A Bioequivalence Study of Injections of Mirikizumab Solution Using Investigational 1-mL and 2-mL Pre-Filled Syringes and Investigational 1-mL and 2-mL Autoinjectors in Healthy Participants
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

 
 
 
Pr ot oc ol I 6 T- M C -A M B X  
 
 
A Bi oe q ui vale nce St u d y of I n jecti o ns of Miri kiz u ma b S ol uti o n Usi n g I n vesti gati o nal 1- m L a n d 
2- m L  Pre - Fille d S yri n ges a n d I n vesti gati o nal 1- m L a n d 2- m L A ut oi nject ors i n Healt h y 
Partici pa nts  
 
 
N C T 0 5 0 6 9 8 9 6 
 
A p pr o val Date: 1 1- A u g - 2 0 2 1 
 
 
 
 
 
 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
1
Title P a ge
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of cli ni c al i n v e sti g at or s. It i s t h e p r o p ert y of 
Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al 
i n v e sti g ati o n of miri ki z u m a b ( L Y3 0 7 4 8 2 8 ), u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt wit h Eli Lill y a n d 
C o m p a n y or it s s u b si di ari e s. 
N ot e t o R e g ul at or y A ut h oriti e s: T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n 
e x e m pt fr o m p u bli c di s cl o s ur e. Eli Lill y a n d C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bl i c r el e a s e. 
I n t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or 
ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s .
Pr ot oc ol Title:
A Bi oe q ui vale nce St u d y  of I njecti ons o f Mi rikiz u ma b S ol ut i on Usi n g I n vest i gati o nal 1- m L a n d 
2- m L Pre -Fille d S yr i n ges a n d I n vesti gati onal 1 -m L a n d 2 -m L A ut oi nject ors i n Healt h y
P arti cip a nts
Pr ot oc ol N u m ber: I 6 T-M C -A M B X
A me n d me nt N u m ber: T his is t he i nit ial pr ot oc ol
C o m p o u n d : Mir i kiz u ma b ( L Y 3 0 7 4 8 2 8)
St u d y P h ase: 1
S h ort Title: A bi oe q ui vale nce st u d y  of inject i ons of  miri kiz u ma b s ol uti on usi n g i n vest i gati onal 
1- m L a n d 2 -m L pre -fille d s yri n ges a n d i n vesti gati o nal 1-m L a n d 2 -m L
a ut oi nject ors i n healt h y partici pa nt s
S p o ns or N a me: El i Lill y  a n d C o mpa n y
Le g al Re gistere d A d dress: I n dia na p olis, I n dia na 4 6 2 8 5, U S A
Re g ul at or y A ge nc y I de ntifier N u m ber
I N D: 1 3 0 0 5 2
A p pr o v al D ate: Pr ot oc ol El ectr o nicall y Si g ne d a n d A p pr o ve d b y Lill y o n date pr o vi de d bel o w.
A p pr o v al D at e: 1 1- A u g- 2 0 2 1 G M T

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
2
Me dic al M o nit or N a me a n d C o nt act I nf or m ati o n will be pr o vi de d se p ar atel y

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
3
T a ble of C o nte nts
1.
Pr ot oc ol S u m m ar y ......................................................................................................6
1. 1.
S y n o psis .......................................................................................................................6
1. 2.
Sc he ma .........................................................................................................................7
1. 3.
Sc he d ule of Act i vities ( S o A) ........................................................................................8
2.
I ntr o d ucti o n ..............................................................................................................1 1
2. 1.
St u d y  Ratio nale ..........................................................................................................1 1
2. 2.
Bac k gr o u n d ................................................................................................................1 1
2. 2. 1.
S af et y .........................................................................................................................1 1
2. 2. 2.
Deat hs, Seri o us A d verse E ve nts, a n d Disc o nt i n uati o ns d ue t o a n 
A d verse E ve nt ............................................................................................................1 2
2. 2. 3.
Ot her Treat me nt -E m er ge nt A d verse E ve nts ................................................................1 2
2. 2. 4.
P har mac o ki net ics........................................................................................................1 2
2. 2. 5.
I mm u n o ge nicit y ..........................................................................................................1 3
2. 3.
Be nefit/ Ris k Assess me nt ............................................................................................1 3
3.
O bjecti ves a n d E n d p oi nts .........................................................................................1 5
4.
St u d y Desi g n .............................................................................................................1 6
4. 1.
O verall Desi g n ............................................................................................................1 6
4. 2.
S ci e nt ific Rati o nale f or St u d y Desi g n.........................................................................1 7
4. 3.
J ustificati o n f or D ose..................................................................................................1 8
4. 4.
E n d of St u d y  Defi niti on ..............................................................................................1 8
5.
St u d y P o p ul ati o n ......................................................................................................1 9
5. 1.
I ncl usi on Cri t eria ........................................................................................................1 9
5. 2.
E xcl u sio n  Crit eria .......................................................................................................2 0
5. 3.
Lifest yle C o nsi derat i ons .............................................................................................2 3
5. 3. 1.
Meals a n d Dietar y  Restrict i ons ...................................................................................2 3
5. 3. 2.
Caffei ne, Alc o h o l, a n d T o bacc o..................................................................................2 3
5. 3. 3.
Act i vity ......................................................................................................................2 3
5. 4.
Scree n Fail ures ...........................................................................................................2 3
6.
St u d y I nter ve nti o n a n d C o nc o mit a nt T her a p y .......................................................2 4
6. 1.
St u d y  I nter ve nti on A d mi nistere d ................................................................................2 4
6. 1. 1.
A d mi nistrati o n Details ................................................................................................2 4
6. 1. 2.
Me dical De vices .........................................................................................................2 4
6. 2.
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y .............................................................2 5
6. 3.
Meas ures t o Mi ni mize Bias: Ra n d o mizat i on a n d Bli n di n g ..........................................2 5
6. 4.
St u d y  I nter ve nti on C o m plia nce ...................................................................................2 5
6. 5.
C o nc o mita nt T hera p y ................................................................................................. 2 6
6. 6.
D ose M o dificat i on ......................................................................................................2 6
6. 7.
I nter ve nti o n after t he E n d of t he St u d y........................................................................2 6
7.
Disc o nti n u ati o n of St u d y I nter ve nti o n a n d P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al ....................................................................................2 7
7. 1.
Di sc o nti n uatio n of  St u d y I nter ve nti on ........................................................................2 7
7. 2.
P arti cipa nt Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y .............................................2 7

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
4
7. 3.
L ost t o F oll o w - u p .......................................................................................................2 7
8.
St u d y Assess me nts a n d Pr oce d ures .........................................................................2 8
8. 1.
Efficac y Assess me nts ................................................................................................. 2 8
8. 2.
S af et y Assess me nts ....................................................................................................2 8
8. 2. 1.
P h ysical E xa mi nat i ons ................................................................................................2 8
8. 2. 2.
Vi t al Sig ns.................................................................................................................. 2 9
8. 2. 3.
Electr ocar di o gra ms .....................................................................................................2 9
8. 2. 4.
Cli nical Safet y  La b orat or y Assess me nts .....................................................................3 0
8. 2. 5.
Ot her Tests .................................................................................................................3 1
8. 2. 6.
S af et y M o ni t ori n g.......................................................................................................3 1
8. 3.
A d verse E ve nts, Seri o us A d verse E ve nts, a n d Pr o d uct 
C o m plai nt s .................................................................................................................3 3
8. 3. 1.
Ti mi n g a n d Mec ha nis m f or C ollect i n g E ve nts ............................................................3 4
8. 3. 2.
A d verse E ve nts of S pecial I nterest ..............................................................................3 6
8. 4.
Treat me nt of O ver d ose ...............................................................................................3 6
8. 5.
P har mac o ki net ics........................................................................................................3 6
8. 5. 1.
Bi oa nal ysis .................................................................................................................3 6
8. 6.
P har mac o d y na mics .....................................................................................................3 7
8. 7.
Ge net ics .....................................................................................................................3 7
8. 8.
Bi o m ar kers .................................................................................................................3 7
8. 9.
I mm u n o ge nicit y Assess me nts .....................................................................................3 7
8. 1 0.
Heal t h Ec o n o mics.......................................................................................................3 7
9.
St atistic al C o nsi der ati o ns .........................................................................................3 8
9. 1.
Stati stical H y p ot heses................................................................................................. 3 8
9. 2.
A nal yses Sets .............................................................................................................3 8
9. 3.
Stati stical A nal yses .....................................................................................................3 8
9. 3. 1.  
G e neral C o nsi derati o ns ...............................................................................................3 8
9. 3. 2.
P har mac o ki net ic A nal yses ..........................................................................................3 9
9. 3. 3.
S af et y A nal yses ..........................................................................................................3 9
9. 3. 4.
Ot her A nal yses ...........................................................................................................4 0
9. 4.
I nteri m A nal ysis .........................................................................................................4 0
9. 5.
S a m ple Si ze Deter mi nat i on .........................................................................................4 0
1 0.
S u p p orti n g D oc u me nt ati o n a n d O per ati o n al C o nsi der ati o ns ................................4 1
1 0. 1.
A p pe n di x 1: Re g ulat or y , Et hical, a n d St u d y O versi g ht 
C o nsi derati o ns ............................................................................................................4 1
1 0. 1. 1.
Re g ulat or y  a n d Et hical C o nsi derati ons ........................................................................4 1
1 0. 1. 2.
Fi na ncial Discl o s ure ...................................................................................................4 1
1 0. 1. 3.
I nf or me d C o nse nt Pr ocess ..........................................................................................4 2
1 0. 1. 4.
Data Pr otecti o n ...........................................................................................................4 2
1 0. 1. 5.
Di sse mi nati on of Cli nical St u d y  Data .........................................................................4 2
1 0. 1. 6.
Data Q ualit y Ass ura nce ..............................................................................................4 3
1 0. 1. 7.
S o urce D oc u me nts ......................................................................................................4 4
1 0. 1. 8.
St u d y  a n d Site Start a n d Clos ure .................................................................................4 4
1 0. 1. 9.
P u blicat i on P olic y .......................................................................................................4 5
1 0. 2.
A p pe n di x 2: Cli nical La b orat or y  Tests........................................................................4 6

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
5
1 0. 2. 1.
Bl o o d S a m pli n g S u m mar y ..........................................................................................4 8
1 0. 3.
A p pe n di x 3: A d verse E ve nts: Defi nit i ons a n d Pr oce d ures f or 
Rec or di n g, E val uat i n g, F oll o w-u p, a n d Re p orti n g .......................................................4 9
1 0. 3. 1.
Defi nit i on o f A E .........................................................................................................4 9
1 0. 3. 2.
Defi nit i on o f S A E .......................................................................................................5 0
1 0. 3. 3.
Defi nit i on o f Pr o d uct C o m plai nt s ...............................................................................5 1
1 0. 3. 4.
Rec or di n g a n d F o ll ow- U p of A E a n d/ or S A E a n d P Cs ................................................5 2
1 0. 3. 5.
Re p orti n g of S A Es ......................................................................................................5 3
1 0. 3. 6.
Re g ulat or y  Re p orti n g Re q uire me nts...........................................................................5 4
1 0. 4.
A p pe n di x 4: C o ntrace pti ve G ui da nce a n d C o llecti o n of 
Pre g na nc y I nf or mati o n ...............................................................................................5 5
1 0. 5.
A p pe n di x 5: Ge netics ................................................................................................. 5 9
1 0. 6.
A p pe n di x 6: Li ver Safet y:  S u g geste d Acti o ns a n d F oll o w- u p 
Assess me nts ...............................................................................................................6 0
1 0. 7.
A p pe n di x 7: Rec o m me n de d La b orat or y Test i n g f or 
H y perse nsi tivi t y E ve nts..............................................................................................6 2
1 0. 8.
A p pe n di x 8: Me dical De vice A d verse E ve nts, A d verse De vice 
Effects, Seri o us A d verse E ve nts, a n d De vice Deficie ncies: 
Defi nit i on a n d Pr oce d ures f or Rec or di n g, E val uat i n g, F oll ow- u p, 
a n d Re p orti n g .............................................................................................................6 3
1 0. 9.
A p pe n di x 9: A b bre viat i ons .........................................................................................6 4
1 1.
Refere nces .................................................................................................................6 7

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
6
1.
Pr ot oc ol S u m m ar y
1. 1.
S y n o psis
Pr ot oc ol Title: A Bi oe q ui vale nce St u d y  of I njecti o ns of Miri kiz u ma b S ol uti on Usi n g 
I n vesti gati onal 1 -m L a n d 2 -m L Pre -Fille d S yr i n ges a n d I n vesti gati onal 1 -m L a n d 2- m L 
A ut oi nject ors i n Healt h y Partici pa nts
S h ort Title: A bi oe q ui vale nce st u d y  of inject i ons of  miri kiz u ma b s ol uti on usi n g i n vest i gati onal 
1- m L a n d 2 -m L pre -fille d s yri n ges a n d i n vesti gati o nal 1-m L a n d 2 -m L a ut oi nject ors i n healt h y 
parti ci pa nts
R ati o n ale :
St u d y  I 6 T-M C -A M B X ( A M B X) will assess t he p har mac o ki net ics ( P K), safety,  a n d t olera bilit y 
of  a 3 0 0-m g s u bc uta ne o us ( S C) d ose of miri kiz u ma b ( L Y 3 0 7 4 8 2 8 ; t he pr o p osed ma i nte na nce 
d ose f or Cr o h n’s disease patie nts ) s ol uti on f or mul ati o n a d mi nistere d usi n g i n ves tigat i onal 
ma n ual pre -fille d s yri n ges ( P F S; 1- a n d 2-m L) or i n vesti gati o nal a ut oi nject or s ( AI; 1- a n d 2-m L ). 
B ot h de vices will be e val uate d at 3 differe nt i nject i o n sites (ar m, t hi g h, a n d a b d o me n) i n or der t o 
e x pa n d t he o pti o ns f or a d mi nistrati o n i n pat ien t use.
 
 
O bjecti ves a n d E n d p oi nt s
O bject i ves
E n d p oi nts
Pri mar y

T o e val uate t he P K of S C i njecti ons of 
3 0 0 m g mir i kiz u ma b s ol uti on 
a d mi nistere d usi n g 1- m L a n d 2 -m L 
P F S a n d 1- m L a n d 2 -m L A Is i n 
healt h y parti ci pa nts

C m a x , A U C( 0-∞), a n d A U C( 0 -tlast)
Sec o n dar y

T o descri be t he safet y a n d t olera bilit y 
of  miri kiz u ma b i n health y part ici pa nts

T E A Es a n d S A Es
A b bre viati o ns: AI = a ut oi nject or; A U C( 0 -∞) = area u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m ti me zer o t o 
i nfi nit y; A U C( 0-tlast) = area u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m ti me zer o t o ti me t, w here t is t he last 
ti me p oi nt wit h a meas ura ble c o nce ntrati o n; C ma x = ma xi m u m o bser ve d dr u g c o nce ntrati o n; P F S = pre -fille d 
s yri n ge; P K = p har mac o ki netics; S A E = seri o us a d verse e ve nt; S C = s u bc uta ne o us; T E A E = treat me nt-e mer ge nt
a d verse e ve nt.
O ver all Desi g n
St u d y  A M B X is a P hase 1, o pe n-lab el, 2-ar m, ra n d o mize d, parallel-desi g n, si n gle -d ose, 
m ult i-site st u d y in heal t h y p artici pa nts.
C CI

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
7
Scree ni n g
All partici pa nts will be scree ne d wit hi n 2 8 da ys pri or t o e nr oll me nt. At scree ni n g, partici pa nts 
will be stratifie d i nt o 1 of 3 wei g ht cate g ories (less t ha n 7 0 k g, 7 0 t o 8 0 k g, a n d m ore t ha n 
8 0 k g).
Tre at me nt a n d Assess me nt Peri o d
Eli gi ble partici pa nts wil l be a d mitte d t o t he cli nical researc h u nit ( C R U) o n Da y  - 1.
Wit hi n t he 3 wei g ht cate g ories, partici pa nts will be ra n d o mize d usi n g a c o m p uter -ge nerate d 
all ocat i on c o de:

1: 1 t o deli ver y  de vice (eit her P F S [refere nce] or AI [test])

wi t hi n eac h deli ver y de vic e gr o u p 1: 1: 1 t o i nject i on- sit e ( ar m, t hig h, or a b d o m e n)
O n Da y  1, p artici pa nts will recei ve a t otal of 3 m L ( 30 0 m g miri kiz u ma b) as 2 S C i njecti o ns of 
1 m L a n d 2 m L deli vere d via P F S or AI i n t he l ocati o n assi g ne d b y t he ra n d omizat i on.
P arti cipa nts ma y  be allo w e d t o l ea ve t he C R U after c o m plet i n g t he 4-h o ur safet y assess me nts o n
D a y  1, or later at t he i n vest i gat or’s discreti o n, a n d will ret ur n f or P K a n d i m m u n o ge nicity
sa m pli n g a n d safety assess me nts at pre defi ne d ti mes u p t o 1 2 wee ks p ost d ose. Partici pa nt s will
be m o nit ore d f or safet y bet wee n o ut patie nt visits b y  w a y of tele p h o ne assess me nt.
S af et y a n d t olera bilit y will  be assesse d t hr o u g h cli nical la b orat or y tests, vit al si g ns
meas ure me nts, E C Gs, rec or di n g of a d verse e ve nts, rec or di n g of i njecti on -sit e r eactio ns, p h ysical 
e xa mi nat i on, a n d i m m u n o ge nicit y.
Discl os ure St ate me nt : T hi s is a n o pe n-lab el , parallel-gr o u p bi oe q ui vale nce st u d y  wit h 2 ar ms.
N u m ber of P artici p a nt s:
U p t o a p pr o xi matel y  2 4 0 participa nts ma y  be e nr olle d s o t hat a p pr o xi matel y 2 1 6 partici pa nts 
( 1 0 8 i n t he P F S gr o u p a n d 1 0 8 i n t he AI gr o u p) c o m plete t he st u d y.
I nter ve nti o n Gr o u ps a n d D ur ati o n :
All partici pa nts will be scree ne d wit hi n 2 8 da ys pri or t o e nr oll me nt. A si n gle d ose of 
mir i kiz u ma b will be a d mi nistere d S C b y eit her P F S or AI i nt o t he ar m, t hi g h, or a b d o me n o n 
D a y  1 a n d partici pa nts will be f oll owe d t hr o u g h Da y  8 5.
D at a M o nit ori n g C o m mittee: N o
1. 2.
Sc he m a
N ot a p plica ble .

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
8
1. 3.
Sc he d ule of Acti vities ( S o A)
St u d y Sc he d ule Pr ot oc ol I 6 T -M C -A M B X
Scree ni n g
St u d y D a y
C o m me nts
Pr oce d ure
-2 8 t o - 2 
da y s pri or 
t o Da y 1
- 1 
1 
3
5
± 1 d
8
± 1 d
1 1
± 1 d
1 5
± 2 d
2 2
± 2 d
2 9
± 2 d
3 6
± 2 d
4 3
± 2 d
5 0
± 2 d
5 7
± 3 d
6 4
± 2 d
7 1
± 3 d
8 5
± 3 d or 
E D
I nf or me d c o nse nt
X
Me dical hist or y  a n d 
de m o gra p hics
X
Re vie w a n d c o nfir m 
i ncl usi o n a n d 
e xcl usi o n criteria
X  
X
A d missi o n t o C R U
X
Disc har ge fr o m C R U
X
Partici pa nts ma y be disc har ge d 
after c o m pleti n g t he 4 -h o ur safet y 
assess me nts o n Da y 1, or later at 
t he i n vesti gat or’s discreti o n.
O ut patie nt visit
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Safet y assess me nt 
(tele p h one call)
X  
X  
X
T o c hec k o n t he prese nce of a n y 
A Es a n d c o nc o mita nt 
me dicati o ns.
Ra n d o mizati o n
X
Partici pa nts will be ra n d o mize d 
1: 1 t o 1 of 2 deli ver y de vices a n d 
1: 1: 1 t o 1 of 3 i njecti o n l ocati o ns 
per deli ver y de vice. 
Hei g ht, wei g ht, a n d 
B MI
X
X
O nl y wei g ht will be meas ure d o n 
Da y 8 5 or E D.
B o d y te m perat ure
X  
X 
P  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
P h y sical e xa mi nati o n
X  
X
X
C o m plete p h ysical e xa mi nati o n at 
Scree ni n g . S y m pt o m-directe d 
e xa mi nati o ns a n d assess me nts at 
ot her ti mes, a n d as dee me d 
necessar y b y t he i n vesti gat or.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
9
Scree ni n g
St u d y D a y
C o m me nts
Pr oce d ure
-2 8 t o - 2 
da y s pri or 
t o Da y 1
- 1 
1 
3
5
± 1 d
8
± 1 d
1 1
± 1 d
1 5
± 2 d
2 2
± 2 d
2 9
± 2 d
3 6
± 2 d
4 3
± 2 d
5 0
± 2 d
5 7
± 3 d
6 4
± 2 d
7 1
± 3 d
8 5
± 3 d or 
E D
Vital si g ns ( p ulse rate 
a n d bl o o d press ure) 
(sitti n g) ( h o urs)
X
P,
2 t o 
4 h
X
X
X
Da y  1: 2- t o 4-h o ur assess me nt t o 
be c o n d ucte d at least 2 h o urs after 
sec o n d i njecti o n a n d pri or t o 
disc har ge at a p pr o xi matel y 
4 h o urs p ost d ose. Ti me p oi nts 
m a y  be a d de d if warra nte d a n d 
a gree d u p o n bet wee n Lill y a n d t he 
i n vesti gat or.
Cli nical la b orat or y 
tests
X  
X  
X
X  
X
X
See Secti o n 1 0. 2 , Cli nical 
La b orat o r y Tests, f or details.
Ser ol o g y
X
See Secti o n 1 0. 2 , Cli nical 
La b orat o r y Tests, f or details.
Q ua nti F E R O N ® -T B 
G ol d test
X
Et ha n ol test a n d dr u g 
scree n
X  
X
Ur i ne dr u g test will be c o n d ucte d 
at scree ni n g a n d c h ec k-i n 
( Da y - 1). A uri ne et ha n ol test will 
be c o n d ucte d at scree ni n g a n d a 
br eat h -test at c hec k-i n on D a y - 1.
Tests ma y be re peate d l ocall y at 
a d diti o nal ti me p oi nts at t he 
discreti o n of t he i n vesti gat or.
F S H
X
Fe males o nl y. See Secti o n 1 0. 4 . 
Pre g na nc y test 
(fe males o nl y)
X  
X
X
Ser u m pre g na nc y test will be 
perf or me d at scree ni n g a n d 
Da y  -1. Uri ne pre g na nc y test will
be perf or me d l ocall y at Da y 8 5 or 
E D. See Secti o n 1 0. 4 . 
Si n gle 1 2 -lea d E C G 
(s u pi ne)
X  
X
X
Ma y  be o btai ne d at a d diti o nal 
ti mes, w h e n  dee me d cli nicall y 
necessar y.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
1 0
Scree ni n g
St u d y D a y
C o m me nts
Pr oce d ure
-2 8 t o - 2 
da y s pri or 
t o Da y 1
- 1 
1 
3
5
± 1 d
8
± 1 d
1 1
± 1 d
1 5
± 2 d
2 2
± 2 d
2 9
± 2 d
3 6
± 2 d
4 3
± 2 d
5 0
± 2 d
5 7
± 3 d
6 4
± 2 d
7 1
± 3 d
8 5
± 3 d or 
E D
Miri kiz u ma b 
a d mi nistrati o n 
( 2 i njecti o ns per 
d ose)
X
See Secti o n 6. 1 . 
Miri kiz u ma b P K 
sa m ple
P  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
I m m u n o ge nicit y 
sa m ple
P
X  
X
X
P har mac o ge netic 
sa m ple
P
A E a n d c o nc o mita nt 
me dicati o n
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
If a n A E of I S R is re p orte d, t he 
i n vesti gat or or desi g nee will 
c o m plete a s u p ple me ntal I S R A E 
f or m. 
A b bre viati o ns: A E = a d verse e ve nt; B MI = b o d y mass i n de x; C R U = cli nical researc h u nit; d = da y ; E C G = electr ocar di o gra m; E D = earl y disc o nti n uati o n; 
F S H = f ollicle -sti m ulati n g h or m o ne; h = h o ur(s); I S R = i njecti o n-site reacti o n; P = pr e d ose; P K = p har mac o ki netic; T B = t u berc ul osis.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
1 1
2.
I ntr o d ucti o n
2. 1.
St u d y R ati o n ale
St u d y  I 6 T-M C -A M B X ( A M B X) will assess t he p har m ac o ki net ics (P K ), safety,  a n d t olera bilit y 
of  a 3 0 0-m g s u bc uta ne o us (S C ) d ose of miri kiz u ma b ( L Y 3 0 7 4 8 2 8 ;
 
 s oluti o n f or m ulati o n a d mi nistere d usi n g i n vest i gati onal 
ma n ual pre -fille d s yri n ge (P F S ) ( 1- a n d 2-m L) or i n vesti gati o nal a ut oi nject or ( AI ) ( 1- a n d 2-m L). 
B ot h de vices will be e val uate d at 3 differe nt i nject i o n sites (ar m, t hi g h, a n d a b d ome n) i n or der t o 
e x pa n d t he o pti o ns f or a d mi nistrati o n i n pat ient  use. 
 
