date + 1) a n d w ill be s u m marize d usi n g descri pti ve statistics a n d as t he n u m ber a n d 
perce nta ge of s u bjects e x p ose d f or at least 1 da y , 2, 4, 6, a n d 1 2 m o nt hs, a n d e ver y 6 m o nt hs 
t hereafter.
4. 2. 2.
A d here nce t o St u d y Dr u g
A d here nce ( %) wit h i delalisi b will be calc ulate d as:
A d he re nce ( %) = (s u m of pills dis pe nse d mi n us pills ret ur ne d) di vi de d b y (s u m o ver all d osi n g 
peri o d of [t otal dail y pills x d osi n g d urati o n]), ta ki n g i nt o acc o u nt i n vesti gat o r-prescri be d 
i nterr u pti o n, re d ucti o ns, a n d escalati o ns.
Descri pti ve statistics f or a d here nce al o n g wit h t he n u m ber a n d perce nta ge of s u bjects bel o n gi n g 
t o a d here nce cate g ories (e g, < 7 5 % or ≥ 7 5 %) will be pr o vi de d.
A se parate b y- s u bject listi n g of st u d y dr u g a d mi nistrati o n a n d dr u g acc o u nta bilit y will be 
pr o vi de d b y s u bject I D n u m ber (i n a sce n di n g or der) a n d visit (i n c hr o n ol o gical or der).
4. 3. 
Pr ot oc ol De vi ati o ns 
Pr ot oc ol de viati o ns occ urri n g after s u bjects e ntere d t he st u d y  are d oc u me nte d d uri n g r o uti ne 
m o nit ori n g. T he n u m ber a n d perce nta ge of s u bjects wit h i m p orta nt pr ot oc ol de viati o ns b y  
de viati o n reas o n (e g, n o na d here nce t o st u d y dr u g, vi olati o n of select i ncl usi o n/e xcl usi o n criteria) 
will be s u m marize d b y  d ose le vel c o h ort f or t he All E nr olle d A nal y sis Set. A b y -s u bject listi n g 
will be pr o vi de d f or t h ose s u bjects wit h i m p orta nt pr ot oc ol de viati o n.


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5.
B A S E LI N E C H A R A C T E RI S TI C S
5. 1.
De m o gr a p hics
S u bject de m o gra p hic varia bles (ie, a ge, se x, race, a n d et h nicit y) will be s u m marize d b y usi n g 
descri pti ve statistics f or a ge , a n d usi n g n u m ber a n d perce nta ge of s u bjects f or se x, race, a n d 
et h nicit y. T he s u m mar y of de m o gra p hic data will be pr o vi de d f or t he F A S .
A b y -s u bject de m o gra p hic listi n g will be pr o vi de d b y  s u bject I D n u m ber i n asce n di n g or der.
5. 2.
Ot her B aseli ne C h ar acteristi cs
Ot her baseli ne c haracteristics i ncl u de b o d y  wei g ht (i n k g), hei g ht (i n c m), a n d b o d y  mass i n de x 
( B MI; i n k g/ m2). T hese baseli ne c haracteristics will be s u m marize d usi n g descri pti ve statistics 
f or c o nti n u o us varia bles a n d usi n g n u m ber a n d perce nta ge of su bjects f or cate g orical varia bles. 
T he s u m mar y  of baseli ne c haracteristics will be pr o vi de d f or t he F A S .
A b y -s u bject listi n g of ot her baseli ne c haracteristics will be pr o vi de d b y s u bject I D n u m ber i n 
asce n di n g or der.
5. 3.
Me dic al Hist or y
Me dical hist or y  will be c ollecte d at scree ni n g f or ge neral c o n diti o ns (ie, c o n diti o ns n ot s pecific 
t o t he disease bei n g st u die d).
Ge neral me dical hist or y data will n ot be c o de d, b ut will be liste d o nl y .
A b y -s u bject listi n g of ge neral me dical hist or y i ncl u di n g c o n diti o ns wit h start a n d st o p dates will 
be pr o vi de d b y s u bject I D n u m ber i n asce n di n g or der.
5. 4.
Dise ase Hist or y
N u m ber a n d perce nta ge of s u bjects wit h t ype of ca ncer, sc ori n g s ys te m a n d rist at dia g n osis, 
sc ori n g sys te m a n d rist at scree ni n g, a n d J A K stat us assess me nt wil l be s u m marize d usi n g 
s u m mar y statistics f or cate g orical varia bles.
Ti me si nce dia g n osis will be s u m marize d b y  usi n g s u m mar y statistics f or c o nti n u o us varia bles.
Ti me si nce dia g n osis ( y ears) will be calc ulate d as ( date of first d ose of st u d y  dr u g – date of
dia g n osis)/ 3 6 5. 2 5. 
All disease hist or y  wit h partial dia g n osis date will be i de ntifie d a n d t he partial dates will be 
i m p ute d as f oll o ws:

If da y a n d m o nt h are missi n g b ut year is a vaila ble, t he n t he i m p ute d da y  a n d m o nt h will be 
0 1 Ja n. 

If da y is missi n g b ut t he m o nt h a n d y ear are a vaila ble, t he n t he i m p ute d da y  will be t he first 
da y  of t he m o nt h. 


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N o i m p utati o n will be d o ne if t he year of dia g n osis is missi n g.
A b y -s u bject listi n g of disease hist or y a n d stat us will be pr o vi de d b y  s u bject I D n u m ber i n 
asce n di n g or der.
5. 5.
Pri or A ntic a ncer T her a p y a n d Pri or R a di ati o n
F or pri or t hera p y, n u m ber of pri or re gi me ns a n d ti me si nce t he c o m pleti o n of last re gi me n will 
be s u m marize d b y  d ose le vel c o h ort usi n g descri pti ve stat istics base d o n t he F A S . A partial 
c o m plet i o n date will be i m p ute d as f oll o ws:

If da y a n d m o nt h are missi n g b ut year is a vaila ble, t he n t he i m p ute d da y  a n d m o nt h will be 
0 1 Ja n.

If da y is missi n g b ut t he m o nt h a n d year are a vaila ble, t he n t he i m p ute d da y  will be t he first 
da y  of t he m o nt h.

Partial date will n ot be i m p ute d if t he y ear is missi n g.
T he re gi me ns a n d pri or t hera pies t hat t he s u bjects recei ve d will be s u m marize d. T he last re gi me n 
s u bjects recei ve d pri or t o st u d y e ntr y a n d t he best res p o nse t o t he last re gi me n will be 
s u m marize d.
N u m ber o f s u bjects w h o recei ve d pri or a n d o n -st u d y ra diati o n t hera py will be liste d.


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6.
E F FI C A C Y  AN A L Y S E S
D ue t o t he ea rl y ter mi nati o n of t he st u d y, t he pres pecifie d efficac y a nalys es ca nn ot be c o n d ucte d. 


