Clinical trial NCT03113760
Conditions: NLRC4-MAS XIAP Deficiency
Sponsor: AB2 Bio Ltd.
Start date: 2017-07-21; Completion date: 2023-11-02
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 3 study to assess the safety and efficacy of Tadekinig alfa in patients with monogenic, interleukin-18 (IL 18) driven autoinflammation due to Nucleotide-binding oligomerization domain, leucine-rich repeat and caspase recruiting domain (CARD domain) containing 4 (NLRC4) - Macrophage activation syndrome (MAS) mutation (NLRC4-MAS mutation) or X-linked inhibitor of apoptosis (XIAP) deficiency. Because of the likelihood for pathogenic IL-18 in certain monogenic diseases, patients known to harbor deleterious mutations in NLRC4-MAS or XIAP and who have a history of ongoing inflammation will be enrolled if they have ferritin ≥ 500 ng/mL or persistent C reactive protein (CRP) elevation ≥ 2 times the upper limit of normal (ULN) and the patients should have a Modified Autoinflammatory Disease Activity Index (mAIDAI) ≥ 4.

Detailed description:
The study is designed with single-arm, open-label phase (SAOL) of Tadekinig alfa treatment duration for 18-week followed by an up to 16-week Randomized Withdrawal (RW) period for efficacy and safety evaluation, with no interruption between the two phases of treatment. The screening period will occur before the SAOL phase and before the first dose of Investigational Medicinal Product (IMP)

Arms: arm 1: Patients that showed response to treatment in the SAOL phase will receive Tadekinig alfa for up to 16 weeks. arm 2: Patients that showed response to treatment in the SAOL phase will receive placebo comparator for up to 16 weeks.
Interventions: intervention 1: Tadekinig alfa intervention 2: 0.9% sodium chloride
Intervention descriptions: intervention 1: Tadekinig alfa is a soluble glycoprotein of 164 amino acids produced from Chinese Hamster Ovary cell line. Tadekinig alfa is supplied as a colorless to slightly yellow, sterile solution for injection in glass vials containing sodium chloride, and 0.02M sodium phosphate buffer as excipients. It is available in a concentration of 20mg/0.5mL. intervention 2: To ensure that the treatment remains blinded for the entire study period, the placebo solutions will be supplied in identical vials and similar labelling as the active drug and will be indistinguishable in terms of their texture, color, and smell.

Protocol documents:
Prot_000.pdf: 
 
 
C O N FI D E N TI A L  
S T U D Y P R O T O C O L 
V er si o n 6. 0 
M ulti c e nt er , d o u bl e -bli n d, pl a c e b o -c o ntr oll e d, r a n d o mi z e d 
wit h dr a w al tri al wit h T a d e ki ni g alf a (r -hI L -1 8 B P) i n p ati e nt s wit h 
I L-1 8 dri v e n m o n o g e ni c a ut oi nfl a m m at or y c o n diti o n s: N L R C 4 
m ut ati o n a n d XI A P d efi ci e n c y   
 
 
S H O R T TI T L E  
T H E R A P E U TI C U S E O F T A D E KI NI G A L F A I N N L R C 4  M U T A TI O N 
A N D  XI A P D E FI CI E N C Y  
D at e:  
0 3  S e p  2 0 2 1  
V er si o n:  
6 . 0 
Pr ot o c ol N° : 
N L R C 4 / XI A P. 2 0 16 .0 0 1  
 
I N D N°: 
E u dr a C T N o:  
 
1 2 7 9 5 3  
2 0 1 8 -0 0 3 2 9 7 -2 7  
 
S p o n s or : 
A B 2  Bi o Lt d  
E P F L I n n o v ati o n P ar k 
B uil di n g B, 4t h fl o or  
C H -1 0 1 5 L a u s a n n e, S wit z erl a n d  
T h e  i nf or m ati o n  c o nt ai n e d  h er ei n  i s  c o nfi d e nti al  a n d  t h e  pr o pri et ar y  pr o p ert y  of  A B 2  Bi o  a n d  a n y  
u n a ut h ori z e d u s e or di s cl o s ur e of s u c h i nf or m ati o n wit h o ut t h e pri or writt e n a ut h ori z ati o n of A B 2 Bi o i s 
e x pr e s sl y pr o hi bit e d  
 
 


 
 
 
P a g e 2 of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
T A B L E O F C O N T E N T S  
1  Li st of A b br e vi ati o n s  ....................................................................................................... 7 
2  C o or di n ati n g I n v e sti g at or Si g n at ur e P a g e  ...................................................................... 9 
3  I n v e sti g at or Pr ot o c ol A gr e e m e nt .................................................................................. 1 0  
4  S p o n s or T e a m Si g n at ur e s P a g e  .................................................................................. 1 1  
5  St u d y C o nt a ct I nf or m ati o n  ............................................................................................ 1 2  
6  S y n o p si s  ....................................................................................................................... 1 3  
7  S c h e d ul e of E v e nt s  ...................................................................................................... 3 2  
8  I ntr o d u cti o n .................................................................................................................. 3 4  
8. 1  
B a c k gr o u n d I nf or m ati o n  .............................................................................................. 3 4  
8. 2  
S u m m ar y of Ri s k s a n d B e n efit s ( R/ B a s s e s s m e nt)  .................................................... 3 6  
8. 3  
Pri m ar y O bj e cti v e s – Effi c a c y  ..................................................................................... 3 7  
8. 3. 1  
Pri m ar y Effi c a c y E n d p oi nt s  ........................................................................... 3 7  
8. 3. 2  
S e c o n d ar y Effi c a c y E n d p oi nt s  ...................................................................... 3 8  
8. 3. 3  
J u stifi c ati o n f or r e vi s e d Effi c a c y E n d p oi nt s  ................................................... 4 1  
8. 4  
S e c o n d ar y O bj e cti v e – Effi c a c y  .................................................................................. 4 2  
8. 4. 1  
Effi c a c y E n d p oi nt s i n t h e S A O L p h a s e  ......................................................... 4 2  
8. 5  
S e c o n d ar y O bj e cti v e – S af et y a n d T ol er a bilit y  ........................................................... 4 2  
8. 5. 1  
S af et y a n d T ol er a bilit y E n d p oi nt s  .................................................................. 4 2  
9  St u d y D e si g n  ................................................................................................................ 4 3  
9. 1  
T y p e of Tri al  ................................................................................................................ 4 3  
9. 2  
P ati e nt s, Gr o u p s a n d C e nt er s  ..................................................................................... 4 7  
9. 3  
E x p e ct e d St u d y D ur ati o n  ............................................................................................ 4 7  
1 0  St u d y P o p ul ati o n  .......................................................................................................... 4 8  
1 0. 1  
D e s cri pti o n  .................................................................................................................. 4 8  
1 0. 2  
P ati e nt I n cl u si o n Crit eri a  ............................................................................................. 4 8  
1 0. 3  
P ati e nt E x cl u si o n Crit eri a  ............................................................................................ 4 9  
1 0. 4  
P ati e nt Wit h dr a w al Crit eri a  .......................................................................................... 5 0  
1 0. 5  
Bli n di n g/ u n bli n di n g Arr a n g e m e nt s  .............................................................................. 5 1  
1 1  St u d y Pr o d u ct  ............................................................................................................... 5 2  
1 1. 1  
St u d y Pr o d u ct D e s cri pti o n  ........................................................................................... 5 2  
1 1. 1. 1  C o m p o siti o n  .................................................................................................. 5 2  
1 1. 1. 2  Q u alit y C o ntr ol  .............................................................................................. 5 2  
1 1. 1. 3  P a c k a gi n g a n d L a b elli n g  ............................................................................... 5 2  
1 1. 2  
St u d y Pr o d u ct A d mi ni str ati o n  ...................................................................................... 5 2  
1 1. 2. 1  A m o u nt, D o s e, C o n c e ntr ati o n, Fr e q u e n c y  .................................................... 5 2  
1 1. 2. 2  R o ut e of A d mi ni str ati o n  ................................................................................. 5 3  


 
 
 
P a g e 3 of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
1 1. 2. 3  P ati e nt C o m pli a n c e  ....................................................................................... 5 4  
1 1. 2. 4  C o n c o mit a nt Tr e at m e nt  ................................................................................. 5 4  
1 1. 3  
St u d y Pr o d u ct H a n dli n g  .............................................................................................. 5 5  
1 1. 3. 1  St or a g e a n d Di stri b uti o n  ................................................................................ 5 5  
1 1. 3. 2  St u d y Pr o d u ct A c c o u nt a bilit y a n d R e c o n cili ati o n  .......................................... 5 5  
1 2  A s s e s s m e nt of Effi c a c y  ................................................................................................ 5 6  
1 2. 1  
D E FI NI TI O N O F R E S P O N S E T O T H E R A P Y  ............................................................. 5 6  
1 2. 2  
D E FI NI TI O N O F DI S E A S E R E A C TI V A TI O N  .............................................................. 5 8  
1 3  A s s e s s m e nt of S af et y  ................................................................................................... 5 9  
1 4  C o n d u ct of t h e St u d y  .................................................................................................... 6 0  
1 4. 1  
S c h e d ul e of E v e nt s  ..................................................................................................... 6 0  
1 4. 2  
P ati e nt R e cr uit m e nt - S cr e e ni n g Vi sit ( b ef or e tr e at m e nt st art at V 1)  .......................... 6 0  
1 4. 3  
B a s eli n e vi sit at W e e k 0 ( V 1 - Tr e at m e nt I niti ati o n) – S A O L P h a s e  ............................ 6 1  
1 4. 4  
Vi sit s at W e e k s 1, 2, 3 ( V 2/ D a y 7, V 3/ D a y 1 4, V 4/ D a y 2 1)  ......................................... 6 2  
1 4. 5  
Vi sit at W e e k 4 ( V 5/ D a y 2 8)  ........................................................................................ 6 2  
1 4. 6  
Vi sit s at W e e k 8, 1 2 ( V 6/ D a y 5 6, V 7/ D a y 8 4) – M o nt hl y Vi sit s  ................................... 6 3  
1 4. 7  
Vi sit at W e e k 1 8 ( V 8/ D a y 1 2 6): E n d of S A O L P h a s e/ St art of R W P h a s e  ................... 6 3  
1 4. 8  
Vi sit s at W e e k s 2 0, 2 2, 2 6, 3 0 ( V 9/ D a y 1 4 0, V 1 0/ D a y 1 5 4, V 1 1/ D a y 1 8 2, V 1 2/ D a y 2 1 0)
 
6 4  
1 4. 9  
St u d y C o m pl eti o n Vi sit at W e e k 3 4 ( V 1 3/ D a y 2 3 8)/ St u d y C o m pl eti o n f or P ati e nt s 
e x p eri e n ci n g di s e a s e r e a cti v ati o n s d uri n g R W/ E arl y T er mi n ati o n f or Di s c o nti n u e d P ati e nt s: 6 4  
1 4. 1 0  C LI NI C A L L A B O R A T O R Y T E S T S  .............................................................................. 6 5  
1 5  D at a M a n a g e m e nt  ........................................................................................................ 6 7  
1 5. 1  
D at a C oll e cti o n  ............................................................................................................ 6 7  
1 6  St ati sti c s  ....................................................................................................................... 6 8  
1 6. 1  
G e n er al C o n si d er ati o n s  .............................................................................................. 6 8  
1 6. 2  
I nt eri m A n al y si s ........................................................................................................... 6 8  
1 6. 3  
S a m pl e Si z e C al c ul ati o n s  ........................................................................................... 6 8  
1 6. 4  
P ati e nt Tr e at m e nt R a n d o mi z ati o n  ............................................................................... 7 0  
1 6. 5  
D at a s et s f or A n al y si s  .................................................................................................. 7 0  
1 6. 6  
St ati sti c al A n al y si s  ...................................................................................................... 7 0  
1 6. 6. 1  R a n d o m iz e d wit h dr a w al p h a s e  ..................................................................... 7 0  
1 6. 6. 2  S A O L P h a s e  ................................................................................................. 7 1  
1 6. 7  
S u b gr o u p A n al y si s  ...................................................................................................... 7 1  
1 6. 8  
Wit h dr a w al s, Dr o p -o ut s, Mi s si n g V al u e s  ..................................................................... 7 1  
1 7  H a n dli n g of A d v er s e E v e nt s  ......................................................................................... 7 2  
1 7. 1  
N o n -S eri o u s a n d S eri o u s A d v er s e E v e nt s  .................................................................. 7 2  
1 7. 2  
D efi niti o n of a n A d v er s e E v e nt ( A E)  ............................................................................ 7 2  
1 7. 3  
D efi niti o n of a S eri o u s A d v er s e E v e nt ( S A E)  .............................................................. 7 5  
1 7. 4  
Ot h er R e p ort a bl e I nf or m ati o n.  ..................................................................................... 7 5  


 
 
 
P a g e 4 of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
1 7. 5  
M e di c ati o n Err or s  ........................................................................................................ 7 6  
1 7. 6  
Cli ni c al L a b or at or y A b n or m aliti e s a n d Ot h er A b n or m al A s s e s s m e nt s  ........................ 7 6  
1 7. 7  
R e c or di n g of A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s  ....................................... 7 8  
1 7. 7. 1  S e v erit y of A d v er s e E v e nt  ............................................................................. 7 9  
1 7. 7. 2  C a u s alit y of A d v er s e E v e nt ( A E)  ................................................................... 8 0  
1 7. 7. 3  A d v er s e E v e nt O ut c o m e s  ............................................................................. 8 0  
1 7. 7. 4  A cti o n T a k e n wit h t h e St u d y Dr u g  ................................................................. 8 1  
1 7. 7. 5  F oll o w -u p of A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s  .......................... 8 1  
1 7. 7. 6  P o st- st u d y A d v er s e E v e nt s or S eri o u s A d v er s e E v e nt s  ................................ 8 1  
1 7. 8  
R e p orti n g R e q uir e m e nt s f or S A E s  .............................................................................. 8 1  
1 7. 8. 1  R e p orti n g of All S A E s a n d A E s R e s ulti n g i n Wit h dr a w al fr o m t h e St u d y  ...... 8 1  
1 7. 8. 2  U n e x p e ct e d or E x p e ct e d S A E  ....................................................................... 8 2  
1 7. 9  
R e p orti n g a n d D o c u m e nt ati o n  .................................................................................... 8 3  
1 7. 1 0  P ati e nt E m er g e n c y C o nt a ct C ar d  ................................................................................ 8 3  
1 7. 1 1  N otifi c ati o n  .................................................................................................................. 8 3  
1 7. 1 2  S af et y R e p orti n g  ......................................................................................................... 8 3  
1 8  L e g al a n d Et hi c al Pr er e q ui sit e s  .................................................................................... 8 4  
1 8. 1  
L e g al R e q uir e m e nt s  .................................................................................................... 8 4  
1 8. 2  
Et hi c al A s p e ct s  ............................................................................................................ 8 4  
1 8. 2. 1  Pr ot e cti o n of t h e P ati e nt' s C o nfi d e nti alit y  ...................................................... 8 4  
1 8. 2. 2  I nf or m e d C o n s e nt .......................................................................................... 8 4  
1 8. 2. 3  I n stit uti o n al R e vi e w B o ar d/ Et hi c s C o m mitt e e A p pr o v al ................................ 8 4  
1 8. 2. 4  D e cl ar ati o n of H el si n ki  .................................................................................. 8 4  
1 9  Q u alit y C o ntr ol a n d Q u alit y A s s ur a n c e  ......................................................................... 8 5  
1 9. 1  
M o nit ori n g  ................................................................................................................... 8 5  
1 9. 2  
S o ur c e D o c u m e nt s  ...................................................................................................... 8 5  
1 9. 3  
Q u alit y C o ntr ol  ............................................................................................................ 8 5  
1 9. 3. 1  Q u alit y C o ntr ol of E s s e nti al D o c u m e nt s  ........................................................ 8 5  
1 9. 3. 2  C o -m o nit ori n g  ................................................................................................ 8 5  
1 9. 4  
A u di t s a n d I n s p e cti o n s ................................................................................................ 8 5  
1 9. 5  
R e s p o n si biliti e s of I n v e sti g at or  .................................................................................... 8 5  
2 0  St u d y E n d Pr o c e d ur e s  ................................................................................................. 8 7  
2 0. 1  
Pr e m at ur e T er mi n ati o n of St u d y  ................................................................................. 8 7  
2 0. 2  
T er mi n ati o n of St u d y  ................................................................................................... 8 7  
2 0. 3  
E n d of Tri al  .................................................................................................................. 8 7  
2 1  P u bli c ati o n s  .................................................................................................................. 8 8  
2 2  C o nfi d e nti alit y  ............................................................................................................... 8 8  
R ef er e n c e s  ........................................................................................................................ 8 9  
A P P E N DI X 1:  M O DI FI E D A U T O -I N F L A M M A T O R Y DI S E A S E A C TI VI T Y I N D E X ........... 9 1  
A P P E N DI X 2:  L O C A L T O L E R A BI LI T Y I N D E X  ................................................................. 9 2  


 
 
 
P a g e 5 of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
A P P E N DI X 3:  P H Y SI CI A N G L O B A L A S S E S S M E N T O F DI S E A S E -R E L A T E D 
( A U T OI N F L A M M A T O R Y) S Y M P T O M S - Q U E S TI O N S F O R I N V E S TI G A T O R S  .............. 9 3  
A P P E N DI X 4:  D E C L A R A TI O N O F H E L SI N KI  .................................................................. 9 5  
A P P E N DI X 5:  E X A M P L E P A TI E N T E M E R G E N C Y C O N T A C T C A R D  .......................... 1 0 0  
 
 


 
 
 
P a g e 6 of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
LI S T O F T A B L E S  
T a bl e 1 : S c h e d ul e of E v e nt s  ................................................................................................................ 3 2  
T a bl e 2:  Cli ni c al L a b or at or y T e st s  ....................................................................................................... 6 6  
T a bl e 3:  Sit e R e a cti o n s t o I nj e cti o n s a n d I nf u si o n s  ............................................................................. 7 4  
T a bl e 4:  Gr a di n g of a d v er s e e v e nt s d u e t o l o w l e v el s of Cr e ati ni n e Cl e ar a n c e or e G F R  ................... 7 7  
T a bl e 5:  Gr a di n g of a d v er s e e v e nt s d u e t o l o w l e v el s of h e m o gl o bi n  ................................................. 7 7  
T a bl e 6:  Gr a di n g of a d v er s e e v e nt s d u e t o l o w l e v el s of w hit e bl o o d c ell s  ......................................... 7 8  
T a bl e 7:  Gr a di n g of a d v er s e e v e nt s d u e t o l o w l e v el s of n e utr o p hil s  .................................................. 7 8  
 
LI S T O F FI G U R E S  
Fi g ur e 1:  P o w er v s. H a z ar d R ati o  ....................................................................................................... 3 1  
Fi g ur e 2  P o w er v s. H a z ar d R ati o  ........................................................................................................ 6 9  
 
LI S T O F A P P E N DI C E S  
A P P E N DI X 1:  M O DI FI E D A U T O -I N F L A M M A T O R Y DI S E A S E A C TI VI T Y I N D E X ............................. 9 1  
A P P E N DI X 2:  L O C A L T O L E R A BI LI T Y I N D E X  ................................................................................... 9 2  
A P P E N DI X 3:  P H Y SI CI A N G L O B A L A S S E S S M E N T O F DI S E A S E -R E L A T E D 
( A U T OI N F L A M M A T O R Y) S Y M P T O M S - Q U E S TI O N S F O R I N V E S TI G A T O R S  ............................... 9 3  
A P P E N DI X 4:  D E C L A R A TI O N O F H E L SI N KI  .................................................................................... 9 5  
A P P E N DI X 5:  P A TI E N T E M E R G E N C Y C O N T A C T C A R D  .............................................................. 1 0 0  
 
 
 
 
 


 
 
 
P a g e 7 of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
1 
LI S T O F A B B R E VI A TI O N S  
A b br e vi ati o n  
D efi niti o n/ T er m  
A C R 2 0, A C R 5 0  
A m eri c a n S c or e of R h e u m at ol o g y ( s c or e of r h e u m at oi d art hriti s i m pr o v e m e nt b y 
2 0 %, 5 0 % …)   
A D A  
A nti -Dr u g A nti b o d y  
A E  
A d v er s e E v e nt  
A E SI  
A d v er s e E v e nt of S p e ci al I nt er e st  
A L P 
Al k ali n e P h o s p h at a s e  
A N C O V A  
A n al y si s of c o v ari a n c e  
a nti- r hI L-1 8 B P  
A nti -re c o m bi n a nt H u m a n I nt erl e u ki n -1 8 Bi n di n g Pr ot ei n  
A O S D  
A d ult o n s et Still’ s Di s e a s e  
A U C  
Ar e a u n d er t h e c o n c e ntr ati o n -ti m e c ur v e  
Bf Ar M  
B u n d e si n stit ut f ür Ar z n ei mitt el u n d M e di zi n pr o d u kt e ( G er m a n H e alt h A ut h orit y)  
C 
C el si u s  
C A P S  
Cr y o p yri n -A s s o ci at e d P eri o di c S y n dr o m e s  
C m a x  
M a xi m al c o n c e ntr ati o n  
C A R D  
C a s p a s e  R e cr uiti n g D o m ai n  
C o n m e d  
C o n c o mit a nt M e di c ati o n  
C M V  
C yt o m e g al o vir u s  
C R F  
C a s e R e p ort F or m  
C R O  
Cli ni c al R e s e ar c h Or g a ni z ati o n  
C R P  
C- r e a cti v e p r ot ei n 
C T C A E  
C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt  
DI R A  
D efi ci e n c y of I L -1 R e c e pt or A nt a g o ni st  
D M A R D  
D i s e a s e M o dif yi n g A nti-r h e u m ati c Dr u g 
D S G C S  
Di s e a s e S p e cifi c  Gl o b al C o m p o sit e S c or e  
D S M B  
D at a S af et y M o nit ori n g B o ar d  
E B V  
E p st ei n -B arr Vir u s  
E C  
Et hi c s C o m mitt e e  
e C C G  
e C R F C o m pl eti o n G ui d eli n e s  
E C G  
El e ctr o c ar di o gr a m  
e C R F  
El e ctr o ni c C a s e R e p ort F or m  
E D C  
El e ctr o ni c D at a C a pt ur e  
E S R  
Er yt hr o c yt e S e di m e nt ati o n R at e  
F A S 
F ull A n al y si s S et  
F D A 
F o o d a n d Dr u g A d mi ni str ati o n  
F H L 
F a mili al H e m o p h a g o c yti c L y m p h o hi sti o c yt o si s  
F P F V 
Fir st P ati e nt Fir st Vi sit  
G C P  
G o o d Cli ni c al Pr a cti c e  
G F R 
Gl o m er ul ar filtr ati o n r at e  
G G T  
G a m m a -gl ut a m yl Tr a n sf er a s e  
GI  
G a str oi nt e sti n al  
G M P  
G o o d M a n uf a ct uri n g Pr a cti c e  
H A Q -DI  
H e alt h A s s e s s m e nt Q u e sti o n n air e Di s a bilit y I n d e x  
H C N  
H o m e C ar e N ur s e  
H C V  
H e p atiti s C vir u s  
H B V  
H e p atiti s B vir u s  
HI V  
H u m a n I m m u n o d efi ci e n c y Vir u s  
H L H  
H e m o p h a g o c yti c -L y m p h o hi sti o c yt o si s  
i. p. 
I ntr a p erit o n e al I nj e cti o n 
I C F 
I nf or m e d C o n s e nt F or m 
I E C 
I n d e p e n d e nt Et hi c s C o m mitt e e 
I F N-Υ  
I nt erf er o n g a m m a  
I L-1 8  
I nt erl e u ki n-1 8  
I L-1 8 B P  
I nt erl e u ki n-1 8 bi n di n g pr ot ei n  
I N D 
I n v e sti g ati o n al N e w Dr u g  
I M P 
I n v e sti g ati o n al M e di ci n al Pr o d u ct  
I R B 
I n stit uti o n al R e vi e w B o ar d 


 
 
 
P a g e 8 of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
I R R 
I n ci d e n c e R at e R e d u cti o n 
I U D 
I ntr a ut eri n e D e vi c e 
I U S 
I ntr a ut eri n e H or m o n e-r el e a si n g S y st e m 
K d  
Di s s o ci ati o n c o n st a nt  
k D  
Kil o d alt o n  
K g  
Kil o gr a m  
L P L V 
L a st P ati e nt L a st Vi sit  
m AI D AI  
M o difi e d A ut oi nfl a m m at or y Di s e a s e A cti vit y I n d e x  
M A S  
M a cr o p h a g e A cti v ati o n S y n dr o m e  
M e d D R A  
M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s  
m g  
Milli gr a m  
mi n  
Mi n ut e  
m L  
Millilit er   
N CI  
N ati o n al C a n c er I n stit ut e  
n g  
N a n o gr a m  
N L R C 4  
 N u cl e oti d e -bi n di n g oli g o m eri z ati o n d o m ai n,  l e u ci n e ri c h r e p e at a n d C A R D 
d o m ai n c o nt ai ni n g 4   
M RI  
M a g n eti c R e s o n a n c e I m a gi n g  
N S AI D  
N o n -St er oi d al A nti -I nfl a m m at or y Dr u g 
p g 
Pi c o gr a m  
P B O  
Pl a c e b o  
P D  
P h ar m a c o d y n a mi c  
P G A  
P h y si ci a n Gl o b al A s s e s s m e nt  
P K  
P h ar m a c o ki n eti c  
P M  
Pr oj e ct M a n a g er   
P O  
P er o s ( b y m o ut h)  
P P S  
P er -Pr ot o c ol d at a s et  
P s o  
P s ori a si s  
P T  
Pr ot hr o m bi n Ti m e  
P T T  
P arti al T hr o m b o pl a sti n Ti m e  
P T  
Pr ef err e d T er m  
Q O L  
Q u alit y of lif e  
R A  
R h e u m at oi d Art hriti s  
r-hI L -1 8 B P  
H u m a n R e c o m bi n a nt I nt erl e u ki n -1 8 Bi n di n g Pr ot ei n  
R W  
R a n d o mi z e d Wit h dr a w al  
s. c.  
S u b c ut a n e o u s  
S A E  
S eri o u s A d v er s e E v e nt  
S A P  
St ati sti c al A n al y si s Pl a n  
S A S  
S af et y A n al y si s d at a s et  
S D  
St a n d ar d D e vi ati o n  
S D AI  
Si m pl e Di s e a s e A cti vit y I n d e x  
S D V  
S o ur c e D at a V erifi c ati o n  
SI V  
Sit e I niti ati o n Vi sit  
S O C  
St a n d ar d of C ar e  
S U S A R  
S eri o u s U n e x p e ct e d S u s p e ct e d A d v er s e R e a cti o n  
T B 
T u b er c ul o si s  
T h 1 / T h 1 7 c ell  
T h el p er c ell t y p e 1 / t y p e 1 7  
T m a x  
Ti m e t o M a xi m al C o n c e ntr ati o n  
T N F- α  
T u m or N e cr o si s F a ct or α  
U L N  
U p p er Li mit of N or m al  
U P T  
Uri n e Pr e g n a n c y T e st  
V 
Vi sit  
W B C  
W hit e Bl o o d C ell s  
XI A P  
X- li n k e d i n hi bit or of a p o pt o si s 
μ L  
Mi cr olit er  




 
 
 
P a g e 1 0  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
3   I N V E S TI G A T O R P R O T O C O L A G R E E M E N T 
 
Pr ot o c ol Titl e:  
M ulti c e nt er, d o u bl e -bli n d, pl a c e b o -c o ntr oll e d, r a n d o mi z e d wit h dr a w al tri al 
wit h T a d e ki ni g alf a (r -hI L -1 8 B P) i n p ati e nt s wit h I L -1 8 dri v e n m o n o g e ni c 
a ut oi nfl a m m at or y c o n diti o n s: N L R C 4 m ut ati o n a n d XI A P d efi ci e n c y  
  
  
 
Pr ot o c ol N u m b er: N L R C 4/ XI A P. 2 0 1 6. 0 0 1  
                                  
 
B y m y si g n at ur e, I c o nfir m t h at m y st aff a n d I h a v e c ar ef ull y r e a d a n d u n d er st a n d t hi s pr ot o c ol or 
pr ot o c ol a m e n d m e nt, a n d a gr e e t o c o m pl y wit h t h e c o n d u ct a n d t er m s of t h e st u d y s p e cifi e d. F or 
pr ot o c ol a m e n d m e nt s, I a gr e e n ot t o i m pl e m e nt t h e a m e n d m e nt wit h o ut a gr e e m e nt fr o m t h e S p o n s or 
a n d pri or s u b mi s si o n t o a n d writt e n a p pr o v al ( w h er e r e q uir e d) fr o m t h e I n d e p e n d e nt Et hi c s 
C o m mitt e e (I E C), or t h eir e q ui v al e nt, a n d r e g ul at or y a ut h orit y, e x c e pt w h e n n e c e s s ar y t o eli mi n at e a n 
i m m e di at e h a z ar d t o t h e p ati e nt s, or f or a d mi ni str ati v e a s p e ct s of t h e st u d y ( w h er e p er mitt e d b y all 
a p pli c a bl e r e g ul at or y r e q uir e m e nt s).  
 
 
 
I n v e sti g at or’ s N a m e  
 
 
 
 
 
I n stit uti o n N a m e, A d dr e s s,  
C o nt a ct D et ail s  
 
 
 
 
 
 
 
I n v e sti g at or’ s Si g n at ur e 
 
D at e  
 
 
 
 






 
 
 
P a g e 1 3  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
6 
S Y N O P SI S  
 
N A M E O F S P O N S O R : A B 2 BI O Lt d . 
N A M E O F S T U D Y D R U G: T A D E KI NI G A L F A  
H u m a n R e c o m bi n a nt I nt erl e u ki n-1 8 Bi n di n g Pr ot ei n ( r-h I L-1 8 B P)  
P R O T O C O L N° : N L R C 4/ XI A P. 2 0 1 6. 0 0 1  
TI T L E O F S T U D Y  
M ulti c e nt er, d o u bl e -bli n d, pl a c e b o -c o ntr oll e d, r a n d o mi z e d wit h dr a w al tri al wit h T a d e ki ni g alf a (r -
hI L -1 8 B P) i n p ati e nt s wit h I L -1 8 dri v e n m o n o g e ni c a ut oi nfl a m m at or y c o n diti o n s: N L R C 4 m ut ati o n 
a n d XI A P d efi ci e n c y  
 
D E V E L O P M E N T P H A S E : 3 
S T U D Y D E SI G N                    
T hi s i s a P h a s e 3 st u d y t o a s s e s s t h e s af et y a n d effi c a c y of T a d e ki ni g alf a i n 
p ati e nt s wit h m o n o g e ni c, i nt erl e u ki n -1 8 (I L -1 8) dri v e n a ut oi nfl a m m ati o n d u e 
t o  N u cl e oti d e-bi n di n g  oli g o m eri z ati o n  d o m ai n,  l e u ci n e -ri c h  r e p e at  a n d  
c a s p a s e  r e cr uiti n g  d o m ai n  ( C A R D  d o m ai n) c o nt ai ni n g  4  ( N L R C 4)  – 
M a cr o p h a g e a cti v ati o n s y n dr o m e ( M A S ) m ut ati o n  ( N L R C 4-M A S m ut ati o n)  or 
X- li n k e d i n hi bit or of a p o pt o si s ( XI A P) d efi ci e n c y. B e c a u s e of t h e li k eli h o o d f or 
p at h o g e ni c I L -1 8 i n c ert ai n m o n o g e ni c di s e a s e s, p ati e nt s k n o w n t o h ar b or 
d el et eri o u s m ut ati o n s i n N L R C 4 -M A S or XI A P a n d w h o h a v e a hi st or y of 
o n g oi n g i nfl a m m ati o n will b e e nr oll e d if t h e y h a v e f erriti n ≥ 5 0 0 n g/ m L or 
p er si st e nt  C -r e a cti v e  pr ot ei n  ( C R P)  el e v ati o n  > 2  ti m e s  t h e  u p p er  li mit  of  
n or m al  ( U L N)  a n d  t h e  p ati e nt s  s h o ul d  h a v e  a  M o difi e d  A ut oi nfl a m m at or y  
Di s e a s e A cti vit y I n d e x ( m AI D AI) ≥ 4. 
T h e  st u d y  i s  d e si g n e d  wit h  a si n gl e -ar m,  o p e n -l a b el  p h a s e  ( S A O L)  of  
T a d e ki ni g  alf a  tr e at m e nt  d ur ati o n  f or  1 8 -w e e k s f oll o w e d  b y  a  1 6 -w e e k 
R a n d o mi z e d W it h dr a w al ( R W) p h a s e  f or effi c a c y a n d s af et y e v al u ati o n, wit h 
n o i nt err u pti o n b et w e e n t h e t w o p h a s e s of tr e at m e nt . 
T h e s cr e e ni n g p eri o d will  o c c ur  b ef or e t h e S A O L p h a s e a n d b ef or e t h e fir st 
d o s e  of I n v e sti g ati o n al M e di ci n al Pr o d u ct (I M P). 
M et h o d ol o g y  
•  
Si n gl e -ar m, o p e n -l a b el P h a s e  
T h e S cr e e ni n g vi sit ( V 0) will o c c ur b ef or e t h e st art of t h e st u d y tr e at m e nt . At 
V 0, t h e p ati e nt a n d/ or t h e p ati e nt’ s l e g al g u ar di a n( s) will si g n a C hil d A s s e nt 
F or m  a n d/ or  a n  I nf or m e d  C o n s e nt  F or m  t h at  will  b e  c oll e ct e d  b y  t h e  
I n v e sti g at or. All eli gi bilit y crit eri a will b e r e vi e w e d d uri n g t h e s cr e e ni n g p eri o d 
A N D m u st all b e m et i n or d er t o d et er mi n e p ati e nt eli gi bilit y i nt o t h e st u d y. 
Eli gi bilit y crit eri a s h o ul d b e c o nfir m e d a g ai n at t h e B a s eli n e Vi sit ( V 1) . 
P ati e nt s e x p eri e n ci n g a n a cti v e di s e a s e  will st art T a d e ki ni g alf a tr e at m e nt at 
V 1. 
B e gi n ni n g at V 1, T a d e ki ni g alf a  ( T A) will b e a d mi ni st er e d  i n a d diti o n t o t h e 
st a n d ar d of c ar e ( S O C) tr e at m e nt u s e d f or t h e c o ntr ol of t h e a cti v e di s e a s e. 


 
 
 
P a g e 1 4  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
I n  t h e  a b s e n c e  of  a n  a p pr o v e d  m e di c ati o n  f or  t hi s  di s e a s e,  t h e  S O C  a s 
d efi n e d  i n  t hi s  pr ot o c ol  c o n si st s  of  gl u c o c orti c oi d s  ( G C), wit h  a  2 8 -d a y  
t a p eri n g s c h e d ul e a s f oll o w s:  
•  
2 8 -d a y s ( 4 w e e k s ): D ail y P O/ I V D e x a m et h a s o n e 1 0 m g/ m 2 x 7 d a y s, 
5 m g/ m 2 x 7 d a y s, 2. 5 m g/ m 2 x 7 d a y s, 1. 2 5 m g/ m 2 x 7 d a y s  
P ati e nt s w h o  r e s p o n d t o t h e i niti al T A + G C 2 8-d a y c o ur s e ( s e e D efi niti o n of 
P arti al a n d C o m pl et e R e s p o n s e t o T h er a p y ) will r e c ei v e T a d e ki ni g alf a f or 1 4 
a d diti o n al w e e k s . 
P ati e nt s  w h o  r e s p o n d e d  t o  T A  +  S O C  i niti al  c o ur s e  a n d  h a v e  a  di s e a s e  
r e a cti v ati o n a g ai n d uri n g t h e c o ur s e of t h e st u d y will r e c ei v e a n ot h er c o ur s e 
of T A + S O C wit h t h e s a m e G C d o s a g e a n d t a p eri n g s c h e d ul e u s e d f or t h e 
i niti al tr e at m e nt of t h e a cti v e di s e a s e ( s e e e x pl a n ati o n s b el o w ). M ai nt e n a n c e 
tr e at m e nt, wit h t h e p er mitt e d m e di c ati o n s, at st a bl e a n d at t h e s a m e d o s e s 
utili z e d at st u d y e ntr y ar e all o w e d. D o s e i n cr e m e nt s f or t h e p er mitt e d c o -
m e di c ati o n s  or  t h eir  i ntr o d u cti o n  aft er  t h e  b e gi n ni n g  of  t h e  st u d y  ar e  n ot  
p er mitt e d  a n d  r e pr e s e nt  tr e at m e nt  f ail ur e s  a n d  st u d y  e arl y  t er mi n ati o n.  If  
p er mitt e d c o -m e di c ati o n s ar e w e a n e d off d uri n g t h e c o ur s e of t h e st u d y a n d 
t h e i n v e sti g at or d e ci d e s t o r e-i ntr o d u c e t h e m, t h e y ar e p er mitt e d a s l o n g a s 
t h e d o s e s ar e t h e s a m e or l o w er t h a n t h e d o s e s u s e d at st u d y e ntr y.  
U p o n l a c k of r e s p o n s e t o c o m bi n e d tr e at m e nt aft er e nr oll m e nt or u p o n t h e 
o c c urr e n c e of a di s e a s e r e a cti v ati o n  d uri n g t h e c o ur s e of t h e S A O L aft er 
i niti al r e s p o n s e, t h e i n v e sti g at or m a y d e ci d e t o tr e at t h e p ati e nt wit h r e s c u e 
i m m u n o s u p pr e s s or s. T hi s d e ci si o n r e s ult s i n p ati e nt di s c o nti n u ati o n f or t h e 
st u d y.  
T a d e ki ni g alf a  will b e a d mi ni st er e d a t 2 m g/ k g s u b c ut a n e o u sl y ( s. c. ) f or u p t o 
a p pr o xi m at el y 1 8 w e e k s .  
At V 0 a n d V 1, p ati e nt s will u n d er g o a p h y si c al e x a mi n ati o n, m e a s ur e m e nt of 
vit al  si g n s,  a n d  r o uti n e  l a b or at or y  t e sti n g  (i n cl u di n g  h e m at ol o g y,  cli ni c al  
c h e mi str y,  uri n al y si s,  er yt hr o c yt e  s e di m e nt ati o n  r at e  ( E S R),  C R P,  a n d  
c o a g ul ati o n  p a n el).  Bi ol o gi c al  e v al u ati o n  a n d  g e n eti c  di a g n o si s  of  
a ut oi nfl a m m at or y  c o n diti o n s  ( N L R C 4 -M A S,  XI A P  d efi ci e n c y,  a n d  ot h er  
m o n o g e ni c a s s o ci ati o n s wit h M a cr o p h a g e A cti v ati o n S y n dr o m e [ M A S]) will 
b e  d o n e  at  V 0.  S a m pl e s  f or   fl o w  c yt o m etr y  will  b e  a n al y z e d  d uri n g  t h e  
s cr e e ni n g p eri o d  a n d pri or t o V 1 . C o m pl et e m e di c al a n d di s e a s e hi st or y will 
al s o  b e  c oll e ct e d  d uri n g  V 0.  I n  a d diti o n,  pri or  t o  i niti ati o n  of  t h er a p y,  
c yt o m e g al o vir u s ( C M V) a n d E p st ei n -B arr vir u s ( E B V) t e st s, s er ol o g y t e st s, 
a n d a c o m pl et e i nf e cti o u s w or k u p will b e p erf or m e d.  
S p e cifi c l a b or at or y d et er mi n ati o n s s u c h a s t ot al a n d fr e e I L -1 8 a n d I L - 1 8 B P 
will b e p erf or m e d at V 1 a n d s u b s e q u e nt vi sit s.  
T h e gl o b al di s e a s e a cti vit y will b e a s s e s s e d b y t h e m AI D AI. T h e m AI D AI will 
b e a p pli e d at all st u d y vi sit s a n d will b e a v ail a bl e f or r e vi e w t hr o u g h o ut t h e 
st u d y. F or t h e e v al u ati o n of r e s p o n s e t o t h er a p y a n d di s e a s e r e a cti v ati o n, 
o nl y t h e o bj e cti v e p ar a m et er s of t h e m AI D AI will b e t a k e n i nt o c o n si d er ati o n. 
A P h y si ci a n Gl o b al A s s e s s m e nt ( P G A) t o ol will  al s o  b e a p pli e d at all st u d y 
vi sit s b y t h e p h y si ci a n t o a s s e s s t h e gl o b al di s e a s e st at u s . T h e  p ati e nt ’ s or 
c ar e gi v er ’ s e v al u ati o n  of t h e h e alt h  st at u s q u e sti o n n air e  will b e a p pli e d at V 1 


 
 
 
P a g e 1 5  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
a n d t h e e n d of t h e S A O L p h a s e.  
A s s e s s m e nt s d uri n g t h e S A O L p h a s e, tr e at m e nt p eri o d of 1 8 w e e k s ( V 1 t o 
V 8) , will i n cl u d e c o m pl et e p h y si c al e x a mi n ati o n, r e vi e w of all a d v er s e e v e nt s 
( A E s), a n d r o uti n e a n d s p e cifi c l a b or at or y a n al y si s (f or f urt h er d et ail s, r ef er 
t o t h e s af et y a n d effi c a c y a s s e s s m e nt s e cti o n).  
S a m pl e s  f or  a nti -dr u g  a nti b o di e s  ( A D A s)  will  b e  c oll e ct e d  at  B a s eli n e  of  
S A O L ( V 1), W e e k 2 ( V 3), W e e k 4 ( V 5), W e e k 1 2 ( V 7), a n d W e e k 1 8 ( V 8).  
At t h e e n d of t h e S A O L p h a s e, all p ati e nt s w h o c o m pl et e d t h e p h a s e  wit h a 
p arti al or c o m pl et e r e s p o n s e  at V 8 will b e e nr oll e d i n t h e R W  p h a s e.  
•  
R a n d o mi z e d Wit h dr a w al ( R W) P h a s e  
All p ati e nt s w h o h a v e c o m pl et e d 1 8 w e e k s of tr e at m e nt d uri n g t h e S A O L 
p h a s e a n d s h o wi n g a p arti al or c o m pl et e r e s p o n s e  at W e e k 1 8 ( V 8) will b e 
bli n dl y r a n d o mi z e d t o o n e of t h e t w o tr e at m e nt ar m s i n a 1: 1 r ati o t o b e gi n 
tr e at m e nt i n t h e R W p h a s e.  W e e k 1 8 will b e t h e b a s eli n e of t h e R W p h a s e.  
E x p eri e n ci n g a di s e a s e r e a cti v ati o n  at a n y p oi nt d uri n g t h e 1 8 -w e e k S A O L 
p h a s e will n ot pr e v e nt a s u bj e ct fr o m e nr oll m e nt i nt o t h e R W p h a s e; r at h er, 
p ati e nt s ar e r e q uir e d t o m e et t h e crit eri a f or o n g oi n g T A tr e at m e nt t hr o u g h o ut 
t h e  S A O L  p h a s e  a n d  s h o w  a  p arti al  or  c o m pl et e  r e s p o n s e at  W e e k  1 8.  
P ati e nt s will r e c ei v e t h e st u d y tr e at m e nt ( pl a c e b o or T A ) f or u p t o a d diti o n al 
1 6 w e e k s. R e si d u al c o m p o n e nt s of di s e a s e m a y b e pr e s e nt b ut if t h e y still 
m e et t h e d efi niti o n of at l e a st p arti al r e s p o n s e,  p ati e nt s will b e e nr oll e d i n t h e 
R W p h a s e.  
T r e at m e nt  i nt err u pti o n  i s  n ot r e c o m m e n d e d  b et w e e n  t h e  t w o  p h a s e s.  
B a s eli n e  d at a  f or t h e  R W  p h a s e will 
b e  t h e  d at a  c oll e ct e d  pri or  t o  
r a n d o mi z ati o n at t h e W e e k 1 8 ( V 8) vi sit.  
D uri n g t h e R W p h a s e , vi sit s will b e s c h e d ul e d  at  W e e k 2 0 ( V 9), W e e k 2 2 
( V1 0) , W e e k 2 6 ( V 1 1 ), W e e k 3 0 ( V 1 2) a n d W e e k 3 4 ( V 1 3/ E n d of St u d y) .  
At  R W  vi sit s , p ati e nt s  will  u n d er g o  a  c o m pl et e  p h y si c al  e x a mi n ati o n  a n d  
l a b or at or y t e sti n g (i n cl u di n g h e m at ol o g y, cli ni c al c h e mi str y, uri n al y si s, E S R, 
C R P, f err iti n, a n d c o a g ul ati o n p a n el), d et er mi n ati o n s of t ot al a n d fr e e I L-1 8 
a n d of I L -1 8 B P . T h e m AI D AI a n d P G A will b e a p pli e d at all vi sit s i n t h e R W 
p h a s e.  T h e  p ati e nt ’ s or  c ar e gi v er ’ s e v al u ati o n  of  t h e  h e alt h  st at u s 
q u e sti o n n air e  will b e a p pli e d at t h e e n d of t h e R W p h a s e.  
S a m pl e s f or a nti -dr u g a nti b o di e s ( A D A s ) will b e c oll e ct e d at R W W e e k 2 2 
( V 1 0), W e e k 2 6 ( V 1 1) , a n d W e e k 3 4 ( V 1 3). 
D uri n g  t h e  R W  p h a s e,  p ati e nt s  w h o  d e v el o p  a  p arti al  or  f ull  di s e a s e  
r e a cti v ati o n b ef or e t h e 1 6 -w e e k tr e at m e nt  i s c o m pl et e d will pr o c e e d t o t h e 
E n d of St u d y vi sit a n d c o m pl et e t h e R W p h a s e.  Th e i n v e sti g at or m a y al s o 
d e ci d e t o st art r e s c u e i m m u n o s u p pr e s si o n a n d di s c o nti n u e tr e at m e nt . 
If  a p pli c a bl e,  d at a  o n  a d mi ni str ati o n  of  ot h er  m e di c ati o n s  or  r e s c u e  
i m m u n o s u p pr e s si o n d uri n g b ot h p h a s e s ( S A O L a n d R W) will b e c oll e ct e d, 
i n cl u di n g t h e ti m e of tr e at m e nt st art a n d fi ni s h a n d w h et h er or n ot t h er e w a s 
a r e s p o n s e t o t h e r e s c u e tr e at m e nt.   


 
 
 
P a g e 1 6  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
P ati e nt s w h o  di s c o nti n u e tr e at m e nt pri or t o t h e e n d of eit h er tr e at m e nt p h a s e 
( S A O L or R W)  will b e f oll o w e d f or all k e y effi c a c y a n d s af et y a s s e s s m e nt s.  
N O T E: T h e F D A dr aft g ui d a n c e ( E nri c h m e nt Str at e gi e s f or Cli ni c al Tri al s t o 
S u p p ort A p pr o v al of H u m a n Dr u g s a n d Bi ol o gi c al Pr o d u ct s , D e c e m b er 2 0 1 2) 
i n di c at e s  t h at  t h e  R W  d e si g n  s h o ul d  i n cl u d e  p ati e nt s  w h o  d e m o n str at e d 
tr e at m e nt r e s p o n s e.  
 
•  
A d diti o n al St a n d ar d of C ar e C y cl e s or R e s c u e I m m u n o s u p pr e s si o n  i n 
S A O L P h a s e:   
A) If n o r e s p o n s e aft er t h e fir st c o m bi n e d tr e at m e nt c o ur s e  ( S O C + I M P) at 
t h e i niti ati o n of t h e S A O L p h a s e:  
If p ati e nt s d o n ot  r e s p o n d t o t h er a p y ( s e e D efi niti o n of P arti al  a n d C o m pl et e  
R e s p o n s e t o T h er a p y  a n d Di s e a s e I m pr o v e m e nt ) aft er t h e i niti al c o m bi n e d  
tr e at m e nt c o ur s e, t h e y will  b e tr e at e d wit h r e s c u e i m m u n o s u p pr e s si o n or wit h 
n e w/ i n cr e a s e d d o s e s of P er mitt e d C o n c o mit a nt Tr e at m e nt s. P ati e nt s tr e at e d 
wit h  r e s c u e  i m m u n o s u p pr e s si o n  or  n e w/  i n cr e a s e d  d o s e s  of  P er mitt e d  
C o n c o mit a nt Tr e at m e nt s will b e c o n si d er e d tr e at m e nt f ail ur e s a n d e xit t h e 
st u d y  
B) P ati e nt s wit h a di s e a s e r e a cti v ati o n  aft er h a vi n g r e s p o n d e d t o t h er a p y i n 
t h e S A O L P h as e.  
If p ati e nt s s h o w si g n s of s y st e mi c i nfl a m m at or y r e a cti v ati o n (i. e. p arti al or f ull 
di s e a s e r e a cti v ati o n ) aft er h a vi n g r e s p o n d e d t o t h er a p y  i n t h e S A O L p h a s e, 
t h e y will r e c ei v e a n ot h er c y cl e of S O C i n a d diti o n t o t h e IM P.  
C) P ati e nt s wit h a di s e a s e r e a cti v ati o n  d uri n g t h e t a p eri n g d o w n of  t h e S O C 
d uri n g t h e c o m bi n e d tr e at m e nt  i n t h e S A O L P h a s e:  
If, aft er a n i niti al i m pr o v e m e nt i n r e s p o n s e p ar a m et er s, t h e p ati e nt s  s h o w  
a g ai n si g n s o f i n cr e a si n g i nfl a m m ati o n (i. e. p arti al or f ull di s e a s e r e a cti v ati o n ) 
d uri n g t h e t a p eri n g d o w n of S O C w hil e i n  c o m bi n e d tr e at m e nt, a n ot h er f ull 
c y cl e of e xt e n d e d S O C  ( 4 w e e k s) i n a d diti o n t o t h e I M P will b e i niti at e d at t h e 
ori gi n al d o s e.  
I n t h e l a st c a s e s ( B or  C) , t h e I n v e sti g at or m a y al s o d e ci d e t o st art  r e s c u e 
i m m u n o s u p pr e s si o n tr e at m e nt, a n d  i n  t hi s  c a s e  t h e  p ati e nt  s h o ul d  
di s c o nti n u e st u d y tr e at m e nt d u e t o tr e at m e nt f ail ur e .  
 
N ot e t o tr e at m e nt f ail ur e:  
A n y p ati e nt st arti n g r e s c u e i m m u n o s u p pr e s si o n tr e at m e nt will b e c o n si d er e d 
a  tr e at m e nt  f ail ur e  a n d  will  pr o c e e d  t o  t h e  st u d y  di s c o nti n u ati o n/ e arl y 
t er mi n ati o n pr o c e d ur e s. D at a r el at e d t o r e s p o n s e t o t h e r e s c u e tr e at m e nt will 
b e c oll e ct e d  i n cl u di n g all k e y effi c a c y a n d s af et y a s s e s s m e nt s. 
 
It i s r e c o m m e n d e d t h at p ati e nt s s uff eri n g fr o m s e v er e C N S m a nif e st ati o n s 
ar e p ut o n r e s c u e i m m u n o s u p pr e s si o n tr e at m e nt.  
 


 
 
 
P a g e 1 7  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
N ot e t o tr e at m e nt of di s e a s e r e a cti v ati o n s : 
P ati e nt s  t h at  pr e s e nt  a  p arti al  or  f ull  di s e a s e  r e a cti v ati o n  aft er  pr e vi o u s  
r e s p o n s e t o S O C + T A i n t h e S A O L p h a s e c a n r e m ai n i n t h e st u d y, a n d 
r e c ei v e a n ot h er c y cl e of S O C i n a d diti o n t o t h e c o nti n u o u s T A tr e at m e nt, if 
a c c or di n g  t o  tr e ati n g  p h y si ci a n,  t h e  s e v erit y  d o e s  n ot  r e q uir e  r e s c u e  
i m m u n o s u p pr e s si o n.  
P ati e nt s t h at pr e s e nt a p arti al or f ull di s e a s e r e a cti v ati o n  i n t h e R W p h a s e 
b ef or e t h e 1 6 -w e e k tr e at m e nt i s c o m pl et e d will pr o c e e d t o t h e E n d of St u d y 
Vi sit a n d c o m pl et e t h e R W p h a s e.  
N ot e - n or m al r a n g e s f or f erriti n a n d C R P:  
T h e n or m al r a n g e s of f erriti n a n d C R P diff er p er a g e a n d r e s p e cti v e n or m al 
r a n g e s p er a g e at t h e c e ntr al or l o c al l a b or at or y will b e u s e d a s r ef er e n c e. 
D at a S af et y M o nit ori n g B o ar d  
T h e D at a S af et y M o nit ori n g B o ar d ( D S M B) will b e n otifi e d b y t h e c o ntr a ct e d 
Cli ni c al R e s e ar c h Or g a ni z ati o n ( C R O) of cli ni c al or bi ol o gi c al w or s e ni n g of 
t h e st at u s of st u d y  s u bj e ct s (i. e ., S eri o u s A d v er s e E v e nt s ( S A E s)) a n d al s o 
of tr e at m e nt f ail ur e s. T h e D S M B will a s s e s s t h e gl o b al s af et y of T a d e ki ni g 
alf a a n d a d vi s e w h et h er t o c o nti n u e or di s c o nti n u e t h e st u d y. D S M B r ol e s 
a n d  r e s p o n si biliti e s  ar e  d eli n e at e d  i n  t h e  D S M B  c h art er  al o n g  wit h  t h e 
r e p orti n g r e q uir e m e nt s of t h e S p o n s or/ C R O t o t h e D S M B. T h e I n v e sti g at or  
will e v al u at e s af et y f or e a c h i n di vi d u al p ati e nt a n d d e ci d e w h et h er t o st o p or 
c o nti n u e tr e at m e nt , or w h e n t o st art t h e  r e s c u e i m m u n o s u p pr e s si o n.  
B A C K G R O U N D ( R A TI O N A L E)  
A ut oi nfl a m m at or y di s e a s e s ar e c a u s e d b y i n n at e i m m u n e d y sr e g ul ati o n a n d 
t y pi c all y pr e s e nt i n e arl y c hil d h o o d wit h f e v er a n d di s e a s e-s p e cifi c p att er n s 
of s y st e mi c a n d or g a n -s p e cifi c i nfl a m m ati o n a n d d y sf u n cti o n. M a n y g e n eti c 
c a u s e s of a ut oi nfl a m m at or y di s e a s e s h a v e b e e n i d e ntifi e d, a n d a s s o ci ati o n s 
b et w e e n s p e cifi c g e n e s a n d di sti n ct a ut oi nfl a m m at or y c o n diti o n s  h a v e b e e n 
e st a bli s h e d .  T h e  m ol e c ul ar  li n k s  b et w e e n  c a u s ati v e  g e n e s,  s p e cifi c  
i nfl a m m at or y  p at h w a y s,  a n d  d efi n e d  di s e a s e  p h e n ot y p e s  r e pr e s e nt  
s u b st a nti al pr o gr e s s i n i d e ntif yi n g r ati o n al t h er a pi e s i n fr e q u e ntl y r efr a ct or y 
cli ni c al c o n diti o n s.  
I L-1 bl o c ki n g t h er a pi e s h a v e r e pr e s e nt e d a n i m p ort a nt st e p f or w ar d i n t h e 
tr e at m e nt of a ut oi nfl a m m at or y c o n diti o n s. I L-1 bl o c k a d e i n t h e N L R P 3 r el at e d 
Cr y o p yri n- A s s o ci at e d  P eri o di c  S y n dr o m e s  ( C A P S)  a n d  D efi ci e n c y  of  I L -1 
R e c e pt or  A nt a g o ni st  ( DI R A)  h a s  b e e n  s h o w n  t o  b e  v er y  effi c a ci o u s . 
H o w e v er, i n ot h er a ut oi nfl a m m at or y c o n diti o n s, t h e r e s p o n s e t o tr e at m e nt 
h a s b e e n a n e c d ot al a n d li mit e d t o c a s e r e p ort s. T h u s, t h e e xt e n si o n of I L -1 
bl o c k a d e  fr o m  C A P S  t o  ot h er  a ut oi nfl a m m at or y  e ntiti e s  h a s  b e e n  l ar g el y  
e m piri c.  
Ot h er a ut o -i nfl a m m at or y c o n diti o n s ar e r el at e d t o diff er e nt g e n eti c d ef e ct s 
t h at  tri g g er  ot h er  c ell ul ar  p at h w a y s  of  a cti v ati o n  wit h  t h e  pr o d u cti o n  of  
diff er e nt m e di at or s. S p o nt a n e o u s g ai n -of -f u n cti o n m ut ati o n s of t h e N L R C 4 
i nfl a m m as o m e  h a v e  b e e n  a s s o ci at e d  wit h  s e v er e  e arl y -o n s et  a ut o -
i nfl a m m at or y c o n diti o n s wit h r e c urr e nt M A S-li k e fl ar e s, a n d s o m e p ati e nt s 
m a y  pr e s e nt  wit h  s e v er e  e nt er o c oliti s.  N L R C 4  m ut ati o n s  al s o  r e s ult  i n  


 
 
 
P a g e 1 8  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
c o n stit uti v e I L -1 8 h y p er s e cr eti o n.  
A p ati e nt s uff eri n g fr o m N L R C 4 m ut ati o n w a s tr e at e d wit h T a d e ki ni g alf a 
wit hi n  t h e  fr a m e  of  a n  e m er g e n c y  i n di vi d u al  p ati e nt  I N D  
 
a p pr o v e d  b y t h e F D A   on J u n e 9, 2 0 1 5. T h e  
 ol d i nf a nt d e v el o p e d 
g e n er ali z e d,  s e v er e,  lif e -t hr e at e ni n g  M A S  wit h  s e v er e  e nt er o c oliti s,  
i nt ol er a n c e  t o  e nt er al  f e e di n g, d u e  t o  a n  N L R C 4  p at h o g e ni c  m ut ati o n 
( V 3 4 1 A). T h e p ati e nt s h o w e d el e v at e d t ot al I L -1 8 ( > 5 0, 0 0 0 p g/ m L)  a n d fr e e 
I L-1 8 . A g gr e s si v e tr e at m e nt wit h a c o m bi n ati o n t h er a p y i n cl u di n g st er oi d s, 
c y cl o s p ori n e,  I L -1 β,  T N F α,  a n d  i nt e gri n  α 4/ β 7  i n hi bit or s  r e s ult e d  i n  sli g ht 
cli ni c al i m pr o v e m e nt. Aft er r e c ei vi n g a  2-m g/ k g d o s e of T a d e ki ni g alf a, t h e 
p ati e nt r e s p o n d e d i m m e di at el y t o t h e tr e at m e nt wit h r a pi d i m pr o v e m e nt s i n 
C R P a n d f erriti n, wit h  fr e e -I L-1 8 l e v el s dr o p pi n g t o b el o w d et e cti o n  l e v el s. 
C o nti n u o u s tr e at m e nt wit h 2- m g/ k g T a d e ki ni g alf a, e v er y ot h er d a y, r e s ult e d 
i n dr a m ati c n or m ali z ati o n of di s e a s e a cti vit y m e a s ur e s s u c h a s f erriti n a n d 
C R P  l e v el s  a n d  e nt er o p at h y.  Or al  i nt a k e  w a s  i m pr o v e d.  C o- m e di c ati o n s, 
i n cl u di n g c y cl o s p ori n e a n d c orti c o st er oi d s, w er e p h a s e d o ut. T h e p ati e nt w a s 
di s c h ar g e d fr o m t h e h o s pit al aft er 2 0 d a y s of tr e at m e nt. T h e p ati e nt i s still o n 
tr e at m e nt wit h o ut s y m pt o m s or m ar k er s of di s e a s e a cti vit y a s of S e p 2 0 2 1 . 
X- li n k e d  i n hi bit or  of  a p o pt o si s  ( XI A P  i s  fr e q u e ntl y  a s s o ci at e d  wit h  
H e m o p h a g o c yti c -L y m p h o hi sti o c yt o si s ( H L H), a M A S -li k e s y n dr o m e, b ut c a n 
al s o h a v e ot h er p h e n ot y p e s of di s e a s e pr e s e nt ati o n. Si mil arl y t o p ati e nt s wit h 
N L R C 4 -M A S a n d t h o s e wit h ot h er M A S -pr o n e di s or d er s, p ati e nt s wit h XI A P 
d efi ci e n c y a n d a M A S -li k e p h e n ot y p e al s o s h o w hi g h l e v el s of s er u m I L-1 8.  
A B 2 Bi o, i n c oll a b or ati o n wit h Dr. 
 fr o m Ci n ci n n ati C hil dr e n' s 
H o s pit al  M e di c al  C e nt er , c o n d u ct e d  a  st u d y  i n  XI A P  d efi ci e n c y  p e di atri c 
p ati e nt s t o e x a mi n e t h e l e v el s of fr e e I L -1 8 d uri n g e pi s o d e s of a cti v e di s e a s e 
a n d d uri n g di s e a s e r e mi s si o n. P ati e nt s wit h XI A P d efi ci e n c y h a v e cir c ul ati n g 
fr e e  I L-1 8  d uri n g  a cti v e  di s e a s e  a n d  i n  r e mi s si o n. Hi g h er  l e v el s  w er e  
o b s er v e d d uri n g di s e a s e fl ar e s. T hi s o b s er v ati o n s u p p ort s t h e c o nt e nti o n t h at 
fr e e  I L-1 8  m a y  c o ntri b ut e  t o  t h e  pr o p e n sit y  of  t h e s e  p ati e nt s  t o  d e v el o p  
M A S/ H L H. 
T h e  c o n stit uti v e  pr o d u cti o n  a n d  s e cr eti o n  of  I L -1 8  b y  m o n o c yt e s,  
m a cr o p h a g e s a n d pr o b a bl y ot h er c ell t y p e s, a n d t h e pr e s e n c e of s er u m -fr e e 
I L-1 8  i n  b ot h p e di atri c  M A S -li k e  c o n diti o n s,  N L R C 4 - M A S, a n d  XI A P  
d efi ci e n c y, i n  c o ntr a st  wit h  ot h er  e arl y-o n s et  a ut oi nfl a m m at or y  c o n diti o n s  
s u c h a s N O MI D, s u g g e st s t h at I L -1 8 bl o c k a d e r e pr e s e nt s n ot m er el y a n ot h er 
o pti o n  f or  t h e  tr e at m e nt  of  a ut oi nfl a m m at or y  di s e a s e s,  b ut  t h e  m o st  
a p pr o pri at e tr e at m e nt f or t hi s c at e g or y of p ati e nt s.  
T h e e xtr e m el y l o w i n ci d e n c e of b ot h g e n eti c c o n diti o n s ( 1 -2 c a s e s p er milli o n  
li v e birt h s), t h e c o m m o n pr o p e n sit y t o d e v el o p r e c urr e nt M A S e pi s o d e s, a n d 
t h e i m m u n o d o mi n a nt r ol e of I L-1 8 , ar e  f a ct or s t h at h a v e l e nt s u p p ort t o gr o u p 
t h e t w o e ntiti e s  i n t hi s tri al. T hi s w a s d e ci d e d o n aft er c o n s ult ati o n wit h t h e 
F D A.  
S T U D Y C E N T E R ( S)  / P A R TI CI P A TI N G C O U N T RI E S   
A p pr o xi m at el y  1 1 cli ni c al s it e s i n t h e Unit e d S t at e s, C a n a d a a n d G er m a n y  
 


 
 
 
P a g e 1 9  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
O B J E C TI V E S  
Pri m ar y Effi c a c y  O bj e cti v e s   
o  T o
 a s s e s s
 cli ni c al
 effi c a c y
 of
 T a d e ki ni g
 alf a
 i n
 m o n o g e ni c
 
a ut oi nfl a m m at or y  di s e a s e s  wit h  o n g oi n g  i nfl a m m ati o n  a n d  d el et eri o u s  
m ut ati o n s of N L R C 4 -M A S  or XI A P   
o  T o a s s e s s l a b or at or y/ bi ol o gi c al e vi d e n c e of effi c a c y  
S e c o n d ar y  Effi c a c y O bj e cti v e   
o  M ai n cli ni c al f e at ur e s a n d l a b or at or y bi o m ar k er s  ( c h ar a ct eri sti c s of e a c h 
p ati e nt pr ofil e) will b e a s s e s s e d  l o n git u di n all y d uri n g t h e S A O L p h a s e f or 
e a c h e x p eri m e nt al s u bj e ct  
S e c o n d ar y S af et y O bj e cti v e  
o  T o  a s s e s s  t h e  s af e t y  a n d  t ol er a bilit y of T a d e ki ni g  alf a  tr e at m e nt i n 
m o n o g e ni c ,  aut oi nfl a m m at or y di s e a s e h ar b ori n g d el et eri o u s m ut ati o n s 
of N L R C 4 - M A S or XI A P  
 
N U M B E R O F P A TI E N T S   
A n e sti m at e d  m a xi m u m of 1 5  p ati e nt s  will b e e nr oll e d i n t h e st u d y  
N ot e : A m a xi m u m of 1 5 p ati e nt s e nr oll e d  will e n s ur e  t h e r a n d o mi z ati o n of at l e a st 1 0 p ati e nt s 
i n t h e R W p h a s e.   
I N C L U SI O N C RI T E RI A  
A ll e ntr a n c e crit eri a m u st b e m et i n or d er t o e nr oll ;  
Eli gi bilit y crit eri a  s h o ul d b e  ev al u at e d at S cr e e ni n g ( V 0) pri or t o V 1  a n d r e c h e c k e d at B a s eli n e 
( V 1) pri or t o st u d y tr e at m e nt . 
1.  P ati e nt s  wit h  g e n eti c  di a g n o si s  of  N L R C 4 - M A S m ut ati o n  or  XI A P  
d efi ci e n c y  (c a u s e d b y BI R C 4  g e n e m ut ati o n) a s c o nfir m e d b y a n al y si s 
p erf or m e d at t h e c e ntr al g e n eti c s l a b or at or y.  If p o s si bl e, fl o w c yt o m etr y 
a s s a y  will  b e  p erf or m e d  i n  p ar all el  t o  c o nfir m  di a g n o si s  of  XI A P  
d efi ci e n c y. ( N ot e: Pr e vi o u s fl o w c yt o m etr y a s s a y r e s ult s will b e p er mitt e d 
f or c o nfir m ati o n of XI A P d efi ci e n c y di a g n o si s.) A g e n eti c di a g n o si s fr o m 
a l o c al l a b or at or y will b e a c c e pt e d f or e nr ol m e nt  a n d st art of tr e at m e nt, 
t o a v oi d a n y tr e at m e nt d el a y s f or t h e s e s e v er e c o n diti o n s. H o w e v er, t h e 
g e n eti c di a g n o si s h a s t o b e c o nfir m e d b y t h e c e ntr al l a b or at or y. If t h e 
g e n eti c di a g n o si s i s n ot c o nfir m e d, t h e p ati e nt will di s c o nti n u e t h e st u d y.   
2.  P ati e nt s  wit h  XI A P  d efi ci e n c y  a n d  a  pr e vi o u s  b o n e  m arr o w  
tr a n s pl a nt ati o n ar e  all o w e d,  if  t h e y  s h o w  e vi d e n c e  of  pri m ar y  or  
s e c o n d ar y gr aft f ail ur e, or f ail ur e t o a c hi e v e p h e n ot y pi c c orr e cti o n wit h 
e vi d e n c e  of  XI A P- r el at e d  di s e a s e  r e c urr e n c e  or cli ni c all y  si g nifi c a nt  
mi x e d c hi m eri s m . F or t h e s e p ati e nt s, g e n eti c di a g n o si s at t h e c e ntr al 
l a b or at or y m a y s h o w c hi m eri s m; t h u s, l o c al g e n eti c di a g n o si s pri or t o t h e 
b o n e  m arr o w  tr a n s pl a nt ati o n  will  b e  t h e  m ai n  s o ur c e  t o  c o nfir m  t h e  
g e n eti c di a g n o si s.  
3.  F erriti n ≥ 5 0 0 n g/ m L or p er si st e nt el e v ati o n of C R P ≥ 2 x U L N a n d m AI D AI 
≥ 4   
4.  P ati e nt s r e c ei vi n g c orti c o st er oi d s, n o n -st er oi d al a nti -i nfl a m m at or y dr u g s 
(N S AI D s ) or  di s e a s e m o dif yi n g a nti -r h e u m ati c dr u g s (D M A R D s ), a n d/ or 


 
 
 
P a g e 2 0  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
I L-1 bl o c k a d e wit h i n s uffi ci e nt r e s p o n s e t o tr e at m e nt  u p o n  e nr oll m e nt  ar e 
all o w e d i nt o t h e st u d y. P ati e nt s n ot r e c ei vi n g a n y of t h e s e tr e at m e nt s 
b ef or e st art of t h er a p y ar e al s o all o w e d . 
5.  W o m e n  of  c hil d b e ari n g  p ot e nti al  wit h  n e g ati v e  uri n e pr e g n a n c y  t e st  
( U P T) at all vi sit s (if U P T i s p o siti v e, a bl o o d t e st f or h u m a n c h ori o ni c 
g o n a d otr o pi n ( h C G) t o b e p erf or m e d) a n d  w h o a gr e e t o f oll o w hi g hl y 
eff e cti v e  birt h  c o ntr ol  r e c o m m e n d ati o n s  d uri n g  t h e  st u d y  a n d  u ntil  1  
m o nt h aft er t h e e n d of t h e tr e at m e nt. Birt h c o ntr ol m et h o d s c o n si d er e d 
hi g hl y eff e cti v e ar e: c o m bi n e d ( e str o g e n a n d pr o g e st o g e n c o nt ai ni n g) 
h or m o n al  c o ntr a c e pti o n  a s s o ci at e d  wit h  i n hi biti o n  of  o v ul ati o n,  
pr o g e st o g e n -o nl y h or m o n al c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of 
o v ul ati o n,  i ntr a ut eri n e  d e vi c e  (I U D),  i ntr a ut eri n e  h or m o n e -r el e a si n g 
s y st e m (I U S), bil at er al t u b al o c cl u si o n, v a s e ct o mi z e d p art n er or s e x u al 
a b sti n e n c e. I n e a c h c a s e of d el a y e d m e n str u al p eri o d ( o v er o n e m o nt h 
b et w e e n  m e n str u ati o n s,  c o nfir m ati o n  of  a b s e n c e  of  pr e g n a n c y  i s  
str o n gl y r e c o m m e n d e d. T hi s r e c o m m e n d ati o n al s o a p pli e s t o w o m e n of 
c hil d b e ari n g  p ot e nti al  wit h  i nfr e q u e nt  or  irr e g ul ar  m e n str u al  c y cl e s.  A 
p o st -st u d y c o ntr a c e pti o n d ur ati o n of 4 w e e k s i s r e c o m m e n d e d t a ki n g 
i nt o a c c o u nt t h e m e di a n h alf-lif e of T a d e ki ni g alf a of al m o st 4 0 h a n d  5 
h alf -li v es r e pr e s e nti n g a  d ur ati o n of 2 0 0 h o ur s . 
 
E X C L U SI O N C RI T E RI A  
1.  P ati e nt s wit h lif e-t hr e at e ni n g c o -m or bi diti e s  n ot  a s s o ci at e d  wit h  t h e  
u n d erl yi n g N L R C 4 -m ut ati o n or XI A P d efi ci e n c y    
2.  P o siti v e  t e st  f or  or  pri or  hi st or y  of  HI V , H e p atiti s  B  or  H e p atiti s  C  
( s er ol o g y) 
3.  Pr e s e n c e of a cti v e i nf e cti o n s or a hi st or y of p ul m o n ar y T B i nf e cti o n wit h 
or wit h o ut d o c u m e nt e d a d e q u at e t h er a p y  ( Q u a nti F E R O N-T B t e st)  
4.  Pr e s e n c e of lif e-t hr e at e ni n g i nf e cti o n s ( cli ni c all y a n d q u a ntit at e d P C R if 
n e c e s s ar y)  
5.  O n c ol o gi c  c a u s e s  of  s y m pt o m s;  c urr e nt  or  pr e vi o u s  hi st or y  of  
m ali g n a n c y  
6.  Pr e s e n c e of C N S m a nif e st ati o n s (i. e. s ei z ur e s, alt er e d m e nt al st at u s, 
si g n s  of  i n cr e a s e d  i ntr a cr a ni al  pr e s s ur e,  c hr o ni c  p a pill e d e m a,  l o s s  of  
vi si o n, ot h er s e n s ori n e ur al d efi ci e n ci e s, et c.)  
7.  P ati e nt s s uff eri n g fr o m bi all eli c m ut ati o n s i n a n y of t h e f oll o wi n g g e n e s: 
P R F 1/ P erf ori n, U N C 1 3 D/ M u n c 1 3 -4, S T X 1 1/ S y nt a xi n 1 1, S T X B 2/ M u n c 
1 8 -2,  R A B 2 7 A/ R a b 2 7 a  ( Gri s c elli  s y n dr o m e  t y p e  2),  L Y S T ( C h e di a k-
Hi g a s hi  s y n dr o m e),  A P 3 B 1,  A D T B 3 A,  H P S 2  m ut ati o n s  ( H er m a n s k y -
P u dl a k s y n dr o m e 2)  a n d X -li n k e d l y m p h o pr olif er ati v e s y n dr o m e ( X L P)-1 
wit h S H 2 D 1 A m ut ati o n  
8.  P ati e nt s w h o ar e pr e g n a nt or n ur si n g, w o m e n of c hil d b e ari n g p ot e nti al 
w h o  ar e  u n willi n g  t o  u s e  hi g hl y  eff e cti v e  birt h  c o ntr ol  m et h o d s  ( s e e  
d efi niti o n i n I n cl u si o n Crit eri a a b o v e) t hr o u g h 4 w e e k s aft er t h e e n d of 
t h eir p arti ci p ati o n i n t h e st u d y  
9.  C o n c o mit a nt  u s e  of  i m m u n o s u p pr e s si o n  t h er a pi e s  e x cl u d e d  b y  t h e  
pr ot o c ol . N ot e: N S AI D s, gl u c o c orti c oi d s, c y cl o s p ori n e, t a cr oli m u s, a n d 
I L-1  i n hi bit or s  ( a n a ki nr a,  c a n a ki n u m a b,  or  ril o n a c e pt,  or  ot h er s )  ar e  
all o w e d  




 
 
 
P a g e 2 2  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
E F FI C A C Y A S S E S S M E N T   
Effi c a c y a s s e s s m e nt i s r el at e d t o t h e i n ci d e n c e of di s e a s e r e a cti v ati o n s  a n d will 
c o v er:  
Cli ni c al  e v al u ati o n ( m o stl y  c a pt ur e d i n t h e m AI D AI ): 
o  C o m pl et e p h y si c al e x a mi n ati o n i n cl u di n g:  vit al si g n s  ( s y st oli c a n d 
di a st oli c bl o o d pr e s s ur e, h e art r at e, r e s pir at or y r at e, w ei g ht,  a n d 
b o d y t e m p er at ur e)  
o  All fi n di n g s s h o ul d b e d o c u m e nt e d: j oi nt s w elli n g, h e p at o m e g al y 
a n d  s pl e n o m e g al y,  pr e s e n c e  of  s ki n  r a s h ,  o p ht h al mi c  c o ntr ol  
( pr e s e n c e of u v eiti s). O p ht h al mi c e x a mi n ati o n will b e p erf or m e d t o 
e x a mi n e  t h e  pr e s e n c e/ a b s e n c e  of  u v eiti s  a n d,  if  pr e s e nt,  t h e  
e v ol uti o n d uri n g t h e st u d y  
o  S y m pt o m s  s h o ul d  b e  d o c u m e nt e d:  a b d o mi n al  p ai n,  di arr h e a,  
n a u s e a, v o miti n g  
o  All c li ni c al c o m p o n e nt s (i n cl u di n g cli ni c al fi n di n g s a n d s y m pt o m s) 
of  t h e  di s e a s e  will  b e  c a pt ur e d  i n  a  bi n ar y  w a y  a s  eit h er  b ei n g  
pr e s e nt  or  a b s e nt.  T h e  j u d g e m e nt,  of  w h et h er  a n  e n d  or g a n  
c at e g or y i s aff e ct e d, i s d o n e b y t h e tr e ati n g p h y si ci a n a c c or di n g t o 
cli ni c al  st a n d ar d s,  a s  al s o  pr e vi o u sl y  d o n e  f or  all  m AI D AI 
c o m p o n e nt s . 
o  D ail y w ei g ht, st o ol o ut p ut, a n d P O i nt a k e m e a s ur e m e nt s i n cl u di n g 
n u m b er  of  e m e si s  e pi s o d e s  will  b e  p erf or m e d  o n  p ati e nt s  wit h  
i nt e sti n al d y sf u n cti o n, o nl y w h e n t h e p ati e nt s ar e h o s pit ali z e d 
o  R a di ol o gi c  fi n di n g s if  a s s e s s e d  a s n e c e s s ar y  b y  t h e  tr e ati n g  
p h y si ci a n  
M ai nt e n a n c e c o -tr e at m e nt: 
o  T ot al w e e kl y gl u c o c orti c oi d s  
o  I L-1 bl o c k er s  
o  Ot h er tr e at m e nt s * (e. g.,  D M A R D s , et c.)  
*R ef er t o S e cti o n 1 1 . 2. 4: C o n c o mit a nt tr e at m e nt 
L a b or at or y  ( s e e T a bl e 2) : 
o  S er u m C R P  
o   S er u m F erriti n  
o  C o m pl et e bl o o d c o u nt s  
o  S er u m l e v el s of t ot al I L -1 8, fr e e I L -1 8, I L -1 8 B P  
 
N ot e 1:  G a str oi nt e sti n al ( GI )-r el at e d p ar a m et er s will b e a s s e s s e d i n p ati e nt s 
wit h GI d y sf u n cti o n  
 
N ot e 2:  F or o ut p ati e nt t h er a p y t h e cli ni c al e v al u ati o n will b e p erf or m e d at t h e 
m o nt hl y vi sit s  
 
 


 
 
 
P a g e 2 3  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
D E FI NI TI O N O F A C TI V E DI S E A S E U P O N E N R O L M E N T  
o  I n cr e a s e d i nfl a m m at or y m ar k er s, i. e. s er u m f erriti n l e v el s  ≥ 5 0 0 n g/ m L  or 
s er u m C R P ≥ 2 x U L N, a n d  
o  
A cti v e cli ni c al di s e a s e a s e vi d e n c e d b y m AI D AI ≥ 4 or C N S m a nif e st ati o n s 
(i. e.  s ei z ur e s,  alt er e d  m e nt al  st at u s,  si g n s  of  i n cr e a s e d  i ntr a cr a ni al  
pr e s s ur e, 
c hr o ni c  p a pill e d e m a,  l o s s  of  vi si o n,  ot h er  s e n s ori n e ur al  
d efi ci e n ci e s, et c.)  
F or t h e d efi niti o n of a cti v e di s e a s e u p o n e nr ol m e nt, all m AI D AI c o m p o n e nt s 
( s u bj e cti v e  a n d  o bj e cti v e)  will  b e  e v al u at e d  i n  li n e  wit h  pr e vi o u s  pr ot o c ol  
v er si o n s.  
 