 
2. 2.
B ac k gr o u n d
Mi rikiz u ma b is a h u ma nize d i m m u n o gl o b uli n G 4 ‒ varia nt m o n o cl o nal a nt i b o d y t hat is directe d 
a gai nst t he p 1 9 s u b u nit of i nterle u ki n (I L)-2 3 a n d d oes n ot bi n d I L -1 2. Mi rikiz u ma b is bei n g 
de vel o pe d f or t he treat me nt of a ut oi m m u ne diseases, i ncl u di n g ps oriasis, C D, a n d u lcerati ve 
c olit is (U C ), i n w hic h t he I L-2 3 pat h wa y  is t h o u g ht t o ha ve a si g nifica nt pat h o ge nic r ole. 
Cli nical p har mac o l og y  st u dies ha ve de m onstrate d a n acce pta ble safet y pr ofile i n healt h y 
parti ci pa nts f oll owi n g si n gle -d ose i ntra ve n o us (I V) a d mi nistrati o n u p t o 2 4 0 0 m g (see 
Secti o n 2. 2. 1 ). 
T he rel at i ve b i oa vaila bilit y o f 1 2 5 m g mir i kiz u ma b w he n a d mi nistere d as 1- m L S C i njecti ons b y 
eit her P F S or AI at differe nt i nject i on sites was e val uate d i n S t u d y I 6 T-M C -A M B E ( A M B E). 
 
 
2. 2. 1.
S afet y
As of t he I n vesti gat or’s Br oc h ure (I B) c ut off date (1 3 Se pte m ber 2 0 2 0) , t here ha ve bee n 
a p pr o xi matel y 2 7 4 5 partici p a nts i ncl u de d i n P hase 1 t o 3 stu dies of mir i kiz u ma b. T hese st u dies 
i ncl u de 1 7 2 8 parti ci pa nts wit h ps oriasis, 7 partici pa nts wit h ge neralize d p ust ular ps oriasis ,
1 1 partici pa nts wit h er yt hr o der mic ps oriasis, 2 3 0 parti ci pa nts wit h U C, 1 8 6 partici pa nts wit h 
C D, a n d 5 8 3 healt h y part ici pa nts w h o were e x p ose d t o at least o ne d ose of mir i kiz u ma b wi t h
si n gle d oses ra n gi n g fr om 5 t o 2 4 0 0 m g a n d m ult i ple d oses reac hi n g a ma xi m u m of 1 0 0 0 m g I V 
or 3 0 0 m g S C. 
I n cli nical p har mac o l og y  st u dies, si n gle I V d oses of u p t o 2 4 0 0 m g ha ve bee n a d mi nistere d t o 
healt h y Ca ucasia n a n d Ja pa nese partici pa nts ( St u d y I 6 T -M C -A M A D). N o d ose -relate d safety or 
t olera bilit y iss ues were o bser ve d i n t his st u d y or i n ot her o n g oi n g cli nical p har macol o g y  st u dies 
wi t h si n gle S C d oses ra n gi n g fr om 1 2 0 t o 2 4 0 0 m g a n d at m ul tiple d oses u p t o a m a xi m u m of 
3 0 0 m g. 
Si x c o mplete d st u di es (I 6 T -M C -A M A L [ A M A L], I 6 T -M C -A M A E [ A M A E], I 6 T -M C -A M A Q 
[ A M A Q], I 6 T-M C -A M A R [ A M A R], I 9 O -M C -A A B C [ A A B C], a n d A M B E) a n d o n g oin g st u d y  
C CI
C CI
C CI

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
1 2
I 6 T-M C -A M B W ( A M B W; n o data a vaila ble c urre nt l y) c o m pare d t he bi oa vaila bilit y,  safety,  a n d 
t olera bilit y of vari o us f or m ulat i ons of miri kiz u ma b deli vere d b y eit her P F S, AI, or S C i nf usi o n. 
Mi rikiz u ma b was well t olerate d; h o we ver, as y m pt o mat ic re d uctio ns i n ne utr o p hil c o u nts were 
see n i n a mi n ority of  p artici pa nts. T he i nci de nce of i njecti o n-site reactio ns ( I S Rs) was hi g hl y 
varia ble acr oss st u dies d ue t o t heir differi n g desi g ns a n d treat me nts; h o we ver, I S Rs c o m prise d 
m o stl y mil d t o m o derate pai n a n d ve r y sli g ht t o well-defi ne d er y t he ma.
2. 2. 2.
De at hs, Seri o us A d verse E ve nts, a n d Disc o nti n u ati o ns d ue t o a n A d verse E ve nt
N o deat hs ha ve bee n re p orte d in a n y of t he c o m plete d or o n g oi n g cli nical p har mac ol o g y  st u dies.
O ne partici pa nt i n P hase 1 S t u d y A A B C was disc o n tin ue d d ue t o 1 seri o us a d verse e ve nt (S A E )
of  mali g na nt brai n ne o plas m; t he e ve nt was n ot c o nsi dere d t o be relate d t o st u d y  treat me nt b y t he 
i n vesti gat or.I n P hase 2 a n d 3 st u dies with parti ci pa nts ha vi n g ps oriasis, U C, or C D, u p t o t he I B 
c ut off date, 1 deat h occ urre d fr o m m y ocar dial i nfarcti o n , 1 deat h occ urre d fr o m l u n g ca ncer , 1 
s u d de n deat h occ urre d fr o m a p ost-o perati ve u n k n o w n ca use , 1 deat h occ urre d fr o m p ost -
pr oce d ural  c o mplicat i on, a n d 2 deat h s occ urre d d ue t o C O VI D - 1 9, n o ne of  w hic h were
c o nsi dere d relate d t o st u d y dr u g b y t he i n vesti gat or.
S eri o us a d verse e ve nts ( A Es) a n d disc o nt i n uati ons d ue t o A Es are s u m marize d i n t he I B.
2. 2. 3.
Ot her Tre at me nt -E mer ge nt A d verse E ve nts
I n P hase 1 st u dies t hat were i nte grate d f or safety a nal yses i n t he I B, t he most f re q ue ntl y re p orte d 
(≥5. 0 %) treat me nt -e mer ge nt A Es ( T E A Es ) i n t he 5 8 3 healt h y part ici pa nts treate d wit h 
mir i kiz u ma b were I S Rs (2 0. 9 % ), nas o p har y n gitis ( 8. 4 %), a n d hea dac he ( 5. 7 %). 
A d mi nistrati o n of  miri kiz u ma b usi n g AI s has pre vi o usl y s h o w n t o be safe a n d well t olerate d i n 
healt h y partici pa nts , base d o n T E A Es a n d i nject i on- sit e p ain, f or t he 1- m L AI i n s t u dies A M B E 
a n d A M A Q a n d f or t he 2 -m L AI i n st u dies A M A Q a n d A M A R . 
Treat me nt -e mer ge nt A Es i n P hase 2 a n d 3 st u dies wit h partici pa nts ha vi n g ps oriasis, U C, or C D 
are s u m marize d i n t he I B.
2. 2. 4.
P h ar m ac o ki netics
St u di es i n healt h y partici pa nts a n d partici pa nts wit h ps oriasis, U C, or C D f o u n d t hat s y ste mic 
e x p os ure of  miri kiz u ma b i ncreases i n pr o p orti o n t o d ose, a n d t hat miri kiz u ma b has a half -life 
of a p pr o xi matel y 1 0 da ys a n d S C bi oa vaila bility of 4 0 %.
St u di es A M A R a n d A M B E c o m pare d t he P K of miri kiz u ma b f o ll owi n g S C deli ver y  of 
mir i kiz u ma b usi n g P F S vers us AI. F oll o wi n g a d mi nistrati o n of 2 5 0 m g mir i kiz u ma b deli vere d as 
1 x 2- m L AI, ge o metric least s q uares (L S ) me a n A U C fr o m ti me zer o t o i nfi nit y ( A U C [0- ∞] ) 
a n d ma xi m u m o bser ve d dr u g c o nce ntrati o n ( C m a x ) i ncrease d 5 % a n d 1 9 %, res pecti vel y, relati ve 
t o t he sa me miri kiz u ma b d ose deli vere d as 2 x 1-m L P F S. F oll o wi n g a d mi nistrati o n of 1 2 5 m g 
mir i kiz u ma b deli vere d as 1 x 1-m L AI, ge o metric L S mea n A U C( 0 -∞) a n d C m a x i ncrease d 1 2 % 
r elat i ve t o t he sa me miri kiz u ma b d ose deli vere d as 1 x 1-m L P F S. I n b ot h st u dies, n o differe nces 
i n me dia n time t o m a xi m u m obser ve d dr u g c o nce ntrati o n ( tma x ) of  miri kiz u ma b were n ote d 
bet wee n treat me nt ar ms. 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
1 3
E x p os ure b y  inject i on l ocatio n i n st u d y A M B E de m o nstrate d statist icall y si g nifica nt differe nces 
(t hat is, t he 9 0 % c o nfi de nce i nter val [ CI ] f or t he rati o of ge o metric L S me a ns e xcl u de d u nit y)  
w he n c o m par i n g t he 2 a d mi nistrati o n met h o ds:

P F S a n d AI a d mi nistrati o n i nt o t he a b d o me n
o
e x p os ure i ncrease d b y u p t o 6 2 % f oll o wi n g a d mi nistrati o n usi n g t he AI c o m pare d 
t o P F S.
O verall, t he miri kiz u ma b P K is e x pecte d t o be si milar f or AI a n d P F S de vices base d o n t he 
res ults of t hese e x pl orat or y parallel-gr o u p st u di es.
2. 2. 5. 
I m m u n o ge nicit y
Treat me nt -e mer ge nt a nt i dr u g a nti b o dies ( T E-A D A) ha ve bee n o bser ve d i n part ici pa nts i n all 
cli nical trials i n v o l vi n g miri kiz u ma b a d mi nistrati o n. I n t he maj ority of  T E-A D A + partici pa nts, 
titers were lo w a n d ha d n o clear i m pact o n dr u g e x p os ure a n d, if meas ure d, efficac y. Wit h a fe w 
parti ci pa nts wi t h mo d er at e -t o-se vere ps oriasis, titers were s ufficie ntl y hi g h t o i m pact dr u g 
e x p os ure. T here was n o clear ass ociat i on wi t h t he de vel o p me nt of i m m u n o ge nicity t o 
mir ikiz u ma b a n d pat ient s re p orti n g I S Rs/ h yperse nsi tivit y e ve nts.
2. 3.
Be nefit/ Ris k Assess me nt
As wi t h ot her i m m u n om o d ul at or y t hera pies, miriki z u m a b ma y increase t he ri s k of de vel o pi n g a n 
i nfecti on or ma y e xacer bate a n e xist i n g i nfecti on. T hese ma y i ncl u de o p p ort u nist ic i nfecti ons 
a n d react i vati on of late nt i nfecti o ns, s uc h as tu berc ul osis ( T B ) a n d he pat itis B, alt h o u g h s uc h 
i nfecti ons ha ve n ot bee n re p orte d i n healt h y v o l unt eer cli nical trials a d mi nisteri n g miri kiz u ma b 
to date. T heref ore, partici pa nts testi n g p ositi ve f or he pat itis B/ C, h u ma n i m m u n o deficie nc y  vir us 
(HI V ), or T B at scree ni n g will n ot be per mitte d t o partici pate i n t his st u d y. I m m u n om o d ul at or y 
t hera pies ma y i ncrease t he ris k of mali g na ncies; h o we ver, d ue t o t he si n gle d ose of miri kiz u ma b 
bei n g a d mi nistere d i n t his st u d y , it is n ot c o nsi dere d necessar y t o mo ni t or for s uc h effects.
I mme diate h y perse nsi tivi t y reacti ons (a na p h ylact ic reactio n a n d i nf usi o n- r elate d h y perse nsit i vity 
reactio n), i ncl u di n g urticaria, a n gioe de ma, a n d a na p h yla xis, ha ve rarel y  bee n re p orte d wit h t he 
a d mi nistrati o n of miri kiz u ma b.
N o ot her cli nicall y  si g nifica nt safety or t ol era bilit y c o ncer ns ha ve bee n i de nt ifie d t o date i n 
parti ci pa nts e x p ose d t o miri kiz u ma b u p t o t he hi g hest d oses gi ve n (si n gle 2 4 0 0-m g I V a n d S C 
d oses). Of n ote, t he 2 4 0 0 -m g S C d ose of mir i kiz u ma b was a d mi nistere d i n c o nj u ncti on wi t h 
h u ma n rec o m bi na nt h yal ur o ni dase as a n i nte gral c o m p o ne nt of t he f or m ulat i on.
Heal t h y participa nts are n ot e x pecte d t o deri ve a n y be nefit fr o m parti ci pat i n g i n st u dies i n w hic h 
mir i kiz u ma b is a d mi nistere d.
As t hi s st u d y will use P F S a n d AIs, de vice-base d ris ks will be e val uate d base d o n I S R A Es a n d 
blee di n g / br uisi n g assess me nts. P ossi ble de vice-base d ris ks i ncl u de l ocal effects s uc h as pai n at 
t he i nject i on sites fr o m eit her t he nee dle or t he s ol uti o n e ntr y int o t he S C ti ss ue, s welli n g, 
er yt he ma, blee di n g, a n d br uisi n g. T hese ris ks are mit i gate d b y trai ni n g of i n vesti gati ve site staff 
o n pr o per i njecti o n tec h ni q ues. S yste mic effects ma y  incl u de s weati n g, feeli n g fai nt, or fe ver, as 
a sig n of  infecti o n.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
1 4
M ore detaile d i nf or mat i on a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o na bl y 
e x pecte d A Es of  mir i kiz u ma b ma y b e f o u n d i n t he I B a n d ris ks as well as reas o na bl y a ntici pate d 
a d verse de vic e effects of t he AI are f o u n d i n t he de vice I B .

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
1 5
3.
O bjecti ves a n d E n d p oi nts
O bject i ves
E n d p oi nts
Pri mar y

T o e val uate t he P K of S C i nject i ons of 
3 0 0 m g mi rikiz u ma b s o l uti on 
a d mi nistere d usi n g 1 -m L a n d 2 -m L 
P F S a n d 1 -m L a n d 2 -m L AIs i n 
healt h y parti ci pa nts.

C m a x , A U C( 0-∞), a n d A U C( 0 -tlast)
Sec o n dar y

T o descri be t he safet y a n d t olera bilit y 
of  miri kiz u ma b i n health y part ici pa nts

T E A Es a n d S A Es
A b bre viati o ns: AI = a ut oi nject or; A U C( 0 -∞) = area u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m ti me zer o t o 
i nfi nit y; A U C( 0-tlast) = area u n der t he c o nce ntrat i on vers us ti me c ur ve fr o m ti me zer o t o ti me t, w here t is t he last 
ti m e p oi nt wit h a meas ura ble c o nce ntrati o n; C ma x = ma xi m u m o bser ve d dr u g c o nce ntrati o n; P F S = pr e-fille d 
s yri n ge; P K = p har mac o ki netics; S A E = seri o us a d verse e ve nt; S C = s u bc uta ne o us; 
T E -A D A = treat me nt-e mer ge nt a nti dr u g a nti b o d y; T E A E = treat me nt-e mer ge nt a d verse e ve nt. 
C CI

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
1 6
4.
St u d y Desi g n
4. 1.
O ver all Desi g n
St u d y  A M B X is a P hase 1, o pe n-label, 2 -ar m, ra n d o mize d, parallel-desi g n, si n gle -d ose, 
m ult i-site st u d y in heal t h y p artici pa nts. 
Scree ni n g
All partici pa nts will be scree ne d wit hi n 2 8 da ys pri or t o e nr oll me nt. At scree ni n g, partici pa nts 
will be stratifie d i nt o 1 of 3 wei g ht cate g ories (less t ha n 7 0 k g, 7 0 t o 8 0 k g, a n d m ore t ha n 
8 0 k g). 
Tre at me nt a n d Assess me nt Peri o d
Eli gi ble partici pa nts wi ll be a d mitte d t o t he cli nical researc h u nit (C R U ) o n Da y  -1. 
Wit hi n t he 3 wei g ht cate g ories, partici pa nts will be ra n d o mize d ( Ta ble A M B X. 1 ) usi n g a 
c o mp uter -ge nerate d all ocati o n c o de ( Secti o n 6. 3 ):

1: 1 t o deli ver y  de vice (eit her P F S [refere nce] or AI [test])

wi t hi n eac h deli ver y-de vice gr o u p 1: 1: 1 t o i njecti o n-sit e ( ar m, t hig h, or a b d o m e n)
O n Da y  1, p artici pa nts will recei ve a t otal of 3 m L ( 3 0 0 mg miri kiz u ma b) as 2 S C i njecti o ns of 
1 m L a n d 2 m L deli vere d via P F S or AI i n t he l ocati o n assi g ne d b y t he ra n d o mizat i on.
P arti cipa nts ma y  be allo w e d t o l ea ve t he C R U after c o m plet i n g t he 4-h o ur safet y assess me nts o n 
D a y  1, or later at t he i n vest i gat or’s discreti o n, a n d will ret ur n f or P K a n d i m m u n o ge nicity 
sa m pli n g a n d safety assess me nts at pre defi ne d ti mes u p t o 1 2 wee ks p ost d ose. Partici pa nts will 
be m o n itore d f or safet y bet wee n o ut patie nt visits b y  w a y of tele p h o ne assess me nt.
S af et y a n d t olera bilit y will  be assesse d t hr o u g h cli nical la b orat or y tests, vit al si g ns 
meas ure me nts, E C Gs, rec or di n g of a d verse e ve nts, rec or di n g of i nject i on -site reactio ns, a n d 
p h ysical e xa mi nat i on.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
1 7
T a bl e A M B X. 1.
St u d y A M B X Str atifi c ati o n a n d R a n d o mi z ati o n Pl a n
Wei g ht C ate g or y 
( P artici p a nts)a
I njecti o n De vice
S u bc ut a ne o us I njecti o n 
L oc ati o n b
Desire d N u m ber 
of P artici p a nts
L o w
< 7 0 k g
( ~7 2 partici pa nts)
1 x 1- m L + 1 x 2 -m L P F S ( Refere nce)
or
Ar m
1 2
1 x 1 -m L + 1 x 2 -m L AI ( Test)
1 2
1 x 1- m L + 1 x 2 -m L P F S ( Refere nce)
or
A b d o me n
1 2
1 x 1 -m L + 1 x 2 -m L AI ( Test)
1 2
1 x 1 -m L + 1 x 2 -m L P F S ( Refere nce)
or
T hi g h
1 2
1 x 1 -m L + 1 x 2 -m L AI ( Test)
1 2
Me di u m
7 0 – 8 0 k g
( ~ 7 2 partici pa nts)
1 x 1- m L + 1 x 2 -m L P F S ( Refere nce)
or
Ar m
1 2
1 x 1 -m L + 1 x 2 -m L AI ( Test)
1 2
1 x 1 -m L + 1 x 2 -m L P F S ( Refere nce)
or
A b d o me n
1 2
1 x 1 -m L + 1 x 2 -m L AI ( Test)
1 2
1 x 1 -m L + 1 x 2 -m L P F S ( Refere nce)
or
T hi g h
1 2
1 x 1 -m L + 1 x 2 -m L AI ( Test)
1 2
Hi g h
> 8 0 k g
( ~ 7 2 partici pa nts)
1 x 1- m L + 1 x 2 -m L P F S ( Refere nce)
or
Ar m
1 2
1 x 1 -m L + 1 x 2 -m L AI ( Test)
1 2
1 x 1 -m L + 1 x 2 -m L P F S ( Refere nce)
or
A b d o me n
1 2
1 x 1 -m L + 1 x 2 -m L AI ( Test)
1 2
1 x 1 -m L + 1 x 2 -m L P F S ( Refere nce)
or
T hi g h
1 2
1 x 1 -m L + 1 x 2 -m L AI ( Test)
1 2
A b bre viati o ns: ~ = a p pr o xi matel y; AI = a ut oi nject or; P F S = pre -fille d s yri n ge. 
a.
A p pr o xi mate l y e q ual n u m bers of partici pa nts will be recr uite d t o eac h wei g ht cate g or y.
b.
A d ose of st u d y i nter ve nti o n will c o nsist of 2 s u bc uta ne o us i njecti o ns of miri kiz u ma b i nt o t he ar m, t hi g h, 
or  a b d o me n. All d oses will be a d mi nistere d b y trai ne d site staff. 
4. 2.
Scie ntific R ati o n ale f or St u d y Desi g n
 
 p o p ulatio n of  healt hy 
parti ci pa nts is fre q ue ntl y use d i n t he assess me nt of t he P K of b ot h s mall a n d lar ge m olec ules.
Si n gle 3 0 0- m g d ose s of miri kiz u ma b a n d t he P K sa m pli n g ti me p oi nts ha ve bee n selecte d t o 
ge nerate P K pr ofiles s ufficie nt t o f ulfill t he st u d y  o bjecti ves.
P arti cipa nts will be ra n d o mize d t o recei ve i nject i ons i n t he ar m, t hi g h, or a b d o me n, as i njecti on 
l ocat i on has bee n o bser ve d t o ha ve a n i m pact o n bi oa vaila bilit y i n s ome st u dies wit h
mir i kiz u ma b.
Pre vi o us p o p ulati o n P K a nal yses ha ve s h o w n t hat patie nts wit h a l o wer b o d y wei g ht te n de d t o 
ha ve a l o wer cleara nce a n d/ or ce ntral v o l ume of distri b ut i on. W hile t he effects of b o d y  w eig ht o n 
C CI

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
1 8
t hese P K para meters were statist icall y si g nifica nt, it was n ot c o nsi dere d t o be cli nicall y rele va nt. 
H o we ver, t o mit i gate t hese p ote ntiall y c o nf o u n di n g effects, a p pr o xi matel y e q ual n u m bers of 
parti ci pa nts i n eac h wei g ht cate g or y are pr o p ose d t o a v oi d a lar ge differe nce i n mea n wei g ht 
bet wee n t he test a n d t he refere nce deli ver y- de vice gr o u ps. A partici pa nt p o p ulat i on of 7 2 per 
w ei g ht gr o u p i s a n a p pr o xi mate tar get wit h t he rec o m me n de d wei g ht cate g ories selecte d base d 
o n t he di stri b uti on of wei g ht s i n prior st u di es. T he n u m ber of partici pa nts assi g ne d t o eac h 
deli ver y  de vice a n d t he n u m ber of partici pa nts assi g ne d t o eac h site of i njecti on is desire d t o be 
bala nce d. 
A parallel -gr o u p desi g n is c h ose n beca use miri kiz u ma b has a half -life of a p pr o ximatel y 1 0 da ys. 
A d dit i onall y , a cr oss o ver st u d y c o uld c o nf o u n d P K data if partici pa nts de vel o p ne utralizi n g 
a nt i dr u g a nti b o dies (A D As ).
4. 3.
J u stific ati o n f or D ose
T he 3 0 0 -m g d ose of miri kiz u ma b c h ose n f or t his st u d y is base d o n :