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S A F E T Y  AN A L Y S E S
Safet y  data will be descri be d a n d s u m marized f or t he first 2 8 da y s of idelalisi b a d mi nistrati o n 
a n d o ver t he e ntire idelalisi b treat me nt peri o d.
7. 1.
A d verse E ve nts a n d De at hs
7. 1. 1.
A d verse E ve nt Dicti o n ar y
Cli nical a n d la b orat or y  a d verse e ve nts ( A Es) will be c o de d usi n g t he c urre nt versi o n of Me dical 
Dicti o nar y  f or Re g ulat or y Acti vities (Me d D R A ). S yste m or ga n class ( S O C), hi g h-le vel gr o u p 
ter m ( H L G T), hi g h-le vel ter m ( H L T), preferre d ter m ( P T), a n d l o wer-le vel ter m ( L L T) will be 
pr o vi de d i n t he A E dataset.
7. 1. 2.
A d verse E ve nt Se verit y
A d verse e ve nts are gra d e d b y t he i n vestigat or as Gra de 1, 2, 3, 4, or 5 acc or di n g t o C o m m o n 
T o xicit y  Criteria f or A d verse E ve nts (C T C A E ) Versi o n 4. 0 3 . T he se verit y gra de of e ve nts f or 
w hic h t he i n vesti gat or di d n ot rec or d se verit y will be cate g orize d as “ missi n g” f or ta b ular 
s u mmaries a n d data listi n gs . T he missi n g cate g or y will be liste d last i n s u m mar y prese ntati o n.
7. 1. 3.
Rel ati o ns hi p of A d verse E ve nts t o St u d y Dr u g
Relate d A Es are t h ose f or w hic h t he i n vesti gat or selecte d “ Relate d” o n t he A E C R F t o t he 
q uesti o n of “ Relate d t o St u d y  Treat me nt.” Relate d ness will al wa y s defa ult t o t he i n vesti gat or’s
c h oice, n ot t hat of t he me dical m o nit or. E ve nts f or w hic h t he i n vesti gat or di d n ot rec or d 
relati o ns hi p t o st u d y dr u g will be c o nsi dere d relate d t o st u d y dr u g f or s u m mar y p ur p oses. 
H o we ver, b y- s u bject data listi n gs will s h o w t he relati o ns hi p as missi n g.
7. 1. 4.
Seri o us A d verse E ve nts
Seri o us a d verse e ve nts ( S A Es) will be i de ntifie d a n d ca pt ure d as S A Es if t he A Es met t he 
defi niti o ns of S A E s t hat were s pecifie d i n t he st u d y pr ot oc ol. S A Es ca pt ure d a n d st ore d i n t he 
cli nical data base will be rec o ncile d wit h t he S A E data base fr o m t he Gilea d Dr u g Safet y a n d 
P u blic Healt h De part me nt bef ore data fi nalizati o n.
7. 1. 5.
Tre at me nt -E m er ge nt A d verse E ve nts
7. 1. 5. 1.
Defi niti o n of Treat me nt -E mer ge nt A d verse E ve nts
Treat me nt -e mer ge nt a d verse e ve nts ( T E A Es) are defi ne d as 1 or b ot h of t he f oll o wi n g:

A n y  A Es wit h a n o nset date o n or after t he st u d y  dr u g start date a n d n o later t ha n 3 0 d a y s 
after per ma ne nt disc o nti n uati o n of st u d y  dr u g

A n y  A Es lea di n g t o pre mat ure disc o nti n uati o n of st u d y dr u g.


I delalisi b
G S -U S -3 9 7 -1 2 4 5
Statistical A nal ysis Pla n
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 1
2 Fe br uar y 2 0 1 8
7. 1. 5. 2.
I nc o m plete Dates
All A Es wit h partial o nset or st o p dates will be i de ntifie d a n d t he partial dates will be i m p ute d as 
f oll o ws:

F or A E o nset date: If da y a n d m o nt h are missi n g b ut y ear is a vaila ble, t he n t he i m p ute d da y  
a n d m o nt h will be 0 1 Ja n or t he first d osi n g date if t he y ha ve t he sa me y ear, w hic he ver is 
later. If da y is missi n g b ut t he m o nt h a n d year are a vaila ble, t he n t he i m p ute d da y will be t he 
first da y of t he m o nt h or t he first d osi n g date if t he y ha ve t he sa me m o nt h a n d y ear, 
w hic he ve r is later. 

F or A E st o p date: If da y a n d m o nt h are missi n g b ut year is a vaila ble, t he n t he i m p ute d da y  
a n d m o nt h will be 3 1 Dec of t hat y ear. If day is missi n g b ut t he m o nt h a n d y ear are a vaila ble, 
t he n t he i m p ute d da y will be t he last d a y of t he m o nt h or deat h date, w hic he ver is earlier.
I m p ute d A E o nset date s h o ul d be o n or bef ore t he A E st o p date. I n fe w circ u msta nces w here A E 
st o p pe d bef ore t he first d osi n g date a n d t he i m p ute d A E o nset date bec o mes later t ha n A E st o p 
date, A E start date will be set t o A E st o p date.
7. 1. 6.
S u m m aries of A d verse E ve nts a n d De at hs
Treat me nt -e mer ge nt A Es will be s u m marize d base d o n t he F A S .
7. 1. 6. 1. 
S u m maries of A E I nci de nce b y  Se verity 
T he n u m ber a n d perce nta ge of s u bjects w h o e x perie nce d at least 1 T E A E will be pr o vi de d a n d 
s u m marize d b y  SO C, P T, a n d d ose le vel c o h ort . F or ot her A Es descri be d bel o w, s u m maries will 
be pr o vi de d b y  S O C, P T, ma xi m u m se verit y , a n d d ose le vel c o h ort :

T E A Es

T E A Es of Gra de 3 or hi g her

T E i delalisi b-relate d A Es

T E r u x oliti ni b -relate d A Es

T E i delalisi b-relate d A Es of Gra de 3 or hi g her

T E r u x oliti ni b -relate d A Es of Gra de 3 or hi g her

T E S A Es

T E i delalisi b-relate d S A Es 

T E r u x oliti ni b -relate d S A Es


I delalisi b
G S -U S -3 9 7 -1 2 4 5
Statistical A nal ysis Pla n
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 2
2 Fe br uar y 2 0 1 8