D E FI NI TI O N O F R E S P O N S E  T O T H E R A P Y  
1.  I n t h e 1 6 -w e e k R W p h a s e, r e s p o n s e t o t h er a p y ( a s pri m ar y e n d p oi nt of 
effi c a c y) will b e a s s e s s e d b y pr e v e nti o n of di s e a s e r e a cti v ati o n s  d uri n g  
t h e 1 6-w e e k tr e at m e nt i n t h e R W p h a s e 
2.  I n  t h e  S A O L p h a s e ,  r e s p o n s e  t o  t h er a p y  ( a s  s e c o n d ar y  e n d p oi nt  of  
effi c a c y) will b e a s s e s s e d t hr o u g h t h e c o ntr ol of t h e a cti v e di s e a s e   
F or  r e s p o n s e  t o  t h er a p y,  o nl y  t h e  o bj e cti v e  m AI D AI  c o m p o n e nt s  will  b e  
e v al u at e d  a s  i n di c at e d  b el o w. S u bj e cti v e  m AI D AI  c o m p o n e nt s  ( s e e  
A p p e n di x  I) will n ot b e c o n si d er e d t o a v oi d a n y bi a s i n t h e effi c a c y a s s e s s m e nt  
i n t h e o p e n l a b el p art of t h e st u d y. J u stifi c ati o n f or t h e r e vi s e d r e s p o n s e t o 
t h er a p y d efi niti o n s i s i n cl u d e d i n s e cti o n 8. 3.3.  
 
o  C o m pl et e r e s p o n s e  
N o m aj or e n d or g a n d a m a g e  ( = o bj e cti v e m AI D AI c o m p o n e nt s) 
•  N o f e v er ( b o d y t e m p er at ur e ≤1 0 0. 4 º F/ 3 8 ° C)  
•  N o di arr h e a  
•  N o tr a n s a mi niti s a n d/ or h e p at o m e g al y  
•  N o s pl e n o m e g al y a n d/ or a d e n o p at h y  
•  N o r a s h  
•  N o u v eiti s  
•  N o art hriti s  
•  N o r a di ol o gi c C N S i n v ol v e m e nt  
•  N o c yt o p e ni a ( H g B ≥ 9. 0 a n d/ or P L T ≥1 0 0 a n d/ or W B C ≥3. 0)  
N o s y st e mi c i nfl a m m ati o n  
•  N o h y p erf erriti n e mi a ( s er u m l e v el < 5 0 0 n g/ m L ) 
•  N o i n cr e a s e d C R P ( s er u m l e v el < 2 x U L N ) 
I m m u n o s u p pr e s si v e t h er a pi e s 
•  Di s c o nti n u ati o n of s y st e mi c c orti c o st er oi d s  ( e x cl u di n g hy dr o c orti s o n e 
f or pr e v e nti o n of a dr e n al i n s uffi ci e n c y) or ot h er i m m u n o s u p pr e s si v e  
t h er a pi e s i n cl u di n g bi ol o gi c s o n g oi n g at b a s eli n e 
•  N o  st art  or  d o s e  i n cr e a s e  of  ot h er  i m m u n o s u p pr e s si v e  t h er a pi e s  
i n cl u di n g bi ol o gi c s 
 
 
 
 


 
 
 
P a g e 2 4  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
o  P arti al r e s p o n s e  
At l e a st 5 0 % r e d u cti o n of t h e n u m b er of aff e ct e d o bj e cti v e e n d or g a n 
d a m a g e c at e g ori e s at b a s eli n e a n d  
•   
At l e a st 5 0 % of t h e s y st e mi c i nfl a m m at or y m ar k er s (f erriti n a n d/ or 
C R P) i n cr e a s e d at b a s eli n e r e a c hi n g l e v el s f or c o m pl et e r e s p o n s e 
or  
•  
Di s c o nti n u ati o n 
 
of
 s y st e mi c
 c orti c o st er oi d s  
( e x cl u di n g 
h y dr o c orti s o n e  f or  pr e v e nti o n  of  a dr e n al  i n s uffi ci e n c y ) or  ot h er  
i m m u n o s u p pr e s si v e t h er a pi e s  i n cl u di n g  bi ol o gi c s  o n g oi n g  at  
b a s eli n e  
 
o  Di s e a s e I m pr o v e m e nt  
A t hir d r e s p o n s e c at e g or y of Di s e a s e I m pr o v e m e nt i s i ntr o d u c e d t o b e utili z e d 
a s a  d e s cri pti o n  of  b e st  r e s p o n s e  a n d i n  or d er  t o  b ett er  d e s cri b e  i niti al  
tr e at m e nt r e s p o n s e t o t h er a p y a n d di s e a s e e v ol u ti o n o v er ti m e. T hi s i s o nl y 
u s e d f or a n al y si s p ur p o s e s a n d will n ot b e e v al u at e d f or t h e d e ci si o n  w h et h er 
t o b e eli gi bl e f or t h e st art of t h e R W p h a s e . Di s e a s e I m pr o v e m e nt i s d efi n e d 
a s:  
•   
Re d u cti o n of t h e n u m b er of aff e ct e d o bj e cti v e e n d or g a n d a m a g e 
c at e g ori e s at b a s eli n e  b y at l e a st 1 or  
•  
N or m ali z ati o n  (i. e.  r e a c hi n g  l e v el s  f or  c o m pl et e  r e s p o n s e)  or 
i m pr o v e m e nt ( > 5 0 % c h a n g e fr o m b a s eli n e f or l a b or at or y m ar k er s 
b ut still e x c e e di n g  l e v el s f or c o m pl et e r e s p o n s e) of at l e a st 5 0 % of 
t h e s y st e mi c i nfl a m m at or y m ar k er s aff e ct e d at b a s eli n e  
•  
S y st e mi c c orti c o st er oi d s ( e x cl u di n g h y dr o c orti s o n e f or pr e v e nti o n of 
a dr e n al  i n s uffi ci e n c y ) or  ot h er  i m m u n o s u p pr e s si v e  t h er a pi e s  
i n cl u di n g bi ol o gi c s m u st b e at t h e s a m e or l o w er d o s e s c o m p ar e d t o 
b a s eli n e  
 
 
D E FI NI TI O N O F DI S E A S E R E A C TI V A TI O N  
F or di s e a s e  r e a cti v ati o n,  o nl y  t h e  o bj e cti v e  m AI D AI  c o m p o n e nt s  will  b e  
e v al u at e d  a s  i n di c at e d  b el o w. S u bj e cti v e  m AI D AI  c o m p o n e nt s  ( s e e  
A p p e n di x  I)  will  n ot  b e  c o n si d er e d  t o  a v oi d  a n y  bi a s  i n  t h e  a s s e s s m e nt. 
J u stifi c ati o n  f or  t h e  r e vi s e d  di s e a s e  r e a cti v ati o n  d efi niti o n s  i s  i n cl u d e d  i n  
s e cti o n 8. 3. 3.  
D uri n g t h e R W -p h a s e, t h e r ef er e n c e f or a di s e a s e r e a cti v ati o n (f or t h e pri m ar y 
e n d p oi nt a s s e s s m e nt) will b e t h e e n d of t h e S A O L p h a s e  ( V 8); f or t h e S A O L 
p h a s e, r ef er e n c e will t h e pr e vi o u s vi sit, a s p ati e nt s e nt er t h e S A O L p h a s e wit h 
a n a cti v e di s e a s e.  
o  P arti al di s e a s e r e a cti v ati o n ,  
•  
I n cr e a s e  i n t h e n u m b er  of  aff e ct e d  o bj e cti v e  e n d  or g a n  d a m a g e  
c at e g ori e s b y at l e a st 2 or  
•  
I n cr e a s e  i n t h e n u m b er  of  aff e ct e d  o bj e cti v e  e n d  or g a n  d a m a g e  
c at e g ori e s b y  at  l e a st  1  a n d  w or s e ni n g  of  at  l e a st  1  s y st e mi c  
i nfl a m m at or y m ar k er (i. e. s er u m f erriti n l e v el s ≥ 5 0 0 n g/ m L or s er u m 
C R P ≥ 2 x U L N ) t h at w a s m e eti n g c o m pl et e r e s p o n s e crit eri a b ef or e 


 
 
 
P a g e 2 5  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
o  F ull di s e a s e r e a cti v ati o n  
•  
I n cr e a s e  i n  t h e  n u m b er of  aff e ct e d  o bj e cti v e e n d  or g a n  d a m a g e  
c at e g ori e s t o at l e a st  t h e n u m b er of aff e ct e d o bj e cti v e e n d or g a n 
d a m a g e c at e g ori e s at  b a s eli n e  ( V 1) a n d  
•   
Ex a c er b ati o n of at l e a st 1 s y st e mi c i nfl a m m at or y m ar k er (i. e. s er u m 
f erriti n  l e v el s  ≥ 5 0 0  n g/ m L  or  s er u m  C R P  ≥ 2 x  U L N)  t h at  w a s  
m e eti n g c o m pl et e r e s p o n s e crit eri a b ef or e  
 
N ot e: It i s r e c o m m e n d e d t h at p ati e nt s s uff eri n g fr o m s e v er e  C N S m a nif e st ati o n s ar e p ut o n 
r e s c u e i m m u n o s u p pr e s si o n tr e at m e nt.  
 
S A F E T Y A S S E S S M E N T  
T h e I n v e sti g at or will a s s e s s p ati e nt s af et y t hr o u g h o ut t h e st u d y. I n a d diti o n, 
t h e  D S M B,  a n  i n d e p e n d e nt  c o m mitt e e,  will  a n al y z e  cli ni c al  or  bi ol o gi c al  
w or s e ni n g  of  t h e  st at u s of  st u d y  p ati e nt s (i. e., S A E s)  a n d  al s o  tr e at m e nt 
f ail ur e s a n d  will a s s e s s t h e gl o b al s af et y of T a d e ki ni g alf a ( s e e d et ail s i n 
St u d y D e si g n s e cti o n of S y n o p si s).  
 
S af et y a s s e s s m e nt d uri n g t h e st u d y will i n cl u d e:  
 
o  Pri or  t o  i niti ati o n  of  t h er a p y,  p h y si c al  e x a mi n ati o n,  vit al  si g n s,  
t e sti n g  f or  a cti v e a n d  lif e -t hr e at e ni n g  i nf e cti o n s,  c o m pl et e  bl o o d  
c o u nt , cli ni c al c h e mi str y , c o a g ul ati o n a n d uri n al y si s .  
o  D uri n g
 tr e at m e nt
 p h a s e,
 p h y si c al
 e x a mi n ati o n,
 i n cl u di n g 
o p ht h al m i c e x a mi n ati o n, vit al si g n s , r o uti n e l a b or at or y ( c o m pl et e 
bl o o d c o u nt, cli ni c al c h e mi str y, uri n al y si s), A E s, i n cl u di n g A E s  of 
S p e ci al I nt er e st ( A E SI), c o n c o mit a nt m e di c ati o n s, l o c al t ol er a bilit y 
i n d e x, i m m u n o g e ni cit y, a n d c o a g ul ati o n t e st s.  
o  R e g ar di n g i m m u n o g e ni cit y , A D A s a s s e s s m e nt will b e p erf or m e d at 
V 1 , W e e k 2 ( V 3), W e e k 4 ( V 5), W e e k 1 2 ( V 7) , W e e k 1 8 ( V 8) , a n d 
R W W e e k 2 2 ( V 1 0) , W e e k 2 6 ( V 1 1) a n d  W e e k 3 4 ( V 1 3) . 
o  S af et y  a n d  di s e a s e  a cti vit y  l a b s  will  b e  a s s e s s e d  d uri n g 
h o s pit ali z ati o n  a s  r e q uir e d,  w e e kl y  d uri n g  vi sit s  f or  t h e  fir st  f o ur  
w e e k s , t h e n a p pr o xi m at el y m o nt hl y d uri n g vi sit s u ntil c o m pl eti o n of 
t h e st u d y, or at u n s c h e d ul e d vi sit s.  
 
• 
w e e kl y fr o m Vi sit 0 t o Vi sit 5;  
• 
m o nt hl y fr o m Vi sit 6 t o Vi sit 7;  
• 
at Vi sit 9 ( 2 w e e k s fr o m Vi sit 8);  
• 
at Vi sit 1 0 ( 2 w e e k s fr o m Vi sit 9);  
• 
m o nt hl y fr o m Vi sit 1 1  t o Vi sit 1 3. 
 
A E s will b e c oll e ct e d fr o m t h e ti m e of i nf or m e d c o n s e nt t hr o u g h t h e e n d of 
t h e  st u d y.  D efi niti o n s  a n d  r e p orti n g  pr o c e d ur e s  f or  A E s  a n d  S A E s  ar e  
pr o vi d e d i n S e cti o n 1 6 . “ H a n dli n g of A d v er s e E v e nt s”. 


 
 
 
P a g e 2 6  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
D et ail s  o n  r o uti n e  s af et y  l a b or at or y  a s s e s s m e nt s,  vir ol o g y,  a n d  s er ol o g y  
t e st s, a n d c oll e cti o n of s a m pl e s f or A D A s (i m m u n o g e ni cit y) ar e pr o vi d e d i n 
T a bl e 2 .  
P h y si c al e x a mi n ati o n s a n d vit al si g n s ( s y st oli c a n d di a st oli c bl o o d pr e s s ur e, 
h e art r at e, r e s pir at or y r at e, w ei g ht a n d b o d y t e m p er at ur e) will b e c oll e ct e d at 
all vi sit s.  H ei g ht i s c oll e ct e d at S cr e e ni n g.  
T h e L o c al T ol er a bilit y I n d e x i s pr o vi d e d i n A p p e n di x 2 .  
 
* N O T E:  
L a b or at or y s af et y a n d effi c a c y e n d p oi nt s will b e st u di e d at t h e vi sit s b y t h e 
c e ntr al l a b. F or h o s pit ali z e d p ati e nt s , l o c al l a b s will p erf or m , i n a d diti o n, 
a n al y s e s a s r e q uir e d b y t h e st a n d ar d of c ar e  a n d  t hi s i nf or m ati o n will b e 
e nt er e d i n t h e st u d y e C R F . 
 
P RI M A R Y E N D P OI N T S:  E F FI C A C Y  
o  T h e pri m ar y o ut c o m e i s t h e ti m e t o fir st o c c urr e n c e of di s e a s e r e a cti v ati o n 
(i n cl u di n g  f ull  a n d  p arti al  di s e a s e  r e a cti v ati o n) d uri n g  t h e  1 6 -w e e k  R W  
p h a s e.  
 
S E C O N D A R Y E N D P OI N T S  
K e y S e c o n d ar y Effi c a c y E n d p oi nt  
o  R e s p o n s e t o t h er a p y (i n cl u di n g c o m pl et e r e s p o n s e a n d p arti al r e s p o n s e) i n 
t h e  S A O L  p h a s e  fr o m  W e e k  1 0  o n w ar d s a n d o b s er v e d  at  l e a st  at  2  
c o n s e c uti v e vi sit s at l e a st 2 w e e k s a p art d uri n g t h e S A O L p h a s e  
Ot h er S e c o n d ar y Effi c a c y E n d p oi nt s  
o  B e st r e s p o n s e  t o  t h er a p y d uri n g  t h e  S A O L  p h a s e  (i n cl u di n g  c o m pl et e  
r e s p o n s e a n d p arti al r e s p o n s e a n d di s e a s e i m pr o v e m e nt ) 
o  D ur ati o n of r e s p o n s e t o t h er a p y (i n cl u di n g c o m pl et e r e s p o n s e a n d p arti al 
r e s p o n s e) d uri n g t h e S A O L p h a s e  
o  Di s e a s e  r e a cti v ati o n  r at e  f or  i n di vi d u al  s u bj e ct s  ( n u m b er  of  di s e a s e 
r e a cti v ati o n s e x p eri e n c e d  p er  w e e k  w hil e  e a c h  s u bj e ct  i s  o n  t h e  st u d y  
tr e at m e nt d uri n g t h e S A O L p h a s e ). 
o   Tr e at m e nt  f ail ur e s (i. e.  p ati e nt s  w h o  e x p eri e n c e  at  l e a st  o n e  di s e a s e 
r e a cti v ati o n) 
o  I nt e n sit y of di s e a s e r e a cti v ati o n s  ( d efi n e d b y t h e l e v el of a cti vit y gi v e n b y 
t h e m AI D AI – b ot h o bj e cti v e a n d s u bj e cti v e crit eri a ) 
o   S er u m C R P  
o   S er u m F erriti n 
o  I m pr o v e m e nt of f e v er s (if pr e s e nt at B a s eli n e )  
o  I m pr o v e m e nt of h e p at o/ s pl e n o m e g al y (if pr e s e nt at B a s eli n e )  
o  I m pr o v e m e nt  i n  s er u m  al b u mi n  a n d  li v er  tr a n s a mi n a s e s,  a n e mi a  a n d/ or  
pl at el et c o u nt  (if pr e s e nt at B a s eli n e) 


 
 
 
P a g e 2 7  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
o  H o s pit al l e n gt h of st a y  
o  P h y si ci a n Gl o b al A s s e s s m e nt  
o  P ati e nt` s/ C ar e gi v er` s q u alit ati v e e v al u ati o n of h e alt h s t at u s  
o  Pr e s e n c e of s ki n r a s h ( e v ol uti o n if pr e s e nt at B a s eli n e or a p p e ar a n c e d uri n g 
t h e st u d y) 
o  T ol er a n c e  t o  or al/ e nt er al  n utriti o n  f or  h o s pit ali z e d  p ati e nt s  if  i nt e sti n al  
d y sf u n cti o n w a s pr e s e nt at B a s eli n e  
o  I m pr o v e m e nt of st o ol o ut p ut f or h o s pit ali z e d p ati e nt s if i nt e sti n al d y sf u n cti o n 
w a s pr e s e nt at B a s eli n e  
 
D uri n g t h e S A O L p h a s e , p ati e nt e v ol uti o n will b e d e s cri b e d b y pl otti n g o v er ti m e t h e m AI D AI, P G A, 
F erriti n, a n d C R P a s w ell a s  t h e m o st pr o mi n e nt cli ni c al f e at ur e s a c c or di n g t o t h e i n di vi d u al p ati e nt 
pr ofil e s . A b s ol ut e  a n d  p er c e nt a g e  of  c h a n g e  fr o m  b a s eli n e  will  b e  c al c ul at e d  f or  c o nti n u o u s  
v ari a bl e s.  R e s p o n s e t o tr e at m e nt i n t h e i niti al a cti v e di s e a s e, n u m b er, fr e q u e n c y a n d s e v erit y of 
di s e a s e r e a cti v ati o n s  d uri n g t h e st u d y will b e c o m p ar e d t o i n ci d e n c e a n d s e v erit y d e s cri b e d i n t h e 
m e di c al hi st or y of i n di vi d u al p ati e nt s.  
 
- S e c o n d ar y S af et y a n d T ol er a bilit y E n d p oi nt s  
o   Ad v er s e e v e nt s  [i n cl u di n g A E SI] will b e r e p ort e d  
o   Ph y si c al e x a mi n ati o n  fi n di n g s: cli ni c all y si g nifi c a nt c h a n g e s fr o m B a s eli n e  
o  Vit al si g n s: cli ni c all y si g nifi c a nt c h a n g e s fr o m B a s eli n e  
o  L a b or at or y a s s e s s m e nt s  (*): i n cl u di n g cli ni c all y si g nifi c a nt c h a n g e s fr o m 
B a s eli n e i n h e m at ol o g y wit h pl at el et c o u nt s, C R P, E S R, f erriti n, fi bri n o g e n, 
D- di m er, li v er e n z y m e s, (N ot e: a ll cli ni c all y si g nifi c a nt a b n or m al l a b or at or y 
r e s ult s or a s s e s s m e nt s m u st b e f oll o w e d u ntil t h e y r e s ol v e (i. e., r et ur n t o 
n or m al  or  B a s eli n e  v al u e s)  or  st a bili z e,  or  u ntil  t h e y  ar e  j u d g e d  b y  t h e  
I n v e sti g at or t o b e n o l o n g er cli ni c all y si g nifi c a nt)  
o  I m m u n o g e ni cit y  e v al u ati o n:  G e n er ati o n  of  a nti-r e c o m bi n a nt  h u m a n  I L-
1 8 B P  ( a nti-r hI L-1 8 B P) a nti b o di e s  
o  L o c al  t ol er a bilit y  at  t h e  i nj e cti o n  sit e  ( e v al u at e d  b y  a  st a n d ar di z e d  
a s s e s s m e nt)  
 
(*) N O T E:  
L a b or at or y s af et y a n d effi c a c y e n d p oi nt s will b e st u di e d at t h e vi sit s b y t h e 
c e ntr al  l a b.  F or  h o s pit ali z e d  p ati e nt s , l o c al  l a b s  will  p erf or m,  i n  a d diti o n,  
a n al y s e s a s r e q uir e d b y t h e st a n d ar d of c ar e a n d t hi s i nf or m ati o n will b e 
e nt er e d  i n t h e st u d y e C R F.  
 
C H A R A C T E RI Z A TI O N O F T H E P H A R M A C O KI N E TI C ( P K) P R O FI L E O F T A D E KI NI G A L F A 
A F T E R R E P E A T E D S. C. I N J E C TI O N S  
E nr oll e d p ati e nt s  will  b e  a s s e s s e d  f or  P K  at  V 1  ( w e e k 1)  a n d  V 5  ( w e e k 4).  
A d diti o n al s a m pl e f or P K st u d y will b e c oll e ct e d at V 1 a n d V 5 pri or t o tr e at m e nt 
a n d at 2 h, 4 h, 6 h a n d 2 4 h p o st tr e at m e nt  ( wit h a +/- 3 0 mi n ut e wi n d o w at e a c h 
s a m pl e c oll e cti o n). Tr o u g h l e v el s ar e c al c ul at e d b a s e d o n bl o o d s a m pl e s u s e d 
f or l a b t e sti n g t a k e n at e v er y vi sit pri or t o tr e at m e nt a d mi ni str ati o n ( n o e xtr a 
s a m pl e n e e d e d).  P ati e nt s w h o ar e n ot h o s pit ali z e d will r e q uir e s e p ar at e st u d y 


 
 
 
P a g e 2 8  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
vi sit s at W e e k 0 / D a y 2, a n d W e e k 4 / D a y 2 9, a n d will n e e d t o pr e s e nt t o t h e 
sit e 2 4 h o ur s p o st -tr e at m e nt f or fi n al P K s a m pl e c oll e cti o n s, a s w ell a s A E a n d 
c o n c o mit a nt m e di c ati o n a s s e s s m e nt s.  
P K 
E n d p oi nt s 
- Ti m e  t o  m a xi m al  c o n c e ntr ati o n  ( T m a x ),  t h e  m a xi m al  
c o n c e ntr ati o n ( C m a x ), tr o u g h c o n c e ntr ati o n, ar e a u n d er t h e c ur v e d uri n g t h e fir st 
2 4  ho u r s of tr e at m e nt ( A U Ct 0-2 4 ) a n d t h e eli mi n ati o n h alf-lif e will b e d et er mi n e d 
i n s er u m.  T h e st e a d y st at e c o n c e ntr ati o n will b e e x pl or e d at V 5 ( w e e k 4 ).  
S T O P PI N G R U L E ( S) F O R DI S C O N TI N UI N G T R E A T M E N T I N I N DI VI D U A L P A R TI CI P A N T  
P ati e nt  wit h dr a w al/ P h y si ci a n  di s c o nti n u ati o n   
T h e p h y si ci a n s a n d t h e p ati e nt s ( or l e g al r e pr e s e nt ati v e) will h a v e t h e o pti o n 
t o di s c o nti n u e t h e tr e at m e nt if t h e y f e el t h at p ur s ui n g t h e tr e at m e nt i s n ot 
a p pr o pri at e.  
T h e p h y si ci a n c a n d e ci d e a n yti m e t o st art r e s c u e i m m u n o s u p pr e s si o n a n d 
t h er ef or e di s c o nti n u e t h e p ati e nt  fr o m t h e st u d y*. 
* All k e y s af et y a n d effi c a c y o ut c o m e s will b e f oll o w e d u p . P ati e nt s will c o nti n u e t o c o m e t o t h e 
s c h e d ul e d vi sit s f or s af et y a n d effi c a c y a s s e s s m e nt s.  
Tr e at m e nt di s c o nti n u ati o n  
T h e o c c urr e n c e of a d v er s e e v e nt s of gr a d e s 3 a n d 4 of s e v erit y ( s e cti o n 1 6) 
m a y  r e s ult i n tr a n si e nt or p er m a n e nt tr e at m e nt di s c o nti n u ati o n. If tr e at m e nt 
i nt err u pti o n  i s  m or e  t h a n  3  w e e k s, t h e  s u bj e ct  will  b e  p er m a n e ntl y  
di s c o nti n u e d fr o m t h e st u d y.  
St u d y di s c o nti n u ati o n  
St o p pi n g of t h e st u d y will b e stri ctl y d et er mi n e d f or s af et y c o n c er n s.  
At a n y ti m e, t h e D S M B m a y r e c o m m e n d t o t h e S p o n s or t h e e arl y t er mi n ati o n 
of  t h e  st u d y  aft er  r e vi e wi n g  st u d y  s af et y  d at a  i n cl u di n g  A E s,  S A E s,  a n d  
s u s p e ct e d u n e x p e ct e d s eri o u s a d v er s e r e a cti o n s ( S U S A R s ).  
At a n y ti m e, t h e S p o n s or m a y r e c o m m e n d t er mi n ati n g t h e st u d y .  
 
 
C o n d u ct of t el e m e di ci n e st u d y vi sit s  
I n or d er t o pr ot e ct t h e p ati e nt’ s a n d c ar e gi v er’ s s af et y a n d w elf ar e d uri n g t h e 
C O VI D -1 9  p a n d e mi c ,  c o n d u cti o n  of  o n-sit e  st u d y  vi sit s  m a y  n ot  b e  
c o n si d er e d a p pr o pri at e ; m o st p ati e nt s h a v e t o tr a v el t o t h eir st u d y sit e a n d 
o n -sit e st u d y vi sit s m a y e x p o s e b ot h t h e p ati e nt s a n d c ar e gi v er s a s w ell a s 
st u d y sit e p er s o n n el t o a n i n cr e a s e d ri s k of i nf e cti o n.  
M or e o v er, d u e t o t h e ultr a -r ar e i n di c ati o n of t hi s st u d y, c o n d u cti n g o n-sit e 
st u d y vi sit s at sit e s oft e n l o c at e d f ar a w a y fr o m t h e p ati e nt` s h o m e h a s m a d e 
st u d y c o n d u ct c h all e n gi n g.   
T h u s, i n  a n  eff ort  t o  a c c o m m o d at e  t h e  p ati e nt s  a n d  t h eir  f a mili e s w hil e 
e n s uri n g t h e r el e v a nt st u d y d at a i s c oll e ct e d , s c h e d ul e d st u d y vi sit s ( ex c e pt 
f or t h e B a s eli n e vi sit) m a y b e c o n d u ct e d a s t el e m e di ci n e vi sit s  i n v ol vi n g t h e 
u s e of el e ctr o ni c c o m m u ni c ati o n s (f or e x a m pl e, li v e i nt er a cti v e vi d e o a n d 


 
 
 
P a g e 2 9  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
a u di o) t o e n a bl e sit e st aff t o c o n d u ct “ virt u al” ( n ot i n -p er s o n) vi sit s wit h t h eir 
p ati e nt s. T h e s e vi sit s m a y b e s u p p ort e d b y h o m e h e alt h n ur s e s a s si sti n g i n 
p h y si c al  e x a mi n ati o n  or  p erf or m a n c e  of  bl o o d  dr a w s.  L a b or at or y  
a s s e s s m e nt s m a y b e al s o p erf or m e d at q u alifi e d l o c al l a b or at ori e s. T h e st u d y 
sit e m a y al s o utili z e a p h y si c al e x a m i n ati o n fr o m t h e p ati e nt’ s m o st r e c e nt 
st a n d ar d  of  c ar e  vi sit  c o n d u ct e d  b y  t h e  l o c al  tr e ati n g  p h y si ci a n,  f or  t h e  
p ur p o s e of t h e st u d y.  
P ati e nt s  a n d/ or  p ar e nt s  ( or  l e g al  r e pr e s e nt ativ e,  if  a p pli c a bl e)  will  si g n  a  
r e s p e cti v e a s s e nt/i nf or m e d c o n s e nt pri or t o t h e c o n d u ct of s u c h t el e m e di ci n e 
vi sit s.  
F urt h er d et ail s a b o ut t h e diff er e nt p o s si biliti e s f or t h e c o n d u ct of t el e m e di ci n e 
vi sit s ar e d e s cri b e d i n s e cti o n 1 4. 1.  
 
 


 
 
 
P a g e 3 0  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0 - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
 
C O N FI D E N TI A L  
S T A TI S TI C A L A N A L Y SI S  
St ati sti c al a n al y si s:  
D at a  will  b e  a n al y z e d  o n  a n  i nt e nt -t o-tr e at  b a si s.  B a s eli n e  p ati e nt  a n d 
di s e a s e c h ar a ct eri sti c s a c c or di n g t o tr e at m e nt ar m will b e pr e s e nt e d u si n g 
st a n d ar d d e s cri pti v e st ati sti c s.  
C o m p ar ati v e st ati sti c al a n al y s e s will b e p erf or m e d o n d at a c oll e ct e d d uri n g 
t h e R W p h a s e. T h e pri m ar y e n d p oi nt i s ti m e t o fir st o c c urr e n c e of di s e a s e 
r e a cti v ati o n (i n cl u di n g f ull a n d p arti al di s e a s e r e a cti v ati o n) d uri n g t h e R W 
p h a s e. T a d e ki ni g alf a will b e c o m p ar e d t o pl a c e b o u si n g t h e l o g r a n k t e st at 
t h e al p h a = 0. 0 5 l e v el of si g nifi c a n c e ( 2-si d e d). K a pl a n -M ei er e sti m at e s of 
t h e  di stri b uti o n  of  ti m e-t o-e v e nt  will  b e  s u m m ari z e d  a n d  gr a p h e d  b y  
tr e at m e nt gr o up. 
T o t e st t h e effi c a c y of T a d e ki ni g alf a o n s e c o n d ar y o ut c o m e s  d uri n g t h e R W , 
Fi s h er' s e x a ct t e st will b e utili z e d f or bi n ar y o ut c o m e s (i. e. tr e at m e nt f ail ur e 
r at e) a n d a n o n-p ar a m etri c, M a n n – W hit n e y – Wil c o x o n t e st will b e utili z e d f or 
c o nti n u o u s o ut c o m e s (i. e. c h a n g e i n t h e m AI D AI). T o a s s e s s t h e i m p a ct of 
p o s si bl e  v ari ati o n  i n  b a s eli n e  m e a s ur e s,  a n a n al y si s  of  c o v ari a n c e  
( A N C O V A) m o d el wit h c o v ari at e a dj u st m e nt f or B a s eli n e m a y b e c o n si d er e d  
a s  a  s e n siti vit y  a n al y si s,  or  alt er n ati v e  n o n -p ar a m etri c  a p pr o a c h e s  if  
n or m alit y a s s u m pti o n s ar e n ot m et .  
If  t h e  pri m ar y  a n al y si s  i s  st ati sti c all y  si g nifi c a nt  ( p < 0. 0 5),  t h e  f oll o wi n g  
s e c o n d ar y e n d p oi nt s m e a s ur e d d uri n g t h e R W p h a s e will b e a n al y z e d u si n g 
a fi x e d -s e q u e n c e t e sti n g pr o c e d ur e i n t h e or d er s p e cifi e d b el o w t o c o ntr ol 
t h e o v er all l e v el of si g nifi c a n ce:  
•  
Tr e at m e nt f ail ur e  r at e; 
•  
C h a n g e fr o m R W b a s eli n e t o W e e k 3 4 (i. e. W e e k 1 6 of t h e R W p h a s e) 
or E n d of St u d y Vi sit i n t h e m AI D AI t ot al s c or e; a n d  
•  
C h a n g e fr o m R W b a s eli n e t o W e e k 3 4 or E n d of St u d y Vi sit i n t h e P G A 
s y m pt o m s e v erit y s c or e.  
F or e a c h of t h e s e e n d p oi nt s, t h e tr e at m e nt gr o u p s will b e c o m p ar e d u si n g a 
t w o-si d e d t e st at al p h a = 0. 0 5 l e v el of si g nifi c a n c e. H o w e v er, o n c e a n o n -
si g nifi c a nt r e s ult (i. e. p > 0. 0 5) o c c ur s, t h e r e s ult s of all s u b s e q u e nt a n al y s e s 
will b e e x pl or at or y r at h er t h a n c o nfir m at or y.  
I n  a d diti o n,  all  e n d p oi nt s  will  b e  e v al u at e d  d e s cri pti v el y  i n cl u di n g  9 5 %  
c o nfi d e n c e i nt er v al s f or t h e m e a n a n d pr o p orti o n s.  
A n al y si s of d at a c oll e ct e d d uri n g t h e S A O L p h a s e wi ll b e d e s cri pti v e i n n at ur e , 
t o i n cl u d e 9 5 % CI s ar o u n d s el e ct m e a n e sti m at e s a n d pr o p orti o n s of i nt er e st. 
A b s ol ut e  a n d  p er c e nt a g e  of  c h a n g e  fr o m  b a s eli n e  will  b e  c al c ul at e d  f or  
c o nti n u o u s  v ari a bl e s.  R e s p o n s e  t o  tr e at m e nt  i n  t h e  i niti al  a cti v e  di s e a s e , 
n u m b er, fr e q u e n c y a n d s e v erit y of di s e a s e r e a cti v ati o n s  d uri n g t h e st u d y will b e 
c o m p ar e d t o i n ci d e n c e a n d s e v erit y d e s cri b e d i n t h e m e di c al hi st or y of i n di vi d u al 
p ati e nt s.  
 
In di vi d u al s u bj e ct’ s r a w d at a will b e c a pt ur e d wit h d at a li sti n g s a n d i n di vi d u al 
p ati e nt pl ot s at e a c h ti m e p oi nt t o vi s u ali z e t h e diff er e nt r e s p o n s e s ( e. g. i n 
t er m s of m AI D AI, P G A, F erriti n a n d C R P a s w ell a s t h e m o st pr o mi n e nt 




 
 
 
P a g e 3 2  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
7 
S C H E D U L E O F E V E N T S  
T a bl e 1 : S c h e d ul e of E v e nt s  -- N ot e: Fl e xi bilit y i n t h e vi sit s c h e d uli n g i s all o w e d ( ± 3 d a y s) f or V 2 t hr o u g h V 1 3 – T h e t a bl e s h o w s w e e k n u m b er s a p pr o xi m at el y  
 
S A O L P h a s e h  
R W P h a s e 
 
Pri or t o V 1 
V 0  
 
S cr e e ni n g 
Vi sit  
W 0  
V 1/ 
D a y 0   
B a s eli n e 
W 1  
V 2/ 
D a y 7 
S O C  
T a p er  
W 2  
V 3/ 
D a y 1 4 
S O C  
T a p er  
W 3  
V 4/ 
D a y 2 1 
S O C  
T a p er  
W 4  
V 5/  
D a y 2 8  
S O C  
T a p er  
W 8  
V 6/  
D a y 
5 6  
W 1 2  
V 7/  
D a y 
8 4  
W 1 8  
V 8/  
D a y 
1 2 6 
W 2 0 
V 9/  
D a y 
1 4 0  
W 2 2 
V 1 0/ 
D a y 
1 5 4  
W 2 6   
V 1 1/ 
D a y 
1 8 2  
 
W 3 0 
V 1 2/  
D a y 
2 1 0  
W 3 4   
V 1 3/  
D a y 2 3 8  
St u d y 
c o m pl eti o n  
R e vi e w a n d si g ni n g of C hil d A s s e nt a n d I nf or m e d 
C o n s e nt F or m (I C F) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
D e m o gr a p hi c s a n d m e di c al hi st or y ( pr e vi o u s 
tr e at m e nt s a n d c o m or bi diti e s) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
O p ht h al mi c e x a mi n ati o n  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
I n cl u si o n/ e x cl u si o n crit eri a r e vi e w 
X 
X a  
 
 
 
 
 
 
 
 
 
 
 
 
P h y si c al e x a m wit h s p e cifi c a s s e s s m e nt of 
h e p at o s pl e n o m e g al y a n d vit al si g n s 
X k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
R a n d o mi z ati o n t o T a d e ki ni g alf a or pl a c e b o 
( a p pli c a bl e f or t h e R W p h a s e o nl y) 
 
N/ A 
 
 
 
 
 
 
X 
 
 
 
 
 
St a n d ar d of C ar e ( S O C) T a p eri n g f 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Tr e at m e nt wit h T a d e ki ni g alf a ( S A O L p h a s e o nl y) 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Tr e at m e nt wit h T a d e ki ni g alf a or pl a c e b o a s 
r a n d o mi z e d i n t h e d o u bl e bli n d R W p h a s e ( s. c. 
e v er y 2 d a y s) b  
 
 
 
 
 
 
 
 
X i 
X 
X 
X 
X 
X 
R e vi e w of a d v er s e e v e nt s ( A E s, A E SI s) & 
c o n c o mit a nt m e di c ati o n s 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
L o c al T ol er a bilit y I n d e x a s s e s s m e nt c 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
P h y si ci a n gl o b al cli ni c al e v al u ati o n: m AI D AI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
P h y si ci a n Gl o b al A s s e s s m e nt ( P G A)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
P ati e nt` s/ c ar e gi v er` s e v al u ati o n of h e alt h st at u s 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
G e n eti c e v al u ati o n, i nf e cti o n e v al u ati o n s ( C M V, 
E B V, et c.), a n d s er ol o g y ( HI V, H C V, H B V),  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
H e m at ol o g y, cli ni c al c h e mi str y, E S R ( at l o c al l a b), 
uri n al y si s, C R P a n d F erriti n, c o a g ul ati o n ( pl at el et s, 
fi bri n o g e n, D-di m er, P T T, P T) --  (s a m pl e t a k e n 
pri or t o tr e at m e nt ), pr e g n a n c y t e stg l 
T B bl o o d t e st d l  
X l 
 
 
X d l  
X  
 
X  
X  
 
X  
 
X  
 
X  
 
X  
 
X l 
 
X  
 
X  
 
X  
 
X  
 
X  
 


 
 
 
P a g e 3 3  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
C M V = c yt o m e g al o vir u s; C R P = C-r e a cti v e pr ot ei n; E B V = E p st ei n- B arr Vir u s; E S R = er yt hr o c yt e s e di m e nt ati o n r at e; F U = F oll o w u p; H B V = h e p atiti s B vir u s; H C V = h e p atiti s C vir u s; HI V = H u m a n 
I m m u n o d efi ci e n c y Vir u s; I C F = I nf or m e d C o n s e nt F or m; I L- 1 8 = i nt erl e u ki n- 1 8; I L- 1 8 B P = i nt erl e u ki n- 1 8 bi n di n g pr ot ei n; m AI D AI = M o difi e d A ut oi nfl a m m at or y Di s e a s e A cti vit y I n d e x; P K = p h ar m a c o ki n eti c; P T = 
pr ot hr o m bi n ti m e; P T T = p arti al t hr o m b o pl a sti n ti m e;  R W = R a n d o mi z e d Wit h dr a w al p h a s e; S A O L p h a s e = Si n gl e ar m o p e n l a b el p h a s e; s. c. = s u b c ut a n e o u s; T B = t u b er c ul o si s  
 
a 
R e a s s e s s m e nt of i n cl u si o n/ e x cl u si o n crit eri a pri or t o tr e at m e nt st art  
 
b 
I n v e sti g ati o n al pr o d u ct ( T a d e ki ni g alf a or pl a c e b o) will b e a d mi ni st er e d e v er y 2 d a y s ± 5 h o ur s t o t h e p ati e nt. If t h e p ati e nt i s l o c at e d wit hi n cl o s e vi ci nit y t o t h e sit e, 
s/ h e h a s t h e o pti o n t o g o t o t h e sit e f or tr e at m e nt a d mi ni str ati o n or a H o m e C ar e N ur s e m a y a d mi ni st er t h e tr e at m e nt at t h e p ati e nt’ s r e si d e n c e. At V 1 ( W e e k 0), t h e 
fir st d os e will b e a d mi ni st er e d at t h e st u d y c e nt er a n d t h e p ati e nt will r e m ai n at t h e sit e f or a 2 -h o ur o b s er v ati o n.  
 
c 
L o c al T ol er a bilit y I n d e x will b e a s s e s s e d b y t h e I n v e sti g at or  or st u d y n ur s e  at t h e i n -cli ni c vi sit s  i n cl u di n g W e e k 0/ Vi sit 1 w h e n p ati e nt i s at sit e u n d er o b s er v ati o n aft er 
fir st d o s e, a n d b y t h e h o m e c ar e n ur s e o n t h e s u bj e ct’ s d o s e a d mi ni str ati o n d a y s, a p pr o xi m at el y e v er y ot h er d a y. 
 
d     T B bl o o d t e sti n g ( Q u a nti F E R O N T B t e st) s h o ul d  b e d o n e at t h e l o c al ( h o s pit al) l a b or c e ntr al l a b, pri or t o tr e at m e nt i niti ati o n  
 
e  
A d diti o n al s a m pl e f or P K st u d y will b e c oll e ct e d at V 1 a n d V 5 pri or t o tr e at m e nt a n d at 2 h, 4 h, 6 h a n d 2 4 h p o st tr e at m e nt  ( wit h a +/- 3 0 mi n ut e s wi n d o w at e a c h 
s a m pl e c oll e cti o n).  Tr o u g h l e v el s ar e c al c ul at e d b a s e d o n bl o o d s a m pl e s u s e d f or l a b t e sti n g ( n o e xtr a s a m pl e n e e d e d). P ati e nt s w h o ar e n ot h o s pit ali z e d will n e e d t o 
pr e s e nt t o t h e sit e 2 4 h p o st -tr e at m e nt f or fi n al P K s a m pl e c oll e cti o n, a s w ell a s A E a n d c o n c o mit a nt m e di c ati o n a s s e s s m e nt s. 
 
f 
If t h e p ati e nt h a s a di s e a s e r e a cti v ati o n d uri n g t h e t a p eri n g d o w n, 2 8 -d a y ( 4- w e e k ) S O C t a p eri n g c y cl e s m a y b e u s e d a n d c a n b e r e p e at e d d uri n g t h e 1 8 -w e e k S A O L 
st u d y p eri o d.   
 
g  A uri n e pr e g n a n c y t e st will b e p erf or m e d at e a c h st u d y vi sit o n all f e m al e s of c hil d b e ari n g p ot e nti al.  If t h e uri n e pr e g n a n c y t e st i s p o siti v e, a s er u m pr e g n a n c y t e st will 
b e p erf or m e d.  
 
h 
W 1 8/ Vi sit 8 will s er v e a s t h e E n d of t h e S A O L  p eri o d  vi sit f or t h o s e p ati e nt s w h o di s c o nti n u e d tr e at m e nt d uri n g t h e  S A O L  p h a s e  ( a n e arl y t er mi n ati o n f or m s h o ul d b e 
c o m pl et e d f or t h e s e p ati e nt s). T h e s e p ati e nt s will n ot c o nti n u e i nt o t h e R W p h a s e of t h e st u d y.  
 
i 
Tr e at m e nt of st u d y dr u g a d mi ni st er e d t o p ati e nt s at W 1 8/ Vi sit 8 w o ul d b e d et er mi n e d b y r a n d o mi z ati o n i nt o R W p h a s e. Fi n al d o s e of tr e at m e nt u n d er t h e S A O L  p h a s e 
of t h e st u d y will o c c ur 2 d a y s pri or t o W 1 8/ Vi sit 8.  All W 1 8 a s s e s s m e nt s m u st b e p erf or m e d pri or t o a d mi ni str ati o n of st u d y dr u g at W 1 8/ Vi sit 8.  
 
k  
H ei g ht c oll e ct e d at s cr e e ni n g  
 
l    C oll e cti o n of B a s eli n e l a b s a m pl e s m a y o c c ur u p t o 3 d a y s pri or t o t h e s c h e d ul e d W e e k 0/ D a y 0 a n d W e e k 1 8/  D a y 1 2 6  vi sit i n or d er t o h a v e r e s ult s a v ail a bl e t o c o nfir m 
p ati e nt eli gi bilit y pri or t o st u d y tr e at m e nt.   
 
m    Fl o w c yt o m etr y st u di e s ar e n e c e s s ar y w h e n a XI A P g e n eti c a b n or m alit y h a s b e e n f o u n d i n t h e g e n eti c t e sti n g. It i s n ot r e q uir e d f or p ati e nt s wit h N L R C 4 g e n eti c 
m ut ati o n s. 
Fl o w C yt o m etr y m  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
S er u m: T ot al I L- 1 8, fr e e I L- 1 8, I L- 1 8 B P ( s a m pl e 
t a k e n pri or t o tr e at m e nt) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
A nti- T a d e ki ni g alf a a nti b o di e s ( s a m pl e t a k e n 
pri or t o tr e at m e nt ) 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
 
X 
P K st u d y m e a s ur e m e nt s e  
 
X e  
 
 
 
X e  
 
 
 
 
 
 
 
 


 
 
 
P a g e 3 4  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
8 
I N T R O D U C TI O N  
8. 1  B a c k gr o u n d I nf or m ati o n  
I nt erl e u ki n 1 8 (I L-1 8) i s a m e m b er of t h e I L -1 s u p erf a mil y of c yt o ki n e s a n d w a s i niti all y d e s cri b e d a s 
a n I F N -γ -i n d u ci n g f a ct or pr o d u c e d b y a cti v at e d m a cr o p h a g e s s u b s e q u e nt t o mi cr o bi al sti m ul ati o n  
{ N a k a m ur a et al., 2 0 0 0}. Ma cr o p h a g e s  a n d d e n driti c c ell s ar e i m p ort a nt s o ur c e s of I L -1 8 b ut I L- 1 8  
e x pr e s si o n h a s b e e n al s o d e s cri b e d i n : k er ati n o c yt e s, o st e o bl a st s, i nt e sti n al e pit h eli al c ell s, a dr e n al 
c ort e x c ell, mi cr o gli al, a n d s y n o vi al fi br o bl a st s  { Gr a ci e et al., 2 0 0 3}.  I L-1 8  i s c o n si d er e d a n i m p ort a nt 
m e di at or of i nfl a m m at or y r e s p o n s e s a n d a c e ntr al pl a y er i n p at h o p h y si ol o gi c al c o n diti o n s s u c h a s 
a ut oi nfl a m m at or y  a n d  a ut oi m m u n e  di s e a s e s { A kir a,  2 0 0 0}. Si mil arl y  t o  I L -1  β , I L-1 8  i s  fir st  
s y nt h e si z e d  a s a n i n a cti v e pr e c ur s or wit h o ut a si g n al p e pti d e , r e m ai ni n g a s a n i ntr a c ell ul ar c yt o ki n e 
{ Di n ar ell o et al., 2 0 1 3}. T h e I L-1 8  g e n e i s c o n stit uti v el y a cti v e r e s ulti n g i n c o nti n u o u s e x pr e s si o n of 
I L-1 8 m R N A  { T o n e et al., 1 9 9 7}. T L R a n d I F N-γ si g n ali n g a n d N F - k B a cti v ati o n h a v e b e e n al s o 
r e c o g ni z e d a s e n h a n c er s of I L -1 8 g e n e e x pr e s si o n , { Gr a ci e et al., 2 0 0 3}. 
 
T h e  i ntr a c ell ul ar I L-1 8 pr e c ur s or i s cl e a v e d  b y c a s p a s e- 1 t o f or m a cti v e I L-1 8 t h at i s s e cr et e d t o t h e 
e xtr a c ell ul ar c o m p art m e nt. C a s p a s e -1 r e q uir e s, i n t ur n, a cti v ati o n b y t h e i nfl a m m a s o m e/ a p o pt o si s -
a s s o ci at e d S p e c k -li k e pr ot ei n wit h a c a s p a s e-r e cr uit m e nt d o m ai n (A S C) c o m pl e x. T h e l e a d erl e s s 
s e cr eti o n of I L -1 β  a n d  I L -1 8 i s i n d e p e n d e nt of t h e e n d o pl a s mi c r eti c ul u m/ G ol gi  p at h w a y  a n d i s 
d e p e n d e nt o n c a s p a s e 1 a cti v ati o n  { R at hi n a m a n d Fit z g er al d, 2 0 1 6}. 
 
I L-1 8 si g n al s t hr o u g h t h e I L -1 8 r e c e pt or c o m pl e x, a h et er o di m er of I L -1 8 R α a n d I L -1 8 R β . I L-1 8 R α  
i s  t h e  bi n di n g  sit e  of  I L-1 8, w h er e a s  I L -1 8 R β i s  a  si g n ali n g  m ol e c ul e .  I L-1 8 R  i s  e x pr e s s e d  o n  
l y m p h o c yt e s, m o n o c yt e s, d e n driti c c ell s, a n d ot h er c ell t y p e s  s u c h a s e n d ot h eli u m a n d e pit h eli u m . 
{ S m elt z et al., 2 0 0 1} { T U C CI et al., 2 0 0 7}. 
 
T h e br o a d s p e ctr u m of i m m u n or e g ul at or y a cti viti e s of I L -1 8 i s r el at e d t o pl ei otr o pi c eff e ct s d e p e n d e nt 
o n si g n ali n g c a s c a d e s s et i nt o m oti o n wit hi n v ari o u s  t ar g et c ell s { C arr oll et al., 2 0 0 8}. I L-1 8 i n d u c e s  
I F N-γ s y nt h e si s a n d s y n er gi z e s wit h I L -1 2 i n T h 1 c ell s  { X u et al., 1 9 9 8}. I L-1 8 al s o i n d u c e s I F N-γ  
t hr o u g h N K c ell  a cti v ati o n  { A kir a, 2 0 0 0}, a n d p ot e nti at e s t h e a cti o n of ot h er c yt o ki n e s o n i n n at e a n d 
a d a pti v e N K f u n cti o n s { Ni el s e n et al., 2 0 1 6} .  
 
I L-1 8 si g n al tr a n s d u cti o n i s pri m aril y m e di at e d b y t h e M Y D 8 8 -d e p e n d e nt p at h w a y wit h t h e r e s ult of 
N F -k B  tr a n sl o c ati o n  t o  t h e  n u cl e u s  f or  pr oi nfl a m m at or y  g e n e  a cti v ati o n  { S a cr e  et  al.,  2 0 0 7}.  I n 
a d diti o n t o t h e M Y D 8 8/I R A K// T R A F 6 si g n ali n g a r ol e f or mit o g e n -a cti v at e d pr ot ei n ki n a s e s ( M A P K) 
h a v e b e e n d e s cri b e d f or I L -1 8 si g n ali n g { Gr a ci e et al., 2 0 0 3}.  M or e o v er , I L-1 8 e n h a n c e s  t h e I F N-γ -
i n d u c e d  m R N A  e x pr e s si o n  a n d  s e cr eti o n  of  C X C L 9,  C X C L 1 0  a n d  C X C L 1 1  i n  p ar all el  t o  t h e  
a cti v ati o n of N F -k B, S T A T 1 a n d I F N -r e g ul at or y f a ct or (I R F)-1{ K a n d a et al., 2 0 0 7}.  
 
I L-1 8 bi ol o gi c al a cti vit y n e e d s a ti g ht r e g ul ati o n. I ntr a c ell ul ar pr o-I L-1 8 i s c o n v ert e d i nt o t h e a cti v e 
m e di at or s u b s e q u e nt t o i nfl a m m a s o m e a cti v ati o n a n d c a s p a s e -1 pr o c e s si n g. I n t h e e xtr a c ell ul ar 
e n vir o n m e nt  I L-1 8  bi n di n g  pr ot ei n  (I L - 1 8 B P) bi n d s  I L -1 8  wit h  hi g h  affi nit y  a n d  i n hi bit s  I L -1 8 
pr oi nfl a m m at or y  a cti vit y.  S ol u bl e  I L-1 8 R s,  α  a n d  β, c a n  i n hi bit  I L -1 8  i n d u c e d  I F N -Υ  pr o d u cti o n  
{ R e z ni k o v et al., 2 0 0 2}.  
 
I L-1 8 B P  is  a  cir c ul ati n g  i n hi bit or  of  I L-1 8.  T h e I L-1 8 B P  g e n e i s  c o n stit uti v el y  e x pr e s s e d  i n  
m o n o n u cl e ar c ell s a n d I F N-Υ i n d u c e s it s e n h a n c e d e x pr e s si o n  { H ur gi n et al., 2 0 0 2} e st a bli s hi n g a 
n e g ati v e f e e d b a c k l o o p. T h e I L-1 8 B P  g e n e e n c o d e s 4 diff er e nt i s of or m s of I L -1 8 B P, a, b, c, a n d d. 
I L-1 8 B P i s of or m s a a n d c n e utr ali z e t h e bi ol o gi c al a cti vit y of I L -1 8, w hil e i s of or m s b a n d d l a c k t hi s 
bi ol o gi c al a cti vit y . I L- 1 8 B P a n e utr ali z e s t h e a cti vit y of I L -1 8 b y bi n di n g t o it wit h a sl o w di s s o ci ati o n 
r at e ( 6. 4 3 + 0. 4 s e c-4) a n d a hi g h affi nit y c o n st a nt ( K d = 4 0 0 p M)  ({ Ki m et al., 2 0 0 0  
 
M a n y  i nfl a m m at or y c o n diti o n s ar e a s s o ci at e d wit h el e v at e d s er u m l e v el s of t ot al I L-1 8 a s c o m p ar e d 
t o h e alt h y c o ntr ol s  ({ Gr a ci e et al., 1 9 9 9, # 7 3 6 5 9}, { K a w a s hi m a et al., 2 0 0 1}, { M a e n o et al., 2 0 0 2}, 
{ M a e n o  et  al.,  2 0 0 4}).  Cert ai n  c o n diti o n s , pr o n e  t o  t h e  d e v el o p m e nt  of  M a cr o p h a g e  A cti v ati o n 




 
 
 
P a g e 3 6  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
mi ni m u m l e v el wit hi n 1 8 d a y s. T h e c oliti s r e s ol v e d, a n d c o -m e di c ati o n s,  i n cl u di n g c y cl o s p ori n e a n d 
m et h yl pr e d ni s ol o n e,  w er e  p h a s e d  o ut.  B y  J ul y  8,  2 0 1 5,  aft er  2 0  d a y s  of  tr e at m e nt,  t h e  p ati e nt  
r e m ai n e d af e bril e, pr o gr e s s e d t o f ull br e a st mil k f e e d s, h a d n or m al st o ol o ut p ut, a n d w a s di s c h ar g e d 
fr o m t h e h o s pit al o n A u g u st 6, 2 0 1 5.  C o m p a s si o n at e tr e at m e nt of T a d e ki ni g alf a h a s c o nti n u e d f or 
t h e i nf a nt a s of S e p 2 0 2 1 . 
 
A B 2 Bi o, i n c oll a b or ati o n Dr. 
 fr o m Ci n ci n n ati C hil dr e n' s H o s pit al M e di c al C e nt er, 
h a s c o n d u ct e d a st u d y i n XI A P d efi ci e n c y p e di atri c p ati e nt s t o e x a mi n e t h e l e v el s of fr e e I L -1 8 d uri n g 
e pi s o d e s  of  a cti v e  di s e a s e  a n d  d uri n g  di s e a s e  r e mi s si o n.  P ati e nt s  wit h  XI A P  d efi ci e n c y  h a v e  
cir c ul ati n g fr e e I L -1 8 d uri n g a cti v e di s e a s e a n d i n r e mi s si o n.  Hi g h er l e v el s w er e o b s er v e d d uri n g 
di s e a s e  fl ar e s.  T hi s  o b s er v ati o n  s u p p ort s  t h e  c o nt e nti o n  t h at  fr e e  I L -1 8  m a y  c o ntri b ut e  t o  t h e  
pr o p e n sit y of t h e s e p ati e nt s t o d e v el o p M A S/ H L H.  
 
It i s h y p ot h e si z e d t h at i n hi biti o n of fr e e I L-1 8 b y T a d e ki ni g alf a w o ul d s er v e a s a di s e a s e -m o dif yi n g  
t h er a p e uti c i n t h e s e c o n diti o n s.  
 
T h e ai m of A B 2  Bi o i s t o d e v el o p T a d e ki ni g alf a i n t h e U S f or t h e tr e at m e nt of a cl u st er of r ar e 
p e di atri c  di s e a s e s, n a m el y, M A S a n d M A S -li k e di s or d er s d o mi n at e d b y t h e a cti v ati o n of t h e I L -1 8 
p at h w a y.  
8. 2  S u m m ar y of Ri s k s a n d B e n efit s  ( R/ B a s s e s s m e nt) 
It i s h y p ot h e si z e d t h at di s e a s e m o difi c ati o n b y t h er a p e uti c t ar g eti n g of I L-1 8 wit h T a d e ki ni g alf a m a y 
off er si g nifi c a nt b e n efit  i n p ati e nt s s uff eri n g fr o m m ut ati o n s i n N L R C 4 a n d XI A P d efi ci e n c y, d u e t o 
I L-1 8 n e utr ali z ati o n t o g et h er wit h bl o c ki n g d o w n str e a m c yt o ki n e s s u c h a s I L -6 a n d t u m or n e cr o si s 
f a ct or– α ( T N F -α ). 
 
A f e m al e i nf a nt pr e s e nt e d at  
 of a g e (I N D # 
) wit h a n u nr e m ar k a bl e u p p er r e s pir at or y 
i nf e cti o n a s s o ci at e d wit h p o siti v e P ol y m er a s e C h ai n R e a cti o n t e sti n g p o siti v e f or p ar ai nfl u e n z a t y p e 
3.  C o u g h  a n d  c or y z a  i m pr o v e d  a n d  vir al  R N A  cl e ar e d,  b ut  h e cti c  f e v er s  a n d  er yt hr o d er m  r a s h  
p er si st e d f or s e v er al w e e k s. Aft er t hr e e w e e k s of f e v er, s h e a c ut el y d e v el o p e d or al i nt ol er a n c e a n d 
s e v er e s e cr et or y di arr h e a t h at p er si st e d d e s pit e c e s s ati o n of or al i nt a k e. H er c o n diti o n w or s e n e d 
wit h a c ut e ri s e i n i nfl a m m at or y m ar k er s, r el ati v e t hr o m b o c yt o p e ni a, a n d ri si n g f erriti n all c o n si st e nt 
wit h  a  M A S -li k e  s y n dr o m e.  U p p er  a n d  l o w er  e n d o s c o p y  s h o w e d  s e v er e  m u c o s al  i nfl a m m ati o n  
e xt e n di n g fr o m t h e st o m a c h t hr o u g h l ar g e i nt e sti n e. F u n cti o n al a s s e s s m e nt f or i m p air e d c yt ot o xi cit y, 
w hi c h c a u s e s a si mil ar p h e n ot y p e k n o w n a s f a mili al H e m o p h a g o c yti c L y m p h o hi sti o c yt o si s ( F H L), 
w a s n or m al. T h e p ati e nt’ s pr e s e nt ati o n w a s r e mi ni s c e nt of r e c e nt r e p ort s of e arl y -o n s et e nt er o c oliti s 
wit h  M A S  a s s o ci at e d  wit h  m ut ati o n s  i n  N L R C 4 . A d e  n o v o  h et er o z y g o u s  m ut ati o n  i n  N L R C 4  
( c. 1 0 2 2 T > C, p. V al 3 4 1 Al a) w a s c o nfir m e d b y S a n g er s e q u e n ci n g a n d pr e vi o u sl y a s s o ci at e d wit h a 
si mil ar, b ut ulti m at el y f at al, pr e s e nt ati o n  { R o m b er g et al., 2 0 1 4}. 
 
T h e p ati e nt w a s tr e at e d a g gr e s si v el y wit h c orti c o st er oi d s a n d I L - 1β  bl o c k a d e  wit h  mi ni m al r e s p o n s e. 
T h e  a d diti o n  of  m a xi m al  d o s e s  of  T F N α -bl o c k a d e  (i nfli xi m a b),  c y cl o s p ori n e,  a n d  α 4 β 7 -i nt e gri n 
i n hi biti o n ( v e d oli z u m a b) s u c c e e d e d i n st a bili zi n g t h e p ati e nt’ s f e v er s a n d c o a g ul o p at h y b ut di d n ot 
i m pr o v e t h e a n e mi a, h y p erf erriti n e mi a, or e nt er o c oliti s. T h e p ati e nt’ s s er u m w a s a s s e s s e d f or t ot al 
I L-1 8,  a s  w ell  a s  fr e e  I L -1 8  a n d  b ot h  w er e  f o u n d  t o  b e  e xtr a or di n aril y  el e v at e d.  U n d er  a  
c o m p a s si o n at e -u s e I N D a ut h ori z ati o n, t h e p ati e nt w a s gi v e n T a d e ki ni g alf a  at a d o s e of 2 m g/ k g 
s u b c ut a n e o u sl y  ( s. c.) e v er y 4 8 h o ur s. Wit hi n t h e fir st t w o d o s e s, t h e p ati e nt i m pr o v e d r a pi dl y i n 
a s s o ci ati o n wit h a c ut e dr o p i n fr e e I L -1 8 . H er r e m ai ni n g i nfl a m m at or y f e at ur e s, i n cl u di n g e nt er o c oliti s, 
al s o  i m pr o v e d  st e a dil y  a n d  all o w e d  w e a ni n g  of  ot h er  i m m u n o s u p pr e s si o n  a n d  r ei ntr o d u cti o n  of  
e nt er al f e e di n g.  
 
Aft er m or e t h a n 3 m o nt h s of c o m bi n e d I L - 1β  a n d I L -1 8 bl o c k a d e, t h e p ati e nt st o p p e d all ot h er  
i m m u n o m o d ul ati o n a n d m a d e a f ull r e c o v er y. I m p ort a ntl y, n o a d v er s e e v e nt s ( A E s), o p p ort u ni sti c 
i nf e cti o n s, or l o s s of effi c a c y h a v e b e e n o b s er v e d. 
 


 
 
 
P a g e 3 7  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
X- li n k e d l y m p h o pr olif er ati v e s y n dr o m e 2 or XI A P d efi ci e n c y  i s a f or m of f a mili al or pri m ar y H L H 
c a u s e d b y l o s s -of -f u n cti o n or i n a cti v ati n g XI A P m ut ati o n s. XI A P d efi ci e n c y i s m o stl y a p e di atri c  
c o n diti o n wit h H L H a s a fr e q u e nt cli ni c al pr e s e nt ati o n ( 5 4 %) a n d r e c urr e nt s pl e n o m e g al y ( 5 7 %) a n d 
I B D ( 2 6 %) a s ot h er fr e q u e nt p h e n ot y p e s ( L at o ur et al. 2 0 1 5). I L-1 8 i s stri ki n gl y el e v at e d i n XI A P -
H L H p ati e nt s; it r e m ai n s hi g h at r e c o v er y b ut i n cr e a s e s si g nifi c a ntl y d uri n g di s e a s e a cti v ati o n ( W a d a 
et al. 2 0 1 4). M a n y i m m u n o m o d ul at or y f u n cti o n s h a v e b e e n a s cri b e d t o XI A P. A m o n g ot h er f u n cti o n s, 
XI A P i s a n e g ati v e r e g ul at or of i nfl a m m a s o m e s i n cl u di n g N L R C 4 . Alt h o u g h n o cli ni c al e vi d e n c e f or 
t h e effi c a c y of I L-1 8 bl o c k a d e e xi st s o f ar f or XI A P d efi ci e n c y it i s hi g hl y pl a u si bl e t h at I L -1 8 i s t h e 
c o m m o n d o mi n a nt  i m m u n e  m e di at or  i n  b ot h  m o n o g e ni c  c o n diti o n s , N L R C 4 -M A S  a n d  XI A P  
d efi ci e n c y.  
T o g et h er, t h e P K a n d t o xi c ol o gi c al e v al u ati o n of T a d e ki ni g alf a a s s e s s e d i n a ni m al s a n d t h e d at a 
o bt ai n e d wit h si n gl e a n d r e p e at e d S C a d mi ni str ati o n of d o s e s u p t o 3 2 0 m g i n h u m a n s, t h e o n g oi n g 
P h a s e II cli ni c al st u d y a n d c a s e r e p ort of t h e N L R C 4 m ut ati o n,  h a v e s o f ar d e m o n str at e d a f a v or a bl e 
s af et y a n d t ol er a bilit y pr ofil e, s u p p orti n g t h e i niti ati o n of t h e pl a n n e d p h a s e 3 st u d y.  
 
T h e  sli g ht  a n d  r e v er si bl e  s af et y  fi n di n g s  pr e vi o u sl y  i d e ntifi e d  d uri n g  t h e  n o n cli ni c al  a n d  cli ni c al  
pr o gr a m  will  b e  cl o s el y  m o nit or e d  t hr o u g h  t h e  c oll e cti o n  of  A E s ,  i n cl u di n g  t h e  e v al u ati o n  of 
i m m u n o g e ni cit y, f oll o w-u p.   T h e  D at a  S af et y  M o nit ori n g  B o ar d   (D S M B )  will  p erf or m  a  s af et y  
e v al u ati o n.  
 
I n c o n cl u si o n, i n hi biti n g I L-1 8 i n t h e s e p ati e nt s m a y bri n g a t h er a p e uti c s ol uti o n t h at i s n ot off er e d 
b y e xi sti n g tr e at m e nt s.   Th e c oll e ct e d d at a s u g g e st t h at T a d e ki ni g alf a di s pl a y s a f a v or a bl e s af et y 
pr ofil e at t h e d o s e s t o b e t e st e d.    
 
I n a d diti o n, m e a s ur e s ar e i n pl a c e a s i n a Fir st -i n-H u m a n s et u p, i n c a s e of e m er g e n ci e s  (i. e. s e e 
e x a m pl e p ati e nt e m er g e n c y c ar d, a p p e n di x 5) .  
8. 3  Pri m ar y O bj e cti v e s – Effi c a c y   
T h e pri m ar y o bj e cti v e s of t h e st u d y will b e  t o: 
1.   As s e s s  cli ni c al  effi c a c y  of  T a d e ki ni g  alf a  i n  m o n o g e ni c  a ut oi nfl a m m at or y  
di s e a s e s  wit h  o n g oi n g  i nfl a m m ati o n  a n d  d el et eri o u s  m ut ati o n s  of  N L R C 4 -
M A S  or XI A P  
2.   As s e s s l a b or at or y/ bi ol o gi c al e vi d e n c e of effi c a c y  
8. 3. 1    Pri m ar y Effi c a c y E n d p oi nt s  
o  T h e pri m ar y o ut c o m e i s t h e ti m e t o fir st o c c urr e n c e of di s e a s e r e a cti v ati o n 
(i n cl u di n g f ull a n d p arti al di s e a s e r e a cti v ati o n) d uri n g t h e 1 6 -w e e k R W p h a s e.  
 
Effi c a c y a s s e s s m e nt i s r el at e d t o t h e i n ci d e n c e of di s e a s e r e a cti v ati o n s  a n d will c o v er:   
i) Cli ni c al  e v al u ati o n ( c a pt ur e d m o stl y i n t h e m AI D AI ) 
o  C o m pl et e p h y si c al e x a mi n ati o n i n cl u di n g: vit al si g n s ( s y st oli c a n d di a st oli c 
bl o o d pr e s s ur e, h e art r at e, r e s pir at or y r at e, w ei g ht, a n d b o d y t e m p er at ur e)  
o  All  fi n di n g s  s h o ul d  b e  d o c u m e nt e d:  j oi nt  s w elli n g,  h e p at o m e g al y  a n d  
s pl e n o m e g al y, pr e s e n c e of s ki n r a s h, o p ht h al mi c c o ntr ol ( pr e s e n c e of u v eiti s). 
O p ht h al mi c e x a mi n ati o n w ill b e p erf or m e d f or a s s e s s m e nt of u v eiti s.  
o  S y m pt o m s  s h o ul d  b e  d o c u m e nt e d:  a b d o mi n al  p ai n,  di arr h e a,  n a u s e a,  
v o miti n g   
o  All  cli ni c al  c o m p o n e nt s  (i n cl u di n g  cli ni c al  fi n di n g s  a n d  s y m pt o m s)  of  t h e  
di s e a s e will b e c a pt ur e d i n a bi n ar y w a y a s eit h er b ei n g pr e s e nt or a b s e nt.  
T hi s  bi n ar y  s y st e m  i s  c o n si d er e d  t h e  m o st  stri n g e nt  t o ol  t o  d e s cri b e  a  
cli ni c all y  r el e v a nt  l e v el  of  i m pr o v e m e nt  a n d  c o ntr ol  of  t h e  s e v er e  cli ni c al  


 
 
 
P a g e 3 8  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
m a nif e st ati o n s i n t h e p ati e nt s tr e at e d wit h T a d e ki ni g alf a.  T h e j u d g e m e nt, of 
w h et h er a n e n d or g a n c at e g or y i s aff e ct e d, i s d o n e b y t h e tr e ati n g p h y si ci a n 
a c c or di n g  t o  cli ni c al  st a n d ar d s,  a s  al s o  pr e vi o u sl y  d o n e  f or  all   m AI D AI 
c o m p o n e nt s . 
o  D ail y w ei g ht, st o ol o ut p ut, a n d P O i nt a k e m e a s ur e m e nt s i n cl u di n g n u m b er of 
e m e si s e pi s o d e s will b e p erf or m e d o n p ati e nt s wit h i nt e sti n al d y sf u n cti o n, 
o nl y w h e n t h e p ati e nt s ar e h o s pit ali z e d  
o  R a di ol o gi c fi n di n g s if a s s e s s e d a s n e c e s s ar y b y t h e tr e ati n g p h y si ci a n  
ii) M ai nt e n a n c e of c o -tr eat m e nt  
o  T ot al w e e kl y gl u c o c orti c oi d s  
o  I L-1 bl o c k er s  
o  Ot h er tr e at m e nt s* ( i. e. D M A R D s , et c.) 
* R ef er t o S e cti o n 1 1 . 2. 4: C o n c o mit a nt tr e at m e nt 
iii) L a b or at or y  a s s e s s m e nt s : 
o  S er u m C R P  
o   S er u m F erriti n  
o  C o m pl et e bl o o d c o u nt s  
o  S er u m l e v el s of t ot al I L -1 8, fr e e I L -1 8, I L -1 8 B P  
8. 3. 2  S e c o n d ar y Effi c a c y E n d p oi nt s  
K e y S e c o n d ar y Effi c a c y E n d p oi nt  
o  R e s p o n s e t o t h er a p y (i n cl u di n g c o m pl et e r e s p o n s e a n d p arti al r e s p o n s e) i n 
t h e  S A O L  p h a s e  fr o m  W e e k  1 0  o n w ar d s  a n d  o b s er v e d  at  l e a st  at  2  
c o n s e c uti v e vi sit s at l e a st 2 w e e k s a p art  d uri n g t h e S A O L p h a s e  
Ot h er  S e c o n d ar y Effi c a c y E n d p oi nt s 
o  B e st  r e s p o n s e  t o  t h er a p y  d uri n g  t h e  S A O L  p h a s e  (i n cl u di n g  c o m pl et e  
r e s p o n s e a n d p arti al r e s p o n s e a n d di s e a s e i m pr o v e m e nt) 
o  D ur ati o n of r e s p o n s e t o t h er a p y (i n cl u di n g c o m pl et e r e s p o n s e a n d p arti al 
r e s p o n s e) d uri n g t h e S A O L p h a s e  
o  Di s e a s e  r e a cti v ati o n  r at e  f or  i n di vi d u al  s u bj e ct s  ( n u m b er  of  di s e a s e 
r e a cti v ati o n s e x p eri e n c e d  p er  w e e k  w hil e  e a c h  s u bj e ct  i s  o n  t h e  st u d y  
tr e at m e nt d uri n g t h e S A O L p h a s e ). 
o  Tr e at m e nt  f ail ur e s  (i. e.  p ati e nt s  w h o  e x p eri e n c e  at  l e a st  o n e  di s e a s e 
r e a cti v ati o n) 
o  I nt e n sit y of di s e a s e r e a cti v ati o n s ( d efi n e d b y t h e l e v el of a cti vit y gi v e n b y t h e 
m AI D AI – b ot h o bj e cti v e a n d s u bj e cti v e crit eri a ) 
o  S er u m C R P  
o  S er u m F erriti n  
o  I m pr o v e m e nt of f e v er s (if pr e s e nt at B a s eli n e)  
o  I m pr o v e m e nt of h e p at o/ s pl e n o m e g al y (if pr e s e nt at B a s eli n e) 
o  I m pr o v e m e nt  i n  s er u m  al b u mi n  a n d  li v er  tr a n s a mi n a s e s,  a n e mi a  a n d/ or  
pl at el et c o u nt (if pr e s e nt at B a s eli n e)  
o  H o s pit al l e n gt h of st a y  
o  P h y si ci a n Gl o b al A s s e s s m e nt  


 
 
 
P a g e 3 9  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
o   Pati e nt’ s or c ar e gi v er’ s q u alit ati v e e v al u ati o n of h e alt h st at u s  
o  Pr e s e n c e of s ki n r a s h ( e v ol uti o n if pr e s e nt at B a s eli n e or a p p e ar a n c e d uri n g 
t h e st u d y) 
o  T ol er a n c e  t o  or al/ e nt er al  n utriti o n  f or  h o s pit ali z e d  p ati e nt s  wit h  i nt e sti n al  
d y sf u n cti o n w a s pr e s e nt at B a s eli n e   
o  I m pr o v e m e nt of st o ol o ut p ut f or h o s pit ali z e d p ati e nt s if i nt e sti n al d y sf u n cti o n 
w a s pr e s e nt at B a s eli n e  
D uri n g t h e S A O L p h a s e, p ati e nt e v ol uti o n will b e d e s cri b e d b y pl otti n g o v er ti m e t h e m AI D AI, 
P G A, F erriti n, a n d C R P a s w ell a s t h e m o st pr o mi n e nt cli ni c al f e at ur e s a c c or di n g t o t h e i n di vi d u al 
p ati e nt  pr ofil e s.  A b s ol ut e  a n d  p er c e nt a g e  of  c h a n g e  fr o m  b a s eli n e  will  b e  c al c ul at e d  f or  
c o nti n u o u s v ari a bl e s. R e s p o n s e t o tr e at m e nt i n t h e i niti al a cti v e di s e a s e, n u m b er, fr e q u e n c y a n d 
s e v erit y of di s e a s e r e a cti v ati o n s  d uri n g t h e st u d y will b e c o m p ar e d t o i n ci d e n c e a n d s e v erit y 
d e s cri b e d i n t h e m e di c al hi st or y of i n di vi d u al p ati e nt s.  
 