3 0 0 m g bei n g f o u n d safe a n d t olera ble i n P hase 2 st u dies,

3 0 0 m g bei n g e val uate d i n t he P hase 3 
de vel o p me nt pr o gra m, a n d

t he v ol u me o f s ol uti on t hat ca n be deli vere d t hr o u g h 2 P F S/ AI (a 1 m L a n d a 2 m L
P F S/ AI) a n d t he s o l ubilit y of miri kiz u ma b ( 1 0 0 m g/ m L).
4. 4.
E n d of St u d y Defi niti o n
A partici pa nt is c o nsi dere d t o ha ve c o m p lete d t he st u d y if he/s he has c o m p lete d all re q uire d 
p hases of t he st u d y  incl u di n g t he last visit s h o w n i n t he S o A (Secti o n 1. 3 ).
T he e n d o f t he st u d y is defi ne d as t he date of t he last visit of t h e last partici pa nt i n t he st u d y.
C CI
C CI

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
1 9
5.
St u d y P o p ul ati o n
Eli gi bilit y of  p artici pa nts f or e nr oll me nt i n t he st u d y will be base d o n t he res ults of scree ni n g 
me dical hist or y , p h ysical e xa mi nat i on, vit al sig ns, cli nical la b orat or y  t ests, a n d 
ele ctr o car di o gra m ( E C G). T he nat ure of a n y c o n diti o ns prese nt at t he ti me of t he p h ysical 
e xa mi nat i on a n d a n y pre e xist i n g c o n ditio ns will be d oc u m e nte d.
T he i ncl usi o n a n d e xcl usi o n cri t eria use d t o deter mi ne eli gi bilit y s h o uld be a p plie d at scree ni n g 
o nl y , u nless s pecifie d ot her wise, a n d n ot c o nti n u o usl y t hr o u g h o ut t he st u d y.
P arti cipa nts will be s cree ne d wi t hi n 2 8 da ys pri or t o e nr oll me nt. Partici pa nts w h o are n ot 
e nr o lle d wit hi n 2 8 da ys of  scree ni n g ma y u n der g o a n a d dit i onal me dical assess me nt a n d/ or 
cli nical meas ure me nts t o c o nfir m t heir eli gi bilit y.  I n s uc h i nsta nces, re peat t he f oll o wi n g 
scree ni n g tests a n d pr oce d ures: wei g ht, vital si g ns, E C G, cli nical la b orat or y tests, a n d pre g na nc y 
test (fe males o nl y).
Pr os pecti ve a p pr o val o f pr ot oc ol  de viatio ns t o recr ui t me nt a n d e nr o ll me nt criteria, als o k n o w n as 
pr ot oc ol  wai vers or e xe m pti ons, is n ot per mitte d.
5. 1.
I ncl usi o n Criteri a
P arti cipa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all o f t he fol l owi n g criter ia a p pl y:
A ge
1.
P arti cip a nt m ust be 1 8 t o 6 5 years of a ge , i ncl usi ve, at t he ti me of si g ni n g t he i nf or me d 
c o nse nt.
T y pe of P artici p a nt a n d Dise ase C h ar acteristics
2.
P articipa nts w h o are o vertl y healt h y, as deter mi ne d b y  me dical e val uat i on i ncl u di n g:

me dical hist or y

p h ysical e xa mi nat i on

cli nical la b orat or y t ests

E C G a n d

vit al si g ns.
3.
H a ve cli nical la b orat or y test res ults wit hi n n or mal refere nce ra n ge f or t he p o p ulat i on or 
i n vesti gati ve site, or res ults wit h acce pta ble de viati o ns t hat are j u d ge d t o be n ot cli nicall y 
sig nifica nt b y  t he i n vesti gat or
4.
H a ve ve n o us access s ufficie nt t o all o w f or bl o o d sa m pli n g as per t he pr ot oc ol
5.
A gree n ot t o d o nate bl o o d or plas ma u nt il after t he e n d of t heir partici pati on i n t he st u d y
6.
A re relia ble a n d willi n g t o ma ke t he msel ves a vaila ble f or t he d urati o n of t he st u d y a n d 
are willi n g t o f o ll ow st u d y  pr oce d ures.
Wei g ht
7.
B o d y  mass i n de x wi t hi n t he ra n ge 1 8. 0 t o 3 2. 0 k g/ m 2 (incl usi ve).

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
2 0
Se x
8.
Males a n d fe males.
C o ntrace pti ve use b y parti ci pa nts s h o uld be c o nsiste nt wit h l ocal re g ulat i ons re gar di n g t he 
met h o ds of c o ntrace pti o n f or t h ose partici pat i n g i n cli nical st u dies.
a.
Male parti ci pa nts:
i.
Males ma y  p artici pate i n t his st u d y.
b.
Fe male partici pa nts:
i.
W o me n of c hil d beari n g p ote ntial ma y  p artici pate i n t his st u d y.
ii.
W o me n n ot of c hil d beari n g p ote ntial ma y partici pate i n t his st u d y.
Pl ease refer t o Secti o n 1 0. 4 f or defi niti ons a n d a d dit i onal g ui da nce relate d t o c o ntrace pti o n.
I nf or me d C o nse nt
9.
Ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt as descri be d i n Sect i on 1 0. 1 , w hic h i ncl u des 
c o mplia nce wi t h t he re q uir e me nts a n d restrict i ons liste d i n t he i nf or me d c o nse nt f or m 
(I C F) a n d i n t his pr ot oc ol.
5. 2.
E xcl usi o n Criteri a
P arti cipa nts are e xcl u de d fr o m  t he st u d y if a n y of t he f o ll owi n g cri t eria a p pl y:
Me dic al C o n diti o ns
1.
H a ve k n o w n aller gies t o miri kiz u ma b, relate d c o m p o u n ds, or a n y  c o mp o ne nts of 
t he f or mulat i on, or hi st or y of si g nifica nt at o p y
2.
H a ve self- percei ve d d ull ness or l oss of se nsati on i n eit her ar m or t hi g h or o n 
eit her si de of t he a b d o me n
3.
H a ve a n a b n or malit y i n t he 1 2-lea d E C G t hat, in t he o pi ni o n o f t he i n vest i gat or, 
i ncreases t he ris ks ass ociate d wit h partici pati n g i n t he st u d y
4.
H a ve a n a b n or mal bl o o d press ure, p ulse rate, or b o d y t e mperat ure deter mi ne d t o
be cli nicall y  si g nifica nt b y t he i n vesti gat or
5.
H a ve a hist or y or prese nce of car di ovasc ular, res pirat or y, he pat ic, re nal, 
gastr oi ntesti nal, e n d ocri ne, he mat ol o gical, ne ur ol o gical, or der mat ol o gical 
di s or ders ca pa ble of sig nifica nt l y alteri n g t he a bs or ptio n , meta b olis m, or 
eli mi nat i on of dr u gs; of c o nstit uti n g a ris k w he n ta ki n g t he st u d y  int er ve ntio n; or 
of  int erferi n g wit h t he i nter pretati o n of data

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
2 1
6.
I nfecti o ns:
a.
H a ve ha d a seri o us i nfect i on (s uc h as p ne u m o nia, cell ulit is, se psis), or
ha ve bee n h os pitalize d or ha ve recei ve d I V a nt i bi otics f or a n i nfect i on 
wi t hi n 1 2 wee ks pri or t o Da y  1; ha ve ha d a seri o us b o ne or j oi nt i nfecti on 
wi t hi n 2 4 wee ks prior t o Da y  1 or ha ve e ver ha d a n i nfecti on of a n 
artificial j o i nt; or are i m m u n oc o m pr omise d t o a n e xte nt t hat part ici pati on 
i n t he st u d y w o uld p ose a n u nacce pta ble ris k t o t he partici pa nt as 
deter mi ne d b y t he i n vest i gat or
b.
H a ve or ha ve ha d a n i nfect i on t y pi c al  of a n i m m u n oc o mpr o mise d h ost 
a n d/ or t hat occ urs wit h i ncrease d i nci de nce i n a n i m m u n oc o m pr o mise d 
h ost (i ncl u di n g, b ut n ot li mite d t o, P ne u m ocystis jir ovecii p ne u m o nia, 
hist o pl as mosis, or c occi di oi d o m yc osis) or ha ve a k n o w n 
i m m u n o deficie nc y
c.
H a ve or ha ve ha d a her pes z oster i nfect i on or a n y  ot her cli nicall y a p pare nt 
varicella -z oster vir us i nfecti on wi t hi n 1 2 wee ks of Da y 1
d.
H a ve ha d a n y ot her acti ve or rece nt i nfect i on wi t hi n 4 wee ks of Da y 1 
t hat, i n t he o pi ni o n of t he i n v est i gat or, w o ul d p ose a n u nacce pta ble ris k t o 
t he partici pa nt if partici pat i n g i n t he st u d y; t hese partici pa nts ma y be 
rescree ne d ( o nce) at least 4 wee ks after d oc u me nte d res ol uti o n o f 
s y m pt o ms.
7.
H a ve k n o w n or o n g oi n g ps yc hiatric dis or ders dee me d cli nicall y sig nifica nt b y  t he 
i n vesti gat or
8.
R e g ularl y use k n o w n dr u gs of a b use a n d/ or s h o w p osit i ve fi n di n gs o n 
dr u g scree ni n g
9.
S h o w e vi de nce of HI V i nfect i on a n d/ or p osit i ve HI V a nti b o dies
1 0. S h o w e vi de nce of he pat itis C a n d/ or p ositi ve he patitis C a nti b o d y
1 1. S h o w e vi de nc e of he pat itis B a n d/ or p ositi ve he patitis B s urface a nti ge n or 
he pat itis B c ore a nti b o d y
1 2. A r e fe males w h o are pre g na nt or lactati n g
1 3. S h o w e vi de nce of act i ve or late nt T B, as d oc u me nte d t hr o u g h me dical hist or y, 
e xa mi nat i on, a n d T B testi n g ( p osit i ve [ n ot i n deter mi nate] Q ua nti F E R O N® -T B 
G ol d test; if a re peat test is als o i n deter mi nate, t he partici pa nt will n ot be eli gi ble); 
or ha ve ha d h o use h o l d c o ntact wit h a pers o n wit h acti ve T B, u nless a p pr o priate 
a n d d oc u me nte d pr o p h yla xis treat me nt has bee n c o mplete d . Parti ci pa nts wit h a n y 
hist or y  of acti ve T B are e xcl u de d fr o m t he st u d y, re gar dless of pre vi o us or c urre nt 
T B treat me nts
1 4. H a ve si g nifica nt aller gies t o h u ma nize d m o n ocl o nal a nt i b o dies
1 5. H a ve cli nicall y si g nifica nt mul tiple or se vere dr u g aller gies, or i nt olera nce t o 
t o pical c ortic ost er oids, or se vere p osttreat me nt h y perse nsit i vity 
reactio ns (incl u di n g, b ut n ot li mite d t o, er y t he ma m ultif or me major, 
li near i m m u n o gl o b uli n A der mat osis, t o xic e pi der mal necr ol ysis, or e xf oliati ve 
d er m at itis)

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
2 2
1 6. H a ve ha d l y m p h o ma, le u ke mia, or a n y mali g na nc y wit hi n t he past 5 years, e xce pt 
f or basal cell or s q ua mo us e pi t helial carci n o mas o f t he s ki n t hat ha ve bee n 
resecte d wit h n o e vi de nce of metastatic disease f or 3 years
1 7. H a ve ha d breast ca ncer wit hi n t he past 1 0 years
Pri or/ C o nc o mit a n t T her a p y
1 8. I nt e n d or are li kel y t o use o ver -t he- c o u nter or prescri pt i on me d icati on wi t hi n 7 da ys prior 
t o d ose a d mi nistrati o n. Partici pa nts o n sta ble d oses of s ome me dicat i ons (s uc h as stati ns 
a n d a nt i h y perte nsi ves) ma y be eli gi ble f or e nr oll me nt f oll owi n g disc ussi o n wi t h t he 
s p o ns or ( Secti o n 6. 5 )
1 9. H a ve e ver recei ve d a nt i-I L-1 2 p 4 0 a nt i b o dies (e. g., uste ki n u ma b [ Stelara® ]) or 
a nt i-I L-2 3 p 1 9 a nt i b o dies (e. g., risa n kiz u ma b [ BI-6 5 5 0 6 6], brazi k u ma b [ M E DI 2 0 7 0], 
g usel k u ma b [ C N T O 1 9 5 9], or til dra kiz u ma b [ M K -3 2 2 2]) f or a n y  in dicat i on, i ncl u di n g 
i n vesti gati onal use
2 0. H a ve recei ve d li ve vacci ne(s), i ncl u di n g atte n uate d li ve vacci nes a n d t h ose a d mi nistere d 
i ntra nasall y, wi t hi n 8 wee ks of scree ni n g, or i nte n d t o d uri n g t he st u d y ( n o n-li ve or 
i nacti vate d vacci nati ons are n ot all o we d 2 wee ks pri or t o, or 2 wee ks after miri kiz u ma b 
d osi n g, a n d t he n t he y  must be gi ve n at a n i njecti o n -site re mot e f r o m miri kiz u ma b 
a d mi nistrati o n)
2 1. Ha ve bee n treate d wit h oral ster oi ds wit hi n 1 m o nt h of scree ni n g, or i nte n d t o d uri n g t he 
st u d y ( mil d t o pical st er oid crea ms/ oi nt me nt s are per mitte d, wit h t he e xce pti on of 
± 2 4 h o urs fr o m i nject i on of t he st u d y  int er ve nt i on as s pecifie d i n Sect i on 6. 5 )
Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce
2 2. Are c urre nt l y e nr olle d i n a cli nical st u d y in v o l vi n g a n i n vesti gati o nal pr o d uct or a n y 
ot her t y pe of me dical researc h j u d ge d n ot t o be scie ntificall y or me dicall y c om pat i ble 
wi t h t his st u d y
2 3. H a ve part ici pate d i n a cli nical trial i n v ol vi n g a n i n vesti gati o nal pr o d uct wit hi n 3 0 da ys or 
5 half -li ves ( w hic he ver is l on ger) pri or t o scree ni n g. If t he cli nical trial i n v o l ve d 
treat me nt wit h biol o gi c a ge nts (s uc h as mo n o cl o nal  a nti b o dies, i ncl u di n g mar kete d 
dr u gs), at least 3 m o nt hs or 5 half -li ves ( w hic he ver is l o n ger) s h o ul d ha ve ela pse d pri or t o 
D a y  1
2 4. Ha ve pre vi o usl y c o m p lete d or wit h dra w n fr om t his st u d y or a n y ot her stu d y i n vesti gati n g 
mir i kiz u ma b, a n d ha ve pre vi o usl y recei ve d miri kiz u ma b
Ot her E xcl usi o ns
2 5. A re i n vesti gati ve site pers o n nel directl y affiliate d wit h t his st u d y a n d t heir i m me diate 
fa milies. I m me diate fa mil y is defi ne d as a s p o use, bi ol ogical  or le gal g uar dia n, c hil d, or 
si bli n g
2 6. A re Lill y or La bc or p e m p l oyees
2 7. H a ve d o nate d bl o o d or plas ma of m ore t ha n 5 0 0 m L wit hi n 1 m o nt h pri or t o scree ni n g 
2 8. H a ve a n a vera ge wee kl y alc o h o l i nta ke t hat e xcee ds 2 1 u nits per wee k ( males) a n d 
1 4 u nits per wee k (fe males), ha v e a p ositive test f or et ha n o l, or are u n willi n g t o a bi de b y 
t he alc o h o l restrict i ons descri be d i n Sect i on 5. 3. 2 of 3 u ni ts per da y ( males) or 2 u nits per 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
2 3
d a y  (fe males) ( 1 u nit = 1 2 o z  or 3 6 0 m L of beer; 5 oz or 1 5 0 m L of wi ne; 1. 5 oz or 
4 5 m L of dist ille d s pirits)
2 9. H a ve a t o bacc o c o ns u m pt i on of m ore t ha n 1 0 ci garettes per da y  ( or e q ui vale nt), or w h o 
are u n willi n g t o a bi de b y t he C R U s mo ki n g g ui deli nes descri be d i n Secti o n 5. 3. 2
3 0. H a ve e xcessi ve tatt o os, scars, m o les, s ki n h y per pi g me ntati o n, birt h mar ks, or stretc h 
mar ks o ver eit her ar m, eit her t hi g h, or eit her si de of t he a b d o me n t hat w o ul d i nterfere 
wi t h injecti o n -site assess me nts
3 1. I n t he o pi ni o n o f t he i n vest i gat or, are u ns uita ble f or i ncl usi o n i n t he st u d y.
5. 3.
Lifest yle C o nsi der ati o ns
5. 3. 1.  
Me als a n d Diet ar y Restricti o ns
P arti cipa nts will recei ve a li g ht brea kfast o n t he m or ni n g of Da y  1 prior t o d osi n g. Sta n dar d 
meals will be pr o vi de d at all ot her ti mes w hile partici pa nts are reside nt at t he C R U, per t he 
C R U’s p olic y. P arti ci pa nts ma y c o ns u me water a d li bit u m.
5. 3. 2.  
C affei ne, Alc o h ol, a n d T o b acc o
P arti cipa nts will f oll ow cli nic caffei ne r estrictio ns w hile resi de nt at t he C R U, b ut ot her wise 
parti ci pa nts will be all o we d t o mai ntai n t heir re g ular caffei ne c o ns u m pt i on.
Alc o h o l c o ns u m pt i on is n ot per mitte d w hile partici pa nts are resi de nt at t he C R U a n d f or 
2 4 h o urs pri or t o eac h st u d y  visit. Alc o h ol i nta ke d uri n g o ut patie nt peri o ds s h o ul d n ot e xcee d 
3 u nits per da y  for m ales or 2 u nits per da y  for f e m ales.
P arti cipa nts m ust a bi de b y  t he C R U s mo ki n g restricti o ns d uri n g st u d y  visits a n d w hile resi de nt at 
t he C R U.
5. 3. 3.
Acti vit y
P arti cipa nts will be a d vise d t o mai ntai n t heir re g ular le vels of p h ysical act i vity/ e xercise; 
h o we ver, t he y  s h o uld n ot u n derta ke vi g or o us or pr ol o n ge d e xercise wit hi n 4 8 h o urs pri or t o a n y  
visit i n w hic h la b orat or y  safety tests will occ ur (S cree ni n g, Da y  -1, Da y  1, Da y 3, Da y 1 5, 
D a y 2 9, a n d Da y 8 5). W hile certai n st u d y  pr oce d ures are i n pr o gress at t he site, partici pa nts ma y 
be re q uire d t o re mai n rec u m be nt or sitti n g.
5. 4.
Scree n F ail ures
Scree n fail ures are defi ne d as part ici pa nts w h o c o nse nt t o partici pate i n t he cli nical st u d y b ut are 
n ot s u bse q ue ntl y e nr olle d i n t he st u d y. 
I n di vi d uals w h o d o n ot meet t he criteria f or partici patio n i n t his st u d y  (scree n fail ure) ma y n ot be 
r escree ne d. Re peati n g o f lab orat or y  tests d uri n g t he scree ni n g peri o d or re peati n g scree ni n g tests 
t o c o mpl y wit h t he pr ot oc ol desi g nate d scree ni n g peri o d d oes n ot c o nstit ute rescree ni n g.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
2 4
6.
St u d y I nter ve nti o n a n d C o n c o mit a nt T her a p y
St u d y  i nter ve nt i on is defi ne d as a ny i n vesti gati onal i nter ve nt i on (s), mar kete d pr o d uct(s), 
pl ace b o , or m e dical de vice(s) i nte n de d t o be a d mi nistere d t o / use d b y a st u d y partici pa nt 
acc or di n g t o t he st u d y pr ot oc ol .
6. 1.
St u d y I nter ve nti o n A d mi nistere d
T his st u d y  in v o l ves a c o m paris o n of 2 × S C i njecti o ns ( 1 m L [ 1 0 0 m g] + 2 m L [ 2 0 0 m g]) of  
mir i kiz u ma b usi n g P F S or AI i nt o t he ar m, t hi g h, or a b d o me n f or a t otal a d mi nistere d d ose of 
3 0 0 m g.
T a bl e A M B X . 2.
St u d y I nt er v e nti o n s A d mi ni st er e d
St u d y I nter ve nti o n 
Miri kiz u ma b P F S
Miri kiz u ma b AI
D os a ge F or m ul ati o n
S ol uti o n f or i njecti o n
S ol uti o n f or i njecti o n
U nit D ose 
Stre n gt h(s)/ D os a ge Le vel(s)
1 0 0 m g/ m L i n a 1 -m L P F S 
1 0 0 m g/ m L (t otal 2 0 0 m g) i n a 2 -m L P F S 
1 0 0 m g/ m L i n a 1 -m L AI
1 0 0 m g/ m L (t otal 2 0 0 m g) i n a 2 -m L AI 
R o ute of A d mi nistr ati o n
S u bc uta ne o us
S u bc uta ne o us
D osi n g I nstr ucti o ns
1 × 1 -m L i njecti o n a n d 1 × 2- m L i njecti o n
at site acc or di n g t o t he ra n d o mizati o n
1 × 1 -m L i njecti o n a n d 1 × 2- m L i njecti o n
at site acc or di n g t o t he ra n d o mizati o n
A b bre viati o ns: AI = a ut oi nject or; P F S = pre -fille d s yri n ge. 
6. 1. 1.
A d mi nistr ati o n Det ails
P arti cipa nt s will recei ve mir i kiz u ma b a d mi nistere d via t he P F S or AI base d o n t he ra n d o mizat i on 
sc he d ule (Ta ble A M B X. 1 ).
P arti cipa nts ra n d o mize d t o a gr o u p wit h t he ar m or t hi g h as t he i njecti o n area will ha ve :
1.
t he first i njecti on ( 2 m L) a d mi nistere d t o t he left li m b, a n d 
2.
t he sec o n d i nject i on ( 1 m L) a d mi nistere d t o t he c orres p o n di n g (c o ntra -lateral) 
rig ht li m b. 
P arti cipa nts ra n d o mize d t o t he gr o u p wit h t he a b d o me n as t he i nject i on area will ha ve :
1.
t he first i nject i on ( 2 m L) a d mi nistere d t o t he lo wer left q ua dra nt, a n d
2.
t he sec o n d i nject i on ( 1 m L) a d mi nistere d t o t he l o wer ri g ht q ua dra nt of t he 
a b d o me n. 
6. 1. 2.
Me dic al De vices
1.
T he Lill y -ma n ufact ure d me dical de vices ( or de vices ma n ufact ure d f or Lill y b y  a 
t hir d part y) pr o vide d f or use i n t his st u d y are:

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
2 5
a.
the f ull y asse m ble d miri kiz u ma b 1 -m L P F S
b.
the f ull y asse m ble d miri kiz u ma b 1-m L AI.
c.
t he f ull y asse m ble d miri kiz u ma b 2- m L P F S
d.
t he f ull y asse m ble d miri kiz u ma b 2- m L AI.
2.
I nstr uctio ns f or m e dical de vice use will be pr o vide d as part of t he St u d y  Materials 
pr o vi de d t o i n vest i gat ors a n d sites.
3.
All de vice deficie ncies (i ncl u di n g malf u nct i on, use err or, a n d i na de q uate la bel i n g) 
s hall be d oc u me nte d a n d re p orte d b y t he i n vesti gat or t hr o u g h o ut t he cli nical 
i n vesti gati on (see Sect i on 1 0. 8 ) a nd a p pr o priatel y ma na ge d b y  t he s p o ns or.
4.
Eac h de vice will be la bel e d acc or di n g t o t he c o u ntr y’s re g ulat or y re q uire me nts.
6. 2.
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y
T he i n vest i gat or or desi g nee m ust c o nfir m a p pr o priate st ora ge c o n diti o ns ha ve bee n mai ntai ne d 
d uri n g tra nsit f or all st u d y  int er ve nt i on recei ve d a n d a n y  discre pa ncies are re p orte d a n d res ol ve d 
bef ore use of t he st u d y  int er ve ntio n.
O nl y partici pa nts e nr o lled i n t he st u d y  ma y recei ve st u d y int er ve nt i on. O nl y a ut h orize d st u d y  
pers o n nel ma y s u p pl y , pre pare, or a d mi nister st u d y int er ve nt i on. All st u d y  int er ve nt i on m u st be 
st ore d i n a sec ure, e n vir o n me ntall y c o ntr olle d, a n d m o nit ore d ( ma n ual or a ut o mate d) area i n
acc or da nce wit h t he la bele d st ora ge c o n dit i ons wit h access li mite d t o t he i n vest i gat or a n d 
a ut h orize d st u d y pers o n nel.
T he i n vest i gat or or a ut h orize d st u d y pers o n nel are res p o nsi ble f or st u d y i nter ve nti o n 
acc o u nta bilit y, rec o nciliat i on, a n d rec or d mai nte n a nce (i.e., receipt, rec o nciliat i on, a n d fi nal 
di s p ositio n rec or ds).
N ote:  I n s o me cases, sites ma y destr o y  t h e mat erial if, d uri n g t he i n vesti gati ve site selecti on, t he 
e val uat or has verifie d a n d d oc u me nte d t hat t he site has a p pr o priate facilit ies a n d writte n 
pr oce d ures t o dis p ose of cli nical materials.
6. 3.
Me as ures t o Mi ni mize Bi as: R a n d o miz ati o n a n d Bli n di n g
T his is a n o pe n -la bel ra n d o mize d st u d y; p ote ntial bias will be re d uce d b y ce ntral ra n d omizati o n.
O n Da y  1, p artici pa nts will be assi g ne d a u ni q ue n u m be r (ra n d o mizati on n u m ber). T he 
ra n d omizat i on n u m ber e nc o des t he partici pa nt’s assi g n me nt, wit hi n t heir wei g ht stratificat i on 
cate g or y, t o o ne of t he 2 p ossi ble deli ver y de vices ( P F S or AI) a n d 3 p ossi ble i njecti on sites 
(ar m, t hig h, or a b d o me n), acc or di n g t o t he ra n d o mizat i on sc he d ule ge nerate d pri or t o t he st u d y  
b y t he Statist ics De part me nt at La bc or p Dr u g De vel o p me nt . Eac h partici pa nt will be dis pe nse d 
st u d y int er ve ntio n la bele d wi t h his/ her u ni q ue ra n d o mizati on n u m ber.
6. 4.
St u d y I nter ve nti o n C o m pli a nce
St u d y  i nter ve nt i on will be a d mi nistere d u n der me dical s u per visi o n b y t he i n vest i gat or or 
desi g nee. T he d ose of st u d y  int er ve nt i on a n d st u d y partici pa nt i de nt ificati o n will be c o nfir me d 
pri or t o t he ti me o f d osi n g. T he date a n d ti me of eac h d ose a d mi nistere d will be rec or de d i n t he 
s o urce d oc u me nts a n d i n t he case re p ort f or m (C R F ).