T E A Es lea di n g t o pre mat ure disc o nti n uati o n of i delalisi b

T E A Es lea di n g t o deat h

T E A Es lea di n g t o te m p orar y i nterr u pti o n of i delalisi b 

T E A Es lea di n g t o d ose re d ucti o n of i delalisi b
A brief, hi g h -le vel s u m mar y of A Es descri be d a b o ve wil l be pr o vi de d by d ose le vel c o h ort a n d 
b y  t he n u m ber a n d perce nta ge of s u bjects w h o e x perie nce d t he a b o ve A Es .
M ulti ple e ve nts will be c o u nte d o nl y  o nce per s u bject i n eac h s u m mar y . A d verse e ve nts will be 
s u m marize d a n d liste d first i n al p ha betic or der of S O C a n d H L T wit hi n eac h S O C (if a p plica ble), 
a n d t he n b y P T i n desce n di n g or der of t otal fre q ue nc y wit hi n eac h S O C. F or s u m maries by 
se verity gra de, t he m ost se vere gra de will be use d f or t h ose A Es t hat occ urre d m ore t ha n o nce i n 
an i n di vi d ual s u bject d uri n g t he st u d y. 
I n a d diti o n t o t he a b o ve s u m mar y ta bles, all T E A Es will be s u m marize d b y  P T o nl y, i n
desce n di n g or der of t otal fre q ue nc y .
I n a d diti o n, data listi n gs will be pr o vi de d f or t he f oll o wi n g:

All A Es , i n dicati n g w het her t he e ve nt is treat me nt e mer ge nt

All A Es of Gra de 3 or hi g her

S A Es

Deat hs

A Es lea di n g t o deat h

A Es lea di n g t o i nterr u pti o n, re d u cti o n a n d pre mat ure disc o nti n uati o n of i delalisi b
7. 1. 7.
Tre at me nt -E m er ge nt A d verse E ve nts of I nterest
T he treat me nt -e mer ge nt A Es of i nterest ( A EI) i ncl u de:

≥ Gra de 3 diarr hea/c olitis

≥ Gra de 3 ras h i n Me dical Searc h Ter m ( ter ms are defi ne d i n A p pe n di x 2 of t his S A P.)

A n y  gra de p ne u m o nitis

A n y  g ra de or ga niz i n g pne u m o nia

A n y  g ra de b o wel perf orati o n 

A n y  g ra de pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y ( P M L)


I delalisi b
G S -U S -3 9 7 -1 2 4 5
Statistical A nal ysis Pla n
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 3
2 Fe br uar y 2 0 1 8

≥ Gra de 3 fe brile ne utr o pe nia

≥ Gra de 3 i nfecti o n

A n y  gra de P ne u m ocystis jir oveci i p ne u m o nia ( PJ P)

A n y  g ra de c yt o me gal o vir us ( C M V) i nfecti o n
T a ble 1 .
Gr o u pe d Ter ms f or A d verse E ve nts of I nterest
A EI
Gr o u pe d Ter ms
Diarr he a/colitis
P T: Diarr h oea or colitis
P ne u m o nitis
P T: P ne u m o nitis
Or ga ni z i n g p ne u m o nia
P T: Or ga niz i n g pne u m o nia
Fe brile n e utr o pe nia
P T: Fe brile ne utr o pe nia
P M L
P T: Pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y
I nfecti o n
S O C: I nfecti o ns a n d i nfestati o ns or
P T: Fe brile ne utr o pe nia
PJ P
H L T: P ne u m oc ystis i nfecti o ns
C M V
H L T: C yt o me gal o viral i nfecti o ns or
P T: C yt o me gal o vir us test p ositi ve 
B o w el p erf or ati o n
F oll o w i n g ter ms base d o n P T:
Rectal perf orati o n
D u o de nal perf orati o n
D u o de nal ulcer perf orati o n
D u o de nal ulcer perf orati o n, o bstr ucti ve
Di vertic ular perf orati o n
Gastr oi ntesti nal perf orati o n
Gastr oi ntesti nal ulcer perf orati o n
A p pe n dicitis perf orate d
Ileal perf orati o n
Ileal ulcer perf orati o n
I ntesti nal perf orati o n
I ntesti nal ulcer perf orati o n
Jej u nal perf orati o n
Jej u nal ulcer perf orati o n
Lar ge i ntesti nal ulcer perf orati o n
Lar ge i ntesti ne perf or ati o n
S m all i ntesti nal perf orati o n
S m all i ntesti nal ulcer perf orati o n
T he A EIs will be s u m marize d si milarl y t o T E A Es b y d ose le vel c o h ort .


I delalisi b
G S -U S -3 9 7 -1 2 4 5
Statistical A nal ysis Pla n
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 4
2 Fe br uar y 2 0 1 8
7. 2.
L a b or at or y E v al u ati o ns
La b orat or y  data c ollecte d d uri n g t he st u d y will be a nalyz e d a n d s u m marize d usi n g b ot h 
q ua ntitati ve a n d q ualitati ve met h o ds. S u m maries of la b orat or y data will be pr o vi de d f or t he F A S
a n d will i ncl u de data c ollecte d u p t o t he last d ose of st u d y  dr u g pl us 3 0 da ys f or s u bjects w h o 
ha ve per ma ne ntl y disc o nti n ue d st u d y  dr u g. T he a nal y sis will be base d o n val ues re p orte d i n SI
u nits. W he n val ues are bel o w t he L O Q , t he y will be liste d as s uc h, a n d t he cl osest i m p ute d val ue 
will be use d f or t he p ur p ose of calc ulati n g s u m mar y statistics as s pecifie d i n Secti o n 3. 7 .
A b y -s u bject listi n g f or la b orat or y test res ults will be pr o vi de d b y s u bject I D n u m ber a n d visit i n 
c hr o n ol o gical or der.
7. 2. 1. 
S u m m aries of N u meric L a b or at or y Res ults
Descri pti ve statistics wil l be pr o vi de d by d ose le vel c o h ort f or eac h la b orat or y test s pecifie d i n 
the st u d y  pr ot oc ol as f oll o ws:

Baseli ne val ues 

Val ues at eac h p ost baseli ne visit

C ha n ge fr o m baseli ne at eac h p ost baseli ne visit
A baseli ne la b orat or y  val ue will be defi ne d as t he last meas ure me nt o btai ne d o n or pri or t o t he 
date/ti me of first d ose of st u d y dr u g. C ha n ge fr o m baseli ne t o a p ost baseli ne visit will be defi ne d 
as t he visit val ue mi n us t he baseli ne val ue. T he mea n, me dia n, Q 1, Q 3, mi ni m u m, a n d ma xi m u m 
val ues will be dis pla y e d t o t he re p orte d n u m ber of di gits; St D val ues will be dis pla y e d t o t he 
re p orte d nu m ber of di gits pl us 1.
I n t he case of m ulti ple val ues i n a n a nalys is wi n d o w, data will be selecte d f or a nalys is as 
descri be d i n Secti o n 3. 8. 3 .
7. 2. 2.  
Gr a de d L a b or at or y V al ues
T he C T C A E, Versi o n 4. 0 3, will be use d t o assi g n t o xicit y  gra des ( 0 t o 4) t o la b orat or y res ults f or 
a nal ys is. Gra de 0 i ncl u des all val ues t hat d o n ot meet t he criteria f or a n a b n or malit y of at least 
Gra de 1. F or la b orat or y  tests wit h criteria f or b ot h i ncrease d a n d decrease d le vels, a nal ys es f or 
eac h directi o n (ie, i ncrease d, decrease d) will be prese nte d se paratel y. O nl y l ocal la bs will be 
c ollecte d f or t his st u d y a n d will be gra de d base d o n ce ntral la b n or mal ra n ges wit h a n i n-h o use 
macr o.
7. 2. 2. 1.
Treat me nt -E mer ge n t La b orat or y A b n or malities
Treat me nt -e mer ge nt la b orat or y a b n or malities are defi ne d as val ues t hat i ncrease at least 
1 t o xicit y gra de fr o m baseli ne at a ny p ost baseli ne ti me p oi nt, u p t o a n d i ncl u di n g t he date of last 
d ose of st u d y  dr u g pl us 3 0 da y s f or s u bjects w h o per ma ne ntl y disc o nti n ue d st u d y  dr u g. If t he 
rele va nt baseli ne la b orat or y val ue is missi n g, a n y a b n or malit y of at least Gra de 1 o bser ve d 
wit hi n t he ti me fra me s pecifie d a b o ve will be c o nsi dere d treat me nt e mer ge nt.


I delalisi b
G S -U S -3 9 7 -1 2 4 5
Statistical A nal ysis Pla n
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 5
2 Fe br uar y 2 0 1 8
7. 2. 2. 2.
S u m maries of La b orat or y  A b n or malities
La b orat or y  data t hat are cate g orical will be s u m marize d usi n g t he n u m ber a n d perce nta ge of 
s u bjects i n t he st u d y wit h t he gi ve n res p o nse at baseli ne a n d eac h sche d ule d p ost baseli ne visit .
T he f oll o wi n g s u m maries ( n u m ber a n d perce nta ge of s u bjects) f or treat me nt-e mer ge nt la b orat or y 
a b n or malities will be pr o vi de d b y  la b test a n d d ose le vel c o h ort ; s u bjects will be cate g orize d 
acc or di n g t o t he m ost se vere p ost baseli ne a b n or malit y  gra de f or a gi ve n la b test. F or all 
s u m maries of la b orat or y a b n or malities, t he de n o mi nat or is t he n u m ber of s u bjects i n t he F A S.
A b y -s u bject listi n g of treat me nt-e mer ge nt la b orat or y a b n or malities will be pr o vi de d b y s u bject 
I D n u m ber a n d visit i n c hr o n ol o gical or der. T his listi n g will i ncl u de all test res ults t hat were 
c ollecte d t hr o u g h o ut t he st u d y  f or t he la b test of i nterest, wit h all a p plica ble se verity gra des 
dis pla y e d.
7. 2. 3.
Li ver -rel ate d L a b or at or y E v al u ati o ns
7. 2. 3. 1.
Tra nsa mi nase Ele vati o n
A nal yses of tra nsa mi nase ele vati o ns will be base d o n la b orat o ry val ues usi n g t he F A S . T he 
n u m ber a n d perce nta ge of s u bjects will be s u m marize d b y d ose le vel c o h ort :

wit h Gra de 3 or 4 treat me nt-e mer ge nt a la ni ne a mi n otra nsferase ( AL T )/ as partate 
a mi n otra nsferase (A S T ) ele vati o n

wit h Gra de 3 or 4 treat me nt-e mer ge nt A L T/ A S T ele vati o n t hat res ol ve d t o b ot h A L T a n d 
A S T of Gra de 1 or less
7. 2. 3. 2.
Li ver - Relate d La b orat or y E val uati o ns
T he n u m ber a n d perce nt a ge of s u bjects will be s u m marize d f or t he f oll o wi n g li ver-relate d 
la b orat or y tests a n d cate g ories:

A S T: (a) > 3 ti mes of t he u p per li mit of refere nce ra n ge  ( U L N); ( b) > 5 x U L N; 
(c) > 1 0 x U L N; ( d) > 2 0 x U L N

A L T: (a) > 3 x U L N; ( b) > 5 x U LN; (c) > 1 0 x U L N; ( d) > 2 0 x U L N

A S T or A L T: (a) > 3 x U L N; ( b) > 5 x U L N; (c) > 1 0 x U L N; ( d) > 2 0 x U L N

T otal bili ru bi n: (a) > U L N, ( b ) > 2 x U L N

Al kali ne p h os p hatase ( A L P) > 1. 5 x U L N

A S T or A L T > 3 x U L N: (a) t otal bilir u bi n > 1. 5 x U L N; ( b) t otal bilir u bi n > 2 x U L N; 
(c) t otal bilir u bi n > 2 x U L N a n d A L P < 2 x U L N


I delalisi b
G S -U S -3 9 7 -1 2 4 5
Statistical A nal ysis Pla n
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 6
2 Fe br uar y 2 0 1 8
T he s u m mar y  will i ncl u de data fr o m all p ost baseli ne visits u p t o 3 0 da y s after t he last d ose of 
st u d y dr u g. F or i n di vi d ual la b orat or y tests, s u bjects will be c o u nte d o nce base d o n t he m ost 
se vere p ost baseli ne val ues. F or b ot h t he c o m p osite e n d p oi nt of A S T or A L T a n d t otal bilir u bi n, 
s u bjects will be c o u nte d o nce w he n t he criteria are met at t he sa me p ost baseli ne visit date. T he 
de n o mi nat or is t he n u m ber of s u bjects i n t he F A S w h o ha ve n o n missi n g p ost baseli ne val ues of 
all rele va nt tests at t he sa me p ost baseli ne visit date. 
I n a d diti o n, a listi n g of s u bjects w h o met at least 1 of t he a b o ve criteria will be pr o vi de d.
7. 2. 4.
S hifts Rel ati ve t o t he B aseli ne V al ue
S hift ta bles will be prese nte d b y  s h o wi n g c ha n ge i n se verity gra de fr o m baseli ne t o w orst gra de 
p ost baseli ne.
7. 3.
B o d y Wei g ht a n d Vit al Si g ns
Descri pti ve statist ics will be pr o vi de d by d ose le vel c o h ort f or b o d y wei g ht a n d vital si g ns as 
f oll o ws:

Baseli ne val ue

Val ues at eac h p ost baseli ne visit

C ha n ge fr o m baseli ne at eac h p ost baseli ne visit
A baseli ne val ue will be defi ne d as t he last a vaila ble val ue c ollec te d o n or pri or t o t he date of 
first d ose of st u d y dr u g. C ha n ge fr o m baseli ne t o a p ost baseli ne visit will be defi ne d as t he 
p ost baseli ne val ue mi n us t he baseli ne val ue .
I n t he case of m ulti ple val ues i n a n a nalys is wi n d o w, data will be selecte d f or a nalys is as
descri be d i n Secti o n 3. 8. 3 . N o f or mal statistical testi n g is pla n ne d.
A b y -s u bject listi n g of vital si g ns will be pr o vi de d b y s u bject I D n u m ber a n d visit i n 
c hr o n ol o gica l or der.
7. 4.
Pri or a n d C o nc o mit a nt Me dic ati o ns
Me dicati o ns c ollecte d at scree ni n g a n d d uri n g t he st u d y  will be c o de d usi n g t he c urre nt versi o n 
of t he W orl d Healt h Or ga nizati o n ( W H O) Dr u g dicti o nar y .
7. 4. 1. 
Pri or Me dic ati o ns
Pri or me dicati o ns are defi ne d as a n y me dicati o ns ta ke n bef ore a s u bject t o o k t he first st u d y  dr u g. 
A s u m mar y  of pri or me dicati o ns will n ot be pr o vi de d.


I delalisi b
G S -U S -3 9 7 -1 2 4 5
Statistical A nal ysis Pla n
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 7
2 Fe br uar y 2 0 1 8
7. 4. 2.
C o nc o mit a nt Me dic ati o ns
C o nc o mita nt me dicati o ns are defi ne d as me dicati o ns ta ke n w hile a s u bject t o o k st u d y  dr u g. Use 
of c o nc o mita nt me dicati o ns will be s u m marize d b y preferre d na me usi n g t he n u m ber a n d 
perce nta ge of s u bjects f o r eac h d ose le vel. A s u bject re p orti n g t he sa me me dicati o n m ore t ha n 
o nce will be c o u nte d o nl y o nce w he n calc ulati n g t he n u m ber a n d perce nta ge of s u bjects w h o 
recei ve d t hat me dicati o n. T he s u m mar y will be or dere d b y preferre d ter m i n desce n di n g o verall 
freq ue nc y . F or dr u gs wit h t he sa me fre q ue nc y, s orti n g will be d o ne al p ha beticall y.
F or t he p ur p oses of a nal ysis, a n y me dicati o ns wit h a start date pri or t o or o n t he first d osi n g date 
of st u d y  dr u g a n d c o nti n ue d t o be ta ke n after t he first d osi n g date, or starte d after t he first d osi n g 
date b ut pri or t o or o n t he last d osi n g date of st u d y dr u g will be c o nsi dere d c o nc o mita nt 
me dicati o ns. Me dicati o ns starte d a n d st o p pe d o n t he sa me da y as t he first d osi n g date or t he last 
d osi n g date of st u d y  dr u g will als o be co nsi dere d c o nc o mita nt. Me dicati o ns wit h a st o p date pri or 
t o t he date of first d osi n g date of st u dy dr u g or a start date after t he last d osi n g date of st u d y dr u g 
will be e xcl u de d fr o m t he c o nc o mita nt me dicati o n s u m mar y . If a partial st o p date is e ntere d, an y  
me dicati o n wit h t he m o nt h a n d y ear (if da y is missi n g) or ye ar (if da y a n d m o nt h are missi n g) 
pri or t o t he date of first st u d y  dr u g a d mi nistrati o n will be e xcl u de d fr o m t he c o nc o mita nt 
me dicati o n s u m mar y . If a partial start date is e ntere d, a ny me dicati o n wit h t he m o nt h a n d y ear 
(if d a y  is missi n g) or ye ar (if da y a n d m o nt h are missi n g) after t he st u d y dr u g st o p date will be 
e xcl u de d fr o m t he c o nc o mita nt me dicati o n s u m mar y . Me dicati o ns wit h c o m pletel y missi n g start 
a n d st o p dates will be c o nsi dere d as a c o nc o mita nt me dicati o n.
All pri or a n d c o nc o mita nt me dicati o ns ( ot her t ha n per- pr ot oc ol st u d y  dr u gs) will be pr o vi de d i n a 
b y -s u bject listi n g s orte d b y s u bject I D n u m ber a n d a d mi nistrati o n date i n c hr o n ol o gical or der.
7. 5.
Ot her S afet y Me as ures
A data listi n g wi ll be pr o vi de d f or s u bjects w h o beca me pre g na n t d uri n g t he st u dy.
Data listi n gs will als o be pr o vi de d f or s ur geries a n d pr oce d ures, b o ne marr o w assess me nt, 
perf or ma nce stat us , a n d tra nsf usi o n.
7. 6.
C h a n ges Fr o m Pr ot oc ol -S pecifie d S afet y A n al yses
D ue t o t he ear l y st u d y ter mi nati o n, o nl y  safet y-relate d e n d p oi nts will be liste d f or t he s u bjects 
e nr olle d i n t he st u d y.


I delalisi b
G S -U S -3 9 7 -1 2 4 5
Statistical A nal ysis Pla n
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 8
2 Fe br uar y 2 0 1 8
8.
P H A R M A C O KI N E TI C A N A L Y S E S
I n di vi d ual s u bject c o nce ntrati o n data f or i delalisi b, its meta b olite G S - 5 6 3 1 1 7, a n d r u x oliti ni b
will be liste d a n d s u m marize d usi n g descri pti ve statistics b y d ose le vel c o h ort a n d visit . 
S u m mar y  statistics ( n, mea n, St D, c oefficie nt of variati o n [ % C V], me dia n, mi n, ma x, Q 1, a n d 
Q 3) will be prese nte d f or i n di vi d ual s u bject c o nce ntrati o n data b y ti me p oi nt.


I delalisi b
G S -U S -3 9 7 -1 2 4 5
Statistical A nal ysis Pla n
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 9
2 Fe br uar y 2 0 1 8
9.
S O F T WA R E
S A S ® S oft ware Versi o n 9. 4 . S A S Instit ute I nc., Car y , N C, U S A.