N ot e s:  
- GI r el at e d p ar a m et er s will b e a s s e s s e d i n s u bj e ct s wit h GI d y sf u n cti o n  
- F or o ut p ati e nt t h er a p y t h e cli ni c al e v al u ati o n will b e p erf or m e d at t h e vi sit s  
- L a b or at or y s af et y a n d effi c a c y e n d p oi nt s will b e st u di e d at t h e vi sit s b y t h e c e ntr al l a b. F or 
h o s pit ali z e d p ati e nt s , l o c al l a b s will p erf or m, i n a d diti o n, a n al y s e s a s r e q uir e d b y t h e st a n d ar d 
of c ar e a n d t hi s i nf or m ati o n will b e e nt er e d i n t h e st u d y e C R F.  
 
A cti v e di s e a s e u p o n e nr ol m e nt  i s d efi n e d a s: 
o  I n cr e a s e d i nfl a m m at or y m ar k er s, i. e. s er u m f erriti n l e v el s  ≥ 5 0 0 n g/ m L  or 
s er u m C R P ≥ 2 x U L N, a n d  
o  A cti v e cli ni c al di s e a s e a s e vi d e n c e d b y m AI D AI ≥ 4 or C N S m a nif e st ati o n s 
(i. e. s ei z ur e s, alt er e d m e nt al st at u s, si g n s of i n cr e a s e d i ntr a cr a ni al pr e s s ur e, 
c hr o ni c p a pill e d e m a, l o s s of vi si o n, ot h er s e n s ori n e ur al d efi ci e n ci e s, et c.)  
F or t h e  d efi niti o n  of  a cti v e  di s e a s e  u p o n  e nr ol m e nt, all m AI D AI  c o m p o n e nt s  
( s u bj e cti v e a n d o bj e cti v e) will b e e v al u at e d i n li n e wit h pr e vi o u s pr ot o c ol v er si o n s. 
 
R e s p o n s e t o T h er a p y i s d efi n e d a s:  
1.  I n  t h e  1 6 -w e e k  R W  p h a s e,  r e s p o n s e  t o  t h er a p y  ( a s  pri m ar y  e n d p oi nt  of  
effi c a c y) will b e a s s e s s e d b y pr e v e nti o n of di s e a s e r e a cti v ati o n s   d uri n g t h e 
1 6 -w e e k tr e at m e nt i n t h e R W p h a s e.  
2.  I n t h e  S A O L p h a s e , r e s p o n s e t o t h er a p y ( a s s e c o n d ar y e n d p oi nt of effi c a c y) 
will b e a s s e s s e d t hr o u g h t h e c o ntr ol of t h e a cti v e di s e a s e   
F or r e s p o n s e t o t h er a p y, o nl y t h e o bj e cti v e m AI D AI c o m p o n e nt s will b e e v al u at e d 
a s i n di c at e d b el o w.  S u bj e cti v e m AI D AI c o m p o n e nt s ( s e e A p p e n di x  I) will n ot b e 
c o n si d er e d t o a v oi d a n y bi a s i n t h e effi c a c y a s s e s s m e nt i n t h e o p e n l a b el p art of 
t h e st u d y. 
 
o  C o m pl et e r e s p o n s e  
N o m aj or e n d or g a n d a m a g e  ( = o bj e cti v e m AI D AI c o m p o n e nt s) 
•  N o f e v er ( b o d y t e m p er at ur e ≤1 0 0. 4 º F/ 3 8 ° C)  
•  N o di arr h e a  
•  N o tr a n s a mi niti s a n d/ or h e p at o m e g al y  
•  N o s pl e n o m e g al y a n d/ or a d e n o p at h y  
•  N o r a s h  


 
 
 
P a g e 4 0  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
•  N o u v eiti s  
•  N o art hriti s  
•  N o r a di ol o gi c C N S i n v ol v e m e nt  
•  N o c yt o p e ni a ( H g B ≥ 9. 0 a n d/ or P L T ≥1 0 0 a n d/ or W B C ≥3. 0)  
N o s y st e mi c i nfl a m m ati o n  
•  N o h y p erf erriti n e mi a ( s er u m l e v el < 5 0 0 n g/ m L)  
•  N o i n cr e a s e d C R P ( s er u m l e v el < 2 x U L N ) 
I m m u n o s u p pr e s si v e t h er a pi e s 
•  Di s c o nti n u ati o n of s y st e mi c c orti c o st er oi d s  ( e x cl u di n g hy dr o c orti s o n e 
f or  pr e v e nti o n  of  a dr e n al  i n s uffi ci e n c y) or  ot h er  i m m u n o s u p pr e s si v e  
t h er a pi e s i n cl u di n g bi ol o gi c s o n g oi n g at b a s eli n e  
•  N o  st art  or  d o s e  i n cr e a s e  of  ot h er  i m m u n o s u p pr e s si v e  t h er a pi e s  
i n cl u di n g bi ol o gi c s 
 
o  P arti al r e s p o n s e  
At  l e a st  5 0 %  r e d u cti o n  of  t h e  n u m b er  of  aff e ct e d  o bj e cti v e  e n d  or g a n  
d a m a g e c at e g ori e s at b a s eli n e a n d  
•   
At  l e a st  5 0 %  of  t h e  s y st e mi c  i nfl a m m at or y  m ar k er s  (f erriti n  a n d/ or  
C R P) i n cr e a s e d at b a s eli n e r e a c hi n g l e v el s f or c o m pl et e r e s p o n s e or  
•  
Di s c o nti n u ati o n of s y st e mi c c orti c o st er oi d s  ( e x cl u di n g hy dr o c orti s o n e 
f or pr e v e nti o n of a dr e n al i n s uffi ci e n c y) or ot h er i m m u n o s u p pr e s si v e 
t h er a pi e s i n cl u di n g bi ol o gi c s o n g oi n g at b a s eli n e 
P arti al r e s p o n s e i s t h u s a m e a s ur e of t h e c o m pl et e r e s ol uti o n of cli ni c al 
m a nif e st ati o n s i n at l e a st 5 0 % of i n v ol v e d s p e cifi c or g a n cl a s s e s  t o g et h er 
wit h a r e d u cti o n of t h e s y st e mi c i nfl a m m at or y m ar k er s m o st r el e v a nt f or 
t hi s  di s e a s e or  t h e  p o s si bilit y  t o  r e d u c e  ot h er  i m m u n o s u p pr e s si v e  
t h er a pi e s. 
o  Di s e a s e I m pr o v e m e nt  
A t hir d r e s p o n s e c at e g or y of Di s e a s e I m pr o v e m e nt i s i ntr o d u c e d t o b e utili z e d a s 
a d e s cri pti o n of b e st r e s p o n s e  a n d i n or d er t o b ett er d e s cri b e i niti al tr e at m e nt 
r e s p o n s e t o  t h er a p y a n d  di s e a s e  e v ol u ti o n  o v er  ti m e.  T hi s  i s  o nl y  u s e d  f or  
a n al y si s p ur p o s e s a n d will n ot b e e v al u at e d f or t h e d e ci si o n w h et h er t o b e eli gi bl e 
f or t h e st art of t h e R W p h a s e. Di s e a s e I m pr o v e m e nt i s d efi n e d a s:  
•   
Re d u cti o n  of  t h e  n u m b er  of  aff e ct e d  o bj e cti v e e n d  or g a n  d a m a g e  
c at e g ori e s at b a s eli n e  b y at l e a st 1 or  
•  
N or m ali z ati o n  (i. e.  r e a c hi n g  l e v el s  f or  c o m pl et e  r e s p o n s e) or 
i m pr o v e m e nt ( > 5 0 % c h a n g e fr o m b a s eli n e f or l a b or at or y m ar k er s b ut 
still e x c e e di n g  l e v el s f or c o m pl et e r e s p o n s e) of at l e a st 5 0 % of t h e 
s y st e mi c i nfl a m m at or y m ar k er s aff e ct e d at b a s eli n e  
•  
S y st e mi c c orti c o st er oi d s ( e x cl u di n g hy dr o c orti s o n e f or pr e v e nti o n of 
a dr e n al i n s uffi ci e n c y ) or ot h er i m m u n o s u p pr e s si v e t h er a pi e s i n cl u di n g 
bi ol o gi c s m u st b e at t h e s a m e or l o w er d o s e s c o m p ar e d t o b a s eli n e   
 
 
A Di s e a s e r e a cti v ati o n  o c c ur s if:  
F or  di s e a s e  r e a cti v ati o n,  o nl y  t h e  o bj e cti v e  m AI D AI  c o m p o n e nt s  will  b e  
e v al u at e d a s i n di c at e d b el o w. S u bj e cti v e m AI D AI c o m p o n e nt s ( s e e A p p e n di x  I) 
will n ot b e c o n si d er e d t o a v oi d a n y bi a s i n t h e a s s e s s m e nt.  


 
 
 
P a g e 4 1  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
D uri n g t h e R W -p h a s e, t h e r ef er e n c e f or a di s e a s e r e a cti v ati o n (f or t h e pri m ar y 
e n d p oi nt a s s e s s m e nt) will b e t h e e n d of t h e S A O L p h a s e ( V 8); f or t h e S A O L 
p h a s e, r ef er e n c e will t h e pr e vi o u s vi sit, a s p ati e nt s e nt er t h e S A O L p h a s e wit h 
a n a cti v e di s e a s e.  
o  P arti al di s e a s e r e a cti v ati o n  
•  
I n cr e a s e  i n  t h e  n u m b er  of  aff e ct e d  o bj e cti v e  e n d  or g a n  d a m a g e  
c at e g ori e s b y at l e a st 2 or  
•  
I n cr e a s e  i n  t h e  n u m b er  of  aff e ct e d  o bj e cti v e  e n d  or g a n  d a m a g e  
c at e g ori e s  b y  at  l e a st  1  a n d  w or s e ni n g  of  at  l e a st  1  s y st e mi c  
i nfl a m m at or y m ar k er (i. e. s er u m f erriti n l e v el s ≥ 5 0 0 n g/ m L or s er u m 
C R P ≥ 2 x U L N) t h at w a s m e eti n g c o m pl et e r e s p o n s e crit eri a b ef or e 
o  F ull di s e a s e r e a cti v ati o n  
•  
I n cr e a s e  i n  t h e  n u m b er  of  aff e ct e d  o bj e cti v e  e n d  or g a n  d a m a g e  
c at e g ori e s  t o  at  l e a st  t h e  n u m b er  of  aff e ct e d  e n d  or g a n  d a m a g e  
c at e g ori e s at b a s eli n e ( V 1) a n d  
•  
E x a c er b ati o n of at l e a st 1 s y st e mi c i nfl a m m at or y m ar k er (i. e. s er u m 
f erriti n  l e v el s  ≥
 5 0 0  n g/ m L  or  s er u m  C R P  ≥
 2 x  U L N)  t h at  w a s  
m e eti n g c o m pl et e r e s p o n s e crit eri a b ef or e  
 
N ot e:  It  i s  r e c o m m e n d e d  t h at  p ati e nt s  s uff eri n g  fr o m  s e v er e  C N S  m a nif e st ati o n s  ar e  p ut  o n  
r e s c u e i m m u n o s u p pr e s si o n tr e at m e nt.  
 
8. 3. 3  J u stifi c ati o n f or r e vi s e d  Effi c a c y E n d p oi nt s  
 
T h e c h a n g e s i n t h e d efi niti o n s of r e s p o n s e  t o t h er a p y ( c o m pl et e a n d p arti al) a n d fl ar e/ di s e a s e 
r e a cti v ati o n (f ull a n d p arti al) wit h pr ot o c ol v er si o n 6 t a k e i nt o c o n si d er ati o n t h e n e wl y g ai n e d 
di s e a s e i nf or m ati o n si n c e t h e i niti al st u d y d e si g n. I n t h e pr e vi o u s cli ni c al pr ot o c ol v er si o n s , a fi x 
m AI D AI of 4 w a s c o n si d er e d t h e c ut -off t o  d et er mi n e w h et h er a p ati e nt h a s a n a cti v e di s e a s e or  
di s e a s e r e a cti v ati o n t hr o u g h o ut t h e st u d y t o g et h er wit h a si m ult a n e o u s i n cr e a s e i n i nfl a m m at or y 
m ar k er s. T hi s fi x m AI D AI c ut -off di d  n ot t a k e i nt o c o n si d er ati o n t h e i n di vi d u al di s e a s e s e v erit y of 
e a c h p ati e nt  a n d h et er o g e n eit y of t h e di s e a s e , w hi c h h a s b e e n o b s er v e d b ot h i n t h e e nr oll e d 
p ati e nt s a s w ell a s p ati e nt s d e s cri b e d i n t h e lit er at ur e. T o d e m o n str at e a cli ni c all y m e a ni n gf ul 
i m pr o v e m e nt f or t h e p ati e nt, t h e cli ni c al e n d or g a n d a m a g e a s a m aj or crit eri o n i s a s s e s s e d 
s e p ar at el y  fr o m t h e l a b or at or y s y st e mi c i nfl a m m at or y m ar k er s. I n a d diti o n, a di s c o nti n u ati o n  of 
br o a d -s p e ctr u m i m m u n o s u p pr e s si v e t h er a p y i s a d d e d t o t h e e v al u ati o n, a s t hi s r e pr e s e nt s a 
m aj or cli ni c al  m e a ni n gf ul a c hi e v e m e nt f or t h e s e p ati e nt s.  B y u si n g t h e a b o v e d efi niti o n s of  f ull 
a n d p arti al di s e a s e r e a cti v ati o n, t h e r e -o c c urr e n c e of t h e i nfl a m m ati o n will b e e v al u at e d i n a m or e 
s e n siti v e w a y t a ki n g i nt o a c c o u nt t h e o b s er v e d di s e a s e h et er o g e n eit y.   
 
C o m pl et e  a n d  p arti al  r e s p o n s e  t o  t h er a p y  fr o m  w e e k  1 0  o n w ar d s  w a s  a d d e d  a s  n e w  k e y  
s e c o n d ar y e n d p oi nt.  Th e e vi d e n c e pr o vi d e d i n t h e o p e n l a b el p art t o c o ntr ol t h e di s e a s e aft er t h e 
p ati e nt s h a v e e nt er e d t h e st u d y i n a st at u s of hi g h i nfl a m m at or y a cti vit y i s a cr u ci al p art t o pr o vi d e 
e vi d e n c e of t h e effi c a c y  of T a d e ki ni g alf a tr e at m e nt. T h e 1 0 -w e e k ti m e p oi nt t o b e gi n a s s e s si n g 
t h e r e s p o n s e t o t h er a p y w a s c h o s e n b a s e d o n t h e ti m eli n e f or st er oi d di s c o nti n u ati o n a n d t h e 
n e e d f or t h e r e si d u al eff e ct of st er oi d s t o n o l o n g er b e pr e s e nt. P er t h e pr ot o c ol, p ati e nt s m a y 
r e c ei v e T a d e ki ni g alf a i n a d diti o n t o st a n d ar d of c ar e s y st e mi c st er oi d s. T h e st er oi d s ar e t a p er e d 
d o w n b y d a y 2 8 aft er st u d y i niti ati o n. H o w e v er, a p ati e nt m a y r e c ei v e a n ot h er 2 8 d a y c y cl e of 
st er oi d s u p o n i niti al di s e a s e r e a cti v ati o n, w hi c h i s e x p e ct e d t o o c c ur d uri n g or s h ortl y aft er t h e 
fir st st er oi d t a p eri n g. T hi s r e s ult s i n a t ot al e x p e ct e d ti m e of 8 w e e k s of st er oi d t a p er. If p ati e nt s 
ar e  n ot  st a bili z e d  aft er  t h e  s e c o n d  st er oi d  t a p er,  t h e y  ar e  e x p e ct e d  t o  st art  r e s c u e  
i m m u n o s u p pr e s si o n  a n d  di s c o nti n u e  st u d y  tr e at m e nt.  T h er ef or e,  at  w e e k  1 0,  p ati e nt s  ar e  
e x p e ct e d t o n o l o n g er r e q uir e st er oi d s a n d a n y r e si d u al eff e ct s will n ot b e pr e s e nt.  


 
 
 
P a g e 4 2  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
 
A p ati e nt’ s or c ar e gi v er’ s q u alit ati v e e v al u ati o n of h e alt h st at u s  w a s a d d e d wit h pr ot o c ol v er si o n 
6. Gi v e n t h e h et er o g e n e o u s p ati e nt p o p ul ati o n ( a g e r a n g e,  di s e a s e s y m pt o m a n d i m p a ct s)  a n d 
r e g ul at or y  c o n c er n s  t h at  g e n eri c  v ali d at e d  q u alit y  of  lif e  q u e sti o n n air e s  w o ul d  n ot b e  fit -f or-
p ur p o s e  f or  u s e  i n  t hi s tri al  t o  s u p p ort  r e g ul at or y  d e ci si o n s,  a  n o n-v ali d at e d  q u e sti o n n air e  
s p e cifi c all y d e si g n e d f or t hi s  p ati e nt p o p ul at i o n a n d st u d y d e si g n  i s u s e d. It c a pt ur e s t h e p ati e nt’ s 
or c ar e gi v er’ s q u alit ati v e e v al u ati o n of h e alt h st at u s  si mil ar t o t h e p h y si ci a n gl o b al a s s e s s m e nt 
( P G A), t h e s e v erit y of i n di vi d u al s y m pt o m s a n d t h e p er c ei v e d c h a n g e i n s y m pt o m s  at t h e e n d of 
t h e S A O L a n d R W p h a s e. 
 
8. 4  S e c o n d ar y O bj e cti v e – Effi c a c y    
T h e s e c o n d ar y effi c a c y o bj e cti v e i s t o a s s e s s  t h e m ai n cli ni c al f e at ur e s a n d l a b or at or y bi o m ar k er s  
( c h ar a ct eri sti c s  of  e a c h  p ati e nt  pr ofil e)  l o n git u di n all y  d uri n g  t h e  S A O L  p h a s e  f or  e a c h  
e x p eri m e nt al s u bj e ct.  
8. 4. 1  Effi c a c y E n d p oi nt s i n t h e S A O L p h a s e  
Effi c a c y e n d p oi nt s e v al u at e d d uri n g t h e S A O L  p h a s e will i n cl u d e r e s p o n s e t o t h er a p y, b e st r e s p o n s e 
t o t h er a p y, d ur ati o n of r e s p o n s e, a s w ell a s pl otti n g o v er ti m e t h e m AI D AI, P G A,  F erriti n, a n d C R P 
a s w ell a s t h e m o st pr o mi n e nt cli ni c al f e at ur e s  a c c or di n g t o t h e i n di vi d u al p ati e nt pr ofil e s. A b s ol ut e 
a n d  p er c e nt a g e  of  c h a n g e  fr o m  b a s eli n e  will  b e  c al c ul at e d  f or  c o nti n u o u s  v ari a bl e s.  N u m b er,  
fr e q u e n c y a n d s e v erit y of di s e a s e r e a cti v ati o n s d uri n g t h e st u d y will b e c o m p ar e d t o i n ci d e n c e a n d 
s e v erit y of di s e a s e r e a cti v ati o n s d e s cri b e d i n t h e m e di c al hi st or y of i n di vi d u al p ati e nt s.  
 
8. 5  S e c o n d ar y O bj e cti v e  – S af et y a n d T ol er a bilit y  
T h e s e c o n d ar y  o bj e cti v e  i s  t o  a s s e s s  t h e  s af et y  a n d  t ol er a bilit y  of T a d e ki ni g  alf a  tr e at m e nt i n 
m o n o g e ni c, a ut oi nfl a m m at or y di s e a s e h ar b ori n g d el et eri o u s m ut ati o n s of N L R C 4 -M A S  or XI A P.  
8. 5. 1    S af et y a n d T ol er a bilit y E n d p oi nt s  
o  A d v er s e e v e nt s  [i n cl u di n g A E SI] will b e r e p ort e d  
o  P h y si c al e x a mi n ati o n fi n di n g s: cli ni c all y si g nifi c a nt c h a n g e s fr o m B a s eli n e  
o  Vit al si g n s: cli ni c all y si g nifi c a nt c h a n g e s fr o m B a s eli n e  
o  L a b or at or y  a s s e s s m e nt s  (*):  i n cl u di n g  cli ni c all y  si g nifi c a nt  c h a n g e s  fro m 
B a s eli n e i n h e m at ol o g y wit h pl at el et c o u nt s, C R P, E S R, f erriti n, fi bri n o g e n, 
D- di m er, li v er e n z y m e s, cr e ati ni n e a n d gl o m er ul ar filtr ati o n r at e (n ot e: all 
cli ni c all y si g nifi c a nt a b n or m al l a b or at or y r e s ult s or a s s e s s m e nt s m u st  b e 
f oll o w e d u ntil t h e y r e s ol v e (r et ur n t o n or m al or B a s eli n e v al u e s) or st a bili z e, 
or  u ntil  t h e y  ar e  j u d g e d  b y  t h e  I n v e sti g at or  t o  b e  n o  l o n g er  cli ni c all y  
si g nifi c a nt)  
o  I m m u n o g e ni cit y e v al u ati o n: G e n er ati o n of a nti-r h-I L-1 8 B P a nti b o di e s  
o  L o c al  t ol er a bilit y  at  t h e  i nj e cti o n  sit e  ( e v al u at e d  b y  a  st a n d ar di z e d  
a s s e s s m e nt)  
 
(*) N O T E: L a b or at or y s af et y ( a n d effi c a c y) e n d p oi nt s will b e st u di e d at t h e 
vi sit s b y t h e c e ntr al l a b. F or h o s pit ali z e d p ati e nt s , l o c al l a b s will p erf or m, i n 
a d diti o n, a n al y s e s a s r e q uir e d b y t h e st a n d ar d of c ar e a n d t hi s i nf or m ati o n 
will b e e nt er e d i n t h e st u d y e C R F.  
 


 
 
 
P a g e 4 3  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
9  
S T U D Y  DE SI G N  
9. 1  T y p e of T ri al 
T hi s i s a P h a s e 3 st u d y t o a s s e s s t h e s af et y a n d effi c a c y of T a d e ki ni g alf a i n p ati e nt s wit h m o n o g e ni c, 
i nt erl e u ki n-1 8 (I L -1 8) dri v e n a ut oi nfl a m m ati o n d u e t o N u cl e oti d e -bi n di n g oli g o m eri z ati o n d o m ai n, 
l e u ci n e ri c h r e p e at a n d C A R D d o m ai n c o nt ai ni n g 4 – M a cr o p h a g e a cti v ati o n s y n dr o m e ( N L R C 4 -
M A S m ut ati o n) or X- li n k e d i n hi bit or of a p o pt o si s ( XI A P) d efi ci e n c y. B e c a u s e of t h e li k eli h o o d f or 
p at h o g e ni c I L -1 8 i n c ert ai n m o n o g e ni c di s e a s e s, p ati e nt s k n o w n t o h ar b or d el et eri o u s m ut ati o n s i n 
N L R C 4 -M A S or XI A P a n d w h o h a v e a hi st or y of o n g oi n g i nfl a m m ati o n will b e e nr oll e d if t h e y h a v e 
f erriti n >= 5 0 0 n g/ m L or p er si st e nt C -r e a cti v e pr ot ei n ( C R P) el e v ati o n ≥ 2 ti m e s t h e u p p er li mit of 
n or m al ( U L N) a n d t h e p ati e nt s h a v e a m AI D AI ≥ 4 .  
 
T h e st u d y i s d e si g n e d wit h si n gl e -ar m, o p e n -l a b el p h a s e ( S A O L) of T a d e ki ni g alf a tr e at m e nt 
d ur ati o n f or 1 8 -w e e k f oll o w e d b y a 1 6 -w e e k R a n d o mi z e d Wit h dr a w al ( R W) p h a s e  f or effi c a c y a n d 
s af et y e v al u ati o n, wit h n o i nt err u pti o n b et w e e n t h e t w o p h a s e s of tr e at m e nt.  
 
Si n gl e -ar m, o p e n -l a b el P h a s e ( S A O L) 
T h e S cr e e ni n g vi sit ( V 0) will o c c ur b ef or e t h e st art of t h e st u d y tr e at m e nt. At V 0, t h e p ati e nt a n d/ or 
t h e p ati e nt’ s l e g al g u ar di a n( s) will si g n a C hil d A s s e nt F or m a n d/ or a n I nf or m e d C o n s e nt F or m 
t h at will b e c oll e ct e d b y t h e I n v e sti g at or. All eli gi bilit y crit eri a will b e r e vi e w e d d uri n g t h e s cr e e ni n g 
p eri o d A N D m u st all b e m et i n or d er t o d et er mi n e p ati e nt eli gi bilit y i nt o t h e st u d y. Eli gi bilit y crit eri a 
s h o ul d b e c o nfir m e d a g ai n at t h e B a s eli n e Vi sit ( V 1).  
P ati e nt s e x p eri e n ci n g a cti v e di s e a s e  will st art T a d e ki ni g alf a tr e at m e nt at V 1.  
B e gi n ni n g at V 1, T a d e ki ni g alf a ( T A) will b e a d mi ni st er e d i n a d diti o n t o t h e st a n d ar d of c ar e ( S O C) 
tr e at m e nt u s e d f or t h e c o ntr ol of t h e a cti v e di s e a s e . I n t h e a b s e n c e of a n a p pr o v e d m e di c ati o n 
f or t hi s di s e a s e, th e S O C a s d efi n e d i n t hi s pr ot o c ol c o n si st s of gl u c o c orti c oi d s ( G C), wit h a 2 8 -
d a y t a p eri n g s c h e d ul e a s f oll o w s  
•  
2 8 -d a y s ( 4 w e e k s ): D ail y P O/ I V D e x a m et h a s o n e 1 0 m g/ m2  x 7 d a y s, 
5 m g/ m 2  x 7 d a y s, 2. 5 m g/ m 2  x 7 d a y s, 1. 2 5 m g/ m 2  x 7 d a y s  
P ati e nt s w h o r e s p o n d t o t h e i niti al T A + G C 2 8 -d a y c o ur s e ( s e e D efi niti o n of P arti al a n d C o m pl et e 
R e s p o n s e t o T h er a p y) will r e c ei v e T a d e ki ni g alf a f or 1 4 a d diti o n al w e e k s.  
P ati e nt s w h o r e s p o n d e d t o T A + S O C i niti al c o ur s e a n d h a v e a di s e a s e r e a cti v ati o n  a g ai n d uri n g 
t h e S A O L p h a s e  will r e c ei v e a n ot h er c o ur s e of T A + S O C wit h t h e s a m e G C d o s a g e a n d t a p eri n g 
s c h e d ul e  u s e d  f or  t h e  i niti al  tr e at m e nt  of  t h e  a cti v e  di s e a s e    ( s e e  e x pl a n ati o n s  b el o w).  
M ai nt e n a n c e tr e at m e nt, wit h t h e p er mitt e d m e di c ati o n s, at st a bl e a n d at t h e s a m e d o s e s utili z e d 
at st u d y e ntr y ar e all o w e d. D o s e i n cr e m e nt s f or t h e p er mitt e d c o -m e di c ati o n s or t h eir i ntr o d u cti o n 
aft er t h e b e gi n ni n g of t h e st u d y a r e n ot p er mitt e d a n d r e pr e s e nt tr e at m e nt f ail ur e s a n d st u d y e arl y 
t er mi n ati o n. If p er mitt e d c o-m e di c ati o n s ar e w e a n e d off d uri n g t h e c o ur s e of t h e st u d y a n d t h e 
i n v e sti g at or d e ci d e s t o r e-i ntr o d u c e t h e m, t h e y ar e p er mitt e d a s l o n g a s t h e d o s e s ar e t h e s a m e 
or l o w er t h a n t h e d o s e s u s e d at st u d y e ntr y.  
U p o n  l a c k  of  r e s p o n s e  t o  c o m bi n e d  tr e at m e nt  aft er  e nr oll m e nt  or  u p o n  t h e  o c c urr e n c e  of  a 
di s e a s e r e a cti v ati o n  d uri n g t h e c o ur s e of t h e S A O L aft er i niti al r e s p o n s e , t h e i n v e sti g at or m a y 
d e ci d e  t o  tr e at  t h e  p ati e nt  wit h  r e s c u e  i m m u n o s u p pr e s s or s.  T hi s  d e ci si o n  r e s ult s  i n  p ati e nt  
di s c o nti n u ati o n f r o m t h e st u d y. 
T a d e ki ni g alf a will b e a d mi ni st er e d at 2 m g/ k g ( wit h a m a xi m u m of 1 6 0 m g) s u b c ut a n e o u sl y ( s. c.) 
f or u p t o a p pr o xi m at el y 1 8 w e e k s.  


 
 
 
P a g e 4 4  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
At V 0 a n d V 1, p ati e nt s will u n d er g o a p h y si c al e x a mi n ati o n, m e a s ur e m e nt of vit al si g n s, a n d 
r o uti n e  l a b or at or y  t e sti n g  (i n cl u di n g  h e m at ol o g y,  cli ni c al  c h e mi str y,  uri n al y si s,  er yt hr o c yt e  
s e di m e nt ati o n  r at e  ( E S R),  C R P,  a n d  c o a g ul ati o n  p a n el).  Bi ol o gi c al  e v al u ati o n  a n d  g e n eti c  
di a g n o si s of a ut oi nfl a m m at or y c o n diti o n s ( N L R C 4 -M A S, XI A P d efi ci e n c y, a n d ot h er m o n o g e ni c 
a s s o ci ati o n s wit h M a cr o p h a g e A cti v ati o n S y n dr o m e [ M A S]) will b e d o n e at V 0. S a m pl e s f or fl o w 
c yt o m etr y will b e a n al y z e d d uri n g t h e s cr e e ni n g p eri o d  a n d pri or t o V 1. C o m pl et e m e di c al a n d 
di s e a s e  hi st or y  will  al s o  b e  c oll e ct e d  d uri n g  V 0.  I n  a d diti o n,  pri or  t o  i niti ati o n  of  t h er a p y,  
c yt o m e g al o vir u s  ( C M V)  a n d  E p st ei n -B arr  vir u s  ( E B V)  t e st s,  s er ol o g y  t e st s,  a n d  a  c o m pl et e  
i nf e cti o u s w or k u p will b e p erf or m e d. 
S p e cifi c l a b or at or y d et er mi n ati o n s s u c h a s t ot al a n d fr e e I L -1 8 a n d I L -1 8 B P will b e p erf or m e d at 
V 1 a n d s u b s e q u e nt vi sit s.  
T h e gl o b al di s e a s e a cti vit y will b e a s s e s s e d b y t h e m AI D AI. T h e m AI D AI will b e a p pli e d  at all 
st u d y vi sit s a n d will b e a v ail a bl e f or r e vi e w t hr o u g h o ut t h e st u d y. F or t h e e v al u ati o n of r e s p o n s e 
t o t h er a p y a n d di s e a s e r e a cti v ati o n, o nl y t h e o bj e cti v e p ar a m et er s of t h e m AI D AI will b e t a k e n 
i nt o c o n si d er ati o n. A P h y si ci a n Gl o b al A s s e s s m e nt ( P G A) t o ol will al s o b e a p pli e d at all st u d y 
vi sit s b y t h e p h y si ci a n t o a s s e s s t h e gl o b al di s e a s e st at u s.  T h e p ati e nt’ s or c ar e gi v er’ s e v al u ati o n  
of t h e h e alt h  st at u s q u e sti o n n air e  will b e a p pli e d at V 1 a n d t h e e n d of t h e S A O L p h a s e.  
A s s e s s m e nt s d uri n g t h e S A O L p h a s e, tr e at m e nt p eri o d of 1 8 w e e k s ( V 1 t o V 8), will i n cl u d e 
c o m pl et e  p h y si c al  e x a mi n ati o n,  r e vi e w  of  all a d v er s e  e v e nt s  ( A E s),  a n d  r o uti n e a n d  s p e cifi c 
l a b or at or y a n al y si s (f or f urt h er d et ail s, r ef er t o t h e s af et y a n d effi c a c y a s s e s s m e nt s e cti o n).  
S a m pl e s f or a nti -dr u g a nti b o di e s ( A D A s) will b e c oll e ct e d at B a s eli n e of S A O L ( V 1), W e e k 2 ( V 3), 
W e e k 4 ( V 5), W e e k 1 2 ( V 7), a n d W e e k 1 8 ( V 8).  
At t h e e n d of t h e S A O L p h a s e, all p ati e nt s w h o c o m pl et e d t h e p h a s e  wit h  a p arti al or c o m pl et e 
r e s p o n s e at V 8 will b e e nr oll e d i n t h e R W p h a s e . 
R a n d o mi z e d Wit h dr a w al ( R W) P h a s e  
All p ati e nt s w h o h a v e c o m pl et e d 1 8 w e e k s of tr e at m e nt d uri n g t h e S A O L p h a s e a n d s h o wi n g a 
p arti al or c o m pl et e r e s p o n s e  at W e e k 1 8 ( V 8) will b e r a n d o mi z e d t o o n e of t h e t w o tr e at m e nt ar m s 
i n a 1: 1 r ati o t o b e gi n tr e at m e nt i n t h e R W p h a s e (B a s eli n e of t h e R W p h a s e ). E x p eri e n ci n g a 
di s e a s e r e a cti v ati o n  at a n y p oi nt d uri n g t h e 1 8 -w e e k S A O L p h a s e will n ot pr e v e nt a s u bj e ct fr o m 
e nr oll m e nt  i nt o  t h e  R W  p h a s e;  r at h er,  p ati e nt s  ar e  r e q uir e d  t o  m e et  t h e  crit eri a  f or  o n g oi n g  
T a d e ki ni g alf a tr e at m e nt t hr o u g h o ut t h e S A O L p h a s e a n d s h o w a p arti al or c o m pl et e r e s p o n s e  at 
W e e k 1 8.  P ati e nt s will r e c ei v e t h e st u d y tr e at m e nt ( pl a c e b o or T a d e ki ni g alf a) f or u p t o a d diti o n al 
1 6 w e e k s.  R e si d u al c o m p o n e nt s of t h e di s e a s e m a y b e pr e s e nt b ut if t h e y  still m e et t h e d efi niti o n 
of at l e a st p arti al r e s p o n s e,  p ati e nt s will b e e nr oll e d i n t h e R W p h a s e.  
Tr e at m e nt i nt err u pti o n i s n ot r e c o m m e n d e d b et w e e n t h e t w o p h a s e s. B a s eli n e d at a f or t h e R W 
p h a s e will b e t h e d at a c oll e ct e d pri or t o r a n d o mi z ati o n at t h e W e e k 1 8 ( V 8) vi sit.  
D uri n g t h e R W p h a s e, vi sit s will b e s c h e d ul e d at W e e k 2 0 ( V 9), W e e k 2 2 ( V 1 0), W e e k 2 6 ( V 1 1) , 
W e e k 3 0 ( V 1 2) a n d W e e k 3 4 ( V 1 3/ E n d of St u d y) .  
At  R W  vi sit s,  p ati e nt s  will  u n d er g o  a  c o m pl et e  p h y si c al  e x a mi n ati o n  a n d  l a b or at or y  t e sti n g  
(i n cl u di n g h e m at ol o g y, cli ni c al c h e mi str y, uri n al y si s, E S R, C R P, f erriti n, a n d c o a g ul ati o n p a n el), 
d et er mi n ati o n s of t ot al a n d fr e e I L -1 8 a n d of I L -1 8 B P. T h e m AI D AI  a n d P G A will b e a p pli e d at all 
vi sit s i n t h e R W p h a s e. T h e p ati e nt’ s or c ar e gi v er’ s e v al u ati o n  of t h e h e alt h  st at u s q u e sti o n n air e 
will b e a p pli e d at t h e e n d of t h e R W p h a s e.  
S a m pl e s f or a nti -dr u g a nti b o di e s ( A D A s) will b e c oll e ct e d at R W W e e k 2 2 ( V 1 0) , W e e k 2 6 ( V 1 1)  
a n d W e e k 3 4 ( V 1 3) . 


 
 
 
P a g e 4 5  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
D uri n g t h e R W p h a s e, p ati e nt s w h o d e v el o p a p arti al or f ull di s e a s e r e a cti v ati o n  b ef or e t h e 1 6 -
w e e k tr e at m e nt i s c o m pl et e d will  pr o c e e d t o t h e E n d of St u d y vi sit a n d c o m pl et e t h e R W p h a s e .  
T h e i n v e sti g at or m a y al s o d e ci d e t o st art r e s c u e i m m u n o s u p pr e s si o n a n d di s c o nti n u e tr e at m e nt.  
If a p pli c a bl e, d at a o n a d mi ni str ati o n of ot h er m e di c ati o n s or r e s c u e i m m u n o s u p pr e s si o n d uri n g 
b ot h p h a s e s ( S A O L a n d R W) will b e c oll e ct e d, i n cl u di n g t h e ti m e of tr e at m e nt st art a n d fi ni s h a n d 
w h et h er or n ot t h er e w a s a r e s p o n s e t o t h e r e s c u e tr e at m e nt.  
P ati e nt s w h o di s c o nti n u e tr e at m e nt pri or t o t h e e n d of eit h er tr e at m e nt p h a s e ( S A O L or R W) will 
b e f oll o w e d f or all k e y effi c a c y a n d s af et y a s s e s s m e nt s  u p t o t h e E n d of St u d y vi sit. 
N O T E: T h e F D A dr aft g ui d a n c e ( E nri c h m e nt Str at e gi e s f or Cli ni c al Tri al s t o S u p p ort A p pr o v al of 
H u m a n Dr u g s a n d Bi ol o gi c al Pr o d u ct s, D e c e m b er 2 0 1 2) i n di c at e s t h at t h e R W d e si g n s h o ul d 
i n cl u d e p ati e nt s w h o d e m o n str at e d tr e at m e nt r e s p o n s e.  
 
A d diti o n al St a n d ar d of C ar e C y cl e s or R e s c u e I m m u n o s u p pr e s si o n i n S A O L P h a s e:  
 
A) If n o r e s p o n s e aft er t h e fir st c o m bi n e d tr e at m e nt c o ur s e ( S O C + I M P) at t h e i niti ati o n of 
t h e S A O L p h a s e:  
If p ati e nt s d o n ot r e s p o n d t o st u d y tr e at m e nt ( s e e S e cti o n 1 2. 1 D efi niti o n of P arti al a n d C o m pl et e 
R e s p o n s e t o T h er a p y  a n d Di s e a s e I m pr o v e m e nt ) aft er t h e i niti al c o m bi n e d tr e at m e nt c o ur s e , t h e y 
will  b e  tr e at e d  wit h  r e s c u e  i m m u n o s u p pr e s si o n  or  wit h  n e w/  i n cr e a s e d  d o s e s  of  P er mitt e d  
C o n c o mit a nt Tr e at m e nt s. T h e s e c a s e s will b e c o n si d er e d tr e at m e nt f ail ur e s a n d will e xit t h e 
st u d y.  
B) P ati e nt s wit h a di s e a s e r e a cti v ati o n  aft er h a vi n g r e s p o n d e d t o t h er a p y i n t h e S A O L 
P h a s e : 
If p ati e nt s s h o w si g n s of s y st e mi c i nfl a m m at or y r e a cti v ati o n (i. e. p arti al or f ull di s e a s e r e a cti v ati o n 
aft er h a vi n g r e s p o n d e d t o t h er a p y i n t h e S A O L p h a s e, t h e y will r e c ei v e a n ot h er c y cl e of S O C i n 
a d diti o n t o t h e I M P.  
C) P ati e nt s wit h a di s e a s e r e a cti v ati o n  d uri n g t h e t a p eri n g d o w n of t h e S O C d uri n g t h e 
c o m bi n e d tr e at m e nt i n t h e S A O L P h a s e:  
If aft er a n i niti al i m pr o v e m e nt i n r e s p o n s e p ar a m et er s , t h e p ati e nt s s h o w a g ai n si g n s of i n cr e a si n g 
i nfl a m m ati o n  (i. e. p artial or f ull di s e a s e r e a cti v ati o n ) d uri n g t h e t a p eri n g d o w n of S O C w hil e i n 
c o m bi n e d tr e at m e nt, a n ot h er f ull c y cl e of e xt e n d e d S O C ( 4 w e e k s) i n a d diti o n t o t h e I M P, will b e 
i niti at e d at t h e ori gi n al d o s e.  
 
I n t h e l a st c a s e s  ( B or  C), t h e I n v e sti g at or m a y al s o d e ci d e t o st art r e s c u e i m m u n o s u p pr e s si o n 
tr e at m e nt, a n d i n t hi s c a s e t h e p ati e nt s h o ul d di s c o nti n u e st u d y tr e at m e nt d u e t o tr e at m e nt 
f ail ur e. 
 
N ot e t o tr e at m e nt f ail ur e:  
A n y p ati e nt st arti n g r e s c u e i m m u n o s u p pr e s si o n tr e at m e nt or tr e at e d wit h n e w/ i n cr e a s e d d o s e s 
of P er mitt e d C o n c o mit a nt Tr e at m e nt s will b e c o n si d er e d a tr e at m e nt f ail ur e a n d will pr o c e e d t o 
t h e st u d y di s c o nti n u ati o n/ e arl y t er mi n ati o n pr o c e d ur e s. D at a r el at e d t o r e s p o n s e t o t h e r e s c u e 
tr e at m e nt will b e c oll e ct e d i n cl u di n g all k e y effi c a c y a n d s af et y a s s e s s m e nt s. 
 
It i s r e c o m m e n d e d t h at p ati e nt s s uff eri n g fr o m s e v er e C N S m a nif e st ati o n s ar e p ut o n r e s c u e 
i m m u n o s u p pr e s si o n tr e at m e nt.  
 
N ot e t o tr e at m e nt of di s e a s e r e a cti v ati o n s : 


 
 
 
P a g e 4 6  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
P ati e nt s t h at pr e s e nt a p arti al or f ull di s e a s e r e a cti v ati o n  aft er pr e vi o u s r e s p o n s e t o S O C + T A i n 
t h e S A O L p h a s e c a n r e m ai n i n t h e st u d y, a n d r e c ei v e a n ot h er c y cl e of S O C i n a d diti o n t o t h e 
c o nti n u o u s T A tr e at m e nt, if a c c or di n g t o tr e ati n g p h y si ci a n, t h e s e v erit y d o e s n ot r e q uir e r e s c u e 
i m m u n o s u p pr e s si o n.  
P ati e nt s t h at pr e s e nt a p arti al or f ull di s e a s e r e a cti v ati o n  i n t h e R W P h a s e b ef or e t h e 1 6-w e e k 
tr e at m e nt i s c o m pl et e d will pr o c e e d t o t h e E n d of St u d y Vi sit a n d c o m pl et e t h e R W P h a s e. 
 
N ot e - n or m al r a n g e s f or f erriti n a n d C R P:  
T h e n or m al r a n g e s of f erriti n a n d C R P diff er p er a g e a n d r e s p e cti v e n or m al r a n g e s p er a g e at t h e 
c e ntr al or l o c al l a b or at or y will b e u s e d a s r ef er e n c e . 
 
D at a S af et y M o nit ori n g B o ar d  
T h e  D at a  S af et y  M o nit ori n g  B o ar d  ( D S M B)  will  b e  n otifi e d  b y  t h e  c o ntr a ct e d  Cli ni c al  R e s e ar c h 
Or g a ni z ati o n ( C R O) of cli ni c al or bi ol o gi c al w or s e ni n g of t h e st at u s of st u d y s u bj e ct s (i. e., S eri o u s 
A d v er s e E v e nt s ( S A E s)) a n d al s o of tr e at m e nt f ail ur e s. T h e D S M B will a s s e s s t h e gl o b al s af et y of 
T a d e ki ni g  alf a  a n d  a d vi s e  w h et h er  t o  c o nti n u e  or  di s c o nti n u e  t h e  st u d y.  D S M B  r ol e s  a n d  
r e s p o n si biliti e s ar e d eli n e at e d i n t h e D S M B c h art er al o n g wit h t h e r e p orti n g r e q uir e m e nt s of t h e 
S p o n s or/ C R O t o t h e D S M B. T h e I n v e sti g at or will e v al u at e s af et y f or e a c h i n di vi d u al p ati e nt a n d 
d e ci d e w h et h er t o st o p or c o nti n u e tr e at m e nt, or w h e n t o st art t h e r e s c u e i m m u n o s u p pr e s si o n.  
 
C o n d u ct of t el e m e di ci n e st u d y vi sit s  
I n or d er t o pr ot e ct t h e p ati e nt` s a n d c ar e gi v er` s s af et y a n d w elf ar e d uri n g t h e C O VI D-1 9 p a n d e mi c, 
c o n d u cti o n of o n -sit e st u d y vi sit s m a y n ot b e c o n si d er e d a p pr o pri at e; m o st p ati e nt s h a v e t o tr a v el t o 
t h eir st u d y sit e a n d o n-sit e st u d y vi sit s m a y e x p o s e b ot h t h e p ati e nt s a n d c ar e gi v er s a s w ell a s st u d y 
sit e p er s o n n el t o a n i n cr e a s e d ri s k of i nf e cti o n.  M or e o v er, d u e t o t h e ultr a -r ar e i n di c ati o n of t hi s st u d y, 
c o n d u cti n g o n -sit e st u d y vi sit s at sit e s oft e n l o c at e d f ar a w a y fr o m t h e p ati e nt` s h o m e h a s m a d e 
st u d y c o n d u ct c h all e n gi n g.  
T h u s, i n a n eff ort t o a c c o m m o d at e t h e p ati e nt s a n d t h eir f a mili e s w hil e e n s uri n g t h e r el e v a nt st u d y 
d at a  i s  c oll e ct e d , s c h e d ul e d  st u d y  vi sit s   ( ex c e pt  f or  t h e  B a s eli n e  vi sit ) m a y  b e  c o n d u ct e d  a s  
t el e m e di ci n e vi sit s i n v ol vi n g t h e u s e of el e ctr o ni c c o m m u ni c ati o n s (f or e x a m pl e, li v e i nt er a cti v e vi d e o 
a n d a u di o) t o e n a bl e sit e st aff t o c o n d u ct “ virt u al” ( n ot i n -p er s o n) vi sit s wit h t h eir p ati e nt s. T h e s e 
vi sit s m a y b e s u p p ort e d b y h o m e h e alt h n ur s e s a s si sti n g i n p h y si c al e x a mi n ati o n or p erf or m a n c e of 
bl o o d dr a w s. L a b or at or y a s s e s s m e nt s m a y b e al s o p erf or m e d at q u alifi e d l o c al l a b or at ori e s. T h e 
st u d y sit e m a y al s o utili z e a p h y si c al e x a mi n ati o n fr o m t h e p ati e nt’ s m o st r e c e nt st a n d ar d of c ar e 
vi sit c o n d u ct e d b y t h e l o c al tr e ati n g p h y si ci a n, f or t h e p ur p o s e of t h e st u d y.  
P ati e nt s a n d/ or p ar e nt s ( or l e g al r e pr e s e nt ati v e, if a p pli c a bl e) will si g n a r e s p e cti v e  a s s e nt/i nf or m e d 
c o n s e nt  pri or  t o  t h e  c o n d u ct  of  s u c h  t el e m e di ci n e  vi sit s.  F urt h er  d et ail s  a b o ut  t h e  diff er e nt  
p o s si biliti e s f or t h e c o n d u ct of t el e m e di ci n e vi sit s ar e d e s cri b e d i n s e cti o n 1 4. 1.  
 
 


 
 
 
P a g e 4 7  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
9. 2  P ati e nt s , G r o u p s a n d C e nt er s  
A m a xi m u m of 1 5 p ati e nt s will b e e nr oll e d i n t hi s st u d y .  
 
St u d y C e nt er s:  
A p pr o xi m at el y 1 1 cli ni c al sit e s i n t h e U nit e d St at e s, C a n a d a a n d G er m a n y. 
9. 3  E x p e ct e d S t u d y D ur ati o n  
A p pr o xi m at el y 6 y e ar s fr o m Fir st -P ati e nt - Fir st-Vi sit ( F P F V) t o L a st -P ati e nt -L a st -Vi sit ( L P L V).  
Aft er s cr e e ni n g, p ati e nt s will e nt er t h e S A O L p h a s e of 1 8 -w e e k s d ur ati o n. S u b s e q u e ntl y, eli gi bl e 
p ati e nt s will e nt er t h e 1 6 -w e e k R W p h a s e.  
 
 
 


 
 
 
P a g e 4 8  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
1 0  S T U D Y P O P U L A TI O N  
A m a xi m u m of 1 5 eli gi bl e m al e or f e m al e p ati e nt s, s uff eri n g  fr o m N L R C 4 -M A S or XI A P d efi ci e n c y  
will b e e nr oll e d i n t h e st u d y.  Eli gi bl e p ati e nt s will e nt er t h e S A O L  p h a s e. All p ati e nt s w h o  c o m pl et e 
t h e 1 8 w e e k s of tr e at m e nt wit h a p arti al or c o m pl et e r e s p o n s e at V 8 will b e e nr oll e d i n t h e R W  p h a s e 
f or u p t o e xtr a 1 6 -w e e k tr e at m e nt  p eri o d . P ati e nt s will b e all o w e d t o r e c ei v e m ai nt e n a n c e ( p er mitt e d) 
tr e at m e nt at st a bl e d o s e s. 
P ati e nt s s h o ul d m e et all i n cl u si o n a n d e x cl u si o n crit eri a ( S e cti o n s 1 0. 2  a n d 1 0. 3 ).  
1 0. 1  D e s cri pti o n  
1 0. 2  P ati e nt In cl u si o n C rit eri a 
All e ntr a n c e crit eri a m u st b e m et i n or d er t o e nr oll;  
Eli gi bilit y crit eri a s h o ul d b e e v al u at e d at S cr e e ni n g V 0  pri or t o V 1  a n d r e c h e c k e d at  V 1 pri or t o 
st u d y tr e at m e nt i niti ati o n i n t h e S A O L p h a s e . 
1.  P ati e nt s  wit h  g e n eti c  di a g n o si s  of  N L R C 4 -M A S  m ut ati o n  or  XI A P  
d efi ci e n c y  ( c a u s e d b y BI R C 4  g e n e m ut ati o n) a s c o nfir m e d b y a n al y si s 
p erf or m e d  at  t h e  c e ntr al  g e n eti c s’  l a b or at or y.   If  p o s si bl e,  fl o w  
c yt o m etr y a s s a y will b e p erf or m e d i n p ar all el t o c o nfir m di a g n o si s of 
XI A P d efi ci e n c y. ( N ot e: Pr e vi o u s fl o w c yt o m etr y a s s a y r e s ult s will b e 
p er mitt e d  f or  c o nfir m ati o n  of  XI A P  d efi ci e n c y  di a g n o si s.)   A g e n eti c 
di a g n o si s fr o m a l o c al l a b or at or y will b e a c c e pt e d f or e nr ol m e nt  a n d 
st art  of  tr e at m e nt,  t o  a v oi d  a n y  tr e at m e nt  d el a y s  f or  t h e s e  s e v er e  
c o n diti o n s . H o w e v er, t h e g e n eti c di a g n o si s h a s t o b e c o nfir m e d b y t h e 
c e ntr al l a b or at or y. If t h e g e n eti c di a g n o si s i s n ot c o nfir m e d, t h e p ati e nt 
will di s c o nti n u e t h e st u d y.  
2.  P ati e nt s  wit h  XI A P  d efi ci e n c y  a n d  a  pr e vi o u s  b o n e  m arr o w  
tr a n s pl a nt ati o n  ar e  all o w e d,  if  t h e y  s h o w  e vi d e n c e  of  pri m ar y  or  
s e c o n d ar y gr aft f ail ur e, or f ail ur e t o a c hi e v e p h e n ot y pi c c orr e cti o n wit h 
e vi d e n c e of XI A P -r el at e d di s e a s e r e c urr e n c e or cli ni c all y sig nifi c a nt 
mi x e d c hi m eri s m.  F or t h e s e p ati e nt s, g e n eti c di a g n o si s at t h e c e ntr al 
l a b or at or y m a y s h o w c hi m eri s m; t h u s, l o c al g e n eti c di a g n o si s pri or t o 
t h e b o n e m arr o w tr a n s pl a nt ati o n will b e t h e m ai n s o ur c e t o c o nfir m t h e 
g e n eti c di a g n o si s.  
3.  F erriti n ≥ 5 0 0  n g/ m L or p er si st e nt el e v ati o n of C R P ≥ 2 x U L N a n d 
m AI D AI ≥ 4  
4.  P ati e nt s  r e c ei vi n g  c orti c o st er oi d s,  n o n -st er oi d al  a nti -i nfl a m m at or y 
dr u g s ( N S AI D s) or di s e a s e m o dif yi n g a nti -r h e u m ati c dr u g s ( D M A R D s), 
a n d/ or  I L -1  bl o c k a d e  wit h  i n s uffi ci e nt  r e s p o n s e  t o  tr e at m e nt  u p o n  
e nr oll m e nt ar e all o w e d i nt o t h e st u d y. P ati e nt s n ot r e c ei vi n g a n y of 
t h e s e tr e at m e nt s b ef or e st art of t h er a p y ar e al s o all o w e d 
5.  W o m e n of c hil d b e ari n g p ot e nti al wit h n e g ati v e uri n e pr e g n a n c y t e st  ( U P T) 
at  all  vi sit s  (if  U P T  i s  p o siti v e,  a  bl o o d  t e st  f or  h u m a n  c h ori o ni c  
g o n a d otr o pi n  ( h C G)  t o  b e  p erf or m e d)  a n d  w h o  a gr e e  t o  f oll o w  hi g hl y  
eff e cti v e birt h c o ntr ol r e c o m m e n d ati o n s d uri n g t h e st u d y a n d u ntil 1 m o nt h 
aft er t h e e n d of t h e tr e at m e nt. Birt h c o ntr ol m et h o d s c o n si d er e d hi g hl y 
eff e cti v e ar e: c o m bi n e d ( e str o g e n a n d pr o g e st o g e n c o nt ai ni n g) h or m o n al 
c o ntr a c e pti o n  a s s o ci at e d  wit h  i n hi biti o n  of  o v ul ati o n,  pr o g e st o g e n -o nl y 
h or m o n al  c o ntr a c e pti o n  a s s o ci at e d  wit h  i n hi biti o n  of  o v ul ati o n,  
i ntr a ut eri n e d e vi c e (I U D), i ntr a ut eri n e h or m o n e-r el e a si n g s y st e m (I U S), 
bil at er al t u b al o c cl u si o n, v a s e ct o mi z e d p art n er or s e x u al a b sti n e n c e. I n 
e a c h  c a s e  of  d el a y e d  m e n str u al  p eri o d  ( o v er  o n e  m o nt h  b et w e e n  


 
 
 
P a g e 4 9  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
m e n str u ati o n s,  c o nfir m ati o n  of  a b s e n c e  of  pr e g n a n c y  i s  str o n gl y  
r e c o m m e n d e d.  T hi s  r e c o m m e n d ati o n  al s o  a p pli e s  t o  w o m e n  of  
c hil d b e ari n g p ot e nti al wit h i nfr e q u e nt or irr e g ul ar m e n str u al c y cl e s. A p o st -
st u d y  c o ntr a c e pti o n  d ur ati o n  of  4  w e e k s  i s  r e c o m m e n d e d  t a ki n g  i nt o  
a c c o u nt t h e m e di a n h alf -lif e of T a d e ki ni g alf a of al m o st 4 0 h a n d 5 h alf-
li v e s r e pr e s e nti n g a d ur ati o n of 2 0 0 h o ur s. 
 
1 0. 3  P ati e nt E x cl u si o n C rit eri a 
S u bj e ct s r e pr e s e nti n g o n e or m or e of t h e f oll o wi n g crit eri a ar e e x cl u d e d fr o m p arti ci p ati o n i n t h e 
st u d y:  
1.  P ati e nt s wit h lif e-t hr e at e ni n g  c o-m or bi diti e s  n ot  a s s o ci at e d  wit h  t h e  
u n d erl yi n g N L R C 4 -m ut ati o n or XI A P d efi ci e n c y  
2.  P o siti v e  t e st  f or  or  pri or  hi st or y  of  HI V,  H e p atiti s  B  or  H e p atiti s  C  
( s er ol o g y) 
3.  Pr e s e n c e of a cti v e i nf e cti o n s or a hi st or y of p ul m o n ar y T B i nf e cti o n 
wit h or wit h o ut d o c u m e nt e d a d e q u at e t h er a p y ( Q u a nti F E R O N -T B t e st)  
4.  Pr e s e n c e of lif e -t hr e at e ni n g i nf e cti o n s ( cli ni c all y a n d q u a ntit at e d P C R 
if n e c e s s ar y) 
5.  O n c ol o gi c  c a u s e s  of  s y m pt o m s;  c urr e nt  or  pr e vi o u s  hi st or y  of  
m ali g n a n c y  
6.  Pr e s e n c e of C N S m a nif e st ati o n s (i. e. s ei z ur e s, alt er e d m e nt al st at u s, 
si g n s of i n cr e a s e d i ntr a cr a ni al pr e s s ur e, c hr o ni c p a pill e d e m a, l o s s of 
vi si o n, ot h er s e n s ori n e ur al d efi ci e n ci e s, et c.)  
7.  P ati e nt s s uff eri n g fr o m bi all eli c m ut ati o n s i n a n y of t h e f oll o wi n g g e n e s: 
P R F 1/ P erf ori n,
 U N C 1 3 D/ M u n c
 1 3 -4,
 S T X 1 1/ S y nt a xi n 1 1,
 
S T X B 2/ M u n c  1 8 -2,  R A B 2 7 A/ R a b 2 7 a  ( Gri s c elli  s y n dr o m e  t y p e  2),  
L Y S T
 ( C h e di a k -Hi g a s hi
 s y n dr o m e),
 A P 3 B 1,
 A D T B 3 A,
 H P S 2
 
m ut ati o n s
 ( H er m a n s k y -P u dl a k
 s y n dr o m e
 2)
 a n d
 X -li n k e d 
l y m p h o pr olif er ati v e s y n dr o m e ( X L P)-1 wit h  S H 2 D 1 A m ut ati o n  
8.  P ati e nt s w h o ar e pr e g n a nt or n ur si n g, w o m e n of c hil d b e ari n g p ot e nti al 
w h o ar e u n willi n g t o u s e hi g hl y eff e cti v e birt h c o ntr ol m et h o d s ( s e e 
d efi niti o n i n I n cl u si o n Crit eri a a b o v e) t hr o u g h 4 w e e k s aft er t h e e n d of 
t h eir p arti ci p ati o n i n t h e st u d y 
9.  C o n c o mit a nt  u s e  of  i m m u n o s u p pr e s si o n  t h er a pi e s  e x cl u d e d  b y  t h e  
pr ot o c ol. N ot e: N S AI D s, gl u c o c orti c oi d s, c y cl o s p ori n e, t a cr oli m u s, a n d 
I L-1 i n hi bit or s ( a n a ki nr a, c a n a ki n u m a b, or ril o n a c e pt, or ot h er s) ar e 
all o w e d  
1 0.  P ati e nt s  a n d/ or  p ar e nt s  ( or  l e g al  r e pr e s e nt ati v e,  if  a p pli c a bl e)  n ot  
willi n g t o si g n a s s e nt/i nf or m e d c o n s e nt  
1 1.  H y p er s e n siti vit y t o t h e a cti v e s u b st a n c e or o n e of t h e e x ci pi e nt s of t h e 
i n v e sti g ati o n al pr o d u ct.  
 
* N O T E S:  
F or E x cl u si o n Crit eri o n 7 , l a b t e sti n g will b e p erf or m e d at S cr e e ni n g ( V 0). 
R e s ult s  s h o ul d  b e  a v ail a bl e  f or  V 1  t o  c o nfir m  eli gi bilit y  pri or  t o  st u d y 
tr e at m e nt. I n c a s e tr e at m e nt i s st art e d b a s e d o n l o c al l a b or at or y g e n eti c 
r e s ult s, w hi c h d o n`t i n cl u d e t h e a b o v e li st e d g e n e s, g e n eti c r e s ult s h a v e t o 
b e c o nfir m e d b y c e ntr al l a b or at or y r etr o s p e cti v el y a s f or i n cl u si o n crit eri o n 1.  


 
 
 
P a g e 5 0  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
F or In cl u si o n C rit eri o n 1 , r e s ult s fr o m g e n eti c t e sti n g will b e a v ail a bl e pri or 
t o st u d y tr e at m e nt  i niti ati o n. 
 
1 0. 4  P ati e nt W it h dr a w al C rit eri a 
A p ati e nt m a y b e wit h dr a w n fr o m t h e st u d y at a n y ti m e f or r e a s o n s i n cl u di n g, b ut n ot li mit e d t o, t h e 
f oll o wi n g:  
1.  T h e p ati e nt will st o p t h e st u d y f or s af et y c o n c er n s i n t h e o pi ni o n of t h e 
I n v e sti g at or  
2.  St o p pi n g f or i n eff e cti v e n e s s s h o ul d o nl y b e r el at e d t o s eri o u s m a nif e st ati o n s 
(i. e., M A S) u n c o ntr oll e d b y t h e dr u g. I n t h e c a s e of st u d y di s c o nti n u ati o n f or 
l a c k of r e s p o n s e t o tr e at m e nt a n d st art of r e s c u e i m m u n o s u p pr e s si o n, all k e y 
s af et y a n d effi c a c y o ut c o m e s will b e f oll o w e d u p t hr o u g h o ut t h e d o u bl e -bli n d 
p eri o d o n all r a n d o mi z e d p ati e nt s  
3.  P h y si ci a n d e ci si o n d u e t o s af et y c o n c er n s or l a c k of effi c a c y  
4.  T h e p ati e nt wit h dr a w s c o n s e nt  
5.  If IM P h a s b e e n a d mi ni st er e d a n d t h e p ati e nt e x p eri e n c e s i nt ol er a n c e  (i. e. 
m a nif e st ati o n s of h y p er s e n siti vit y)  t h at c a n n ot b e c o ntr oll e d d e s pit e t h e b e st 
eff ort s of t h e p h y si ci a n  
6.  P arti ci p ati o n i n t h e st u d y i s n o l o n g er i n t h e b e st i nt er e st s of t h e p ati e nt, i n 
t h e j u d g m e nt of t h e m a n a gi n g cli ni ci a n or t h e S p o n s or  
7.  T h e st u d y i s t er mi n at e d pri or t o t h e e n d of t h e p ati e nt’ s p arti ci p ati o n.  
8.  T h e p ati e nt i s u n willi n g or u n a bl e t o a d h er e t o pr ot o c ol r e q uir e m e nt s or 
r e q uir e s a c o n c o mit a nt m e di c ati o n pr o hi bit e d b y t h e pr ot o c ol 
 
If a p ati e nt i s di s c o nti n u e d pr e m at ur el y fr o m t h e st u d y, t h e I n v e sti g at or m u st pr o vi d e a n e x pl a n ati o n 
i n t h e A d diti o n al C o m m e nt s s e cti o n a n d c o m pl et e t h e E arl y T er mi n ati o n p a g e of t h e el e ctr o ni c c a s e 
r e p ort f or m ( e C R F). If I M P h a s b e e n a d mi ni st er e d, t h e I n v e sti g at or s h o ul d m a k e e v er y eff ort t o 
p erf or m s c h e d ul e d e v al u ati o n s pri or t o di s c h ar g e, pr o vi d e d t h e e v al u ati o n s d o n ot j e o p ar di z e t h e 
s af et y  or  o n -g oi n g  m e di c al  c ar e  of  t h e  p ati e nt (i. e.,  p h y si c al  e x a mi n ati o n,  vit al  si g n s,  cli ni c al  
l a b or at or y t e st s,  i m m u n ol o gi c a s s e s s m e nt s,  a n d  A E  a s s e s s m e nt s).  All  k e y  effi c a c y  a n d  s af et y 
e n d p oi nt s will b e c oll e ct e d f or t h e l e n gt h of t h e st u d y.  
I n t h e e v e nt t h at a p ati e nt di s c o nti n u e s pr e m at ur el y d u e t o a n S A E, t h e p ati e nt will b e f oll o w e d u ntil 
r e s ol uti o n, u ntil t h e c o n diti o n st a bili z e s , or u ntil t h e p ati e nt i s lo st t o f oll o w -u p. S e e S e cti o n 2 0  f or 
di s c u s si o n of m a n a g e m e nt of s u bj e ct s w h o di s c o nti n u e pr e m at ur el y b e c a u s e of a n A E or S A E.  
T h e p h y si ci a n s a n d t h e p ati e nt will h a v e t h e o pti o n t o di s c o nti n u e t h e tr e at m e nt if t h e y f e el t h at 
p ur s ui n g t h e tr e at m e nt i s n ot a p pr o pri at e. I n c a s e of di s c o nti n u ati o n a n d st art of a n ot h er m e di c ati o n, 
it i s i m p ort a nt t o c a pt ur e t hi s i nf or m ati o n t o o, a n d al s o t o r e p ort w h et h er a r e s p o n s e w a s o b s er v e d 
i n c a s e of c h a n g e. All k e y effi c a c y a n d s af et y e n d p oi nt s will al s o b e c oll e ct e d f or t h e l e n gt h of t h e 
st u d y . 
A p ati e nt  w h o di s c o nti n u e s pr e m at ur el y aft er o n e or m or e tr e at m e nt s will n ot b e r e pl a c e d.  
 
 


 
 
 
P a g e 5 1  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
1 0. 5  Bli n di n g/ u n bli n di n g Arr a n g e m e nt s  
S p o n s or, p ati e nt s, i n v e sti g at or s, i n v e sti g at or st aff, p er s o n s p erf or mi n g t h e a s s e s s m e nt s, a n d d at a 
a n al y st s will r e m ai n bli n d e d t o t h e i d e ntit y of t h e a s si g n e d st u d y tr e at m e nt fr o m t h e ti m e of 
r a n d o mi z ati o n i nt o t h e R W p h a s e u ntil t h e fi n al d at a b a s e l o c k, u si n g t h e f oll o wi n g m et h o d s: 
 
1)  R a n d o mi z ati o n d at a ar e k e pt stri ctl y c o nfi d e nti al u ntil t h e ti m e of u n bli n di n g, a n d will n ot b e 
a c c e s si bl e b y a n y o n e el s e i n v ol v e d i n t h e tr e at m e nt a d mi ni str ati o n, tr e at m e nt o ut c o m e 
a s s e s s m e nt or d at a c oll e cti o n or a n al y si s, wit h t h e e x c e pti o n of t h e D S M B m e m b er s a s 
d e s cri b e d i n t h e D S M B C h art er.  
2)  T h e i d e ntit y of t h e tr e at m e nt s will b e c o n c e al e d b y t h e u s e of st u d y dr u g s ( T a d e ki ni g alf a 
a n d Pl a c e b o) t h at ar e all i d e nti c al i n p a c k a gi n g, l a b eli n g, s c h e d ul e of a d mi ni str ati o n, 
a p p e ar a n c e a n d o d or.  
3)  T h e r a n d o mi z ati o n  c o d e f or a n i n di vi d u al p ati e nt m a y o nl y b e u n bli n d e d i n e m er g e n c y 
sit u ati o n s, w h er e t h e i n v e sti g at or d e ci d e s t h at a p ati e nt c a n n ot b e a d e q u at el y tr e at e d 
wit h o ut k n o wi n g t h e i d e ntit y of t h eir tr e at m e nt all o c ati o n. T o br e a k t h e r a n d o mi z ati o n c o d e , 
t h e i n v e sti g at or m u st o p e n t h e e m er g e n c y u n bli n di n g e n v el o p e s pr o vi d e d. If a n y u n bli n di n g 
e n v el o p e i s o p e n e d, t h e ti m e, d at e, s u bj e ct n u m b er a n d r e a s o n f or o p e ni n g m u st b e 
d o c u m e nt e d.  
 
T h e pri m ar y e n d p oi nt, ti m e t o fir st di s e a s e r e a cti v ati o n, i s a p ar a m et er w hi c h i s o bj e cti v el y 
a s s e s s e d b y r e p orti n g a ti m e a n d m e a s uri n g s er u m f erriti n l e v el s, s er u m C R P a n d a s s e s si n g 
m AI D AI. m AI D A I i s c o m pri s e d of 1 4 it e m s of w hi c h 4 s y m pt o m s c o ul d b e c o n si d er e d s u bj e cti v e 
a n d t h u s a r e e x cl u d e d fr o m t h e d efi niti o n of r e s p o n s e t o t h er a p y a n d di s e a s e r e a cti v ati o n ( s e e 
A p p e n di x I) . All 1 4 it e m s will c o nti n u e t o b e c oll e ct e d a n d will b e pl ott e d o v er ti m e i n t h e d e s cri pti v e 
a n al y si s.  
 
 
 




 
 
 
P a g e 5 3  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
u si n g a st eril e, si n gl e u s e s yri n g e. B ef or e tr e at m e nt, t h e  vi al s will b e br o u g ht t o r o o m t e m p er at ur e 
( 1 8 – 2 5° C) b y r e m o vi n g t h e m fr o m t h e r efri g er at or 1 5 mi n pri or t o a d mi ni str ati o n. T h e I M P will b e 
wit h dr a w n i nt o a st eril e s yri n g e a n d a d mi ni st er e d wit h o ut d el a y .  
F urt h er i n str u cti o n s o n I M P h a n dli n g a n d st or a g e will b e pr o vi d e d b y t h e S p o n s or/ C R O.  
N ot e: m or e t h a n 1 vi al mi g ht b e r e q uir e d t o d eli v er t h e c al c ul at e d d o s e.  
Dr u g pr o d u ct s el e ct e d d o s e:  T h e s af et y a n d t ol er a bilit y of T a d e ki ni g alf a h a s b e e n st u di e d i n a d ult 
h u m a n  v ol u nt e er s  f oll o wi n g  si n gl e  s. c.  i nj e cti o n s  wit h  d o s e s  r a n gi n g  fr o m  2 0 m g  t o  3 5 0 m g  a n d  
r e p e at e d s. c. d o s e s ( 3 5 m g a n d 1 7 5 m g) a d mi ni st er e d o n alt er n at e d a y s. I n a d diti o n,  6 w e e k s d ur ati o n 
P h a s e I b st u di e s (t hr e e a d mi ni str ati o n s p er w e e k) h a v e b e e n c o m pl et e d i n R h e u m at oi d Art hriti s ( R A) 
( n = 3 5) s u bj e cts a n d P s ori a si s ( P s o) ( n = 3 6) s u bj e ct s wit h d o s e s r a n gi n g fr o m 2 0 m g t o 1 6 0 m g i n t h e 
f or m er, a n d 2 0 m g t o 3 2 0 m g i n t h e l att er. N o S A E s w er e o b s er v e d i n a n y of t h e st u di e s a n d t h e m o st 
fr e q u e nt A E ( mil d t o m o d er at e) w er e i nj e cti o n sit e r e a cti o n s ( wit h a c a u s alit y d e s cri b e d a s “ pr o b a bl y 
r el at e d” t o T a d e ki ni g alf a).  
A p h a s e II Cli ni c al Tri al i n A d ult O n s et Still’ s Di s e a s e ( A O S D) s u bj e ct s ( n = 2 3) i s c o m pl et e d.  1 0 
s u bj e ct s w er e  tr e at e d wit h 8 0 m g a n d 1 3 s u bj e ct s w er e  tr e at e d wit h 1 6 0 m g f or 1 2 w e e k s (t hr e e 
a d mi ni str ati o n s p er w e e k). O n e p ati e nt  i n t h e 8 0 m g c o h ort s uff er e d fr o m a g a str o e nt eriti s t h at 
r e q uir e d h o s pit ali z ati o n, S A E ( gr a d e 3) n ot r el at e d t o t h e I M P a s p er I n v e sti g at or. A p ati e nt  of t h e 
1 6 0  m g c o h ort s uff er e d fr o m T o xi c O pti c u s N e ur o p at h y t h at r e q uir e d h o s pit ali z ati o n, S A E ( gr a d e 3) 
a n d w a s c o n si d er e d p o s si bl y r el at e d t o t h e I M P b y t h e p h y si ci a n.  
U n d er  a  c o m p a s si o n at e -u s e I N D,  a  p ati e nt  s uff eri n g  fr o m  a  s e v er e  n e o n at al  a ut oi nfl a m m at or y  
c o n diti o n c a u s e d b y a n N L R C 4 m ut ati o n, w a s gi v e n r -hI L -1 8 B P at a d o s e of 2 m g/ k g s. c. e v er y 4 8 
h o ur s. Wit hi n t h e fir st t w o d o s e s, t h e p ati e nt ’ s o v er all st at u s i m pr o v e d r a pi dl y i n c orr el ati o n wit h a c ut e 
dr o p ( n o n -d et e ct a bl e) i n fr e e I L -1 8. All r e m ai ni n g i nfl a m m at or y f e at ur e s, i n cl u di n g e nt er o c oliti s, al s o 
i m pr o v e d st e a dil y a n d all o w e d w e a ni n g of ot h er i m m u n o s u p pr e s si o n a n d r ei ntr o d u cti o n of e nt er al 
f e e di n g. T h e tr e at m e nt h a s c o nti n u e d f or m or e t h a n 6 y e ar s , at t h e s a m e d o s e, wit h cli ni c al a n d 
bi ol o gi c al r e mi s si o n a n d wit h o ut o b s er v e d si d e eff e ct s. T h er ef or e,  fr o m a s af et y p oi nt of vi e w, t h e 
c oll e ct e d h u m a n d at a s u p p ort s t h e s el e ct e d d o s e r a n g e of t h e st u d y.  
 