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
2 6
6. 5.
C o nc o mit a nt T her a p y
P arti cipa nts o n sta ble c o nc o mita nt me dicat i on at t he ti me of st u d y  e ntr y s h o uld c o nti n ue t heir 
re g ular, u nc ha n ge d d ose t hr o u g h o ut t he st u d y. Per mitte d c o nc o mita nt me dicati ons, at t he 
di scretio n of  t he i n vesti gat or, i ncl u de h or m o nal c o ntrace pti ves, h or m o ne-re place me nt t hera p y, 
a n d t h yr oid r e pl ace me nt. I n a d diti on, occasi o nal  aceta mi n o p he n is acce pta ble at t he discreti o n of 
t he i n vest i gat or. H o we ver, aceta mi n o p he n s h o ul d n ot be a d mi nistere d o n t he d osi n g da y withi n 
4 h o urs pri or t o a n d 4 h o urs after d osi n g. N o m ore t ha n 3 g of  aceta mi n o p he n will be per mitte d 
i n a n y 2 4-h o ur peri o d. I ncl usi o n  of p artici pa nts o n a n y ot her c o nc o mita nt me dicat i on (e . g., 
stati ns a n d a ntih y perte nsi ves ) is c o nti n ge nt u p o n a p pr o val f oll owi n g c o ns ultati o n wit h t he 
s p o ns or.
P arti cipa nts will be restricte d fr o m a p pl yi n g a n y crea ms or l oti o ns o n t he ar m, t hi g h, or 
a b d o mi nal s ki n wit hi n 2 4 h o urs pri or t o or after t he i nject i ons a n d partici pa nts s h o ul d n ot recei ve 
a n y a d dit i onal S C i nject i ons at t he site of miri kiz u ma b a d mi nistrati o n f or t he d urati o n of t he 
st u d y.
A n y me dicat i on i ncl u di n g o ver-t he-c o u nter or prescri pt i on me d ici nes, vita mi ns, a n d/ or her bal 
s u p ple me nts t hat t he partici pa nt is recei vi n g at t he ti me of e nr oll me nt or recei ves d uri n g t he 
st u d y must be rec or de d al o n g wit h:

reas o n f or use

dates of a d mi nistrati o n i ncl u di n g start a n d e n d dates

d osa ge i nf or mati o n i ncl u di n g d ose a n d fre q ue nc y f or c o nc o mita nt t hera p y  of s pecial 
i nterest.
T he Lill y cli nical p har ma c olo gis t (C P) or cli nical researc h p h ysician ( C R P ) s h o uld be c o ntacte d 
if t here are a n y q uest i ons re gar di n g c o nc o mita nt or pri or t hera p y .
If t he nee d f or a n y a d ditio n al c o nc o mit a nt me dicati o n arises, i ncl usi o n or c o nti n uat i on of t he 
parti ci pa nt ma y be at t he discreti on of t he i n vesti gat or after c o ns ultat i on wi t h a Lill y C P or C R P.
6. 6.
D o se M o dific ati o n
N ot a p plica ble f or t his si n gle -d ose st u d y .
6. 7.
I nter ve nti o n after t he E n d of t he St u d y
N ot a p plica ble f or t his st u d y .

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
2 7
7.
Disc o nti n u ati o n of St u d y I nter ve nti o n a n d P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al
7. 1.
Disc o nti n u ati o n of St u d y I nter ve nti o n
N ot a p plica ble f or t his si n gle-d ose st u d y .
7. 2.
P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al fr o m t he St u d y
A parti ci pa nt ma y wi t hdra w fr o m  t he st u d y:
●
at a n y ti me at his/ her o w n re q uest 
●
at t he re q uest of his/ her desi g nee (f or e xa m ple, pare nts or le gal g uar dia n)
●
a t t he discretio n of  t he i n vesti gat or f or safety,  be ha vior al , c o mplia nce, or a d mi nistrati ve 
reas o ns
●
if t he partici pa nt bec ome s pre g na nt d uri n g t he st u d y
●
if e nr oll me nt i n a n y ot her cli nical st u d y i n v ol vi n g a n i n vesti gati onal pr o d uct or 
e nr o ll me nt i n a n y ot h er t yp e of  me dical researc h j u d ge d n ot t o be scie nt ificall y or 
me dicall y c o m pat i ble wit h t his st u d y
●
if t he parti ci pa nt , for a n y  reas o n, re q uires treat me nt wit h a n ot her t hera pe utic a ge nt t hat 
has bee n de m o nstrate d t o be effect i ve f or treat me nt of t he st u d y in dicat i on, 
di sc o nti n uati on fr om t he st u d y occ urs prior t o i ntr o d ucti o n of  t he ne w a ge nt.
Di sc o nti n uatio n is e x pecte d t o be u nc o m m o n.
At  t he ti me of disc o nti n ui n g fr o m t he st u d y, if p ossi ble, a n earl y disc o nti n uati on visit s h o ul d be 
c o n d ucte d, as s h o w n i n t he S o A ( Sectio n 1. 3 ). See t he S o A f or data t o be c ollecte d at t he ti me of 
st u d y disc o nti n uati on a n d f o ll ow- u p a n d f or a n y  furt her e val uat i ons t hat nee d t o be c o m plete d.
T he parti ci pa nt will be per ma ne ntl y disc o nt i n ue d b ot h fr om t he st u d y int er ve nt i on a n d fr o m t he 
st u d y at t hat ti me.
If t he parti ci pa nt wi t hdra ws c o nse nt f or discl osur e of  fut ure i nf or m at i on, t he s p o ns or m a y retai n 
a n d c o nt i n ue t o use a n y data c ollecte d bef ore s uc h a wit h dra wal o f c o nse nt . If a partici pa nt
wi t hdra ws fr o m t he st u d y, he/s he ma y re q uest destr uctio n of  a n y sa mples ta ke n a n d n ot teste d ,
a n d t he i n vest i gat or m ust d oc u me nt t his i n t he site st u d y rec or ds.
7. 3.
L ost t o F oll o w - u p
A partici pa nt will be c o nsi dere d l ost t o f oll o w -u p if  he or s he re peate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d b y t he st u d y sit e. Si te pers o n nel or desi g nee are 
e x pecte d t o ma ke dili ge nt atte m pts t o c o ntact partici pa nts w h o f ail t o ret ur n f or a sc he d ule d visit 
or were ot her wise u na ble t o be f o ll owe d u p b y t he site.
Di sc o nti n uatio n of  s pecific sites or of t he st u d y as a w h ole are ha n dle d as part of Secti o n 1 0. 1 .

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
2 8
8.
St u d y Assess me nts a n d Pr oce d ures
St u d y  pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he S o A ( Sectio n 1. 3 ).
I mme diate safety c o ncer ns s h o uld be disc usse d wit h t he s p o ns or i m me diatel y  u p o n occ urre nce or 
a ware ness t o deter mi ne if t he partici pa nt s h o ul d c o nt i n ue or disc o nti n ue st u d y i nter ve nt i on.
A d here nce t o t he st u d y  desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A, is esse nt ial 
a n d re q uire d f or st u d y c o n d uct.
All scree ni n g e val uati ons m u st be c o mplete d a n d re vie we d t o c o nfir m t hat p ote nti al part ici pa nts 
meet all eli gi bilit y criteria. T he i n vesti gat or will mai ntai n a scree ni n g l o g t o rec or d details of a ll 
parti ci pa nt s scree ne d a n d t o c o nfir m eli gi bilit y or rec or d reas o ns f or sc ree ni n g fail ure, as 
a p plica ble.
T he s pecificat i ons i n t his pr ot oc ol f or t he ti mi n gs of safety a n d sa m ple c o llecti on are gi ve n as 
tar gets t o be ac hie ve d withi n reas o na ble li mits. M o dificat i ons ma y be ma de t o t he ti me p o i nts 
base d u p o n e mer gi n g cli nical i nf or mat i on. T he sc he d ule d t i me p oi nts ma y be s u bject t o mi n or 
alt er atio ns; h o we ver, t he act ual ti me m ust be c orrectl y  rec or de d i n t he electr o nic C R F ( e C R F). 
Fail ure or bei n g late (t hat is, o utsi de sti p ulate d ti me all o wa nces) t o perf or m pr oce d ures or o btai n 
sa m ples d ue t o le giti mate cli nical iss ues (s uc h as e q ui p me nt tec h nical pr o ble ms, ve n o us access 
diffic ult y, or partici pa nt defa ult i n g or t ur ni n g u p late o n a n a gree d sc he d ule d pr oce d ure) will n ot 
be c o nsi dere d as pr ot oc ol de viat i ons b ut t he C R U will st ill be re q uire d t o n otif y t he s p o ns or i n 
wri ti n g via a file n ote.
A p pe n di x 2 ( Secti o n 1 0. 2 ) lists t he la b orat or y tests t hat will be perf or me d f or t his st u d y.
A p pe n di x 2 ( Secti o n 1 0. 2. 1 ) pr o vi des a s u m mar y of t he ma xi m u m n u m ber a n d v ol ume of 
i n vasi ve sa m ples, f or all sa m pli n g, d uri n g t he st u d y.
U nless ot her wise state d i n s u bsect i ons bel o w , all sa mples c ollecte d f or s pecifie d la b orat or y  tests 
will be destr o y e d wit hi n 6 0 da ys of recei pt of c o nfir me d test res ults. Certai n sa m ples ma y be 
retai ne d f or a l o n ger peri o d, if necessar y, t o c o mpl y  wit h a p plica ble la ws, re g ulati ons, or 
la b orat or y certificati o n sta n dar ds.
8. 1.
Effic ac y Assess me nts
Efficac y is n ot e val uate d i n t his st u d y .
8. 2.
S afet y Assess me nts
Pl a n ne d ti me p o i nts f or all safety assess me nts are pr o vi de d i n t he S o A ( Secti o n 1. 3 ).
8. 2. 1.
P h ysic al E x a mi n ati o ns
C o m plete p h ysical  e xa mi nati ons or s y m pt o m -di recte d p h ysical e xa mi nati ons will be c o n d ucte d 
at t he ti me p oi nts s pecifie d i n Sect i on 1. 3 . S y m pt o m-di recte d p h ysical e xa mi nati ons m a y be 
c o n d ucte d, as deter mi ne d b y t he i n vesti gat or, if a partici pa nt prese nts wit h c o m plai nts. A 
c o mplete p h ysical e xa mi nat i on will i ncl u d e, at a mi ni m u m, assess me nts of t he:

ge neral a p peara nce

hea d

e yes

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
2 9

ears/ n ose/ m o ut h/t hr oat 

nec k

he mat ol o gi c/l y m p hat ic

car dio vasc ular

res pir at or y

gastr oi ntesti nal

e xtre mit ies

i nte g u me ntar y, a n d

ne ur o l ogi cal s yste ms.
H ei g ht a n d wei g ht will  als o be meas ure d a n d rec or de d at t he ti me p oi nts s pecifie d i n Secti on 1. 3 .
8. 2. 2.
Vit al Si g ns
F or eac h parti ci pa nt , vit al sig ns me as ure me nts s h o ul d be c o n d ucte d acc or di n g t o t he S o A
( Sectio n 1. 3 ).
Bl o o d press ure a n d p ulse rate s h o ul d be meas ure d after at least 5 mi n utes sitti n g.
U nsc he d ule d ort h ostatic vital si g ns s h o ul d be assesse d, if p ossi ble, d uri n g a n y A E of dizzi ness or 
p ost ure -i n d uce d s y m pt o ms. A d diti onal vit al si g ns ma y be meas ure d d uri n g t he st u d y, if 
warra nte d.
If ort h ostatic meas ure me nts are re q uire d, partici pa nts sh o ul d be s u pi ne f or at l east 5 mi n utes a n d 
sta n d f or at least 3 mi n utes.
If t he partici pa nt feels u na ble t o sta n d, s u pi ne vital si g ns o nl y will be rec or de d.
8. 2. 3.
Electr oc ar di o gr a ms
All E C Gs s h o ul d be ta ke n after a n a p pr o xi mate 5- t o 1 0-mi n ute rest i n t he s u pi n e p ositio n.
Si n gle 1 2 -lea d E C Gs will be o btai ne d as o utli ne d i n t he S o A (see Secti o n 1. 3 ) usi n g a n E C G 
mac hi ne t hat a ut o mat icall y calc ulates t he heart rate a n d meas ures P R, Q R S, a n d Q T i nter vals.
F or eac h partici pa nt, a si n gle 1 2- lea d di gital E C G will be c ollecte d acc or di n g t o t he S o A . 
Electr ocar di o gra ms m ust be rec or de d bef ore c ollecti n g a n y bl o o d sa m ples. Partici pa nts m ust be 
s u pi ne f or a p pr o xi matel y 5 t o 1 0 mi n utes bef ore E C G c ollecti on a n d re m ai n s u pi ne b ut a wa ke 
d uri n g E C G c ollect i on. El ectr ocar dio gr a m s ma y be o btai ne d at a d diti onal t i mes, w he n dee me d 
cli nicall y necessar y. All E C Gs rec or de d s h o uld be st ore d at t he i n vest i gati onal site.
Electr ocar di o gra ms will be i nter prete d b y  a q ualifie d i n vesti gat or (t he i n vesti gat or or q ualifie d 
desi g nee) as s o o n after t he ti me of E C G c olle ct i on as p ossi ble, a n d i deall y w hile t he partici pa nt 
is still prese nt, t o deter mi ne w het her t he partici pa nt meets e ntr y criteria at t he rele va nt visit(s) 
a n d f or i m me diate partici pa nt ma na ge me nt, s h o ul d a n y cli nicall y rele va nt fi n di n gs be i de ntifie d.
If a cli nicall y si g nifica nt fi n di n g is i de nt ifie d (i ncl u di n g, b ut n ot li mite d t o, c ha n ges i n Q T/ Q Tc 
i nter val fr o m baseli ne) after e nr oll me nt, t he i n vesti gat or will deter mi ne if t he partici pa nt ca n 
c o nti n ue i n t he st u d y. T he i n vesti gat or, or q ualifie d desi g nee, is res p o nsi ble f or deter mi ni n g if 
a n y c ha n ge i n part ici pa nt ma na ge me nt is nee de d, a n d m ust d oc u me nt his/ her re vie w of t he E C G 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
3 0
pri nte d at t he ti me of c o llecti on. A n y ne w cli nicall y rele va nt fi n di n g s h o ul d be re p orte d as a n 
A E .
8. 2. 4.
Cli nic al S afet y L a b or at or y Ass ess me nts
See A p pe n di x 2 ( Sectio n 1 0. 2 ) f or t he list of cli nical la b orat or y tests t o be perf or me d a n d t he 
S o A (Secti o n 1. 3 ) f or t he ti mi n g a n d fre q ue nc y.
P arti cipa nts will be faste d o ver ni g ht (at least 8 h o urs) bef ore c ollect i on of bl o o d sa m ples f or 
cli nical safet y la b orat or y tests.
T he i n vest i gat or m ust re vie w the la b orat or y res ults, d oc u me nt t his re vie w, a n d re p ort a n y 
cli nicall y rele va nt c ha n ges occ urri n g d uri n g t he st u d y as a n A E . T he l a b orat or y res ults must be 
retai ne d wit h s o urce d oc u me nts u nless a S o urce D oc u me nt A gree me nt or c o mpara ble d oc u me nt 
cites a n ele ctr o nic lo c ati o n t hat acc o m m o dates t he e x pecte d rete nti o n d urati o n. Cli nicall y 
sig nifica nt a b n or m al la b orat or y fi n di n gs are t h ose w hic h are n ot ass ociate d wit h t he u n derl yi n g 
di sease, u nless j u d ge d b y t he i n vesti gat or t o be m ore se vere t ha n e x pecte d f or the partici pa nt's 
c o n ditio n.
All la b orat or y tests wit h val ues c o nsi dere d cli nicall y si g nifica ntl y a b n or mal d uri n g partici pat i on 
i n t he st u d y s h o uld be re peate d u ntil t he val ues ret ur n t o n or mal or baseli ne or are n o l o n ger 
c o nsi dere d cli nicall y si g nifica nt b y t he i n vesti gat or or me dical m o nit or.

If s uc h val ues d o n ot ret ur n t o n or mal/ baseli ne withi n a perio d of  ti me j u d ge d reas o na ble 
b y t he i n vesti gat or, t he eti o l og y s h o ul d be i de ntifie d a n d t he s p o ns or n otifie d.

All pr ot oc ol -re q uire d la b orat or y assess me nts, as defi ne d i n A p pe n di x 2 ( Secti on 1 0. 2 ), 
m ust be c o n d ucte d i n acc or da nce wit h t he S o A, sta n dar d c ollecti o n re q uire me nts, a n d 
la b orat or y ma n ual.
If la b orat or y val ues fr o m n o n- pr ot oc ol  s pecifie d la b orat or y assess me nts perf or me d at a n
i n vesti gat or-desi g nate d l ocal la b orat or y re q uire a c ha n ge i n partici pa nt ma na ge me nt or are 
c o nsi dere d cli nicall y si g nifica nt b y t he i n vestigat or (e. g., S A E or A E or d ose m o dificati o n), t he n
re p ort t he i nf or mati o n as a n A E.
8. 2. 4. 1.
T u berc ul osis Testi n g
P arti cip a n ts will be teste d as i n dicate d i n t he S o A ( Secti o n 1. 3 ) for e vi de nce of acti ve or late nt 
T B usi n g t he Q ua nt i F E R O N T B G ol d test. If t he test is i n deter mi nate, 1 retest is all o we d. If t he 
retest is i n deter mi nate, t he partici pa nt will be e xcl u de d fr om t he st u d y.
P arti cipa nts w h o ha ve ha d h o use h ol d c o ntact wit h a pers o n wit h act i ve T B m ust be e xcl u de d, 
u nless a p pr o priate a n d d oc u me nte d pr o p h yla xis treat me nt  for T B has bee n c o m plete d.
P arti cip a nts wi t h a n y hist or y of acti ve T B are e xcl u de d fr om t he st u d y, re gar dless of pre vi o us or 
c urre nt T B treat me nts.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
3 1
8. 2. 5.
Ot her Tests
8. 2. 5. 1.
I njecti o n-Site Re acti o ns
Alt h o u g h t here will be n o pr os pecti ve c ollect i on of I S R i nf or mat i on, s p o nta ne o usl y re p orte d 
I S Rs b y t he partici pa nt will be rec or de d as A Es, with t he I S R eC R F use d t o c ollect s u p ple me ntal 
data o n t he f o ll owi n g s pecific fi n di n gs: 

i n d urati o n

pai n

e de ma

pr uri t us, a n d 

er yt he ma.
T he fi n di n gs of I S R f or a s pecific i njecti o n wi ll be ca pt ure d as a si n gle A E of I S R, if 1 or mor e 
t ha n 1 of t he fi n di n gs is p osit i ve, a n d t he se verity t hat is rec or de d o n t he I S R A E f or m will be t he 
hi g hest se verit y acr oss t he fi n di n gs at eac h a p plica ble visit.
If i njecti on- site pai n is re p orte d at a n y time d uri n g t he st u d y , t he i nte nsity of  pai n will be 
q ua nt ifie d usi n g t he 1 0 0-m m vali date d pai n vi s ual a nal o g scale (V A S ). T he V A S is a well 
vali date d t o ol ( Willia ms o n a n d H o g gart 2 0 0 5) t o assess i njecti o n -site pai n; it is prese nte d as a 
1 0 0- m m li ne a nc h ore d b y ver bal d es cript ors, us uall y  “ n o pai n” a n d “ w orst i ma gi na ble pai n.” T he 
parti ci pa nt will be as ke d t o rate a n y pai n at t he i njectio n -site o n a scale of 0 t o 1 0 0 o n t he li ne as 
s o o n as is practical f oll o wi n g re p orti n g of t he e ve nt.
I njecti on -sit e assess me nts s h o ul d be c o n d ucte d at t he ne xt pla n ne d visit f o ll owi n g t he re p orti n g 
of  a n i njecti on- r elate d A E.
8. 2. 5. 2.
Blee di n g/ Br uisi n g Assess me nt
T here will be n o pr os pecti ve c o llecti on of I S R i nf o r mat i on; t he prese nce of visi ble 
blee di n g/ br uisi n g at t he i njecti o n- site will be rec or de d o n t he e C R F as a p plica ble a n d will be 
rec or de d as a n A E if j u d ge d t o be m ore se vere t ha n e x pecte d wit h a t ypical  S C a d mi nistratio n. 
A ba n da ge ma y be place d o n t he i nject i on- sit e after assess me nt.
8. 2. 6.
S afet y M o nit ori n g
T he Lill y C P or C R P /scie nt ist will m onit or safet y data t hr o u g h o ut t he c o urse of t he st u d y .
Lill y will re vie w S A Es wit hi n t i me fra mes ma n date d b y c om pa n y pr oce d ures. T he Lill y C P or 
C R P will peri o dicall y re vie w :