I delalisi b
G S -U S -3 9 7 -1 2 4 5
Statistical A nal ysis Pla n
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 0
2 Fe br uar y 2 0 1 8
1 0.
S A P  R E VI SI O N
Re visi o n D ate
(D D M M M Y Y Y Y )
Secti o n
S u m m ar y of Re visi o n
Re as o n f or Re visi o n


I delalisi b
G S -U S -3 9 7 -1 2 4 5
Statistical A nal ysis Pla n
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 1
2 Fe br uar y 2 0 1 8
1 1.
A P P E N DI C E S
A p pe n di x 1.
Sc he d ule of Assess me nts
A p pe n di x 2.
Ras h Me dical Searc h Ter m


I delalisi b
G S -U S -3 9 7 -1 2 4 5
Statistical A nal ysis Pla n
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 2
2 Fe br uar y 2 0 1 8
A p pe n di x 1.
Sc he d ule of A ssess me nts
Wee ks 1 t o 4
Peri o d
Scree ni n g
Tre a tme nt
Wee k
1
2
3 
4
St u d y D a y
- 2 8 t o - 1 
1
4
1 0
1 5 
2 2
H o urs rel ati ve 
t o d osi n g
Pre 
d ose
0
0. 5
1
1. 5
2 
3 
4 
6 
8
1 2
Pre 
d ose
0
0. 5
1
1. 5
2 
3 
4 
6 
8
1 2
I nf or me d c o nse nt
X
M P N- S A F a
X
X
X  
X
Me dical &
me dicati o n 
hist or y b
X
Vital si g nsc
X  
X  
X
X
X  
X
P h ysical e xa m d
X  
X
X
X  
X
E C O G
X  
X
X
X  
X
DI P S S e
X
1 2 -lea d E C G
X
He mat ol o g y f
X  
X
X
X  
X
C he mistr y g
X  
X
X
X  
X
Uri nal ysis
X
E S R
X
C oa g ulati o n
X
Pre g na nc y test h
X  
X
HI V scree n
X
P ne u m oc ystis 
jir o veci
p ne u m o nia (PJ P)
P r o p h yla xis s
X
X
X  
X


I delalisi b
G S -U S -3 9 7 -1 2 4 5
Statistical A nal ysis Pla n
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 3
2 Fe br uar y 2 0 1 8
Peri o d
Scree ni n g
Tre a t ment
Wee k
1
2
3 
4
St u d y D a y
- 2 8 t o - 1 
1
4
1 0
1 5 
2 2
H o urs rel ati ve 
t o d osi n g
Pre 
d ose
0
0. 5
1
1. 5
2 
3 
4 
6 
8
1 2
Pre 
d ose
0
0. 5
1
1. 5
2 
3 
4 
6 
8
1 2
C M V Testi n g r
X
X
I m m u ne
M o nit ori n g
X
X
He patitis 
ser ol o g y
X
R u x oliti ni b P K i
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Idelalisi b & 
R u x oliti ni b P K j
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
B o ne marr o w 
bi o ps y a n d 
as pirate l
X
R u x oliti ni b 
d osi n g m
X
X
X
X
X  
X  
X  
X
I delalisi b d osi n g n
X
X  
X  
X  
X
I delalisi b 
dis pe nsi n g, 
acc o u nta bility o
X
X
X  
X  
X
A E, C o n me d sp
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
M RI
q
X
a
T he M P N -S A F will be c o m plete d wee kl y fr o m Wee k 1 t o 2 4 t he n m o nt hl y after Wee k 2 4 a n d at E O S . W he n visits are sc he d ule d, it s h o ul d be c o m plete d at t he cli nic.
S u bjects will recei ve a c o p y of t he q uesti o n naire t o c o m plete at h o me bet wee n cli nic visits be gi n ni n g Wee k 4.
b
T he me dical a n d me dicati o n hist or y will i ncl u de t he J A K 2V 6 1 7 F m utati o n stat us if k n o w n, r u x oliti ni b d ose a n d tra nsf usi o n hist or y wit hi n 3 m o nt hs of scree ni n g.
c
Vital si g ns i ncl u de bl o o d press ure, heart rate, res pirat or y rate , a n d oral te m perat ure.
d 
B o d y wei g ht, p al pati o n of t he s plee n a n d li ver will be perf or me d at eac h P E. H ei g ht will be perf or me d at scree ni n g o nl y. 
e
DI P S S Pl us s h o ul d be c o m plete d f or s u bjects w h o ha ve c yt o ge netics i nf or mati o n
C CI
.


I delalisi b
G S -U S -3 9 7 -1 2 4 5
Statistical A nal ysis Pla n
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 4
2 Fe br uar y 2 0 1 8
C CI
f
He mat ol o g y: C B C wit h differe ntial, retic ul oc yte c o u nt. A N C m o nit ore d at least e ver y t w o wee ks f or t he first 2 4 wee ks of i delalisi b treat me nt.
g
C he mistr y: C o m pre he nsi ve meta b olic pa nel wit h A L T, A S T, G G T, ir o n, L D H, ma g nesi u m, p h os p h or us t otal bilir u bi n, direct bilir u bi n , uric aci d.
h 
F or fe males of c hil d beari n g p ote ntial o nl y. Ser u m pre g na nc y test will be perf or me d d uri n g scree ni n g o nl y . A uri ne pre g na nc y test will be o btai ne d t hr o u g h o ut t he rest of t he 
st u d y.
i
T he r u x oliti ni b Da y 1 P K sa m ple wil l be dra w n pre d ose. T he 1 2 h o ur p ost d ose P K ti me p oi nt o n Da y 4 will be perf or me d pri or t o t he sec o n d r u x oliti ni b d osi n g.
j
Bl o o d sa m ples will be c ollecte d f or r u x oliti ni b, i delalisi b a n d/ or meta b olite P K be gi n ni n g Da y 1 0. T he 1 2 h o ur p ost d ose P K ti me p oi nt o n Da y 1 0 will be perf or me d pri or t o 
i delalisi b a n d r u x oliti ni b d osi n g. Be gi n ni n g Da y 1 5 P K sa m ples will be c ollecte d pre d ose a n d 1. 5 h o urs p ost d ose. 
l
B o ne marr o w bi o ps y a n d as pirate will be c ollecte d at S cree ni n g if o ne has n ot bee n d o ne i n t he past 3 m o nt hs or res ults are n ot a vaila ble, Da y s 7 8, 1 6 2 a n d e ver y 2 4 wee ks 
d uri n g t he e xte nsi o n peri o d. It will als o be c ollecte d at E O S , if o ne has n ot bee n d o ne i n t he past 2 4 wee ks. B o ne marr o w st u dies i ncl u de c yt o ge netics, c ore bi o ps y, tric hr o me 
stai n f or retic uli n, a n d ir o n stai n.
m
R u x oliti ni b d osi n g will be i n cli nic w he n visits are sc he d ule d.
n
Idelalisi b d osi n g will be i n t he cli nic w he n visits are sc he d ule d.
o 
I delalisi b w ill be dis pe nse d i n cli nic o n Da y 4 f or t he s u bject t o self-a d mi nister be gi n ni n g Da y 5. Idelalisi b acc o u nta bilit y s h o ul d be d o ne at e ver y cli nic visit.
p  
A d verse e ve nts a n d c o nc o mita nt me dicati o ns will be assesse d a n d d oc u me nte d t hr o u g h o ut t he st u d y. F or assess me nt of Diarr hea/ C olitis see Secti o n 6. 2. 1 7 of t he pr ot oc ol . 
q
T hree di me nsi o nal M RI ( or C T , if M RI n ot feasi ble) f or t he li ver a n d s plee n size b y v ol u metric i ma gi n g. A n M RI s h o ul d be d o ne at t he E O S visit o nl y if it has n ot bee n d o ne 
wit hi n 1 2 w ee ks of t he visit.
r
C M V testi n g will be perf or me d e ver y 4 wee ks starti n g at Scree ni n g a n d e n d at E O S.
I 