Fr o m a cli ni c al effi c a c y p oi nt of vi e w,  it i s i m p ort a nt t o u n d erli n e t h at d o s e s of 2 0 m g 3 ti m e s a w e e k 
s h o w e d n o effi c a c y i n R A a n d P s o a d ult s u bj e ct s. T h o s e d o s e s will b e li k el y al s o i n eff e cti v e i n A o S D 
s u bj e ct s c o n si d eri n g t h at bl o o d l e v el s of I L -1 8 i n A o S D ar e hi g h er t h a n t h o s e r e p ort e d i n t h e t w o 
c o n diti o n s n ot e d a b o v e  
 
I n c o n cl u si o n, b a s e d o n pr e cli ni c al a n d pr e vi o u s h u m a n st u di e s p erf or m e d wit h T a d e ki ni g alf a a n d 
i n or d er t o a v oi d pr o vi di n g i n effi ci e nt d o s e s t o p ati e nt s s uff eri n g fr o m N L R C 4 m ut ati o n a n d XI A P 
d efi ci e n c y t h e s el e ct e d d o s e i s of 2 m g/ k g . 
1 1. 2. 2  R o ut e of A d mi ni str ati o n  
T h e pr o d u ct c o m e s a s a s ol uti o n t o b e a d mi ni st er e d b y t h e s. c. r o ut e.  Gl a s s vi al s c o nt ai n 0. 5 m L  
c orr e s p o n di n g t o a d o s e of 2 0 m g of t h e a cti v e pr o d u ct,  a n d a 0. 1 2 m L o v erfill  i s i n cl u d e d.  
T h e sit e of t h e s. c. i nj e cti o n s h o ul d b e alt er n at e d e. g. t h e o ut si d e of t h e t hi g h s, ar m s a n d t h e v ari o u s 
q u a dr a nt s  of  t h e  a nt eri or  a b d o mi n al  w all.  T h e  p er s o n n el  of  t h e  p arti ci p ati n g  sit e s  s h all  gi v e  
i n str u cti o n s f or pr o p er i nj e cti o n pr o c e d ur e s t o t h e st u d y n ur s e  ( ho m e c ar e n ur s e or sit e n ur s e)  i n 
or d er t o mi ni mi z e i nj e cti o n sit e r e a cti o n s d u e t o p o or i nj e cti o n pr o c e d ur e.  A B 2 Bi o will pr o vi d e writt e n 
s. c. i nj e cti o n i n str u cti o n s. U s e d s yri n g e s  a n d n e e dl e s  will b e di s p o s e d of i n a p u n ct ur e -r e si st a nt 
c o nt ai n er. U s e d gl a s s vi al s will b e di s p o s e d of at t h e sit e, p er t h e sit e’ s I M P d e str u cti o n p oli c y,  aft er 
I MP a c c o u nt a bilit y a n d r e c o n cili ati o n i s p erf or m e d.  H o w e v er, u n u s e d vi al s will b e r et ur n e d t o t h e 
dr u g s u p pli er f or d e str u cti o n.  
 
 


 
 
 
P a g e 5 4  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
1 1. 2. 3  P ati e nt C o m pli a n c e  
I n  or d er  t o  e n h a n c e  s u bj e ct s’  c o m pli a n c e,  l o c al  s ki n  tr e at m e nt  will  b e  pr o p o s e d  t o  t h e  
p ar e nt s/ p ati e nt s t o miti g at e l o c al i nfl a m m at or y r e a cti o n s.  
Aft er p ati e nt di s c h ar g e fr o m t h e h o s pit al t h e  p ar e nt s/ p ati e nt  will c o m pl et e a d ail y di ar y r e c or di n g 
c urr e nt  h e alt h  st at u s  i n cl u di n g  b o d y  t e m p er at ur e,  s ki n  r a s h,  v o miti n g,  di arr h e a,  c h a n g e s  i n  
c o n c o mit a nt m e di c ati o n, a n d a n y ot h er u n u s u al, r e m ar k a bl e s y m pt o m s . 
N O T E: T e m p or ar y S t o p of T r e at m e nt 
T e m p or ar y tr e at m e nt i nt err u pti o n s will b e all o w e d i n c a s e t h e p ati e nt  s h o w s f e v er or a n y si g n of 
u n d er g oi n g a n i nf e cti o n pr o c e s s u nr el at e d t o t h e tr e at e d c o n diti o n. F or t h e i nj e cti o n s d o n e b y t h e 
h o m e  c ar e  n ur s e  ( H C N)  e v er y 2  d a y s,  t h e  H C N  s h o ul d  c o nt a ct  t h e  I n v e sti g at or f or  a d vic e  o n  
tr e at m e nt  c o nti n u ati o n  or  st o p pi n g.  I n  c a s e  of  a n y  d o u bt,  t h e  tr e at m e nt  m a y b e  di s c o nti n u e d  
t e m p or aril y.  
I n c a s e of tr e at m e nt st o p of m or e t h a n 3 w e e k s t h e eff e ct of t h e i n v e sti g ati o n al dr u g i s l o st a n d t h e 
c a s e will b e c o n si d er e d a dr o p o ut  ( di s c o nti n u ati o n). 
1 1. 2. 4  C o n c o mit a nt T r e at m e nt 
All c o n c o mit a nt m e di c ati o n s (t o g et h er wit h r o ut e of a d mi ni str ati o n) a n d tr e at m e nt i niti at e d d uri n g t h e 
p eri o d of t h e st u d y b et w e e n s cr e e ni n g a n d e n d of t h e st u d y  will b e r e c or d e d i n t h e c o n c o mit a nt 
tr e at m e nt s e cti o n of t h e e C R F. 
P er mitt e d C o n c o mit a nt T r e at m e nt s 
P ati e nt s  c a n  m ai nt ai n  tr e at m e nt  wit h  st a bl e  d o s e s  of  N o n -St er oi d al  a nti -i nfl a m m at or y 
Dr u g s ( N S AI D s), c y cl o s p ori n e, t a cr oli m u s a n d I L -1 i n hi bit or s ( a n a ki nr a, c a n a ki n u m a b, or 
ril o n a c e pt,  or  ot h er s). D o s e 
i n cr e m e nt s  f or  t h e  p er mitt e d  c o-m e di c ati o n s  or  t h eir  
i ntr o d u cti o n aft er t h e b e gi n ni n g of t h e st u d y ar e n ot p er mitt e d a n d r e pr e s e nt tr e at m e nt 
f ail ur e s  a n d  st u d y  e arl y  t er mi n ati o n.  F or  c y cl o s p ori n e  a n d  sir oli m u s  tr e at m e nts ,  t h e  
p h y si ci a n  m a y  n e e d  t o  c h a n g e  t h e  d o s e  sli g htl y  t o  r e a dj u st  s er u m  l e v el s.  D o s e  
a dj u st m e nt s f or k e e pi n g st a bl e s er u m l e v el s i s a c c e pt a bl e d uri n g t h e st u d y . T h e w e a ni n g 
of p er mitt e d  c o -m e di c ati o n s  aft er  t h e  b e gi n ni n g  of  t h e  st u d y  ar e  p er mitt e d  a n d  ar e 
e v al u at e d a s a d diti o n al p ar a m et er f or r e s p o n s e t o t h er a p y; t h e d e ci si o n f or w e a ni n g ot h er 
i m m u n o s u p pr e s si v e  t h er a pi e s  ot h er t h a n  t h e  S O C  st er oi d s  i s at  t h e  di s cr eti o n  of  t h e  
tr e ati n g  p h y si ci a n a n d  s h o ul d  b e  b a s e d  o n  t h e  i n di vi d u al  p ati e nt’ s  di s e a s e  st at u s . If 
p er mitt e d  c o -m e di c ati o n s  ar e  w e a n e d  off  d uri n g  t h e  c o ur s e  of  t h e  st u d y  a n d  t h e  
i n v e sti g at or d e ci d e s t o r e-i ntr o d u c e t h e m, t h e y ar e p er mitt e d a s l o n g a s t h e d o s e s ar e t h e 
s a m e or l o w er t h a n t h e d o s e s t h at w er e a d mi ni st er e d  at st u d y e ntr y . 
 
U n a ut h ori z e d C o n c o mit a nt  Tr e at m e nt s 
T h e st u d y -a s si g n e d tr e at m e nt s ( T a d e ki ni g alf a or pl a c e b o a s r a n d o mi z e d, pl u s S O C)  ar e, i n a d diti o n 
t o t h e p er mitt e d c o n c o mit a nt m e di c ati o n s if pr e s cri b e d b y t h e tr e ati n g p h y si ci a n, t h e o nl y tr e at m e nt 
all o w e d d uri n g t h e st u d y tr e at m e nt p eri o d.  
T h e n e e d t o u s e r e s c u e i m m u n o s u p pr e s si o n will b e c o n si d er e d a s tr e at m e nt f ail ur e  a n d t h e 
p ati e nt will di s c o nti n u e st u d y tr e at m e nt .  
 
T h e y i n cl u d e c yt o a bl ati v e dr u g s a s et o p o si d e , c y cl o p h o s p h a mi d e , et c. S p e cifi c c ell-d e pl eti n g 
a g e nt s s u c h a s al e mt u z u m a b , rit u xi m a b, a nti -t h y m o c yt e gl o b uli n. Im m u n o s u p pr e s si v e  
a nti m et a b olit e s s u c h a s 6 -m er c a pt o p uri n e a n d a z at hi o pri n e a n d  m y c o p h e n ol at e m of etil t h at 
i n hi bit s t h e pr olif er ati o n of i m m u n e c ell s. Ot h er bi ol o gi c s diff er e nt t o I L -1 bl o c k er s will al s o b e 
c o n si d er e d a s r e s c u e i m m u n o s u p pr e s si o n, i. e. a nti -T N F a nti b o di e s, t o cili z u m a b, v e d oli z u m a b .  
 
If t h e I n v e sti g at or f e el s t h e cli ni c al sit u ati o n of t h e p ati e nt i s li k el y t o r e q uir e a n y of t h e a b o v e r e s c u e 
i m m u n o s u p pr e s si o n m e di c ati o n s, t h e p ati e nt will b e c o n si d er e d a tr e at m e nt f ail ur e a n d di s c o nti n u e 
st u d y tr e at m e nt . If t h e i n v e sti g at or s c o n si d er n e c e s s ar y t h e i ntr o d u cti o n of a n ot h er m e di c ati o n t h at 
i s n ot i n cl u d e d i n t h e li st or c at e g or y a b o v e, t h e I n v e sti g at or s h o ul d c o nt a ct t h e M e di c al M o nit or.  


 
 
 
P a g e 5 5  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
 
1 1. 3  St u d y P r o d u ct H a n dli n g  
1 1. 3. 1  St or a g e a n d D i stri b uti o n 
T h e S p o n s or  will s u p pl y t h e I M P. T h e tr a n s p ort of t h e dr u g pr o d u ct t o t h e cli ni c al s u p pl y v e n d or will 
b e p erf or m e d u n d er c o ntr oll e d t e m p er at ur e c o n diti o n s ( b et w e e n 2 -8 ° C). T h e st or a g e of t h e b ul k 
m at eri al at t h e cli ni c al s u p pl y v e n d or will b e p erf or m e d u n d er c o ntr oll e d t e m p er at ur e c o n diti o n s ( 2-
8° C). T h e cli ni c al s u p pl y v e n d or will pr e p ar e tr e at m e nt kit s c o nt ai ni n g 2 0 m g vi al s or pl a c e b o vi al s i n 
kit c art o n s  wit h  c art o n l a b el s, a n d vi al l a b el s.  S yri n g e s a n d n e e dl e s will b e pr o vi d e d s e p ar at el y f or 
tr e at m e nt a d mi ni str ati o n.  T h e  kit s  a n d  s u p pli e s  will  b e  s hi p p e d  fr o m  t h e  cli ni c al  s u p pl y  v e n d or  
( c e ntr al st or a g e) t o t h e h o s pit al p h ar m a c y or p ati e nt’ s h o m e  aft er  o n c e a p ati e nt  h a s b e e n s cr e e n e d, 
si g n e d t h e I C F a n d all r e q uir e d d o c u m e nt ati o n ar e a v ail a bl e at t h e sit e. T h e Pr oj e ct M a n a g er ( P M) , 
or d e si g n e e,  at t h e C R O will b e i n c h ar g e of t h e c o m m u ni c ati o n t o t h e c e ntr al v e n d or f or pr o d u ct 
s hi p m e nt t o t h e sit e s.  I niti al I M P r el e a s e t o sit e s i s a p pr o v e d b y t h e S p o n s or P M or d e si g n e e  u p o n 
ti m el y r e c ei pt of all r e q uir e d d o c u m e nt s fr o m t h e C R O. 
 
T h e kit s will  c o nt ai n eit h er t h e a cti v e s u b st a n c e or pl a c e b o.  
  
T h e kit s will b e st or e d at t h e h o s pit al  p h ar m a c y  or p ati e nt’ s h o m e u n d er  c o ntr oll e d  t e m p er at ur e 
c o n diti o n s  ( 2-8° C) .   
 
F or a m b ul at or y p ati e nt s, if t h e p ati e nt ’ s h o m e i s l o c at e d n e ar t h e h o s pit al, a n d  c a u s e s  n o m aj or 
i n c o n v e ni e n c e s t o t h e  p ati e nt, t h e p ati e nt  will g o  t o t h e h o s pit al e v er y 2 d a y s f or t h e tr e at m e nt 
a d mi ni str ati o n  b y t h e sit e n ur s e.  
 
F or a n y p ati e nt w h o c a n n ot att e n d  t h e h o s pit al f or t h e i nj e cti o n s e v er y 2 d a y s, a st u d y h o m e c ar e 
n ur s e  m a y b e i n v ol v e d . T h e sit e will di s c u s s wit h t h e p ati e nt a n d r e q u e st H C N i n a d v a n c e t o all o w 
ti m el y tr ai ni n g a n d l o gi sti c s et u p at p ati e nt h o m e ( e. g. l o c k e d fri d g e, IM P s hi p m e nt t o p ati e nt h o m e).  
 
If p ati e nt h o m e i s cl o s e b y t h e sit e, th e H C N  will g o t o t h e h o s pit al p h ar m a c y t o r e c o v er t h e I M P f or 
t h e tr e at m e nt of t h e d a y, i n v ali d at e d c o oli n g b a g s. T h e m a xi m u m d ur ati o n all o w e d f or IM P tr a n s p ort 
u n d er 2 -8° C i s 4  ho ur s i n a v ali d at e d c o oli n g  b a g . T h e H C N will g o fr o m t h e sit e t o t h e p ati e nt  h o m e 
f or t h e IM P a d mi ni str ati o n  a n d will d o c u m e nt a n y o b s er v ati o n s ( e v e n if n o m aj or o b s er v ati o n s) d uri n g 
I M P tr a n sit, a n d b ef or e IM P a d mi ni str ati o n.  
 
A c o uri er m a y b e i n v ol v e d f or I M P s hi p m e nt fr o m sit e /IM P d e p ot  t o p ati e nt h o m e if di st a n c e i s t o o 
f ar a w a y.  
 
F urt h er i n str u cti o n s a n d a dj u st m e nt s t o t hi s l o gi sti c will b e pr o vi d e d i n a s e p ar at e m a n u al t o t h e sit e.  
1 1. 3. 2   Stu d y P r o d u ct A c c o u nt a bilit y a n d R e c o n cili ati o n  
All I M P r e c ei v e d a n d di s p e n s e d b y t h e I n v e sti g at or s/ p h ar m a ci st s of e a c h sit e will b e i n v e nt ori e d a n d 
a c c o u nt e d f or t hr o u g h o ut t h e tri al p eri o d b y t h e I n v e sti g at or s/ p h ar m a ci st s o n t h e c orr e s p o n di n g 
“M a st er I MP A c c o u nt a bilit y  Lo g” a n d “ S u bj e ct I M P Ac c o u nt a bilit y L o g”  (t o b e pr o vi d e d pri or t o t h e 
S it e Initi ati o n V i sit ( SI V). 
 
T h e I n v e sti g at or s a gr e e n ot t o s u p pl y t h e I M P t o a n y p er s o n e x c e pt t o st u d y st aff, t h e H C N  or c o uri er 
s er vi c e if i n v ol v e d t o s hi p I M P t o p ati e nt h o m e . 
 
U n u s e d I MP m u st n ot b e tr a d e d. U s e d a n d u n u s e d I M P at c o m pl eti o n of t h e st u d y s h o ul d b e r et ur n e d 
t o t h e I MP d e p ot  f or d e str u cti o n. U s e d vi al s m a y b e d e str o y e d at t h e sit e, a c c or di n g t o t h e sit e ’ s 
pr o c e d ur e s, aft er c o m pl eti o n of I M P a c c o u nt a bilit y .  U s e d vi al s will b e d e str o y e d o nl y at t h e dr u g 
s u p pli er pr e mi s e s a c c or di n g t o t h eir o w n pr o c e d ur e s .  
 
 


 
 
 
P a g e 5 6  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
1 2  A S S E S S M E N T O F E F FI C A C Y  
Effi c a c y a s s e s s m e nt i s r el at e d t o t h e i n ci d e n c e of di s e a s e r e a cti v ati o n s  a n d will c o v er:  
 
Cli ni c al e v al u ati o n ( m o stl y c a pt ur e d i n t h e m AI D AI):  
o  C o m pl et e  p h y si c al  e x a mi n ati o n  i n cl u di n g:  vit al  si g n s  ( s y st oli c  a n d  di a st oli c  
bl o o d pr e s s ur e, h e art r at e, r e s pir at or y r at e, w ei g ht, a n d b o d y t e m p er at ur e)  
o  All  fi n di n g s  s h o ul d  b e  d o c u m e nt e d:  j oi nt  s w elli n g,  h e p at o m e g al y  a n d  
s pl e n o m e g al y, pr e s e n c e of s ki n r a s h, o p ht h al mi c c o ntr ol ( pr e s e n c e of u v eiti s).  
O p ht h al mi c e x a mi n ati o n will b e p erf or m e d t o e x a mi n e t h e pr e s e n c e/ a b s e n c e 
of u v eiti s  a n d, if pr e s e nt, t h e e v ol uti o n d uri n g t h e st u d y . 
o  S y m pt o m s s h o ul d b e d o c u m e nt e d: a b d o mi n al p ai n, di arr h e a, n a u s e a, v o miti n g  
o  All  cli ni c al  c o m p o n e nt s  (i n cl u di n g  cli ni c al  fi n di n g s  a n d  s y m pt o m s)  of  t h e  
di s e a s e will b e c a pt ur e d i n a bi n ar y w a y a s eit h er b ei n g pr e s e nt or a b s e nt. T h e 
j u d g e m e nt,  of  w h et h er  a n  e n d  or g a n  c at e g or y  i s  aff e ct e d,  i s  d o n e  b y  t h e  
tr e ati n g p h y si ci a n a c c or di n g t o cli ni c al st a n d ar d s, a s al s o pr e vi o u sl y  d o n e f or 
all  m AI D AI c o m p o n e nt s.  
o  D ail y w ei g ht, st o ol o ut p ut, a n d P O i nt a k e m e a s ur e m e nt s i n cl u di n g n u m b er of 
e m e si s e pi s o d e s will b e p erf or m e d o n p ati e nt s wit h i nt e sti n al d y sf u n cti o n, o nl y 
w h e n t h e p ati e nt s ar e h o s pit ali z e d  
o  R a di ol o gi c fi n di n g s if a s s e s s e d a s n e c e s s ar y b y t h e tr e ati n g p h y si ci a n  
M ai nt e n a n c e c o -tr e at m e nt: 
o  T ot al w e e kl y gl u c o c orti c oi d s  
o  I L-1 bl o c k er s  
o  Ot h er tr e at m e nt s * ( e. g., D M A R D s … et c.)  
* R ef er t o S e cti o n 1 1. 2. 4: C o n c o mit a nt  tr e at m e nt 
L a b or at or y ( s e e T a bl e 2):  
o  S er u m C R P  
o  S er u m F erriti n  
o  C o m pl et e bl o o d c o u nt s  
o  S er u m l e v el s of t ot al I L -1 8, fr e e I L -1 8, I L -1 8 B P  
 
N ot e 1:  GI -r el at e d p ar a m et er s will b e a s s e s s e d i n p ati e nt s wit h GI d y sf u n cti o n  
 
N ot e 2:  F or o ut p ati e nt t h er a p y t h e cli ni c al e v al u ati o n will b e p erf or m e d at t h e m o nt hl y vi sit s  
 
1 2. 1  D E FI NI TI O N O F R E S P O N S E T O T H E R A P Y  
1.  I n  t h e  1 6 -w e e k  R W  p h a s e,  r e s p o n s e  t o  t h er a p y  ( a s  pri m ar y  e n d p oi nt  of  
effi c a c y) will b e a s s e s s e d b y pr e v e nti o n of di s e a s e r e a cti v ati o n s  d uri n g t h e 
1 6 -w e e k tr e at m e nt i n t h e R W p h a s e  
2.  I n t h e S A O L p h a s e , r e s p o n s e t o t h er a p y ( a s s e c o n d ar y e n d p oi nt of effi c a c y) 
will b e a s s e s s e d t hr o u g h t h e c o ntr ol of t h e a cti v e di s e a s e  
 


 
 
 
P a g e 5 7  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
F or r e s p o n s e t o t h er a p y, o nl y t h e o bj e cti v e m AI D AI c o m p o n e nt s will b e e v al u at e d 
a s i n di c at e d b el o w.  S u bj e cti v e m AI D AI c o m p o n e nt s ( s e e A p p e n di x  I) will n ot b e 
c o n si d er e d t o a v oi d a n y bi a s i n t h e effi c a c y a s s e s s m e nt i n t h e o p e n l a b el p art of 
t h e st u d y. J u stifi c ati o n f or t h e r e vi s e d r e s p o n s e t o t h er a p y d efi niti o n s i s i n cl u d e d 
i n s e cti o n 8. 3. 3. 
 
o  C o m pl et e r e s p o n s e  
N o m aj or e n d or g a n d a m a g e  ( = o bj e cti v e m AI D AI c o m p o n e nt s) 
•  N o f e v er ( b o d y t e m p er at ur e ≤1 0 0. 4 º F/ 3 8 ° C)  
•  N o di arr h e a  
•  N o tr a n s a mi niti s a n d/ or h e p at o m e g al y  
•  N o s pl e n o m e g al y a n d/ or a d e n o p at h y  
•  N o r a s h  
•  N o u v eiti s  
•  N o art hriti s  
•  N o r a di ol o gi c C N S i n v ol v e m e nt  
•  N o c yt o p e ni a ( H g B ≥ 9. 0 a n d/ or P L T ≥1 0 0 a n d/ or W B C ≥3. 0)  
N o s y st e mi c i nfl a m m ati o n  
•  N o h y p erf erriti n e mi a ( s er u m l e v el < 5 0 0 n g/ m L)  
•  N o i n cr e a s e d C R P ( s er u m l e v el < 2 x U L N ) 
I m m u n o s u p pr e s si v e t h er a pi e s 
•  Di s c o nti n u ati o n of s y st e mi c  c orti c o st er oi d s  ( e x cl u di n g hy dr o c orti s o n e 
f or  pr e v e nti o n  of  a dr e n al  i n s uffi ci e n c y) or  ot h er  i m m u n o s u p pr e s si v e  
t h er a pi e s i n cl u di n g bi ol o gi c s o n g oi n g at b a s eli n e 
•  N o  st art  or  d o s e  i n cr e a s e  of  ot h er  i m m u n o s u p pr e s si v e  t h er a pi e s  
i n cl u di n g bi ol o gi cs 
o  P arti al r e s p o n s e  
At  l e a st  5 0 %  r e d u cti o n  of  t h e  n u m b er  of  aff e ct e d  o bj e cti v e e n d  or g a n  
d a m a g e c at e g ori e s at b a s eli n e a n d  
•   
At  l e a st  5 0 %  of  t h e  s y st e mi c  i nfl a m m at or y  m ar k er s  (f erriti n  a n d/ or  
C R P) i n cr e a s e d at b a s eli n e r e a c hi n g l e v el s f or c o m pl et e r e s p o n s e or  
•  
Di s c o nti n u ati o n of s y st e mi c c orti c o st er oi d s  ( e x cl u di n g hy dr o c orti s o n e 
f or pr e v e nti o n of a dr e n al i n s uffi ci e n c y) or ot h er i m m u n o s u p pr e s si v e 
t h er a pi e s i n cl u di n g bi ol o gi c s o n g oi n g at b a s eli n e 
 
o  Di s e a s e I m pr o v e m e nt  
A t hir d r e s p o n s e c at e g or y of Di s e a s e I m pr o v e m e nt i s i ntr o d u c e d t o b e utili z e d a s 
a d e s cri pti o n of b e st r e s p o n s e a n d i n or d er t o b ett er d e s cri b e i niti al tr e at m e nt 
r e s p o n s e  t o  t h er a p y  a n d  di s e a s e  e v ol uti o n  o v er  ti m e.  T hi s  i s  o nl y  u s e d  f or  
a n al y si s p ur p o s e s a n d will n ot b e e v al u at e d f or t h e d e ci si o n w h et h er t o b e eli gi bl e 
f or t h e st art of t h e R W p h a s e. Di s e a s e I m pr o v e m e nt i s d efi n e d a s:  
•  R e d u cti o n  of  t h e  n u m b er  of  aff e ct e d  o bj e cti v e  e n d  or g a n  d a m a g e  
c at e g ori e s at b a s eli n e b y at l e a st 1 or  
•  N or m ali z ati o n  (i. e.  r e a c hi n g  l e v el s  f or  c o m pl et e  r e s p o n s e)  or  
i m pr o v e m e nt ( > 5 0 % c h a n g e fr o m b a s eli n e f or l a b or at or y m ar k er s b ut 
still  e x c e e di n g  l e v el s  f or  c o m pl et e  r e s p o n s e)  of  at  l e a st  5 0 %  of  t h e  
s y st e mi c i nfl a m m at or y m ar k er s aff e ct e d at b a s eli n e  
•  S y st e mi c  c orti c o st er oi d s  ( e x cl u di n g  h y dr o c orti s o n e  f or  pr e v e nti o n  of  
a dr e n al i n s uffi ci e n c y ) or ot h er i m m u n o s u p pr e s si v e t h er a pi e s i n cl u di n g 
bi ol o gi c s m u st b e at t h e s a m e or l o w er d o s e s c o m p ar e d t o b a s eli n e  


 
 
 
P a g e 5 8  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
1 2. 2  D E FI NI TI O N O F DI S E A S E R E A C TI V A TI O N  
F or di s e a s e  r e a cti v ati o n,  o nl y  t h e  o bj e cti v e  m AI D AI  c o m p o n e nt s  will  b e  
e v al u at e d a s i n di c at e d b el o w. S u bj e cti v e m AI D AI c o m p o n e nt s ( s e e A p p e n di x  I) 
will n ot b e c o n si d er e d t o a v oi d a n y bi a s i n t h e a s s e s s m e nt. J u stifi c ati o n f or t h e 
r e vi s e d di s e a s e r e a cti v ati o n d efi niti o n s i s i n cl u d e d i n s e cti o n 8. 3.3 .  
D uri n g t h e R W -p h a s e, t h e r ef er e n c e f or a di s e a s e r e a cti v ati o n (f or t h e pri m ar y 
e n d p oi nt a s s e s s m e nt) will b e t h e e n d of t h e S A O L p h a s e ( V 8); f or t h e S A O L 
p h a s e, r ef er e n c e will t h e pr e vi o u s vi sit, a s p ati e nt s e nt er t h e S A O L p h a s e wit h 
a n a cti v e di s e a s e.  
o  P arti al di s e a s e r e a cti v ati o n  
•  
I n cr e a s e  i n  t h e n u m b er  of  aff e ct e d  o bj e cti v e e n d  or g a n  d a m a g e  
c at e g ori e s b y at l e a st 2 or  
•  
I n cr e a s e  i n  t h e n u m b er  of  aff e ct e d  o bj e cti v e e n d  or g a n  d a m a g e  
c at e g ori e s b y  at  l e a st  1  a n d  w or s e ni n g  of  at  l e a st  1  s y st e mi c  
i nfl a m m at or y m ar k er (i. e. s er u m f erriti n l e v el s ≥ 5 0 0 n g/ m L or s er u m 
C R P ≥ 2 x U L N) t h at w a s m e eti n g c o m pl et e r e s p o n s e crit eri a b ef or e  
o  F ull di s e a s e r e a cti v ati o n  
•  
I n cr e a s e  i n  t h e  n u m b er  of  aff e ct e d  o bj e cti v e  e n d  or g a n  d a m a g e  
c at e g ori e s  t o  at  l e a st  t h e  n u m b er  of  aff e ct e d  e n d  or g a n  d a m a g e  
c at e g ori e s at b a s eli n e ( V 1) a n d  
•  
E x a c er b ati o n of at l e a st 1 s y st e mi c i nfl a m m at or y m ar k er (i. e. s er u m 
f erriti n  l e v el s  ≥
 5 0 0  n g/ m L  or  s er u m  C R P  ≥
 2 x  U L N)  t h at  w a s  
m e eti n g c o m pl et e r e s p o n s e crit eri a b ef or e  
 
N ot e: It  i s  r e c o m m e n d e d  t h at  p ati e nt s  s uff eri n g  fr o m  s e v er e  C N S  m a nif e st ati o n s  ar e  p ut  o n  
r e s c u e i m m u n o s u p pr e s si o n tr e at m e nt. 
 
 
 


 
 
 
P a g e 5 9  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
1 3  A S S E S S M E N T O F S A F E T Y  
T h e  I n v e sti g at or  will  a s s e s s  p ati e nt  s af et y  t hr o u g h o ut  t h e  st u d y.  I n  a d diti o n,  t h e  D S M B,  a n  
i n d e p e n d e nt c o m mitt e e, will a n al y z e cli ni c al or bi ol o gi c al w or s e ni n g of t h e st at u s of st u d y p ati e nt s 
(i. e., S A E s) a n d al s o tr e at m e nt f ail ur e s a n d will a s s e s s t h e gl o b al s af et y of T a d e ki ni g alf a ( s e e d et ail s 
i n St u d y D e si g n s e cti o n). 
 
S af et y a s s e s s m e nt d uri n g t h e st u d y will i n cl u d e:  
 
o  Pri or t o i niti ati o n of t h er a p y, p h y si c al e x a mi n ati o n, vit al si g n s, t e sti n g f or  
a cti v e  a n d  lif e-t hr e at e ni n g i nf e cti o n s,  c o m pl et e  bl o o d  c o u nt,  cli ni c al  
c h e mi str y, c o a g ul ati o n a n d uri n al y si s.  
o  D uri n g  tr e at m e nt  p h a s e,  p h y si c al  e x a mi n ati o n,  i n cl u di n g  o p ht h al mi c 
e x a mi n ati o n,  vit al si g n s, r o uti n e l a b or at or y ( c o m pl et e bl o o d c o u nt, cli ni c al 
c h e mi str y,  uri n al y si s),  A E s,  i n cl u di n g  A E s  of  S p e ci al  I nt er e st  ( A E SI),  
c o n c o mit a nt  m e di c ati o n s,  l o c al  t ol er a bilit y  i n d e x,  i m m u n o g e ni cit y,  a n d  
c o a g ul ati o n t e st s.  
o  R e g ar di n g i m m u n o g e ni cit y, A D A s a s s e s s m e nt will b e p erf or m e d at B a s eli n e 
V 1, W e e k 2 ( V 3), W e e k 4 ( V 5), W e e k 1 2 ( V 7), W e e k 1 8 ( V 8), a n d R W W e e k 
2 2 ( V 1 0) , W e e k 2 6 ( V 1 1)  a n d  W e e k 3 4 ( V 1 3) . 
o  S af et y a n d di s e a s e a cti vit y l a b s will b e a s s e s s e d d uri n g h o s pit ali z ati o n a s 
r e q uir e d, w e e kl y d uri n g vi sit s f or t h e fir st f o ur w e e k s, t h e n a p pr o xi m at el y 
m o nt hl y d uri n g vi sit s u ntil c o m pl eti o n of t h e st u d y, or at u n s c h e d ul e d vi sit s.  
• w e e kl y fr o m Vi sit 0 t o Vi sit 5;  
• m o nt hl y fr o m Vi sit 6 t o Vi sit 7;  
• at Vi sit 8 ( 6 w e e k s fr o m Vi sit 7);  
• at Vi sit 9 ( 2 w e e k s fr o m Vi sit 8);  
• at Vi sit 1 0 ( 2 w e e k s fr o m Vi sit 9);  
• m o nt hl y fr o m Vi sit 1 1  t o Vi sit 1 3. 
A E s will b e c oll e ct e d fr o m t h e ti m e of i nf or m e d c o n s e nt t hr o u g h t h e e n d of t h e st u d y. D efi niti o n s 
a n d r e p orti n g pr o c e d ur e s f or A E s a n d S A E s ar e pr o vi d e d i n S e cti o n 1 6 . “ H a n dli n g of A d v er s e 
E v e nt s”.  
D et ail s o n r o uti n e s af et y l a b or at or y a s s e s s m e nt s, vir ol o g y, a n d s er ol o g y t e st s, a n d c oll e cti o n of 
s a m pl e s f or A D A s (i m m u n o g e ni cit y) ar e pr o vi d e d i n T a bl e 2 .  
P h y si c al  e x a mi n ati o n s  a n d  vit al  si g n s  ( s y st oli c  a n d  di a st oli c  bl o o d  pr e s s ur e,  h e art  r at e,  
r e s pir at or y r at e, w ei g ht a n d b o d y t e m p er at ur e) will b e c oll e ct e d at all vi sit s. H ei g ht i s c oll e ct e d at 
S cr e e ni n g.  
T h e L o c al T ol er a bilit y I n d e x i s pr o vi d e d i n A p p e n di x 2 .  
 
* N O T E:  
L a b or at or y  s af et y  a n d  effi c a c y  e n d p oi nt s  will  b e  st u di e d  at  t h e  vi sit s  b y  t h e  c e ntr al  l a b.  F or  
h o s pit ali z e d p ati e nt s l o c al l a b s will p erf or m, i n a d diti o n, a n al y s e s a s r e q uir e d b y t h e st a n d ar d of 
c ar e a n d t hi s i nf or m ati o n will b e e nt er e d i n t h e st u d y e C R F.  
 


 
 
 
P a g e 6 0  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
1 4  C O N D U C T O F  TH E S T U D Y  
1 4. 1  S c h e d ul e of E v e nt s  
S e e s e cti o n 7 , T a bl e 1 . 
I n or d er t o pr ot e ct t h e p ati e nt` s a n d c ar e gi v er` s s af et y a n d w elf ar e d uri n g t h e C O VI D-1 9 p a n d e mi c, 
o n -sit e st u d y vi sit s m a y n ot b e c o n si d er e d a p pr o pri at e; m o st p ati e nt s h a v e t o tr a v el t o t h eir st u d y 
sit e a n d o n -sit e st u d y vi sit s m a y e x p o s e b ot h t h e p ati e nt s a n d c ar e gi v er s a s w ell a s st u d y sit e 
p er s o n n el t o a n i n cr e a s e d ri s k of i nf e cti o n. M or e o v er, d u e t o t h e ultr a -r ar e i n di c ati o n of t hi s st u d y, 
c o n d u cti n g o n -sit e st u d y vi sit s at sit e s oft e n l o c at e d f ar a w a y fr o m t h e p ati e nt` s h o m e h a s m a d e 
st u d y c o n d u ct c h all e n gi n g.  
T h u s, i n a n eff ort t o a c c o m m o d at e t h e p ati e nt s a n d t h eir f a mili e s w hil e e n s uri n g t h e r el e v a nt st u d y 
d at a  i s  c oll e ct e d , s c h e d ul e d  st u d y  vi sit s  ( e x c e pt  f or  t h e  B a s eli n e  vi sit)  m a y  b e  c o n d u ct e d  a s  
t el e m e di ci n e vi sit s i n v ol vi n g t h e u s e of el e ctr o ni c c o m m u ni c ati o n s (f or e x a m pl e, li v e i nt er a cti v e vi d e o 
a n d a u di o) t o e n a bl e sit e st aff t o c o n d u ct “ virt u al” ( n ot i n -p er s o n) vi sit s wit h t h eir p ati e nt s. T h e s e 
vi sit s m a y b e s u p p ort e d b y h o m e h e alt h n ur s e s a s si sti n g i n p h y si c al e x a mi n ati o n  ( b y p erf or mi n g a 
b o d y a s s e s s m e nt s u p p orti n g t h e p h y si c al e x a mi n ati o n d o n e b y t h e i n v e sti g at or vi a t el e m e di ci n e) , 
c oll e cti o n of vit al si g n s  or p erf or m a n c e of c e ntr al l a b or at or y bl o o d dr a w s. L a b or at or y a s s e s s m e nt s 
m a y b e al s o p erf or m e d at q u alifi e d l o c al l a b or at ori e s. T h e st u d y sit e m a y al s o utili z e a p h y si c al 
e x a mi n ati o n  fr o m t h e p ati e nt’ s m o st r e c e nt st a n d ar d of c ar e vi sit c o n d u ct e d b y t h e l o c al tr e ati n g 
p h y si ci a n, f or t h e p ur p o s e of t h e st u d y.   
P ati e nt s a n d/ or p ar e nt s ( or l e g al r e pr e s e nt ati v e, if a p pli c a bl e) will si g n a r e s p e cti v e  a s s e nt/i nf or m e d 
c o n s e nt pri or t o t h e c o n d u ct of s u c h t el e m e di ci n e vi sit s.  
It i s e x p e ct e d t h at t h e B a s eli n e Vi sit will b e c o n d u ct e d a s a n o n -sit e vi sit, a s p ati e nt s ar e h a vi n g a n 
a cti v e di s e a s e  at t h at ti m e  a n d eli gi bilit y n e e d s t o b e c o nfir m e d d uri n g a n o n -sit e vi sit . F or t h e 
S cr e e ni n g vi sit, eli gi bilit y m a y b e e v al u at e d d uri n g  a t el e m e di ci n e vi sit. T hi s vi sit s h all b e  b a s e d o n 
l o c al l a b or at or y r e s ult s a n d st a n d ar d of c ar e p h y si c al e x a mi n ati o n , i n cl u di n g vit al si g n s, c o n d u ct e d 
b y t h e l o c al tr e ati n g p h y si ci a n. T hi s m a y b e p er mitt e d  i n or d er t o a v oi d l o n g-di st a n c e tr a v el f or t h e 
p ati e nt s wit h u n c ert ai nti e s w h et h er t h e y m e et t h e pr ot o c ol d efi niti o n s f or a n a cti v e di s e a s e st at u s . 
F or all vi sit s aft er t h e S cr e e ni n g a n d B a s eli n e vi sit s, t h e ri s k s a n d b ur d e n of tr a v el t o t h e st u d y sit e 
v er s u s  t h e  r e q uir e m e nt  f or  a  cl o s e  p ati e nt  f oll o w -u p  i n  li n e  wit h  pr ot o c ol  r e q uir e m e nt s  will  b e  
e v al u at e d  f or  e a c h  i n di vi d u al  p ati e nt.  A s p e ct s  t o  c o n si d er  i n cl u d e  t h e  di s e a s e  s e v erit y  of  e a c h  
p ati e nt, t h e di st a n c e fr o m t h e p ati e nt` s h o m e t o t h e st u d y sit e, t h e p ati e nt` s  l o c al sit u ati o n of t h e 
C O VI D -1 9 p a n d e mi c  a n d t h e p o s si biliti e s a n d l o c al r e g ul at or y r e q uir e m e nt s f or t el e m e di ci n e vi sit s  
at t h e st u d y si t e s.  
 
S A O L P h a s e  
1 4. 2  P ati e nt  Re cr uit m e nt  - S cr e e ni n g Vi sit ( b ef or e tr e at m e nt st art at V 1) 
•  
R e vi e w a n d si g ni n g of C hil d A s s e nt  a n d/ or  I nf or m e d C o n s e nt F or m (I C F)  
•  
C oll e cti o n of A E s st art s aft er si g ni n g I C F  
•  
D e m o gr a p hi c s a n d m e di c al hi st or y   
•  
C o m pl eti o n of t h e I n cl u si o n/ e x cl u si o n c h e c kli st b y t h e p h y si ci a n  
•  
P h y si c al e x a mi n ati o n  wit h s p e cifi c a s s e s s m e nt of h e p at o s pl e n o m e g al y  a n d  
vit al si g n s  (i n cl u di n g h ei g ht) 
•  
Cli ni c al e v al u ati o n b y t h e p h y si ci a n u si n g t h e m AI D AI ( A p p e n di x 1)  
•  
P h y si ci a n Gl o b al A s s e s s m e nt ( P G A)  ( A p p e n di x 3) 
•  
L a b t e sti n g  
o  G e n eti c e v al u ati o n s  


 
 
 
P a g e 6 1  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
o  I nf e cti o n e v al u ati o n s ( C M V, E BV, et c. )  
o  S er ol o g y ( HI V, H C V, H B V)   
o  Pr e g n a n c y t e st  ( U P T a n d/ or h C G a s a p pli c a bl e) 
o   He m at ol o g y, cli ni c al c h e mi str y, E S R ( at l o c al l a b), uri n al y si s, C R P, 
F erriti n,  T B bl o o d t e sti n g  ( N ot e: Q u a nti F E R O N- T B t e sti n g s h o ul d b e 
d o n e  eit h er  at  c e ntr al  l a b  or  l o c al  [ h o s pit al]  l a b,  pri or  t o  tr e at m e nt  
i niti ati o n) 
o  Fl o w c yt o m etr y  
o  C o a g ul ati o n  (T hr o m b o c yt e s, F i bri n o g e n, D-di m er, P T T, P T)  
•  
S p e ci ali z e d  l a b t e sti n g 
o  S er u m: T ot al I L -1 8, fr e e I L -1 8, I L -1 8 B P  
 
1 4. 3  B a s eli n e  vi sit  at W e e k 0 ( V 1 - Tr e at m e nt Initi ati o n ) – S A O L P h a s e  
•  
R e a s s e s s m e nt of i n cl u si o n a n d e x cl u si o n crit eri a pri or t o  tr e at m e nt wit h T a d e ki ni g 
alf a st art  
•  
P h y si c al e x a mi n ati o n wit h s p e cifi c a s s e s s m e nt of h e p at o s pl e n o m e g al y  a n d  
vit al si g n s  
•  
Tr e at m e nt st art wit h T a d e ki ni g alf a  
•  
R e vi e w of A E s a n d c o n c o mit a nt m e di c ati o n s  
•  
Cli ni c al e v al u ati o n b y t h e p h y si ci a n u si n g t h e m AI D AI  
•  
P h y si ci a n Gl o b al A s s e s s m e nt ( P G A)   
•  
P ati e nt` s/ c ar e gi v er` s q u alit ati v e e v al u ati o n of h e alt h st at u s ( st u d y s p e cifi c 
q u e sti o n n air e f or all p ati e nt s i m pl e m e nt e d i n pr ot o c ol v er si o n 6)  
•  
L o c al T ol er a bilit y I n d e x A s s e s s m e nt b y I n v e sti g at or  
•  
O p ht h al mi c e x a mi n ati o n will b e p erf or m e d f or t h e di a g n o si s 
( pr e s e n c e/ a b s e n c e), s e v erit y a n d e v ol uti o n of u v eiti s a n d o c c urr e n c e of 
o p ht h al mi c a d v er s e e v e nt s (i. e. t o xi c n e ur o p at h y)  
 
•  
L a b  t e sti n g ( S a m pl e s t a k e n pri or t o tr e at m e nt) 
o   He m at ol o g y, cli ni c al c h e mi str y, E S R ( at l o c al l a b),  uri n al y si s, C R P, 
F erriti n,   
o  C o a g ul ati o n ( T hr o m b o c yt e s, F i bri n o g e n, D-di m er, P T T, P T)  
o  Uri n e pr e g n a n c y t e st, a s a p pli c a bl e  
•  
S p e ci ali z e d l a b t e sti n g  
o  S er u m: T ot al I L -1 8, fr e e I L -1 8, I L -1 8 B P  ( S a m pl e s t a k e n pri or t o 
tr e at m e nt) 
o  S er u m: A nti -T a d e ki ni g alf a a nti b o di e s  ( m e a s ur e m e nt p erf or m e d o n 
bl o o d dr a w n b ef or e T a d e ki ni g alf a a d mi ni st er e d f or all p ati e nt s )  
o  A d diti o n al s a m pl e f or P K st u d y will b e c oll e ct e d at 2 h, 4 h, 6 h a n d 
2 4 h  p o st  tr e at m e nt . Tr o u g h  l e v el s  ar e  c al c ul at e d  b a s e d  o n  bl o o d  
s a m pl e s u s e d f or l a b t e sti n g ( n o e xtr a s a m pl e n e e d e d)  
•  
Tr e at m e nt i niti ati o n  


 
 
 
P a g e 6 2  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
•  
T w o -h o ur  p ati e nt o b s er v ati o n aft er fir st tr e at m e nt  
 
1 4. 4  Vi sit s  at W e e k s 1 , 2, 3 ( V 2/ D a y 7, V 3/ D a y 1 4, V 4/ D a y 2 1)  
 
•  
P h y si c al e x a mi n ati o n wit h s p e cifi c a s s e s s m e nt of h e p at o s pl e n o m e g al y  a n d  
vit al si g n s  
•  
Tr e at m e nt wit h T a d e ki ni g alf a  ( e v er y 2 d )  
•  
R e vi e w of A E s a n d c o n c o mit a nt m e di c ati o n s  
•  
Cli ni c al e v al u ati o n b y t h e p h y si ci a n u si n g t h e m AI D AI  
•  
P h y si ci a n Gl o b al A s s e s s m e nt ( P G A)  
•  
L o c al T ol er a bilit y I n d e x A s s e s s m e nt b y I n v e sti g at or  
•   La b t e sti n g ( S a m pl e s t a k e n pri or t o tr e at m e nt)  
o   He m at ol o g y, cli ni c al c h e mi str y, E S R ( at l o c al l a b),  uri n al y si s, C R P , 
F erriti n  
o  C o a g ul ati o n ( T hr o m b o c yt e s, F i bri n o g e n, D-di m er, P T T, P T)  
o  Uri n e pr e g n a n c y t e st, a s a p pli c a bl e  
•  
S p e ci ali z e d l a b t e sti n g  
o  S er u m: T ot al I L -1 8,  fr e e I L-1 8, I L -1 8 B P  ( S a m pl e s t a k e n pri or t o 
tr e at m e nt) 
o  S er u m: A nti -T a d e ki ni g alf a a nti b o di e s ( m e a s ur e m e nt p erf or m e d o n 
bl o o d dr a w n b ef or e T a d e ki ni g alf a a d mi ni st er e d f or all p ati e nt s) will 
b e p erf or m e d at V 3  
 
1 4. 5  Vi sit at W e e k 4 ( V 5/ D a y 2 8) 
•  
P h y si c al e x a mi n ati o n wit h s p e cifi c a s s e s s m e nt of h e p at o s pl e n o m e g al y  a n d  
vit al si g n s  
•   
Tr e at m e nt wit h T a d e ki ni g alf a ( e v er y 2 d )  
•  
R e vi e w of A E s a n d c o n c o mit a nt m e di c ati o n s  
•  
Cli ni c al e v al u ati o n b y t h e p h y si ci a n u si n g t h e m AI D AI  
•  
P h y si ci a n Gl o b al A s s e s s m e nt ( P G A)  
•  
L o c al T ol er a bilit y I n d e x A s s e s s m e nt b y I n v e sti g at or  
•  
L a b t e sti n g  ( S a m pl e s t a k e n pri or t o tr e at m e nt) 
o   He m at ol o g y, cli ni c al  c h e mi str y,  E S R (l o c al  l a b),  uri n al y si s, C R P , 
F erriti n  
o  C o a g ul ati o n ( T hr o m b o c yt e s, F i bri n o g e n, D-di m er, P T T, P T)  
o  Uri n e pr e g n a n c y t e st, a s a p pli c a bl e  
•  
S p e ci ali z e d l a b t e sti n g   
o  S er u m: T ot al I L -1 8, fr e e I L -1 8, I L -1 8 B P  ( S a m pl e s t a k e n pri or t o 
tr e at m e nt) 


 
 
 
P a g e 6 3  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
o  S er u m: A nti -T a d e ki ni g alf a a nti b o di e s ( m e a s ur e m e nt p erf or m e d o n 
bl o o d dr a w n b ef or e T a d e ki ni g alf a a d mi ni st er e d f or all p ati e nt s)  
o   P K a s s e s s m e nt  - A d diti o n al s a m pl e f or P K st u d y will b e c oll e ct e d at 
at 2 h, 4 h, 6 h a n d 2 4 h p o st tr e at m e nt. Tr o u g h l e v el s ar e c al c ul at e d 
b a s e d o n bl o o d s a m pl e s u s e d f or l a b t e sti n g ( n o e xtr a s a m pl e 
n e e d e d)  
 
1 4. 6  Vi sit s at W e e k 8 , 1 2 ( V6 / D a y 5 6, V 7 / D a y 8 4) – Mo nt hl y V i sit s 
•  
P h y si c al e x a mi n ati o n wit h s p e cifi c a s s e s s m e nt of h e p at o s pl e n o m e g al y  a n d  
vit al si g n s  
•  
Tr e at m e nt wit h T a d e ki ni g alf a  ( e v er y 2 d )  
•  
R e vi e w of A E s a n d c o n c o mit a nt m e di c ati o n s  
•  
Cli ni c al e v al u ati o n b y t h e p h y si ci a n u si n g t h e m AI D AI  
•  
P h y si ci a n Gl o b al A s s e s s m e nt ( P G A)  
•  
L o c al T ol er a bilit y I n d e x A s s e s s m e nt b y I n v e sti g at or 
•   La b t e sti n g ( S a m pl e s t a k e n pri or t o tr e at m e nt) 
o   He m at ol o g y, cli ni c al c h e mi str y, E S R, uri n al y si s,  C R P , f erriti n 
o  C o a g ul ati o n ( T hr o m b o c yt e s, F i bri n o g e n, D-di m er, P T T, P T)  
o  Uri n e pr e g n a n c y t e st, a s a p pli c a bl e  
•  
S p e ci ali z e d l a b t e sti n g  
o  S er u m: T ot al I L -1 8, fr e e I L -1 8, I L -1 8 B P  ( S a m pl e s t a k e n pri or t o 
tr e at m e nt)  
o  S er u m: A nti -T a d e ki ni g alf a a nti b o di e s  ( m e a s ur e m e nt p erf or m e d o n 
bl o o d dr a w n b ef or e T a d e ki ni g alf a a d mi ni st er e d f or all p ati e nt s)  at 
W e e k 1 2 ( V 7)  
 
1 4. 7  Vi sit at W e e k 1 8 ( V 8/ D a y 1 2 6): E n d of S A O L P h a s e/ St art of R W P h a s e  
•  
P h y si c al e x a mi n ati o n wit h s p e cifi c a s s e s s m e nt of h e p at o s pl e n o m e g al y a n d 
vit al si g n s  
•  
R e vi e w of A E s a n d c o n c o mit a nt m e di c ati o n s  
•  
Cli ni c al e v al u ati o n b y t h e p h y si ci a n u si n g t h e m AI D AI  
•  
P h y si ci a n Gl o b al A s s e s s m e nt ( P G A)  
•  
P ati e nt` s/ c ar e gi v er` s q u alit ati v e e v al u ati o n of h e alt h st at u s  
•  
L o c al T ol er a bilit y I n d e x A s s e s s m e nt b y I n v e sti g at or  
•  
L a b t e sti n g ( S a m pl e s t a k e n pri or t o tr e at m e nt)  
o  H e m at ol o g y, cli ni c al c h e mi str y, E S R, uri n al y si s, C R P, f erriti n  
o  C o a g ul ati o n ( T hr o m b o c yt e s, Fi bri n o g e n, D- di m er, P T T, P T)  
o  Uri n e pr e g n a n c y t e st, a s a p pli c a bl e  
•  
S p e ci ali z e d l a b t e sti n g  


 
 
 
P a g e 6 4  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
o  S er u m: T ot al I L -1 8, fr e e I L -1 8, I L -1 8 B P ( S a m pl e s t a k e n pri or t o 
tr e at m e nt)  
o  S er u m:  A nti -T a d e ki ni g  alf a  a nti b o di e s  ( m e a s ur e m e nt  p erf or m e d  o n  
bl o o d  dr a w n  b ef or e  T a d e ki ni g  alf a  or  pl a c e b o  a d mi ni st er e d  f or  all  
p ati e nt s) at W e e k 1 8 ( V 8)  
•  
Tr e at m e nt wit h T a d e ki ni g alf a or pl a c e b o ( e v er y 2  da y s ) a s r a n d o mi z e d f or 
R W p h a s e  
o  N ot e:  St u d y dr u g a d mi ni str ati o n s h o ul d o c c ur aft er all V 8 a s s e s s m e nt s 
h a v e b e e n p erf or m e d  
1 4. 8  Vi sit s at W e e k s 2 0 , 2 2 , 2 6, 3 0 ( V9 / D a y 1 4 0, V1 0 / D a y 1 5 4 , V 1 1/ D a y 1 8 2, V 1 2/ D a y 
2 1 0 )  
•  
P h y si c al e x a mi n ati o n wit h s p e cifi c a s s e s s m e nt of h e p at o s pl e n o m e g al y a n d 
vit al si g n s  
•  
Tr e at m e nt wit h T a d e ki ni g alf a or pl a c e b o ( e v er y 2  da y s ) a s r a n d o mi z e d f or 
R W p h a s e  
•  
R e vi e w of A E s a n d c o n c o mit a nt m e di c ati o n s  
•  
Cli ni c al e v al u ati o n b y t h e p h y si ci a n u si n g t h e m AI D AI  
•  
P h y si ci a n Gl o b al A s s e s s m e nt ( P G A)  
•  
L o c al T ol er a bilit y I n d e x A s s e s s m e nt b y I n v e sti g at or  
•  
L a b t e sti n g ( S a m pl e s t a k e n pri or t o tr e at m e nt)  
o  H e m at ol o g y, cli ni c al c h e mi str y, E S R, uri n al y si s, C R P, f erriti n  
o  C o a g ul ati o n ( T hr o m b o c yt e s, Fi bri n o g e n, D -di m er, P T T, P T)  
o  Uri n e pr e g n a n c y t e st, a s a p pli c a bl e  
•  
S p e ci ali z e d l a b t e sti n g  
o  S er u m: T ot al I L -1 8, fr e e I L -1 8, I L -1 8 B P ( S a m pl e s t a k e n pri or t o 
tr e at m e nt) 
o  S er u m: A nti -T a d e ki ni g alf a a nti b o di e s ( o nl y at W e e k s 2 2 (V 1 0)  a n d 
2 6 ( V 1 1) ) 
 
1 4. 9  St u d y C o m pl eti o n Vi sit at W e e k 3 4 (V 1 3 / D a y 2 3 8)/St u d y C o m pl eti o n f or P ati e nt s 
e x p eri e n ci n g 
di s e a s e  r e a cti v ati o n s  d uri n g  R W / E arl y  T er mi n ati o n  f or 
Di s c o nti n u e d P ati e nt s:  
 
•  
P h y si c al e x a mi n ati o n wit h s p e cifi c a s s e s s m e nt of h e p at o s pl e n o m e g al y, vit al 
si g n s  
•  
R e vi e w of A E s a n d c o n c o mit a nt m e di c ati o n s  
•  
Cli ni c al e v al u ati o n b y t h e p h y si ci a n u si n g t h e m AI D AI  
•  
P h y si ci a n Gl o b al A s s e s s m e nt  ( P G A) 
•  
P ati e nt` s/ c ar e gi v er` s q u alit ati v e e v al u ati o n of h e alt h st at u s  
•  
L o c al T ol er a bilit y I n d e x A s s e s s m e nt b y I n v e sti g at or  
•  
L a b t e sti n g  


 
 
 
P a g e 6 5  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
o  H e m at ol o g y, cli ni c al c h e mi str y, E S R  ( at l o c al l a b), uri n al y si s, C R P, 
F erriti n  
o  C o a g ul ati o n ( T hr o m b o c yt e s, fi bri n o g e n, D -di m er, P T T, P T)  
o  Uri n e pr e g n a n c y t e st, if a p pli c a bl e  
•  
R e c or di n g ot h er m e di c ati o n s gi v e n t o t h e p ati e nt  aft er st u d y tr e at m e nt  st o p, 
a n d if ( or n ot) a n y r e s p o n s e t o n e w m e di c ati o n  
•  
S p e ci ali z e d l a b  t e sti n g 
o  S er u m: T ot al I L -1 8, fr e e I L -1 8, I L -1 8 B P ( S a m pl e s t a k e n pri or t o 
tr e at m e nt) 
o  S er u m: A nti -T a d e ki ni g alf a a nti b o di e s  
 
N ot e: A p ati e nt e x p eri e n ci n g a p arti al or f ull di s e a s e r e a cti v ati o n  duri n g t h e 1 6 w e e k  R W p h a s e a n d 
t h u s pr o c e e di n g t o t h e E n d of St u d y Vi sit will n ot b e c o n si d er e d a s h a vi n g e arl y  t er mi n at e d fr o m t h e 
st u d y.  
 
1 4. 1 0  C LI NI C A L L A B O R A T O R Y T E S T S  
S a m pl e a n al y si s will b e p erf or m e d i n t h e c e ntr al l a b  a n d  l o c al l a b s ( a s a p pli c a bl e). A li st of all 
s a m pl e s c oll e ct e d a n d a s s o ci at e d l a b or at or y a s s e s s m e nt s i s pr o vi d e d i n T a bl e 2 .  A p pr o xi m at el y 
1 0 -2 0 ml of bl o o d will b e t a k e n at vi sit s w h e n l a b or at or y t e st s ar e r e q uir e d, t h e a ct u al v ol u m e will 
d e p e n d  o n  t h e  p ati e nt  w ei g ht.   D u e  t o  s a m pl e  v ol u m e  li mit ati o n s  d u pli c ati o n  of  d et er mi n ati o n s 
b et w e e n t h e c e ntr al a n d t h e l o c al l a b s will b e a v oi d e d w h e n p o s si bl e.  
Ot h er cli ni c al l a b or at or y t e st s m a y b e p erf or m e d l o c all y b y t h e I n v e sti g at or, a s d e e m e d n e c e s s ar y, 
t o e n s ur e p ati e nt s af et y. 
 


 
 
 
P a g e 6 6  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
T a bl e 2:  Cli ni c al L a b or at or y T e st s  
Bi o c h e mi str y   
H a e m at ol o g y   
 
G O T/ A S T  
 
H e m at o crit  
G P T/ A L T  
H a e m o gl o bi n   
G a m m a -gl ut a m yl tr a n sf er a s e ( G G T)  
R e d bl o o d c ell ( R B C) c o u nt  
C o m pl et e bl o o d c o u nt,  
W hit e Bl o o d C ell  ( W B C) 
c o u nt  
Al k ali n e p h o s p h at a s e ( A L P)  
 
T ot al bilir u bi n  
   N e utr o p hil s  
B U N  
   L y m p h o c yt e s  
L D H  
   M o n o c yt e s  
Cr e ati ni n e  
   E o si n o p hil s  
Uri c a ci d  
   B a s o p hil s  
P ot a s si u m  
   Pl at el et s  
S o di u m   
M C C  
C hl ori d e   
M C H C  
C al ci u m  
M C V  
T ot al pr ot ei n                                       
S er u m al b u mi n                                
Gl u c o s e   
 
C o a g ul ati o n    
T ot al c h ol e st er ol  
P T  
Tri gl y c eri d e s   
P T T , D-Di m er a n d Fi bri n o g e n  
C R P  
 
E S R ( Er yt hr o c yt e S e di m e nt ati o n R at e)  
 
Vir al I nf e cti o n –   
C M V, E B V  
C yt o ki n e s  a n d i nfl a m m at or y 
m e di at or s   
G e n eti c A n al y si s –   
 
I L-1 8 t ot al  
Fl o w C yt o m etr y  
I L-1 8 fr e e                                                      
I L-1 8 B P                                                      
 
 
S er ol o g y    
HI V ( a nti -HI V 1 a n d a nti -HI V 2 a nti b o di e s ,  
 
HI V 1 A g)  
P K st u d y  
H e p atiti s C  
H e p atiti s B  
 I L-1 8 B P  
Pr e g n a n c y T e st  ( U P T a n d/ or h C G a s a p pli c a bl e) 
F erriti n s y st e m   
 
F erriti n  
 
Uri n al y si s  
 
 
D i p sti c k: pr ot ei n, er yt hr o c yt e s ( bl o o d), l e u k o c yt e s, 
nitrit e, bilir u bi n, ur o bili n o g e n, gl u c o s e, k et o n e b o di e s, 
p H, s p e cifi c gr a vit y  
A nti -dr u g a nti b o di e s  


 
 
 
P a g e 6 7  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
1 5  D A T A M A N A G E M E N T  
1 5. 1  D at a C oll e cti o n  
•  
P ati e nt d at a will b e c oll e ct e d o n e C R F s a n d will b e s u b st a nti at e d b y s o ur c e d o c u m e nt s at 
t h e cli ni c al sit e. L a b or at or y r e s ult s fr o m o ut si d e l a b or at ori e s will b e r e c ei v e d b y t h e sit e a n d 
e nt er e d fr o m h ar d c o p y pri nt -o ut s i nt o t h e e C R F.  
•  
Pri or  t o  t h e  st art  of  t h e  st u d y,  t h e  I n v e sti g at or  will  c o m pl et e  a  R e gi str y  of  Si g n at ur e s  /  
D el e g ati o n of R e s p o n si bilit y L o g s h o wi n g t h e si g n at ur e s a n d h a n d writt e n i niti al s of all sit e 
st aff i n di vi d u al s w h o ar e a ut h ori s e d t o m a k e or c h a n g e e ntri e s o n e C R F s . T h e e C R F s will b e 
c o m pl et e d a c c or di n g t o t h e e C R F C o m pl eti o n G ui d eli n e s  ( e C C G s) pr o vi d e d b y t h e C R O i n 
writi n g a n d/ or v er b all y.  
•  
D at a will b e c oll e ct e d u si n g, a w e b -b a s e d el e ctr o ni c d at a c a pt ur e ( E D C) s y st e m. T h e St u d y 
M o nit or will r e vi e w all e C R F d at a t o 1 0 0 % s o ur c e d at a v erifi c ati o n  ( S D V) t o e n s ur e a d e q u at e 
q u alit y c o ntr ol a n d c o m pl et e p ati e nt d at a. A n y di s cr e p a n ci e s f o u n d d uri n g t h e e C R F r e vi e w 
will b e cl arifi e d b y t h e I n v e sti g at or ( or hi s/ h er d e si g n at e d st aff). T hi s i n cl u d e s e C R F r e vi e w s 
at t h e sit e b y t h e S p o n s or or it s d e si g n e e, or d uri n g q u alit y a s s ur a n c e r e vi e w of t h e d at a or 
a u dit s.  
•  
T h e I n v e sti g at or or d e si g n e e m u st r e c or d all r e q uir e d p ati e nt d at a u si n g t h e e C R F s. T h e 
I n v e sti g at or m u st el e ctr o ni c all y si g n a n d d at e a d e cl ar ati o n o n t h e e C R F att e sti n g t o hi s/ h er 
r e s p o n si bilit y f or t h e q u alit y of all d at a r e c or d e d, a n d t h at t h e d at a r e pr e s e nt a c o m pl et e a n d 
a c c ur at e r e c or d of e a c h p ati e nt ’ s p arti ci p ati o n i n t h e st u d y. All I n v e sti g at or s a ut h ori z e d  t o 
a p pr o v e e C R F s will si g n a d e cl ar ati o n st ati n g t h at t h eir  h a n d writt e n si g n at ur e i s t h e l e g al 
e q ui v al e nt of a n el e ctr o ni c si g n at ur e. E a c h p ati e nt e C R F will b e r et ai n e d b y t h e I n v e sti g at or . 
•   
A p ati e nt di ar y  will b e c o m pl et e d b y/ f or p ati e nt s d o s e d at h o m e. T h e di ar y d o e s n ot n e e d t o 
b e c o m pl et e d if t h e p ati e nt i s h o s pit ali z e d. T h e di ar y m a y b e pr o vi d e d el e ctr o ni c all y or i n h ar d 
c o p y b o o kl et s t o  b e c o m pl et e d b y t h e s u bj e ct s or b y a n ot h er p er s o n ot h er t h a n t h e p ati e nt 
( e. g., C ar e gi v er).  
•  
D at a will b e c oll e ct e d t o t h e e xt e nt p o s si bl e f or s u bj e ct s w h o di s c o nti n u e t h e tr e at m e nt. I n 
c a s e of s u c h di s c o nti n u ati o n a n d st art of a n ot h er m e di c ati o n, it i s i m p ort a nt t o c a pt ur e t hi s 
i nf or m ati o n t o o a n d al s o t o r e p ort w h et h er a r e s p o n s e w a s o b s er v e d i n c a s e of c h a n g e. 
•  
All D M a cti viti e s ar e d o n e a c c or di n g t o C R O S O P s.  
 
 


 
 
 
P a g e 6 8  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
1 6  S T A TI S TI C S 
1 6. 1  G e n er al C o n si d er ati o n s  
T h e st ati sti c al a n al y si s will b e c o n d u ct e d b y t h e a s si g n e d C R O. St ati sti c al m et h o d s will b e pr e-
s p e cifi e d  a n d  d o c u m e nt e d  i n  d et ail  i n  a  St ati sti c al  A n al y si s  Pl a n  ( S A P)  t o  b e  fi n ali z e d b ef or e  
d at a b a s e l o c k a n d br e a ki n g t h e tr e at m e nt bli n d o n all s u bj e ct s.  A n y d e vi ati o n s fr o m t h e a n al y si s pr e -
pl a n n e d i n t h e pr ot o c ol or t h e S A P will b e d e s cri b e d a n d j u stifi e d i n t h e fi n al st u d y r e p ort. All st ati sti c al 
a n al y s e s will b e g e n er ati n g u si n g v ali d at e d B a s e S A S ®  s oft w a re, V er si o n 9 or hi g h er.  
1 6. 2  I nt eri m A n al y si s 
N o i nt eri m a n al y si s will b e p erf or m e d at t hi s st a g e.  
1 6. 3  S a m pl e S i z e C al c ul ati o n s 
P o w er C al c ul ati o n s  
T h e pri m ar y e n d p oi nt of t h e st u d y i s ti m e t o fir st o c c urr e n c e of di s e a s e r e a cti v ati o n (i n cl u di n g f ull 
a n d p arti al di s e a s e r e a cti v ati o n)  d uri n g t h e R W p h a s e of t h e st u d y. T h er e i s li mit e d hi st ori c al d at a 
f or t hi s di s e a s e c o n diti o n, f or eit h er a c o ntr ol or a n e x p eri m e nt al t e st pr o d u ct, h o w e v er t h e fr e q u e nt 
r e c urr e n c e of di s e a s e r e a cti v ati o n s w a s e x p e ct e d i n t h e c o ntr ol ar m ( W a d a 2 0 1 4). Ori gi n all y, a n 8 -
w e e k e v e nt r at e w a s a s s u m e d t o b e 9 0 % a n d a c o n si d er a bl e r e d u cti o n i n di s e a s e r e a cti v ati o n s  f or 
s u bj e ct s r e c ei vi n g T a d e ki ni g alf a w a s e x p e ct e d. H o w e v er, a l o w er e v e nt w a s o b s er v e d fr o m t h e 
c urr e ntl y e nr oll e d ( still bli n d e d) p ati e nt s. T h u s, t h e R W p h a s e i s pr ol o n g e d t o a m a xi m u m of 1 6 
w e e k s  t o b ett er a s s e s s t h e eff e ct of T a d e ki ni g alf a wit h dr a w al.  T h e p o w er c al c ul ati o n s b el o w will 
a s s u m e t h e s a m e 9 0 % e v e nt r at e i n t h e S O C ar m at 1 6 w e e k s.   
 
 




 
 
 
P a g e 7 0  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
1 6. 4  P ati e nt T r e at m e nt R a n d o mi z ati o n 
 
R a n d o mi z ati o n t o T a d e ki ni g alf a or Pl a c e b o c o n c er n s o nl y t h e R W p h a s e of t h e st u d y.   
P ati e nt s w h o will b e eli gi bl e t o e nt er t h e R W p h a s e of t h e st u d y will b e r a n d o mi z e d t o o n e of t h e t w o 
tr e at m e nt ar m s ( T a d e ki ni g alf a / Pl a c e b o) i n a 1: 1 r ati o at W e e k  1 8 ( V 8).  T h e r a n d o mi z ati o n will b e 
str atifi e d b y di s e a s e c o n diti o n at R W p h a s e e ntr y ( N L R C 4 -M A S m ut ati o n or XI A P d efi ci e n c y). T h e 
r a n d o mi z ati o n  will  b e  d e si g n e d  t o  b e  d y n a mi c  y et  n o n-d et er mi ni sti c  s u c h  t h at  s u bj e ct s  ar e  
r a n d o mi z e d i n a 1: 1 r ati o wit hi n e a c h di s e a s e c o n diti o n, w hil e al s o e n s uri n g t h at t h e o v er all all o c ati o n 
i s e x a ctl y b al a n c e d if t h e t ot al n u m b er of s u bj e ct s r a n d o mi z e d i s a n e v e n n u m b er a n d diff er e nt b y 
n o m or e t h a n o n e if o d d . 
 
1 6. 5  D at a s et s f or A n al y si s 
F or t h e st ati sti c al a n al y si s t h e p ati e nt s will b e di vi d e d u p i nt o t h e f oll o wi n g d at a s et s:  
T h e f oll o wi n g d efi niti o n s ar e a p pli c a bl e:  
S A O L F ull  A n al y si s 
S et ( S A O L -F A S)  
All p ati e nt s w h o ar e eli gi bl e a n d r e c ei v e d at l e a st o n e d o s e of 
i n v e sti g ati o n al m e di ci n al pr o d u ct at V 1 . 
S A O L P K A n al y si s 
S et  
(S A O L -P K A S ) 
All p ati e nt s i n t h e S A O L-F A S w h o h a v e s uffi ci e nt pl a s m a 
c o n c e ntr ati o n d at a t o c al c ul at e P K p ar a m et er s . 
R W F ull A n al y si s  
S et ( R W -F A S) 
All p ati e nt s w h o m e et t h e crit eri a f or r a n d o mi z ati o n a n d r e c ei v e 
at l e a st o n e d o s e of bli n d e d st u d y tr e at m e nt d uri n g t h e R W 
p h a s e  
R W P er -Pr ot o c ol 
A n al y si s S et ( R W -
P P A S)  
All p ati e nt s i n t h e R W -F A S w h o c o m p et e t h e R W p h a s e u p 
t hr o u g h W e e k 2 2 ( V 1 0) f or w h o m n o r el e v a nt pr ot o c ol 
d e vi ati o n s w er e d o c u m e nt e d  
T h e  a n al y si s  of  s af et y a n d effi c a c y d uri n g  t h e  R W p h a s e will  b e  b a s e d  o n  t h e  R W - F A S. 
A d diti o n all y , e x pl or at or y a n al y si s of effi c a c y o n t h e R W - P P AS m a y b e d o n e.  
S af et y a n d effi c a c y a n al y si s d uri n g t h e S A O L p h a s e will b e b a s e d o n t h e S A O L - F A S. 
T h e d e ci si o n w h et h er a pr ot o c ol d e vi ati o n i s r el e v a nt or n ot f or t h e e x cl u si o n of s u bj e ct s fr o m 
t h e R W -P P A S will b e m a d e o n a c a s e -b y -c a s e b a si s i n a bli n d d at a r e vi e w m e eti n g.  
 
1 6. 6  St ati sti c al A n al y si s  
1 6. 6. 1  
R a n d o mi z e d wit h dr a w al p h a s e  
D at a  will  b e  a n al y z e d  o n  a n  i nt e nt -t o-tr e at  b a si s.  B a s eli n e  p ati e nt  a n d  di s e a s e  c h ar a ct eri sti c s  
a c c or di n g t o tr e at m e nt ar m will b e pr e s e nt e d u si n g st a n d ar d d e s cri pti v e st ati sti c s.  
C o m p ar ati v e st ati sti c al a n al y s e s will b e p erf or m e d o n d at a c oll e ct e d d uri n g t h e R W p h a s e. T h e 
pri m ar y e n d p oi nt i s ti m e t o fir st o c c urr e n c e of di s e a s e r e a cti v ati o n (i n cl u di n g f ull a n d p arti al di s e a s e 
r e a cti v ati o n) d uri n g t h e R W p h a s e. T a d e ki ni g alf a will b e c o m p ar e d t o pl a c e b o u si n g t h e l o g r a n k 
t e st at t h e al p h a = 0. 0 5 l e v el of si g nifi c a n c e ( 2-si d e d). K a pl a n -M ei er e sti m at e s of t h e di stri b uti o n of 
ti m e-t o-e v e nt will b e s u m m ari z e d a n d gr a p h e d b y tr e at m e nt gr o u p.   
T o t e st t h e effi c a c y of T a d e ki ni g alf a o n s e c o n d ar y o ut c o m e s d uri n g t h e R W  p h a s e , Fi s h er' s e x a ct 
t e st will b e utili z e d f or bi n ar y o ut c o m e s (i. e. tr e at m e nt f ail ur e r at e) a n d a n o n-p ar a m etri c, M a n n –
W hit n e y – Wil c o x o n t e st will b e utili z e d f or c o nti n u o u s o ut c o m e s (i. e. c h a n g e i n t h e m AI D AI). T o 
a s s e s s t h e i m p a ct of p o s si bl e v ari ati o n i n b a s eli n e m e a s ur e s, a n a n al y si s of c o v ari a n c e ( A N C O V A) 
m o d el  wit h  c o v ari at e  a dj u st m e nt  f or  B a s eli n e  m a y  b e  c o n si d er e d  a s  a  s e n siti vit y  a n al y si s,  or  
alt er n ati v e n o n -p ar a m etri c a p pr o a c h e s if n or m alit y a s s u m pti o n s ar e n ot m et.  