tre n ds i n safet y d at a

la b orat or y a nal ytes, a n d 

A Es.
W he n a p p r o priate, t he Lill y C P or C R P will c o ns ult wit h t he f u nct i onall y  in de pe n de nt Gl o bal 
P ati e nt Safet y me dical p h ysicia n or cli nical researc h scie nt ist.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
3 2
8. 2. 6. 1.
He p atic S afet y
Cl ose he pat ic m o nit ori n g
La b orat or y  tests ( Sectio n 1 0. 2 ), i ncl u di n g a la ni ne a mi n otra nsferase (A L T ), as partate 
a mi n otra nsfera se (A S T ), al kali ne p h os p hatase (A L P ), total  bilir u bi n le vel (T B L ), di rect bilir u bi n, 
ga m m a- gl u ta m yl tra nsferase, a n d creati ne k i nase, s h o uld be re peate d wi t hi n 4 8 t o 7 2 h o urs t o 
c o nfir m t he a b n or malit y a n d t o deter mi ne if it is i ncreasi n g or decreasi n g, if o ne or m ore of t hese 
c o n ditio ns occ ur:
If a partici pa nt wit h baseli ne res ults of ... 
de vel o ps t he f oll o wi n g ele vati o ns:
A L T or A S T < 1. 5 x u p per li mit of n or mal ( U L N )
A L T or A S T ≥3 x U L N
A L P < 1. 5 x U L N
A L P ≥2 x U L N
T B L < 1. 5 x U L N
T B L ≥2 x U L N (e xce pt f or patie nts wit h Gil bert’s s y n dr o me)
A L T or A S T ≥1. 5 x U L N
A L T or A S T ≥2 x baseli ne
A L P ≥1. 5 x U L N
A L P ≥2 x baseli ne
T B L ≥1. 5 x U L N
T B L ≥1. 5 x baseli ne (e xce pt f or patie nts wit h Gil bert’s 
s yn dr o me)
If t he a b n or mality persists or w orse ns, cli nical a n d la b orat or y  mo ni t ori n g, a n d e val uati on f or 
p ossi ble ca uses of a b n or mal li ver tests s h o ul d be i nit iate d b y t he i n vesti gat or i n c o ns ultati on wi t h 
t he Lill y-desi g nate d m e dical m o nit or. At a mi ni m u m, t his e va l uati on s h o ul d i ncl u de p h ysical 
e xa mi nat i on a n d a t h or o u g h me dical hist or y , i ncl u di n g s y m pt o ms, rece nt ill nesses (f or e xa m ple, 
heart fail ure, s yste mic i nfect i on, h y p ote nsi o n, or seiz ures), rece nt tra vel, hist or y  of c o nc o mit a nt 
me dicat i ons (i ncl u di n g o ver -the -c o u nter), her bal a n d dietar y s u p ple me nts, hist or y of alc o h o l 
dri n ki n g a n d ot her s u bsta nce a b use. 
I nitiall y, mo ni t ori n g of s y m pt o ms a n d he patic bi oc he mical tests s h o ul d be d o ne at a fre q ue nc y o f 
1 t o 3 ti mes wee kl y , base d o n t he partici pa nt’s cli nical co n di tio n a n d he pat ic bi oc he mical tests. 
S u bse q ue ntl y, t he fre q ue nc y  of mo ni t orin g m a y be lo were d t o o nce e ver y  1 t o 2 wee ks, if t he 
parti ci pa nt’s cli nical c o n dit i on a n d l a borat or y res ults sta bilize. M o nit ori n g of A L T, A S T, A L P, 
a n d T B L s h o ul d c o nti n ue u nt il le vels n or malize or ret ur n t o a p pr o xi mate baseli ne le vels.
C o m pre he nsi ve he patic e val uati o n
A c o m pre he nsi ve e val uat i on s h o ul d be perf or m e d t o searc h f or p ossi ble ca uses of li ver i nj ur y if 
o ne or m ore of t hese c o n dit i ons occ ur:
If a partici pa nt wit h baseli ne res ults of... 
de vel o ps t he f oll o wi n g ele vati o ns:
A L T or A S T < 1. 5 x U L N
A L T or A S T ≥3 x U L N wit h he patic si g ns/s y m pt o ms *, or 
A L T or A S T ≥5 x U L N
A L P < 1. 5 x U L N
A L P ≥3 x U L N
T B L < 1. 5 x U L N
T B L ≥2 x U L N (e xce pt f or patie nts wit h Gil bert’s s y n dr o me)
A L T or  A S T ≥1. 5 x U L N
A L T or A S T ≥2 x baseli ne wit h he patic si g ns/s y m pt o ms *, or
A L T or A S T ≥3 x baseli ne
A L P ≥1. 5 x U L N
A L P ≥2 x baseli ne
T B L ≥1. 5 x U L N
T B L ≥2 x baseli ne (e xce pt f or patie nts wit h Gil bert’s s y n dr o me) 
* He patic si g ns/s y m pt o ms are se vere fati g ue, na usea, v o miti n g, ri g ht u p per q ua dra nt a b d o mi nal pai n, fe ver, ras h, 
a n d/ or e osi n o p hilia > 5 %.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
3 3
At  a mi ni m u m, t his e val uati on s h o ul d i ncl u de p h ysical e xa mi nat i on a n d a t h or o u g h me dical 
hist or y , as o utli ne d a b o ve, as well as tests f or p r ot hr o m bi n ti me-i nter nat i onal n or malize d rat i o; 
tests f or viral he patitis A, B, C, or E; tests f or a ut oi m m u ne he patitis; a n d a n a b d omi nal i ma gi n g 
st u d y (for e xa m ple, ul tras o u n d or c o m p ute d t o m o gra p h y sca n). 
Base d o n t he patie nt’s his t or y a n d i nitial res ults, furt her testi n g s h o ul d be c o nsi dere d i n 
c o ns ultati o n wit h t he Lill y -desi g nate d m e dical mo ni t or, i ncl u di n g tests f or he patitis D vir us, 
c yt o me galo vir us, E pstei n -Barr vir us, aceta mi n o p he n le vels, aceta mi n o p he n pr otei n a d d ucts, 
uri ne t o xic o l og y  scree n, Wils on’s disease, bl o o d alc o h ol le vels, uri nar y et h yl gl uc ur o ni de, a n d 
bl o o d p h os p hat i dylet ha n o l. Base d o n t he circ u msta nces a n d t he i n vesti gat or’s assess me nt of t he 
parti ci pa nt’s cli nical c o n dit i on, t he i n vest i gat or s h o ul d c o nsi der referri n g t he partici pa nt f or a 
he pat ol o gi st or gastr oe nter ol o gist c o ns ultati o n, ma g netic res o na nce c h olan gi o pa ncreat o gra p h y , 
e n d osc o pic retr o gra de c h ola n gi o pa ncreat o gra p h y, c ar diac ec h ocar dio gr a m , or a li ver bi o ps y.
A d diti o n al he p atic d at a c ollecti o n ( he p atic s afet y eC R F) i n st u d y p artici p a nts w h o h a ve 
a b n or m al li ver tests d uri n g t he st u d y 
A d dit i onal he patic safet y data c ollect i on ( he pat ic safety eC R F) s h o ul d be perf or m e d i n st u d y 
parti ci pa nts w h o meet 1 or m ore of t he f o ll owi n g 5 c o n di tio ns:
1.
Ele vat i on of se r u m A L T t o ≥5 x U L N o n 2 or m ore c o nsec uti ve bl o o d tests (if baseli ne 
A L T < 1. 5 x U L N)

I n partici pa nts wit h baseli ne A L T ≥1. 5 x U L N, t he t hres h o l d is A L T ≥3 x baseli ne 
o n 2 or m ore c o nsec uti ve tests
2.
Ele vate d T B L t o ≥2 x U L N (if baseli ne T B L < 1. 5 x U L N) (e xce pt f or cases of k n o w n 
Gil bert’s s y n dr o me)

I n partici pa nts wit h baseli ne T B L ≥1. 5 x U L N, t he t hres h o l d s h o ul d be T B L ≥2 x 
baseli ne
3.
Ele vat i on of ser u m A L P t o ≥2 x U L N o n 2 or m ore c o nsec uti ve bl o o d tests (if baseli ne 
A L P < 1. 5 x U L N)

I n partici pa nts wit h baseli ne A LP ≥1. 5 x U L N, t he t hres h o l d is A L P ≥2 x baseli ne 
o n 2 or m ore c o nsec uti ve bl o o d tests
4.
He pati c e ve nt c o nsidere d t o be a n S A E
5.
Di sc o nti n uatio n of  st u d y dr u g d ue t o a he patic e ve nt .
N ote: t he i nter val bet wee n t he 2 c o nsec uti ve bl o o d tests s h o ul d be at least 2 d a ys.
8. 3.
A d verse E ve nts , Seri o us A d verse E ve nts , a n d Pr o d uct C o m pl ai nts
T he defi nit i ons of t he f o ll owi n g e ve nts ca n be f o u n d i n A p pe n di x 3 ( Sectio n 1 0. 3 ):

A Es

S A Es

Pr o d uct c o m plai nts ( P Cs) .
T hese e ve nts will be re p orte d b y  t he partici pa nt ( or, w he n a p pr o priate, b y a care gi ver, s urr o gate, 
or t he partici pa nt's le gall y a ut h orize d re prese ntati ve).

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
3 4
T he i n vest i gat or a n d a n y q ualifie d desi g nees are res p o nsi ble for detecti n g, d oc u me nti n g, a n d 
rec or di n g e ve nts t hat meet t hese defi niti ons a n d re mai n res p o nsi ble f or f o ll owi n g u p e ve nts t hat 
are serio us, c o nsi dere d relate d t o t he st u d y  int er ve nt i on or st u d y  pr oce d ures, or t hat ca use d t he 
parti ci pa nt t o disc o nti n ue t he st u d y (see Secti o n 7 ).
Care will be ta ke n n ot t o i ntr o d uce bias w he n detecti n g e ve nts. O pe n -e n de d a n d n o n-lea di n g 
ver bal q uest i oni n g of t he partic i pa nt is t he preferre d met h o d t o i n q uire a b o ut e ve nt occ urre nces.
After t he i nit ial re p ort, t he i n vesti gat or is re q uire d t o pr oacti vel y f oll ow eac h partici pa nt at 
s u bse q ue nt visits/c o ntacts. All S A Es will be f o ll owe d u nt il res ol uti on, sta bilizat i on, t he e ve nt is 
ot her wi se e x plai ne d, or t he partici pa nt is l ost t o f oll o w- up (as defi ne d i n Sect i on 7. 3 ). F or P Cs , 
t he i n vest i gat or is res p o nsi ble f or e ns uri n g t hat f oll o w-u p i ncl u des a n y s u p ple me ntal 
i n vesti gati ons as i n di cate d t o eluci date t he nat ure a n d/ or ca usalit y.  Furt her i nf or mati o n o n 
f oll ow -u p pr oce d ures is pr o vi de d i n Sect i on 1 0. 3 .
8. 3. 1.
Ti mi n g a n d Mec h a nis m f or C ollecti n g E ve nts
T h is ta ble descri bes t he ti mi n g, dea dli nes, a n d mec ha nis m f or c ollect i n g e ve nts.
E ve nt
C ollecti o n 
St art
C ollecti o n 
St o p
Ti mi n g f or Re p orti n g 
t o t he S p o ns or or 
D esi g nee
Mec h a nis m f or 
Re p orti n g
B ac k -u p 
Met h o d of 
Re p orti n g
A d verse E ve nt
A E
S i g ni n g of 
t he I C F
P artici pati o n 
i n st u d y has 
e n de d
As s o o n as p ossi ble 
u p o n site a ware ness
A E e C R F
N/ A
Seri o us A d verse E ve nt
S A E a n d S A E 
u p dates – pri or 
t o start of st u d y 
i nter ve nti on a n d
dee me d 
reas o na bl y 
p ossi bl y relate d 
wit h st u d y 
pr oce d ures
S i g ni n g of 
t he I C F
S tart of 
i nter ve nti on
Wit hi n 2 4 h o urs of 
a ware ness
S A E pa per f or m 
S A E pa per 
f or m
S A E a n d S A E 
u p dates – after 
start of st u d y 
i nter ve nti on
S tart of 
i nter ve nti on
P artici pati o n 
i n st u d y has 
e n de d
Wit hi n 2 4 h o urs of 
a ware ness
S A E pa per f or m
S A E pa per 
f or m

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
3 5
E ve nt
C ollecti o n 
St art
C ollecti o n 
St o p
Ti mi n g f or Re p orti n g 
t o t he S p o ns or or 
D esi g nee
Mec h a nis m f or 
Re p orti n g
B ac k -u p 
Met h o d of 
Re p orti n g
S A E – after 
partici pa nt’s 
st u d y 
partici pati o n has 
e n de d a n d t he 
i n vesti gat or 
bec o mes a ware
After 
partici pa nt’s 
st u d y 
partici pati o n 
has e n de d
N/ A
Pr o m ptl y
S A E pa per f or m
N/ A
Pre g n a nc y
Pre g na nc y i n 
fe male 
partici pa nts a n d 
fe male part ners 
of male 
partici pa nts
After t he 
start of st u d y 
i nter ve nti on
8 4 da ys 
p ost d ose 
( Da y 8 5)
Wit hi n 2 4 h o urs of 
lear ni n g of t he 
pre g na nc y
Pre g n a nc y pa per 
f or m
S A E pa per 
f or m
Pr o d uct C o m pl ai nts
P C ass ociate d 
wit h a n S A E or 
mi g ht ha ve le d 
t o a n S A E
Start of st u d y 
i nter ve nti on
E n d of st u d y 
i nter ve nti on
Wit hi n 2 4 h o urs of 
a ware ness
Pr o d uct C o m plai nt 
f or m
N/ A
P C n ot 
ass ociate d wit h 
a n S A E
Start of st u d y 
i nter ve nti on
E n d of st u d y 
i nter ve nti on
Wit hi n 1 b usi ness da y 
of a ware ness
Pr o d uct C o m plai nt 
f or m
N/ A
U p date d P C 
i nf ormati o n
—
—
As s o o n as p ossi ble 
u p o n site a ware ness
Ori gi nall y 
c o m plete d Pr o d uct 
C o m plai nt f orm 
wit h all c ha n ges 
si g ne d a n d date d b y 
t he i n vesti gat or
N/ A
P C (if 
i n vesti gat or 
bec o mes a ware)
Partici pati o n 
i n st u d y has 
e n de d
N/ A
Pr o m ptl y
Pr o d uct C o m plai nt 
f or m
A b bre viati o ns: A E = a d verse e ve nt; e C R F = electr o nic case re p ort f or m; I C F = i nf or me d c o nse nt f or m; P C = 
pr o d uct c o m plai nt; S A E = seri o us a d verse e ve nt

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
3 6
8. 3. 2.
A d verse E ve nts of S peci al I nterest 
T he f o ll owi n g A Es of s pecial i nterest will be use d t o deter mi ne t he safet y a n d t olera bilit y of 
mir i kiz u ma b a d mi nistere d t hr o u g h P F S or AI i n t his cli nical st u d y:

i nfecti on

s yste mic aller gic/ h y perse nsiti vity reacti ons.
If i nfecti o ns or aller gic/ h y perse nsiti vity reacti ons are re p orte d, site staff will pr o vi de details o n 
t hese e ve nts as i nstr ucte d o n t he e C R F. A P K, i m m u n o ge nicit y,  a n d h y perse nsitivit y c yt o ki ne 
pa nel ( A p pe n di x 7, Secti o n 1 0. 7 ) will be c ollecte d w he n p ossi ble f or a n y partici pa nt w h o 
e x perie nces a n A E of s yste mic aller gic/ h y perse nsiti vit y reacti on d uri n g t he st u d y .
8. 4.
Tre at me nt of O ver d ose
F or t hi s st u d y, a n y d ose of  mir i kiz u ma b greater t ha n t he i nte n de d d ose of 3 0 0 m g will  be 
c o nsi dere d a n o ver d ose.
T he s p o ns or d oes n ot rec o m me n d s pecific treat me nt f or a n o ver d ose.
I n t he e ve nt of a n o ver d ose, t he i n vesti gat or s h o ul d:
1.
C o ntact t he m e dical m o ni t or i m me diatel y.
2.
Cl os el y  mo ni t or t he partici pa nt f or a n y A E/ S A E a n d la b orat or y a b n or malities u nt il n o 
l on ger has a cli nical effect or ca n n o l o n ger be detecte d s yste micall y at least 8 4 d a y s
p ost d ose ( Da y  8 5). Refer t o Secti o n 8. 3 f or re p orti n g details.
3.
D oc u m e nt t he q ua ntit y of t he e xcess d ose as well as t he d urati o n of t he o ver d ose i n t he 
eC R F.
Decisi o ns re gar di n g d ose i nterr u pti o ns or m o dificati o ns will be ma de b y t he i n vesti gat or i n 
c o ns ultati o n wit h t he m e dical m o ni t or base d o n t he cli nical e val uati o n of t he partici pa nt.
8. 5.
P h ar m ac o ki netics
Bl o o d sa m ples of a p pr o xi matel y 3 m L will be c ollecte d f or meas ure me nt of ser u m
c o nce ntrati o ns of mir i kiz u ma b as s pecifie d i n t he S o A ( Secti o n 1. 3 ).
A ma xi m u m of 3 sa m ples ma y be c ollecte d at a d diti o nal t i me p oi nts d uri n g t he st u d y if 
warra nte d a n d a gree d u p o n bet wee n t he i n ves tigat or a n d t he s p o ns or. T he ti mi n g of sa m pli n g
ma y be altere d d uri n g t he c o urse of t he st u d y  base d o n ne wl y a vaila ble data (e. g., t o o btai n data 
closer t o t he ti me of pea k ser u m c o nce ntratio ns) t o e ns ure a p pr o priate m o nit ori n g. 
I nstr uctio ns f or t he c olle ct i on a n d ha n dli n g of bi o l o gical sa m ples will be pr o vi de d b y t he 
s p o ns or. T he act ual date a n d ti me ( 2 4- h o ur cl oc k ti me) of eac h sa m ple will be rec or de d.
8. 5. 1.
Bi o a n al ysis
S a m ples will  be a nal yze d at a la b orat or y a p pr o ve d b y t he s p o ns or a n d st ore d at a facility 
d esi g nate d b y t he s p o ns or.
C o nce ntrati o ns of miri kiz u ma b will be assa ye d usi n g a vali date d e nz y me -li n ke d i m m u n os or be nt 
assa y met h o d. 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
3 7
Bi oa nal y tic al sa m ples c ollecte d t o meas ure miriki z u m a b c o nce ntratio ns will be retai ne d f or a 
ma xi m u m o f 1 year f oll owi n g t h e last participa nt visi t for t he st u d y . D uri n g t his ti me, sa m ples 
r e mai ni n g after t he bi oa nal yses ma y be use d f or e x plorat or y  a nal yses s uc h as meta b olis m w or k, 
pr otei n bi n di n g, a n d/ or bi oa nal yt ical met h o d cr oss-vali dat i on.
8. 6.
P h ar m ac o d y n a mics
P har mac o d y na mic para meters a re n ot e val uate d i n t his st u d y.
8. 7.
Ge netics
A bl o o d sa mpl e f or D N A i s olati on will be c ollecte d fr o m parti ci pa nts as s pecifie d i n t he S o A
(Secti o n 1. 3 ).
See A p pe n di x 5 ( Secti o n 1 0. 5 ) for i nf or mati o n re gar di n g ge netic researc h . 
8. 8.
Bi o m ar kers
Bi o m ar kers are n ot e valuate d i n t hi s st u d y.
8. 9.
I m m u n o ge nicit y Assess me nts
At  t he visits a n d ti mes s pecifie d i n t he S o A (Secti o n 1. 3 ), ve n o us bl o o d sa m ples of 
a p pr o xi matel y 1 0 m L eac h will be c ollecte d t o deter mi ne a nti b o d y pr o d uctio n a gai nst 
mir i kiz u ma b. T o i nter pret t he resul ts of im m u n o ge nicit y,  ve n o us bl o o d sa m ples will be c o llecte d 
at t he sa me ti me p o i nts t o deter mi ne t he ser u m c o nce ntrati o ns of miri kiz u ma b. I nstr uctio ns f or 
t he c ollect i on a n d ha n dli n g of bl o o d sa m ples will be pr o vi de d b y t he s p o ns or. T he act ual date 
a n d ti me ( 2 4-h o ur cl oc k ti me) of eac h sa m pli n g will be rec or de d.
Treat me nt -e mer ge nt A D As are defi ne d i n Sect i on 2. 2. 3 .
I mm u n o ge nicit y will  be assesse d usi n g a vali date d assa y desi g ne d t o detect A D As i n t he 
prese nce of miri kiz u ma b at a la b orat or y  a p pr o ve d b y t he s p o ns or. A nti b o dies will be e val uate d 
f or t h eir a bilit y t o ne utralize t he acti vity of  miri kiz u ma b.
S a m ples will  be retai ne d f or a ma xi m u m of 1 5 years after t he last partici pa nt visit, or f or a 
s h orter peri o d if l ocal re g ulat i ons a n d inst itut i onal re vie w b o ar d s (I R Bs)/i n de pe n de nt et hics 
c o m mittees (I E Cs) all o w, at a facilit y selecte d b y t he s p o ns or. T he d urati o n all o ws t he s p o ns or t o 
res p o n d t o f ut ure re g ulat or y re q uests relate d t o mir i kiz u ma b. A n y sa m ples re mai ni n g after 
1 5 years will be destr o y e d.
8. 1 0.
He alt h Ec o n o mic s
T his sect i on is n ot a p plica ble f or t his st u d y. 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
3 8
9.
St atistic al C o nsi der ati o ns
T he stati stical a nal ysis pla n ( S A P) will be fi nalize d pri or t o first partici pa nt first visit a n d it will 
i ncl u de a m ore tec h nical a n d detaile d descri pti on of t he statist ical a nal yses descri be d i n t his 
secti on. T his sect i on is a s u m mar y of t he pla n ne d statistical a nal yses of t he m ost i m p orta nt 
e n d p o i nts i ncl u di n g pri mar y a n d k e y  sec o n dar y e n d p oi nts.
9. 1.
St atistic al H y p ot heses
T he pri mar y  o bjecti ve of t his st u d y is t o e valuate P K f o ll owi n g a d mi nistrati o n usi n g P F S a n d AI.
9. 2.
A n al yses Sets
F or t he p ur p oses of a nal ysis, t he f o ll owi n g p o p ul atio n s are defi ne d:
P o p ul ati o n
Descri pti o n
E nr olle d
All partici pa nts ra n d o ml y assi g ne d t o st u d y  int er ve nt i on.
S af et y
All partici pa nts ra n d o ml y assi g ne d t o st u d y  i nter ve nt i on a n d w h o 
recei ve st u d y i nter ve nt i on . P artici pa nts will be a nal yze d 
acc or di n g t o t he i nter ve nt i on t he y act uall y recei ve d.
P ha r mac o ki net ic A nal ysis
All e nr olle d partici pa nts w h o recei ve a f ull d ose of st u d y  
i nter ve nt i on a n d ha ve e val ua ble P K data .
9. 3.
St atistic al A n al yses
Stati stical a nal ysis of t his st u d y will be t he res p o nsi bilit y of  t he sp o ns or or i ts desig nee.
P har mac o ki net ic a nal yses will be c o n d ucte d o n data fr om all partici pa nts w h o recei ve at least a 
f ull d ose of t he i n vest i gati onal pr o d uct a n d ha ve e val ua ble P K data .
S af et y a nal yses will be c o n d ucte d f or all e nr o lle d partici pa nts w h o recei ve d st u d y i nter ve ntio n, 
w het her or n ot t he y  c o mplete d all pr ot oc ol re q uire me nts.
A d dit i onal e x plor at or y  a nal yses of t he data will be c o n d ucte d as dee me d a p pr o priate. St u d y 
res ults ma y be p o ole d wit h t he res ults of ot her st u dies f or safety a n d p o p ulat i on P K a nal ysis 
p ur p oses t o a v oid iss ues wi t h p ost-h oc a nal yses a n d i nc o m plete discl os ures of a nal yses.
9. 3. 1.
Ge ner al C o nsi der ati o ns
Data list i n gs will be pr o vi de d f or all data t hat are data base d. Data listi n gs will be pr o vi de d f or all 
parti ci pa nts u p t o t he p oi nt of wit h dra wal, wit h a n y partici pa nts e xcl u de d fr o m t he rele va nt 
p o p ul at i on hi g hli g hte d.
S u m mar y  statistics a n d statistical a nal ysis will o nl y be prese nte d f or data w here detaile d i n t he 
S A P. S u m mar y statist ics a n d statistical a nal yses will ge nerall y o nl y be perf or me d f or 
parti ci pa nts i ncl u de d i n t he rele va nt a nal ysis p o p ulati o n. F or t he calc ulat i on of s u m mar y  
statistics a n d statistical a nal ysis, u nr o u n de d data will be use d.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
3 9
9. 3. 2.
P h ar m ac o ki netic A n al yses
9. 3. 2. 1.
P h ar m ac o ki netic P ar a meter Esti m ati o n
P har mac o ki net ic para meter esti mates f or miri kiz u ma b will be calc ulate d usi n g sta n dar d 
n o nc o m part me nt al met h o ds of a nal ysis.
T he pri mar y para meters f or a nal ysis will be t he C m a x , A U C( 0-∞), a n d A U C fr o m ti me zer o t o 
ti me t, w here t is t he last ti me p oi nt wi t h a meas ura ble c o nce ntratio n ( A U C[ 0-tlast]) of  
mir i kiz u ma b. T he sec o n dar y para meter f or a nal ysis will be t he tma x of  miri kiz u ma b. Ot her 
n o nc o m part me nt al para meters, s uc h as half-life ass ociate d wit h t he ter mi nal rate c o nsta nt (t1/ 2), 
a p pare nt t otal b o d y cleara nce of dr u g calc ulate d after e xtra-vasc ular a d mi nistrati o n ( C L/ F), a n d 
a p pare nt v ol u me o f distri b ut i on d uri n g t he ter mi nal p hase after e xtra -vasc ular a d mi nistrati o n 
( Vz/ F), ma y be re p orte d. Wei g ht -n or malize d P K para m eter esti mates ma y be e x pl ore d if dee me d 
a p pr o priate.
9. 3. 2. 2.
P h ar m ac o ki netic St atistic al I nfere nce
T he C m a x , A U C( 0-∞), a n d A U C( 0 -tlast) will be l og- tra nsf or me d a n d a nal yze d usi n g a li near 
fi xe d-effects mo d el . T he mo d el  will i ncl u de deli ver y de vice, i njecti on l ocatio n, a n d wei g ht 
stratificati on as fi xe d -effects. T he d osi n g re gi me n d iffere nces bet wee n AI a n d P F S 
a d mi nistrati o ns will be bac k -tra nsf or me d t o prese nt t he ratios of  ge o metric L S mea ns a n d t he 
c orres p o n di n g 9 0 % CI. C o m paris o ns will be ma de bet wee n t he 2 deli ver y de vices a n d t he n 
bet wee n t he 3 i nject i on l ocat i ons.
T he 2 deli v er y de vices will be c o nsi dere d bi oe q ui vale nt if t he 9 0 % CIs of t he rati o of ge o metric 
L S mea ns fall wit hi n 0. 8 t o 1. 2 5. 
T he t ma x of  miri kiz u ma b bet wee n AI a n d P F S a d mi nistrati o ns will be a nal yze d usi n g a Wilc o x o n 
ra n k s u m test. Esti mates of t he me dia n differe nce, 9 0 % CIs, a n d p-val ues fr o m t he Wilc o x o n 
ra n k s u m test will be calc ulate d.
A d dit i onal P K a nal yses ma y be c o n d ucte d if dee me d a p pr o priate.
9. 3. 3.
S afet y A n al yses
9. 3. 3. 1.
Cli nic al E v al u ati o n of S afet y
All st u d y int er ve nt i on a n d pr ot oc ol pr oce d ure A Es a n d P Cs will b e liste d, a n d, if t he fre q ue nc y 
of  e ve nts all o ws, safety data will be s u m marize d usi n g descri pt i ve met h o d ol o g y .
T he i nci de nce of s y m pt o ms f or eac h treat me nt will be prese nte d b y  se verit y a n d b y ass ociat i on 
wi t h st u d y int er ve nt i on as percei ve d b y t he i n vest i gat or. S y m pt o ms re p orte d t o occ ur pri or t o 
st u d y e ntr y will b e disti n g uis he d fr o m t h ose re p orte d as ne w or i ncrease d i n se verity d uri n g t he 
st u d y. Eac h s y m pt o m will be classifie d b y t h e most s ui ta ble ter m fr o m t h e me dical re g ulat or y 
di ct i onar y .
T he n u m ber of  st u d y int er ve nt i on- a n d de vice-relate d S A Es a n d a n y relate d P Cs will be re p orte d.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
4 0
9. 3. 3. 2.
St atistic al E v al u ati o n of S afet y
S af et y para m eters t hat will be assesse d i ncl u de cli nical la b orat or y para meters a n d vital si g ns. 
T he para meters a n d c ha n ges fr o m baseli ne ( pre d ose), w here a p pr o priate, will be liste d a n d 
s u m marize d usi n g sta n dar d descri pt i ve statistics. A d diti onal a nal yses will be perf or me d if 
warra nte d u p o n re vie w of t he data.
9. 3. 4.
Ot her A n al yses
9. 3. 4. 1.
I njecti o n-site Assess me nts
If a vaila ble, a n y inci de nce o f er yt he ma, i n d urat i on, pai n, pr urit us, e de ma, blee di n g, a n d br uisi n g 
will be liste d.
9. 3. 4. 2.
E v al u ati o n of I m m u n o ge nicit y
Res ults fr o m i m m u n o ge nicity testi n g will be liste d. T he fre q ue nc y a n d perce nta ge of partici pa nts 
wi t h pree xist i n g A D As a n d wit h T E -A D As t hat ar e p ositive ( T E -A D A +) t o miri kiz u ma b will be 
ta b ulate d. Treat me nt - e mer ge nt A D As are defi ne d as t h ose wit h a titer 2-f ol d ( 1 dil uti on) or 
greater t ha n t he mi ni m u m re q uire d dil ut i on if n o A D As were detecte d at baseli ne 
(treat me nt-i n d uce d A D A) or t h ose wit h a 4- f ol d or greater ( 2 dil uti o ns) i ncrease i n titer 
c o mpare d t o baseli ne if A D As were detecte d at baseli ne (treat me nt -b o oste d A D A). F or t he 
T E -A D A + partici pa nts, t he distri b ut i on of ma xi m u m t iters will be descri be d. T he fre q ue nc y o f 
ne utralizi n g a nt i b o dies will als o be ta b ulate d i n T E-A D A + partici pa nts.
T he rel at i ons hi p bet wee n t he prese nce of a nt i b o dies a n d P K a n d safety para meters of 
mir i kiz u ma b ma y be assesse d.
9. 4.
I nteri m A n al ysis 
N o i nteri m a nal ysis is pla n ne d.
9. 5.
S a m ple Size Deter mi n ati o n
U p t o a p pr o xi matel y  2 4 0 participa nts ma y  be e nr olle d s o t hat a p pr o xi matel y 2 1 6 participa nts 
( 1 0 8 i n t he P F S [refere nce] gr o u p a n d 1 0 8 i n t he AI [test] gr o u p) c o m plete t he st u d y. 
A sa m ple size o f 1 0 8 partici pa nts per treat me nt gr o u p will pr o vi de a p pr o xi mat el y 9 0 % p o wer 
t hat t he 9 0 % CI of t he ge o metric mea n rati o of C m a x a n d A U C bet wee n gr o u ps will fall wit hi n 
e q ui vale nce ra n ge of 0. 8 t o 1. 2 5. T his sa m ple size calc ulat i on was base d o n t he ass u m pt i ons t hat 
t he P K para meters ha ve l o g -n or m al distri b uti on, t he p erce nt c o efficie nt of variati o n ( C V ) of  
C m a x a n d A U C are a p pr o xi matel y 4 0 % ( base d o n pre vi o us trials), t he e x pecte d rati o of 
ge o m etric mea ns is 1. 0 7, a n d t he perce nt C V are t he sa me f or partici pa nts fr o m eac h treat me nt 
gr o u p.
P arti cipa nts w h o are ra n d o mize d b ut n ot a d mi nistere d treat me nt a n d partici pa nts w h o d o n ot 
c o mplete P K sa m pli n g t hr o u g h Da y  8 5 ma y be re place d t o e ns ure t hat a p pr o xi matel y  
2 1 6 partici pa nts ( 1 0 8 i n eac h gr o u p) c o m plete t he st u d y.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
4 1
1 0.
S u p p orti n g D oc u me nt ati o n a n d O per ati o n al C o nsi der ati o ns
1 0. 1.
A p pe n di x 1: Re g ul at or y, Et hic al, a n d St u d y O versi g ht 
C o nsi der ati o ns
1 0. 1. 1.
Re g ul at or y a n d Et hic al C o nsi der ati o ns
T his st u d y  will be c o n d ucte d i n acc or da nce with t he pr ot oc ol a n d wit h t he f o ll owi n g:

C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes i ncl u di n g t he 
Declarati o n of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizat i ons of Me dical Scie nces 
I nter nati o nal Et hical G ui deli nes

A p plica ble Int er nat i onal C o u ncil f or Har m o nisati o n (I C H) go o d cli nical p r a ctic e ( G C P)
G ui deli nes

A p plica ble la ws a n d re g ulati o ns .
T he pr ot oc ol, pr ot oc ol a me n d me nts, I C F, I B, a n d ot her rele va nt d oc u me nts (f or e xa m ple, 
a d vert ise me nts) m ust be s u b mitte d t o a n I R B/I E C b y t he i n vesti gat or a n d re vie we d a n d a p pr o ve d 
b y t he I R B/I E C bef ore t he st u d y is i nit iate d.
A n y a me n d me nts t o t he pr ot oc ol will re q uire I R B/I E C a p pr o val bef ore i m ple me ntati o n of 
c ha n ges ma de t o t he st u d y desi g n, e xce pt f or c ha n ges necessar y t o eli mi nate a n i m me diate 
hazar d t o st u d y  p artici pa nts.
Pr ot oc ol s a n d a n y s u bsta ntial a me n d me nts t o t he pr ot oc ol will re q uire heal t h a ut h orit y a p pr o val 
pri or t o i nit iati on e xce pt f or c ha n ges necessar y t o eli mi nate a n i m me diate hazar d t o st u d y  
parti ci pa nts.
T he i n vest i gat or will be res p o nsi ble f or t he f oll owi n g:

Pr o vi di n g wri tte n s u m maries of t he stat us of t he st u d y t o t he I R B/I EC a n n uall y or m ore 
fre q ue ntl y i n acc or da nce wit h t he re q uire me nts, p olicies, a n d pr oce d ures esta blis he d b y 
t he I R B/I E C

N otif yi n g t he I R B/I E C of S A Es or ot her si g nifica nt safet y fi n di n gs as re q uire d b y 
I R B/I E C pr oce d ures

Pr o vi di n g o versi g ht of st u d y c o n d uct f or participa nts u n der t hei r res p o nsi bility a n d 
a d here nce t o re q uire me nts of 2 1 C o de of Fe deral Re g ulati o ns ( C F R), I C H g uideli nes, t he 
I R B/I E C, E ur o pea n re g ulati o n 5 3 6/ 2 0 1 4 f or cli nical st u dies (if a p plica ble), a n d all ot her 
a p plica ble l ocal re g ulat i ons .
I n vesti gat or sites are c o m pe nsate d f or partici pati on i n t he st u d y as detaile d i n t he C li nical T rial
A gree me nt .
1 0. 1. 2.
Fi n a nci al Discl os ure
I n vesti gat ors a n d s u b-i n vesti gat ors will pr o vi de t he s p o ns or wit h s ufficie nt, acc urate fi na ncial 
i nf or mat i on as re q ueste d t o all o w t he s p o ns or t o s u b mit c o m plete a n d acc urate fi na ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ulat or y  a ut h orities. I n vestigat ors are 
res p o nsi ble f or pr o vi di n g i nf or mati on o n fi na ncial i nterests d uri n g t he c o urse of t he st u d y  a n d f or 
1 year after c o m plet i on of t he st u d y .

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
4 2
1 0. 1. 3.
I nf or me d C o nse nt Pr ocess
T he i n vest i gat or or his/ her re prese ntati ve will e x plai n t he nat ure of t he st u d y, i ncl u di n g t he ris ks 
a n d be nefits, t o t he partici pa nt or his/ her le gall y a ut h orize d re prese ntative a n d a ns we r all
q uesti o ns re gar di n g t he st u d y .
P arti cipa nts m ust be i nf or m e d t hat t heir partici pat i o n is v ol unt ar y. Participa nts or t hei r le gall y 
a ut h orize d re prese ntati ve will be re q uire d t o si g n a state me nt of i nf or me d c o nse nt t hat meets t he 
re q uire me nts of 2 1 C F R 5 0, l o c al  re g ulatio ns, I C H g ui deli nes, Heal t h I ns ura nce P orta bility a n d 
Acc o u nta bilit y Act re q uire me nts, w here a p plica ble, a n d t he I R B/I E C or st u d y ce nter.
T he m e dical rec or d must i ncl u de a state m e nt t hat writte n i nf or me d c o nse nt was o btai ne d bef ore 
t he partici pa nt was e nter e d i n t he st u d y a n d t he date t he writte n c o nse nt was o btai ne d. T he 
a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he I C F.
P arti cipa nts m ust be re -c o nse nte d t o t he m ost c urre nt versi o n of t he I C F(s) d uri n g t h eir 
parti cipat i on i n t he st u d y.
A c o p y  of t he I C F(s) must be pr o vi de d t o t he partici pa nt or t he partici pa nt’s le gall y  a ut h orize d 
re prese ntative a n d is ke pt o n file.
1 0. 1. 4.
D at a Pr otecti o n
P arti cipa nts will be assi g ne d a u ni q ue i de nt ifier b y t he s p o ns or. A n y partici pa nt rec or ds, datasets ,
or ti ss ue sa m ples t hat are tra nsferre d t o t he s p o ns or will c o ntai n t he i de ntifier o nl y; partici pa nt 
na mes or a n y  inf or m at i on w hic h w o ul d ma ke t he partici pa nt i de nt ifia ble will n ot be tra nsferre d.
T he parti ci pa nt m ust be i nf or me d t hat his/ her pers o nal st u d y -r elate d data will be use d b y t he 
s p o ns or i n acc or da nce with l ocal data pr otectio n la w. T he l e v el of dis clos ure m ust als o b e 
e x plai ne d t o t he partici pa nt w h o will be re q uire d t o gi ve c o nse nt f or his/ her data t o be use d as 
descri be d i n t he i n f or me d c o nse nt .
T he parti ci pa nt must be i nf or m e d t hat his/ h er me dical rec or ds ma y be e xa mi ne d b y Cli nical 
Q ualit y Ass ura nce a u dit ors or ot her a ut h orize d pers o n nel a p p o i nte d b y t he s p o ns or, b y 
a p pr o priate I R B/I E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y  a ut h orities.
T he sp o ns or has pr ocesses i n place t o e ns ure data pr otecti o n, i nf or mat i on sec urit y, a n d data 
i nte grit y. T hese pr ocesses i ncl u de a p pr o priate c o nti n ge nc y pla n(s) f or a p pr o priate a n d ti mel y 
res p o nse i n t he e ve nt of a data sec urity breac h.
1 0. 1. 5.
Disse mi n ati o n of Cli nic al St u d y D at a
C o m m u nic ati o n of S us pe n de d or Ter mi n ate d D osi n g
If a decisi on is ta ke n t o s us pe n d or ter mi nate d osi n g i n t he st u d y d ue t o safet y fi n di n gs, t his 
decisi o n will be c o m m u nicate d b y Lill y t o all i n vesti gat ors (f or e xa m ple, b y p h o ne a n d/ or e mail) 
as s o o n as p ossi ble. It will be a re q uire me nt t hat i n vesti gat ors res p o n d u p o n recei pt t o c o nfir m 
t hat t he y u n dersta n d t he c o m m u nicati o n a n d ha ve ta ke n t he a p pr o priate acti o n pri or t o f urt her 
d osi n g a n y partici pa nts wit h st u d y  int er ve nt i on. A n y i n vesti gat or n ot res p o n di n g will be 
f oll owe d u p b y  Lill y pers o n nel prior t o a n y  furt her pla n ne d d osi n g. If a d ose is pla n ne d 
i m mi ne ntl y, Lill y pers o n nel will i m me diatel y, a n d c o nti n uall y, use all eff orts t o reac h 
i n vesti gat ors u ntil c o ntact is ma de a n d i nstr ucti o ns verifie d.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
4 3
Re p orts
T he s p o ns or will discl ose a s u m mar y o f st u d y inf o r mat i on, i ncl u di n g ta b ular st u d y res ults, o n 
p u blicl y  a vaila ble we bsites w here re q uire d b y lo c al  la w or re g ulat i on. 
D at a 
T he s p o ns or d oes n ot pr oacti vel y  s hare data fr o m P hase 1 cli nical trials. Re q uests f or access t o 
P hase 1 cli nical trial data are e val uate d o n a case b y case basis ta ki n g i nt o c o nsi derat i on t he 
a bilit y t o a n o n y mize t he data a n d t he nat ure of t he data c ollecte d.
1 0. 1. 6.
D at a Q u alit y Ass ur a nce
All partici pa nt data rela tin g t o t he st u d y  will be rec or de d o n pri nte d or C R Fs u nless tra ns mitte d 
t o t he s p o ns or or desi g nee electr o nicall y (f or e xa m ple, la b orat or y data). T he i n vesti gat or is 
res p o nsi ble f or verif yi n g t hat data e ntries are acc urate a n d c orrect b y p h ysicall y or electr o nicall y 
sig ni n g t he C R F.
T he i n vest i gat or m ust mai ntai n acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mat i on e ntere d i n t he eC R F. S o urce data ma y i ncl u de la b orat or y  tests, me dical rec or ds, a n d 
cli nical n otes.
T he i n vest i gat or m ust per mit st u d y-r elat e d mo ni t ori n g, a u dits, I R B/I E C re vie w, a n d re g ulat or y 
a ge nc y ins pect i ons a n d pr o vi de direct a ccess t o s o urce data d oc u me nts.
Q ualit y t olera nce li mits will be predefi ne d t o ide ntif y  s yste matic iss ues t hat ca n i m pact 
parti ci pa nt safet y a n d/ or r elia bilit y of  st u d y res ults. T hese predefi ne d para meters will be 
m o nit ore d d uri n g t he st u d y  a n d i m p orta nt e xc ursi o ns fr o m t he q ualit y t olera nce li mits a n d 
r e me dial a ctio ns ta ke n will be s u m marize d i n t he cli nical st u d y  re p ort.
M o ni t ori n g details descri bi n g strate g y (f or e xa m ple, ris k-base d i nit iati ves i n o perati o ns a n d 
q ualit y s uc h as ris k ma na ge me nt a n d mit i gati on strate gi es a n d a nal ytical ris k-base d m o nit ori n g), 
met h o ds, res p o nsi bilit ies, a n d re q uire me nts, i ncl u di n g ha n dli n g of n o nc o m p lia nce iss ues a n d 
m o nit ori n g tec h ni q ues are pr o vi de d i n t he M o nit ori n g Pla n.
T he s p o ns or or desi g nee is res p o nsi ble f or t he data ma na ge me nt of t his st u d y  incl u di n g q ualit y 
c hec ki n g o f t he data.
T he s p o ns or ass u mes acc o u nta bilit y f or actio ns dele gate d t o ot her i n di vi d uals (e . g., c o nt ract 
researc h or ga nizati ons ).
St u d y  mo ni t ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data e ntere d i nt o 
t he eC R F b y a ut h orize d site pers o n nel are acc urate, c o m plete, a n d verifia ble fr o m s o urce 
d oc u m e nts; t hat t he safet y a n d rig h ts of partici pa nts are bei n g pr otecte d; a n d t hat t he st u d y  is 
bei n g c o n d ucte d i n acc or da nce wit h t he c urre nt l y a p pr o ve d pr ot oc ol a n d a n y ot her st u d y 
a gree me nts, I C H G C P, a n d all a p plica ble re g u lator y  re q uire me nts.
Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Fs, pertai ni n g t o t he c o n d uct of t his st u d y  must be 
retai ne d b y t he i n vesti gat or f or t he ti me peri o d o utli ne d i n t he Cli nical Trial A gree me nt u nless 
l ocal re g ulatio ns or i nst itut i onal p o licies re q uire a l o n ger rete nti o n peri o d. N o rec or ds ma y be 
destr o y e d d uri n g t he rete nti o n peri o d wit h o ut t he writte n a p pr o val of t he s p o ns or. N o rec or ds 
ma y be tra nsferre d t o a n ot her l ocati o n or part y  wit ho ut wri tte n n otificati on t o t he s p o ns or .