I delalisi b
G S -U S -3 9 7 -1 2 4 5
Statistical A nal ysis Pla n
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 5
2 Fe br uar y 2 0 1 8
Wee ks 6 t o 2 4
Peri o d
Tre at m e nt
E xte nsi o n peri o d o
E O S q
F oll o w U p r
Wee k
6 
8
1 0 
1 2 
1 4 
1 6 
1 8 
2 0 
2 2 
2 4
Q 4 W
Q 1 2 W p
Q 2 4 W p
3 0 ± 7 d a ys
after E O S
St u d y D a y
3 6 
5 0 
6 4 
7 8 
9 2 
1 0 6 
1 2 0 
1 3 4 
1 4 8 
1 6 2
Visit Wi n d o w ( D a ys)
± 3 
± 3 
± 3 
± 3 
± 3
± 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
M P N -S A F a
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
Vital si g ns b
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X  
X
P h y sical e xa mc
X  
X  
X  
X  
X  
X  
X  
X
X  
X
E C O G
X  
X  
X  
X  
X  
X  
X  
X
X  
X
H e m at ol o g y d
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X  
X
C he mistr y e
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X  
X
C M V Testi n g s
X  
X  
X  
X  
X  
X  
X  
X  
X
I m m u ne M o nit ori n g
X
X
X  
X  
X
Pre g na nc y test f
X
X  
X  
X  
X  
X
X  
X
Idelalisi b & R u x oliti ni b P K g
X
X
X
B o ne marr o w  bi o ps y a n d as pirate i
X
X
X  
X
R u x oliti ni b d osi n g j
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Idelalisi b d osi n g k
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Idelalisi b dis pe nsi n g, 
acc o u nta bilit y l
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
A E, C o n me ds m
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X  
X
M RI
n
X
X
X
X
C CI
a
T he M P N -S A F will be c o m plete d wee kl y fr o m Wee k 1 t o 2 4 t he n m o nt hl y after Wee k 2 4 a n d at E O S . W he n visits are sc he d ule d, it s h o ul d be c o m plete d at t he cli nic.
S u bjects will recei ve a c o p y of t he q uesti o n naire t o c o m plete at h o me bet wee n cli nic visits be gi n ni n g Wee k 4.
b
Vital si g ns i ncl u de bl o o d press ure, heart rate, res pirat or y rate a n d oral te m perat ure.
c 
B o d y wei g ht, p al pati o n of t he s plee n a n d li ver will be p erf or me d at eac h P E. Hei g ht will be perf or me d at scree ni n g o nl y. P h ysical e xa ms will be sc he d ule d e ver y 4 wee ks 
d uri n g t he e xte nsi o n peri o d e xce pt after a s u bject has bee n o n st u d y f or 1 year, w he n it will be sc he d ule d e ver y 1 2 wee ks.
d
He mat ol o g y: C B C wit h differe ntial, retic ul o c yte c o u nt . A N C m o nit ore d at least e ver y t w o wee ks f or t he first 2 4 wee ks of i delalisi b treat me nt.
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -


I delalisi b
G S -U S -3 9 7 -1 2 4 5
Statistical A nal ysis Pla n
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 6
2 Fe br uar y 2 0 1 8
C CI
e
C he mistr y: C o m pre he nsi ve meta b olic pa nel wit h A L T, A S T, G G T, ir o n, L D H, ma g nesi u m, t otal bilir u bi n, p h os p h or us , uric aci d.
f 
F or fe males of c hil d beari n g p ote ntial o nl y. Ser u m pre g na nc y test will be perf or me d d uri n g scree ni n g o nl y. A uri ne pre g na nc y test will be o btai ne d t hr o u g h o ut t he rest of t he 
st u d y.
g
Bl o o d sa m ples will be c ollecte d f or r u x oliti ni b, i delalisi b a n d/ or meta b olite P K be gi n ni n g Da y 1 0. Be gi n ni n g Da y 1 5 P K sa m ples will be c ollecte d pre d ose a n d 1. 5 h o urs 
p ost d ose .
i
B o ne marr o w bi o ps y a n d as pirate will be o btai ne d at scree ni n g if o ne has n ot bee n d o ne i n t h e past 3 m o nt hs or res ults are n ot a vaila ble, Da ys 7 8, 1 6 2 a n d e ver y 2 4 wee ks 
d uri n g t he e xte nsi o n peri o d . It will als o be o btai ne d at E O S if o ne has n ot bee n d o ne i n t he past 2 4 wee ks. B o ne marr o w st u dies i ncl u de c yt o ge netics, c ore bi o ps y, tric hr o me 
stai n f or retic uli n, a n d ir o n stai n.
j
R u x oliti ni b d osi n g will be i n cli nic w he n visits are sc he d ule d.
k 
I delalisi b d osi n g will be i n t he cli nic w he n visits are sc he d ule d.
l 
Idelalisi b will be dis pe nse d i n cli nic o n Da y 4 f or t he s u bject t o self -a d mi nister be gi n ni n g Da y 5. Idelalisi b acc o u nta bilit y s h o ul d be d o ne at e ver y cli nic visit.
m  
A d verse e ve nts a n d c o nc o mita nt me dicati o ns will be assesse d a n d d oc u me nte d t hr o u g h o ut t he st u d y. F or assess me nt of Diarr hea/ C olitis please see Secti o n 6. 2. 1 7
of t he 
pr ot oc ol .
n
T hree di me nsi o nal M RI ( or C T , if M RI n ot feasi ble) f or t he li ver a n d s plee n size b y v ol u metric i ma gi n g. A n M RI s h o ul d be d o ne at t he E O S visit o nl y if it has n ot bee n d o ne 
wit hi n 1 2 wee ks of t he visit.
o
If s u bjects are deri vi n g cli nical be nefit (as deter mi ne d b y t he i n vesti gat or) a n d c o m plete Wee k 2 4 , s u bjects ca n e nter e xte nsi o n peri o d u ntil t he y de m o nstrate pr o gressi ve 
disease a n d/ or ha ve u nacce pta ble t o xicit y, as defi ne d b y t he pr ot oc ol. P h ysical e xa ms will be sc he d ule d e ver y 4 wee ks d uri n g t he e xte nsi o n peri o d e xce pt after a s u bject has 
bee n o n st u d y f or 1 year, w he n it will be sc he d ule d e ver y 1 2 wee ks.
p
Q 1 2 W a n d Q 2 4 W assess me nts will o verla p wit h Q 4 W assess me nts a n d will be sc he d ule d at t he sa me visit.
q
If t he E O S visit c oi nci des wit h Wee k
2 4 (Da y 1 6 2 ), the pre d ose bl o o d sa m ple f or P K m ust be c ollecte d.
r
T he safet y f oll o w u p visit is wit hi n 3 0 da ys of E O S.
s
C M V testi n g will be perf or me d e ver y 4 wee ks starti n g at Scree ni n g a n d e n d at E O S.
I 