 
 
 
P a g e 7 1  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
If  t h e  pri m ar y  a n al y si s  i s  st ati sti c all y  si g nifi c a nt  ( p < 0. 0 5),  t h e  f oll o wi n g  s e c o n d ar y  e n d p oi nt s  
m e a s ur e d d uri n g t h e R W p h a s e will b e a n al y z e d u si n g a fi x e d -s e q u e n c e t e sti n g pr o c e d ur e i n t h e 
or d er s p e cifi e d b el o w t o c o ntr ol t h e o v er all l e v el of si g nifi c a n c e:  
•   
Tr e at m e nt f ail ur e r at e; 
•  
C h a n g e fr o m R W b a s eli n e t o W e e k 3 4 (i. e. W e e k 1 6 of t h e R W p h a s e) or E n d of St u d y Vi sit  
i n t h e m AI D AI t ot al s c or e; a n d 
•  
C h a n g e fr o m R W b a s eli n e t o W e e k 3 4 or E n d of St u d y Vi sit  i n t h e P G A s y m pt o m s e v erit y 
s c or e.  
F or e a c h of t h e s e e n d p oi nt s, t h e tr e at m e nt gr o u p s will b e c o m p ar e d u si n g a t w o -si d e d t e st at al p h a 
= 0. 0 5 l e v el of si g nifi c a n c e. H o w e v er, o n c e a n o n -si g nifi c a nt r e s ult (i. e. p > 0. 0 5) o c c ur s, t h e r e s ult s 
of all s u b s e q u e nt a n al y s e s will b e e x pl or at or y r at h er t h a n c o nfir m at or y.  
I n a d diti o n, all e n d p oi nt s will b e e v al u at e d d e s cri pti v el y i n cl u di n g 9 5 % c o nfi d e n c e i nt er v al s f or t h e 
m e a n a n d pr o p orti o n s.  
1 6. 6. 2   
S A O L Ph a s e  
A n al y si s of d at a c oll e ct e d d uri n g t h e S A O L p h a s e wil l b e d e s cri pti v e i n n at ur e, t o i n cl u d e 9 5 % CI s 
ar o u n d s el e ct m e a n e sti m at e s a n d pr o p orti o n s of i nt er e st. A b s ol ut e a n d p er c e nt a g e of c h a n g e fr o m 
b a s eli n e  will  b e  c al c ul at e d  f or  c o nti n u o u s  v ari a bl e s.  R e s p o n s e  t o  tr e at m e nt  i n  t h e  i niti al  a cti v e 
di s e a s e , n u m b er, fr e q u e n c y a n d s e v erit y of di s e a s e r e a cti v ati o n s d uri n g t h e st u d y will b e c o m p ar e d 
t o i n ci d e n c e a n d s e v erit y d e s cri b e d i n t h e m e di c al hi st or y of i n di vi d u al p ati e nt s. 
I n di vi d u al s u bj e ct’ s r a w d at a will b e c a pt ur e d wit h d at a li sti n g s a n d i n di vi d u al p ati e nt pl ot s at e a c h 
ti m e p oi nt t o vi s u ali z e t h e diff er e nt r e s p o n s e s ( e. g. i n t er m s of m AI D AI, P G A, F erriti n a n d C R P a s 
w ell  a s  t h e  m o st  pr o mi n e nt  cli ni c al  f e at ur e s  a n d  r e s ult s  fr o m  p ati e nt` s/ c ar e gi v er` s  q u alit ati v e  
e v al u ati o n of h e alt h st at u s)  at e a c h ti m e p oi nt t o t h e a s si g n e d tr e at m e nt i n a d e s cri pti v e m a n n er.  
1 6. 7  S u b gr o u p A n al y si s  
N o s u b gr o u p a n al y si s i s pl a n n e d.  
1 6. 8  Wit h dr a w al s, D r o p-o ut s, Mi s si n g V al u e s  
T h e a n al y si s of t h e pri m ar y e n d p oi nt, ti m e t o fir st di s e a s e r e a cti v ati o n (i n cl u di n g f ull a n d p arti al 
di s e a s e r e a cti v ati o n) , will b e b a s e d o n K M s ur vi v al a n al y si s t e c h ni q u e s, w h er e p ati e nt s w h o d o n ot 
e x p eri e n c e  a  di s e a s e  r e a cti v ati o n  d uri n g  t h e  R W  p h a s e  will  b e  c e n s or e d  at  d at e  of  t h eir  l a st  
a s s e s s m e nt f or di s e a s e s y m pt o m s . 
D et ail s t o a c c o u nt f or mi s si n g d at a i n t h e a n al y si s of s e c o n d ar y effi c a c y e n d p oi nt s will b e d e s cri b e d 
i n t h e st ati sti c al a n al y si s pl a n. 
 
 


 
 
 
P a g e 7 2  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
1 7  H A N D LI N G O F A D V E R S E E V E N T S  
1 7. 1  N o n - Seri o u s a n d S eri o u s A d v er s e E v e nt s  
A n a d v er s e e v e nt ( A E) i s a n y u n d e sir a bl e si g n, s y m pt o m, or m e di c al c o n diti o n o c c urri n g aft er si g ni n g 
t h e I nf or m e d c o n s e nt f or m (I C F) t hr o u g h t h e e n d of st u d y at f oll o w u p (V 1 3). 
I nf or m ati o n  a b o ut  all  A E s,  w h et h er  v ol u nt e er e d  b y  t h e  s u bj e ct,  di s c o v er e d  b y  q u e sti o ni n g,  or  
d et e ct e d t hr o u g h p h y si c al e x a mi n ati o n, l a b or at or y t e sti n g, or ot h er m e a n s, will b e c oll e ct e d a n d 
r e c or d e d o n t h e A E C R F p a g e a n d f oll o w e d a s a p pr o pri at e. 
All r el e v a nt m e di c al c o n diti o n s pr e s e nt pri or t o st u d y e ntr y will b e d o c u m e nt e d i n t h e M e di c al Hi st or y 
C R F. H o w e v er, m e di c al c o n diti o n s o c c urri n g aft er si g ni n g t h e I C F ar e t o b e r e c or d e d a s  A E s. T hi s 
i n cl u d e s w or s e ni n g of a pr e-e xi sti n g c o n diti o n. A E s o c c urri n g pri or t o a d mi ni str ati o n of st u d y dr u g 
will b e c o n si d er e d n o n -tr e at m e nt e m er g e nt, a n d t h o s e o c c urri n g aft er t h e st art of st u d y dr u g will b e 
c o n si d er e d tr e at m e nt e m er g e nt.  
A d v er s e e v e nt s will b e m o nit or e d a n d r e c or d e d fr o m t h e ti m e t h e i nf or m e d c o n s e nt  i s si g n e d. T h e 
I n v e sti g at or i s r e s p o n si bl e f or t h e d et e cti o n a n d d o c u m e nt ati o n of e v e nt s m e eti n g t h e crit eri a a n d 
d efi niti o n of a n A E, a n S A E a n d a n A E of s p e ci al i nt er e st ( A E SI) a s pr o vi d e d i n t hi s pr ot o c ol  ( s e e 
S e cti o n s 1 7 . 2 a n d 1 7 . 3).  All  A E s (i n cl u di n g  A E SI s) a n d  S A E s  will  b e  r e c or d e d  i n  t h e  s o ur c e  
d o c u m e nt s. A E s will b e e nt er e d o n t h e a p pr o pri at e e C R F p a g e fr o m t h e ti m e of si g ni n g i nf or m e d 
c o n s e nt  u ntil c o m pl eti o n of t h e  st u d y  ( Vi sit 1 3 ) or pr e m at ur e wit h dr a w al.  
T hr o u g h o ut t h e st u d y , d uri n g cli ni c vi sit s, h o m e vi sit s a n d ot h er c o nt a ct s, aft er t h e p ati e nt h a s h a d 
a n o p p ort u nit y t o s p o nt a n e o u sl y m e nti o n a n y pr o bl e m s, t h e I n v e sti g at or s h o ul d i n q uir e a b o ut t h e 
o c c urr e n c e  of  A E s.  T h e H C N will  i n q uir e  a b o ut  p ot e nti al A E s at  t h e  m o m e nt  of  tr e at m e nt  
a d mi ni str ati o n. If a n A E i s r e p ort e d, t h e n ur s e will c o m m u ni c at e t o t h e sit e r e s p o n si bl e p h y si ci a n. 
T h e f oll o wi n g ar e e x a m pl e s of o p e n -e n d e d q u e sti o n s t h at m a y b e u s e d t o o bt ai n t hi s i nf or m ati o n  at 
t h e sit e s d uri n g t h e pr o gr a m m e d vi sit s or b y t h e h o m e c ar e n ur s e: 
•  
“ H o w ar e y o u f e eli n g ?” 
•  
" H a v e y o u h a d a n y m e di c al pr o bl e m s si n c e y o ur l a st vi sit/ a s s e s s m e nt ?"  
•  
" H a v e y o u t a k e n a n y n e w m e di ci n e s, ot h er t h a n t h o s e gi v e n t o y o u i n t hi s st u d y, si n c e y o ur 
l a st vi sit/ a s s e s s m e nt ?" 
 
1 7. 2  D efi niti o n  of a n  A d v er s e E v e nt  ( A E) 
A n  a d v er s e  e v e nt  ( al s o  r ef err e d  t o  a s  a n  a d v er s e  e x p eri e n c e)  c a n  b e  a n y  u nf a v or a bl e  a n d  
u ni nt e n d e d si g n ( e. g.,  a n a b n or m al l a b or at or y fi n di n g), s y m pt o m, or di s e a s e t e m p or all y a s s o ci at e d 
wit h t h e u s e of a dr u g, a n d d o e s n ot i m pl y a n y j u d g m e nt a b o ut c a u s alit y. A n a d v er s e e v e nt c a n ari s e 
wit h a n y u s e of t h e dr u g ( e. g., off -l a b el u s e, u s e i n c o m bi n ati o n wit h a n ot h er dr u g) a n d wit h a n y r o ut e 
of a d mi ni str ati o n, f or m ul ati o n, or d o s e, i n cl u di n g a n o v er d o s e  
 
All A E s m u st b e d o c u m e nt e d a n d a s s e s s e d f or : 
•  
D ur ati o n ( st art a n d e n d d at e s)  
•  
S e v erit y gr a d e  
•  
Fr e q u e n c y  
•   
Rel ati o n s hi p t o t h e st u d y pr o d u ct.   
•  
A cti o n( s) t a k e n  
•  
O ut c o m e  
 
 
 


 
 
 
P a g e 7 3  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
E x a m pl e s of a n A E i n cl u d e:  
•  
E x a c er b ati o n of a c hr o ni c or i nt er mitt e nt pr e -e xi sti n g c o n diti o n i n cl u di n g eit h er a n i n cr e a s e 
i n fr e q u e n c y or i nt e n sit y ( s e v erit y) of t h e c o n diti o n.   
o  T hi s e x cl u d e s di s e a s e r e a cti v ati o n s  of t h e c o n diti o n u n d er st u d y b ei n g c oll e ct e d a s  
st u d y  e n d p oi nt s.  A c c or di n g  t o  t h e  F D A  G ui d a n c e  ( G ui d a n c e  f or  I n d u str y  a n d  
I n v e sti g at or s S af et y R e p orti n g R e q uir e m e nt s f or I N D s a n d B A/ B E St u di e s; C D E R, 
C B E R,  D e c e m b er  2 0 1 2),  r e a cti v ati o n s of  t h e  c o n diti o n  u n d er  st u d y  w o ul d  n ot  
or di n aril y  b e  r e p ort e d  a s  A E s  a n d/ or  I N D  s af et y  r e p ort s,  e x c e pt  w h e n  t h er e  i s  
e vi d e n c e s u g g e sti n g a c a u s al r el ati o n s hi p b et w e e n t h e dr u g a n d t h e e v e nt ( 2 1 C F R 
3 1 2. 3 2( c)( 5).  
•  
A n e w c o n diti o n d et e ct e d or di a g n o s e d aft er st u d y tr e at m e nt i niti ati o n e v e n t h o u g h it m a y 
h a v e b e e n pr e s e nt pri or t o t h e st art of t h e st u d y.  
•  
Si g n s, s y m pt o m s, or cli ni c al s e q u el a e of a s u s p e ct e d o v er d o s e of eit h er st u d y tr e at m e nt or 
a c o n c urr e nt m e di c ati o n (“ o v er d o s e” p er s e, s h o ul d n ot b e r e p ort e d a s a n A E/ S A E).  
•   
Pr e- or p o st -tr e at m e nt e v e nt s t h at o c c ur a s a r e s ult of pr ot o c ol-m a n d at e d pr o c e d ur e s ( e. g. 
i n v a si v e pr ot o c ol-d efi n e d pr o c e d ur e s, m o difi c ati o n of a p ati e nt ’ s pr e vi o u s dr u g tr e at m e nt 
r e gi m e n).  
A n A E d o e s n ot i n cl u d e:  
•  
M e di c al or s ur gi c al pr o c e d ur e s ( e. g., c ol o n o s c o p y, bi o p s y). T h e m e di c al c o n diti o n t h at l e a d s 
t o t h e pr o c e d ur e m a y b e a n A E u nl e s s t h e m e di c al or s ur gi c al pr o c e d ur e w a s pr e -pl a n n e d 
( pri or t o c o m m e n c e m e nt of st u d y, a n d t h e m e di c al c o n diti o n t h at l e d t o t h e pr o c e d ur e di d n ot 
w or s e n aft er B a s eli n e).  
•  
S o ci al or c o n v e ni e n c e h o s pit al a d mi s si o n s w h er e a n u nt o w ar d m e di c al o c c urr e n c e di d n ot 
o c c ur. H o s pit ali z ati o n of s u bj e ct s m a y b e c o n si d er e d b a s e d o n  t h e c o ur s e of t h e di s e a s e a n d 
t h e p ati e nt a c c e s si bilit y t o t h e sit e. 
•  
D a y t o d a y fl u ct u ati o n s of pr e -e xi sti n g di s e a s e or c o n diti o n s pr e s e nt or d et e ct e d at t h e st art 
of t h e st u d y t h at d o n ot w or s e n.  
 
All r el e v a nt m e di c al c o n diti o n s pr e s e nt pri or t o st u d y e ntr y will b e d o c u m e nt e d i n t h e M e di c al  
Hi st or y e C R F  (i n cl u di n g c o-m or bi diti e s).  M e di c al c o n diti o n s o c c urri n g aft er si g ni n g t h e I C F ar e t o b e 
r e c or d e d a s A E s.  
 
A E s o c c urri n g pri or t o a d mi ni str ati o n of st u d y dr u g  will b e c o n si d er e d n o n -tr e at m e nt e m er g e nt, w hil e 
t h o s e o c c urri n g aft er t h e st art of st u d y dr u g will b e c o n si d er e d tr e at m e nt e m er g e nt. 
 
A tr e at m e nt -e m er g e nt A E ( T E A E) i s d efi n e d a s a n y a d v er s e e v e nt n ot pr e s e nt pri or t o e x p o s ur e t o 
st u d y m e di c ati o n (i. e., a n e v e nt t h at o c c ur s aft er st arti n g o n st u d y dr u g) or a n y c o n diti o n alr e a d y 
pr e s e nt a s p art of t h e p ati e nt’ s m e di c al hi st or y t h at w or s e n s i n eit h er i nt e n sit y or fr e q u e n c y f oll o wi n g 
e x p o s ur e t o t e st m e di c ati o n.  
A  pr ot o c ol -r el at e d  A E  i s  a n  A E  o c c urri n g  d uri n g  a  cli ni c al  st u d y  t h at  i s  n ot  r el at e d  t o  t h e  
I n v e sti g ati o n al Dr u g, b ut i s c o n si d er e d b y t h e I n v e sti g at or or t h e M e di c al M o nit or ( or d e si g n e e) t o b e 
r el at e d t o t h e r e s e ar c h c o n diti o n s, i. e., r el at e d t o t h e f a ct t h at t h e p ati e nt i s p arti ci p ati n g i n t h e st u d y. 
F or e x a m pl e, a pr ot o c ol -r el at e d A E m a y b e a n u nt o w ar d e v e nt o c c urri n g d uri n g a w a s h o ut p eri o d or 
a n e v e nt r el at e d t o a m e di c al pr o c e d ur e r e q uir e d b y t h e pr ot o c ol.  
 
A d v er s e E v e nt of S p e ci al I nt er e st ( A E SI):  
•  
I nj e cti o n sit e r e a cti o n s (i n cl u di n g pr urit u s, er yt h e m a, s w elli n g)  
I S R s ar e t o b e r e p ort e d r e g ar dl e s s w h et h er t h e y ar e d u e t o h y p er s e n siti vit y t o t h e st u d y dr u g or 
r el at e d t o t h e a d mi ni str ati o n pr o c e d ur e. H o w e v er, t h e r el ati o n s hi p t o eit h er t h e st u d y dr u g or t h e 
a d mi ni str ati o n pr o c e d ur e n e e d s t o b e i d e ntifi e d a n d r e c or d e d i n t h e C R F.  


 
 
 
P a g e 7 4  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
 
T a bl e 3:  Sit e R e a cti o n s t o I nj e cti o n s a n d I nf u si o n s 
P ar a m et er  
Gr a d e 1  
Mil d  
Gr a d e 2  
M o d er at e  
Gr a d e 3  
S e v er e  
Gr a d e 4  
P ot e nti all y Lif e -
T hr e at e ni n g  
I nj e cti o n Sit e 
P ai n or 
T e n d er n e s s  
R e p ort o nl y o n e  
P ai n or 
t e n d er n e s s 
c a u si n g n o or 
mi ni m al 
li mit ati o n of u s e 
of li m b  
P ai n or 
t e n d er n e s s 
c a u si n g gr e at er 
t h a n mi ni m al 
li mit ati o n of u s e 
of li m b  
P ai n or 
t e n d er n e s s 
c a u si n g i n a bilit y 
t o p erf or m u s u al 
s o ci al & 
f u n cti o n al 
a cti viti e s  
P ai n or 
t e n d er n e s s 
c a u si n g i n a bilit y 
t o p erf or m b a si c 
s elf -c ar e 
f u n cti o n O R  
H o s pit ali z ati o n 
i n di c at e d  
I nj e cti o n Sit e 
Er yt h e m a or 
R e d n e s s  
R e p ort o nl y o n e  
> 1 5 y e ar s of 
a g e  
2. 5 t o < 5 c m i n 
di a m et er O R  
6. 2 5 t o < 2 5 c m 2 
s urf a c e ar e a 
A N D  S y m pt o m s 
c a u si n g n o or 
mi ni m al 
i nt erf er e n c e wit h 
u s u al s o ci al & 
f u n cti o n al 
a cti viti e s  
≥ 5 t o < 1 0 c m i n 
di a m et er O R  ≥ 
2 5 t o < 1 0 0 c m 2 
s urf a c e ar e a O R  
S y m pt o m s 
c a u si n g gr e at er 
t h a n mi ni m al 
i nt erf er e n c e wit h 
u s u al s o ci al & 
f u n cti o n al 
a cti viti e s  
≥ 1 0 c m i n 
di a m et er O R  ≥ 
1 0 0 c m 2 s urf a c e 
ar e a O R  
Ul c er ati o n O R  
S e c o n d ar y 
i nf e cti o n O R  
P hl e biti s O R  
St eril e a b s c e s s 
O R  Dr ai n a g e 
O R  S y m pt o m s 
c a u si n g i n a bilit y 
t o p erf or m u s u al 
s o ci al & 
f u n cti o n al 
a cti viti e s  
P ot e nti all y lif e -
t hr e at e ni n g 
c o n s e q u e n c e s 
( e. g., a b s c e s s, 
e xf oli ati v e 
d er m atiti s, 
n e cr o si s 
i n v ol vi n g d er mi s 
or d e e p er 
ti s s u e)  
I nj e cti o n Sit e 
Er yt h e m a or 
R e d n e s s R e p ort 
o nl y o n e ≤ 1 5 
y e ar s of a g e  
≤ 2. 5 c m i n 
di a m et er  
> 2. 5 c m i n 
di a m et er wit h < 
5 0 % s urf a c e 
ar e a of t h e 
e xtr e mit y 
s e g m e nt 
i n v ol v e d ( e. g., 
u p p er ar m or 
t hi g h)  
≥ 5 0 % s urf a c e 
ar e a of t h e 
e xtr e mit y 
s e g m e nt 
i n v ol v e d ( e. g., 
u p p er ar m or 
t hi g h) O R  
Ul c er ati o n O R  
S e c o n d ar y 
i nf e cti o n O R  
P hl e biti s O R  
St eril e a b s c e s s 
O R  Dr ai n a g e  
P ot e nti all y lif e -
t hr e at e ni n g 
c o n s e q u e n c e s 
( e. g., a b s c e s s, 
e xf oli ati v e 
d er m atiti s, 
n e cr o si s 
i n v ol vi n g d er mi s 
or d e e p er 
ti s s u e)  
I nj e cti o n Sit e 
I n d ur ati o n or 
S w elli n g  
R e p ort o nl y o n e  
> 1 5 y e ar s of 
a g e  
S a m e a s f or 
I nj e cti o n Sit e 
Er yt h e m a or 
R e d n e s s, > 1 5 
y e ar s of a g e  
S a m e a s f or 
I nj e cti o n Sit e 
Er yt h e m a or 
R e d n e s s, > 1 5 
y e ar s of a g e  
S a m e a s f or 
I nj e cti o n Sit e 
Er yt h e m a or 
R e d n e s s, > 1 5 
y e ar s of a g e  
S a m e a s f or 
I nj e cti o n Sit e 
Er yt h e m a or 
R e d n e s s, > 1 5 
y e ar s of a g e  
≤ 1 5 y e ar s of 
a g e  
S a m e a s f or 
I nj e cti o n Sit e 
Er yt h e m a or 
R e d n e s s, ≤ 1 5 
y e ar s of a g e  
S a m e a s f or 
I nj e cti o n Sit e 
Er yt h e m a or 
R e d n e s s, ≤ 1 5 
y e ar s of a g e  
S a m e a s f or 
I nj e cti o n Sit e 
Er yt h e m a or 
R e d n e s s, ≤ 1 5 
y e ar s of a g e  
S a m e a s f or 
I nj e cti o n Sit e 
Er yt h e m a or 
R e d n e s s, ≤ 1 5 
y e ar s of a g e  
I nj e cti o n Sit e 
Pr urit u s  
It c hi n g l o c ali z e d 
t o t h e i nj e cti o n 
It c hi n g b e y o n d 
t h e i nj e cti o n sit e 
G e n er ali z e d 
it c hi n g c a u si n g 
N A  


 
 
 
P a g e 7 5  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
P ar a m et er  
Gr a d e 1  
Mil d  
Gr a d e 2  
M o d er at e  
Gr a d e 3  
S e v er e  
Gr a d e 4  
P ot e nti all y Lif e -
T hr e at e ni n g  
sit e t h at i s 
r eli e v e d 
s p o nt a n e o u sl y 
or i n < 4 8 h o ur s 
of tr e at m e nt  
t h at i s n ot 
g e n er ali z e d O R  
It c hi n g l o c ali z e d 
t o t h e i nj e cti o n 
sit e r e q uiri n g ≥ 
4 8 h o ur s 
tr e at m e nt  
i n a bilit y t o 
p erf or m u s u al 
s o ci al & 
f u n cti o n al 
a cti viti e s  
 
S ki n  si g n s  a n d  s y m pt o m s  of  gr a d e s  3  a n d  4  will  r e s ult  i n  tr a n si e nt  or  p er m a n e nt  tr e at m e nt  
di s c o nti n u ati o n.  
 
1 7. 3  D efi niti o n of a S eri o u s A d v er s e E v e nt  ( S A E) 
A S A E i s a n y u nt o w ar d m e di c al o c c urr e n c e t h at at a n y d o s e: 
•  
R e s ult s i n d e at h  
•  
I s lif e-t hr e at e ni n g. N ot e: T h e t er m “lif e-t hr e at e ni n g” i n t h e d efi niti o n of “ s eri o u s” r ef er s t o a n e v e nt 
i n w hi c h t h e p ati e nt w a s at ri s k of d e at h at t h e ti m e of t h e e v e nt; it d o e s n ot r ef er t o a n e v e nt, 
w hi c h h y p ot h eti c all y mi g ht h a v e c a u s e d d e at h if it w er e m or e s e v er e  
•  
R e q uir e s i n p ati e nt h o s pit ali z ati o n or pr ol o n g ati o n of e xi sti n g h o s pit ali z ati o n. N ot e: C o m pli c ati o n s 
t h at o c c ur d uri n g h o s pit aliz ati o n ar e A E s. If a c o m pli c ati o n pr ol o n g s h o s pit ali z ati o n or f ulfil s a n y 
ot h er s eri o u s crit eri a, t h e e v e nt i s s eri o u s. H o s pit ali z ati o n f or el e cti v e tr e at m e nt of a pr e -e xi sti n g 
c o n diti o n t h at di d n ot w or s e n fr o m B a s eli n e; h o s pit ali z ati o n or s ur g er y r el at e d t o c a n c er tr e at m e nt; 
h o s pit ali z ati o n s c h e d ul e d t o f a cilit at e t h e tr e at m e nt or st u d y pr o c e d ur e s ar e n ot c o n si d er e d t o b e 
a n A E  
•  
R e s ult s  i n  p er si st e nt  or  si g nifi c a nt  di s a bilit y/i n c a p a cit y.  N ot e:  T h e  t er m  di s a bilit y  m e a n s  a  
s u b st a nti al di sr u pti o n of a p er s o n’ s a bilit y t o c o n d u ct n or m al lif e f u n cti o n s. T hi s d efi niti o n i s n ot 
i nt e n d e d t o i n cl u d e e x p eri e n c e s of r el ati v el y mi n or m e di c al si g nifi c a n c e s u c h a s u n c o m pli c at e d 
h e a d a c h e, n a u s e a, v o miti n g, di arr h e a , i nfl u e n z a, or a c ci d e nt al tr a u m a ( e. g., s pr ai n e d a n kl e) t h at 
m a y i nt erf er e or pr e v e nt e v er y d a y lif e f u n cti o n s b ut d o n ot c o n stit ut e a s u b st a nti al di sr u pti o n  or  
•  
I s a c o n g e nit al a n o m al y/ birt h d ef e ct 
•  
I m p ort a nt  m e di c al  e v e nt s  t h at  m a y  n ot  b e  i m m e di at el y  lif e-t hr e at e ni n g  or  r e s ult  i n  d e at h  or  
h o s pit ali z ati o n b ut m a y j e o p ar di z e t h e p ati e nt or m a y r e q uir e i nt er v e nti o n t o pr e v e nt o n e of t h e 
o ut c o m e s li st e d i n t h e d efi niti o n a b o v e s h o ul d al s o u s u all y b e c o n si d er e d s eri o u s. E x a m pl e s of 
s u c h e v e nt s ar e i nt e n si v e tr e at m e nt i n a n e m er g e n c y r o o m or at h o m e f or all er gi c br o n c h o s p a s m, 
bl o o d d y s cr a si a s, or c o n v ul si o n s t h at d o n ot r e s ult i n h o s pit ali z ati o n; or d e v el o p m e nt of dr u g 
d e p e n d e n c y or dr u g a b u s e . 
1 7. 4  Ot h er R e p ort a bl e Inf or m ati o n.  
Ot h er R e p ort a bl e I nf or m ati o n  i n cl u d e s c ert ai n i nf or m ati o n  t h at, alt h o u g h n ot c o n si d er e d a n S A E, 
m u st b e r e c or d e d, r e p ort e d, a n d f oll o w e d u p a s i n di c at e d f or a n S A E. T hi s i n cl u d e s t h e f oll o wi n g:  
Pr e g n a n c y  e x p o s ur e  t o  a n  I n v e sti g ati o n al  Dr u g.  If  a  pr e g n a n c y  i s  c o nfir m e d,  u s e  of  t h e  
I n v e sti g ati o n al Dr u g m u st b e di s c o nti n u e d i m m e di at el y. I nf or m ati o n a b o ut pr e g n a n c y e x p o s ur e 
i n cl u d e s t h e e ntir e c o ur s e of pr e g n a n c y a n d d eli v er y, a n d p eri n at al a n d n e o n at al o ut c o m e s, e v e n 
if t h er e ar e n o a b n or m al fi n di n g s. B ot h m at er n al a n d p at er n al e x p o s ur e s ar e c o n si d er e d ot h er 
r e p ort a bl e  i nf or m ati o n.  F or  e x p o s ur e  i n v ol vi n g  t h e  f e m al e  p artn er  of  a  m al e  p ati e nt ,  t h e  
n e c e s s ar y i nf or m ati o n m u st b e c oll e ct e d fr o m t h e p ati e n t, w hil e r e s p e cti n g t h e c o nfi d e nti alit y of 
t h e p art n er.  
L a ct ati o n e x p o s ur e t o a n I n v e sti g ati o n al Dr u g wit h or wit h o ut a n A E.  


 
 
 
P a g e 7 6  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
O v er d o s e of a n I n v e sti g ati o n al Dr u g a s s p e cifi e d i n t hi s pr ot o c ol wit h or wit h o ut a n A E. B a b y 
f or m ul a o v er d o s e s wit h o ut a n y A E s ar e e x cl u d e d. 
I n a d v ert e nt or a c ci d e nt al e x p o s ur e t o a n I n v e sti g ati o n al Dr u g wit h or wit h o ut a n A E. 
 
1 7. 5  M e di c ati o n E rr or s 
M e di c ati o n err or s ar e t h e r e s ult of a d mi ni str ati o n or c o n s u m pti o n of t h e wr o n g pr o d u ct b y t h e wr o n g 
p ati e nt , at t h e wr o n g ti m e, a n d/ or b y t h e wr o n g a d mi ni str ati o n r o ut e, d u e t o h u m a n err or. 
M e di c ati o n err or s i n cl u d e, b ut ar e n ot li mit e d t o, t h e f oll o wi n g:  
o  T h e a d mi ni str ati o n of t h e I n v e sti g ati o n al Dr u g t h at h a s n ot b e e n a s si g n e d t o t h e p ati e nt  
o  T h e a d mi ni str ati o n of t h e e x pir e d I n v e sti g ati o n al Dr u g w h e n it i s a s s o ci at e d wit h a n A E  
o  Err or s i n v ol vi n g r at e of a d mi ni str ati o n, r e c o n stit uti o n a n d dil uti o n, i n cl u di n g u s e of a p pr o pri at e 
dil u e nt a n d t h e ti m e fr a m e i n w hi c h I n v e sti g ati o n al Dr u g s h o ul d b e u s e d aft er r e c o n stit uti o n 
a n d/ or dil uti o n  
o  Err or s r el at e d t o st or a g e or r efri g er ati o n r e q uir e m e nt s  
All A E s a n d S A E s m u st b e h a n dl e d a s s p e cifi e d i n t hi s pr ot o c ol w h et h er or n ot t h e y ar e a s s o ci at e 
wit h a m e di c ati o n err or. A m e di c ati o n err or a s s o ci at e d wit h a n S A E (i n cl u di n g o v er d o s e, i n a d v ert e nt 
e x p o s ur e, a n d / or a c ci d e nt al e x p o s ur e) will b e r e p ort e d wit h t h e S A E, o n t h e S A E f or m. All ot h er 
m e di c ati o n err or s will b e c a pt ur e d i n t h e d at a b a s e a s d e vi ati o n s t o t h e pr ot o c ol a n d r e p ort e d t o A B 2 
Bi o a s s o o n a s p o s si bl e . 
 
1 7. 6  Cli ni c al L a b or at or y A b n or m aliti e s a n d Ot h er A b n or m al A s s e s s m e nt s  
A b n or m al cli ni c al l a b or at or y fi n di n g s t h at ar e j u d g e d b y t h e I n v e sti g at or a s cli ni c all y si g nifi c a nt m u st 
b e r e c or d e d  a s A E s or S A E s if t h e y m e et t h e d efi niti o n of a n A E or a n S A E, a s d efi n e d i n 1 6 . 2 a n d 
S e cti o n   1 6. 3 r e s p e cti v el y.  Cli ni c all y  si g nifi c a nt  a b n or m al  l a b or at or y  fi n di n g s  or  ot h er  a b n or m al  
a s s e s s m e nt s t h at ar e d et e ct e d d uri n g t h e st u d y or ar e pr e s e nt at B a s eli n e a n d si g nifi c a ntl y w or s e n 
f oll o wi n g t h e st art of t h e st u d y m a y b e r e p ort e d a s A E s or S A E s. 
T h e I n v e sti g at or will e x er ci s e m e di c al j u d g m e nt i n d e ci di n g w h et h er a b n or m al l a b or at or y v al u e s ar e 
cli ni c all y si g nifi c a nt.  
T h e gr a di n g of s e v erit y of A E s s h o ul d t a k e i nt o a c c o u nt t h e r ef er e n c e v al u e s a c c or di n g t o t h e a g e s 
of t h e s u bj e ct s i n t h e st u d y.  
 
T h e ki d n e y f u n cti o n will b e a s s e s s e d b y t h e c al c ul ati o n of t h e gl o m er ul ar filtr ati o n r at e u si n g t h e 
S c h w art z f or m ul a:  
 
G F R = K L/ P cr a n d it i s e x pr e s s e d i n ml/ mi n p er 1. 7 3 m 2 b o d y s urf a c e ar e a. L r e pr e s e nt s b o d y l e n gt h 
i n c e nti m et er, P cr r e pr e s e nt pl a s m a cr e ati ni n e c o n c e ntr ati o n i n m g p er dl a n d K i s a c o n st a nt t h at 
v ari e s a s a f u n cti o n of a g e a n d s e x, b ei n g 0. 3 3 i n pr et er m i nf a nt s, 0. 4 5 i n f ull -t er m i nf a nt s, 0. 5 5 i n 
c hil dr e n a n d a d ol e s c e nt girl s a n d 0. 7 0 i n a d ol e s c e nt b o y s  
 
 


 
 
 
P a g e 7 7  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
T a bl e 4:  Gr a di n g of a d v er s e e v e nt s d u e t o l o w l e v el s of Cr e ati ni n e Cl e ar a n c e or e G F R  
P ar a m et er  
Gr a d e 1  
Mil d  
Gr a d e 2  
M o d er at e  
Gr a d e 3  
S e v er e  
Gr a d e 4  
P ot e nti all y Lif e -
T hr e at e ni n g  
Cr e ati ni n e 
Cl e ar a n c e 1  or 
e G F R, L o w  
R e p ort o nl y o n e  
N A  
< 9 0 t o 6 0 
ml/ mi n or 
ml/ mi n/ 1. 7 3 m
2  
O R   
1 0 % t o < 3 0 % 
d e cr e a s e fr o m 
b a s eli n e  
< 6 0 t o 3 0 
ml/ mi n or 
ml/ mi n/ 1. 7 3 m
2  
O R  
 ≥ 3 0 % t o < 5 0 % 
d e cr e a s e fr o m 
b a s eli n e  
< 3 0 ml/ mi n or 
ml/ mi n/ 1. 7 3 m
2 
O R   
≥ 5 0 % d e cr e a s e 
fr o m b a s eli n e or 
di al y si s n e e d e d  
1  U s e t h e a p pli c a bl e f or m ul a (i. e., C o c kr oft -G a ult i n m L/ mi n or S c h w atr z i n m L/ mi n/ 1. 7 3 m 2)  
L o w l e v el s of Cr e ati ni n e Cl e ar a n c e or e G F R r e a c hi n g gr a d e s 3 a n d 4 will r e s ult i n tr a n si e nt or 
p er m a n e nt tr e at m e nt di s c o nti n u ati o n ( s e e r ef er e n c e v al u e s i n t h e R ef er e n c e St u d y M a n u al ) 
 
T a bl e 5:  Gr a di n g of a d v er s e e v e nt s d u e t o l o w l e v el s of h e m o gl o bi n  
P ar a m et er  
Gr a d e 1  
Mil d  
Gr a d e 2  
M o d er at e  
Gr a d e 3  
S e v er e  
Gr a d e 4  
P ot e nti all y Lif e -
T hr e at e ni n g  
H e m o gl o bi n, L o w  
( g/ d L; m m ol/ L )1  
≥ 1 8 y e ar s of 
a g e (b ot h 
g e n d er s ) 
1 0. 0 t o < L L N  
6. 2 t o < L L N  
8. 0 t o < 1 0. 0  
4. 9 t o < 6. 2  
7. 0 t o < 8. 0  
4. 3 4  t o < 4. 9  
 
< 7. 0  
< 4. 3 4  
≥ 1 3 t o < 1 8 
y e ar s of a g e 
( m al e o nl y) 
1 0. 0 t o 1 0. 9  
6. 1 9 t o 6. 7 6  
9. 0 t o < 1 0. 0  
5. 5 7 t o < 6. 1 9  
7. 0 t o < 9. 0  
4. 3 4 t o < 5. 5 7  
< 7. 0  
< 4. 3 4  
≥ 1 3 t o < 1 8 
y e ar s of a g e 
(f e m al e o nl y)  
9. 5 t o 1 0. 4  
5. 8 8 t o 6. 4 8  
8. 5 t o < 9. 5  
5. 2 5 t o < 5. 8 8  
6. 5 t o < 8. 5  
4. 0 3 t o < 5. 2 5  
< 6. 5  
< 4. 0 3  
5 7 d a y s of a g e 
t o < 1 3 y e ar s of 
a g e ( m al e a n d 
f e m al e)  
9. 5 t o 1 0. 4  
5. 8 8 t o 6. 4 8  
8. 5 t o < 9. 5  
5. 2 5 t o < 5. 8 8  
6. 5 t o < 8. 5  
4. 0 3 t o < 5. 2 5  
< 6. 5  
< 4. 0 3  
3 6 t o 5 6 d a y s of 
a g e ( m al e a n d 
f e m al e)  
8. 5 t o 9. 6  
5. 2 6 t o 5. 9 9  
7. 0 t o < 8. 5  
4. 3 2 t o < 5. 2 6  
6. 0 t o < 7. 0  
3. 7 2 t o < 4. 3 2  
< 6. 0  
< 3. 7 2  
2 2 t o 3 5 d a y s of 
a g e ( m al e a n d 
f e m al e)  
9. 5 t o 1 1. 0  
5. 8 8 t o 6. 8 6  
8. 0 t o < 9. 5  
4. 9 4 t o < 5. 8 8  
6. 7 t o < 8. 0  
4. 1 5 t o < 4. 9 4  
< 6. 7  
< 4. 1 5  
8 t o ≤ 2 1 d a y s of 
a g e ( m al e a n d 
f e m al e)  
1 1. 0 t o 1 3. 0  
6. 8 1 t o 8. 1 0  
9. 0 t o < 1 1. 0  
5. 5 7 t o < 6. 8 1  
8. 0 t o < 9. 0  
4. 9 6 t o < 5. 5 7  
< 8. 0  
< 4. 9 6  
≤ 7 d a y s of a g e 
( m al e a n d 
f e m al e)  
1 3. 0 t o 1 4. 0  
8. 0 5 t o 8. 7 2  
1 0. 0 t o < 1 3. 0  
6. 1 9 t o < 8. 0 5  
9. 0 t o < 1 0. 0  
5. 5 9 t o < 6. 1 9  
< 9. 0  
< 5. 5 9  
1  T h e c o n v er si o n f a ct or u s e d t o c o n v ert g/ d L t o m m ol/ L i s 0. 6 2 0 6 a n d i s t h e m o st c o m m o nl y u s e d c o n v er si o n f a ct or. F or 
gr a di n g h e m o gl o bi n r e s ult s o bt ai n e d b y a n a n al yti c m et h o d wit h a c o n v er si o n f a ct or ot h er t h a n 0. 6 2 0 6, t h e r e s ult m u st 
b e c o n v ert e d t o g/ d L u si n g t h e a p pr o pri at e c o n v er si o n f a ct or f or t h e p arti c ul ar l a b or at or y; L L N = l o w er li mit of n or m al 
a c c or di n g t o l o c al or c e ntr al l a b or at or y  
L o w l e v el s of h a e m o gl o bi n r e a c hi n g gr a d e s 3 a n d 4 m a y r e s ult i n tr a n si e nt or p er m a n e nt tr e at m e nt 
di s c o nti n u ati o n ( s e e r ef er e n c e v al u e s i n t h e L a b or at or y S p e cifi c ati o n s).  
 
 
 
 


 
 
 
P a g e 7 8  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
T a bl e 6:  Gr a di n g of a d v er s e e v e nt s d u e t o l o w l e v el s of w hit e bl o o d c ell s  
P ar a m et er  
Gr a d e 1  
Mil d  
Gr a d e 2  
M o d er at e  
Gr a d e 3  
S e v er e  
Gr a d e 4  
P ot e nti all y Lif e -
T hr e at e ni n g  
W B C, D e cr e a s e d  
( c ell s/ m m3 ; c ell s/ L )  
> 7 d a y s of a g e  
2, 0 0 0 t o 2, 4 9 9  
2. 0 0 0 x 1 0 9  t o 
2. 4 9 9 x 1 0 9   
1, 5 0 0 t o 1, 9 9 9  
1. 5 0 0 x 1 0 9  t o 
1. 9 9 9 x 1 0 9   
1, 0 0 0 t o 1, 4 9 9  
1. 0 0 0 x 1 0 9  t o 
1. 4 9 9 x 1 0 9   
< 1, 0 0 0  
< 1. 0 0 0 x 1 0 9   
≤ 7 d a y s of a g e  
5, 5 0 0 t o 6, 9 9 9  
5. 5 0 0 x 1 0 9  t o 
6. 9 9 9 x 1 0 9   
4 , 0 0 0 t o 5, 4 9 9  
4. 0 0 0 x 1 0 9  t o 
5. 4 9 9 x 1 0 9   
2, 5 0 0 t o 3, 9 9 9  
2. 5 0 0 x 1 0 9  t o 
3. 9 9 9 x 1 0 9   
< 2, 5 0 0  
< 2. 5 0 0 x 1 0 9   
 
D e cr e a s e i n w hit e bl o o d c ell c o u nt s of gr a d e s 3 a n d 4 m a y r e s ult i n tr a n si e nt or p er m a n e nt 
tr e at m e nt di s c o nti n u ati o n. ( s e e r ef er e n c e v al u e s i n t h e L a b or at or y S p e cifi c ati o n s).  
 
T a bl e 7:  Gr a di n g of a d v er s e e v e nt s d u e t o l o w l e v el s of n e utr o p hil s  
P ar a m et er  
Gr a d e 1  
Mil d  
Gr a d e 2  
M o d er at e  
Gr a d e 3  
S e v er e  
Gr a d e 4  
P ot e nti all y Lif e -
T hr e at e ni n g  
A b s ol ut e N e utr o p hil C o u nt ( A N C), L o w  
( c ell s/ m m3 ; c ell s/ L )  
> 7 d a y s of a g e  
8 0 0 t o 1, 0 0 0  
0. 8 0 0 x 1 0 9  t o 
1. 0 0 0 x 1 0 9   
6 0 0 t o 7 9 9  
0. 6 0 0 x 1 0 9  t o 
0. 7 9 9 x 1 0 9   
4 0 0 t o 5 9 9  
0. 4 0 0 x 1 0 9  t o 
0. 5 9 9 x 1 0 9   
< 4 0 0  
< 0. 4 0 0 x 1 0 9   
2 t o 7 d a y s of 
a g e  
1, 2 5 0 t o 1, 5 0 0  
1. 2 5 0 x 1 0 9  t o 
1. 5 0 0 x 1 0 9   
1, 0 0 0 t o 1, 2 4 9  
1. 0 0 0 x 1 0 9  t o 
1. 2 4 9 x 1 0 9   
7 5 0 t o 9 9 9  
0. 7 5 0 x 1 0 9  t o 
0. 9 9 9 x 1 0 9   
< 7 5 0  
< 0. 7 5 0 x 1 0 9   
≤ 1 d a y of a g e  
4, 0 0 0 t o 5, 0 0 0  
4. 0 0 0 x 1 0 9  t o 
5. 0 0 0 x 1 0 9   
3, 0 0 0 t o 3, 9 9 9  
3. 0 0 0 x 1 0 9  t o 
3. 9 9 9 x 1 0 9   
1, 5 0 0 t o 2, 9 9 9  
1. 5 0 0 x 1 0 9  t o 
2. 9 9 9 x 1 0 9   
< 1, 5 0 0  
< 1. 5 0 0 x 1 0 9   
 
D e cr e a s e i n n e utr o p hil c o u nt s of gr a d e s 3 a n d 4 m a y r e s ult i n tr a n si e nt or p er m a n e nt tr e at m e nt 
di s c o nti n u ati o n ( s e e r ef er e n c e v al u e s i n t h e L a b or at or y S p e cifi c ati o n s ) 
 
1 7. 7  R e c or di n g of A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s  
T h e  I n v e sti g at or  s h o ul d  r e vi e w  all  d o c u m e nt ati o n  ( e. g. , h o s pit al  pr o gr e s s  n ot e s,  l a b or at or y,  or  
di a g n o sti c r e p ort s) r el ati v e t o t h e e v e nt b ei n g r e p ort e d. T h e I n v e sti g at or will t h e n r e c or d all r el e v a nt 
i nf or m ati o n  r e g ar di n g  a n  A E/ S A E  o n  t h e  a p pr o pri at e  e C R F  p a g e.  It  i s  n ot  a c c e pt a bl e  f or  t h e  
I n v e sti g at or  t o  s e n d  p h ot o c o pi e s  of  t h e  p ati e nt s’  m e di c al  r e c or d s  i n  li e u  of  c o m pl eti o n  of  t h e  
a p pr o pri at e A E/ S A E p a g e s. H o w e v er, t h er e m a y b e i n st a n c e s w h e n c o pi e s of m e di c al r e c or d s will 
a s si st i n t h e e v al u ati o n a n d r e p orti n g of a n A E/ S A E. I n t hi s i n st a n c e, all p ati e nt i d e ntifi er s s h o ul d b e 
bli n d e d o n t h e c o pi e s of t h e m e di c al r e c or d s pri or t o s u b mi s si o n.  
T h e I n v e sti g at or will att e m pt t o e st a bli s h a di a g n o si s of t h e e v e nt b a s e d o n si g n s, s y m pt o m s, a n d/ or 
ot h er cli ni c al i nf or m ati o n. I n s u c h c a s e s, t h e di a g n o si s s h o ul d b e d o c u m e nt e d a s t h e A E/ S A E a n d 
n ot t h e i n di vi d u al si g n s a n d s y m pt o m s.  
I nf or m ati o n t o b e r e p ort e d i n cl u d e s t h e n at ur e, t h e  d at es of o n s et a n d r e s ol uti o n of t h e A E/ S A E , 
s e v erit y, d ur ati o n, c a u s alit y, a n d o ut c o m e of t h e e v e nt. E v e n if t h e A E i s a s s e s s e d b y t h e I n v e sti g at or 
a s  n ot  r e a s o n a bl y  attri b ut a bl e  t o  st u d y  pr o d u ct,  it s  o c c urr e n c e  m u st  b e  r e c or d e d i n  t h e  s o ur c e  
d o c u m e nt s a n d r e p ort e d o n t h e C R F.  


 
 
 
P a g e 7 9  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
 
I n v e sti g at or s o bt ai n, a s s e s s,  a n d r e c or d t h e f oll o wi n g i nf or m ati o n a b o ut A E s/ S A E s:  
•  
P ati e nt  
•   
Dat e  of o n s et  
•  
D at e r e s ol v e d  
•  
D e s cri pti o n of e v e nt  
•  
D ur ati o n  
•  
Fr e q u e n c y  
•  
I nt e n sit y ( S e v erit y) 
•  
S eri o u s n e s s  
•  
A cti o n t a k e n  
•  
O ut c o m e of t h e e v e nt a n d a n y s e q u el a e  
•  
R el ati o n s hi p t o t e st pr o d u ct  
 
1 7. 7. 1  S e v erit y of A d v er s e E v e nt  
S e v erit y r ef er s t o t h e e xt e nt t o w hi c h a n A E aff e ct s t h e p ati e nt’ s d ail y a cti viti e s. S e v erit y will b e 
c at e g ori z e d a c c or di n g t o t h e f oll o wi n g crit eri a:  
•  
Mil d ( Gr a d e 1):  Mil d; a s y m pt o m ati c or mil d s y m pt o m s; cli ni c al or di a g n o sti c o b s er v ati o n s 
o nl y; i nt er v e nti o n n ot i n di c at e d.  
•  
M o d er at e ( Gr a d e 2):  M o d er at e; mi ni m al, l o c al or n o ni n v a si v e i nt er v e nti o n i n di c at e d; li miti n g 
a g e -a p pr o pri at e i n str u m e nt al a cti viti e s of d ail y li vi n g ( A D L).  
•  
S e v er e ( Gr a d e 3):  S e v er e or m e di c all y si g nifi c a nt b ut n ot i m m e di at el y lif e -t hr e at e ni n g; 
h o s pit ali z ati o n or pr ol o n g ati o n of h o s pit ali z ati o n i n di c at e d; di s a bli n g; li miti n g s elf -c ar e A D L.  
•  
P ot e nti all y Lif e T hr e at e ni n g ( Gr a d e 4):  Lif e -t hr e at e ni n g c o n s e q u e n c e s; ur g e nt i nt er v e nti o n 
i n di c at e d.  
•  
F at al ( Gr a d e 5):  D e at h r el at e d t o A E.  
 
F or A E s i n cl u d e d i n t h e N ati o n al C a n c er I n stit ut e ( N CI) C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e 
E v e nt s
 ( C T C A E)
 S e v erit y 
Gr a di n g
 S c al e
 ( v 4. 0 3,
 A p p e n di x
 1 1),
 
htt p:// e v s. n ci. 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 ui c k R ef er e n c e 5 x 7. p df ,  
i n cl u di n g 
l a b or at or y a b n or m aliti e s r e p ort e d a s A E s, t h e I n v e sti g at or s h o ul d b a s e s e v erit y a s s e s s m e nt s o n t h e 
s e v erit y gr a di n g s c al e.  
F or e v e nt s n ot li st e d i n t h e C T C A E , t h e I n v e sti g at or will u s e m e di c al j u d g m e nt f or a s si g n m e nt of 
s e v erit y.  
 
 


 
 
 
P a g e 8 0  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
1 7. 7. 2  C a u s alit y of A d v er s e E v e nt ( A E) 
T h e I n v e sti g at or m u st m a k e a c a u s alit y a s s e s s m e nt f or all A E s a n d m u st d e ci d e w h et h er t h er e i s a 
r e a s o n a bl e p o s si bilit y t h at t h e A E m a y h a v e b e e n c a u s e d b y t h e I M P. If t h er e i s a n y v ali d r e a s o n f or 
s u s p e cti n g t h at t h er e i s a c a u s al r el ati o n s hi p b et w e e n t h e A E a n d t h e I M P, t h e A E s h o ul d b e j u d g e d 
“ p o s si bl y r el at e d” t o st u d y m e di c ati o n. U nl e s s a n A E c a n b e e x cl u d e d fr o m c a u s alit y, it m u st b e 
j u d g e d  “ p o s si bl y  r el at e d”  ( p o s si bl e)  t o  st u d y  m e di c ati o n  r at h er  t h a n  n ot  r el at e d  ( n o n e)  t o  st u d y  
m e di c ati o n. S e e b el o w f or f urt h er e x pl a n ati o n.  
T h e I n v e sti g at or  will a s s e s s t h e p o s si bilit y of a li n k b et w e e n t h e st u d y pr o d u ct a n d a n A E o n t h e 
b a si s of t h e f oll o wi n g crit eri a:  
•  
E xi st e n c e of a t e m p or al li n k b et w e e n t h e e v e nt a n d a d mi ni str ati o n of t h e st u d y m e di c ati o n . 
•  
P arti al or c o m pl et e di s a p p e ar a n c e of t h e A E w h e n t h e dr u g i s f ull y st o p p e d or d e cr e a s e d 
i n d o s e ( p o siti v e d e c h all e n g e) 
•  
R e c urr e n c e  of  t h e  a d v er s e  e v e nt  u p o n  r ei ntr o d u cti o n  of  t h e  st u d y  pr o d u ct  ( p o siti v e 
r e c h all e n g e).  F or  a  p o siti v e  r e c h all e n g e  t o  o c c ur,  t h e  A E  h a d  t o  h a v e  pr e vi o u sl y  
di s a p p e ar e d aft er d e c h all e n g e i n or d er f or it t o r e st art.  
•  
Si mil ar r e s ult s aft er pr e vi o u s tr e at m e nt wit h t h e st u d y pr o d u ct  
•  
E v e nt  i s  n ot  e x pl ai n e d  b y  a n y  ot h er  c o n diti o n,  m e a s ur e  or  e n vir o n m e nt al  f a ct or   ( n o 
alt er n ati v e eti ol o g y f or t h e e v e nt i s pr e s e nt) . 
 
1 7. 7. 3  A d v er s e E v e nt O ut c o m e s  
If t h e s a m e A E o c c ur s s e v er al ti m e s i n t h e s a m e s u bj e ct, t h e A E i n q u e sti o n m u st b e d o c u m e nt e d 
a n d a s s e s s e d a s a n e w o n e at e a c h ti m e u nl e s s t h e e v e nt i s c o n si d er e d t o b e a c o nti n u ati o n of t h e 
pr e vi o u sl y r e p ort e d e v e nt r at h er t h a n r e o c c urr e n c e of t h e e v e nt.      
O ut c o m e of t h e A E will b e r e c or d e d a s f oll o w s:  
•  
N ot  r e c o v er e d/ n ot  r e s ol v e d/ o n g oi n g  - t h e  e v e nt  h a s  n ot  i m pr o v e d  or  s u bj e ct  h a s  n ot  
r e c u p er at e d. N o A E st o p d at e s h o ul d b e r e c or d e d .  
•  
R e c o v er e d/ R e s ol v e d - t h e e v e nt h a s i m pr o v e d or s u bj e ct h a s r e c u p er at e d. T h e s u bj e ct 
r e c o v er e d fr o m t h e A E. R e c or d t h e A E st o p d at e. 
•  
R e c o v eri n g/r e s ol vi n g  - t h e e v e nt i s c o nti n ui n g  a n d t h e s u bj e ct i s i n t h e pr o c e s s of r e c o v er y.  
•  
R e s ol v e d wit h s e q u el a e - t h e s u bj e ct r e c u p er at e d, b ut r et ai n e d p at h ol o gi c al c o n diti o n s 
r e s ulti n g fr o m t h e pri or di s e a s e or i nj ur y a n d a c o m pl et e r e c o v er y i s n ot e x p e ct e d . A s e q u el a e 
i s a c o n s e q u e n c e of a pr e vi o u s di s e a s e or i nj ur y. R e c or d t h e A E st o p d at e. T h e A E st o p d at e 
will r e pr e s e nt t h e d at e t h e A E st a bili z e d wit h n o c h a n g e i n e v e nt o ut c o m e a nti ci p at e d.  
•  
U n k n o w n/ L o st t o f oll o w -u p –  r ef er s t o t h e i n a bilit y t o a c c e s s t h e s u bj e ct or t h e s u bj e ct’ s 
r e c or d s t o d et er mi n e t h e o ut c o m e (i. e., s u bj e ct wit h dr a w s c o n s e nt or i s l o st t o f oll o w-u p). N o 
A E st o p d at e s h o ul d b e r e c or d e d.  
•  
F at al - T h e A E dir e ctl y c a u s e d d e at h. R e c or d t h e d at e of d e at h a s t h e A E st o p d at e. Pl e a s e 
n ot e t h at d e at h i s a n o ut c o m e a n d n ot a n e v e nt a n d s h o ul d b e r e c or d e d a s s u c h.  
 
 
 


 
 
 
P a g e 8 1  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
1 7. 7. 4  A cti o n T a k e n wit h t h e St u d y Dr u g  
T h e f oll o wi n g a cti o n s t a k e n a s a r e s ult of a n A E s h o ul d b e r e c or d e d:  
•  
D o s e n ot c h a n g e d  
•  
D o s e i n cr e a s e d  
•  
D o s e r e d u c e d  
•  
Dr u g int err u pt e d  
•  
Dr u g wit h dr a w n  
•  
U n k n o w n  
•  
N ot a p pli c a bl e  
 
1 7. 7. 5  F oll o w -u p of A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s  
Aft er t h e i niti al A E/ S A E r e p ort, t h e I n v e sti g at or i s r e q uir e d t o pr o a cti v el y f oll o w e a c h p ati e nt a n d 
pr o vi d e f urt h er i nf or m ati o n o n t h e p ati e nt’ s c o n diti o n. All A E s a n d S A E s d o c u m e nt e d at a pr e vi o u s 
vi sit/ c o nt a ct t h at ar e d e si g n at e d a s o n -g oi n g u ntil r e s ol v e d a n d s h o ul d b e r e vi e w e d at s u b s e q u e nt 
vi sit s/ c o nt a ct s.  
A E s a n d S A E s will b e f oll o w e d u ntil r e s ol uti o n, u ntil t h e c o n diti o n st a bili z e s , or u ntil t h e p ati e nt i s l o st 
t o f oll o w-u p. O n c e r e s ol v e d, t h e a p pr o pri at e A E/ S A E e C R F p a g e( s) will b e u p d at e d. If a p ati e nt di e s 
d uri n g p arti ci p ati o n i n t h e st u d y, t h e I n v e sti g at or will pr o vi d e a c o p y of a n y p o st -m ort e m fi n di n g s, 
i n cl u di n g hi st o p at h ol o g y. 
N e w or u p d at e d i nf or m ati o n will b e r e c or d e d o n t h e ori gi n all y c o m pl et e d S A E e C R F.   
 
1 7. 7. 6   P o st-st u d y A d v er s e E v e nt s or S eri o u s A d v er s e E v e nt s  
I n v e sti g at or s ar e n ot o bli g at e d t o a cti v el y s e e k A E s or S A E s i n f or m er st u d y p arti ci p a nt s. H o w e v er, 
t h e I n v e sti g at or s h o ul d pr o m ptl y n otif y t h e S p o n s or, or d e si g n e e, if t h e I n v e sti g at or l e ar n s of a n y 
S A E or d e at h of a st u d y p ati e nt wit hi n 3 0  d a y s aft er a p ati e nt h a s b e e n di s c o nti n u e d fr o m t h e st u d y, 
a n d s u c h e v e nt( s) i s ( ar e) r e a s o n a bl y r el at e d t o st u d y p arti ci p ati o n; t h e s e s h o ul d b e r e p ort e d wit hi n 
2 4 h o ur s.  
I n v e sti g at or s s h o ul d pr o m ptl y n otif y t h e S p o n s or, or d e si g n e e, if t h e y b e c o m e a w ar e of a f or m er 
st u d y p arti ci p a nt w h o i s o n e of t h e p ar e nt s of a s u b s e q u e ntl y c o n c ei v e d c hil d wit h a c o n g e nit al 
a n o m al y ( s e e S e cti o n 1 7. 4  o n Pr e g n a n c y I nf or m ati o n).  
 
1 7. 8  R e p orti n g R e q uir e m e nt s f or S A E s   
 
1 7. 8. 1  R e p orti n g of All S A E s a n d A E s R e s ulti n g i n Wit h dr a w al fr o m t h e St u d y  
T h e I n v e sti g at or will pr o m ptl y r e p ort all S A E s t o t h e S p o n s or or A gilit y Cli ni c al ( d e si g n e e) wit hi n t h e 
ti m efr a m e s s p e cifi e d b el o w.  
T h e I n v e sti g at or will c o m pl y wit h t h e a p pli c a bl e l o c al r e g ul at or y r e q uir e m e nt s r el at e d t o r e p orti n g of 
S A E s t o hi s or h er I n stit uti o n al R e vi e w B o ar d (I R B)/I n d e p e n d e nt Et hi c s C o m mitt e e (I E C).  
All A E s t h at m e et a n y s eri o u s n e s s crit eri a, r e g ar dl e s s of e x p e ct e d n e s s or c a u s alit y, m u st b e r e p ort e d 
wit hi n 2 4 h o ur s of t h e I n v e sti g at or or a n y ot h er sit e p er s o n n el’ s k n o wl e d g e of t h e e v e nt ( s e e S e cti o n 
1 7 . 9). 
 


 
 
 
P a g e 8 2  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
T h e c o m pl eti o n of t h e S A E e C R F i s t h e pri m ar y m et h o d f or r e p orti n g S A E s t o t h e d e si g n e e. If t h e 
E D C i s u n a v ail a bl e, a p a p er S A E R e p ort F or m i s pr o vi d e d a s b a c k -u p a n d s h o ul d b e c o m pl et e d a n d 
e m ail e d or f a x e d t o S af et y at A gilit y Cli ni c al wit hi n 2 4  h o ur s of t h e I n v e sti g at or or a n y sit e p er s o n n el’ s 
k n o wl e d g e of a n S A E. T h e S A E m u st b e e nt er e d i nt o t h e E D C w h e n a c c e s si bl e. T h e e S A E s h o ul d 
b e u p d at e d wit hi n 2 4  h o ur s of r e c ei pt of n e w i nf or m ati o n r e g ar di n g t h e e v e nt.  
  
I n a d diti o n, a n y A E r e s ulti n g i n p er m a n e nt wit h dr a w al fr o m t h e st u d y f or a p ati e nt, e v e n if n ot s eri o u s, 
s h o ul d b e r e p ort e d pr o m ptl y ( wit hi n 2 4 h o ur s) t o t h e S p o n s or or A gilit y Cli ni c al . 
 
D o n ot d el a y r e p orti n g S A E s. I n v e sti g at or s s h o ul d n ot w ait t o r e c ei v e a d diti o n al i nf or m ati o n t o f ull y 
d o c u m e nt t h e e v e nt b ef or e n otif yi n g S af et y at A gilit y Cli ni c al of t h e S A E vi a c o m pl eti o n of t h e e S A E 
p a g e i n t h e E D C ( or s e n di n g a n S A E R e p ort F or m). T h e S A E r e p ort s h o ul d pr o vi d e t h e k n o w n 
i nf or m ati o n  at  t h e  ti m e  of  a w ar e n e s s  t h at  a n  S A E  h a s  o c c urr e d.  A  f oll o w-u p  r e p ort  s h o ul d  b e  
c o m pl et e d w h e n a d diti o n al d et ail s ar e k n o w n b y u p d ati n g t h e S A E e C R F.  
 
1 7. 8. 2  U n e x p e ct e d or E x p e ct e d S A E  
A n u n e x p e ct e d A E i s a n e v e nt, t h e n at ur e  or  s e v erit y of w hi c h i s  n ot c o n si st e nt wit h t h e a p pli c a bl e 
pr o d u ct i nf or m ati o n ( i. e., In v e sti g at or' s B r o c h ur e (I B) if a v aila bl e) or t h e a s s e s s m e nt of t h e m e di c al 
s af et y offi c er.  
T h e S p o n s or or d e si g n e e will n otif y t h e C o m p et e nt H e alt h A ut h orit y ( F D A, H e alt h C a n a d a, Bf Ar M) 
b y t el e p h o n e or f a x tr a n s mi s si o n of a n y u n e x p e ct e d, f at al, or lif e -t hr e at e ni n g e x p eri e n c e ( e x p e dit e d 
r e p ort) a s s o ci at e d wit h t h e u s e of t h e I P a s s o o n a s p o s si bl e b ut n o l at er t h a n 7 c al e n d ar d a y s aft er 
t h e i niti al r e c ei pt of t h e i nf or m ati o n. I niti al n otifi c ati o n will b e f oll o w e d b y a writt e n r e p ort wit hi n 1 5 
c al e n d ar d a y s. F or s eri o u s u n e x p e ct e d S U S A R s , t h e S p o n s or or d e si g n e e will n otif y t h e C o m p et e nt 
H e alt h  A ut h orit y  i n  t h e  p arti ci p ati n g  c o u ntri e s,  a s  s o o n  a s  p o s si bl e,  b ut  n o  l at er  t h a n  1 5  d a y s,  
foll o wi n g t h e i niti al r e c ei pt of i nf or m ati o n.  
C o nt a ct i nf or m ati o n f or S af et y at A gilit y Cli ni c al f or n otifi c ati o n  of S A E s i s pr o vi d e d i n S e cti o n 1 7 . 9.  
N ot e t o e m er g e n c y u n bli n di n g:  
I n  t h e  e v e nt  of  a  m e di c al  e m er g e n c y  w hi c h  m a y  w arr a nt  u n bli n di n g  of  a  s u bj e ct' s  tr e at m e nt  
a s si g n m e nt, t h e PI will c o nt a ct t h e M e di c al M o nit or at A B 2 Bi o a n d t h e C R O t o di s c u s s t h e r e q u e st. 
T h e M e di c al M o nit or will r e vi e w t h e r e q u e st a n d d et er mi n e t h e d e ci si o n f or u n bli n di n g. If a p pr o v al 
h a s b e e n gr a nt e d, a s u bj e ct’ s tr e at m e nt a s si g n m e nt i nf or m ati o n m a y b e o bt ai n e d b y e m aili n g a 
c o m pl et e d I n di vi d u al S u bj e ct U n bli n di n g A ut h ori z ati o n F or m (l o c at e d i n t h e I n v e sti g at or Sit e Fil e 
bi n d er) t o: 
. T h e M e di c al M o nit or will di s c u s s t h e 
u n bli n di n g wit h t h e L e a d St ati sti ci a n a n d t h e o ut c o m e of t h e r e q u e st i s c o m pl et e d o n t h e f or m a n d 
r et ur n e d t o t h e sit e.  I n a n eff ort t o mi ni mi z e u n bli n di n g of a d diti o n al sit e st u d y st aff, t h e c o m pl et e d 
S u bj e ct U n bli n di n g A ut h ori z ati o n F or m a n d all ot h er d o c u m e nt ati o n a s s o ci at e d wit h t h e s u bj e ct’ s 
u n bli n di n g m u st b e m ai nt ai n e d i n a s e c ur e l o c ati o n wit hi n t h e P h ar m a c y M a n u al,  w h er e a c c e s s t o 
s u c h i nf or m ati o n i s li mit e d.    
I n a d diti o n, m e a s ur e s ar e i n pl a c e a s i n a Fir st-i n-H u m a n s et u p, i n c a s e of e m er g e n ci e s . ( S e e 
S e cti o n 1 7 . 1 0) 
 
 
 


 
 
 
P a g e 8 3  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
1 7. 9  R e p orti n g a n d D o c u m e nt ati o n  
S eri o u s a d v er s e e v e nt  
S af et y at A gilit y Cli ni c al m u st b e n otifi e d of all s eri o u s or u n e x p e ct e d A E s wit hi n 2 4  h o ur s b y e nt eri n g 
all k n o w n d at a a n d s a vi n g t h e S A E s e cti o n of t h e e C R F i n t h e E D C. I n t h e e v e nt t h e E D C i s n ot 
a v ail a bl e, a p a p er b a c k -u p S A E R e p ort F or m s h o ul d b e c o m pl et e d a n d e m ail e d or f a x e d. O n c e t h e 
E D C i s a c c e s si bl e, t h e S A E m u st b e e nt er e d i nt o t h e s y st e m .   
N otifi c ati o n d o e s n ot d e p e n d o n w h et h er t h er e i s a r el ati o n s hi p t o  st u d y pr o d u ct  or n ot.  
All S A E s m u st al s o b e d o c u m e nt e d o n t h e a p pr o pri at e p a g e s of t h e e C R F ( A E).  
T h e  S A E R e p ort F or m  c a n b e e m ail e d or f a x e d t o: 
  
 
S A E F a x N u m b er: 
 
N o n -s eri o u s a d v er s e e v e nt  
All A E s m u st b e d o c u m e nt e d o n t h e a p pr o pri at e p a g e s of t h e e C R F  ( A E). 
1 7. 1 0  P ati e nt E m er g e n c y C o nt a ct C ar d  
T h e  P ati e nt  E m er g e n c y  C o nt a ct  C ar d  ( s e e  e x a m pl e  i n  A p p e n di x   5)  will  b e  c o m pl et e d  b y  t h e  
I n v e sti g at or f or e a c h p ati e nt r e c ei vi n g t a d e ki ni g alf a st u d y t h er a p y pri or t o t h e st art of st u d y tr e at m e nt. 
T h e P ati e nt E m er g e n c y C o nt a ct C ar d will b e gi v e n t o e a c h p ati e nt  r e c ei vi n g t a d e ki ni g alf a st u d y 
tr e at m e nt a n d/ or  t o  t h e  p ati e nt’ s a ut h ori z e d  r e pr e s e nt ati v e.  T h e  p ati e nt  a n d/ or  t h e  a ut h ori z e d  
r e pr e s e nt ati v e m u st r e a d t h e P ati e nt E m er g e n c y C o nt a ct C ar d pri or t o st arti n g t a d e ki ni g alf a st u d y 
tr e at m e nt. 
 
1 7. 1 1  N otifi c ati o n  
T h e S p o n s or i s r e s p o n si bl e f or t h e o n g oi n g s af et y e v al u at i o n of t h e I M P. 
T h e S p o n s or s h o ul d pr o m ptl y n otif y all c o n c er n e d i n v e sti g at or( s)/i n st ituti o n( s) a n d t h e r e g ul at or y 
a ut h orit y( i e s) of fi n di n g s t h at c o ul d aff e ct a d v er s el y t h e s af et y of p ati e nt s, i m p a ct t h e c o n d u ct of t h e 
st u d y , or alt er t h e I R B/I E C' s a p pr o v al/f a v or a bl e o pi n i o n t o c o nti n u e t h e st u d y. 
1 7. 1 2  S af et y R e p orti n g  
T h e  s p o n s or  s h o ul d  e x p e dit e  t h e  r e p orti n g  t o  all  c o n c er n e d  i n v e sti g at or( s)/i n stit uti o n( s),  t o  t h e  
I R B( S)/I E C( s), w h er e r e q uir e d, a n d t o t h e r e g ul at or y a ut h orit y(i e s) of all a d v er s e dr u g r e a cti o n s 
( A D R s) t h at ar e b ot h s eri o u s a n d u n e x p e ct e d ( s e e S e cti o n 1 7 . 8. 2). S u c h e x p e dit e d r e p ort s s h o ul d 
c o m pl y wit h t h e a p pli c a bl e r e g ul at or y r e q uir e m e nt( s) a n d wit h t h e I C H G ui d eli n e f or Cli ni c al S af et y 
D at a M a n a g e m e nt: D efi niti o n s a n d St a n d ar d s f or E x p e dit e d R e p orti n g.  
 
 
 


 
 
 
P a g e 8 4  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
1 8  L E G A L A N D E T HI C A L P R E R E Q UI SI T E S  
1 8. 1  L e g al R e q uir e m e nt s  
T hi s st u d y will b e c o n d u ct e d i n a c c or d a n c e wit h I C H  g ui d eli n e o n G o o d Cli ni c al Pr a cti c e ( G C P), t h e 
G C P’ s a p pli c a bl e t o a n y r e gi o n w h er e t h e st u d y i s c o n d u ct e d a n d i n a c c or d a n c e wit h t h e et hi c al 
pri n ci pl e s s et f ort h i n t h e D e cl ar ati o n of H el si n ki . 
1 8. 2  Et hi c al A s p e ct s  
1 8. 2. 1  Pr ot e cti o n of t h e P ati e nt ' s C o nfi d e nti alit y  
I d e ntifi c ati o n of p ati e nt s i n C R F s s h all b e b y i niti al s, s cr e e ni n g n u m b er s, or r a n d o mi z ati o n n u m b er s 
o nl y.  If r e q uir e d b y l o c al a g e n ci e s, i niti al s will b e c o d e d p er l o c al r e g ul ati o n s ( e. g., A A A, B B B).  
A d diti o n all y, if r e q uir e d, t h e p ati e nt' s f ull n a m e m a y b e m a d e k n o w n t o a n a ut h ori z e d r e g ul at or y 
a g e n c y or ot h er a ut h ori z e d offi ci al.  
1 8. 2. 2  I nf or m e d C o n s e n t 
C hil d a s s e nt a n d/ or inf or m e d c o n s e nt will b e o bt ai n e d fr o m t h e p ot e nti al p ati e nt  pri or t o a n y st u d y 
r el at e d a cti viti e s a n d i n a c c or d a n c e wit h all a p pli c a bl e r e g ul at or y r e q uir e m e nt s. 
T h e I n v e sti g at or a n d/ or hi s/ h er d e si g n e e will i nf or m t h e p ati e nt  i n a d diti o n t o t h e writt e n i nf or m e d 
c o n s e nt a b o ut all a s p e ct s of t h e p ati e nt ’ s st u d y p arti ci p ati o n.  T h e writt e n I nf or m e d C o n s e nt m u st b e 
a p pr o v e d b y t h e I n stit uti o n al R e vi e w B o ar d (I R B) or I n d e p e n d e nt Et hi c s c o m mitt e e (I E C) a n d/ or  b y 
t h e C o m p et e nt H e alt h A ut h orit y ( a s a p pli c a bl e) .  A n y a m e n d m e nt s t o t h e s e d o c u m e nt s m u st b e 
a p pr o v e d b y t h e I R B/I E C a n d / or C o m p et e nt H e alt h A ut h orit y ( a s a p pli c a bl e) . 
T h e  I n v e sti g at or  a n d/ or  hi s/ h er  d e si g n e e  a n d  t h e  p ati e nt  a n d / or  t h e  p ati e nt ’ s  l e g al  a ut h ori ze d 
r e pr e s e nt ati v e ( g u ar di a n, n e xt of ki n, ot h er a ut h ori z e d i n di vi d u al) m u st si g n a n d d at e t h e Writt e n 
I nf or m e d C o n s e nt pri or t o a n y st u d y r el at e d a cti viti e s ar e p erf or m e d.  T h e p ati e nt  or t h e a ut h ori z e d 
r e pr e s e nt ati v e m u st c o m pl et e t h e pri nt e d n a m e a n d e nt er t h e d at e of si g n at ur e t h e m s el v e s.  If a n 
a ut h ori z e d r e pr e s e nt ati v e si g n s t h e I C F, all eff ort s s h o ul d b e m a d e t o o bt ai n a n a d diti o n al si g n at ur e 
fr o m t h e p ati e nt  hi m s elf/ h er s elf. 
I n c a s e of t h e c o n d u ct of t el e m e di ci n e vi sit s d u e t o t h e C O VI D-1 9 p a n d e mi c  or l o n g di st a n c e fr o m 
t h e p ati e nt` s h o m e t o t h e st u d y sit e, p ati e nt s a n d/ or p ar e nt s ( or l e g al r e pr e s e nt ati v e, if a p pli c a bl e) 
will si g n a r e s p e cti v e  a s s e nt/i nf or m e d c o n s e nt pri or t o t h e c o n d u ct of s u c h vi sit.  
T h e I C F will b e si g n e d i n d o u bl e a n d  t h e p ati e nt a n d/ or t h e a ut h ori z e d r e pr e s e nt ati v e o bt ai n o n e 
ori gi n al of t h e si g n e d w ritt e n I C F.  T h e s e c o n d ori gi n al i s fil e d wit h t h e st u d y d o c u m e nt s at t h e 
i n v e sti g ati o n al sit e. 
T h e d e ci si o n t o p arti ci p at e i n t h e st u d y i s e ntir el y v ol u nt ar y b y t h e p ati e nt  a n d/ or b y t h e a ut h ori z e d 
r e pr e s e nt ati v e.  T h e I n v e sti g at or a n d/ or hi s/ h er d e si g n e e m u st e m p h a si z e t o t h e p ati e nt a n d/ or t h e 
a ut h ori z e d  r e pr e s e nt ati v e  t h at  t h e  c o n s e nt  t o  p arti ci p at e  c a n  b e  wit h dr a w n  at  a n y  ti m e  wit h o ut  
p e n alt y or l o s s of b e n efit s t o w hi c h t h e p ati e nt  i s ot h er wi s e e ntitl e d. 
1 8. 2. 3  I n stit uti o n al R e vi e w B o ar d/Et hi c s C o m mitt e e A p pr o v al  
T h e st u d y pr ot o c ol will b e s u b mitt e d t o t h e I R B/I E C b y t h e I n v e sti g at or f or e x a mi n ati o n a n d writt e n 
a p pr o v al. T h e S p o n s or will e n s ur e t h at t hi s pr ot o c ol a n d all a p pr o pri at e d o c u m e nt ati o n a c c or di n g t o 
t h e a p pli c a bl e r e g ul ati o n s will b e r e vi e w e d a n d a p pr o v e d b y t h e I R B/I E C r e s p o n si bl e f or e a c h sit e. 
C o m m e n c e m e nt of t h e cli ni c al st u d y i s n ot p er mitt e d wit h o ut writt e n a p pr o v al of t h e I R B/I E C a n d t h e 
c o m p et e nt H e alt h A ut h oriti e s  ( F D A, H e alt h C a n a d a, Bf Ar M). 
T h e  I R B/I E C  m u st  b e  n otifi e d  of  all  s u b s e q u e nt  a d diti o n s  or  c h a n g e s  i n  t h e  st u d y  pr ot o c ol.  
N otifi c ati o n of t h e I R B/I E C i s al s o r e q uir e d i n t h e e v e nt of a S A E d uri n g t h e cli ni c al  st u d y . 
1 8. 2. 4  D e cl ar ati o n of H el si n ki  
T hi s st u d y will b e c o n d u ct e d a c c or di n g t o t h e pri n ci pl e s a n d r ul e s l ai d d o w n i n t h e D e cl ar ati o n of 
H el si n ki ( A p p e n di x  4) a n d it s s u b s e q u e nt a m e n d m e nt s. 