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
4 4
I n a d diti on, t he sp o ns or or i ts re prese ntati ves will peri o dicall y c hec k a sa m ple of t he partici pa nt 
data rec or de d a gai nst s o urce d oc u me nts at t he st u d y site. T he st u d y  ma y be a u dite d b y t he 
sp o ns or or i ts re prese ntati ves, a n d/ or re g ulat or y a ge ncies at a n y ti me. I n vesti gat ors will be gi ve n 
n oti ce bef ore a n a u dit occ urs.
D at a C a pt ure S yste m
T he i n vest i gat or is res p o nsi ble f or e ns uri n g t he acc urac y, c o m plete ness, le gi bility,  a n d ti meli ness 
of  t he data re p orte d t o t he s p o ns or.
A n electr o nic data ca pt ure ( E D C) s yst e m will be use d i n t his st u d y for t he c ollect i on of eC R F 
data. T he i n vest i gat or mai ntai ns a se parate s o urce f or t he data e ntere d b y t he i n vesti gat or or 
desi g nee i nt o t he s p o ns or -pr o vi de d E D C s yste m. T he i n vest i gat or is res p o nsi ble f or t he 
i de ntificati on of a n y data t o be c o nsi dere d s o urce a n d f or t he c o nfir mat i on t hat data re p ort e d are 
acc urate a n d c o m plete b y si g ni n g t he C R F.
Data c ollecte d via t he s p o ns or- pr o vi de d data ca pt ure s yste m will be st ore d at a t hird- part y . T he 
i n vesti gat or will ha ve c o nti n u o us access t o t he data d uri n g t he st u d y a n d u ntil dec om missi o ni n g 
of  t he data capt ure s y st e m. Pri or t o dec o m missi o ni n g, t he i n vest i gat or will recei ve a n arc hi val 
c o p y of perti ne nt data f or rete nti o n.
Data m a na ge d b y a ce ntral ve n d or, s uc h as la b orat or y test data, will be st ore d electr o nicall y in 
t he ce ntral ve n d or’s data base s yste m a n d re p orts/electr o nic tra nsfers will be pr o vi de d t o t he 
i n vesti gat or f or re vie w a n d rete nti o n. Data will s u bse q ue ntl y be tra nsferre d fr om t he ce ntral 
ve n d or t o t he sp o ns or data ware h o use.
Data fr o m c o m p lai nt f or ms s u b mitte d t o t he sp o ns or will be e nc o de d a n d st ore d i n t he gl o bal P C
ma na ge me nt s yste m.
1 0. 1. 7.
S o urce D oc u me nts
S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate t he 
i nte grit y of t he data c ollecte d. S o urce d oc u me nts are file d at t he i n vesti gat or’s site.
Data re p orte d o n t he C R F or e ntere d i n t he e C R F t hat are tra nscri be d fr o m s o urce d oc u me nts 
m ust be c o nsiste nt wit h t he s o urce d oc u me nt s or t he discre pa ncies m ust be e x plai ne d. T he 
i n vesti gat or ma y nee d t o re q uest pre vi o us me dical rec or ds or tra nsfer rec or ds, de pe n di n g o n t he 
st u d y. Als o, c urre nt me dical rec or ds m ust be a vaila ble.
T he d efi nit i on of w hat c o nstit utes s o urce data ca n be f o u n d i n Sect i on 1 0. 1. 6 .
1 0. 1. 8.
St u d y a n d Site St art a n d Cl os ure
T he st u d y  start date is t he date o n w hic h t he cli nical st u d y will be o pe n f or recr uitme nt  of 
parti ci pa nts.
T he s p o ns or desi g nee reser ves t he ri g ht t o cl ose t he st u d y  site or ter mi nate t he st u d y at a n y ti me 
f or a n y reas o n at t he s ole discret i on of t he s p o ns or. St u d y  sites will b e close d u p o n st u d y  
c o mplet i on. A st u d y  site is c o nsi dere d close d w he n all re q uire d d oc u me nts a n d st u d y s u p plies 
ha ve bee n c o llecte d a n d a st u d y sit e clos ure visi t has bee n perf or me d.
T he i n vest i gat or ma y i nitiate st u d y sit e clos ure at a n y  time, pr o vi de d t here i s reas o na ble ca use 
a n d s ufficie nt n otice is gi ve n i n a d va nce of t he i nte n de d ter mi nat i on.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
4 5
Reas o ns f or t he earl y cl os ure of a st u d y  site b y t he s p o ns or or i n vesti gat or ma y incl u de b ut are 
n ot li mite d t o:
●
Fail ure of t he i n vest i gat or t o c o m pl y with t he pr ot oc ol, t he re q uire me nts of t he I R B/I E C 
or l o c al  healt h a ut h orities, t he s p o ns or's pr oce d ures, or G C P g ui deli nes
●
I na de q uate recr uitme nt  of p artici pa nts b y t he i n vestigat or
●
Di sc o nti n uatio n of  furt her st u d y  int er ve nt i on de vel o p m e nt .
If t he st u d y is pre mat urel y ter mi nate d or s us pe n de d, t he s p o ns or s hall pr o m ptl y i nf or m the 
in vesti gat ors, t he I E Cs/I R Bs, t he re g ulat or y  a ut h orities, a n d a n y c o ntract researc h or ga nizati on(s) 
use d i n t he st u d y  of t he reas o n f or ter mi nati on or s us pe nsi o n, as s pecifie d b y t he a p plica ble 
re g ulat or y r e q uire me nts. T he in vesti gat or s hall pr o m pt l y i nf or m t he parti ci pa nt a n d ass ure s
a p pr o priate partici pa nt t hera p y a n d/ or f ollo w - u p.
1 0. 1. 9.
P u blic ati o n P olic y
I n acc or da nce wit h t he s p o ns or’s p u blicati o n p olic y, t he res ults of t his st u d y will be s u b mitte d 
f or p u blicati on b y a peer -re vie we d j o ur nal if t he res ults are dee me d t o be of sig nifica nt m e dical 
i m p orta nce.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
4 6
1 0. 2.  
A p pe n di x 2: Cli nic al L a b or at or y Tests
T he tests detaile d b el o w will be perf or me d b y t he ce ntral la b orat or y or l ocal la b orat or y, as 
detaile d i n t he ta ble bel o w .
I n circ u msta nces w here t he s p o ns or a p pr o ves l ocal la b orat or y testi n g i n lie u of ce ntral la b orat or y 
testi n g (i n t he ta ble bel o w), t he l ocal la b orat or y must be q ualifie d i n acc or da nce wit h a p plica ble 
l ocal re g ulatio ns.
Pr ot oc ol -s pecific re q uire me nts f or i ncl usi o n or e xcl usi o n of partici pa nts are detaile d i n Sect i on 5
of  t he pr ot oc ol.
A d dit i onal tests ma y be perf or me d at a n y  time d uri n g t he st u d y  as deter mi ne d necessar y b y t he 
i n vesti gator or re q uire d b y  local re g ulati o ns.
Pre g na nc y testi n g will be c o n d ucte d as detaile d i n t he S o A ( Secti o n 1. 3 ).
I n vesti gat ors m ust d oc u me nt t heir re vie w of t he la b orat or y s afet y res ults.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
4 7
S afet y L a b or at or y Tests a
He m at ol o g y
Cli nic al C he mistr y
He mat ocrit
S o di u m
He m o gl o bi n
P otassi u m
Er y t hr oc yte c o u nt ( R B C)
Bicar b o nate
Mea n cell v ol u me 
C hl ori de
Mea n cell he m o gl o bi n 
Calci u m
Mea n cell he m o gl o bi n c o nce ntrati o n 
P h os p h o r ous
Le u k oc ytes ( W B C) 
Gl uc ose 
B U N
Cell m or p h ol o g y
Ur ic aci d
A bs ol ute c o u nts a n d % of:
T otal c h olester ol
Ne utr o p hils
T otal pr otei n
L y m p h oc y t es
Al b u mi n
M o n oc ytes
T otal bilir u bi n
E osi n o p hils
Direct bilir u bi n
Bas o p hils
A L P
Platelets
A S T
A L T
Uri n al ysis
Creati ni ne
S pecific gra vit y
p H
Pr otei n
Ot her Tests
Gl uc ose
Et ha n ol testi n g c, d
Ket o nes
Ur i ne dr u g scree nd
Bilir u bi n
Pre g na nc y test (fe males o nl y) e
Ur o bili n o ge n
F S H (fe males o nl y) b
Bl o o d
Q ua nti F E R O N ® -T B G ol d b
Nitrite
Micr osc o p y (if di pstic k a b n or mal; bl o o d, pr otei n, or 
nitrites)
Ser ol o g y
He patitis B s urface a nti ge n b
He patitis B c ore a nti b o d y b
He patitis C a nti b o d y b
HI V b
A b bre via ti o ns: A L P = al kali ne p h os p hatase; A L T = ala ni ne a mi n otra nsferase; A S T = as partate a mi n otra nsferase; 
B U N = bl o o d urea nitr o ge n; F S H = f ollicle -sti m ulati n g h or m o ne; HI V = h u ma n i m m u n o deficie nc y vir us; 
R B C = re d bl o o d cell; T B = t u berc ul osis; W B C = w hite bl o o d cell.
a
Perf or me d l ocall y at scr ee ni n g a n d Da y -1 a n d ce ntrall y at all p ost d ose ti me p oi nts u nless ot her wise state d.
b
Perf or me d at scree ni n g o nl y.
c
Ur i ne et ha n ol test will be c o n d ucte d at scree ni n g a n d a breat h -test will be perf or me d at c hec k-i n o n Da y - 1.
d
Ur ine dr u g scree n a n d et ha n ol tests ma y be re peate d l ocall y at a d diti o nal ti me p oi nts at t he discreti o n of t he 
i n vesti gat or.
e
Ser u m pre g na nc y test t o be perf or me d at scree ni n g a n d Da y -1. Uri ne pre g na nc y test t o be perf or me d l ocall y at 
Da y  8 5 or earl y disc o nti n uati o n.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
4 8
1 0. 2. 1.
Bl o o d S a m pli n g S u m m ar y
T his ta ble s u m marizes t he a p pr o xi mate n u m ber of ve ni p u nct ures a n d bl o o d v ol u mes f or all 
bl o o d sa m pli n g (scree ni n g, safet y lab orat ori es, a n d bi oa nal ytical assa ys) d uri n g t he st u d y. 
Pr ot oc ol I 6 T -M C -A M B X S a m pli n g S u m m ar y
P ur p ose
M a xi m u m Bl o o d V ol u me 
per S a m ple ( m L)
N u m ber of Bl o o d 
S a m ples
T ot al V ol u me 
( m L)
Scree ni n g tests a
4 5
1
4 5
L ocal cli nical la b orat or y a n d 
pre g na nc y tests a
1 2 . 5
1
1 2 . 5
Ce ntral cli nical la b orat or y tests a
4. 5
4
1 8
P har mac o ki netics 
3
1 5 b
4 5
I m m u n o ge nicit y
1 0
4
4 0
P har mac o ge netics
1 0
1
1 0
T otal
1 7 0. 5
T otal f or cli nical p ur p oses 
1 7 5
a
A d diti o nal sa m ples ma y be dra w n if nee de d f or safet y p ur p oses. 
b
I ncl u des a d diti o nal 3 sa m ples, if re q uire d.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
4 9
1 0. 3.
A p pe n di x 3: A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or 
Rec or di n g, E v al u ati n g, F oll o w -u p, a n d Re p orti n g
T he defi nit i ons a n d pr oce d ures detaile d i n t his a p pe n di x are i n acc or da nce wit h I nter nati o nal 
Or ga nizat i on f or Sta n dar dizati on 1 4 1 5 5.
B ot h t he i n vest i gat or a n d t he s p o ns or will c o m pl y wit h all l ocal me dical de vice re p ortin g 
re q uire me nts.
T he detecti o n a n d d oc u m e nt atio n pr oce d ures descri be d i n t his pr ot oc ol a p pl y  t o all s p o ns or 
me dical de vices pr o vi de d f or use i n t he st u d y . See Sectio n 6. 1. 2 f or t he list of s p o ns or me dical 
de vices.
1 0. 3. 1.
Defi niti o n of A E
A E Defi niti o n

A n A E i s a n y u nt o war d me dical occ urre nce, u ni nte n de d disease or i nj ur y, or u nt o war d 
cli nical si g ns (i ncl u di n g a b n or mal la b orat or y  fi n di n g) i n st u d y parti ci pa nts, users, or 
ot her pers o ns, w het her or n ot relate d t o t he i n vest i gati o nal me dical de vice. T his 
defi nit i on i ncl u des e ve nts relate d t o t he i n vesti gati o nal me dical de vice or c o m parat or 
a n d e ve nts relate d t o t he pr oce d ures i n v o l ve d e xce pt f or e ve nts i n users or ot her 
pers o ns, w hic h o nl y i ncl u de e ve nts relate d t o i n vesti gat i onal de vices.
E ve nts Meeti n g t he A E Defi niti o n

A n y a b n or mal la b orat or y  test res ults ( he mat olo g y , cli nical c he mistr y, or urinal ysis) or 
ot her safet y assess me nts ( f or e xa m ple, E CG, ra di ol o gical sca ns, vi t al si g ns 
meas ure me nts), i ncl u di n g t h ose t hat w orse n fr o m baseli ne, c o nsi dere d cli nicall y 
sig nifica nt i n t he me dical a n d scie ntific j u d g me nt of t he i n vest i gat or (t hat is, n ot relate d 
t o pr o gressi o n of u n derl yi n g disease).

E xacer bat i on of a c hr o nic or i nter mitte nt pre e xisti n g c o n ditio n i ncl u di n g ei t her a n 
i ncrease i n fre q ue nc y a n d/ or i nte nsity of  t he c o n ditio n .

Ne w c o n dit i ons detecte d or dia g n ose d after st u d y  i nter ve nti on a d mi nistrati o n e ve n 
t ho u g h t he y ma y ha ve bee n prese nt bef ore t he start of t he st u d y .

Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d dr u g -dr u g i nteracti o n.

Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her st u d y  
i nter ve nt i on or a c o nc o mita nt me dicat i on. O ver d ose per se will n ot be re p orte d as a n 
A E/ S A E u nless it is a n i nte nti o nal o ver d ose ta ke n wit h p ossi ble s uici dal/self -har mi n g 
i nte nt. S uc h o ver d ose s h o ul d be re p orte d re gar dless of se q uelae.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
5 0
E ve nts N O T Meeti n g t he A E Defi niti o n

A n y cli nicall y  sig nifica nt a b n or mal la b orat or y fi n di n gs or ot her a b n or mal safety 
assess me nts w hic h are ass ociate d wit h t he u n derl yi n g disease, u nless j u d ge d b y t he 
i n vesti gat or t o be m ore se vere t ha n e x pecte d f or t he partici pa nt’s c o n diti on.

T he disease/ dis or der bei n g st u die d or e x pecte d pr o gressi o n, si g ns, or s y m pt o m s of t he 
di sease/ dis or der bei n g st u die d, u nless m ore se vere t ha n e x pecte d f or t he partici pa nt’s 
c o n ditio n.

Me dical or s ur gical pr oce d ure ( f or e xa m ple, e n d osc o p y, a p pe n dect o m y): t he c o n ditio n 
t hat lea ds t o t he pr oce d ure is t he A E.

Si t u atio ns i n w hic h a n u nt o war d me dical occ urre nce di d n ot occ ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital).

A nt ici pate d da y-t o-da y fl uct uati o ns of pree xist i n g di sease(s) or c o n ditio n(s) prese nt or 
detecte d at t he start of t he st u d y  t hat d o n ot worse n.
1 0. 3. 2.
Defi niti o n of S A E
If a n e ve nt is n ot a n A E per defi niti on a b o ve, t he n it ca n n ot be a n S A E e ve n if seri o us c o n dit i ons 
are met ( f or e xa m ple, h os pitalizati on f or sig ns/s y m pt o m s of t he disease u n der st u d y, deat h d ue t o 
pr o gressi o n of disease).
S A E is defi ne d as a n y u nt o w ar d me dic al occ urre nce t h at, at a n y d ose:
a.
Res ults i n de at h
b.
Is life-t hre ate ni n g
T he ter m  ‘life-t hreate ni n g’ i n t he defi niti on of ‘seri o us’ refers t o a n e ve nt i n w hic h t he 
parti ci pa nt was at ris k of deat h at t he ti me of t he e ve nt. It d oes n ot refer t o a n e ve nt, w hic h 
h y p ot heti call y mi g ht ha ve ca use d deat h, if it were m ore se vere.
c.
Re q uires i n p atie nt h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n

I n ge neral, h os pitalizati on si g nifies t hat t he partici pa nt has bee n a d mitte d t o h os pi t al 
f or o bser vati on a n d/ or treat me nt t hat w o ul d n ot ha ve bee n a p pr o priate i n t he 
p h ysicia n’s office or o ut patie nt setti n g. C o m plicat i o ns t hat occ ur d uri n g h os pi talizatio n 
are A Es. If a c o m plicat i on pr ol o n gs h os pi talizatio n or f ulfills a n y  ot her serio us cri t eria, 
t he e ve nt is seri o us. W he n i n d o u bt as t o w het her “ h os pitalizati o n” occ urre d or was 
necessar y , t he A E s h o uld be c o nsi dere d seri o us.

H os pitalizati o n f or elect i ve treat me nt of a pree xist i n g c o n ditio n t hat di d n ot w orse n 
fr om baseli ne is n ot c o nsi dere d a n A E.
d.
Res ults i n persiste nt dis a bilit y/i nc a p acit y

T he ter m disa bili t y mea ns a s u bsta nt ial disr u pt i on of a pers o n’s a bilit y t o c o n d uct 
n or m al lif e fu nct i ons.

T his defi nit i on is n ot i nte n de d t o i ncl u de e x perie nces of relati vel y mi n or me dical 
sig nifica nce s uc h as u nc o m p licate d hea dac he, na usea, v o miti n g, diarr hea, i nfl ue nza, 

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
5 1
a n d acci de ntal tra u ma ( f or e xa m ple, s prai ne d a n kle) w hic h ma y int erfere wit h or 
pre ve nt e ver y d a y  lif e fu nct i ons b ut d o n ot c o nstit ute a s u bsta nt ial disr u pti o n.
e.
Is a c o n ge nit al a n o m al y/ birt h defect

A b n or m al pre g na nc y o utc o mes (e. g., s p o nta ne o us a b orti o n, fetal deat h, still birt h, 
c o n ge nital a n o ma lies, ect o pic pre g na nc y) are c o nsi dere d S A E s.
f.
Ot her sit u ati o ns:

Me dical or scie nt ific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her S A E re p orti n g 
is a p pr o priate i n ot her sit uati o ns s uc h as i m p orta nt me dical e ve nts t hat ma y n ot be 
i m me diatel y life-t hreate ni n g or res ult i n deat h or h os pitalizati on b ut m a y je o par dize t he 
parti ci pa nt or ma y re q uir e me dical or s ur gical i nter ve nt i on t o pre ve nt o ne of t he ot her 
o utc o m es liste d i n t he a b o ve defi nit i on. T hese e ve nts s h o ul d us uall y be c o nsi dere d 
serio us.

E xa m ples of s uc h e ve nts i ncl u de i n vasi ve or mali g na nt  ca ncers, i nte nsi ve treat me nt i n 
a n e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m, bl o o d d yscrasias or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizat i on, or de vel o p me nt of dr u g de pe n de nc y or 
dr u g a b use.
g.
Res ulte d i n me dical or s ur gical i nter ve nt i on t o pre ve nt life -t hreate ni n g ill ness or i nj ur y or 
p er m a ne nt i m pair me nt t o a bo d y  str uct ure or a b o d y fu nct i on.
1 0. 3. 3.  
Defi niti o n of Pr o d uct C o m pl ai nts
Pr o d uct C o m pl ai nt

A pr o d uct c o m plai nt is a n y writte n, electr o nic, or oral c o m m u nicat i on t hat alle ges 
deficie ncies relate d t o t he i de ntit y,  q uality, d ura bilit y , relia bility, safet y,  effecti ve ness,
or perf or ma nce of a st u d y  int er ve ntio n . W he n t he a bilit y t o use t he st u d y int er ve nt i on 
safel y is i m pacte d, t he f oll owi n g are al s o P Cs :
o
Deficie ncies i n la beli n g i nf or mat i on, a n d
o
Use err ors f or de vice or dr u g -de vice c o m bi nati o n pr o d ucts d ue t o er g o n o mic 
desi g n ele me nts of t he pr o d uct.

Pr o d uct c o m plai nts relate d t o st u d y  int er ve nt i ons use d i n cli nical trials are c ollecte d i n 
or der t o e ns ure t he safet y of  partici pa nts, m o nit or q uality,  a n d t o facilitate pr ocess a n d 
pr o d uct i m pr o ve me nts.

I n vesti gat ors will i nstr uct partici pa nts t o c o ntact t he site as s o o n as p ossi ble if he or s he 
has a pr o d uct c o m plai nt or pr o ble m wit h t he st u d y  i nterve nt i on s o t hat t he sit uati o n ca n 
be assesse d.

A n e ve nt ma y meet t he defi nit i on of b ot h a pr o d uct c o m plai nt a n d a n A E/ S A E. I n s uc h 
cases, it s h o ul d be re p orte d as b ot h a pr o d uct c o m plai nt a n d as a n A E/ S A E .

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
5 2
1 0. 3. 4.
Rec or di n g a n d F oll o w - Up of A E a n d/ or S A E a n d P Cs
A E , S A E , a n d Pr o d uct C o m pl ai nt Rec or di n g

W he n a n A E/ S A E /pr o d uct c o m plai nt occ urs, i t is t he res p o nsi bility of  t he i n vestig at or 
t o re vie w all d oc u me ntatio n ( f or e xa m ple, h os pital pr o gress n otes, la b orat or y re p orts, 
a n d dia g n ostics re p orts) relate d t o t he e ve nt.

T he i n vesti gat or will t he n rec or d all rele va nt A E/S A E /pr o d uct c o m plai nt i nf or mati on 
i n t he partici pa nt’s me dical rec or ds, i n acc or da nce wit h t he i n vest i gat or’s n or mal 
cli nical practice. A E/ S A E i nf or mati o n is re p orte d o n t he a p pr o priate e C R F pa ge a n d 
pr o d uct c o m p lai nt i nf or mati on is re p orte d o n t he Pr o d uct C o m plai nt F or m.
N ote: A n e ve nt ma y meet t he defi nit i on of b ot h a pr o d uct c o m plai nt a n d a n A E/ S A E. 
I n s uc h cases, it s h o ul d be re p orte d as b ot h a pr o d uct c o m plai nt a n d as a n A E/ S A E.

It is n ot acce pta ble f or t he i n vesti gat or t o se n d p h ot oc o pies of t he partici pa nt’s me dical 
rec or ds t o t he sp o ns or or desi g nee i n lie u of c o m pleti o n of t he eC R F pa ge f or A E/ S A E 
a n d t he Pr o d uct C o m plai nt F or m f or P Cs .

T here m a y be i nsta nces w he n c o pies of me dical rec or ds f or certai n ca ses are re q ueste d 
b y t h e sp o ns or or desi g nee . I n t his case, all partici pa nt i de ntifiers, wit h t he e xce pti on of 
t he partici pa nt n u m ber, will be re dacte d o n t he c o pies of t he me dical rec or ds bef ore 
s u b missi on t o t he sp o ns or or desi g nee .

T he i n vest i gat or will att e mpt t o esta blis h a dia g n osis of t he e ve nt base d o n si g ns, 
s y m pt o ms, a n d/ or ot her cli nical i nf or mati on. W he ne ver p ossi ble, t he dia g n osis ( n ot t he 
i n di vi d ual si g ns/s y m pt o ms) will be d oc u me nte d as t he A E/ S A E.
Assess me nt of I nte nsit y
T he i n vest i gat or will ma ke a n assess me nt of i nte nsity f or eac h A E a n d S A E re p orte d d uri n g 
t he st u d y a n d assi g n it t o 1 of  t he f oll owi n g cate g ori es:

Mil d:
A t y pe of A E t hat is us uall y tra nsie nt a n d ma y re q uire o nl y mi ni mal tr e at me nt or 
t hera pe utic i nter ve nt i on. T he e ve nt d oes n ot ge nerall y  int erfere wit h us ual acti vities of 
dail y  li vi n g.

M o derate:
A t y pe of A E t hat is us uall y alle viate d wit h a d dit i onal s pecific t hera pe u tic 
i nter ve nt i on. T he e ve nt i nterferes wit h us ual acti vit ies of dail y li vi n g, ca usi n g 
di sc o mf ort b ut p oses n o si g nifica nt or per ma ne nt ris k of har m t o t he researc h 
parti ci pa nt.

Se vere: A t y pe of A E t hat i nterr u pts us ual act i vities of dail y li vi n g, or si g nifica ntl y 
affects cli nical stat us, or ma y re q uire i nte nsi ve t hera pe utic i nter ve nti o n . A n A E t hat is 
assesse d as se vere s h o ul d n ot be c o nf use d wit h a n S A E. Se vere is a cate g or y  utilize d 
f or r atin g t he i nte nsit y of  a n e ve nt; a n d b ot h A Es a n d S A Es ca n be assesse d as se vere.
A n e ve nt is defi ne d as ‘seri o us’ w he n it meets at least 1 of  t he pre defi ne d o utc o mes as 
descri be d i n t he defi nit i on o f a n S A E, N O T w he n it is rate d as se vere.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
5 3
Assess me nt of C a us alit y

T he i n vest i gat or is o bli gate d t o assess t he relati o ns hi p bet wee n st u d y int er ve nt i on a n d 
eac h occ urre nce of eac h A E/ S A E.

A “reas o na ble p ossi bility” of  a r elat i ons hi p c o n ve ys t hat t here are facts, e vi de nce, 
a n d/ or ar g u me nts t o s u g gest a ca usal relat i ons hi p, rat her t ha n a relat i ons hi p ca n n ot be 
r ule d o ut .

T he i n vest i gat or will use cli nical j u d g me nt t o deter mi ne t he relati ons hi p.

Alt er nat i ve ca uses, s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y, a n d ot her ris k 
fact ors, as well as t he te m p oral relati o ns hi p of t he e ve nt t o st u d y int er ve nt i on 
a d mi nistr atio n will be c o nsi dere d a n d i n vest i gate d.

T he i n vest i gat or will als o c o ns ult t he I B i n his/ her assess me nt.

F or eac h A E/ S A E, t he i n vest i gat or m ust
d oc u me nt i n t he me dical n otes t hat he/s he has 
re vie we d t he A E/ S A E a n d has pr o vi de d a n assess me nt of ca usality.