I delalisi b
G S -U S -3 9 7 -1 2 4 5
Statistical A nal ysis Pla n
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 7
2 Fe br uar y 2 0 1 8
A p pe n di x 2.  
R as h Me dic al Se arc h Ter m
M e d D R A Ter m  N a me
M e d D R A C o de
Ac ute ge neralise d e xa nt he mat o us p ust ul osis
1 0 0 4 8 7 9 9
A n gi na b ull osa hae m orr ha gica
1 0 0 6 4 2 2 3
A ut oi m m u ne d er m atitis
1 0 0 7 5 6 8 9
Blister
1 0 0 0 5 1 9 1
Blister r u pt ure
1 0 0 7 3 3 8 5
B utterfl y ras h
1 0 0 6 7 9 8 2
Cer vical b ulla
1 0 0 5 0 0 1 9
Der m atitis e xf oliati ve
1 0 0 1 2 4 5 5
Der m atitis e xf oliati ve ge neralise d
1 0 0 1 2 4 5 6
Der m at osis
1 0 0 4 8 7 6 8
Dr u g er u pti o n
1 0 0 1 3 6 8 7
Dr u g reacti o n wit h e osi n o p hilia a n d s yste mic s y m pt o ms
1 0 0 7 3 5 0 8
E osi n o p hilic p ust ular f ollic ulitis
1 0 0 5 2 8 3 4
E pi der m ol ysis
1 0 0 5 3 1 7 7
E pi der m ol ysis b ull osa
1 0 0 1 4 9 8 9
Er u pti ve pse u d oa n gi o mat osis
1 0 0 6 8 0 9 5
Er yt he ma m ultif or me
1 0 0 1 5 2 1 8
Er yt he ma n o d os u m
1 0 0 1 5 2 2 6
Er yt hr osis
1 0 0 5 6 4 7 4
E xf oliati ve ras h
1 0 0 6 4 5 7 9
Fi xe d er u pti o n
1 0 0 1 6 7 4 1
Fla gellate der matitis
1 0 0 7 5 4 6 7
I nterstitial gra n ul o mat o us der matitis
1 0 0 6 7 9 7 2
Lic he n oi d kerat osis
1 0 0 6 4 0 0 0
Mac ule
1 0 0 2 5 4 2 1
M uc oc uta ne o us ras h
1 0 0 5 6 6 7 1
M uc oc uta ne o us ulcerati o n
1 0 0 2 8 0 8 4
M uc osa vesicle
1 0 0 2 8 1 0 3
Necr ol ytic mi grat or y er yt he ma
1 0 0 6 0 8 2 1
Ne ur o der matitis
1 0 0 2 9 2 6 3
Oc ul o m uc oc uta ne o us s y n dr o me
1 0 0 3 0 0 8 1
Oral m uc osal blisteri n g 
1 0 0 3 0 9 9 5


I delalisi b
G S -U S -3 9 7 -1 2 4 5
Statistical A nal ysis Pla n
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 8
2 Fe br uar y 2 0 1 8
M e d D R A Ter m  N a me
M e d D R A C o de
Or o p har y n geal blisteri n g 
1 0 0 6 7 9 5 0
Pal mar -pla ntar er yt hr o d ysaest hesia s y n dr o me
1 0 0 3 3 5 5 3
Pal pa ble p ur p ura
1 0 0 5 6 8 7 2
Pa p ule
1 0 0 3 3 7 3 3
Para ne o plastic ras h
1 0 0 7 4 6 8 7
Pe m p hi g oi d
1 0 0 3 4 2 7 7
Pe m p hi g us
1 0 0 3 4 2 8 0
Pe nile blister
1 0 0 5 2 8 9 8
Pr uri g o
1 0 0 3 7 0 8 3
Ras h
1 0 0 3 7 8 4 4
Ras h er yt he mat o us
1 0 0 3 7 8 5 5
Ras h f ollic ular
1 0 0 3 7 8 5 7
Ras h ge neralise d
1 0 0 3 7 8 5 8
Ras h mac ular
1 0 0 3 7 8 6 7
Ras h mac ul o -pa p ular
1 0 0 3 7 8 6 8
Ras h mac ul o vesic ular
1 0 0 5 0 0 0 4
Ras h m or billif or m
1 0 0 3 7 8 7 0
Ras h pa p ular
1 0 0 3 7 8 7 6
Ras h pa p ul os q ua m o us
1 0 0 3 7 8 7 9
Ras h pr uritic
1 0 0 3 7 8 8 4
Ras h p ust ular
1 0 0 3 7 8 8 8
Ras h r u bellif or m
1 0 0 5 7 9 8 4
Ras h scarlati nif or m
1 0 0 3 7 8 9 0
Ras h vesic ular
1 0 0 3 7 8 9 8
Se b orr h oeic der matitis
1 0 0 3 9 7 9 3
S ki n dis or der
1 0 0 4 0 8 3 1
S ki n pla q ue
1 0 0 6 7 7 2 3
S ki n reacti o n
1 0 0 4 0 9 1 4
S ki n t o xicit y
1 0 0 5 9 5 1 6
Ste ve ns -J o h ns o n s y n dr o me
1 0 0 4 2 0 3 3
S y m metrical dr u g -relate d i ntertri gi n o us a n d fle x ural 
e xa nt he ma
1 0 0 7 8 3 2 5
T o xic e pi der mal necr ol ysis
1 0 0 4 4 2 2 3


I delalisi b
G S -U S -3 9 7 -1 2 4 5
Statistical A nal ysis Pla n
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 9
2 Fe br uar y 2 0 1 8
M e d D R A Ter m  N a me
M e d D R A C o de
T o xic er yt he ma of c he m ot hera p y
1 0 0 7 4 9 8 2
T o xic s ki n er u pti o n
1 0 0 5 7 9 7 0
U m bilical er yt he ma
1 0 0 5 5 0 2 9
Urticarial vasc ulitis
1 0 0 4 8 8 2 0
Va gi nal e xf oliati o n
1 0 0 6 4 4 8 3
Vasc ulitic ras h
1 0 0 4 7 1 1 1
Viral ras h
1 0 0 4 7 4 7 6
V ul v o va gi nal ras h
1 0 0 7 1 5 8 8