 
 
 
P a g e 8 5  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
1 9   QU A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  
1 9. 1  M o nit ori n g  
R e g ul ar m o nit ori n g vi sit s b y r e pr e s e nt ati v e s of t h e s p o n s or will b e m a d e d uri n g t h e st u d y.  
M o nit ori n g will b e gi n wit h a n i niti ati o n vi sit pri or t o st u d y c o m m e n c e m e nt t o cl arif y all a s p e ct s of t h e 
pr ot o c ol a n d d o c u m e nt ati o n. T h e p ur p o s e of l at er vi sit s d uri n g t h e i m pl e m e nt ati o n p eri o d will b e t o 
e v al u at e  st u d y  pr o gr e s s  a n d  a d h er e n c e  t o  pr ot o c ol.  T h e  m o nit or  will  c h e c k  t h e e C R F  f or 
c o m pl et e n e s s, cl arit y a n d c o n si st e n c y wit h t h e i nf or m ati o n i n t h e p ati e nt’ s  fil e ( s o ur c e d at a c h e c ki n g). 
D uri n g  t h e  C O VI D -1 9  p a n d e mi c,  w h e n  a c c e s s  t o  t h e  st u d y  sit e  l o c ati o n s  m a y  b e  r e stri ct e d,  
t el e p h o n e/r e m ot e m o nit ori n g m a y b e i m pl e m e nt e d e n s uri n g d at a q u alit y a n d i nt e grit y i n c o m pli a n c e 
wit h I C H / G C P g ui d eli n e s. D et ail s ar e s p e cifi e d i n a cli ni c al m o nit ori n g pl a n, wit h r e s p e ct t o d at a 
pr ot e cti o n  r e g ul ati o n s  p er  sit e/ c o u ntr y , a s  w ell  a s  t h e  i n di vi d u al  sit e  p oli ci e s  r e g ar di n g  r e m ot e  
m o nit ori n g.  
At t h e e n d of t h e st u d y, t h e m o nit or will att e n d a st u d y cl o s ur e vi sit at e a c h sit e t o e n s ur e t h at all 
d o c u m e nt ati o n i s c o m pl et e. I n all c a s e s, it i s t h e r e s p o n si bilit y of t h e C P M / m o nit or t o m ai nt ai n 
p ati e nt c o nfi d e nti alit y . 
1 9. 2  S o ur c e D o c u m e nt s  
A 1 0 0 % S D V will b e p erf or m e d.  
1 9. 3  Q u alit y C o ntr ol  
1 9. 3. 1  Q u alit y C o ntr ol of E s s e nti al D o c u m e nt s  
Q u alit y c o ntr ol of e s s e nti al d o c u m e nt s will b e e n s ur e d b y t h e C P M . 
1 9. 3. 2  C o -m o nit ori n g   
C o -m o nit ori n g  vi sit s  will  b e  p erf or m e d  b y  t h e  C P M  or  d e si g n e e  wit h  t h e  m o nit or  a s  d e e m e d 
n e c e s s ar y.  
1 9. 4  A u dit s a n d In s p e cti o n s  
I n a d diti o n t o t h e r o uti n e m o nit ori n g pr o c e d ur e s, A B 2 Bi o m a y pr o c e e d t o a s p e ci al a u dit. P eri o di c all y 
d uri n g t h e st u d y, a r e pr e s e nt ati v e of A B 2 Bi o m a y c o n d u ct a u dit s of cli ni c al r e s e ar c h a cti viti e s t o 
e v al u at e c o m pli a n c e wit h G C P g ui d eli n e s a n d r e g ul ati o n s.  
T h e I n v e sti g at or( s) i s r e q uir e d t o p er mit dir e ct a c c e s s t o t h e f a ciliti e s w h er e t h e st u d y t o o k pl a c e, 
s o ur c e d o c u m e nt s, C R F a n d a p pli c a bl e s u p p orti n g r e c or d s of p ati e nt p arti ci p ati o n f or a u dit s a n d 
i n s p e cti o n  b y  I R B/I E C,  r e g ul at or y  a ut h oriti e s  a n d  c o m p a n y  a ut h ori z e d  r e pr e s e nt ati v e s.  T h e  
I n v e sti g at or( s) s h o ul d m a k e e v er y eff ort t o b e a v ail a bl e f or t h e a u dit a n d/ or i n s p e cti o n s. If t h e 
I n v e sti g at or( s)  i s  c o nt a ct e d  b y  a n y  r e g ul at or y  a ut h orit y  r e g ar di n g  a n  i n s p e cti o n,  h e/ s h e  s h o ul d  
c o nt a ct A B 2 Bi o i m m e di at el y.  
1 9. 5  R e s p o n si biliti e s of In v e sti g at or  
T h e I n v e sti g at or s ar e r e s p o n si bl e f or t h e f oll o wi n g:  
•  
O bt ai ni n g t h e writt e n a n d d at e d a p pr o v al of t h e l o c al et hi c s c o m mitt e e ( a n d ot h er l o c al 
r e g ul at or y a g e n c y, if a n y) pri or t o t h e b e gi n ni n g of t h e st u d y. 
•  
S el e cti o n of p arti ci p a nt s i n a c c or d a n c e wit h t h e i n cl u si o n a n d e x cl u si o n crit eri a; 
o bt ai ni n g t h e writt e n i nf or m e d c o n s e nt of t h e p ati e nt or l e g al g u ar di a n.  
•  
M ai nt ai n c o nfi d e nti alit y of p ati e nt s a n d p ot e nti al p ati e nt s i n a c c or d a n c e wit h t h e 
D e cl ar ati o n of H el si n ki.  


 
 
 
P a g e 8 6  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
•  
A d h er e n c e t o t h e st u d y pr ot o c ol a n d t h e s pirit of G o o d Cli ni c al Pr a cti c e. If m o difi c ati o n 
b e c o m e s n e c e s s ar y, t h e r ati o n al e will b e pr o vi d e d i n a pr ot o c ol a m e n d m e nt si g n e d b y 
t h e I n v e sti g at or a n d S p o n s or f or s u b mi s si o n t o t h e et hi c s c o m mitt e e. 
•  
A c c ur at e, c o m pl et e a n d ti m eli n e s s d at a r e p ort e d t o t h e S p o n s or ( e C R F).  
•  
D uri n g t h e c o ur s e of t h e st u d y, pr o vi d e p ati e nt s wit h a n y n e wl y a v ail a bl e i nf or m ati o n 
w hi c h m a y b e r el e v a nt t o t h e m.  
•  
I d e ntifi c ati o n of A E s wit h n otifi c ati o n t o S p o n s or, et hi c s c o m mitt e e a n d h e alt h 
a ut h oriti e s, a s a p pli c a bl e.  
•  
C o -o p er ati o n wit h m o nit ori n g vi sit s, a u dit s a n d r e g ul at or y i n s p e cti o n s. Pr o vi di n g dir e ct 
a c c e s s t o s o ur c e d at a a n d d o c u m e nt s.  
•  
I n v e sti g at or m a y s el e ct a s e c o n d c o nt a ct at t h eir st u d y c e nt er t o a s si st i n 
i m pl e m e nt ati o n of t h e st u d y. H o w e v er, i n all c a s e s t h e m ai n r e s p o n si bilit y wit h r e s p e ct 
t o all a s p e ct s of t hi s i m pl e m e nt ati o n r e st wit h t h e pri n ci p al a n d c o-I n v e sti g at or s. 
•  
Ar c hi vi n g of t h e I n v e sti g at or' s fil e (i n cl u di n g t h e ori gi n al si g n e d i nf or m e d c o n s e nt f or m s 
of all p ati e nt s) f or at l e a st 1 5 y e ar s aft er t h e e n d or t h e t er mi n ati o n of t h e st u d y.  
 
 


 
 
 
P a g e 8 7  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
2 0   ST U D Y E N D P R O C E D U R E S  
2 0. 1  Pr e m at ur e T er mi n ati o n of S t u d y 
P ati e nt  wit h dr a w al / P h y si ci a n di s c o nti n u ati o n:  
T h e p h y si ci a n s a n d t h e p ati e nt s ( or l e g al r e pr e s e nt ati v e) will h a v e t h e o pti o n t o 
di s c o nti n u e  t h e  tr e at m e nt  if  t h e y  f e el  t h at  p ur s ui n g  t h e  tr e at m e nt  i s  n ot  
a p pr o pri at e. 
T h e
 p h y si ci a n
 c a n
 d e ci d e
 a n yti m e
 t o
 st art
 r e s c u e
 
i m m u n o s u p pr e s si o n a n d t h er ef or e di s c o nti n u e t h e p ati e nt fr o m t h e st u d y*. 
* All k e y s af et y a n d effi c a c y o ut c o m e s will b e f oll o w e d u p. P ati e nt s will c o nti n u e t o c o m e t o t h e 
s c h e d ul e d vi sit s f or s af et y a n d effi c a c y a s s e s s m e nt s.  
N ot e: A p ati e nt e x p eri e n ci n g a p arti al or f ull di s e a s e r e a cti v ati o n  d uri n g t h e 1 6 w e e k s R W p h a s e 
a n d t h u s pr o c e e di n g t o t h e E n d of St u d y Vi sit will n ot b e c o n si d er e d a s h a vi n g e arl y  t er mi n at e d 
t h e st u d y.  
St u d y di s c o nti n u ati o n:  
St o p pi n g of t h e st u d y will b e stri ctl y d et er mi n e d f or s af et y c o n c er n s.  
At a n y ti m e,  t h e D S M B m a y r e c o m m e n d t o t h e S p o n s or t h e e arl y t er mi n ati o n of 
t h e st u d y aft er r e vi e wi n g st u d y s af et y d at a i n cl u di n g A E s, S A E s, a n d S U S A R s.  
At a n y ti m e, t h e S p o n s or m a y r e c o m m e n d t er mi n ati n g t h e st u d y . 
 
N O T E: T e m p or ar y St o p of T r e at m e nt 
T e m p or ar y  tr e at m e nt i nt err u pti o n s will b e all o w e d i n c a s e t h e p ati e nt s h o w s f e v er or a n y si g n of 
u n d er g oi n g a n i nf e cti o n pr o c e s s u nr el at e d t o t h e tr e at e d c o n diti o n. F or t h e i nj e cti o n s d o n e b y t h e 
h o m e  c ar e  n ur s e  ( H C N)  e v er y 2  d a y s,  t h e  H C N  s h o ul d  c o nt a ct  t h e  I n v e sti g at or f or  a d vic e  o n  
tr e at m e nt  c o nti n u ati o n  or  st o p pi n g.  I n  c a s e  of  a n y  d o u bt,  t h e  tr e at m e nt  m u st  b e  di s c o nti n u e d  
t e m p or aril y.  
I n c a s e of tr e at m e nt i nt erru pti o n s  ≥ 3 w e e k s t h e eff e ct of t h e i n v e sti g ati o n al dr u g i s l o st a n d t h e c a s e 
will b e c o n si d er e d a dr o p o ut.  
2 0. 2  T er mi n ati o n of S t u d y 
Aft er t h e c o m pl eti o n or t er mi n ati o n of t h e st u d y, t h e I n v e sti g at or will i nf or m t h e I R B or I E C of t h e e n d 
of t h e st u d y. A c ertifi c at e of st u d y cl o s ur e will b e e st a bli s h e d. E v er y s eri o u s or u n e x p e ct e d A E t h at 
mi g ht aff e ct t h e p ati e nt’ s s af et y m u st b e br o u g ht  t o t h e I R B’ s/I E C’ s att e nti o n, if r e q uir e d b y hi s/ h er 
I R B/I E C  r e g ul ati o n s. I n  a d diti o n,  e v er y  r e p ort  c o n c er ni n g  a n  A E  t h at  t h e  S p o n s or s e n d s  t o  t h e  
I n v e sti g at or m u st b e s e nt b y t h e l att er t o hi s/ h er I R B/I E C. 
All bi ol o gi c al s a m pl e s will b e d e str o y e d, a s w ell a s t h e st u d y pr o d u ct. C ertifi c at e s of d e str u cti o n will 
b e i s s u e d a n d fil e d i n t h e Tri al M a st er Fil e.  
2 0. 3  E n d of Tri al  
T h e e n d of t h e e ntir e tri al will b e d efi n e d a s t h e d at e of t h e fi n al cli ni c al d at a b a s e l o c k. T hi s  pr o vi d e s 
f or a si n gl e a n d c o n s er v ati v e d efi niti o n a cr o s s all tri al sit e s. 
 
 


 
 
 
P a g e 8 8  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
2 1  P U B LI C A TI O N S  
All m a n u s cri pt s, a b str a ct s or ot h er m o d e s of pr e s e nt ati o n ari si n g fr o m t h e r e s ult s of t h e st u d y m u st 
b e  r e vi e w e d  a n d  a p pr o v e d  i n  writi n g  b y  A B 2 Bi o,  i n  a d v a n c e  of  s u b mi s si o n.  T h e  Sp o n s or  h a s  
pr o pri et ar y ri g ht s t o all i nf or m ati o n g e n er at e d fr o m t hi s st u d y a n d r e s er v e s t h e ri g ht t o u s e it i n a n y 
m a n n er it d e e m s a p pr o pri at e, i n cl u di n g b ut n ot li mit e d t o r e g ul at or y s u b mi s si o n s, a n n u al r e p ort s, 
a n d ot h er s ci e ntifi c or b u si n e s s aff air s of  t h e c o m p a n y. T h e r e vi e w i s ai m e d at pr ot e cti n g A B 2 Bi o' s 
pr o pri et ar y i nf or m ati o n e xi sti n g eit h er at t h e d at e of t h e c o m m e n c e m e nt of t h e st u d y or g e n er at e d 
d uri n g t h e st u d y.  
2 2  C O N FI D E N TI A LI T Y  
D at a c oll e ct e d d uri n g t hi s st u d y m a y b e u s e d t o s u p p ort t h e d e v el o p m e nt, r e gi str ati o n, or m ar k eti n g 
of  t h e  I M P  a n d  d o c u m e nt ati o n  will  r e m ai n  c o nfi d e nti al.  I n di vi d u al  p ati e nt  m e di c al  i nf or m ati o n  
o bt ai n e d a s a r e s ult of t hi s st u d y i s c o n si d er e d c o nfi d e nti al a n d di s cl o s ur e t o t hir d p arti e s i s pr o hi bit e d 
wit h t h e e x c e pti o n s n ot e d b el o w. Aft er p ati e nt s h a v e c o n s e nt e d t o t a k e p art i n t h e st u d y, t h eir m e di c al 
r e c or d s  a n d  t h e  d at a  c oll e ct e d  d uri n g  t h e  st u d y  will  b e  r e vi e w e d  b y  A B 2 Bi o  a n d/ or  it s  
r e pr e s e nt ati v e s. T h e s e r e c or d s a n d d at a m a y, i n a d diti o n, b e r e vi e w e d b y t h e f oll o wi n g: i n d e p e n d e nt 
a u dit or s w h o v ali d at e t h e d at a o n b e h alf of A B 2 Bi o; t hir d p arti e s wit h w h o m A B 2 Bi o m a y d e v el o p, 
r e gi st er or m ar k et A B 2 Bi o’ s pr o d u ct; a n d t h e C o m p et e nt H e alt h A ut h orit y  i n t h e p arti ci p ati n g c o u ntr y 
a n d t h e I R B s/I E C s t h at g a v e t h eir a p pr o v al f or t hi s st u d y t o pr o c e e d.  
I d e ntifi c ati o n of p ati e nt s i n C R F s s h all b e b y i niti al s, s cr e e ni n g n u m b er s, or r a n d o mi z ati o n n u m b er s  
o nl y.  If r e q uir e d b y l o c al a g e n ci e s, i niti al s will b e c o d e d p er l o c al r e g ul ati o n s ( e. g., A A A, B B B).  
A d diti o n all y, if r e q uir e d, t h e p ati e nt' s f ull n a m e m a y b e m a d e k n o w n t o a n a ut h ori z e d r e g ul at or y 
a g e n c y or ot h er a ut h ori z e d offi ci al . 


 
 
 
P a g e 8 9  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
R E F E R E N C E S  
A kir a, S. T h e r ol e of I L -1 8 i n i n n at e i m m u nit y. C urr O pi n I m m u n ol  1 2 , 5 9-6 3 ( 2 0 0 0).  
 
C a n n a, S. W. et al. A n a cti v ati n g N L R C 4 i nfl a m m a s o m e m ut ati o n c a u s e s a ut oi nfl a m m ati o n wit h r e c urr e nt 
m a cr o p h a g e a cti v ati o n s y n dr o m e. N at G e n et  ( 2 0 1 4). 
 
C arr oll, H. P., P a u n o vi ƒ á, V. & G a di n a, M. Si g n alli n g, i nfl a m m ati o n a n d art hriti s: Cr o s s e d si g n al s: t h e r ol e of 
i nt erl e u ki n-1 5 a n d -1 8 i n a ut oi m m u nit y. R h e u m at ol o g y  4 7 , 1 2 6 9-1 2 7 7 ( 2 0 0 8).  
 
 
Di n ar ell o, C. A., N o vi c k, D., Ki m, S. & K a pl a n s ki, G. I nt erl e u ki n -1 8 a n d I L -1 8 Bi n di n g Pr ot ei n. Fr o nt I m m u n ol  
4 , 2 8 9 ( 2 0 1 3). 
 
Gr a ci e, J. A. et al. A pr oi nfl a m m at or y r ol e f or I L -1 8 i n r h e u m at oi d art hriti s. J Cli n I n v e st  1 0 4 , 1 3 9 3-1 4 0 1 
( 1 9 9 9). 
 
Gr a ci e, J. A., R o b ert s o n, S. E. & M cI n n e s, I. B. I nt erl e u ki n -1 8. J o ur n al of L e u k o c yt e Bi ol o g y  7 3 , 2 1 3-2 2 4 
( 2 0 0 3). 
 
 
H ur gi n, V., N o vi c k, D. & R u bi n st ei n, M. T h e pr o m ot er of I L -1 8 bi n di n g pr ot ei n: A cti v ati o n b y a n I F N -Œ ≥-
i n d u c e d c o m pl e x of I F N r e g ul at or y f a ct or 1 a n d C C A A T/ e n h a n c er bi n di n g pr ot ei n Œ ≤. Pr o c e e di n g s of t h e 
N ati o n al A c a d e m y of S ci e n c e s  9 9 , 1 6 9 5 7 -1 6 9 6 2 ( 2 0 0 2).  
 
 
K a n d a, N., S hi mi z u, T. & T a d a …, Y. I L ‐1 8 e n h a n c e s I F N ‐γ ‐i n d u c e d pr o d u cti o n of C X C L 9, C X C L 1 0, a n d 
C X C L 1 1 i n h u m a n k er ati n o c yt e s. E ur o p e a n j o ur n al of  I m m u n ol o g y 3 7 , 3 3 8-3 5 0 ( 2 0 0 7).  
 
 
K a w a s hi m a, M. et al. L e v el s of i nt erl e u ki n -1 8 a n d it s bi n di n g i n hi bit or s i n t h e bl o o d cir c ul ati o n of p ati e nt s wit h 
a d ult -o n s et Still’ s di s e a s e. Art hriti s R h e u m  4 4 , 5 5 0-5 6 0 ( 2 0 0 1).  
 
Ki m, S. H. et al. Str u ct ur al r e q uir e m e nt s of si x n at ur all y o c c urri n g i s of or m s of t h e I L -1 8 bi n di n g pr ot ei n t o 
i n hi bit I L-1 8. Pr o c N atl A c a d S ci U S A  9 7 , 1 1 9 0-1 1 9 5 ( 2 0 0 0).  
 
L at o ur, S. & A g uil ar, C. XI A P d efi ci e n c y s y n dr o m e i n h u m a n s. S e mi n C ell D e v Bi ol  3 9 , 1 1 5-1 2 3 ( 2 0 1 5).  
 
M a e n o, N. et al. Hi g hl y el e v at e d s er u m l e v el s of i nt erl e u ki n -1 8 i n s y st e mi c j u v e nil e i di o p at hi c art hriti s b ut n ot 
i n ot h er j u v e nil e i di o p at hi c art hriti s s u bt y p e s or i n K a w a s a ki di s e a s e: c o m m e nt o n t h e arti cl e b y K a w a s hi m a 
et al. Art hriti s R h e u m  4 6 , 2 5 3 9-4 1; a ut h or r e pl y 2 5 4 1 ( 2 0 0 2).  
 
M a e n o, N. et al. I n cr e a s e d i nt erl e u ki n -1 8 e x pr e s si o n i n b o n e m arr o w of a p ati e nt wit h s y st e mi c j u v e nil e 
i di o p at hi c art hriti s a n d u nr e c o g ni z e d m a cr o p h a g e-a cti v ati o n s y n dr o m e. Art hriti s R h e u m  5 0 , 1 9 3 5-1 9 3 8 
( 2 0 0 4). 
 
N a k a m ur a, S., Ot a ni, T., O k ur a, R. & Ijiri …, Y. E x pr e s si o n a n d r e s p o n si v e n e s s of h u m a n i nt erl e u ki n -1 8 
r e c e pt or (I L-1 8 R) o n h e m at o p oi eti c c ell li n e s. L e u k e mi a ( …  ( 2 0 0 0). 
 
 
Ni el s e n, C. M., W olf, A. -S., G o o di er, M. R. & Ril e y, E. S y n er g y b et w e e n c o m m o n g a m m a c h ai n f a mil y 
c yt o ki n e s a n d I L -1 8 p ot e nti at e s i n n at e a n d a d a pti v e p at h w a y s of N K c ell a cti v ati o n. Fr o nti er s i n I m m u n ol o g y  
7 , ( 2 0 1 6). 
 
 
R at hi n a m, V. A. K. & Fit z g er al d, K. A. I nfl a m m a s o m e C o m pl e x e s: E m er gi n g M e c h a ni s m s a n d Eff e ct or 
F u n cti o n s. C ell  ( 2 0 1 6). 
 
R a v elli, A. M a cr o p h a g e a cti v ati o n s y n dr o m e. C urr e nt o pi ni o n i n r h e u m at ol o g y  ( 2 0 0 2). 
 


 
 
 
P a g e 9 0  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
R e z ni k o v, L. L., Ki m, S. H., Z h o u, L. & B ufl er …, P. T h e C o m bi n ati o n of S ol u bl e I L -1 8 R α a n d I L -1 8 R β 
C h ai n s I n hi bit s I L -1 8 -I n d u c e d I F N-γ. J o ur n al of i nt erf er o n …  ( 2 0 0 2). 
 
R o m b er g, N. et al. M ut ati o n of N L R C 4 c a u s e s a s y n dr o m e of e nt er o c oliti s a n d a ut oi nfl a m m ati o n. N at G e n et  
4 6 , 1 1 3 5-1 1 3 9 ( 2 0 1 4).  
S a cr e, S. M. et al. T h e T oll -Li k e R e c e pt or A d a pt or Pr ot ei n s M y D 8 8 a n d M al/ TI R A P C o ntri b ut e t o t h e 
I nfl a m m at or y a n d D e str u cti v e Pr o c e s s e s i n a H u m a n M o d el of R h e u m at oi d Art hriti s. T h e A m eri c a n J o ur n al 
of P at h ol o g y  1 7 0 , 5 1 8-5 2 5 ( 2 0 0 7).  
 
S hi mi z u, M. et al. I nt erl e u ki n -1 8 f or pr e di cti n g t h e d e v el o p m e nt of m a cr o p h a g e a cti v ati o n s y n dr o m e i n 
s y st e mi c j u v e nil e i di o p at hi c art hriti s. Cli n I m m u n ol  1 6 0 , ( 2 0 1 5). 
 
S m elt z, R. B., C h e n, J., H u -Li, J. & S h e v a c h, E. M. R e g ul ati o n of I nt erl e u ki n (Il) -1 8 R e c e pt or Œ ± C h ai n 
E x pr e s si o n o n C d 4 + T C ell s d uri n g T H el p er ( T h) 1/ T h 2 Diff er e nti ati o n: Criti c al D o w nr e g ul at or y R ol e of I L -4. 
T h e J o ur n al of E x p eri m e nt al M e di ci n e  1 9 4 , 1 4 3-1 5 4 ( 2 0 0 1).  
 
 
T o n e, M., T h o m p s o n, S. A., T o n e, Y., F air c hil d, P. J. & W al d m a n n, H. R e g ul ati o n of I L -1 8 (I F N -g a m m a -
i n d u ci n g f a ct or) g e n e e x pr e s si o n. T h e J o ur n al of I m m u n ol o g y  1 5 9 , 6 1 5 6-6 1 6 3 ( 1 9 9 7).  
 
T U C CI, M. A. R. C. O., Q U A T R A R O, C. O. S. I. M. A., D A M M A C C O, F. R. A. N. C. O. & SI L V E S T RI S, F. R. 
A. N. C. O. I n cr e a s e d I L -1 8 Pr o d u cti o n b y D e n driti c C ell s i n A cti v e I nfl a m m at or y M y o p at hi e s. A n n al s of t h e 
N e w Y or k A c a d e m y of S ci e n c e s  1 1 0 7 , 1 8 4-1 9 2 ( 2 0 0 7).  
 
W a d a, T. et al. S u st ai n e d el e v ati o n of s er u m i nt erl e u ki n -1 8 a n d it s a s s o ci ati o n wit h h e m o p h a g o c yti c 
l y m p h o hi sti o c yt o si s i n XI A P d efi ci e n c y. C yt o ki n e  6 5 , 7 4-7 8 ( 2 0 1 4).  
 
X u, D. et al. S el e cti v e E x pr e s si o n a n d F u n cti o n s of I nt erl e u ki n 1 8 R e c e pt or o n T H el p er ( T h) T y p e 1 b ut n ot 
T h 2 C ell s. T h e J o ur n al of E x p eri m e nt al M e di ci n e  1 8 8 , 1 4 8 5-1 4 9 2 ( 1 9 9 8).  
 
 
 
 
 
 
 
 


 
 
 
P a g e 9 1  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
A P P E N DI X 1:  M O DI FI E D A U T O -I N F L A M M A T O R Y DI S E A S E A C TI VI T Y I N D E X  
 
 
 
 
 
 
 
m AI D AI c o m p o n e nt  
I d e ntifi e d s u bj e cti v e 
c o m p o n e nt  
I n cl u d e d i n o bj e cti v e e v al u ati o n of r e s p o n s e t o t h er a p y a n d 
di s e a s e r e a cti v ati o n  
F e v er > 1 0 0. 4 F/ 3 8 C  
 
x  
A b d o mi n al P ai n/ C oli c  
x  
- 
N a u s e a/ V o miti n g  
x  
- 
Di arr h e a  
 
x  
Tr a n s a mi niti s  
 
x  
Or g a n o m e g al y  
 
x  
(s e p ar at e d i nt o  h e p ati c a n d l y m p h ati c s y st e m)  
R a s h  
 
x  
U v eiti s 3 +/ 4 +  
 
x  
(all gr a d e s gr o u p e d t o g et h er t o cr e at e a n u n w ei g ht e d s c al e ) 
U v eiti s 1 +/ 2 +  
 
Art hr al gi a  
x  
- 
Art hriti s  
 
x  
R a di ol o gi c C N S i n v ol v e m e nt  
 
x  
C N S s y m pt o m s  
x  
- 
C yt o p e ni a ( H g B < 9. 0, P L T < 1 0 0, W B C < 3. 0)  
 
x  
 
 
 
 








 
 
 
P a g e 9 5  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
A P P E N DI X 4 :  D E C L A R A TI O N O F H E L SI N KI  
 
W M A D e cl ar ati o n of H el si n ki - Et hi c al Pri n ci pl e s f or M e di c al R e s e ar c h I n v ol vi n g 
H u m a n S u bj e ct s  
A d o pt e d b y t h e 1 8t h W M A G e n er al A s s e m bl y, H el si n ki, Fi nl a n d, J u n e 1 9 6 4  a n d a m e n d e d b y t h e:  
2 9t h W M A G e n er al A s s e m bl y, T o k y o, J a p a n, O ct o b er 1 9 7 5  3 5t h W M A G e n er al A s s e m bl y, V e ni c e, 
It al y, O ct o b er 1 9 8 3 4 1 st W M A G e n er al A s s e m bl y, H o n g K o n g, S e pt e m b er 1 9 8 9  4 8t h W M A G e n er al 
A s s e m bl y, S o m er s et W e st, R e p u bli c of S o ut h Afri c a, O ct o b er 1 9 9 6  
5 2 n d W M A G e n er al A s s e m bl y, E di n b ur g h, S c otl a n d, O ct o b er 2 0 0 0  5 3r d W M A G e n er al A s s e m bl y, 
W a s hi n gt o n D C, U S A, O ct o b er 2 0 0 2 ( N ot e of Cl arifi c ati o n a d d e d)  5 5t h W M A G e n er al A s s e m bl y, 
T o k y o, J a p a n, O ct o b er 2 0 0 4 ( N ot e of Cl arifi c ati o n a d d e d) 5 9t h W M A G e n er al A s s e m bl y, S e o ul, 
R e p u bli c of K or e a, O ct o b er 2 0 0 8  6 4t h W M A G e n er al A s s e m bl y, F ort al e z a, Br a zil, O ct o b er 2 0 1 3  
Pr e a m bl e  
1. T h e W orl d M e di c al A s s o ci ati o n ( W M A) h a s d e v el o p e d t h e D e cl ar ati o n of H el si n ki a s a st at e m e nt 
of  et hi c al  pri n ci pl e s  f or  m e di c al  r e s e ar c h  i n v ol vi n g  h u m a n  s u bj e ct s,  i n cl u di n g  r e s e ar c h  o n  
i d e ntifi a bl e h u m a n m at eri al a n d d at a. 
T h e D e cl ar ati o n i s i nt e n d e d t o b e r e a d a s a w h ol e a n d e a c h of it s c o n stit u e nt p ar a gr a p h s s h o ul d 
b e a p pli e d wit h c o n si d er ati o n of all ot h er r el e v a nt p ar a gr a p h s.  
2. C o n si st e nt wit h t h e m a n d at e of t h e W M A, t h e D e cl ar ati o n i s a d dr e s s e d pri m aril y t o p h y si ci a n s. 
T h e W M A e n c o ur a g e s ot h er s w h o ar e i n v ol v e d i n m e di c al r e s e ar c h i n v ol vi n g h u m a n s u bj e ct s t o 
a d o pt t h e s e pri n ci pl e s.  
G e n er al Pri n ci pl e s  
 
 
3. T h e D e cl ar ati o n of G e n e v a of t h e W M A bi n d s t h e p h y si ci a n wit h t h e w or d s,  
 “ T h e h e alt h of m y p ati e nt will b e m y fir st c o n si d er ati o n,” a n d t h e I nt er n ati o n al C o d e of M e di c al Et hi c s 
d e cl ar e s t h at, “ A p h y si ci a n s h all a ct i n t h e p ati e nt' s b e st i nt er e st w h e n pr o vi di n g m e di c al c ar e.”  
4. It i s t h e d ut y of t h e p h y si ci a n t o pr o m ot e a n d s af e g u ar d t h e h e alt h, w ell -b ei n g a n d ri g ht s of p ati e nt s, 
i n cl u di n g t h o s e w h o ar e i n v ol v e d i n m e di c al r e s e ar c h. T h e p h y si ci a n' s k n o wl e d g e a n d c o n s ci e n c e 
ar e d e di c at e d t o t h e f ulfil m e nt of t hi s d ut y.  
5. M e di c al pr o gr e s s i s b a s e d o n r e s e ar c h t h at ulti m at el y m u st i n cl u d e st u di e s i n v ol vi n g h u m a n 
s u bj e ct s.  
6. T h e pri m ar y p ur p o s e of m e di c al r e s e ar c h i n v ol vi n g h u m a n s u bj e ct s i s t o u n d er st a n d t h e c a u s e s, 
d e v el o p m e nt  a n d  eff e ct s  of  di s e a s e s  a n d  i m pr o v e  pr e v e nti v e,  di a g n o sti c  a n d  t h er a p e uti c  
i nt er v e nti o n s ( m et h o d s, pr o c e d ur e s a n d tr e at m e nt s). E v e n t h e b e st pr o v e n i nt er v e nti o n s m u st b e 
e v al u at e d c o nti n u all y t hr o u g h r e s e ar c h f or t h eir s af et y, eff e cti v e n e s s, effi ci e n c y, a c c e s si bilit y a n d 
q u alit y.  
7. M e di c al r e s e ar c h i s s u bj e ct t o et hi c al st a n d ar d s t h at pr o m ot e a n d e n s ur e r e s p e ct f or all h u m a n 
s u bj e ct s a n d pr ot e ct t h eir h e alt h a n d ri g ht s.  
8. W hil e t h e pri m ar y p ur p o s e of m e di c al r e s e ar c h i s t o g e n er at e n e w k n o wl e d g e, t hi s g o al c a n n e v er 
t a k e pr e c e d e n c e o v er t h e ri g ht s a n d i nt er e st s of i n di vi d u al r e s e ar c h s u bj e ct s. 
9. It i s t h e d ut y of p h y si ci a n s w h o ar e i n v ol v e d i n m e di c al r e s e ar c h t o pr ot e ct t h e lif e, h e alt h, di g nit y, 


 
 
 
P a g e 9 6  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
i nt e grit y, ri g ht t o s elf-d et er mi n ati o n, pri v a c y, a n d c o nfi d e nti alit y of p er s o n al i nf or m ati o n of r e s e ar c h 
s u bj e ct s.  T h e  r e s p o n si bilit y  f or  t h e  pr ot e cti o n  of  r e s e ar c h  s u bj e ct s  m u st  al w a y s  r e st  wit h  t h e  
p h y si ci a n or ot h er h e alt h c ar e pr of e s si o n al s a n d n e v er wit h t h e r e s e ar c h s u bj e ct s, e v e n t h o u g h t h e y 
h a v e gi v e n c o n s e nt.  
1 0. P h y si ci a n s m u st c o n si d er t h e et hi c al, l e g al a n d r e g ul at or y n or m s a n d st a n d ar d s f or r e s e ar c h 
i n v ol vi n g  h u m a n  s u bj e ct s  i n  t h eir  o w n  c o u ntri e s  a s  w ell  a s  a p pli c a bl e  i nt er n ati o n al  n or m s  a n d  
st a n d ar d s. N o n ati o n al or i nt er n ati o n al et hi c al, l e g al or r e g ul at or y r e q uir e m e nt s h o ul d r e d u c e or 
eli mi n at e a n y of t h e pr ot e cti o n s f or r e s e ar c h s u bj e ct s s et f ort h i n t hi s D e cl ar ati o n.  
1 1.  M e di c al  r e s e ar c h  s h o ul d  b e  c o n d u ct e d  i n  a  m a n n er  t h at  mi ni mi s e s  p o s si bl e  h ar m  t o  t h e  
e n vir o n m e nt.  
1 2. M e di c al r e s e ar c h i n v ol vi n g h u m a n s u bj e ct s m u st b e c o n d u ct e d o nl y b y  i n di vi d u al s wit h t h e  
a p pr o pri at e et hi c s a n d s ci e ntifi c e d u c ati o n, tr ai ni n g a n d  i n di vi d u al s wit h t h e a p pr o pri at e et hi c s a n d 
s ci e ntifi c e d u c ati o n, tr ai ni n g a n d q u alifi c ati o n s. R e s e ar c h o n p ati e nt s or h e alt h y v ol u nt e er s r e q uir e s 
t h e  s u p er vi si o n  of  a  c o m p et e nt  a n d  a p pr o pri at el y  q u alifi e d  p h y si ci a n  or  ot h er  h e alt h  c ar e  
pr of e s si o n al.  
1 3. Gr o u p s t h at ar e u n d err e pr e s e nt e d i n m e di c al r e s e ar c h s h o ul d b e pr o vi d e d a p pr o pri at e a c c e s s 
t o p arti ci p ati o n i n r e s e ar c h. 
1 4. P h y si ci a n s w h o c o m bi n e m e di c al r e s e ar c h wit h m e di c al c ar e s h o ul d i n v ol v e t h eir p ati e nt s i n 
r e s e ar c h o nl y t o t h e e xt e nt t h at t hi s i s j u stifi e d b y it s p ot e nti al pr e v e nti v e, di a g n o sti c or t h er a p e uti c 
v al u e a n d if t h e p h y si ci a n h a s g o o d r e a s o n t o b eli e v e t h at p arti ci p ati o n i n t h e r e s e ar c h st u d y will n ot 
a d v er s el y aff e ct t h e h e alt h of t h e p ati e nt s w h o s er v e a s r e s e ar c h s u bj e ct s.  
1 5. A p pr o pri at e c o m p e n s ati o n a n d tr e at m e nt f or s u bj e ct s w h o ar e h ar m e d a s a r e s ult of p arti ci p ati n g 
i n r e s e ar c h m u st b e e n s ur e d. 
Ri s k s, B ur d e n s a n d B e n efit s  
1 6. I n m e di c al pr a cti c e a n d i n m e di c al r e s e ar c h, m o st i nt er v e nti o n s i n v ol v e ri s k s a n d b ur d e n s.  
M e di c al r e s e ar c h i n v ol vi n g h u m a n s u bj e ct s m a y o nl y b e c o n d u ct e d if t h e i m p ort a n c e of t h e o bj e cti v e 
o ut w ei g h s t h e ri s k s a n d b ur d e n s t o t h e r e s e ar c h s u bj e ct s.  
1 7. All m e di c al r e s e ar c h i n v ol vi n g h u m a n s u bj e ct s m u st b e pr e c e d e d b y c ar ef ul a s s e s s m e nt of 
pr e di ct a bl e ri s k s a n d b ur d e n s t o t h e i n di vi d u al s a n d gr o u p s i n v ol v e d i n t h e r e s e ar c h i n c o m p ari s o n 
wit h f or e s e e a bl e b e n efit s t o t h e m a n d t o ot h er i n di vi d u al s or gr o u p s aff e ct e d b y t h e c o n diti o n u n d er 
i n v e sti g ati o n. 
M e a s ur e s t o mi ni mi s e t h e ri s k s m u st b e i m pl e m e nt e d. T h e ri s k s m u st b e c o nti n u o u sl y m o nit or e d, 
a s s e s s e d a n d d o c u m e nt e d b y t h e r e s e ar c h er.  
1 8. P h y si ci a n s m a y n ot b e i n v ol v e d i n a r e s e ar c h st u d y i n v ol vi n g h u m a n s u bj e ct s u nl e s s t h e y ar e 
c o nfi d e nt t h at t h e ri s k s h a v e b e e n a d e q u at el y a s s e s s e d a n d c a n b e s ati sf a ct oril y m a n a g e d.  
W h e n t h e ri s k s ar e f o u n d t o o ut w ei g h t h e p ot e nti al b e n efit s or w h e n t h er e i s c o n cl u si v e pr o of of 
d efi niti v e o ut c o m e s, p h y si ci a n s m u st a s s e s s w h et h er t o c o nti n u e, m o dif y or i m m e di at el y st o p t h e 
st u d y.  
 
 
 


 
 
 
P a g e 9 7  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
V ul n er a bl e Gr o u p s a n d I n di vi d u al s  
 
1 9. S o m e gr o u p s a n d i n di vi d u al s ar e p arti c ul arl y v ul n er a bl e a n d m a y h a v e a n i n cr e a s e d li k eli h o o d 
of b ei n g wr o n g e d or of i n c urri n g a d diti o n al h ar m.  
All v ul n er a bl e gr o u p s a n d i n di vi d u al s s h o ul d r e c ei v e s p e cifi c all y c o n si d er e d pr ot e cti o n.  
2 0. M e di c al r e s e ar c h wit h a v ul n er a bl e gr o u p i s o nl y j u stifi e d if t h e r e s e ar c h i s r e s p o n si v e t o t h e 
h e alt h n e e d s or pri oriti e s of t hi s gr o u p a n d t h e r e s e ar c h c a n n ot b e c arri e d o ut i n a n o n -v ul n er a bl e 
gr o u p. I n a d diti o n, t hi s gr o u p s h o ul d st a n d t o b e n efit fr o m t h e k n o wl e d g e, pr a cti c e s or i nt er v e nti o n s 
t h at r e s ult fr o m t h e r e s e ar c h. 
S ci e ntifi c R e q uir e m e nt s a n d R e s e ar c h Pr ot o c ol s  
2 1.  M e di c al  r e s e ar c h  i n v ol vi n g  h u m a n  s u bj e ct s  m u st  c o nf or m  t o  g e n er all y  a c c e pt e d  s ci e ntifi c  
pri n ci pl e s, b e b a s e d o n a t h or o u g h k n o wl e d g e of t h e s ci e ntifi c lit er at ur e, ot h er r el e v a nt s o ur c e s of 
i nf or m ati o n, a n d a d e q u at e l a b or at or y a n d, a s a p pr o pri at e, a ni m al e x p eri m e nt ati o n. T h e w elf ar e of 
a ni m al s u s e d f or r e s e ar c h m u st b e r e s p e ct e d.  
2 2. T h e d e si g n a n d p erf or m a n c e of e a c h r e s e ar c h st u d y i n v ol vi n g h u m a n s u bj e ct s m u st b e cl e arl y 
d e s cri b e d a n d j u stifi e d i n a r e s e ar c h pr ot o c ol.  
T h e pr ot o c ol s h o ul d c o nt ai n a st at e m e nt of t h e et hi c al c o n si d er ati o n s i n v ol v e d a n d s h o ul d i n di c at e 
h o w t h e pri n ci pl e s i n t hi s D e cl ar ati o n h a v e b e e n a d dr e s s e d. T h e pr ot o c ol s h o ul d i n cl u d e i nf or m ati o n 
r e g ar di n g  f u n di n g,  s p o n s or s,  i n stit uti o n al  affili ati o n s,  p ot e nti al  c o nfli ct s  of  i nt er e st,  i n c e nti v e s  f or  
s u bj e ct s a n d i nf or m ati o n r e g ar di n g pr o vi si o n s f or tr e ati n g a n d/ or c o m p e n s ati n g s u bj e ct s w h o ar e 
h ar m e d a s a c o n s e q u e n c e of p arti ci p ati o n i n t h e r e s e ar c h st u d y.  
I n cli ni c al tri al s, t h e pr ot o c ol m u st al s o d e s cri b e a p pr o pri at e arr a n g e m e nt s f or p o st-tri al pr o vi si o n s. 
R e s e ar c h Et hi c s C o m mitt e e s  
2 3. T h e r e s e ar c h pr ot o c ol m u st b e s u b mitt e d f or c o n si d er ati o n, c o m m e nt, g ui d a n c e a n d a p pr o v al t o 
t h e  c o n c er n e d  r e s e ar c h  et hi c s  c o m mitt e e  b ef or e  t h e  st u d y  b e gi n s.  T hi s  c o m mitt e e  m u st  b e  
tr a n s p ar e nt i n it s f u n cti o ni n g, m u st b e i n d e p e n d e nt of t h e r e s e ar c h er, t h e s p o n s or a n d a n y ot h er 
u n d u e i nfl u e n c e a n d m u st b e d ul y q u alifi e d. It m u st t a k e i nt o c o n si d er ati o n t h e l a w s a n d r e g ul ati o n s 
of t h e c o u ntr y or c o u ntri e s i n w hi c h t h e r e s e ar c h i s t o b e p erf or m e d a s w ell a s a p pli c a bl e i nt er n ati o n al 
n or m s a n d  st a n d ar d s b ut t h e s e m u st n ot b e all o w e d t o r e d u c e or eli mi n at e a n y of t h e pr ot e cti o n s  
st a n d ar d s b ut t h e s e m u st n ot b e all o w e d t o r e d u c e or eli mi n at e a n y of t h e pr ot e cti o n s f or r e s e ar c h 
s u bj e ct s s et f ort h i n t hi s D e cl ar ati o n.  
T h e  c o m mitt e e  m u st  h a v e  t h e  ri g ht  t o  m o nit or  o n g oi n g  st u di e s.  T h e  r e s e ar c h er  m u st  pr o vi d e  
m o nit ori n g i nf or m ati o n t o t h e c o m mitt e e, e s p e ci all y i nf or m ati o n a b o ut a n y s eri o u s a d v er s e e v e nt s. 
N o a m e n d m e nt t o t h e pr ot o c ol m a y b e m a d e wit h o ut c o n si d er ati o n a n d a p pr o v al b y t h e c o m mitt e e. 
Aft er t h e e n d of t h e st u d y, t h e r e s e ar c h er s m u st s u b mit a fi n al r e p ort t o t h e c o m mitt e e c o nt ai ni n g a 
s u m m ar y of t h e st u d y’ s fi n di n g s a n d c o n cl u si o n s.  
Pri v a c y a n d C o nfi d e nti alit y  
2 4. E v er y pr e c a uti o n m u st b e t a k e n t o pr ot e ct t h e pri v a c y of r e s e ar c h s u bj e ct s a n d t h e c o nfi d e nti alit y 
of t h eir p er s o n al i nf or m ati o n.  
I nf or m e d C o n s e nt 
2 5. P arti ci p ati o n b y i n di vi d u al s c a p a bl e of gi vi n g i nf or m e d c o n s e nt a s s u bj e ct s i n m e di c al r e s e ar c h 
m u st b e v ol u nt ar y. Alt h o u g h it m a y b e a p pr o pri at e t o c o n s ult f a mil y m e m b er s or c o m m u nit y l e a d er s, 


 
 
 
P a g e 9 8  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
n o i n di vi d u al c a p a bl e of gi vi n g i nf or m e d c o n s e nt m a y b e e nr oll e d i n a r e s e ar c h st u d y u nl e s s h e or 
s h e fr e el y a gr e e s.  
2 6. I n m e di c al r e s e ar c h i n v ol vi n g h u m a n s u bj e ct s c a p a bl e of gi vi n g i nf or m e d c o n s e nt, e a c h p ot e nti al 
s u bj e ct m u st b e a d e q u at el y i nf or m e d of t h e ai m s, m et h o d s, s o ur c e s of f u n di n g, a n y p o s si bl e c o nfli ct s 
of i nt er e st, i n stit uti o n al affili ati o n s of t h e r e s e ar c h er, t h e a nti ci p at e d b e n efit s a n d p ot e nti al ri s k s of 
t h e st u d y a n d t h e di s c o mf ort it m a y e nt ail, p o st-st u d y pr o vi si o n s a n d a n y ot h er r el e v a nt a s p e ct s of 
t h e st u d y. T h e p ot e nti al s u bj e ct m u st b e i nf or m e d of t h e ri g ht t o r ef u s e t o p arti ci p at e i n t h e st u d y or 
t o wit h dr a w c o n s e nt t o p arti ci p at e at a n y ti m e wit h o ut r e pri s al. S p e ci al att e nti o n s h o ul d b e gi v e n t o 
t h e s p e cifi c i nf or m ati o n n e e d s of i n di vi d u al p ot e nti al s u bj e ct s a s w ell a s t o t h e m et h o d s u s e d t o 
d eli v er t h e i nf or m ati o n.  
Aft er e n s uri n g t h at t h e p ot e nti al s u bj e ct h a s u n d er st o o d t h e i nf or m ati o n, t h e p h y si ci a n or a n ot h er 
a p pr o pri at el y  q u alifi e d  i n di vi d u al  m u st  t h e n  s e e k  t h e  p ot e nti al  s u bj e ct’ s  fr e el y -gi v e n  i nf or m e d  
c o n s e nt, pr ef er a bl y i n writi n g. If t h e c o n s e nt c a n n ot b e e x pr e s s e d i n writi n g, t h e n o n -writt e n c o n s e nt 
m u st b e f or m all y d o c u m e nt e d a n d wit n e s s e d.  
All  m e di c al  r e s e ar c h  s u bj e ct s  s h o ul d  b e  gi v e n  t h e  o pti o n  of  b ei n g  i nf or m e d  a b o ut  t h e  g e n er al  
o ut c o m e a n d r e s ult s of t h e st u d y.  
 
2 7. W h e n s e e ki n g i nf or m e d c o n s e nt f or p arti ci p ati o n i n a r e s e ar c h st u d y t h e p h y si ci a n m u st b e 
p arti c ul arl y c a uti o u s if t h e p ot e nti al s u bj e ct i s i n a d e p e n d e nt r el ati o n s hi p wit h t h e p h y si ci a n or m a y 
c o n s e nt u n d er d ur e s s. I n s u c h sit u ati o n s t h e i nf or m e d c o n s e nt m u st b e s o u g ht b y a n a p pr o pri at el y 
q u alifi e d i n di vi d u al w h o i s c o m pl et el y i n d e p e n d e nt of t hi s r el ati o n s hi p.  
2 8. F or a p ot e nti al r e s e ar c h s u bj e ct w h o i s i n c a p a bl e of gi vi n g i nf or m e d c o n s e nt, t h e p h y si ci a n m u st 
s e e k i nf or m e d c o n s e nt fr o m t h e l e g all y a ut h ori s e d r e pr e s e nt ati v e. T h e s e i n di vi d u al s m u st n ot b e 
i n cl u d e d i n a r e s e ar c h st u d y t h at h a s n o li k eli h o o d of b e n efit f or t h e m u nl e s s it i s i nt e n d e d t o pr o m ot e 
t h e  h e alt h  of  t h e  gr o u p  r e pr e s e nt e d  b y  t h e  p ot e nti al  s u bj e ct,  t h e  r e s e ar c h  c a n n ot  i n st e a d  b e  
p erf or m e d  wit h  p er s o n s  c a p a bl e  of  pr o vi di n g  i nf or m e d  c o n s e nt,  a n d  t h e  r e s e ar c h  e nt ail s  o nl y  
mi ni m al ri s k a n d mi ni m al b ur d e n.  
2 9. W h e n a p ot e nti al r e s e ar c h s u bj e ct w h o i s d e e m e d i n c a p a bl e of gi vi n g i nf or m e d c o n s e nt i s a bl e 
t o gi v e a s s e nt t o d e ci si o n s a b o ut p arti ci p ati o n i n r e s e ar c h, t h e p h y si ci a n m u st s e e k t h at a s s e nt i n 
a d diti o n  t o  t h e  c o n s e nt  of  t h e  l e g all y  a ut h ori s e d  r e pr e s e nt ati v e.  T h e  p ot e nti al  s u bj e ct’ s  di s s e nt  
s h o ul d b e r e s p e ct e d.  
3 0. R e s e ar c h i n v ol vi n g s u bj e ct s w h o ar e p h y si c all y or m e nt all y i n c a p a bl e of gi vi n g c o n s e nt, f or 
e x a m pl e, u n c o n s ci o u s p ati e nt s, m a y b e d o n e o nl y if t h e p h y si c al or m e nt al c o n diti o n t h at pr e v e nt s 
gi vi n g i nf or m e d c o n s e nt i s a n e c e s s ar y c h ar a ct eri sti c of t h e r e s e ar c h gr o u p. I n s u c h cir c u m st a n c e s 
t h e p h y si ci a n m u st s e e k i nf or m e d c o n s e nt fr o m t h e l e g all y a ut h ori s e d r e pr e s e nt ati v e. If n o s u c h 
r e pr e s e nt ati v e i s a v ail a bl e a n d if t h e r e s e ar c h c a n n ot b e d el a y e d, t h e st u d y m a y pr o c e e d wit h o ut 
i nf or m e d  c o n s e nt  pr o vi d e d  t h at  t h e  s p e cifi c  r e a s o n s  f or  i n v ol vi n g s u bj e ct s  wit h a  c o n diti o n t h at  
r e n d er s t h e m u n a bl e t o gi v e i nf or m e d c o n s e nt h a v e b e e n st at e d i n t h e r e s e ar c h pr ot o c ol a n d t h e 
st u d y h a s b e e n a p pr o v e d b y a r e s e ar c h et hi c s c o m mitt e e. C o n s e nt t o r e m ai n i n t h e r e s e ar c h m u st 
b e o bt ai n e d a s s o o n a s p o s si bl e fr o m t h e s u bj e ct or a l e g all y a ut h ori s e d r e pr e s e nt ati v e.  
3 1. T h e p h y si ci a n m u st f ull y i nf or m t h e p ati e nt w hi c h a s p e ct s of t h eir c ar e ar e r el at e d t o t h e r e s e ar c h. 
T h e r ef u s al of a p ati e nt t o p arti ci p at e i n a st u d y or t h e p ati e nt’ s d e ci si o n t o wit h dr a w fr o m t h e st u d y 
m u st n e v er a d v er s el y aff e ct t h e p ati e nt - p h y si c i a n r el ati o n s hi p. 
3 2. F or m e di c al r e s e ar c h u si n g i d e ntifi a bl e h u m a n m at eri al or d at a, s u c h a s r e s e ar c h o n m at eri al or 
d at a c o nt ai n e d i n bi o b a n k s or si mil ar r e p o sit ori e s, p h y si ci a n s m u st s e e k i nf or m e d c o n s e nt f or it s 
c oll e cti o n,  st or a g e  a n d/ or  r e u s e.  T h er e  m a y  b e  e x c e pti o n al  sit u ati o n s  w h er e  c o n s e nt  w o ul d  b e  
i m p o s si bl e or i m pr a cti c a bl e t o o bt ai n f or s u c h r e s e ar c h. I n s u c h sit u ati o n s t h e r e s e ar c h m a y b e d o n e 
o nl y aft er  f or s u c h r e s e ar c h. I n s u c h sit u ati o n s t h e r e s e ar c h m a y b e d o n e o nl y aft er c o n si d er ati o n 


 
 
 
P a g e 9 9  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
a n d a p pr o v al of a r e s e ar c h et hi c s c o m mitt e e.  
U s e of Pl a c e b o  
3 3. T h e b e n efit s, ri s k s, b ur d e n s a n d eff e cti v e n e s s of a n e w i nt er v e nti o n m u st b e t e st e d a g ai n st t h o s e 
of t h e b e st pr o v e n i nt er v e nti o n( s), e x c e pt i n t h e f oll o wi n g cir c u m st a n c e s:  
W h er e n o pr o v e n i nt er v e nti o n e xi st s, t h e u s e of pl a c e b o, or n o i nt er v e nti o n, i s a c c e pt a bl e; or   
W h er e f or c o m p elli n g a n d s ci e ntifi c all y s o u n d m et h o d ol o gi c al r e a s o n s t h e u s e of a n y i nt er v e nti o n 
l e s s eff e cti v e t h a n t h e b e st pr o v e n o n e, t h e u s e of pl a c e b o, or n o i nt er v e nti o n i s n e c e s s ar y t o  
d et er mi n e t h e effi c a c y or s af et y of a n i nt er v e nti o n  a n d t h e p ati e nt s w h o r e c ei v e a n y i nt er v e nti o n l e s s 
eff e cti v e t h a n t h e b e st pr o v e n o n e, pl a c e b o, or n o i nt er v e nti o n will n ot b e s u bj e ct t o a d diti o n al ri s k s 
of s eri o u s or irr e v er si bl e h ar m a s a r e s ult of n ot r e c ei vi n g t h e b e st pr o v e n i nt er v e nti o n.  
E xtr e m e c ar e m u st b e t a k e n t o a v oi d a b u s e of t hi s o pti o n.  
P o st -Tri al Pr o vi si o n s  
3 4. I n a d v a n c e of a cli ni c al tri al, s p o n s or s, r e s e ar c h er s a n d h o st c o u ntr y g o v er n m e nt s s h o ul d m a k e 
pr o vi si o n s  f or  p o st -tri al  a c c e s s  f or  all  p arti ci p a nt s  w h o  still  n e e d  a n  i nt er v e nti o n  i d e ntifi e d  a s  
b e n efi ci al i n t h e tri al. T hi s i nf or m ati o n m u st al s o b e di s cl o s e d t o p arti ci p a nt s d uri n g t h e i nf or m e d 
c o n s e nt pr o c e s s.  
R e s e ar c h R e gi str ati o n a n d P u bli c ati o n a n d Di s s e mi n ati o n of R e s ult s  
3 5.  E v er y  r e s e ar c h  st u d y  i n v ol vi n g h u m a n  s u bj e ct s  m u st  b e  r e gi st er e d  i n  a  p u bli cl y  a c c e s si bl e  
d at a b a s e b ef or e r e cr uit m e nt of t h e fir st s u bj e ct.  
3 6. R e s e ar c h er s, a ut h or s, s p o n s or s, e dit or s a n d p u bli s h er s all h a v e et hi c al o bli g ati o n s wit h r e g ar d 
t o t h e p u bli c ati o n a n d di s s e mi n ati o n of t h e r e s ult s of r e s e ar c h. R e s e ar c h er s h a v e a d ut y t o m a k e 
p u bli cl y  a v ail a bl e  t h e  r e s ult s  of  t h eir  r e s e ar c h  o n  h u m a n  s u bj e ct s  a n d  ar e  a c c o u nt a bl e  f or  t h e  
c o m pl et e n e s s a n d a c c ur a c y of t h eir r e p ort s. All p arti e s s h o ul d a d h er e t o a c c e pt e d g ui d eli n e s f or 
et hi c al  r e p orti n g.  N e g ati v e  a n d  i n c o n cl u si v e  a s  w ell  a s  p o siti v e  r e s ult s  m u st  b e  p u bli s h e d  or  
ot h er wi s e m a d e  p u bli cl y a v ail a bl e. S o ur c e s of f u n di n g, i n stit uti o n al affili ati o n s a n d c o nfli ct s of i nt er e st  
p u bli cl y  a v ail a bl e.  S o ur c e s  of  f u n di n g,  i n stit uti o n al  affili ati o n s  a n d  c o nfli ct s  of  i nt er e st  m u st  b e  
d e cl ar e d  i n  t h e  p u bli c ati o n.  R e p ort s  of  r e s e ar c h  n ot  i n  a c c or d a n c e  wit h  t h e  pri n ci pl e s  of  t hi s  
D e cl ar ati o n s h o ul d n ot b e a c c e pt e d f or p u bli c ati o n.  
U n pr o v e n I nt er v e nti o n s i n Cli ni c al Pr a cti c e  
3 7. I n t h e tr e at m e nt of a n i n di vi d u al p ati e nt, w h er e pr o v e n i nt er v e nti o n s d o n ot e xi st or ot h er k n o w n 
i nt er v e nti o n s h a v e b e e n i n eff e cti v e, t h e p h y si ci a n, aft er s e e ki n g e x p ert a d vi c e, wit h i nf or m e d c o n s e nt 
fr o m t h e p ati e nt or a l e g all y a ut h ori s e d r e pr e s e nt ati v e, m a y u s e a n u n pr o v e n i nt er v e nti o n if i n t h e 
p h y si ci a n' s j u d g e m e nt it off er s h o p e of s a vi n g lif e, r e -e st a bli s hi n g h e alt h or all e vi ati n g s uff eri n g. T hi s 
i nt er v e nti o n s h o ul d s u b s e q u e ntl y b e m a d e t h e o bj e ct of r e s e ar c h, d e si g n e d t o e v al u at e it s s af et y 
a n d  effi c a c y. I n all c a s e s, n e w i nf or m ati o n m u st b e r e c or d e d a n d, w h er e a p pr o pri at e, m a d e p u bli cl y 
a v ail a bl e.  
© W orl d M e di c al A s s o ci ati o n, I n c. - All Ri g ht s r e s er v e d. © A s o ci a ci ó n m é di c a m u n di al - T o d o s l o s 
d er e c h o s r e s er v a d o s. © L' A s s o ci ati o n M é di c al e M o n di al e - T o u s dr oit s r é s er v é s.  
Di s cl ai m er:  ©  2 0 1 3  W orl d  M e di c al  A s s o ci ati o n,  I n c.  All  Ri g ht s  R e s er v e d.  All  i nt ell e ct u al  
pr o p ert y ri g ht s i n t h e D e cl ar ati o n of H el si n ki ar e v e st e d i n t h e W orl d M e di c al A s s o ci ati o n. 
Pr e vi o u s p er mi s si o n s gr a nt e d t o p u bli s h or r e pr o d u c e ot h er wi s e W M A p oli c y d o n’t a p pl y t o 
t hi s v er si o n of t h e D e cl ar ati o n of H el si n ki u ntil J a n u ar y 1 st, 2 0 1 4. F or f urt h er q u e sti o n s, 
pl e a s e c o nt a ct t h e W M A s e cr et ari at at s e cr et ari at @ w m a. n et . 
 


 
 
 
P a g e 1 0 0  of 1 0 0  
Pr ot o c ol N° N L R C 4/ XI A P. 2 0 1 6. 0 0 1 – V er si o n 6. 0  - D at e: 0 3 S e p 2 0 2 1  
I N D N°: 1 2 7 9 5 3; E u dr a C T N o: 2 0 1 8 -0 0 3 2 9 7 -2 7  
 
C O N FI D E N TI A L  
A P P E N DI X 5 :  E X A M P L E P A TI E N T E M E R G E N C Y C O N T A C T C A R D  
 
P A TI E N T E M E R G E N C Y  C O N T A C T C A R D F O R P A TI E N T O R 
T H EI R L E G A L R E P R E S E N T A TI V E S P A R TI CI P A TI N G T O T H E 
N L R C 4  M U T A TI O N U N D XI A P-D E FI CI T C LI NI C A L S T U D Y  
 
P L E A S E S H O W T HI S C A R D T O A N Y M E DI C A L D O C T O R W H O 
E X A MI N E S Y O U . 
  
I A M C U R R E N T L Y P A R TI CI P A T I N G T O A C LI NI C A L S T U D Y 
WI T H 
T A D E KI NI G  A L F A  (R -H I L-1 8 B P)  WI T H  N L R C 4 -
M U T A TI O N 
A N D XI A P -D E FI CI T .  T H E S T U D Y 
T A K E S 
P L A C E A T :   
  
H O S PI T A L N A M E : _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
A D D R E S S : _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
  
IN  C A S E  O F  E M E R G E N C Y  O R  I F  Y O U  N E E D  M O R E  
I N F O R M A TI O N P L E A S E C A L L U S:  
  
N A M E O F T H E I N V E S TI G A T O R : _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
P H O N E : _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
  
P L E A S E C A R R Y T HI S C A R D A T A L L TI M E S  WI T H Y O U ! 
S P O N S O R O F T H E C LI NI C A L S T U D Y :          
A B 2  BI O L T D.  
E P F L I N N O V A TI O N P A R K  
B UI L DI N G B , 4 T H F L O O R  
C H -1 0 1 5  L A U S A N N E, S WI T Z E R L A N D 
M E DI C A L M O NI T O R ( 2 4/ 2 4H 7/ 7)   
M O BI L E : + X X X X X X X X X X X  
  
C LI NI C A L R E S E A R C H O R G A NI Z A TI O N : 
P R E CI SI O N  F O R  M E DI CI N E , O N C O L O G Y  A N D  R A R E  
DI S E A S E       C A R L S B A D , C A  U S A  
  
P R O T O C O L  NU M B E R : N L R C 4/ XI A P. 2 0 1 6. 0 0 1   
  
P A TI E N T ’S I NI TI A L S : _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
P A TI E N T ’S N U M B E R : _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
  
 
D O S A G E :  
R-HI L -1 8 B P 
D O S E D
 A T  2  
M G /K G
 S U B 
C U T A N E O U S E V E R Y  2  D A Y S (M A XI M A L D O S E : 1 6 0  M G )                
  
 
V E R SI O N X X.  D A T E D D D M M M Y Y Y Y  
 
C o nt a ct d et ail s a n d l a n g u a g e s will b e a d a pt e d t o c o u ntri e s w h er e u s e d; l o c all y a p pr o v e d 
v er si o n t o b e di stri b ut e d t o p ati e nt s  
 

SAP_001.pdf: 
A B 2 Bi o Lt d 
N L R C 4/ XI A P. 2 0 1 6. 0 0 1  
Statistical  A nal ysis  Pla n 
Versi o n  7. 0;  2 5  Se pte m ber 2 0 2 3  
C o nfi de nti al  
Pa ge  1  of  4 6  
 
 
 
 
 
 
 
 
 
 
S T A TI S TI C A L  A N A L Y SI S  P L A N  
A B 2 Bi o Lt d 
N L R C 4/ XI A P. 2 0 1 6. 0 0 1  
 
 
 
 
 
 
 
 
 
Pr ot oc ol  Title:  
M ultice nter, d o u ble -bli n d, place b o -c o ntr olle d, ra n d o mize d 
wit h dra wal  trial wit h  Ta d e ki ni g  alfa (r-hI L - 1 8 B P) i n patie nts 
wit h  I L- 1 8 dri ve n m o n o g e nic a ut o-i nfla m mat or y c o n diti o ns: 
N L R C 4 m utati o n a n d XI A P deficie nc y 
Pr ot oc ol Versi o n 
a n d D ate: 
Versi o n  6. 0; 3 Se pte m ber  2 0 2 1  
S p o ns or:  
A B 2  Bi o Lt d  
E P F L  I n n o v ati o n Par k 
B uil di n g B, 4 t h Fl o or 
C H - 1 0 1 5 La usa n n e,  S witzerla n d  
Pre p are d  B y:  
 
Precisi o n f or Me dici ne 
6 0 0 5 Hi d de n Valle y  R oa d, S uite  1 7 0  
Carls ba d,  C A  9 2 0 1 1  
D oc u m e nt  Versi o n 
a n d D ate:  
Versi o n  7. 0; 2 5 Se pte m ber  2 0 2 3  




A B 2 Bi o Lt d 
N L R C 4/ XI A P. 2 0 1 6. 0 0 1  
Statistical  A nal ysis  Pla n 
Versi o n  7. 0;  2 5  Se pte m ber 2 0 2 3  
C o nfi de nti al  
Pa ge  3  of  4 6  
 
 
2  T A B L E O F  C O N T E N T S  
1  
St atistic al  A n al ysis Pl a n  A p pr o v al  ............................................................................ 2 
2  
T a ble of C o nte nts  ........................................................................................................ 3 
3  
List  of A b bre vi ati o ns  ................................................................................................... 5 
4  
I ntr o d ucti o n ................................................................................................................. 7 
5  
St u d y  O bjecti ves  .......................................................................................................... 7 
5. 1  
Pri m ar y  St u d y  O bjecti ves  ..................................................................................... 7 
5. 2  
Sec o n d ar y  St u d y  O bjecti ves  .................................................................................. 7 
5. 2. 1  
Sec o n d ar y  Effic ac y  O bjecti ve  .......................................................................... 7 
5. 2. 2  
Sec o n d ar y  S afet y  O bjecti ve  ............................................................................. 8 
6  
I n vesti g ati o n al Pl a n  ..................................................................................................... 8 
6. 1  
O ver all  St u d y  Desi g n  ............................................................................................. 8 
6. 1. 1  
Scree ni n g  Peri o d  ............................................................................................... 8 
6. 1. 2  
Si n gle  Ar m  O pe n -L a bel  P h ase  ........................................................................ 9 
6. 1. 3  
R a n d o mize d  Wit h dr a w al P h ase  .................................................................... 1 0  
6. 1. 4  
A d diti o n al  St a n d ar d  of C are  C y cles  or Resc ue  
I m m u n os u p pressi o n ....................................................................................... 1 1  
6. 1. 5  
Ori gi n al  St u d y  Desi g n  .................................................................................... 1 2  
6. 2  
Sc he d ule  of Assess me nts  ...................................................................................... 1 2  
6. 3  
Tre a t me nts ............................................................................................................ 1 2  
6. 3. 1  
Tre at m e nts  A d mi nistere d  .............................................................................. 1 2  
6. 3. 2  
Met h o d  of Assi g ni n g  P atie nts  t o Tre at me nt  Gr o u ps  .................................. 1 3  
6. 4  
Effic ac y  a n d S afet y  V ari a bles  ............................................................................. 1 3  
6. 4. 1  
Effic ac y  V ari a bles  .......................................................................................... 1 3  
6. 4. 2  
Descri pti o n  of S afet y  a n d T oler a bilit y  V ari a bles  ........................................ 1 8  
6. 4. 3  
Descri pti o n  of P h ar m ac o ki netic  V ari a bles  .................................................. 1 9  
6. 5  
D at a Q u alit y Ass ur a nce  ....................................................................................... 1 9  
7  
St atistic al  Met h o ds  .................................................................................................... 2 0  
7. 1  
Ge ner al  Met h o d ol o g y  ........................................................................................... 2 0  
7. 1. 1  
Re p orti n g  C o n ve nti o ns  .................................................................................. 2 0  
7. 1. 2  
Defi niti o n of  B aseli ne  ..................................................................................... 2 1  
7. 1. 3  
S u m m ariz ati o n b y  Visit  ................................................................................. 2 1  
7. 1. 4  
D at a  H a n dli n g  R ules  ...................................................................................... 2 2  
7. 1. 5  
St a n d ar d  C alc ul ati o ns  .................................................................................... 2 2  
7. 1. 6  
P at ie nt C o nsi der ati o n f or Ori gi n al  St u d y  Desi g n  ....................................... 2 3  
7. 2  
A n al ysis P o p ul ati o ns  ............................................................................................ 2 3  
7. 3  
St u d y  P atie nts  ....................................................................................................... 2 4  
7. 3. 1  
Dis p ositi o n  of P atie nts  .................................................................................... 2 4  
7. 3. 2  
Pr ot oc ol De vi ati o ns ......................................................................................... 2 4  
7. 3. 3  
De m o gr a p hic a n d Ot her  B aseli ne  C h ar acteristics  ...................................... 2 5  
7. 3. 4  
Me as ure m e nts  of Tre at me nt  C o m pli a nce  .................................................... 2 6  
7. 4  
Effic ac y  E v al u ati o n  .............................................................................................. 2 6  
7. 4. 1  
D at asets  A n al yze d  .......................................................................................... 2 6  
7. 4. 2  
Pri m ar y  Effic ac y  E n d p oi nt  A n al ysis Met h o ds  ............................................ 2 7  
7. 4. 3  
Ke y  Sec o n d ar y  Effic ac y  E n d p oi nt  A n al ysis Met h o ds  ................................. 2 9  


A B 2 Bi o Lt d 
N L R C 4/ XI A P. 2 0 1 6. 0 0 1  
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C o nfi de nti al  
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7. 4. 4  
Sec o n d ar y  a n d A d diti o n al  Effic ac y  E n d p oi nt  A n al ysis Met h o ds  .............. 2 9  
7. 4. 5  
St atistic al/ A n al ytic al  Iss ues ........................................................................... 3 5  
7. 4. 6  
Ser u m  C o nce ntr ati o ns  ................................................................................... 3 7  
7. 4. 7  
P h ar m ac o ki netic  A n al ysis  ............................................................................. 3 7  
7. 5  
S afet y  E v al u ati o n  .................................................................................................. 3 8  
7. 5. 1  
E xte nt of  E x p os ure  ......................................................................................... 3 8  
7. 5. 2  
A d verse  E ve nts  ............................................................................................... 3 8  
7. 5. 3  
De at hs,  Ot her  Seri o us  A d verse  E ve nts,  a n d Ot her  Si g nific a nt  
A d verse  E ve nts  ............................................................................................... 4 0  
7. 5. 4  
Cli nic al  L a b or at or y E v al u ati o n  .................................................................... 4 0  
7. 5. 5  
Vit al  Si g ns,  P h ysic al Fi n di n gs, a n d  Ot her  O bser v ati o ns Rel ate d t o 
S afet y  ............................................................................................................... 4 1  
7. 6  
Deter mi n ati o n  of S a m ple  Size  ............................................................................. 4 3  
7. 7  
C h a n ges i n t he C o n d uct of t he St u d y  or Pl a n ne d  A n al yses  ............................. 4 4  
8  
Refere nce  List  ............................................................................................................ 4 5  
A p pe n di x  A ....................................................................................................................... 4 6  


A B 2 Bi o Lt d 
N L R C 4/ XI A P. 2 0 1 6. 0 0 1  
Statistical  A nal ysis  Pla n 
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C o nfi de nti al  
Pa ge  5  of  4 6  
 
 
3  LI S T  O F  A B B R E VI A TI O N S  
T a ble 1 
List  of A b bre vi ati o ns  
 
A b bre viati o n  
Defi niti o n  
A D A  
a nti-dr u g  a nti b o d y 
A E  
a d verse e ve nt 
A E SI  
a d verse e ve nts  of  s pecial i nterest 
A T C  
A nat o mical  T hera p e utic  C he mical  
B MI  
b o d y  mass  i n de x 
C A R D  
Cas pase  Recr uiti n g  D o mai n  
C M V  
c yt o me gal o vir us  
C N S  
Ce ntral  Ner v o us  S yste m  
C R P  
C -reacti ve pr otei n  
C S R  
cli nical st u d y re p ort 
D S M B  
Data  Safet y  M o nit ori n g B oar d  
E B V  
E pstei n -Barr  vir us  
e C R F 
electr o nic  Case  Re p ort  F or m  
E O S  
E n d  of  St u d y  
E S R  
er yt hr oc yte s e di me ntati o n rate 
E T  
Earl y  Ter mi nati o n  
F A S  
F ull  A nal ysis  Set  
G C  
gl uc oc ortic oi ds  
GI  
gastr oi nte nsti nal  
I C H 
I nter nati o nal C o u ncil  f or Har m o nisati o n  
I L-1 8  
i nterle u ki n-1 8  
I L-1 8 B P  
I nterle u ki n-1 8  bi n di n g  pr otei n  
I M P 
I n v esti gati o nal Me dici nal  Pr o d uct  
I R R 
i nci de nt rate rati o 
K M  
Ka pla n -Meier  
L O C F  
last o bser vati o n  carrie d f or war d 
m AI D AI  
m o difie d A ut o -I nfla m mat or y Disease Acti vit y  I n de x 
M A S  
Macr o p ha g e  Acti vati o n  S y n dr o me  
Me d D R A  
Me dical  Dicti o nar y  f or R e g ulat or y  Acti vities  
N L R C 4  
N ucle oti de -bi n di n g  oli g o merizati o n  d o mai n,  le uci ne ric h re peat 
a n d C A R D  d o mai n  c o ntai ni n g 4  
P E Y  
Pers o n  E x p os ure  Years  
P G A  
P h ysicia n  Gl o bal  Assess me nt  
P K  
P har mac o ki netics  
P K A S  
P K  A nal ysis  Set  


A B 2 Bi o Lt d 
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C o nfi de nti al  
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A b bre viati o n  
Defi niti o n  
P P S  
Per -Pr ot oc ol  Set  
Q 1  
2 5 t h perce ntile  
Q 3  
7 5 t h perce ntile  
r-hI L -1 8  B P  
H u ma n  Rec o m bi na nt  I nt erle u ki n-1 8  Bi n di n g  Pr otei n  
R D B P C  
Ra n d o mize d  D o u ble -Bli n d  Place b o -C o ntr olle d  
R W  
Ra n d o mize d  Wit h dra wal  
R W S  
Ra n d o mize d  Wit h dra wal  A nal ysis  Set  
S A E  
seri o us a d v erse e ve nt 
S A O L  
Si n gle  Ar m  O pe n -La bel  
S A P  
statistical a nal ysis pla n  
S A S  
Safet y  A nal ysis  Set  
s.c. 
s u bc uta ne o usl y 
SI  
S ystè me  I nter nati o nal 
S O C  
sta n dar d of  care 
T A  
Ta de ki ni g  alfa 
T E A E  
treat me nt-e mer ge nt  a d v erse e ve nt 
U L N  
u p per  li mit of  n or mal  
V  
Visit  
W H O  
W orl d  Healt h  Or ga nizati o n  
XI A P  
X -li n ke d i n hi bit or of  a p o pt osis 


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4  I N T R O D U C TI O N 
T he p ur p ose of t his statistical a nal ysis pla n ( S A P) is t o pr o vi de c o m pre he nsi ve a n d 
detaile d descri pti o ns of t he met h o ds a n d pres e ntati o n of data a n al yses pr o p ose d f or A B 2 
Bi o Lt d Pr ot oc ol N L R C 4/ XI A P. 2 0 1 6. 0 0 1 ( M ultice nter, place b o-c o ntr olle d, ra n d o mize d 
wit h dra wal  trial wit h  Ta d e ki ni g  alfa [r-hI L - 1 8 B P] i n patie nts  wit h  i nterle u ki n- 1 8 [I L- 1 8] 
dri ve n m o n o ge nic a ut o-i nfla m mat or y c o n diti o ns: N L R C 4 m utati o n a n d XI A P 
deficie nc y). Des cri pti o ns of pla n ne d a n al yses are pr o vi de d i n or der t o a v oi d p ost h oc 
decisi o ns t hat ma y aff ect t he i nter pretati o n of t he statistical a nal ysis. T he statistical 
met h o ds a p plie d i n t he desi g n a n d pla n ne d a n al ys es of t his st u d y are c o nsiste nt wit h t he 
I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) g ui deli ne St atistic al Pri nci p als f or 
Cli nic al Tri als ( E 9) ( 1 9 9 8). 
T his S A P will be fi nalize d pri or t o data a n al ysis, bef ore brea ki n g t he treat m e nt bli n d o n 
t he Ra n d o mize d Wit h dra wal ( R W) p has e, a n d pri or t o data base l o c k t o pr o vi de f ull 
details, i ncl u di n g te m plates f or ta bles, listi n gs, a n d fi g ures, t o be prese nt e d  i n t he cli nical 
st u d y re p ort ( C S R). A n y c ha n ges bet w ee n t he st atistical met h o ds pr o vi de d i n t he cli nical 
st u d y pr ot oc ol a n d t his S A P  will  be e x plai ne d herei n;  a n y c h a n ges  or de viati o ns fr o m t his 
S A P relati ve t o t he fi nal  a nal ysis will  be f ull y d oc u me nte d i n t he C S R. Mi n or c ha n ges or 
de viati o ns fr o m t he te m plates f or ta bles, fi g ures, a n d listi n gs nee d n ot be d oc u me nte d i n 
t he C S R. 
5  S T U D Y  O B J E C TI V E S  
5. 1  
Pri m ar y  St u d y  O bjecti ves  
T he  pri mar y  o bjecti ves  of  t his st u d y are: 
•  T o assess cli nical efficac y of Ta de ki ni g alfa ( T A) i n m o n o ge nic a ut o- 
i nfla m mat or y diseases wit h  o n g oi n g i nfla m mati o n a n d deleteri o us m utati o ns of 
N ucle oti de- bi n di n g oli g o merizati o n d o mai n, le uci ne- ric h re peat a n d cas pas e 
recr uiti n g d o mai n ( C A R D d o mai n) c o ntai ni n g 4 ( N L R C 4) – Macr o p ha g e 
acti vati o n s y n dr o me ( M A S) m utati o n or X-li n ke d i n hi bit or of a p o pt osis ( XI A P) 
deficie nc y  
•  T o  assess  la b orat or y/ bi ol o gical e vi de n ce  of efficac y 
5. 2  
Sec o n d ar y  St u d y  O bjecti ves  
5. 2. 1  
Sec o n d ary Effic acy  O bjective  
T he sec o n d ar y efficac y o bjecti ve of t he st u d y is t o assess t he mai n cli nical feat ures a n d 
la b orat or y bi o mar kers (ie, c haract eristics  of eac h p atie nt pr ofile) l o n git u di nall y  d uri n g t he 
si n gle ar m o pe n-la b el ( S A O L) p has e f or eac h e x p eri me ntal patie nt. 


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5. 2. 2  
Sec o n d ary S afety  O bjective  
T he sec o n d ar y  s afet y o bj ecti ve of t he st u d y is t o assess t he safet y a n d t olera bilit y  of T A 
treat me nt i n m o n o ge nic, a ut oi nfla m mat or y diseas e har b ori n g d eleteri o us m utati o ns of 
N L R C 4 -M A S or XI A P.  
6  I N V E S TI G A TI O N A L P L A N  
6. 1  
O ver all  St u d y  Desi g n  
T his is a P hase 3 st u d y t o assess t he safet y a n d effi cac y of T A i n patie nts wit h 
m o n o ge nic, I L - 1 8 dri v e n a ut o-i nfla m mati o n d ue t o N L R C 4-M A S m utati o n or XI A P 
deficie nc y.  Beca use  of t h e li keli h o o d f or pat h o ge nic I L- 1 8 i n certai n m o n o ge nic diseas es, 
patie nts  k n o w n t o har b or deleteri o us  m utati o ns  i n N L R C 4 -M A S  or XI A P  a n d w h o ha ve a 
hist or y of o n g oi n g i nfla m mati o n will be e nr olle d if t he y ha ve ferriti n ≥ 5 0 0 n g/ m L or 
persiste nt C -reacti ve pr ot ei n ( C R P) ele vati o n ≥ 2 ti mes t he u p per li mit of n or mal ( U L N) 
a n d t he patie nts  ha ve a M o difie d A ut o -I nfla m mat or y Diseas e  A cti vit y  I n d e x ( m AI D AI) ≥ 
4.  
T his st u d y is desi g ne d wit h S A O L of  T A  treat me nt d urati o n f or 1 8 wee ks f oll o we d b y a 
1 6- wee k R W p h ase f or efficac y  a n d s afet y  e val uati o n, wit h n o i nterr u pti o n bet wee n t he 
t w o p hases  of tr eat me nt. All patie nts  w h o c o m plet e t he 1 8 wee ks  of  treat me nt d uri n g t he 
S A O L p hase a n d s h o wi n g a partial or c o m plete res p o nse at Wee k 1 8 ( V 8) will be 
ra n d o mize d t o o ne of t he t w o treat me nt ar ms i n a 1: 1 rati o t o be gi n treat me nt i n t he R W 
p hase. Patie nts  will  recei ve t he st u d y treat me nt ( pl ace b o or  T A) f or u p  t o a n a d diti o nal 1 6 
wee ks. D uri n g t he R W p hase, patie nts w h o de v el o p a partial or f ull disease reacti vati o n 
bef ore t h e 1 6 - wee k treat me nt is c o m plete d will pr ocee d t o t he E n d of St u d y visit a n d 
c o m plete t he R W p has e. T he scree ni n g peri o d will occ ur bef ore t he S A O L p hase a n d 
bef ore t h e first d ose of I n vesti gati o nal Me dici nal Pr o d uct (I M P). 
T he p h ysicia ns a n d t he p atie nts ( or le gal re pres e nt ati ve) will ha ve t he o pti o n t o 
disc o nti n ue treat me nt if t he y feel t hat p urs ui n g t he treat me nt is n ot a p pr o pri ate. T he 
p h ysicia n ca n deci de a n y ti me t o start resc ue i m m u n os u p pressi o n a n d t heref ore 
disc o nti n ue t he patie nt fr o m t he st u d y. I n t his case, all ke y  safet y a n d efficac y  o utc o mes 
will  be f oll o we d u p. Patie nts  will  c o nti n ue t o c o me t o t he sc he d ul e d visits f or safet y a n d 
efficac y ass ess me nts. T he occ urre n ce of a d vers e e ve nts of se verit y gra des 3 or 4 ma y 
res ult i n tra nsie nt or per ma ne nt treat me nt disc o nti n uati o n. If treat me nt i nterr u pti o n is 
m ore t ha n 3 wee ks, t he p atie nt will be per ma ne ntl y disc o nti n ue d fr o m t he st u d y. 
A n  esti mate d ma xi m u m  of 1 5 patie nts  will  be e nr olle d i n t his st u d y at a p pr o xi matel y  1 1 
cli nical sites i n t he U nite d States, Ca na da, a n d G er ma n y. A ma xi m u m of 1 5 patie nts 
e nr olle d will e ns ure t he r a n d o mizati o n of at least 1 0 patie nts i n t he R W p hase. 
6. 1. 1  
Scree ni n g  Peri o d  
T he  scr ee ni n g visit ( V 0) will  occ ur bef ore  t he start of t he st u d y treat me nt. At V 0,  t he 
patie nt  a n d/ or t he p atie nt’s  le gal g uar dia n(s) will  si g n a C hil d  Asse nt  F or m  a n d/ or a n 


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I nf or me d C o nse nt F or m t hat will be c ollecte d b y t he I n vesti gat or. All eli gi bilit y criteria 
will  be re vie we d d uri n g t he scree ni n g peri o d A N D m ust all  be met i n  or der t o deter mi ne 
patie nt eli gi bilit y i nt o t he st u d y.  
6. 1. 2  
Si n gle  Ar m  O pe n - L a bel P h ase  
Eli gi bilit y  criteria s h o ul d be c o nfir me d  a gai n at t he Baseli ne  Visit ( V 1). Pati e nts 
e x perie n ci n g a n acti ve disease will be gi n T A treat me nt at V 1.  
Be gi n ni n g at V 1, T A  will  be a d mi nistere d i n  a d diti o n t o t he sta n dar d of care  ( S O C) 
treat me nt use d f or t he c o ntr ol of t he acti ve disease. I n t he a bse n ce of a n a p pr o ve d 
me dicati o n f or t his disease, t he S O C as defi ne d i n t he st u d y pr ot oc ol c o nsists of 
gl uc oc ortic oi ds ( G C), wit h a 2 8- da y ta peri n g sc he d ule as f oll o ws: 
•  2 8- da ys ( 4 wee ks):  Dail y  P O/I V  De xa m et has o ne  1 0  m g/ m 2 x 7 da ys, 5 m g/ m 2 x 7 
da ys, 2. 5 m g/ m 2 x 7 da ys, 1. 2 5 m g/ m2 x 7 da ys. 
Patie nts  w h o res p o n d t o t he i nitial 2 8-da y  c o urs e of  T A  + G C  ( partial or c o m plete 
res p o nse as d efi ne d i n Secti o n 6. 4. 1. 2) will recei v e T A f or 1 4 a d diti o nal wee ks. 
Patie nts  w h o res p o n d t o T A  + S O C  i nitial c o urse a n d ha ve a disease  reacti vati o n a gai n 
d uri n g t he S A O L p hase will recei ve a n ot her c o urse of T A + S O C wit h t he sa me G C 
d osa ge a n d ta p eri n g sc he d ule use d f or t he i nitial treat me nt of t he acti ve disease. 
Mai nte na nce treat me nt, wit h t he per mitte d me dicati o ns, at sta ble a n d at t h e sa me d oses 
utilize d at st u d y  e ntr y are all o we d. D ose i ncre me nts f or t he per mitte d c o- me dicati o ns or 
t heir i ntr o d ucti o n after t h e be gi n ni n g of t he st u d y are n ot per mitte d a n d re prese nt 
treat me nt fail ur es a n d st u d y earl y ter mi nati o n. If p er mitte d c o-me dicati o ns are w ea ne d 
off  d uri n g t he c o urse of t he st u d y a n d t he i n vesti gat or deci des  t o re-i ntr o d u ce t he m, t h e y 
are per mitte d as l o n g as t he d oses are t he sa me or l o wer t ha n t he d oses us e d at st u d y 
e ntr y. 
U p o n lac k of res p o ns e t o c o m bi ne d treat me nt after e nr oll me nt or u p o n t he occ urre nce of 
a disease r eacti vati o n d uri n g t he c o urse of t he S A O L after i nitial res p o ns e, t he 
i n vesti gat or ma y  deci de  t o treat t he patie nt wit h  resc ue i m m u n os u p press ors. T his  decisi o n 
res ults i n patie nt disc o nti n uati o n fr o m t he st u d y. 
Ta de ki ni g alfa will  be a d mi nistere d  at 2 m g/ k g ( wit h a ma xi m u m  of 1 6 0 m g) 
s u bc uta ne o usl y (s.c.) f or u p t o a p pr o xi matel y 1 8 wee ks. 
At V 0 a n d V 1, patie nts will u n der g o a p h ysical e x a mi nati o n, meas ure me nt of  vital si g ns, 
a n d r o uti ne la b or at or y testi n g (i ncl u di n g he mat ol o g y, cli nical c he mistr y, uri nal ysis, 
er yt hr oc yte se di me nt ati o n rate [ E S R], C R P, a n d c oa g ulati o n pa nel). Bi ol o gical e v al uati o n 
a n d ge netic dia g n osis of a ut o- i nfla m mat or y c o n diti o ns ( N L R C 4- M A S, XI A P deficie nc y, 
a n d ot her m o n o ge nic ass ociati o ns wit h M A S) will be d o ne at V 0 (scree ni n g visit). 
Sa m ples  f or fl o w c yt o metr y  f or s us pecte d XI A P  d eficie nc y  will  be a nal yze d d uri n g t he 
scree ni n g p eri o d a n d pri or t o V 1. C o m plete me dical a n d disease hist or y will als o be 
c ollecte d d uri n g V 0. I n  a d diti o n, pri or t o i nitiati o n of t hera p y, c yt o me g al o vir us ( C M V) 


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a n d E pstei n -Barr  vir us ( E B V) tests, ser ol o g y tests, a n d a c o m plete i nfecti o us  w or k u p will 
be perf or me d.  
S pecific la b or at or y  det er mi nati o ns s uc h as t otal a n d free I L- 1 8 a n d I L- 1 8 B P will be 
perf or me d at V 1 a n d s u bse q ue nt visits. 
T he gl o bal disease acti vit y  will be assesse d b y  t he m AI D AI. T h e m AI D AI will be 
a p plie d at all st u d y visits a n d will be a vaila ble f or re vie w t hr o u g h o ut t he st u d y. F or t he 
e val uati o n  of res p o nse t o t hera p y a n d disease reacti vati o n, o nl y t he o bjecti ve  para meters 
of t he m AI D AI will be ta ke n i nt o c o nsi derati o n. A P h ysicia n  Gl o bal Assess me nt ( P G A) 
t o ol will als o be a p plie d at all st u d y visits b y t he p h ysicia n t o assess t he gl o bal disease 
stat us. T he patie nt’s or care gi ver’s e v al uati o n of t he healt h stat us q uesti o n naire will be 
a p plie d at V 1 a n d t he e n d of t he S A O L p hase. 
Assess me nts d uri n g t he S A O L p hase ( V 1 t o V 8) will i ncl u de c o m plete p h ysical 
e xa mi nati o n, re vie w of all a d verse e ve nts ( A Es), a n d r o uti ne a n d s pecifi c la b orat or y 
a nal ysis. Sa m ples  f or a nti- dr u g a nti b o dies ( A D As) will be c ollecte d  at Bas eli ne of S A O L 
( V 1), Wee k 2 ( V 3), Wee k 4 ( V 5), Wee k 1 2 ( V 7), a n d Wee k 1 8 ( V 8). 
6. 1. 3  
R a n d o mize d Wit h dr a w al P h ase:  
All patie nts w h o ha ve c o m plete d 1 8 wee ks of treat me nt d uri n g t he S A O L p hase a n d 
s h o wi n g a partial  or  c o m plete res p o ns e at Wee k 1 8  ( V 8) will  be ra n d o mize d i n a 1: 1 rati o 
t o be gi n treat me nt i n t he R W p hase. Patie nts will  recei ve t h e st u d y treat me nt ( place b o or 
T A) f or u p t o a n a d diti o nal 1 6 wee ks. E x p erie nci n g a disease reacti vati o n at a n y p oi nt 
d uri n g t he 1 8- wee k S A O L p hase will n ot pre ve nt a patie nt fr o m e nr oll me nt i nt o t he R W 
p hase; rat her, patie nts ar e re q uire d t o meet t he crit eria f or o n g oi n g T A treat me nt 
t hr o u g h o ut t he S A O L p hase a n d s h o w a partial or c o m plete res p o nse at Wee k 1 8 ( V 8). 
Treat me nt i nterr u pti o n  is n ot rec o m me n d e d bet w ee n  t he t w o p hases. Baseli ne  data  f or t he 
R W  p hase will  be t he last data  c ollecte d pri or t o ra n d o mizati o n at t he Wee k  1 8 ( V 8) visit.  
D uri n g t he R W p hase, visits will be sc he d ule d at Wee k 2 0 ( V 9), Wee k 2 2 ( V 1 0), a n d 
Wee k 2 6 ( V 1 1), Wee k 3 0 ( V 1 2), a n d Wee k 3 4 ( V 1 3/ E n d of St u d y [ E O S]). At R W visits, 
patie nts will u n der g o a c o m plete p h ysical e xa mi n ati o n a n d la b orat or y t esti n g (i ncl u di n g 
he mat ol o g y, cli nical c he mistr y, uri nal ysis, E S R, C R P, ferriti n, a n d c oa g ul ati o n pa nel), 
a n d deter mi nati o ns of t ot al a n d free I L- 1 8 a n d of I L- 1 8 B P. T he m AI D AI a n d P G A will 
be c ollecte d at all visits i n t he R W p hase. T he p atie nt’s or care gi ver’s e v al uati o n of t he 
healt h  stat us q uesti o n nair e will  be a p plie d at t he e n d of t he R W  p hase. Sa m ples f or A D As 
will be c ollecte d at Wee k 2 2 ( V 1 0), Wee k 2 6 ( V 1 1), a n d Wee k 3 4 ( V 1 3/ E O S). 
D uri n g t he R W p hase, p atie nts w h o de vel o p a partial or f ull disease reacti v ati o n bef ore 
t he 1 6-wee k  R W  treat me nt peri o d is c o m plete d will  pr ocee d  t o t he E n d  of St u d y visit a n d 
c o m plete t he R W p has e. T he i n vesti gat or ma y als o deci de t o start resc ue 
i m m u n os u p pressi o n a n d disc o nti n ue treat me nt. If a p plica ble, data of a d mi nistrati o n of 
ot her me dicati o ns or r esc ue i m m u n os u p pressi o n d uri n g b ot h p hases ( S A O L a n d R W) 
will  be c ollecte d, i ncl u di n g t he ti me of treat me nt start a n d fi nis h a n d w het h er or n ot t here 
was a r es p o nse t o t he r esc ue treat me nt.  


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Patie nts w h o disc o nti n ue treat me nt pri or t o t he e n d of eit her treat me nt p has e ( S A O L or 
R W) will be f oll o we d f or all  ke y  efficac y a n d safet y  assess me nts  u p t o t he E n d of St u d y 
visit.  
6. 1. 4  
A d diti o n al St a n d ar d of C are Cycles  or Res c ue  I m m u n os u p pressi o n 
A)  If n o  res p o nse after  t he first c o m bi ne d  tre at me nt c o urse ( S O C + I M P) at t he 
i niti ati o n of t he S A O L p h ase: 
If patie nts  d o n ot res p o n d t o st u d y treat me nt after t he i nitial c o m bi ne d treat me nt 
c o urse, t he y will be tr eat e d wit h resc u e i m m u n os u p pressi o n or wit h ne w/ 
i ncreas e d d oses of p er mitte d c o nc o mita nt treat me nts. T hese cas es will be 
c o nsi dere d tr eat me nt f ail ures d uri n g t he S A O L p h ase a n d will e xit t he st u d y. 
B)  P atie nts  wit h  a dise ase  re acti v ati o n after  h a vi n g res p o n de d  t o t her a p y i n t he 
S A O L p h ase:  
If patie nts s h o w si g ns of s yste mic i nfla m mat or y reacti vati o n (ie, partial or f ull 
disease  r eacti vati o n) after ha vi n g res p o n de d t o t hera p y i n t he S A O L  p has e p hase, 
t he y will recei ve a n ot her c ycle of S O C i n a d diti o n t o t he I M P. 
C)  P atie nts  wit h  a dise ase  re acti v ati o n d uri n g  t he t a peri n g d o w n  of S O C  d uri n g 
t he c o m bi ne d tre at m e nt i n t he S A O L p h ase: 
If after a n i nitial i m pr o ve me nt i n res p o nse para met ers,  t he patie nts  s h o w si g ns of 
i ncreasi n g i nfla m mati o n (ie, partial or f ull disease reacti vati o n) d uri n g t he 
ta peri n g d o w n of S O C w hile i n c o m bi ne d treat me nt, a n ot her f ull c ycl e of 
e xte n de d S O C ( 4 wee ks) i n a d diti o n t o t he I M P will be i nitiate d at t he ori gi nal 
d ose.  
I n t he l ast cases ( B or C), t he I n v esti gat or ma y als o deci de t o start resc ue 
i m m u n os u p pressi o n, a n d i n t his case, t he patie nt s h o ul d disc o nti n ue st u d y treat me nt d ue 
t o treat me nt fail ure. 
A n y patie nt starti n g resc ue i m m u n os u p pressi o n treat me nt will be c o nsi dere d a treat me nt 
fail ure a n d will pr ocee d t o t he st u d y disc o nti n uati o n/earl y ter mi nati o ns pr o ce d ures. Data 
relate d t o res p o nse t o t he resc ue treat me nt will be c ollecte d i ncl u di n g all ke y  efficac y a n d 
safet y e n d p oi nts. 
It is rec o m me n de d t hat p atie nts s ufferi n g fr o m se v ere C N S  ma nifestati o ns  are p ut o n 
resc ue i m m u n os u p pressi o n treat me nt. 
Patie nts  t hat prese nt a  partial  or f ull  disease  reacti vati o n after pre vi o us res p o nse t o S O C + 
T A i n t he S A O L ca n re m ai n i n t he st u d y a n d recei ve a n ot her c ycle of  S O C i n a d diti o n t o 
t he c o nti n u o us T A treat me nt if, acc or di n g t o t he treati n g p h ysicia n, t he se verit y d oes n ot 
re q uire r esc u e i m m u n os u p pressi o n. Patie nts t hat prese nt a p artial or f ull dis ease 
reacti vati o n i n t he R W P hase bef ore t he 1 6-wee k treat me nt is c o m plete d will pr ocee d t o 
t he E n d of St u d y Visit a n d c o m plete t he R W P has e. 




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dr u g a n d t h e place b o s ol uti o ns will  be s u p plie d i n i de ntical vials  a n d si milar la beli n g a n d 
will be i n disti n g uis ha ble i n ter ms of t heir te xt ure, c ol or, a n d s mell.  
Patie nts  will  recei ve a d ose of 2 m g/ k g ( wit h a ma xi m u m  of 1 6 0 m g) of T A  s.c. e ver y 2 
da ys ± 5 h o urs f or a t otal treat me nt peri o d of 1 8 w ee ks i n t he S A O L p has e. 
Patie nts i n  t he R W  p hase will  be treate d wit h  t he sa me d osa ge or  v ol u me ( 2 m g/ k g, s.c., 
e ver y 2 da ys) of eit her T A or e q ui vale nt v ol u me of place b o, as ra n d o mize d. T he 
treat me nt peri o d i n t his p hase is u p t o 1 6 wee ks. 
6. 3. 2  
Met h o d  of Assi g ni n g  P atie nts  t o Tre at me nt  Gr o u ps  
Patie nts w h o meet all i ncl usi o n a n d n o n- e xcl usi o n criteria will be e nr olle d i n t he S A O L 
p hase a n d will be sc h e d ule d t o recei v e o pe n -la b el T A f or 1 8 w ee ks. All patie nts w h o 
ha ve c o m plete d 1 8 wee ks of treat me nt d uri n g t he S A O L p hase a n d s h o wi n g a partial or 
c o m plete res p o nse at Wee k 1 8 ( V 8) will  be ra n d o mize d t o T A  or  place b o i n  a 1: 1 rati o t o 
be gi n treat me nt i n  t he R W  p has e. E x peri e nci n g a disease  reacti vati o n at a n y p oi nt d uri n g 
t he 1 8- wee k S A O L p has e will n ot pre ve nt a patie nt fr o m e nr oll me nt i nt o t he R W p hase; 
rat her, p atie nts are re q uir e d t o meet t he criteria f or o n g oi n g T A treat me nt t hr o u g h o ut t he 
S A O L p hase a n d b e wit h o ut s h o w a partial or c o m plete res p o nse at Wee k 1 8. T he 
ra n d o mizati o n will be str atifie d b y disease c o n diti o n at R W p hase e ntr y ( N L R C 4-M A S 
m utati o n or XI A P deficie nc y). T he ra n d o mizati o n will be desi g ne d t o be d y na mic yet 
n o n- deter mi nistic s uc h t h at patie nts are ra n d o mize d i n a 1: 1 rati o wit hi n eac h disease 
c o n diti o n, w hile als o e ns uri n g t hat t he o verall all o cati o n is e xactl y bala n ce d if t he t otal 
n u m ber of patie nts r a n d o mize d is a n e ve n n u m ber a n d differe nt b y n o m ore t ha n o ne if 
o d d.  
Gi ve n  t he st u d y s pecificati o ns t o ra n d o mize te n s u bjects i n eac h of  t w o strata defi ne d  b y 
ge netic m utati o n, a ra n d o mizati o n strate g y is defi n e d base d o n a bi n o mial distri b uti o n 
w hic h  all ocates s u bj ects i n  a 1: 1 rati o t o T A or Place b o. T his will be acc o m plis he d b y a 
bl oc ke d ra n d o mizati o n, w herei n wit hi n eac h bl oc k of t w o s u bjects, o ne s u bject is 
ra n d o mize d t o r ecei ve T A a n d t he ot her is ra n d o mize d t o recei ve Place b o. Wit h t he 
pla n ne d fi xe d sa m ple size of N = 1 0 a n d a bl oc k si ze of t w o, t he ra n d o mizati o n list will 
ha ve fi ve bl oc ks. Beca us e t here are t w o p ossi ble c o nfi g urati o ns of eac h bl o c k ( T A, 
Place b o; a n d Place b o, T A), t here are a  t otal of 3 2 differe nt w a ys t he fi ve bl oc ks ca n be 
arra n g e d t o pr o d uce t he r a n d o mizati o n list. 
6. 4  
Effic ac y  a n d S afet y  V ari a bles  
6. 4. 1  
Effic acy  V ari a bles  
Efficac y  ass ess me nt  is relate d t o t he i nci de n ce of disease  reacti vati o ns a n d will  c o ver: 
i) 
Cli nical  e val uati o n  (ca pt ure d m ostl y b y t he m AI D AI):  
o  C o m plete p h ysical e xa mi nati o n i ncl u di n g: vital si g ns (s yst olic a n d 
diast olic bl o o d press ure,  heart  rate, res pirat or y rate, wei g ht, a n d b o d y 
te m perat ure) 


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o  All fi n di n gs s h o ul d be d oc u me nte d: j oi nt s welli n g, he pat o me gal y a n d 
s ple n o me gal y, prese nce  of s ki n ras h, a n d o p ht hal mic c o ntr ol ( pres e nce of 
u veitis). O p ht hal mic e xa mi nati o n will be perf or m e d f or ass ess me nt of 
u veitis;  
o  S y m pt o ms re q uiri n g d oc u me ntati o n: a b d o mi nal pai n, diarr hea,  na usea, 
a n d v o miti n g 
o  All  cli nical c o m p o n e nts (i ncl u di n g cli nical fi n di n gs a n d s y m pt o ms) of t he 
disease will  be ca pt ure d i n a bi nar y wa y  as eit her bei n g prese nt or a bse nt. 
T his bi nar y s yste m is c o nsi dere d t he m ost stri n ge nt t o ol t o descri be a 
cli nicall y rele v a nt le vel of i m pr o ve me nt a n d c o ntr ol of t he se vere cli nical 
ma nifestati o ns  i n t he patie nts  treate d wit h  T A.  T he  j u d ge me nt, of w het her 
a n e n d or ga n cate g or y is affecte d, is d o ne b y t he treati n g p h ysicia n 
acc or di n g t o cli nical sta n dar ds, as als o pre vi o usl y d o ne f or all m AI D AI 
c o m p o ne nts  
o  Dail y  wei g ht, st o ol o ut p ut, a n d P O  i nta ke meas ure me nts  i ncl u di n g n u m ber 
of e mesis e pis o des will be perf or me d o n patie nts wit h i ntesti nal 
d ysf u ncti o n, o nl y w he n t he patie nts are h os pitalize d 
o  Ra di ol o gic fi n di n gs if ass esse d  as n ecessar y  b y t he treati n g p h ysicia n  
ii) 
Mai nte na nce  of c o -treat me nt: 
o  T otal  wee kl y  gl uc oc ortic oi ds  
o  I L- 1 bl oc kers  
o  Ot her  treat me nts (ie, disease m o dif yi n g a nti-r h e u matic dr u g, etc.) 
iii) 
La b orat or y assess me nts:  
o  Ser u m  C R P  
o  Ser u m ferriti n 
o  C o m plete  bl o o d c o u nts 
o  Ser u m  le vels of t otal I L- 1 8, free I L- 1 8, a n d I L-1 8 B P  
 
 
6. 4. 1. 1  
Pri m ary  Effic acy  E n d p oi nt  
T he  pri mar y  efficac y  e n d p oi nt is t he ti me t o first occ urre nce  of disease  reacti vati o n 
(i ncl u di n g f ull a n d partial disease reacti vati o n) d uri n g t he 1 6-wee k R W p h ase.  
A Dise ase  re a cti v ati o n  occ urs  if: 
F or  disease  reacti vati o n, o nl y t he o bjecti ve m AI D AI  c o m p o ne nts will  be e val uate d as 
i n dicate d bel o w. S u bjecti ve m AI D AI c o m p o ne nts (see A p p e n di x I of t he cli nical 
st u d y pr ot oc ol) will n ot be c o nsi dere d t o a v oi d a n y bias i n t he assess me nt. A p pe n di x  


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A  i ncl u des a descri pti o n of t he ma p pi n g of t he m AI D AI c o m p o ne nts i nt o t he 
O bjecti ve m AI D AI t otal sc ore.  
D uri n g t he R W- p has e, t he ref ere n ce f or a disease reacti vati o n (f or t he pri m ar y 
e n d p oi nt assess me nt) will  be t he e n d of t he S A O L  p hase ( V 8); f or t he S A O L  p hase, 
refere nce will be  t he pre vi o us visit, as patie nts  e nter t he S A O L  p h ase  wit h  a n acti ve 
disease.  
o  P arti al dise ase  re acti v ati o n 
•  I n crease i n t he n u m ber of  affecte d  o bjecti ve e n d or ga n da ma ge 
cate g ories b y at least 2 or  
•  I n crease i n t he n u m ber of affecte d o bjecti ve e n d or ga n da ma ge 
cate g ories b y at least 1 a n d w orse ni n g of at least 1 s yste mic 
i nfla m mat or y mar ker  (i. e., ser u m ferriti n le vels ≥5 0 0 n g/ m L or ser u m 
C R P ≥2 x U L N) t hat was meeti n g c o m plete res p o nse criteria b ef ore  
o  F ull  dise ase  re acti v ati o n  
•  I n crease i n t he n u m ber of affect e d o bjecti ve e n d or ga n da ma g e 
cate g ories  t o at least t he n u m ber of  affecte d e n d or ga n d a ma ge 
cate g ories at baseli ne ( V 1) a n d  
•  E xacer bati o n of at least 1 s yste mic i nfla m mat or y mar ker (i. e., ser u m 
ferriti n le vels ≥5 0 0  n g/ m L  or  ser u m C R P  ≥2 x  U L N)  t hat was  meeti n g 
c o m plete res p o nse criteri a bef ore  
N ote:  It is r ec o m me n d e d t hat patie nts s ufferi n g fr o m severe C N S ma nifestati o ns  are p ut 
o n resc ue i m m u n os u p pressi o n treat me nt. 
Ti me t o first occ urr e nce of  disease reacti vati o n will be calc ulate d i n w ee ks as t he date  of 
disease  r eacti vati o n d uri n g t he R W  p hase mi n us t he date  of ra n d o mizati o n d uri n g t he R W 
p hase pl us 1, di vi de d b y 7. Patie nts w h o d o n ot e x perie nce a disease reacti v ati o n d uri n g 
t he R W p hase will  be ce ns ore d at t he dat e  of t heir l ast cli nical assess me nt d uri n g t he R W 
p hase i n dicati n g n o disease reacti vati o n. Patie nts will  be assesse d f or disease  reacti vati o n 
d uri n g t he R W p hase at all sc he d ule d or u nsc he d ul e d visits. 
6. 4. 1. 2  
Sec o n d ary Effic acy  E n d p oi nts  
T he  ke y  sec o n dar y efficac y  e n d p oi nt is 
•  Res p o nse t o t hera p y (i ncl u di n g c o m plete res p o nse a n d partial res p o nse) i n t he 
S A O L  p hase fr o m Wee k  1 0 o n war ds a n d o bs er ve d at  least at 2 c o nsec uti ve visits 
at least 2 wee ks a part d uri n g t he S A O L p hase  
Ot her  sec o n dar y efficac y  e n d p oi nts i ncl u de t he f oll o wi n g: 
•  Best res p o nse t o t hera p y d uri n g t he S A O L  p has e (i ncl u di n g c o m plete res p o nse 
a n d partial r es p o nse a n d disease i m pr o ve me nt) 


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•  D urati o n of res p o nse t o t hera p y (i ncl u di n g c o m plete res p o nse a n d partial 
res p o nse) d uri n g t he S A O L p hase 
•  Disease  reacti vati o n rate (ie, n u m ber of diseas e  reacti vati o ns e x perie nce d  per 
wee k w hile eac h s u bject is o n t he st u d y treat me nt d uri n g t he S A O L p hase) 
•  Treat me nt  fail ures (ie, patie nts  w h o  e x perie nce at l east o ne disease  reacti vati o n), 
d uri n g t he R W p hase 
•  I nte nsit y of disease r eacti vati o ns ( defi ne d b y t he le vel of acti vit y gi ve n b y t he 
m AI D AI  – b ot h o bjecti ve a n d s u bjecti ve criteria),  d uri n g t he R W  p hase a n d t he 
S A O L p hase  
•  Ser u m  C R P  d uri n g t he R W  p has e a n d t he S A O L  p hase  
•  Ser u m  ferriti n d uri n g t he R W  p hase a n d t he S A O L  p hase  
•  I m pr o v e me nt of f e vers (if pres e nt at baseli ne)  d uri n g t he R W  p hase a n d t he 
S A O L p hase  
•  I m pr o v e me nt of h e pat o/s ple n o me gal y (if pres e nt at  baseli ne)  d uri n g t he R W 
p hase a n d t he S A O L p h ase 
•  I m pr o v e me nt i n ser u m al b u mi n a n d li ver tra nsa mi nases, a ne mia  a n d/ or plat elet 
c o u nt (if pres e nt at baseli ne) d uri n g t he R W p has e a n d t he S A O L p hase 
•  N u m ber of h os pitalizati o ns  a n d h os pital le n gt h of sta y d uri n g t he R W  p has e a n d 
t he S A O L p hase 
•  P G A  d uri n g t he R W  p has e a n d t he S A O L  p hase  
•  Patie nt’s  or care gi ver’s  q ualitati ve  e val uati o n of h ealt h  stat us 
•  Prese nce  of s ki n r as h (e v ol uti o n if prese nt at  baseli ne  or a p peara nce d uri n g t he 
st u d y) d uri n g t he R W p hase a n d t he S A O L p h ase 
•  T olera nce t o oral/e nteral n utriti o n f or h os pitalize d patie nts wit h i ntesti nal 
d ysf u ncti o n t hat was pres e nt at baseli ne  d uri n g t he R W  p hase a n d t h e S A O L 
p hase  
•  I m pr o v e me nt of st o ol o ut p ut f or h os pitalize d  patie nts if  i ntesti nal d ysf u ncti o n was 
prese nt at bas eli ne d uri n g t he R W p hase a n d t h e S A O L p hase 
Acti ve  dise ase  u p o n  e nr ol m e nt is defi ne d  as:  
o  I n crease d i nfla m mat or y mar kers,  i.e., ser u m ferriti n le vels ≥ 5 0 0 n g/ m L or 
ser u m C R P ≥ 2 x U L N, a n d 
o  Acti ve  cli nical disease  as  e vi de nce d  b y m AI D AI  ≥ 4 or C N S  ma nifestati o ns 
(i.e., seiz ures, alter e d me ntal  stat us, si g ns of i ncrease d i ntracra nial press ure, 
c hr o nic pa pille de m a, l oss of visi o n, ot her se ns ori n e ural deficie ncies, etc.) 
F or t he d efi niti o n of acti ve disease u p o n e nr ol me nt, all m AI D AI c o m p o ne nts 
(s u bjecti ve a n d o bjecti ve) will  be e val uate d i n  li ne wit h pre vi o us pr ot oc ol versi o ns 
pri or t o versi o n 6. 0. 


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Res p o nse  t o T her a p y  is defi ne d as:  
1.  I n t he 1 6- wee k R W p has e, res p o nse t o t hera p y (as pri mar y e n d p oi nt of 
efficac y) will  be ass esse d b y  pre ve nti o n of diseas e reacti vati o ns  d uri n g t he 1 6- 
wee k treat me nt i n t he R W p hase.  
2.  I n t he S A O L  p hase, res p o nse  t o t hera p y (as sec o n dar y e n d p oi nt of efficac y) 
will be assesse d t hr o u g h t he c o ntr ol of t he acti ve disease 
F or  r es p o nse t o t hera p y, o nl y t he o bjecti ve m AI D AI  c o m p o ne nts will  be e val uate d 
as i n dicate d bel o w. S u bjecti ve m AI D AI c o m p o ne nts (see A p pe n di x I of t he 
cli nical st u d y  pr ot oc ol) will n ot be c o nsi dere d t o a v oi d a n y bias i n t he efficac y 
assess me nt i n t he o pe n la bel part of t he st u d y. 
o  C o m plete  res p o nse 
N o  maj or  e n d or g a n  da m a ge  ( = o bjecti ve m AI D AI c o m p o ne nts) 
•  N o  fe ver ( b o d y te m perat ure ≤1 0 0 . 4ºF / 38 °C)  
•  N o  diarr hea  
•  N o  tra nsa mi nitis a n d/ or he pat o me gal y  
•  N o  s ple n o me gal y a n d/ or a de n o pat h y  
•  N o  ras h 
•  N o  u veitis  
•  N o  art hritis 
•  N o  ra di ol o gic C N S  i n v ol ve me nt 
•  N o  c yt o pe nia ( H g B ≥9. 0  a n d/ or P L T  ≥1 0 0  a n d/ or W B C  ≥3. 0)  
N o s yste mic i nfla m mati o n  
•  N o  h y perferriti ne mia  (s er u m le vel < 5 0 0 n g/ m L)  
•  N o  i ncrease d C R P  (ser u m le vel < 2 x U L N) 
I m m u n os u p pr essi ve t hera pies 
•  Disc o nti n uati o n of s yste mic c ortic oster oi ds (e xcl u di n g h y dr oc ortis o ne f or 
pre ve nti o n of a dre nal i ns ufficie nc y) or ot her i m m u n os u p pressi ve 
t hera pies i ncl u di n g bi ol o gics o n g oi n g at baseli ne 
•  N o start  or d ose i ncrease of ot her i m m u n os u p pressi ve t hera pies i ncl u di n g 
bi ol o gics  
o  P arti al res p o nse 
At least 5 0 %  re d u cti o n of t he n u m ber of affecte d o bjecti ve  e n d or g a n  da ma ge 
cate g ories at baseli ne a n d  


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•  At least 5 0 %  of t he s yste mic i nfla m mat or y mar kers  (ferriti n a n d/ or C R P) 
i ncreas e d at baseli ne reac hi n g le vels f or c o m plete res p o nse or 
•  Disc o nti n uati o n of s yste mic c ortic oster oi ds (e x cl u di n g h y dr oc ortis o ne f or 
pre ve nti o n of a dre nal i ns ufficie nc y) or ot her i m m u n os u p pressi ve 
t hera pies i ncl u di n g bi ol o gics o n g oi n g at baseli ne 
Partial res p o nse is t h us a meas ure of t h e c o m plete res ol uti o n of cli nical 
ma nifestati o ns i n  at least 5 0 % of i n v ol ve d s pecifi c or ga n classes t o get her wit h 
a re d ucti o n of t h e s yste mic i nfla m mat or y mar kers m ost rele va nt f or t his 
disease or t he p ossi bilit y t o re d uce ot her i m m u n os u p pressi ve t hera pies. 
o  Dise ase  I m pr o ve me nt 
A t hir d res p o nse cate g or y of Disease I m pr o ve m e nt is i ntr o d uce d t o be utilize d 
as a descri pti o n of best res p o nse a n d i n or der t o b etter  descri b e i nitial  treat m e nt 
res p o nse t o t her a p y a n d disease e v ol uti o n o ver ti m e. T his is o nl y use d f or 
a nal ysis p ur p oses a n d will n ot be e val uate d f or t he decisi o n w het her t o be 
eli gi ble f or t he start of t h e R W p hase. Dis ease I m pr o ve me nt is defi ne d as:  
•  Re d ucti o n of t he n u m ber of  affecte d o bjecti ve e n d or ga n  da ma g e 
cate g ories at baseli ne b y at least 1 or  
•  N or malizati o n (i.e., reac hi n g le vels f or c o m plete res p o nse) or 
i m pr o ve me nt ( > 5 0 % c h a n ge fr o m baseli ne  f or la b orat or y mar k ers  b ut 
still e xcee di n g le vels f or c o m plete res p o nse) of at least 5 0 % of t he 
s yste mic i nfla m mat or y mar kers affecte d at baseli n e 
•  S yste mic c ortic oster oi ds (e xcl u di n g h y dr oc ortis o ne f or pre ve nti o n of 
a dre nal  i ns uffici e nc y) or  ot her i m m u n os u p pressi ve t hera pies i ncl u di n g 
bi ol o gics m ust be at t he sa me or l o wer d oses c o m p are d t o bas eli ne 
6. 4. 2  
Descri pti o n  of S afety  a n d T oler a bility  V ari a bles  
Safet y  a n d t olera bilit y varia bles  i ncl u de t he f oll o wi n g: 
•  A d verse e ve nts (i ncl u di n g a d verse e ve nts of s pecial i nterest [ A E SI]) 
•  P h ysical  e xa mi nati o n  fi n di n gs i ncl u di n g a n o p ht hal m ol o gical e xa mi nati o n  (ie, 
cli nicall y si g nifica nt c ha n ges fr o m Baseli ne)  
•  Vital si g ns (ie, cli nicall y si g nifica nt c ha n ges fr o m S A O L Baseli ne f or d ata 
c ollecte d d uri n g t h e S A O L  p hase a n d R W  Baseli n e  f or data c ollecte d d uri n g t he 
R W p hase)  
•  La b orat or y assess me nts i ncl u di n g cli nicall y si g nifica nt c ha n g es fr o m S A O L 
Baseli ne f or dat a c ollecte d d uri n g t he S A O L p hase a n d R W Baseli ne f or d at a 
c ollecte d d uri n g t he R W p hase i n he mat ol o g y wit h platelet c o u nts, C R P, E S R, 
ferriti n, fi bri n o ge n, D-di mer,  li ver e nz y m es, creati ni ne, a n d gl o mer ular filtrati o n 
rate 


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•  I m m u n o ge nicit y e val u ati o n:  Ge nerati o n  of a nti-r h-I L- 1 8 B P a nti b o dies  
•  L ocal  t oler a bilit y at t he i njecti o n site, as e val uate d b y a sta n dar dize d assess me nt  
A n  A E SI f or  t his st u d y is defi ne d  as a n e ve nt t hat c o nstit utes  a n i njecti o n site reacti o n, 
i ncl u di n g pr urit us, er yt he ma, a n d s welli n g. 
6. 4. 3  
Descri pti o n  of P h ar m ac o ki netic V ari a bles  
T he  f oll o wi n g p har mac o ki netic ( P K) para m eters  will  be esti mate d at Wee k  0 ( V 1) a n d 
Wee k 4 ( V 5) b y n o n- c o m part me ntal met h o ds usi n g act ual ela ps e d ti me fr o m d osi n g: 
•  A U C 0- 2 4: Area  u n der t he c o nce ntrati o n -ti me c ur ve ( n g × h/ m L) fr o m  ti me zer o 
( pre- d os e) t o 2 4 h o urs p ost-treat me nt, cal c ulate d b y t he li near tra pez oi dal r ule 
•  C ma x : Ma xi m u m c o nce ntrati o n  ( n g × m L),  o btai ne d directl y  fr o m t he o bser ve d 
c o nce ntr ati o n vers us ti me data 
•  T ma x : Ti me  t o ma xi m u m c o nce ntrati o n  ( h o urs), o btai ne d  directl y  fr o m t he 
o bser ve d c o n ce ntr ati o n vers us ti me data 
•  T 1/ 2: A p pare nt ter mi nal h alf -life ( h o urs), deter mi ne d as l n( 2)/ λz 
•  λ z: A p pare nt ter mi nal eli mi nati o n rate c o nsta nt ( 1/ h o urs), deter mi ne d b y li near 
re gressi o n of t er mi nal p oi nts of t he l o g-li near c o n ce ntrati o n-ti me c ur ve. A 
mi ni m u m of 3 data p oi nts are re q uire d f or deter mi nati o n of λ z, wit h a n r-s q uare 
val ue ≥0. 8.  I n a d diti o n, vis ual assess me nt b y  t he p har mac o ki neticist ma y  b e  use d 
t o c o nfir m t he ter mi nal li near p has e of t he c o nce ntrati o n-ti me pr ofile 
F or  calc ulati o ns  usi n g t he li near tra p ez oi dal r ule, t he f oll o wi n g f or m ula will  be use d:  
 
𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 =  
 
6. 5  
D at a Q u alit y Ass ur a nce  
1 
2 (𝐴𝐴𝐴𝐴1 +  𝐴𝐴𝐴𝐴2)(𝑡𝑡𝑡𝑡2 − 𝑡𝑡𝑡𝑡1) 
Re p ort s u m maries  will  be ge n erate d  usi n g vali dat e d  Base  S A S  s oft ware, versi o n 9. 4 or 
hi g her, o n a P C or ser v er- base d platf or m. P K para meters a n d a n al yses will als o be 
ge nerat e d usi n g S A S  s oft ware. A d diti o nal vali date d s oft ware m a y be use d t o ge nerate 
a nal yses, as n ee de d.  
All  S A S pr o gra ms t hat create o ut p uts or s u p p orti n g a nal ysis datasets  will  be vali date d  b y 
a sec o n d statistical  pr o gr a m mer or bi ostatisticia n. At a mi ni m u m, vali dati o n  of pr o gra ms 
will c o nsist of a re vie w of t he pr o gra m l o g, re vie w of o ut p ut or dataset f or m at a n d 
str uct ure, a n d i n de p e n de nt c o nfir mat or y pr o gra m mi n g t o verif y o ut p ut res ults or dataset 
c o nte nt. A d diti o nall y, all o ut p uts will u n der g o a re vie w b y a se ni or le vel tea m me m ber 
bef ore fi nalizati o n.  


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T he  c o nte nt of t he s o ur ce data  will  be re vie w e d o n a n o n g oi n g basis b y pr oject statistical 
pr o gra m mers a n d statisticia ns. Data will be c hec k e d f or missi n g val ues, i n vali d rec or ds, 
a n d e xtre me o utliers t hr o u g h defe nsi ve pr o gra m mi n g a p plicati o ns, a nal ysis- base d e dit 
c hec ks, a n d ot her pr o gra m matic  testi n g pr oce d ures. All  fi n di n gs will  be f or war de d  t o t he 
pr oject data ma n a ger f or a p pr o priate acti o n a n d res ol uti o n. 
7  S T A TI S TI C A L  M E T H O D S  
7. 1  
Ge ner al  Met h o d ol o g y  
Data will be a n al yze d b y Precisi o n f or Me dici ne bi ostatistics pers o n nel. Statistical 
a nal yses will be re p orte d wit h ta bles, fi g ures, a n d listi n gs, prese nte d i n ric h te xt f or mat, 
a n d usi n g rec o m me n de d I C H n u m beri n g. O ut p ut s pecificati o ns f or all ta bles, fi g ures, a n d 
listi n gs will  be i n  c o nf or ma nce wit h  g ui d eli nes s pecifie d b y t he I C H i n A p pe n di x 7 of t he 
Electr o nic C o m m o n Tec h nic al D oc u me nt S pecific ati o n ( A pr 2 0 0 3). 
7. 1. 1  
Re p orti n g C o nve nti o ns  
Ta bles a n d fi g ur es will be s u m marize d f or all  pati e nts c o m bi ne d d uri n g t he S A O L p hase 
a n d b y treat me nt gr o u p d uri n g t he R W p hase. T a bles s u m marizi n g de m o gra p hics a n d 
ot her baseli ne c har acteristics f or t he  R W  p has e will  als o i ncl u de a c ol u m n f or all patie nts 
c o m bi ne d. W her e a p plica ble, se parate s u m mari es will be prese nte d f or eac h st u d y p hase 
( S A O L a n d R W). I n ge n eral, all d ata c ollect e d a n d a n y  deri ve d d ata will be prese nt e d i n 
patie nt data listi n gs, f or all e nr olle d patie nts. Listi n gs will be or dere d b y  site, patie nt 
n u m ber, treat me nt gr o u p, a n d assess me nt or  e v e nt date. T h e  treat me nt gr o u p prese nte d  i n 
listi n gs will be base d o n t he pla n ne d assi g n me nt, u nless ot her wise n ote d. 
I n g e ner al, c o nti n u o us varia bles will be s u m marize d t o i n dicate t he st u d y p o p ulati o n 
sa m ple size ( N), n u m ber of patie nts  wit h  a vaila ble data  ( n), mea n,  S D,  me dia n,  2 5t h ( Q 1) 
a n d 7 5 t h ( Q 3) q uartiles, mi ni m u m, a n d ma xi m u m val ues. Selecte d c o nti n u o us efficac y 
varia bles  will  als o be s u m marize d b y t he 9 5 % CI of t he mea n. Cate g orical varia bles will 
be s u m marize d b y t he p o p ulati o n size ( N), n u m ber of patie nts wit h a vaila bl e data ( n), 
n u m ber of patie nts i n eac h cate g or y, a n d t he perce nta ge of patie nts i n eac h cate g or y. 
U nless  ot her wise n ote d, t he de n o mi nat or t o deter mi ne t he perce nta g e  of p atie nts i n  eac h 
cate g or y will be b ase d o n t he n u m ber of patie nts wit h a vaila ble data. Selecte d or di nal 
data ma y  be s u m marize d usi n g b ot h descri pti ve statistics  a n d c o u nts a n d perce nta ges  of 
patie nts i n eac h cate g or y, as a p pr o priat e.  
N o n -zer o per ce nta g es will be r o u n de d t o o ne deci mal place. R o u n di n g c o n ve nti o ns f or 
prese ntati o n of s u m mar y statistics will be base d o n t he precisi o n of t he v aria ble of 
s u m marizati o n, as it is c ollecte d i n its ra west f or m (ie, o n t he e C R F or as pr o vi de d wit hi n 
a n e xter n al file) a n d are o utli ne d as f oll o ws:  
•  T he mea n  a n d me dia n  will  be r o u n de d t o o ne m ore deci mal  place  t ha n t he 
precisi o n of t he varia ble of s u m marizati o n 


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•  Meas ures  of v aria bilit y  (e g, S D, S E) will  be r o u n de d t o t w o m ore deci mal  places 
t ha n t he precisi o n of t he varia ble of s u m marizati o n 
•  Mi ni m u m  a n d ma xi m u m val ues  will  be prese nte d  usi n g t he sa me precisi o n  as t he 
varia ble of s u m marizati o n  
Ot her statistics  (e g, CIs) will  be prese nte d  usi n g t he sa me ge neral  r ul es o utli ne d a b o ve or 
assesse d f or t h e m ost a p pr o priate prese ntati o n bas e d o n t he u n derl yi n g data. 
Statistical si g nifica nce testi n g will be t w o -si de d a n d perf or me d usi n g α = 0. 0 5. P-val ues 
will  be re p orte d f or all statistical tests, r o u n de d t o f o ur deci mal  places. P -val ues less  t ha n 
0. 0 0 0 1 will be dis pla ye d as “ < 0. 0 0 0 1 ”; p- val ues greater  t ha n 0. 9 9 9 9 will be dis pla ye d as 
“ > 0. 9 9 9 9”.  
7. 1. 2  
Defi niti o n of  B aseli ne  
C ha n ges fr o m bas eli ne,  perce nt a ge  c h a n ges  fr o m baseli ne,  a n d occ urre nce of diseas e 
reacti vati o ns will  be calc ulate d se paratel y  wit hi n eac h  st u d y p has e ( S A O L  a n d R W), 
relati ve t o t he start of d osi n g d uri n g t hat p hase: 
•  S A O L B aseli ne : Baseli ne d uri n g t he S A O L p has e will be defi ne d as t he l ast 
meas ure me nt r e p orte d  pri or t o t he first d ose of o p e n-la bel T A  at Wee k 0 ( V 1) 
•  R W B aseli ne : Baseli ne d uri n g t he R W p hase will be defi ne d as t h e last 
meas ure me nt r e p orte d  pri or t o t he first d ose of d o u ble- bli n d st u d y dr u g ( T A or 
place b o) at Wee k 1 8 ( V 8)  
7. 1. 3  
S u m m ariz ati o n  by Visit  
Data s u m marize d b y st u d y visit will be base d o n t he n o mi nal, sc he d ule d visit la bel as 
re p orte d o n t he e C R F, e x ce pt f or d ata t hat are ca pt ure d at earl y ter mi nati o n or 
u nsc he d ule d visits. Data  c ollecte d at earl y  ter mi nati o n or u nsc he d ule d visits will  o nl y be 
i ncl u de d i n b y-visit s u m maries  if t he y fall wit hi n  a sc he d ule d p ost-b aseli ne  visit wi n d o w 
(see Ta bl e 2) a n d t h ere is n o data fr o m a n o mi nal visit f or t hat s pecific visit. If b ot h a n 
u nsc he d ule d visit a n d a n earl y ter mi nati o n visit fall wit hi n t he sa me visit wi n d o w t he 
earl y ter mi nati o n visit will be use d f or t hat s pecific visit.  


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C o nfi de nti al  
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T a ble 2 
Visit  Wi n d o ws f or E arl y  Ter mi n ati o n a n d U nsc he d ule d Visits  
 
P hase  
A nal ysis  Visit  
Tar get  Da y  
Visit  Wi n d o w  
S A O L  
Wee k  1 
S A O L  Da y  7 
2 ≤ S A O L  Da y  ≤ 1 1  
 
Wee k  2 
S A O L  Da y  1 4  
1 2 ≤ S A O L  Da y  ≤ 1 8  
 
Wee k  3 
S A O L  Da y  2 1  
1 9 ≤ S A O L  Da y  ≤ 2 5  
 
Wee k  4 
S A O L  Da y  2 8  
2 6 ≤ S A O L  Da y  ≤ 4 2  
 
Wee k  8 
S A O L  Da y  5 6  
4 3 ≤ S A O L  Da y  ≤ 7 0  
 
Wee k  1 2  
S A O L  Da y  8 4  
7 1 ≤ S A O L  Da y  ≤ 1 0 5  
 
Wee k  1 8  
S A O L  Da y  1 2 6  
1 0 6  ≤ S A O L  Da y  ≤ E n d  of  S A O L  P hase  
 
Wee k  2 0  
R W Da y  1 4  
2  ≤ R W  Da y  ≤ 2 1  
 
Wee k  2 2  
R W Da y  2 8  
2 2  ≤ R W Da y  ≤ 4 2  
 
Wee k  2 6  
R W Da y  5 6  
4 3  ≤ R W Da y  ≤ 7 0  
 
Wee k  3 0  
R W Da y  8 4  
7 1 ≤ R W Da y  ≤ 9 8  
 
Wee k  3 4  
R W Da y  1 1 2  
9 9 ≤ R W  Da y  ≤ E n d  of R W  P hase  
N ote: S A O L  Da y  is calc ulate d as visit date  – first S A O L  d ose  date  + 1. R W  Da y  is calc ulate d as visit date  – 
first R W d ose date + 1. 
 
Data c ollecte d at all visits will be c o nsi dere d w h e n e n d p oi nt deri vati o ns p ote ntiall y 
i ncl u de m ulti ple  visits  (e g, deter mi nati o n  of bas eli ne  val ue,  deter mi nati o n  w orst p ost- 
baseli ne val ue, etc.). All data will be i ncl u de d i n p atie nt listi n gs.  
7. 1. 4  
D at a  H a n dli n g R ules  
U nless ot her wise n ote d, val ues re p ort e d as greater t ha n or less t ha n s o me q ua ntifia ble 
li mit (e g, “ < 1. 0”) will be s u m marize d wit h t he si g n s u p presse d i n s u m mar y ta bles a n d 
fi g ures, usi n g t he n u meri c val ue re p orte d. D ata  will  dis pla y o n patie nt listi n gs  t o i ncl u de 
t he si g n. 
I n s o me cases, C R P val ues fr o m t he ce ntral la b orat or y were e nt ere d as ‘ < 3 m g/ L’. Si nce 
t he U L N f or C R P is 1 m g/ L, a val ue of < 3 m g/ L d oes n ot all o w deter mi nati o n of 
w het her t he C R P val ue is  ≥ 2 x U L N. I n  t hes e cases, a re-t est of hi g h se nsiti vit y C R P will 
be atte m pte d, a n d t h ose v al ues will be use d t o re pl ace t he < 3 m g/ L val ue. If t he hi g h 
se nsiti vit y C R P val ue is n ot o btai ne d a l ocal la b C R P val ue ma y be use d t o deter mi ne 
w het her t he C R P val ue is ≥ 2 x U L N.  
7. 1. 5  
St a n d ar d C alc ul ati o ns  
W here a p pr o pri ate, t he calc ulate d st u d y da y of eac h assess me nt or e ve nt will be 
prese nte d  wit h  t he assess me nt or  e ve nt date o n patie nt data  listi n gs. T he  calc ulate d st u d y 
da y will be relati ve t o t he start of d osi n g wit hi n eac h p hase: 
•  T he  assess me nt/e v e nt dat e  mi n us t he date  of  first d ose recei ve d d uri n g t he S A O L 
or R W p hase, if t he assess me nt/e ve nt date is pri or t o t he date of first d ose; a n d 


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•  T he  assess me nt/e ve nt dat e  mi n us t he date  of first d ose recei ve d d uri n g t he S A O L 
or R W  p hase, pl us  o ne, if  t he ass ess me nt/e ve nt d ate is o n or after t he date of first 
d ose.  
Ot her  varia bles  re q uiri n g calc ulati o ns  will  be deri ve d usi n g t he f oll o wi n g f or m ulas: 
•  D a ys: A d urati o n bet wee n  t w o dates e x presse d i n  da ys will  be cal c ulate d usi n g 
t he f oll o wi n g c o n ve nti o ns: 
o  Later dat e  – earlier date + 1, if t he earlier date is o n  or after  t he date  of 
first d ose of st u d y dr u g d uri n g t he S A O L or R W p hase; or 
o  Later dat e  – earlier date, if t he earlier dat e is pri or t o  t he date  of  first d ose 
of st u d y dr u g d uri n g t he S A O L or R W p hase. 
•  Wee ks: A d urati o n e x presse d i n wee ks  will  be cal c ulate d b y t h e di vi di n g t he 
d urati o n i n da ys b y se ve n 
•  M o nt hs:  A d urati o n e x presse d i n  m o nt hs will  be calc ulate d b y di vi di n g t he 
d urati o n i n da ys b y ( 3 6 5. 2 5 / 1 2) 
•  Ye ars: A d urati o n e x presse d i n  years  will  be calc ulate d b y di vi di n g t he d urati o n 
i n da ys b y 3 6 5. 2 5 
•  C h a n ge fr o m B aseli ne:  C ha n ge fr o m b aseli ne  will  be calc ulate d as t h e 
p ost- baseli ne val ue mi n us t he baseli ne val ue  
•  Perce nt a ge C h a n ge f r o m B aseli ne: Perce nta ge c ha n ge fr o m baseli ne will be 
calc ulate d  as t he c ha n ge fr o m baseli ne  di vi de d b y t he baseli ne  val ue, m ulti plie d 
b y 1 0 0 
7. 1. 6  
P atie nt  C o nsi der ati o n f or Ori gi n al St u dy Desi g n  
Patie nts e nr olle d u n der t he ori gi nal pr ot oc ol t hr o u g h Pr ot oc ol A me n d me nt 2 ( Versi o n 
3. 0) a n d w h o w ere ra n d o mize d t o T A d uri n g t he R D B P C p hase of t he st u d y will be 
c o nsi dere d f or all a n al yses, c o m bi ne d wit h t h ose patie nts e nr olle d u n der Pr ot oc ol 
A me n d me nt 4 ( Versi o n 4. 0), or a n y s u bse q u e nt a me n d me nts. Patie nts ra n d o mize d t o 
place b o u n der t he ori gi nal st u d y desi g n will  o nl y be i ncl u de d i n patie nt data  listi n gs a n d 
will be c haracterize d se p aratel y i n t he C S R.  
7. 2  
A n al ysis P o p ul ati o ns  
T he  a nal ysis  p o p ulati o ns are d efi ne d  as f oll o ws: 
•  Si n gle Ar m O pe n -L a bel F ull A nal ysis Set ( S A O L -F A S): All  patie nts w h o are 
eli gi ble a n d recei ve at least o ne d ose of o pe n-l a bel T A at Wee k 0 ( V 1) u n der 
A me n d me nt 3 ( Versi o n 4. 0) of t he pr ot o c ol ( or s u bse q ue nt a me n d me nts), or at 


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least o ne d ose of T A  at Wee k 0 ( V 1) d uri n g t he R D B P C  p hase u n der pre vi o us 
pr ot oc ol a me n d me nts. 
•  Si n gle Ar m O pe n- La b el P K A nal ysis Set ( S A O L -P K A S): All patie nts i n t he 
S A O L -F A S w h o h a ve s ufficie nt plas ma c o n ce ntrati o n data t o calc ulate P K 
para meters.  If a n y patie nts  are f o u n d t o be n o nc o m plia nt wit h res pect t o d osi n g or 
ha ve i nc o m plete d ata, a d ecisi o n will be ma de pri or t o D B L o n a cas e - b y-case 
basis as t o t heir i ncl usi o n i n t he a nal ysis. 
•  Ra n d o mize d  Wit h dra w al  F ull  A nal ysis Set ( R W -F A S):  All  patie nts  w h o meet  t he 
criteria f or ra n d o mizati o n a n d are ra n d o mize d t o bli n de d st u d y treat me nt d uri n g 
t he R W p hase. 
•  Ra n d o mize d Wit h dra w al Per - Pr ot oc ol A nal ysis Set ( R W-P P A S): All patie nts i n 
t he R W- F A S w h o c o m plete t he R W p has e u p t hr o u g h Wee k 2 6 ( V 1 1) f or 
pr ot oc ol versi o n 4. 0/ 4. 1 or Wee k 3 4 ( V 1 3) f or pr ot oc ol versi o ns 5. 0 a n d 6. 0 or 
ha ve disease  reacti vati o n a n d f or w h o m n o rele va nt  pr ot oc ol de viati o ns (ie, maj or 
pr ot oc ol de viati o ns) were d oc u me nte d. 
T he  a nal ys es  of safet y a n d efficac y d uri n g t he S A O L  p hase will  be base d  o n  t he S A O L - 
F A S a n d t he a n al yses of safet y  a n d efficac y  d uri n g t he R W p hase will be b ase d o n t he 
R W - F A S. A d diti o nal e x pl orat or y a nal yses of efficac y d uri n g t he R W p has e will be 
perf or me d b ase d o n t he R W- P P A S. A nal ysis of P K plas ma c o nce ntrati o n data a n d P K 
para meters will be perf or me d base d o n t he S A O L- P K A S.  
7. 3  
St u d y  P atie nts  
7. 3. 1  
Dis p ositi o n  of P atie nts  
Patie nt dis p ositi o n  will  be  pres e nte d  se p aratel y f or t he S A O L  p has e a n d R W  p hase.  
S u m maries  d uri n g t he S A O L  p hase will  i ncl u de t he n u m ber a n d perce nta g e  of patie nts i n 
eac h a nal ysis p o p ulati o n, c o m pleti n g T A treat me nt d uri n g t he S A O L p hase, 
disc o nti n ui n g T A earl y d uri n g t he S A O L p hase b y reas o n f or disc o nti n uati o n, starti n g 
ne w me dicati o ns f or treat me nt of t he patie nt diseas e, c o m pleti n g t he S A O L p hase, a n d 
disc o nti n ui n g t he S A O L p hase earl y b y t he pri mar y reas o n f or disc o nti n uati o n. 
S u m maries  d uri n g t he R W  p hase will  be b ase d  o n t he R W -F A S  a n d will  be s u m marize d 
b y ra n d o mize d tr eat me nt recei v e d d uri n g t he R W p hase. T he s u m mar y will i ncl u de t he 
n u m ber a n d perce nt a ge of patie nts c o m pleti n g st u d y treat me nt d uri n g t he R W p hase, 
disc o nti n ui n g st u d y treat me nt d uri n g t he R W p hase b y reas o n f or disc o nti n uati o n, 
starti n g ne w me dicati o ns f or treat me nt of t he patie nt disease, c o m pleti n g  t he R W  p hase, 
a n d disc o nti n ui n g t he R W p hase earl y b y pri mar y reas o n f or disc o nti n uati o n. 
7. 3. 2  
Pr ot oc ol Devi ati o ns  
Maj or pr ot oc ol de vi ati o ns occ urri n g d uri n g t he R W  p hase will  be s u m mari ze d b y 
treat me nt gr o u p a n d o ver all patie nts c o m bi ne d f or t he R W- F A S. Maj or pr ot oc ol 


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de viati o ns ma y  i ncl u de, b ut will  n ot be li mite d t o vi olati o n of eli gi bilit y criteria, 
ra n d o mizati o n err ors, lac k of c o m plia nce wit h st u d y dr u g d osi n g, or o n-st u d y 
a d mi nistrati o n of a pr o hi bite d me dicati o n. 
All maj or pr ot oc ol de viati o ns will be deter mi ne d a n d a p pr o priatel y cate g ori ze d pri or t o 
data base l oc k a n d pri or t o brea ki n g t he bli n d of t h e treat me nt gr o u p assi g n me nts. T he 
decisi o n as t o w het her a pr ot oc ol de viati o n is a maj or pr ot oc ol de viati o n or a maj or 
pr ot oc ol vi olati o n  lea di n g t o e xcl usi o n fr o m t h e R W -P P A S  A nal ysis Set will  be ma de  o n 
a case - b y-case b asis i n a bli n de d data re vie w meeti n g. T he n u m ber a n d p erce nta ge of 
patie nts wit h a n y maj or pr ot oc ol de viati o ns as well as t he n u m ber a n d p erce nta ge of 
patie nts wit h maj or de viati o ns wit hi n eac h cate g or y will be prese nte d.  
All pr ot oc ol de viati o ns c ollecte d o n st u d y d uri n g eit her t he S A O L p has e or R W p hase 
will  be liste d  b y patie nt t o  i ncl u de t he date  t he de viati o n  occ urre d,  t y pe of d e viati o n, a n d 
a descri pti o n. 
7. 3. 3  
De m o gr a p hic a n d Ot her  B aseli ne  C h ar acteristics  
De m o gra p hic varia bles  i ncl u di n g a ge, se x, et h nicit y, a n d race will  be s u m marize d f or t he 
S A O L -F A S, S A O L -P K A S, R W - F A S, a n d R W- P P A S. A ge as re p orte d wit hi n t he 
electr o nic d ata ca pt ure s yste m will be s u m marize d usi n g descri pti ve statistics. Se x, 
et h nicit y, a n d race will be s u m marize d wit h t he n u m ber a n d perce nt a ge of patie nts i n 
eac h p ara met er cate g or y.  
Baseli ne c har acteristics i ncl u de disease hist or y, ot her ma nifestati o ns of i ntesti nal 
d ysf u ncti o n, ot her cli nical s y m pt o ms of disease, me dical  hist or y, disease -s p ecific pri or 
me dicati o n use, hei g ht, wei g ht, a n d b o d y mass i n de x ( B MI). 
Disease hist or y, ot her ma nifestati o ns of i ntesti nal d ysf u ncti o n, a n d ot her cli nical 
s y m pt o ms of disease  will  be s u m marize d f or t he S A O L -F A S,  R W -F A S,  a n d R W -P P A S 
b y treat me nt gr o u p a n d o ver all patie nts c o m bi ne d. 
Hei g ht, wei g ht, B MI,  Me dical  hist or y, a n d pri or  m e dicati o n  use will  be s u m marize d f or 
t he S A O L-F A S.  
Hei g ht, wei g ht, a n d B MI at baseli ne will be s u m marize d usi n g des cri pti ve statistics. 
Fre q u e nc y  c o u nts a n d perce nta g es  t o s u m marize p atie nts  re p orti n g a b n or m al me dical 
hist or y b y b o d y s yste m will be prese nte d. 
Baseli ne  disease  hist or y will  be descri be d b y t he ti me ela pse d ( m o nt hs) si nce dia g n osis of 
disease  a n d t he i nci de n ce of pre vi o us a n d c urre nt disease hist or y  b y s y m pt o m. Ti me  si nce 
dia g n osis of disease will be calc ul ate d as des cri be d i n Secti o n 7. 1. 4  w here c o m plete 
dia g n osis dates are pr o vi de d. If o nl y t he m o nt h a n d year are pr o vi d e d, t he m o nt hs si nce 
dia g n osis will be deter mi ne d as differe n ce i n m o nt hs bet wee n t he dia g n osis m o nt h a n d 
year a n d t h e m o nt h a n d y ear of i nf or me d c o ns e nt. If o nl y t he year of dia g n osis is 
pr o vi de d, t he m o nt hs si nce dia g n osis will be deter mi ne d as t he differe nce b et wee n t he 
dia g n osis year a n d t he y ear of i nf or m e d c o nse nt, m ulti plie d b y 1 2. M o nt hs si nce 
dia g n osis will be s u m marize d usi n g descri pti ve statistics. T he n u m ber a n d perce nt a ge of 


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patie nts  re p orti n g eac h disease  hist or y s y m pt o m, i ncl u di n g ot her ma nifest ati o ns of 
i ntesti nal d ysf u ncti o n a n d ot her cli nical s y m pt o ms a n d/ or si g ns, will be prese nte d 
se parat el y f or pr e vi o us hist or y a n d c urre nt hist or y. 
Disease -s p ecific pri or me dicati o ns will i ncl u de t h ose treat me nts s pecific t o t he treat me nt 
of t he a ut o-i nfla m mat or y c o n diti o n t hat starte d a n d  st o p pe d pri or t o t he dat e  t he i nf or me d 
c o nse nt is si g ne d, as re p orte d o n t he Pri or Me dicati o ns e C R F. Me dicati o ns will be c o de d 
usi n g t he W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y E n ha n ce d ( W H O D D E, versi o n 
Marc h 1, 2 0 1 7). M e dicati o ns e ntere d o n t he e C R F will be ma p pe d t o A nat o mic 
T hera p e utic C he mical ( A T C) dr u g class (le v el 4) a n d dr u g na me. T he n u m b er a n d 
perce nt a ge of p atie nts recei vi n g a n y pri or me di cati o n will be s u m marize d b y treat me nt 
gr o u p a n d o ver all patie nts c o m bi ne d, as will t he n u m ber a n d perce nt a ge recei vi n g a n y 
me dicati o n b y A T C dr u g class a n d ge n eric dr u g n a me. Patie nts re p orti n g use of m ore 
t ha n o ne me dicati o n at eac h le vel  of s u m marizati o n (a n y pri or me dicati o n  recei ve d, A T C 
class, a n d ge n eric dr u g n a me) will be c o u nte d o nl y o nce. A T C class ter ms will be 
dis pla ye d b y desce n di n g or der of i nci de n ce, as will  ge neric  dr u g  na mes  wit hi n  eac h A T C 
class. 
7. 3. 4  
Me as ure me nts  of Tre at me nt  C o m pli a nce  
C o m plia nce t o t he st u d y treat me nt re gi me n will be deter mi ne d as t he t otal n u m ber of 
da ys wit h  a d ose recei ve d di vi de d b y t he e x pecte d n u m ber of da ys wit h  a d ose recei ve d, 
m ulti plie d b y  1 0 0. T he t otal n u m ber of d a ys wit h  a d ose recei ve d will be det er mi ne d b y 
p hase base d  o n e ntries o n t he St u d y Dr u g  A d mi nistrati o n  f or m, w here a d os e recei ve d is 
c o u nte d f or a gi ve n da y if t he res p o nse t o “ Was t h e st u d y dr u g a d mi nistere d” is “ Yes.” 
T he e x pecte d n u m ber of da ys wit h a d ose recei ve d will be calc ulate d as t he date of last 
d ose of st u d y dr u g mi n us t he date of first d ose of st u d y dr u g pl us o ne, di vi de d b y t w o. 
Calc ulati o ns t hat res ult i n a val ue wit h a re mai n d er of  o ne half (ie, t he n u m ber of da ys 
bet wee n  d os es is a n o d d n u m ber) will  be r o u n de d u p t o t he ne xt lar gest i nte ger. T h e  date 
of last d ose of st u d y dr u g is t he date re p orte d o n t h e E n d of Treat me nt f or m, f or b ot h t he 
e n d of d o u ble- bli n d treat me nt a n d t he e n d of treat me nt d uri n g t he R W p hase. 
D osi n g c o m plia nce will be s u m marize d usi n g des cri pti ve statistics, b y treat me nt gr o u p, 
base d o n t he S A O L- F A S f or d osi n g d uri n g t he S A O L p hase a n d b ase d o n t he R W- F A S 
f or d osi n g d uri n g t he R W  p hase. T he n u m ber a n d  perce nta ges  of  patie nts  w h o are < 8 0 % 
c o m plia nt a n d ≥ 8 0 % c o m plia nt wit hi n eac h treat me nt gr o u p will be s u m marize d.  
7. 4  
Effic ac y  E v al u ati o n  
7. 4. 1  
D at asets A n alyze d  
All  efficac y  s u m mari es f or data c ollecte d d uri n g t he R W  p hase will  be bas e d  o n t he R W - 
F A S; selecte d efficac y s u m maries will als o be pr o d uce d o n t he R W - P P A S pr o vi de d t he 
R W -F A S  a n d R W -P P A S  differ b y  at least o ne pati e nt.  A data  listi n g of patie nts  e xcl u de d 
fr o m t he R W-F A S or R W - P P A S, i ncl u di n g t he reas o n f or e xcl usi o n, will be prese nt e d. 
All  efficac y  s u m mari es of data  c ollecte d d uri n g t he S A O L  p has e will  be base d  o n t he 
S A O L -F A S.  


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7. 4. 2  
Pri m ary  Effic acy  E n d p oi nt A n alysis  Met h o ds  
T he pri mar y efficac y e n d p oi nt is t he ti me t o first occ urre nce of diseas e reacti vati o n 
(i ncl u di n g f ull a n d partial  disease  reacti vati o n) d uri n g t he 1 6-wee k  R W  p h ase,  as d efi ne d 
i n Secti o n 6. 4. 1. 1 . 
7. 4. 2. 1  
Pri m ary  Esti m a n d of t he Pri m ary  Effic acy  E n d p oi nt  
T he  pri mar y  esti ma n d f or t he pri mar y  e n d p oi nt will be descri be d  as f oll o ws: 
P o p ulati o n: All patie nts i n t he R W - F A S p o p ulati o n. 
E n d p oi nt: Ti me  t o first occ urre nce  of disease  reacti vati o n d uri n g t he R W  p hase. 
I nterc urre nt e v e nts: 
•  E n d  of R W  p has e:  patie nts  w h o d o n ot e x perie nce a diseas e  reacti vati o n a n d 
c o m plete t he R W p has e will be ce ns ore d at t he ti me of t heir last disease 
assess me nt d uri n g t he R W p hase re gar dl ess of t h e le n gt h of t he R W p has e 
(acc or di n g t o t he pr ot oc ol versi o n t he patie nt was treate d u n der). 
•  Resc ue i m m u n os u p pressi o n treat me nt: patie nts w h o recei v e res c ue 
i m m u n os u p pressi o n treat me nt wit h o ut o bjecti ve disease reacti vati o n a n d 
c o nti n ue i n t he R W p has e will be ce ns ore d at t he ti me of t heir last disease 
assess me nt d uri n g t he R W  p hase, i ncl u di n g assess me nts  u p t o t he start da y  of 
t he resc u e i m m u n os u p pressi o n treat me nt. 
•  Cli nical si g ns of i nfla m mati o n t hat are n ot diseas e relate d: patie nts w h o 
prese nt wit h  cli nical or la b orat or y si g ns of i nfla m mati o n meeti n g  t he criteria 
of disease r eacti vati o n t hat are d eter mi ne d b y t he treati n g p h ysicia n t o be 
relate d t o a n i nfecti o n rat her t ha n disease reacti vati o n  a n d are res ol ve d aft er 
re peat assess me nts wit hi n t he visit wi n d o w will n ot be c o nsi dere d t o h a ve a 
disease reacti vati o n at t h at visit (see Secti o n 7. 4. 2. 2). 
P o p ulati o n- le vel s u m mar y: Ka pla n -Mei er ( K M) esti mates  of t he s ur vi val c ur ves b y 
treat me nt gr o u p, hazar d r ati o i ncl u di n g 9 5 % CI, a n d l o g-ra n k test. 
T he  pri mar y  efficac y  a nal ysis will  test t he f oll o wi n g h y p ot hesis:  
•  H 0: T he  s ur vi val distri b uti o n of ti me t o first occ urre nce of dis ease  reacti vati o n 
d uri n g t he R W p hase is e q ual bet wee n T A a n d place b o 
•  H 1: T he  s ur vi val distri b uti o n of ti me t o first occ urre nce of dis ease  reacti vati o n 
d uri n g t he R W p hase is differe nt b et wee n T A a n d place b o  
T A  will  be c o m par e d  t o place b o usi n g t he l o g ra n k test. Ka pla n -Meier  ( K M) esti mates of 
t he distri b uti o n of ti me-t o-e ve nt will be s u m marize d a n d gra p h e d b y treat me nt gr o u p. 
Gree n w o o d’s f or m ula will be  use d t o esti mate t he sta n dar d err or of t he K M  statistic. T he  


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pri mar y a nal ysis e n d p oi nt will be teste d at a 2 -si de d al p ha le vel of 0. 0 5. T h e 
s u m marizati o n will i ncl u de t he K M esti mate of t h e me dia n, 2 5 t h a n d 7 5t h q uartiles, a n d 
c orres p o n di n g 9 5 % CI,  if esti ma ble. S u m maries  will  i ncl u de t he “at-ris k patie nt”  c o u nts 
at t he sc he d ule d p ost- b as eli ne visits d uri n g t he R W p hase. T h e n u m ber a n d perce nt of 
patie nts e x perie n ci n g a disease reacti vati o n a n d ce ns ore d will be pres e nte d. T he hazar d 
rati o a n d 9 5 % CI will be deter mi ne d bas e d o n a C o x re gressi o n m o del wit h a si n gle 
fact or f or treat me nt gr o u p. 
7. 4. 2. 2  
Pri m ary  Effic acy  E n d p oi nt ev al u ati o n i n c ase of re pe at assess me nts  
T he pri mar y e n d p oi nt is defi ne d as t he ti me t o first occ urre nce of disease reacti vati o n 
d uri n g t he R W  p has e. T o disti n g uis h bet wee n  a disease  reacti vati o n a n d a n a p peara nce of 
cli nical si g ns of a n i nfecti o n, t he treati n g p h ysicia n ma y deci de t o re peat cli nical 
assess me nts wit hi n t he pr ot oc ol defi ne d visit wi n d o w. T h ose a d diti o nal ass ess me nts are 
d oc u me nte d as a s e par ate u nsc he d ule d visit i n t he data base. 
T he  ha n dli n g of s uc h re p eat assess me nts is c urre ntl y n ot descri be d i n t he st u d y pr ot oc ol. 
If s uc h re p eat ass ess me nts are a v aila ble, t he e v al u ati o n of t he treati n g p h ysicia n w h et her 
cli nical or la b orat or y  si g ns of i nfla m mati o n are c o nsi dere d  as tra nsie nt, i nfecti o n-relate d 
ma nifestati o ns or si g ns of a disease reacti vati o n s h o ul d be c o nsi dere d f or t he 
deter mi nati o n  of a disease  reacti vati o n per pr ot oc ol. T his e val uati o n is d o ne i n a bli n de d 
ma n ner pri or t o dat a base l oc k a n d d oc u me nte d acc or di n gl y. 
7. 4. 2. 3  
Se nsitivity  A n alyses  of t he Pri m ary  Effic acy  E n d p oi nt  
T he  pri mar y  e n d p oi nt a n al ysis will  be re peate d o n t he R W -P P A S,  pr o vi de d t he R W -F A S 
a n d R W-P P A S differ b y at least o ne patie nt.  
I n a d diti o n, t he f oll o wi n g ti p pi n g p oi nt a nal yses will be perf or me d f or t he pri mar y 
e n d p oi nt t o assess t he i m pact of t he differe nt le n gt hs of t he R W  p hase d ue t o t he differe nt 
versi o ns of t he pr ot oc ol. F or patie nts e nr olle d i n pr ot oc ol versi o ns 4. 0/ 4. 1 a n d earlier 
w h ose pla n ne d R W  d ur ati o n was  o nl y 8 wee ks  a n d ha d n o disease reacti vati o n d uri n g t he 
R W p hase:  
1.  A w orst -case i m p utati o n will be a p plie d t o patie nts i n b ot h  treat me nt gr o u ps b y 
assi g ni n g patie nts  as ha vi n g disease  reacti vati o n at  t he ne xt da y after  t he last per 
pr ot oc ol visit. 
2.  A best -case i m p utati o n  will  be a p plie d t o patie nts  i n b ot h treat me nt gr o u ps b y 
assi g ni n g patie nts  as n ot ha vi n g  disease  reacti vati o n u ntil Wee k  1 6 of t he R W 
p hase.  
3.  A w orst -cas e i m p utati o n  will  be a p plie d t o patie nts i n t he T A  treat me nt gr o u p a n d 
a best-case i m p utati o n will be a p plie d t o patie nts i n t he Place b o treat me nt gr o u p.  


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7. 4. 3  
Key  Sec o n d ary Effic a cy  E n d p oi nt A n alysis  Met h o ds  
T he  ke y  sec o n dar y efficac y  e n d p oi nt is res p o nse t o t hera p y (i ncl u di n g c o m plete res p o nse 
a n d partial r es p o nse) i n t he S A O L p hase fr o m Wee k 1 0 o n war ds a n d o bser ve d at least 2 
c o nsec uti ve visits at least 2 wee ks a p art. Patie nts w h o d o n ot ac hie ve c o m plete res p o nse 
or partial  r es p o nse at 2 c o nsec uti ve visits at least 2 wee ks a p art at Wee k 1 0 o n war ds or 
dr o p o ut pri or t o Wee k 1 0 will be c o nsi dere d n o n-res p o n ders. Patie nts w h o res p o n d t o 
t hera p y i n t he S A O L p hase wit h c o m plete or partial res p o nse will be s u m marize d b y t he 
n u m ber a n d perce nt of p atie nts al o n g wit h t he ass ociate d 9 5 % e x act Cl o p per- Pears o n 
CIs.  
T he esti ma n d f or t his e n d p oi nt will be descri be d as: 
P o p ulati o n: All  patie nts  i n t he S A O L -F A S  p o p ulati o n 
E n d p oi nt: Res p o n der or n o n-res p o n der. 
I nterc urre nt e ve nts:  
•  Disc o nti n uati o n pri or t o Wee k 1 0: patie nts  w h o disc o nti n ue pri or t o Wee k 1 0 
will be assi g ne d as n o n-res p o n ders. 
•  Resc ue i m m u n os u p pressi o n treat me nt: patie nts w h o recei v e res c ue 
i m m u n os u p pressi o n treat me nt a n d c o nti n ue i n t he S A O L p hase a n d  satisf y t he 
criteria of res p o n der will be c o nsi dere d res p o n d ers. 
P o p ulati o n- le vel s u m mar y: N u m ber a n d  perce nta g e  of res p o n ders a n d  9 5 % e xact 
Cl o p per- Pears o n CIs.  
A se nsiti vit y a nal ysis  will  als o be perf or me d  t hat o nl y c o nsi ders assess me nts  u p t o t he 
start da y of t he r esc ue i m m u n os u p pressi o n treat me nt. 
7. 4. 4  
Sec o n d ary a n d A d diti o n al Effic acy  E n d p oi nt A n alysis  Met h o ds  
Sec o n dar y e n d p oi nts c ollecte d d uri n g t he R W p h ase will be s u m marize d f or t he R W- 
F A S.  Selecte d  sec o n d ar y e n d p oi nts will  als o be s u m marize d f or t he R W -P P A S,  pr o vi de d 
t he R W- F A S a n d R W-P P A S differ b y at least o n e  patie nt. Refere nce Secti o n 7. 4. 6. 5  f or 
detail o n testi n g pr oce d ur es f or sec o n dar y e n d p oi nts (ie, m ulti plicit y a dj ust me nts). 
Sec o n dar y  e n d p oi nts c ollecte d d uri n g t h e S A O L  p hase will  be s u m marize d f or t he 
S A O L -F A S.  
7. 4. 4. 1  
Best  Res p o nse t o T her a p y D uri n g S A O L  
T he  n u m ber a n d p erce nt of  s u bjects i n eac h res p o nse cate g or y  will  be s u m marize d, 
i ncl u di n g: c o m plete res p o nse, partial res p o ns e, disease i m pr o ve me nt, a n d n o 
i m pr o ve me nt or n ot e val uate d. 


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7. 4. 4. 2  
Tre at me nt  F ail ures d uri n g R W  
Patie nts meeti n g t he criteria f or treat me nt fail ure d uri n g t he R W p hase will be 
s u m marize d b y t he n u m b er a n d perce nt of patie nts i n eac h treat me nt gr o u p. T he 
esti mate d differ e nce i n p erce nt a ges ( T A – place b o) a m o n g treat me nt fail ures bet wee n 
treat me nt gr o u ps will  be prese nte d  al o n g wit h  t he ass ociate d  9 5 % e xact CI.  T he  9 5 % CIs 
f or differe nce i n bi n o mial pr o p orti o ns will be c o m p ute d base d o n e x act u nc o n diti o nal 
c o nfi de nce li mits usi n g t he sc ore statistic. Treat m e nt gr o u ps will be c o m pare d f or 
res p o nse t o t her a p y vers us treat me nt fail ure usi n g t he Fis her’s e xact test. 
T he  esti ma n d f or t his sec o n dar y e n d p oi nt will be d escri be d  as  f oll o ws: 
P o p ulati o n: All patie nts i n t he R W - F A S p o p ulati o n. 
E n d p oi nt: Treat me nt  f ail ure ( Yes/ N o). 
I nterc urre nt e ve nts:  All  p atie nts  w h o e x perie n ce  disease  reacti vati o n d uri n g t he R W 
p hase will be c o u nte d as treat me nt fail ure re g ar dless of i nterc urre nt e ve nts.  
P o p ulati o n- le vel s u m mar y: N u m ber a n d p erce nta g e  of treat me nt fail ures, e x act 
u nc o n diti o nal 9 5 % CIs usi n g t he sc ore statistic, a n d Fis her’s e xact test. 
7. 4. 4. 3  
C h a n ge fr o m B aseli ne i n C-re active Pr otei n  a n d S er u m  Ferriti n  
Descri pti ve statistics f or t he o bser ve d C R P a n d ser u m ferriti n val ues a n d t he c ha n g es 
fr o m R W Baseli ne d uri n g t he R W p hase will be prese nte d b y visit f or eac h treat me nt 
gr o u p. Descri pti ve statistics will i ncl u de n u m ber of s u bjects, mea n, sta n d ar d de viati o n, 
9 5 % CI of  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. Mea n  C R P  a n d 
ser u m ferriti n val ues wit h ass ociate d sta n dar d err or bars will be pl otte d b y treat me nt 
gr o u p o ver ti me d uri n g t he R W p hase. T h e pri mar y c o m paris o n of c ha n ge fr o m R W 
Baseli ne  val ues  a m o n g tr eat me nt gr o u ps will  b e  base d  o n t he M a n n -W hit n e y - Wilc o x o n 
test. As se nsiti vit y a nal yses, t he mea n  c h a n ge fr o m  R W baseli ne will  als o be c o m pare d  
a m o n g treat me nt gr o u ps usi n g Welc h’s  t w o-s a m ple test t hat all o ws f or u n e q ual  varia nces, 
as well as b y a li near r e gr essi o n m o del wit h H u ber- w hite sa n d wic h err ors all o wi n g f or 
heter osce dasticit y.  
T o  assess  t he i m pact of p ossi ble varia bilit y  i n R W  Baseli ne meas ures  bet w ee n  gr o u ps, a 
ra n k a nal ysis of c o varia n ce ( A N C O V A) m o del wit h c o variate a dj ust me nt f or R W 
Baseli ne will be perf or me d as a se nsiti vit y  a nal ysis. T his will be perf or me d at all p ost- 
baseli ne visits d uri n g t he R W p hase t hat i ncl u de a s ufficie nt n u m ber of p atie nts wit hi n 
eac h tr eat me nt gr o u p t o all o w f or a p pr o pri ate m o d el testi n g. M o del esti mates f or t he 
li near re gressi o n m o del a n d t he ra n k A N C O V A m o del will be prese nte d t o i ncl u de t he 
esti mate of mea n tr eat me nt differe n ce, ass o ciate d sta n dar d err or, 9 5 % CI of t he mea n 
differe n ce, a n d p -val u e.  
Descri pti ve  statistics f or t he o bser v e d  C R P  a n d ser u m ferriti n val ues  a n d c h a n ges fr o m 
baseli ne d uri n g t he S A O L p hase will be pres e nte d b y visit. 


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7. 4. 4. 4  
M o difie d  A ut o -I nfl a m m at ory Dise ase  Activity  I n dex 
Descri pti ve  statistics f or t he m AI D AI t otal sc ore (i ncl u di n g b ot h o bjecti ve a n d s u bjecti ve 
c o m p o ne nts) a n d c h a n ges fr o m R W Baseli ne d uri n g t he R W p hase will be prese nte d b y 
visit f or eac h tr eat me nt gr o u p. Descri pti ve statistics will i ncl u de n u m ber of s u bjects, 
mea n, sta n dar d d e viati o n, 9 5 % CI of t he mea n, m e dia n, Q 1, Q 3, mi ni m u m, a n d 
ma xi m u m val ues. Mea n m AI D AI t otal sc ore wit h ass ociate d sta n dar d err or bars will be 
pl otte d b y treat me nt gr o u p o ver ti me d uri n g t he R W p hase. 
T he  pri mar y  c o m paris o n f or t he c ha n g e fr o m  baseli ne i n  t he m AI D AI t otal s c ore a m o n g 
treat me nt gr o u ps will be base d o n t he Ma n n-W hit ne y - Wilc o x o n test. 
T he  esti ma n d f or t he sec o n dar y e n d p oi nt of c ha n g e i n m AI D AI t otal  sc ore fr o m R W 
baseli ne t o Wee k 3 4/ E T will be descri be d as f oll o ws: 
P o p ulati o n: All  patie nts  i n t he R W -F A S  p o p ulati o n. 
E n d p oi nt: C ha n ge fr o m R W baseli ne t o Wee k 3 4. 
I nterc urre nt e ve nts:  
•  Disc o nti n uati o n pri or t o Wee k 3 4: c h a n ge fr o m b aseli ne at Wee k 3 4 f or 
patie nts  w h o disc o nti n ue pri or t o Wee k 3 4 or f or p atie nts  w h o were  e nr olle d 
u n der pr ot oc ol v 4. 0/ 4. 1 a n d earlier a n d c o m plete R W at Wee k 2 6 will be 
i m p ute d usi n g last o bser vati o n carri e d f or w ar d ( L O C F). 
•  Resc ue i m m u n os u p pressi o n treat me nt: patie nts w h o recei v e res c ue 
i m m u n os u p pressi o n treat me nt a n d c o nti n ue i n t he R W  p hase will  i ncl u de all 
data ca pt ur e d wit hi n t he R W p hase i ncl u di n g visits after recei vi n g resc u e 
i m m u n os u p pressi o n treat me nt. 
P o p ulati o n- le vel s u m mar y: Descri pti ve  st atistics a n d Ma n n -W hit ne y -Wilc o x o n  test. 
As se nsiti vit y a nal yses, c ha n ge fr o m b aseli ne t o ma xi m u m p ost- baseli ne sc ore a n d 
c ha n ge fr o m baseli ne t o l ast R W assess me nt u p t o t he start da y of resc ue 
i m m u n os u p pressi o n treat me nt will be s u m marize d a n d c o m pare d a m o n g treat me nt 
gr o u ps. I n a d diti o n, t he mea n c ha n g e fr o m R W b aseli ne i n t he m AI D AI t otal sc ore will 
als o be c o m par e d a m o n g treat me nt gr o u ps usi n g Welc h’s t w o- s a m ple t-test t hat all o ws 
f or u ne q ual v aria n ces, as  well  as b y a li near re gressi o n  m o del wit h  H u ber-w hite  sa n d wic h 
err os all o wi n g f or heter osce dasticit y. A ra n k A N C O V A m o del t o i ncl u de a c o vari ate f or 
t he R W Baseli ne sc or e will als o be perf or me d as s e nsiti vit y a nal ysis, si milar t o t he 
a nal ysis of C R P a n d ser u m ferriti n c ha n g es fr o m R W Baseli ne. M o del esti mates f or t he 
li near re gressi o n m o del a n d t he ra n k A N C O V A m o del will be prese nte d t o i ncl u de t he 
esti mate of mea n tr eat me nt differe n ce, ass o ciate d sta n dar d err or, 9 5 % CI of t he mea n 
differe n ce, a n d p -val u e.  
S hifts i n  m AI D AI  r es p o nses fr o m R W  Baseli ne  t o eac h p ost-b aseli ne  visit d uri n g t he R W 
p hase will be s u m marize d b y c o m p o ne nt a n d treat me nt gr o u p (ie, pres e nt or a bse nt at 


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baseli ne t o prese nt or a bs e nt at eac h p ost -baseli ne visit). S u m marizati o n will i ncl u de t he 
t otal c o u nts f or all res p o nses re p orte d at b ot h R W Baseli ne a n d eac h p ost-b aseli ne visit. 
Perce nta g es  will  be base d  o n t he n u m ber of patie nts  wit h  a n o n-missi n g  R W  Baseli ne  a n d 
n o n- missi n g p ost- baseli ne assess me nt at eac h visit.  
T he  n u m ber a n d p erce nt of  patie nts  w h o i m pr o ve wit hi n eac h c o m p o n e nt ( o bjecti ve a n d 
s u bjecti ve) of t he m AI D AI will be s u m marize d d uri n g t he R W p hase b y visit a n d 
treat me nt gr o u p. F or eac h c o m p o ne nt, o nl y t he n u m ber of patie nts w h o re p orte d t he 
assess me nt as  pr ese nt ( 1  or 2) will  be c o nsi dere d f or a nal ysis. T he  pr o p orti o n of patie nts 
w h o re p ort t he assess me nt as a bse nt ( 0, ie, i m pr o ve d relati ve t o bas eli ne) at eac h p ost- 
baseli ne visit d uri n g t he R W p hase will  be c o m pare d a m o n g treat me nt gr o u ps usi n g t he 
Fis her’s e xact test. Patie nts wit h a missi n g assess me nt at a p ost -baseli ne visit will be 
c o nsi dere d t o ha v e n ot i m pr o ve d. 
Descri pti ve statistics f or t he m AI D AI t otal sc ore a n d c ha n ges fr o m baseli ne d uri n g t he 
S A O L  p hase will  be pr es e nte d  b y visit.  S hifts  i n m AI D AI  res p o nses fr o m b aseli ne  d uri n g 
t he S A O L p hase will be prese nte d b y visit. T he n u m ber a n d perce nt of p atie nts w h o 
i m pr o ve wit hi n eac h c o m p o ne nt of t he m AI D AI d uri n g t he S A O L p hase will be 
prese nte d b y visit. 
7. 4. 4. 5  
P hysici a n’s Gl o b al Assess me nt  
Descri pti ve statistics f or t he P G A s y m pt o m se verit y sc ore a n d c ha n ges fr o m R W 
Baseli ne d uri n g t he R W p hase will be pres e nte d b y visit f or eac h treat me nt gr o u p. 
Descri pti ve  statistics will  i ncl u de n u m ber of  s u bjects, mea n,  sta n dar d d e viati o n, 9 5 % CI 
of 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. Mea n P G A s y m pt o m 
sc ores wit h ass oci ate d sta n dar d err or b ars will be pl otte d b y treat me nt gr o u p o ver ti me 
d uri n g t he R W p hase. 
T he pri mar y  c o m paris o n of t he c ha n g e fr o m R W  Baseli ne i n  t he P G A s y m pt o m se verit y 
sc ore a m o n g tr eat me nt gr o u ps will be base d o n t he Ma n n-W hit ne y -Wilc o x o n test.  
T he  esti ma n d f or t he sec o n dar y e n d p oi nt of c ha n g e i n P G A  s y m pt o m se verit y sc ore fr o m 
R W baseli ne t o Wee k 3 4/ E T will be descri be d as f oll o ws:  
P o p ulati o n: All  patie nts  i n t he R W -F A S  p o p ulati o n. 
E n d p oi nt: C ha n ge fr o m R W baseli ne t o Wee k 3 4. 
I nterc urre nt e ve nts:  
•  Disc o nti n uati o n pri or t o Wee k 3 4: c h a n ge fr o m b aseli ne at Wee k 3 4 f or 
patie nts  w h o disc o nti n ue pri or t o Wee k 3 4 or f or p atie nts  w h o were  e nr olle d 
u n der pr ot oc ol v 4. 0/ 4. 1 a n d earlier a n d c o m plete R W at Wee k 2 6 will be 
i m p ute d usi n g L O C F. 
•  Resc ue i m m u n os u p pressi o n treat me nt: patie nts w h o recei v e res c ue 
i m m u n os u p pressi o n treat me nt a n d c o nti n ue i n t he R W p hase will  i ncl u de all 


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data  ca pt ure d  wit hi n  t he R W  p hase i ncl u di n g visits after recei vi n g resc ue 
i m m u n os u p pressi o n treat me nt. 
P o p ulati o n- le vel s u m mar y: Descri pti ve  st atistics a n d Ma n n -W hit ne y -Wilc o x o n  test. 
As se nsiti vit y a nal yses, c ha n ge fr o m R W b aseli ne t o ma xi m u m p ost- baseli ne sc ore a n d 
c ha n ge fr o m baseli ne t o l ast R W assess me nt u p t o t he start da y of resc ue 
i m m u n os u p pressi o n treat me nt will be s u m marize d a n d c o m pare d a m o n g treat me nt 
gr o u ps. I n a d diti o n, t he mea n c ha n g e fr o m R W b aseli ne i n P G A s y m pt o m se verit y sc ore 
will als o be c o m pare d a m o n g treat me nt gr o u ps usi n g Welc h’s t w o- s a m ple t-test t hat 
all o ws f or u ne q u al varia n ces, as w ell as b y a li near re gressi o n m o del wit h H u ber- w hite 
sa n d wic h err os all o wi n g f or heter os ce d asticit y. A ra n k A N C O V A m o del t o i ncl u de a 
c o variate f or t he R W  Baseli ne  sc ore will  als o be p erf or me d  as s e nsiti vit y a nal ysis, si milar 
t o t he a nal ysis of C R P a n d ser u m ferriti n c ha n ges fr o m R W Baseli ne. M o d el esti mates 
f or t he li near re gr essi o n m o del a n d t he ra n k A N C O V A m o del will be pres e nte d t o 
i ncl u de t he esti mate of m ea n treat me nt differe nce, ass ociate d sta n dar d err or, 9 5 % CI of 
t he mea n diff ere n ce, a n d p-val ue.  
S hifts i n  P G A  f or sta bilit y of t he patie nt’s  diseas e -relate d (a ut o-i nfla m mat or y) s y m pt o ms 
o ver t he pr e vi o us t w o wee ks at R W Baseli ne t o eac h p ost- baseli ne visit will be 
s u m marize d b y gr o u p (ie, i m pr o ve d, sta ble or w orse at baseli ne t o i m pr o ve d, sta ble, or 
w orse at eac h p ost -b aseli ne visit). S u m marizati o n will i ncl u de t he t otal c o u nts f or all 
res p o nses r e p orte d at b ot h baseli ne a n d eac h p ost-baseli ne visit. Perce nta g es will be 
base d o n t he n u m ber of p atie nts wit h  a n o n-missi n g R W  Baseli ne a n d n o n- missi n g p ost- 
baseli ne assess me nt at eac h visit.  
Descri pti ve statistics f or t he P G A s y m pt o m se verit y sc ore a n d c ha n ges fr o m baseli ne 
d uri n g t he S A O L p hase will be prese nte d b y visit. S hifts i n P G A f or sta bilit y of t he 
patie nt’s  diseas e -r elate d ( a ut o-i nfla m mat or y) s y m pt o ms d uri n g t he S A O L  p hase will  be 
prese nte d b y visit. 
7. 4. 4. 6  
P atie nt’s  or C are giver’s  Q u alitive  Ev al u ati o n of He alt h  St at us  
Descri pti ve statistics f or t he o verall diseas e -relate d s y m pt o ms sc ore ra n gi n g fr o m 0 
( n o ne) t o 1 0 ( e xtre me) of t he patie nt/care gi ver q ualitati ve e val uati o n of healt h stat us 
q uesti o n naire a n d c h a n ges fr o m R W  Baseli ne  t o e n d of R W  p hase will  be prese nte d f or 
eac h tr eat me nt gr o u p. T h e t otal  d o mai n sc ores (s u m of i n di vi d ual s y m pt o m sc ores) f or 
ge neral w ell bei n g, gastr oi ntesti nal s y m pt o ms, m usc ul os keletal s y m pt o ms, s ki n 
s y m pt o ms, e ye s y m pt o ms, ce ntral ner v o us s yste m, a n d l y m p hatic s yste m will be 
s u m marize d si milarl y. T he t otal d o mai n sc ores will be calc ulate d as t he s u m eac h 
i n di vi d ual s y m pt o m sc ore, ra n gi n g fr o m 0 ( n o ne) t o 5 ( ver y se v ere), wit hi n t he 
c orres p oi n di n g d o mai n. Descri pti ve statistics will i ncl u de n u m ber of s u bjects, mea n, 
sta n dar d de viati o n, 9 5 % CI of t he m ea n, me dia n, Q 1, Q 3, mi ni m u m, a n d ma xi m u m 
val ues.  
T he  patie nt/care gi ver e val uati o n  of c ha n ge i n  s y m pt o ms fr o m R W  Baseli ne  t o e n d of R W 
p hase will als o be s u m marize d b y treat me nt gr o u p. T he e val uati o n of t h e sta bilit y of 


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disease -r elate d s y m pt o ms fr o m R W Baseli ne t o e n d of R W p hase will be s c ore d as 
w orse,  sli g htl y w orse,  sta ble, sli g htl y i m pr o ve d, or i m pr o ve d. S u m marizati o n  will  i ncl u de 
t he n u m ber a n d perce nt of patie nts i n eac h cate g or y. 
S u m maries of t he patie nt/care gi ver q ualitati ve e v al uati o n of healt h stat us d uri n g t he 
S A O L p hase will als o be prese nte d. D escri pti ve st atistics of mea ns a n d mea n c ha n g es 
fr o m S A O L Baseli ne t o e n d of S A O L p hase f or t h e o verall disease-relate d s y m pt o ms 
sc ore a n d eac h  t otal d o m ai n sc ore will  be s u m marize d. T he e val uati o n of  t h e sta bilit y of 
disease -r elate d s y m pt o ms fr o m S A O L Baseli ne t o e n d of S A O L p has e will als o be 
prese nte d.  
7. 4. 4. 7  
H os pit aliz ati o n  
T he n u m ber a n d p erce nt of patie nts wit h n o h os pitalizati o n, 1 h os pitalizati o n, 2 
h os pitalizati o ns, a n d ≥ 3 h os pitalizati o ns occ urri n g d uri n g t he R W p hase will be 
prese nte d  b y tr eat me nt gr o u p, a m o n g t h ose patie nts  w h o were  n ot h os pitalize d d uri n g t he 
S A O L Baseli ne peri o d. Descri pti ve statistics f or t he t otal h os pital le n gt h of sta y i n da ys 
will  als o be prese nte d b y treat me nt gr o u p, w h ere t he t otal le n gt h of sta y f or eac h p atie nt 
is t he s u m of t he d urati o ns f or all i n di vi d ual h os pitalizati o n a d missi o ns. T he d urati o n of 
a n i n di vi d ual h os pitalizati o n is deter mi ne d as t he date of disc har ge mi n us t he date of 
a d missi o n, pl us o ne. 
I m pr o v e me nt i n oral/e nteral n utriti o n a n d st o ol o ut p ut at h os pitalizati o ns occ urri n g 
d uri n g t he R W  p hase will  be assesse d f or  t h ose patie nts  t hat re p ort i ntesti nal d ysf u ncti o n 
d uri n g a baseli ne h os pitalizati o n pri or t o t he first d ose of st u d y dr u g d uri n g t he S A O L 
p hase. S pecificall y, descri pti ve statistics t o i ncl u de c ha n ges fr o m t he baseli n e 
h os pitalizati o n will be prese nte d b y treat me nt gr o u p f or P O i nta ke ( m L), n u m ber of 
e mesis e pis o des, a n d st o ol o ut p ut ( g) f or eac h p ost- baseli ne h os pitalizati o n e x perie n ce d 
i n se q ue nce. 
 
Si milar  s u m maries will  be prese nte d  f or h os pitalizati o ns  a n d i m pr o ve me nt i n oral/e nteral 
n utriti o n a n d st o ol o ut p ut at h os pitalizati o ns occ urri n g d uri n g t he S A O L p h ase. 
7. 4. 4. 8  
Cyt oki nes  a n d I nfl a m m at ory Me di at ors  
Descri pti ve statistics f or t he a d diti o nal efficac y e n d p oi nt a nal ysis of o bser v e d ser u m 
le vels of t otal I L- 1 8, fr ee I L- 1 8, a n d I L- 1 8 B P a n d c ha n ges fr o m baseli ne  d uri n g t he R W 
p hase will be pres e nte d b y visit f or eac h treat me nt gr o u p. A si milar s u m mar y will be 
prese nte d f or t he S A O L p hase.  
7. 4. 4. 9  
D ur ati o n of Res p o nse d uri n g S A O L  
D urati o n of r es p o nse d uri n g t he S A O L  p hase will  be s u m marize d usi n g K M  esti mates f or 
patie nts w h o ac hie v e eit h er c o m plete res p o nse or partial res p o nse d uri n g S A O L. K M 
esti mates will i ncl u de esti mates of q uartiles ( 2 5 t h perce ntile, me di a n, 7 5t h perce ntile) 
al o n g wit h c orr es p o n di n g 9 5 % CIs. D urati o n of res p o nse is defi ne d as t he ti me fr o m first 
assess me nt i n dicati n g partial or c o m plete res p o ns e u ntil t he ti me of s u bse q ue nt disease 
reacti vati o n. Patie nts w h o d o n ot e x perie nce a dis ease reacti vati o n d uri n g S A O L 


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Versi o n  7. 0;  2 5  Se pte m ber 2 0 2 3  
C o nfi de nti al  
Pa ge  3 5  of  4 6  
 
 
f oll o wi n g res p o nse t o t hera p y will  b e  ce ns ore d  at t he date  of t h eir last cli nical assess me nt 
d uri n g t he S A O L p hase. 
7. 4. 4. 1 0  
Dise ase  Re activ ati o n  R ate  per  Week  d uri n g S A O L  
T he n u m ber of disease r eacti vati o ns e x peri e nce d d uri n g t he S A O L p hase will be 
s u m marize d wit h c o u nts a n d perce nta ges, f or t h ose e x peri e nci n g 0, 1, 2, 3 or ≥ 4  disease 
reacti vati o ns. T he n u m b er of disease reacti vati o ns per wee k will be s u m marize d usi n g 
descri pti ve statistics. T he t otal n u m ber of patie nt wee ks o n st u d y treat me nt d uri n g t he 
S A O L  p hase a n d t he t otal n u m ber of disease  reacti vati o ns e x perie n ce d  will  be prese nte d.  
7. 4. 5  
St atistic al/ A n alytic al  Iss ues 
7. 4. 5. 1  
A dj ust me nts f or C ov ari ates  
D ue t o t he s mall patie nt sa m ple size, t he c h a n ges fr o m R W Baseli ne f or c o nti n u o us 
efficac y e n d p oi nts will be a nal yze d usi n g t he n o n- para metri c Ma n n - W hit ne y- Wilc o x o n 
test, wit h n o a dj ust me nts f or c o variates. H o w e ver, t o assess p ossi ble varia bilit y i n R W 
Baseli ne meas ur es  bet wee n  gr o u ps, a ra n k A N C O V A  m o del t o i ncl u de a c o variate f or t he 
R W Baseli ne val ue will be perf or me d as a se nsiti vit y a nal ysis.  
7. 4. 5. 2  
H a n dli n g of Dr o p o uts or Missi n g  D at a  
T he  a nal ysis  of t he pri mar y  e n d p oi nt, ti me t o first occ urre nce  of disease  reacti vati o n, will 
be base d o n K M s ur vi v al a nal ysis tec h ni q ues, w here patie nts w h o d o n ot e x perie nce a 
disease  reacti vati o n d uri n g t he R W  p hase will  be ce ns ore d  at date of t heir l ast assess me nt 
f or disease s y m pt o ms. 
A nal ysis of res p o nse t o t hera p y a n d treat me nt fail ures will c o nsi der t h ose p atie nts w h o 
ha ve missi n g rele va nt dat a f or e v al uati o n  of res p o nse t o be n o n-res p o n ders or  treat me nt 
fail ures. A nal ysis of  t he i m pr o ve me nt i n t he i n di vi d ual c o m p o ne nts of  t he m AI D AI will 
c o nsi der t h ose patie nts wit h a gi ve n s y m pt o m re p orte d as pres e nt at baseli n e w hile 
missi n g t he assess me nt at a p ost - baseli ne visit t o ha ve n ot i m pr o ve d at t hat visit. 
All a nal yses of c h a n ges fr o m baseli ne i n c o nti n u o us meas ures b y visit t o i ncl u de C R P, 
ser u m ferriti n, m AI D AI t otal sc ore, a n d t h e P G A s e verit y sc ore will be base d o n 
o bser ve d dat a. T his will i ncl u de a n a n al ysis at Wee k 2 6 / 3 4 / E T t o ca pt ure t he last 
o bser ve d dat a assesse d f or patie nts w hile o n st u d y treat me nt d uri n g t he R W p hase (i e, 
c o m bi nes data c ollecte d at Wee k 2 6 [ V 1 1]  or Wee k 3 4 [ V 1 3] f or patie nts w h o c o m plete 
t he treat me nt peri o d as pla n ne d wit h  data  c ollecte d  at t he St u d y C o m pleti o n  [ V 1 1 / V 1 3] 
visit f or patie nt w h o disc o nti n ue t he R W p hase earl y). All data will be i ncl u de d i n t he 
statistical a nal yses re g ar dless of a d here nce t o st u d y treat me nt or use of a ncillar y 
me dicati o n.  
E n d p oi nts s u m marize d as a s hift fr o m baseli ne t o i ncl u de m AI D AI res p o ns es b y 
c o m p o ne nt a n d t he P G A  f or sta bilit y of patie nt’s  disease  relate d s y m pt o ms will  be base d 
o n o bser v e d data, w h ere  t he de n o mi nat or t o c o m p ute t he perce nt a ge of pati e nts f or eac h  


A B 2 Bi o Lt d 
N L R C 4/ XI A P. 2 0 1 6. 0 0 1  
Statistical  A nal ysis  Pla n 
Versi o n  7. 0;  2 5  Se pte m ber 2 0 2 3  
C o nfi de nti al  
Pa ge  3 6  of  4 6  
 
 
s hift cate g or y will  b e bas e d  o n t he n u m ber of patie nts  wit h  rele va nt n o n-missi n g  baseli ne 
a n d p ost-baseli ne at t he visit of i nterest.  
F or all patie nts e nr olle d pri or t o pr ot oc ol v 5. 0, t he or ga n o me g al y s u bt y pes were n ot 
e x plicitl y d oc u me nte d wit h t he m AI D AI. T h us, f or eac h visit w here or g a n o me gal y is 
i n dicate d as pres e nt b ut n o e C R F pa ge of “s u bt y pes of or ga n o me gal y” is c o m plete d, t he 
s u bt y pes will be e val uate d b y c orres p o n di n g e ntries i n t he disease hist or y, p h ysical 
e xa mi nati o n, or a d vers e e ve nts. H o we ver,  as t he p h ysical  e xa mi nati o n  after  t he baseli ne 
visit o nl y ca pt ures ne w or w orse n e d c o n diti o ns, a n i m pr o ve me nt of o ne or m ulti ple 
or ga n o me gal y s u bt y pes ma y n ot be d oc u me nte d. T h us, all or ga n o me gal y s u bt y pes will 
be d oc u me nte d as o n g oi n g as l o n g as or ga n o me g al y is i n dicate d as bei n g prese nt. 
7. 4. 5. 3  
I nteri m A n alyses  a n d D at a M o nit ori n g  
T here are n o i nteri m a nal yses pla n ne d f or t his st u d y. A Data Safet y M o nit ori n g B oar d 
( D S M B) will c o n ve ne r e g ularl y t hr o u g h t he d urati o n of t he trial t o assess t he gl o bal 
safet y of  T A  a n d a d vise w het her t o c o nti n ue or disc o nti n ue t he st u d y. C o m plete details  of 
t he D S M B r oles a n d res p o nsi bilities are o utli ne d i n a se parate D S M B c harter. 
7. 4. 5. 4  
M ultice nter  St u dies  
T his is  a m ultice nter st u d y, wit h  a p pr o xi matel y ele ve n cli nical sites i n t he U nite d  States, 
Ca na da, a n d Ger ma n y. Efficac y  data c ollecte d fr o m all st u d y  ce nters will b e p o ole d f or 
data  a nal ysis. T he eff ect of st u d y ce nter o n t he effi cac y a n al ysis res ults ma y be e x pl ore d 
p ost- h oc, as nee de d. 
7. 4. 5. 5  
M ulti ple  C o m p aris o ns/ M ulti plicity  
T he o ver all 2 -si de d le vel of si g nifica nce will be al p ha = 0. 0 5 f or all statistical testi n g t o 
i ncl u de t he pri mar y e n d p oi nt a nal ysis. T he h y p ot hesis testi n g of selecte d sec o n dar y 
e n d p oi nts c ollecte d d uri n g t he R W p hase will be c o n d ucte d usi n g a gate k ee pi n g 
pr oce d ur e base d o n a cl ose d fi xe d -se q u e nce test, pr o vi de d t he pri mar y e n d p oi nt 
c o m paris o n is statisticall y si g nifica nt ( p < 0. 0 5). T his pr oce d ure c o ntr ols t he st u d y- wise 
t y pe I err or as des cri be d bel o w. I n or der t o e val uate t he c o m paris o n f or eac h ste p, all 
prece di n g  c o m paris o ns m ust ha ve bee n  statisticall y si g nifica nt base d o n a 2-si de d al p ha = 
0. 0 5 i n fa v or of  T A.  
1.  Place b o a n d T A  will be c o m pare d wit h  res pect t o t he pri mar y efficac y  e n d p oi nt, 
ti me t o first occ urr e nce of  diseas e  reacti vati o n e x p erie nce d  d uri n g t he R W  p hase 
2.  Place b o a n d  T A  will  be c o m pare d f or t he pr o p orti o n of treat me nt fail ures (i e, 
e x perie n ce at least o ne disease reacti vati o n) d uri n g t he R W p hase  
3.  Place b o a n d  T A  will  be c o m pare d f or res ults of t h e c ha n ge fr o m  R W  Baseli ne  t o 
Wee k 3 4/ E T i n t he m AI D AI t otal sc ore 
4.  Place b o a n d  T A  will  be c o m pare d f or res ults of t h e c ha n ge fr o m  R W  Baseli ne  t o 
Wee k 3 4/ E T i n t he P G A s y m pt o m se verit y sc ore 


A B 2 Bi o Lt d 
N L R C 4/ XI A P. 2 0 1 6. 0 0 1  
Statistical  A nal ysis  Pla n 
Versi o n  7. 0;  2 5  Se pte m ber 2 0 2 3  
C o nfi de nti al  
Pa ge  3 7  of  4 6  
 
 
If t he c o m paris o n is n ot statisticall y si g nifica nt at a n y ste p defi ne d a b o ve usi n g t he 2- 
si de d 0. 0 5 al p ha le vel, t h e n re mai ni n g c o m paris o ns i n t he state d hierarc h y will be 
c o nsi dere d n o mi nal, des cri pti ve, a n d e x pl orat or y. T he st u d y- wise t y pe I err or will be 
mai ntai ne d  wit h  t he a b o v e cl ose d pr oce d ure. All  ot her statistical  testi n g will  be e val uate d 
descri pti vel y.  
7. 4. 5. 6  
Use  of a n “ Effic acy  S u bset ” of P atie nts  
T he pri mar y  efficac y a nal ysis will be perf or me d o n t he R W -F A S. Sec o n dar y  e n d p oi nts 
will  als o be a nal yze d f or  t he R W -P P A S  pr o vi de d t he R W -F A S  a n d R W -P P A S  differ  b y 
at least o ne patie nt.  
7. 4. 5. 7  
Active - C o ntr ol St u dies I nte n de d t o S h o w E q uiv ale nce  
T his  st u d y d oes n ot i ncl u de  a n acti ve-c o ntr ol pr o d uct a n d  is n ot i nte n de d t o de m o nstrate 
e q ui vale nce bet wee n a n y t w o dr u g pr o d ucts. 
7. 4. 5. 8  
Ex a mi n ati o n of S u b gr o u ps  
I m pr o v e me nt i n oral/e nteral  n utriti o n  a n d st o ol o ut p ut at h os pitalizati o ns  occ urri n g will 
be assesse d f or  t he s u bset of patie nts  t hat re p ort i ntesti nal d ysf u ncti o n d uri n g a baseli ne 
h os pitalizati o n.  
Be y o n d t hat, t here are n o pre- pla n n e d a nal yses t o assess effi cac y res ults b y s u b gr o u p 
si nce t he st u d y p o p ulati o n is t o o s mall t o warra nt a n y  mea ni n gf ul i nter pretati o ns. Select 
e n d p oi nts ma y be a nal yze d se paratel y b y u n derl yi n g disease stat us (ie, N L R C 4- M A S, 
XI A P) p ost- h oc, as warra nte d. 
7. 4. 6  
Ser u m  C o nce ntr ati o ns  
Ra w ser u m c o n ce ntrati o n val ues will be s u m marize d f or t he S A O L - P K A S b y sc he d ule d 
sa m pli n g ti me p oi nt usi n g descri pti ve statistics, t o i ncl u de t he ge o metric m ea n a n d C V 
( %). T he g e o metric C V is calc ulate d as 1 0 0 *s qrt[e x p( σ2)-1], w here σ 2 is t he varia n ce of 
t he l o g-tra nsf or me d d ata. Eac h patie nt’s plas m a c o nce ntrati o ns will be pl otte d o ver ti me. 
F or t he p ur p os es of pl otti n g t he data, plas ma c o n ce ntrati o ns bel o w t he li mit of 
q ua ntificati o n ( B L Q) t hat are i m be d de d b et wee n t w o meas ura bl e c o nce ntrati o ns will be 
set t o missi n g;  h o we ver, B L Q  val ues  occ urri n g  pri or t o t he first meas ura ble c o nce ntrati o n 
or after t h e last meas ur a ble c o nce ntrati o n will be set t o zer o. F or s u m maries of plas ma 
c o nce ntr ati o ns, B L Q  val ues  will  be set t o missi n g. T he  n u m ber a n d perce nt a ge  of patie nts 
wit h B L Q val ues will be s u m marize d b y  ti me p oi nt. Mea n I L- 1 8 B P c o nce ntrati o n val ues 
wit h ass ociate d sta n dar d err or b ars will be pl otte d o ver ti me d uri n g t he S A O L p hase. 
7. 4. 7  
P h ar m ac o ki netic A n alysis  
P har mac o ki netic para met ers will be a nal y ze d bas e d o n t he S A O L -P K A S. F or eac h 
patie nt, t he P K para met ers descri be d i n Secti o n 6. 4. 3  will be deter mi ne d b y a n o n- 
c o m part me ntal a p pr oac h. F or t he p ur p os e of t he n o n- c o m part me ntal P K a n al ysis, all 
plas ma  c o nce ntr ati o n  B L Q  val ues  o cc urri n g  pri or t o t he first meas ura ble c o nce ntrati o n  


A B 2 Bi o Lt d 
N L R C 4/ XI A P. 2 0 1 6. 0 0 1  
Statistical  A nal ysis  Pla n 
Versi o n  7. 0;  2 5  Se pte m ber 2 0 2 3  
C o nfi de nti al  
Pa ge  3 8  of  4 6  
 
 
will  be set t o zer o. B L Q  val ues  occ urri n g after t he first meas ura ble plas ma  c o nce ntrati o n 
will be set t o missi n g.  
P K para meters will be s u m marize d usi n g descri pti ve statistics t hat i ncl u des t he C V. 
S u m maries of  Cma x , A U C0- 2 4, a n d T1/ 2  will als o i ncl u de p oi nt esti mates f or t he ge o metric 
mea n  a n d g e o metric  C V. T he  ge o metric mea n  is calc ulate d b y c o m p uti n g t he mea n of t he 
l o g-tra nsf or me d c o nce ntr ati o n val ues a n d t he n prese nte d i n t he ori gi nal scal e b y 
calc ulati n g t he a nti -l o g of t he mea n res ult. T he ge o metric C V is calc ulate d as 
1 0 0 *s qrt[e x p( σ 2)-1], w h ere σ 2 is t he varia nce of t h e l o g-tra nsf or m e d data. Listi n gs of 
calc ulate d P K p ara met ers will be pr o vi de d a n d will i ncl u de t he n u m ber of p oi nts use d t o 
calc ulate λ z. 
7. 5  
S afet y  E v al u ati o n  
Safet y  a nal ysis f or d ata c ollecte d d uri n g t he R W p hase will be base d o n t h e R W- F A S, t o 
i ncl u de all patie nts w h o r ecei ve at least o ne d os e of d o u ble- bli n d st u d y dr u g d uri n g t he 
R W p hase. Patie nts w h o d o n ot c o m plete t he st u d y, f or w hate v er reas o n, will ha ve all 
a vaila ble data  u p u ntil t he ti me of ter mi nati o n i ncl u de d i n t he a nal ysis. F or safet y  a nal ysis 
prese nte d b y st u d y visit, t he R W  Baseli ne val u e will be defi ne d as t he l ast val ue re p orte d 
pri or t o t he first d ose of st u d y dr u g d uri n g t he R W p hase. 
All safet y  s u m maries f or data c ollecte d d uri n g t he S A O L p hase will be bas e d o n t he 
S A O L -F A S, t o  i ncl u de all patie nts  w h o recei ve at l east o ne d ose of T A  d uri n g t he S A O L 
p hase. F or saf et y a nal ysis prese nte d b y st u d y visit, t he S A O L Baseli ne val ue will be 
defi ne d as t he l ast val ue r e p orte d pri or t o t he first d ose of T A d uri n g t he S A O L p hase. 
7. 5. 1  
E xte nt of E x p os ure  
E xte nt of e x p os ure t o st u d y treat me nt d uri n g t he R W p hase will be s u m marize d f or t he 
R W - F A S b y treat me nt gr o u p a n d d uri n g t he S A O L p hase f or t h e S A O L-F A S f or all 
patie nts  c o m bi ne d. T he d urati o n of e x p os ure will  be prese nte d i n  d a ys  a n d calc ulate d as 
t he date of last d ose of st u d y dr u g mi n us t he date of first d ose of st u d y dr u g, pl us o ne. 
T he date  of l ast d ose of st u d y dr u g is t he date re p orte d o n t he E n d of  Treat m e nt f or m, f or 
b ot h t he e n d of t he S A O L  p hase a n d t he e n d of treat me nt d uri n g t he R W  p hase. D urati o n 
of e x p os ure a n d t otal n u m ber of d oses recei ve d will be s u m marize d usi n g descri pti ve 
statistics. 
7. 5. 2  
A dverse  Eve nts  
Treat me nt -e mer ge nt a d v erse e v e nts ( T E A Es) are defi ne d as t h ose a d vers e e ve nts ( A Es) 
wit h  o nset after  t he first d ose of st u d y dr u g or e xisti n g e ve nts t hat w orse ne d after t he first 
d ose d uri n g t he st u d y. Tr eat me nt-e mer ge nt A Es o cc urri n g d uri n g t he R W p hase will be 
s u m marize d b y treat me nt gr o u p; T E A Es occ urri n g d uri n g t he S A O L p hase will be 
s u m marize d f or all patie nts c o m bi ne d. 
Treat me nt - e mer ge nt A Es occ urri n g d uri n g t he S A O L p hase will be restrict e d t o t h ose 
e ve nts wit h  o nset o n or after t he start of d osi n g d uri n g t he S A O L  p hase a n d pri or t o t he 
start of d osi n g d uri n g t he R W p hase or 2 8 da ys aft er t he last d ose  of  st u d y dr u g d uri n g 


A B 2 Bi o Lt d 
N L R C 4/ XI A P. 2 0 1 6. 0 0 1  
Statistical  A nal ysis  Pla n 
Versi o n  7. 0;  2 5  Se pte m ber 2 0 2 3  
C o nfi de nti al  
Pa ge  3 9  of  4 6  
 
 
t he S A O L p hase, w hic h e ver occ urs first. E ve nts re p orte d wit h a partial o nset date (e g, 
m o nt h a n d year are r e p orte d b ut t he da y is missi n g) will be c o nsi dere d t o b e treat me nt- 
e mer ge nt if it ca n n ot be c o nfir me d  t hat t he e ve nt o nset was  pri or t o t he first d ose of st u d y 
dr u g base d o n t he a vaila ble date e ntries.  
Treat me nt - e mer ge nt A Es occ urri n g d uri n g t he R W p hase will be restricte d t o t h ose 
e ve nts wit h  o nset o n or after t he start of d osi n g d uri n g t he R W  p hase a n d pri or t o  t he first 
d ose of st u d y dr u g d uri n g t he o pe n- la bel e xte nsi o n st u d y or 2 8 da ys after t h e last d ose of 
st u d y dr u g d uri n g t he R W p hase, w hi c he ver occ urs first. 
Ver bati m  ter ms o n case r e p ort f or ms will  be ma p p e d  t o preferre d  ter ms a n d s yste m or ga n 
classes usi n g t he Me dical  Dicti o nar y  f or Re g ulat or y Acti vities ( Me d D R A, versi o n  2 0. 0). 
S u m maries  t hat are dis pla ye d b y s yste m or g a n  cl ass a n d preferre d  ter ms will  be or dere d 
b y desce n di n g i nci de n ce of s yste m or ga n class a n d preferre d t er m wit hi n eac h s yste m 
or ga n cl ass. S u m maries  dis pla ye d b y preferre d ter m  o nl y will  be or dere d b y desce n di n g 
i nci de nce of pref err e d ter m. Ter ms wit h t he sa me i nci de nce will be or dere d 
al p ha beticall y. S u m maries of t he f oll o wi n g t y pes will be prese nte d, se p aratel y f or t he 
S A O L p hase a n d R W p h ase:  
•  O verall s u m mar y  of n u m ber of u ni q ue T E A Es a n d treat me nt-e mer ge nt seri o us 
a d verse e ve nts ( S A Es) a n d patie nt i nci de nce of T E A Es  meeti n g  vari o us crit eria  
•  Patie nt  i nci de nce of T E A Es  b y Me d D R A  s yste m or ga n cl ass a n d preferre d  ter m 
•  Patie nt i nci de nce  of T E A Es  b y se verit y gra d e, Me d D R A  s yste m or ga n class, a n d 
preferre d t er m  
•  Patie nt i nci de nce  of T E A Es  b y relati o ns hi p t o st u d y dr u g, Me d D R A s yste m or ga n 
class, a n d preferre d ter m  
•  Patie nt i nci de nce  of T E A Es  wit h  se verit y gra de ≥ 3  a n d relate d t o st u d y dr u g b y 
Me d D R A s yste m or ga n class a n d preferre d ter m  
•  Patie nt i nci de nce  of treat me nt-e mer g e nt a d vers e  e ve nts of s p ecial i nterest ( A E SI) 
b y Me d D R A s yste m or g a n class a n d preferre d ter m  
•  Patie nt i nci de nce  of S A Es b y  Me d D R A  s yste m or ga n class a n d preferre d  ter m 
At eac h le v el  of s u m mari zati o n (e g, a n y A E, s yste m or ga n class, a n d preferre d ter m),  
patie nts  e x perie n ci n g m ore t ha n o ne T E A E will be c o u nte d o nl y o nce. I n  t h e s u m mar y of 
T E A Es  b y se verit y gra de, patie nts will  be c o u nte d o nce at t he hi g h est se verit y  re p orte d at 
eac h le v el of s u m marizati o n; i n t he s u m mar y of T E A Es b y relati o ns hi p, patie nts will be 
c o u nte d o nce at t he cl osest relati o ns hi p t o st u d y dr u g. 
I n a d diti o n t o t he T E A E i nci de nce s u m maries descri be d a b o ve, T E A E i nci d e nce will be 
c orre cte d f or differ e nces i n  st u d y dr u g e x p os ure b y  usi n g pers o n-ti me i n t he de n o mi nat or 


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t o calc ulate i nci d e nce rat es. Eac h  patie nt’s  pers o n e x p os ure years ( P E Y) will  be 
calc ulate d b y t he f oll o wi n g: 
•  As t he date  of o ns et of t h e T E A E of i nterest mi n us t he date of first d ose of st u d y 
dr u g pl us o ne, di vi de d b y 3 6 5. 2 5, f or t h ose s u bjects w h o e x perie nce t he T E A E  of 
i nterest; or 
•  As  t he date of last d ose of st u d y dr u g pl us  2 8 da ys, mi n us  t he date of first d ose of 
st u d y dr u g pl us  o ne, di vi de d b y  3 6 5. 2 5, f or  t h ose s u bjects w h o d o n ot e x perie nce 
t he T E A E of i nter est. 
O ne  P E Y  is t he e q ui vale nt of o ne patie nt  e x p os e d t o st u d y dr u g f or o ne year.  T w o  
patie nts  w h o ar e e x p ose d t o st u d y dr u g f or half a y ear c o ntri b ute  o ne P E Y.  T he  t otal P E Y 
of a treat me nt gr o u p is t he s u m of t he pers o n e x p os ure years of eac h patie nt i n t hat 
treat me nt gr o u p. E x p os ur e-a dj uste d T E A E  i nci de n ce will  be s u m marize d per 1 0 0 P E Y  as 
t he n u m ber of patie nts wit h a n e ve nt f or w h o m pers o n-ti me is a vaila ble, di vi de d b y t he 
t otal P E Y f or eac h treat m e nt gr o u p a n d m ulti plie d b y 1 0 0. E x p os ure-a dj uste d T E A E 
i nci de nce will be s u m marize d se p aratel y f or t he S A O L p hase a n d t he R W p hase. 
A d verse e ve nt data will be prese nt e d i n data listi n gs b y patie nt, treat me nt gr o u p, a n d 
e ve nt. Seri o us A Es, A Es lea di n g t o disc o nti n uati o n of t he st u d y dr u g, a n d A E SIs  will  be 
prese nte d i n se p arat e dat a listi n gs.  
7. 5. 3  
De at hs,  Ot her  Seri o us  A dverse  Eve nts,  a n d Ot her  Si g nific a nt  A dverse  
Eve nts  
All  deat hs d uri n g t he st u d y as re p orte d  o n t he E n d  of Treat me nt  ( S A O L), E n d of  
Treat me nt ( R W), St u d y C o m pleti o n/ St u d y Disc o nti n uati o n, a n d A d verse E ve nt e C R Fs 
will  be liste d  b y patie nt,  t o i ncl u de t he pri mar y  ca use of deat h. Seri o us A Es, A Es lea di n g 
t o st u d y dr u g wit h dra wal, i nterr u pti o n, or d ose re d ucti o n of t he st u d y dr u g, a n d A E SIs 
will  be pr o vi de d i n se par ate patie nt data listi n gs. A E SIs i ncl u d e e ve nts t hat c o nstit ute a n 
i njecti o n site reacti o n, i n cl u di n g pr urit us, er yt he m a, a n d s welli n g. 
7. 5. 4  
Cli nic al  L a b or at ory Ev al u ati o n  
All descri pti ve s u m maries of la b orat or y res ults will be base d o n data a nal yze d b y t he 
ce ntral la b orat or y  a n d pr ese nte d i n S ystè me I nter nati o nal ( SI) u nits, as s u g geste d b y t he 
Ce nter f or Bi ol o gics E val uati o n a n d Researc h a n d t he Ce nter f or Dr u g E val uati o n a n d 
Researc h  P ositi o n o n Use of SI U nits f or L a b Tests ( Oct 2 0 1 3). All data will be i ncl u de d 
i n b y- patie nt data listi n gs. La b orat or y meas ure m e nts i de ntifie d as a b n or mal (ie, o utsi de 
t he n or mal ra n g e) will als o be liste d se parat el y b y patie nt, la b orat or y test, a n d u nit. I n 
a d diti o n, n or mal ra n ges pr o vi de d b y t he ce ntral la b orat or y will  be pres e nte d i n  a se parate 
listi n g. 
Cli nical  la b orat or y meas ure me nts  i ncl u di n g ser u m c he mistr y, he mat ol o g y, c oa g ulati o n, 
a n d er yt hr o c yte se di me nt ati o n rate will be s u m marize d se paratel y f or t he S A O L p hase 
a n d t he R W p hase b y tr eat me nt gr o u p. Descri pti ve statistics will be prese nte d f or 


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o bser ve d val u es a n d  c h a n ges  fr o m eac h  res p ecti ve baseli ne  at eac h visit w here 
para meters were sc h e d ule d t o be c ollecte d per t he cli nical st u d y pr ot oc ol. 
W here  a p plica ble, la b or at or y res ults will  be classifie d as “l o w,”  “ n or mal,” or  “ hi g h” wit h 
res pect t o t he para meter -s pecific refere n ce ra n g es (ie, bel o w t h e l o wer li mit of t he n or mal 
ra n ge, wit hi n t he n or mal ra n ge, or a b o ve t he u p p er li mit of t he n or mal ra n ge). T hree- b y- 
t hree c o nti n ge n c y ta bles will be prese nte d f or eac h st u d y p hase a n d la b orat or y para met er 
t o s u m marize t he s hift fr o m t he baseli ne cat e g or y t o t he w orst p ost-baseli ne 
meas ure me nt, d efi ne d as t he val ue n u mericall y fart hest o utsi de of t he n or mal ra n ge 
acr oss all  p ost- baseli ne visits t hr o u g h t he e n d of t he st u d y. S u m mar y res ults will i ncl u de 
t he c o u nt a n d per ce nta g e of patie nts wit hi n eac h s hift cate g or y a n d treat me nt gr o u p. 
Perce nta g es  will  be base d  o n t he n u m ber of patie nts  wit h  a n o n- missi n g baseli ne val ue 
a n d at least o ne n o n- missi n g p ost- baseli ne val ue.  
W here  a p plica ble,  he mat ol o g y, c he mistr y, a n d c oa g ulati o n res ults f or selecte d para met ers 
will be assi g ne d a t o xicit y gra de bas e d o n t he U. S. De part me nt of Healt h a n d H u ma n 
Ser vices C o m m o n Ter mi n ol o gy Criteri a f or A dverse Eve nts ( C T C A E) , versi o n 5. 0 ( 2 7 
N o v 2 0 1 7). If t he q u a ntitati ve criteria f or gra di n g are e q ui v ale nt f or t w o gra des a n d t he 
differe ntiati o n is descri be d b y cli nical i nter ve nti o ns, t he cli nical i nter ve nti o n c o m p o ne nt 
will n ot be c o nsi dere d a n d t he hi g hest C T C A E gra de will be assi g ne d. Si milarl y, deat h 
relate d t o A E (i e, Gr a de 5) ca n n ot be d eter mi ne d wit h a vaila ble la b orat or y-base d dat a 
c ollecti o n a n d, t h us, will n ot be s u m marize d as a cate g or y. La b orat or y p ara meters t hat 
i ncl u de m ulti ple sets of criteria f or eac h directi o n (e g, se parate criteria f or p otassi u m 
meas ures t o ass ess h y per kale mia a n d h y p o kal e mia) will be s u m marize d s e paratel y t o 
reflect eac h set of criteria. 
Fi ve - b y-fi ve c o nti n ge n c y ta bles will be prese nte d b y st u d y p hase f or la b tests w here 
t o xicit y gra di n g ca n be a p plie d, t o s u m marize t he s hift fr o m t he baseli ne gra de t o t he 
w orst p ost- baseli ne gr a de. Gra des will be prese nte d as n o ne ( Gra de 0; ie, m eas ure m e nt 
di d n ot meet a n y C T C A E criteria f or Gra des 1 t hr o u g h 4), mil d ( Gra de 1), m o derate 
( Gra d e 2), se v ere ( Gr a de 3), or life-t hreate ni n g ( Gra de 4). S u m mar y res ults will i ncl u de 
t he c o u nt a n d per ce nta g e  of patie nts  wit hi n  eac h s hift cate g or y. Perce nta ges  will  be base d 
o n t he n u m ber of patie nts  wit h  a n o n-missi n g  baseli ne val ue  a n d at least o ne  n o n-missi n g 
p ost- baseli ne val ue.  
7. 5. 5  
Vit al  Si g ns,  P hysic al  Fi n di n gs, a n d Ot her  O bserv ati o ns Rel ate d  t o S afety  
7. 5. 5. 1  
Vit al  Si g ns  
Vital si g n para meter m eas ure me nts will be s u m marize d b y st u d y p hase a n d treat me nt 
gr o u p. Descri pti ve  statistics will  be pres e nte d  f or res ults a n d c ha n g e fr o m  p hase -s pecific 
baseli ne at eac h visit w here para meters were sc he d ule d t o be c ollecte d. Dail y 
te m perat ur es will be liste d. I n a d diti o n, t he n u m ber of da ys w h ere fe ver is prese nt, 
defi ne d as te m p erat ur e a b o ve 3 8 ° C, will be prese nte d b y m o nt h f or eac h s u bject. 


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Versi o n  7. 0;  2 5  Se pte m ber 2 0 2 3  
C o nfi de nti al  
Pa ge  4 2  of  4 6  
 
 
7. 5. 5. 2  
L oc al T oler a bility  I n dex Assess me nt  
T he l ocal  t olera bilit y i n de x ass esses  se v erit y of s y m pt o ms f or eac h d osi n g da y. F or eac h 
s y m pt o m, t he w orst se verit y re p orte d f or a n y da y will be s u m marize d wit h c o u nts a n d 
perce nt a ges of p atie nts i n eac h cate g or y b y st u d y p hase a n d treat me nt gr o u p. 
7. 5. 5. 3  
Ski n  R as h  
T he prese n ce a n d se verit y  of a s ki n ras h will be e val uate d at bas eli ne a n d eac h p ost- 
baseli ne  visit. T he n u m ber a n d p erce nt  of p atie nts  will  be pres e nte d  b y st u d y p hase, visit, 
a n d treat me nt gr o u p f or p atie nts wit h a s ki n ras h prese nt a n d f or eac h le v el of se verit y 
( mil d, m o derate, or se v er e). At p ost- baseli ne visits wit hi n eac h p hase, t h e n u m ber a n d 
perce nt of  patie nts  wit h  t he ras h at t he p hase-s pecific baseli ne  still prese nt a n d b y c ha n g e 
cate g or y will be prese nte d b y treat me nt gr o u p. 
7. 5. 5. 4  
I m m u n o ge nicity Ev al u ati o n  
Bl o o d le vels of a nti b o dies t o I L- 1 8 B P a nti b o dies T A (a nti- r h-I L- 1 8 B P) will be 
s u m marize d b y treat me nt gr o u p, se paratel y f or eac h st u d y p hase. Descri pti ve statistics 
will  be prese nte d f or  res ults a n d c h a n ge fr o m  p has e-s pecifi c baseli ne at eac h visit w here 
bl o o d sa m ples were  sc h e d ule d f or c ollecti o n. Bl o o d le vels f or a nti-r h-I L-1 8 B P will  als o 
be prese nt e d gra p hicall y o ver ti me f or eac h i n di vi d ual patie nt. 
7. 5. 5. 5  
P hysic al  Ex a mi n ati o n  
Res ults  of t he p h ysical e x a mi nati o n  will  be prese nt e d i n  patie nt data  listi n gs b y patie nt, 
st u d y visit, a n d b o d y s yste m. 
7. 5. 5. 6  
O p ht h al m ol o gic Ex a mi n ati o n  
Res ults of t he o p ht hal m ol o gic e xa mi nati o n, t o i ncl u de a u veitis assess me nt a n d ot her 
a nteri or c ha m ber  a b n or m al pat h ol o g y fi n di n gs, will  be pres e nte d  i n patie nt d ata  listi n gs 
b y patie nt a n d st u d y visit. 
7. 5. 5. 7  
C o nc o mit a nt a n d Resc ue  Me dic ati o ns  
Me dicati o ns  will  be c o de d usi n g t he W H O D D E  ( v ersi o n Marc h  1, 2 0 1 7). M e dicati o ns 
e ntere d o n  t he e C R F will be ma p pe d t o A T C dr u g class (le vel 4) a n d dr u g n a me. 
C o nc o mita nt me dicati o ns will i ncl u de all me dicati o ns re p orte d o n t he C o n c o mita nt 
Me dicati o ns e C R F. Me di cati o ns will be ma p pe d t o t he st u d y p hase recei ve d 
( S A O L/ R D B P C or R W)  base d  o n t he start a n d e n d dates. All  me dicati o ns  will  be liste d, 
t o i ncl u de t he deri ve d st u d y p hase w he n t h e me dicati o n was recei ve d. 
A c o nc o mita nt me dicati o n d uri n g eac h p h ase is defi ne d as a n y me di cati o n a d mi nistere d 
o n or after  t he date  of t he first d ose of st u d y dr u g f or t hat p hase ( S A O L/ R D B P C or R W). 
A me dicati o n ma y be d efi ne d as bei n g recei ve d d uri n g b ot h t he S A O L/ R D B P C a n d R W 
p hases. If it ca n n ot be det er mi ne d w het her a me di cati o n was recei ve d after t he start of  


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st u d y dr u g d osi n g f or eac h  p hase, it will  be c o nsi dere d  c o nc o mita nt d uri n g  t hat p hase. 
Me dicati o ns  recei ve d d uri n g t he st u d y a n d i de ntifie d  as resc u e i m m u n os u p pressi o n o n 
t he e C R F will be s u m marize d se p aratel y f or t he S A O L a n d R W p has es, a n d liste d. 
F or c o n c o mita nt a n d res c ue me dicati o n use, t he n u m ber a n d perce nt a ge of p atie nts 
recei vi n g a n y m e dicati o n  will  be s u m marize d b y treat me nt gr o u p, as will  t he n u m ber a n d 
perce nt a ge r ecei vi n g a n y  me dicati o n b y A T C dr u g class a n d ge n eric dr u g na me. Patie nts 
re p orti n g use of m or e t ha n o ne me dicati o n at eac h le vel of s u m marizati o n (a n y 
me dicati o n  recei ve d, A T C  class, a n d ge neric  dr u g na me)  will  be c o u nte d o nl y o nce.  A T C 
class ter ms will be dis pla ye d b y desce n di n g or der of i nci de nce, as will ge neric dr u g 
na mes wit hi n eac h A T C class. Ter ms wit h t he sa me i nci de nce will be or d ere d 
al p ha beticall y.  T he  s u m mar y of res c ue me dicati o ns recei ve d will  als o pres e nt  t he n u m ber 
a n d perce nta ge of patie nts w h o res p o n d t o at least o ne resc u e treat me nt.  
7. 6  
Deter mi n ati o n  of S a m ple  Size  
T he pri mar y e n d p oi nt of t he st u d y is ti me t o first occ urre nce of diseas e reacti vati o n 
(i ncl u di n g f ull a n d partial disease reacti vati o n) d uri n g t he R W p hase of t h e st u d y. T here 
is li mite d hist orical data f or  t his disease c o n diti o n, f or eit her a c o ntr ol or a n  e x peri me ntal 
test pr o d uct, h o we ver t he fre q u e nt rec urre nce of disease  reacti vati o ns was  e x pecte d i n t he 
c o ntr ol ar m (Wa da 2 0 1 4 ). Ori gi nall y, a n 8- wee k e ve nt rate is ass u me d t o b e 9 0 % i n t he 
place b o gr o u p a n d a c o nsi dera ble re d u cti o n i n disease  reacti vati o ns f or pati e nts recei vi n g 
T A was e x p ecte d. H o we ver, a l o wer e v e nt rate  w as o bser ve d fr o m t he c urre ntl y e nr olle d 
(still bli n de d) patie nts. T h us, t he R W p hase is pr ol o n ge d t o a ma xi m u m of 1 6 wee ks t o 
better assess t he eff ect of  T A wit h dra wal. T he p o wer calc ulati o ns bel o w will ass u me t he 
sa me 9 0 % e v e nt rate i n t he S O C ar m at 1 6 wee ks. Fi g ure 1  b el o w dis pla ys t he p o wer 
ac hie ve d f or a t w o -ar m st u d y a n d ass u mes t he f oll o wi n g: 
•  T w o -si de d l o g-r a n k test, wit h  i n p ut base d o n t he pr o p orti o n of patie nts  s ur vi vi n g 
(ie, e ve nt-free) at 1 6 w ee ks 
•  T w o -si de d al p h a = 0. 0 5  
•  A 1: 1 ra n d o mizati o n of 1 0 patie nts (ie, 5 patie nts per  ar m) 
•  T he  pr o p orti o n of  patie nts  s ur vi vi n g (ie, e ve nt-free) i n t he c o ntr ol ar m at Wee k 1 6 
of t he R W p hase is 0. 1, w hic h e q uates t o a 9 0 % e ve nt rate 
•  N o patie nts i n eit her gr o u p dr o p o ut of t he st u d y pri or t o e x perie n ci n g  a disease 
reacti vati o n or c o m pleti n g t he 1 6 wee k treat me nt peri o d as pla n ne d 
•  T otal  st u d y ti me is 3 2 wee ks, i ncl u di n g a 1 6-wee k  accr u al  peri o d a n d a 1 6 w ee k 
f oll o w-u p ti me  
•  Var yi n g le vels of a hazar d  rati o, fr o m 0. 1 t o 0. 2 5 i n 0. 0 5 i ncre me nts 




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ter mi nate d t he st u d y earl y. As descri be d i n Secti o n 7. 1. 6 , patie nts ra n d o mize d t o t he T A 
gr o u p d uri n g t he R D B P C p hase of t he ori gi nal st u d y desi g n will be i ncl u de d i n a nal yses 
f or t he u p date d st u d y desi g n, t o be c o m bi ne d wit h t h ose patie nts e nr olle d u n der 
A me n d me nt 4 ( Versi o n 4. 0) a n d a n y s u bse q u e nt a me n d me nts. Pr ot oc ol versi o n 5. 0 a n d 
s u bse q ue nt a me n d me nts e xte n de d t he R W p h ase fr o m 8 wee ks wit h last t he R W visit at 
Wee k 2 6 [ V 1 1] t o 1 6 w ee ks, wit h t he last R W visit at Wee k 3 4 [ V 1 3]. Acc or di n gl y, t he 
R W Per - Pr ot oc ol A nal ysis Set ( R W-P P A S) is a da pte d t o i ncl u de all patie nts i n t he R W - 
F A S  w h o c o m plete t he R W  p hase u p t hr o u g h Wee k  2 6 ( V 1 1) f or pr ot oc ol v ersi o n  4. 0/ 4. 1 
or Wee k 3 4 ( V 1 3) f or pr ot oc ol versi o ns 5. 0 a n d 6. 0 or ha ve disease reacti v ati o n a n d f or 
w h o m n o rele va nt pr ot o c ol de viati o ns were d o c u me nte d. 
Pr ot oc ol versi o n 5. 0 a n d s u bse q ue nt a me n d me nts i de ntif y res p o nse t o t hera p y d uri n g t he 
S A O L  p hase as a ke y  sec o n dar y e n d p oi nt. H o we v er, si nce t his ke y  sec o n d ar y e n d p oi nt is 
o nl y bei n g prese nte d d es cri pti vel y wit h o ut a n y statistical testi n g, it is n ot i ncl u de d i n t he 
heirc hical list f or fi x e d -s e q ue nce testi n g descri be d i n Secti o n 7. 4. 5. 5 . 
A p pe n di x A  i ncl u des a d escri pti o n  of t he ma p pi n g of t he m AI D AI c o m p o n e nts i nt o t he 
O bjecti ve m AI D AI t otal sc ore.  
8  R E F E R E N C E  LI S T  
Wa da, T. et al. S ustai ne d ele vati o n of ser u m i nterle u ki n- 1 8 a n d its ass ociati o n wit h 
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