T here m a y be sit u atio ns i n w hic h a n S A E has occ urre d a n d t he i n vest i gat or has 
mi ni mal i nf or mat i on t o i ncl u de i n t he i nit ial re p ort t o t he sp o ns o r or desi g nee. 
H o we ver, it is ver y  im p orta nt t hat t he i n vest i gat or al wa ys ma ke a n assess me nt of 
ca usalit y f or e ver y e ve nt bef ore t he i nit ial tra ns missi o n of t he S A E data t o t he sp o ns or 
or desi g nee .

T he i n vest i gat or ma y c ha n ge his/ her o pi ni on of ca usalit y in li g ht of f oll ow- u p 
i nf or mat i on a n d se n d a n S A E f oll o w -u p re p ort wi t h t he u p date d ca usality assess me nt.

T he ca usalit y assess me nt is o ne of t he crit eria use d w he n deter mi ni n g re g ulat or y 
re p orti n g re q uire me nts.
F oll o w -u p of A Es a n d S A Es

T he i n vest i gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d uct of s u p ple me ntal 
meas ure me nts a n d/ or e val uat i ons as me dicall y i n dicate d or as re q ueste d b y t he sp o ns or 
or desi g nee t o eluci date t he nat ure a n d/ or ca usalit y of t he A E or S A E as f ull y as 
p ossi ble. T his ma y i ncl u de a d dit i onal la b orat or y  tests or i n vesti gati ons, 
hist o pat h ol o gical e xa mi nat i ons, or c o ns ultati o n wit h ot her healt h care pr ofessi o nals.

If a partici pa nt dies d uri n g partici pati o n i n t he st u d y or d uri n g a rec o g nize d f oll ow- u p 
p eri o d, t he i n vest i gat or will pr o vi de S p o ns or or desi g nee wit h a c o p y of a n y 
p ost -m o rte m fi n di n gs i ncl u di n g hist o pat h ol o g y.
1 0. 3. 5.
Re p orti n g of S A Es
S A E Re p orti n g vi a S A E Re p ort

Facsi mile tra ns missi o n of t he S A E Re p ort is t he preferre d met h o d t o tra ns mit t his 
i nf or mat i on t o t he s p o ns or or desi g nee.

I nitial notificati o n via tele p h o ne d oes n ot re place t he nee d f or t he i n vest i gat or t o 
c o mplete a n d si g n t he S A E Re p ort wit hi n t he desi g nate d re p orti n g ti me fra mes.

C o ntacts f or S A E re p orti n g ca n be f o u n d i n t he S A E Re p ort .

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
5 4
1 0. 3. 6.
Re g ul at or y Re p orti n g Re q uire me nts
S A E Re g ul at or y Re p orti n g

Pr o m pt n otificat i on b y t he i n vest i gat or t o t he s p o ns or of a n S A E is esse nt ial s o 
t hat le gal o bli gat i ons a n d et hical res p o nsi bilit ies t o war ds t he safety of  
parti ci pa nts a n d t he safet y of  a st u d y in ter ve nti on u n der cli nical i n vest i gati on 
are met.
●
T he s p o ns or has a le gal res p o nsi bilit y t o n otif y b ot h t he lo c al  re g ulat or y 
a ut h orit y a n d ot her re g ulat or y a ge ncies a b o ut t he safety of  a st u d y int er ve nt i on 
u n der cli nical i n vest i gati on. T he s p o ns or will c o m pl y wit h c o u ntr y -s pecific 
re g ulat or y r e q uire me nts r elat i n g t o safety re p orti n g t o t he re g ulat or y a ut h orit y, 
I R B/I E C, a n d i n vesti gat ors.
●
A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a n S A E or 
ot her s pecific safet y i nf or mati on (e. g., s u m mar y  or listi n g of S A Es) fr o m t he 
s p o ns or will re vie w a n d t he n file it al on g wi t h t he I B a n d will n otif y  t he 
I R B/I E C, if a p pr o priate acc or di n g t o l ocal re q uire me nts.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
5 5
1 0. 4.
A p pe n di x 4: C o ntr ace pti ve G ui d a nce a n d C ollecti o n of Pre g n a nc y 
I nfor m ati o n
Defi niti o ns:
W o m a n of C hil d be ari n g P ote nti al
Fe males are c o nsi dere d a w o ma n of c hil d beari n g p ote ntial if :

t he y ha ve ha d at least o ne c ycle of me nses, or

t he y ha ve Ta n ner 4 breast de vel o p me nt.
A n y a m o u nt of s p otti n g s h o ul d be c o nsi dere d me narc he.
W o m a n n ot of C hil d be ari n g P ote nti al
Fe males are c o nsi dere d w o me n n ot of  c hil d beari n g p ote ntial if:

t he y ha ve a c o n ge nital a n o ma l y s uc h as M ulleria n a ge nesis, 

t he y are i nfertile d ue t o s ur gical sterilizat i on, or 

t he y are p ost-me n o pa usal.
E xa m ples of s ur gical sterilizat i on i ncl u de: h ysterect o m y, bilateral o o p h orect o m y, t u bal li gati on.
N ote: Deter mi nati o n ca n c o me fr om t he site pers o n nel’s re vie w of t he partici pa nt’s me dical 
rec or ds, me dical e xa mi nati on, or m e dical hist or y int er vie w.
T he p ost -me n o pa usal state is defi ne d as:
1.
A w o ma n at a n y  a ge at least 6 wee ks p ost -s ur gical bilateral  o o p h orect o m y wit h or 
wi t ho ut h ysterect o m y , c o nfir me d b y o perati ve n ote; or
2.
A w o ma n at l east 4 0 years of a ge a n d u p t o 5 5 years of  a ge wi t h a n i ntact uter us, n ot o n 
h or m o ne t hera p y *, w h o has ha d cessat i on of me nses f or at least 1 2 c o nsec ut i ve m o nt hs 
wi t ho ut a n al ter nati ve me d ical ca use, A N D wit h a f ollicle-sti m ulati n g h or m o ne 
> 4 0 mI U/ m L; or
3.
A w o ma n 5 5 years of a ge or ol der n ot o n h or m o ne t hera p y , w h o has ha d at least 
1 2 m o nt hs of s p o nta ne o us a me n orr hea ; or 
4.
A w o ma n at l east 5 5 years of a ge wit h a dia g n osi s of me n o pa use prior t o starti n g
h or m o ne- r e place me nt t hera p y.
* W o me n s h o ul d n ot be ta ki n g me dicat i ons d uri n g a me n orr hea s uc h as oral c o ntrace pti ves,
h or m o nes, g o na d otr o pi n -r eleasi n g h or mo ne, a nt i-estr o ge ns, selecti ve estr o ge n rece pt or
m o d ulat ors, or c he m ot hera p y  t hat c o uld i n d uce tra nsie nt a me n orr hea.
C o ntr ace pti o n G ui d a nce:
M ales
N o m ale c o ntrace pti o n is re q uire d e xce pt i n c o m plia nce wit h s pecific l ocal g o ver n me nt st u d y  
re q uire me nts.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
5 6
Fe m ales
T he ta ble bel o w descri bes c o ntrace pti o n g ui da nce f or w o m e n of c hil d beari n g p ote ntial w h o are 
c o mpletel y a bst i ne nt as t heir preferre d a n d us ual lifestyle, or i n a sa me se x relat i ons hi p, as part 
of  t h eir pr eferre d a n d us ual lifest yle :
M u st …
M u st not …
a gree t o eit her re mai n a bsti ne nt, or

use peri o dic a bsti ne nce met h o ds
o
cale n dar 
o
o v ulati o n 
o
s y m pt ot her mal, or
o
p ost -o v ulati o n 

declare a bsti ne nce j ust f or t he d urati o n of 
a trial, or
sta y i n a sa me se x relati o ns hi p wit h o ut se x ual 
r elati o ns hi ps wit h males

use t he wit h dra wal met h o d
T he ta ble bel o w descri bes c o ntrace pti o n g ui da nce f or w o m e n of c hil d beari n g p ote ntial w h o are 
N O T c o m pletel y a bst i ne nt as t heir preferre d a n d us ual lifestyle, or i n a sa me se x relati o ns hi p, as 
part of t heir preferre d a n d us ual lifest yle :
T o pic
E x pl a n ati o n
Pre g na nc y testi n g
Ne gati ve s er u m r es ult at scree ni n g f oll o we d b y a 
ne gati ve ser u m res ult wit hi n 2 4 h o urs pri or t o 
treat me nt e x p os ure
N ote: s u bse q ue nt pre g na nc y testi n g is c o m p o u n d 
s pecific
C o ntrace pti o n
A gr ee t o use 2 f or ms of effecti ve c o ntrace pti o n, 
w her e at least o ne f or m m ust be hi g hl y effecti ve 
(less t ha n 1 % fail ure rate)
E xa m ples of differe nt f or ms of c o ntrace pti o n: 
Met h o ds
E x a m ples
Hi g hl y effecti ve c o ntrace pti o n 

c o m bi nati o n oral c o ntrace pti ve pill a n d 
mi ni -pill

i m pla nte d c o ntrace pti ves

i njecta ble c o ntrace pti ves

c o ntrace pti ve patc h ( o nl y w o me n 
< 1 9 8 p o u n ds or 9 0 k g)

vasect o m y (if o nl y se x ual part ner)

fall o pia n t u be i m pla nts (if c o nfir me d b y 
h yster osal pi n g o gra m)

c o m bi ne d c o ntrace pti ve va gi nal ri n g, or 

i ntra uteri ne de vices
Effecti ve c o ntrace pti o n 

ma le or fe male c o n d o ms wit h s per mici de 

dia p hra g ms wit h s per mici de or cer vical 
s p o n ges

barrier met h o d wit h use of a s per mici de
o
c o n d o m wit h s per mici de

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
5 7
o
dia p hra g m wit h s per mici de, or
o
fe male c o n d o m wit h s per mici de
N ote: T he barrier met h o d m ust i ncl u de use of a
s permici de (i.e., c o n d o m wit h s per mici de, 
dia p hra g m wit h s per mici de, fe male c o n d o m wit h 
s permici de) t o be c o nsi dere d effecti ve.
Us e of ma le a n d fe male c o n d o ms as a d o u ble 
barrier met h o d is n ot c o nsi dere d effecti ve.
I neffecti ve f or ms of c o ntrace pti o n

s per mici de al o ne 

i m m u n oc o ntrace pti ves

peri o dic a bsti ne nce

f ertilit y a ware ness (cale n dar met h o d, 
te m perat ure met h o d, c o m bi nati o n of 
a b o ve 2, cer vical m uc us, s y m pt ot her mal)

wit h dra wal

p ost c oital d o uc he

lactati o nal a me n orr hea
C ollecti o n of Pre g n a nc y I nf or m ati o n
M ale p artici p a nts wi t h p art ners w h o bec o me pre g n a nt
●
T he i n vest i gat or will atte m pt t o c ollect pre g na nc y i nf or mati on o n a n y male partici pa nt’s 
fe male part ner w h o bec o mes pre g na nt w hile t he male partici pa nt is i n t his st u d y. T his 
a p plies o nl y t o male partici pa nts w h o recei ve mir i kiz u ma b.
●
After o btai ni n g t he necessar y  si g ne d i nf or me d c o nse nt fr o m t he pre g na nt fe male part ner 
di rectl y, t he i n vesti gat or will rec or d pre g na nc y i nf or mati o n o n t he a p pr o priate f or m a n d 
s u b mit it t o t he s p o ns or wit hi n 2 4 h o urs of  lear ni n g of t he part ner’s pre g na nc y. T he 
fe male part ner will als o be f o ll owe d t o deter mi ne t he o utc o me of t he pre g na nc y. 
I nf or mat i on o n t he stat us of t he m ot her a n d c hil d will be f or war de d t o t he s p o ns or. 
Ge nerall y, t he f o ll ow- u p will be n o l o n ger t ha n 6 t o 8 wee ks f o ll owi n g t he esti mate d 
deli ver y  date. A n y t ermi nat i on of t he pre g na nc y will be re p orte d re gar dless of gestati o nal  
a ge, fetal stat us ( prese nce or a bse nce of a n oma lies), or i n dicati on f or t he pr oce d ure. 
Fe m ale p a r tici p a nts w h o bec o me pre g n a nt
●
T he i n vest i gat or will c ollect pre g na nc y i nf or mati o n o n a ny fe male partici pa nt w h o 
bec o me s pre g na nt w hile partici pat i n g i n t his st u d y. T he i nit ial i nf or mati on will be 
rec or de d o n t he a p pr o priate f or m a n d s u b mitte d t o t he s p o ns or wit hi n 2 4 h o urs of  
lear ni n g of a partici pa nt's pre g na nc y. 
●
T he parti ci pa nt will be f oll owe d t o deter mi ne t he o utc o me of t he pre g na nc y . T he 
i n vesti gat or will c ollect f oll ow- u p i nf or m at i on o n t he partici pa nt a n d t he ne o nate a n d t he 
i nf or mat i on will be f or war de d t o t he s p o ns or. Ge nerall y, f o ll ow- u p will n ot be re q ui re d 
f or lo n ger t ha n 6 t o 8 wee ks be y o n d t he esti mate d deli ver y date. A n y ter mi nat i on of 
pre g na nc y will be re p orte d , re gar dless of gestati o n al  a ge, fetal stat us ( prese nce or a bse nce 
of  a n oma lies), or i n dicat i on f or t he pr oce d ure.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
5 8
●
W hile pre g na nc y  itself is n ot c o nsi dere d t o be a n A E or S A E, a n y pre g na nc y 
c o mplicat i on or el ect i ve ter mi nati on of a pre g na nc y  f or me dical reas o ns will be re p orte d 
as a n A E or S A E. 
●
A s p o nta ne o us a b orti o n ( occ urri n g at < 2 0 wee ks gestati o nal a ge) or still birt h ( occ urri n g 
at ≥2 0 wee ks gestati o nal a ge) is al wa ys c o nsi dere d t o be a n S A E a n d will be re p orte d as 
s uc h. 
●
A n y p ost -stu d y pre g na nc y -relate d S A E c o nsidere d reas o na bl y relate d t o t he st u d y  
i nter ve nt i on b y t he i n vesti gat or will be re p orte d t o t he s p o n s or as descri be d i n pr ot oc ol  
Secti o n 8. 3. 1 . W hile t he i n vesti gat or is n ot o bli gate d t o acti vel y see k t his i nf or mati on i n 
f or mer st u d y p artici pa nts, he or s he ma y lear n of a n S A E t hr o u g h s p o nta ne o us re p orti n g.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
5 9
1 0. 5.
A p pe n di x 5 : Ge netics
Use/ A n al ysis of D N A
Ge net ic variat i on ma y i m pact a partici pa nt’s res p o nse t o st u d y int er ve nt i on, s usce pt i bility t o, a n d 
se verity a n d pr o gressio n of  disease. Varia ble res p o ns e t o st u d y int er ve nt i on ma y be d ue t o 
ge net ic deter mi na nts t hat i m pact dr u g a bs or pti o n, distri b uti on, meta b o lis m, a n d e xcreti o n; 
mec ha nis m o f actio n of  t he dr u g; disease eti ol og y; a n d/ or m ol ec ular s u bt y pe of t he disease bei n g 
treate d. T heref ore, w here l ocal re g ulat i ons a n d I R B/I E C all o w, a bl o o d sa mple will be c ollecte d 
f or D N A a nal ysis fr om c o nse nti n g part ici pa nts.
D N A sa m ples will be use d f or researc h relate d t o mir i kiz u ma b or I L- 2 3-me d iate d a ut oi m m u ne 
di sease, a n d relate d diseases. T he y ma y  als o be use d t o de vel o p tests/assa ys i ncl u di n g dia g n ostic 
tests relate d t o miri kiz u ma b a n d/ or i nter ve nti ons of t his dr u g class a n d I L- 2 3- me d iate d 
a ut oi m m u ne disease. Ge net ic researc h ma y c o nsist of t he a nal ysis of o ne or m ore ca n di date 
ge nes or t he a nal ysis of ge net ic mar kers t hr o u g h o ut t he ge n o me or a nal ysis o f t he e nt ire ge n o me
(as a p pr o priate).
T he sa m ples ma y be a nal yze d as part of a m ulti-st u d y assess me nt of ge netic fact ors i n v ol ve d i n 
t he res p o nse t o mir i kiz u ma b or st u d y  int er ve nt i ons of t his class t o u n dersta n d st u d y  disease or 
r elate d c o n ditio ns.
T he res ults of ge net ic a nal yses ma y be re p orte d i n t he cli nical st u d y re p ort or i n a se parate st u d y 
s u m mar y.
T he s p o ns or will st ore t he D N A sa m ples i n a sec ure st ora ge s pace wit h a de q uate meas ures t o 
pr otect c o nfi de nt iality.
T he sa m ples will be retai ne d w hile researc h o n mir i kiz u ma b c o nti n ues b ut n o l o n ger t ha n 
1 5 years or ot her peri o d as per l ocal re q uire me nts.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
6 0
1 0. 6.
A p pe n di x 6: Li ver S afet y: S u g geste d Acti o ns a n d F oll o w - up 
Assess me nts 
He p atic E v al u ati o n Testi n g
See Secti o n 8. 2. 6. 1 f or g uida nce o n a p pr o pri ate test select i on.
T he Lill y -desi g nate d ce ntral la b orat or y  must c o mplete t he a nal ysis of all selecte d testi n g e xce pt 
f or micr o biol o g y  testi n g.
L ocal  testi n g ma y be perf or me d i n a d diti on t o ce ntral testi n g w he n necessar y f or i m me diate 
parti ci pa nt ma na ge me nt.
Res ults will be re p orte d if a vali date d test or calc ulati o n i s a vaila ble.
He m at ol o g y
Cli nic al C he mistr y
He m o gl o bi n
T otal bilir u bi n
He mat ocrit
Direct bilir u bi n
Er yt hr oc ytes ( R B Cs - r ed bl o o d cells)
Al kali ne p h os p hatase ( A L P)
Le u k oc ytes ( W B Cs - w hite bl o o d cells)
Ala ni ne a mi n otra nsferase ( A L T)
Differ e ntial:
As partate a mi n otra nsferase ( A S T)
    Ne utr o p hils, se g me nte d
Ga m ma -gl uta m yl tra nsferase ( G G T)
    L y m p h oc ytes
Creati ne ki nase ( C K)
    M o n oc ytes
Ot her C he mistr y
    Bas o p hils
Aceta mi n o p he n
    E osi n o p hils
Aceta mi n o p he n pr otei n a d d ucts
Platelets
Al kali ne p h os p hatase is oe nz y mes
Cell m or p h ol o g y ( R B C a n d W B C)
Cer ul o plas mi n
C o a g ul ati o n
C o p per
Et h yl alc o h ol ( Et O H)
Pr ot hr o m bi n ti me, i nter nati o nal n or malize d 
rati o ( P T-I N R)
Ha pt o gl o bi n
Ser ol o g y
I m m u n o gl o b uli n I g A ( q ua ntitati ve)
He patitis A vir us ( H A V) testi n g:
I m m u n o gl o b uli n I g G ( q ua ntitati ve)
    H A V t otal a nti b o d y
I m m u n o gl o b uli n I g M ( q ua ntitati ve)
    H A V I g M a nti b o d y
P h os p hati d ylet ha n ol ( P Et h)
He patis B vir us ( H B V) testi n g:
Uri ne C he mistr y
    He patitis B s urface a nti ge n ( H Bs A g)
Dr u g scree n
    He patitis B s urface a nti b o d y (a nti -H Bs)
Et h yl gl uc ur o ni de ( Et G)
    He patitis B c ore t otal a nti b o d y (a nti -H Bc)
Ot her Ser ol o g y
    He patitis B c ore I g M a nti b o d y
A nti -n uclear a nti b o d y ( A N A)
    He patitis B c ore I g G a nti b o d y
A nti -s m o ot h m uscle a nti b o d y ( A S M A) a

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
6 1
    H B V D N A d
A nti -acti n a nti b o d y b
He pa titis C vir us ( H C V) testi n g:
E pstei n -Barr vir us ( E B V) testi n g:
    H C V a nti b o d y
    E B V a nti b o d y
    H C V R N A d
    E B V D N A d
He patitis D vir us ( H D V) testi n g:
C yt o me gal o vir us ( C M V) testi n g:
    H D V a nti b o d y
    C M V a nti b o d y
He patitis E vir us ( H E V) testi n g:
    C M V D N A d
    H E V I g G a nti b o d y
Her pes si m ple x vir us ( H S V) testi n g:
    H E V I g M a nti b o d y
    H S V ( T y pe 1 a n d 2) a nti b o d y 
    H E V R N A d
    H S V ( T y pe 1 a n d 2) D N A
d
Micr o bi ol o g y 
c
Li ver ki d ne y micr os o mal t y pe 1 ( L K M -1) a nti b o d y
C ult ure:
    Bl o o d
    Uri ne
a
N ot re q uire d if a nti -acti n a nti b o d y is teste d.
b
N ot re q uire d if A S M A is teste d.
c
Assa y e d O N L Y b y i n vesti gat or -desi g nate d l ocal la b orat or y; n o ce ntral testi n g a vaila ble.
d
Refle x/c o nfir mati o n de pe n de nt o n re g ulat or y re q uire me nts, testi n g a vaila bilit y, or b ot h.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
6 2
1 0. 7.
A p pe n di x 7: Rec o m me n de d L a b or at or y Testi n g f or H y perse nsiti vit y 
E ve nts
La b orat or y  assess me nts s h o ul d be perf or me d if t he partici pa nt e x perie nces ge neralize d urticaria 
or if a na p h yla xis is s us pecte d.

C ollect sa m ple after t he partici pa nt has bee n sta bilize d, a n d wit hi n 1 t o 2 h o urs of t he 
e ve nt; h o we ver, sa m ples ma y be o btai ne d as late as 1 2 h o urs after t he e ve nt as a nal ytes 
ca n re mai n altere d f or a n e xte n de d peri o d of ti me. Rec or d t he ti me at w hic h t he sa m ple 
was c ollecte d.

O btai n a f o ll ow- u p sa m ple after a p p r o xi matel y 4 wee ks.
Cli nic al L a b or at or y Tests f or H y perse nsiti vit y E ve nts
H y perse nsiti vit y Tests
N otes
Selecte d test ma y be o btai ne d i n t he e ve nt of a na p h yla xis or 
s yste mic aller gic/ h y perse nsiti vit y reacti o ns.
L Y 3 0 7 4 8 2 8 a ntidr u g
a nti b o dies 
(i m m u n o ge nicit y/ A D A)
Assa ye d b y Lill y -desi g nate d la b orat or y. 
Res ults will n ot be pr o vi de d t o t he i n vesti gati ve sites.
L Y 3 0 7 4 8 2 8 c o nce ntrati o ns 
( P K)
Assa ye d b y Lill y -desi g nate d la b orat or y. 
Res ults will n ot be pr o vi de d t o t he i n vesti gati ve sites.
Tr y ptase
Assa ye d b y Lill y -desi g nate d la b orat or y. 
Res ults will n ot be pr o vi de d t o t he i n vesti gati ve sites.
Uri ne N -met h yl hista mi ne testi n g is perf or me d i n a d diti o n t o 
tr y ptase testi n g. C ollect t he first v oi d uri ne f oll o wi n g t he e ve nt. 
C ollect a f oll o w -u p uri ne sa m ple after a p pr o xi matel y 4 wee ks.
N ote: If a tr y ptase sa m ple is o btai ne d m ore t ha n 2 h o urs after t he 
e ve nt (t hat is, wit hi n 2 t o 1 2 h o urs), or is n ot o btai ne d beca use m ore 
t ha n 1 2 h o urs ha ve la pse d si nce t he e ve nt, c ollect a uri ne sa m ple f or 
N -met h yl hista mi ne testi n g. 
N -met h yl hista mi ne
Assa ye d b y Lill y -desi g nate d la b orat or y. 
Res ults will n ot be pr o vi de d t o t he i n vesti gati ve sites.
Bas o p hil acti vat i o n test
Will be perf or me d if a vali date d assa y is a vaila ble.
Assa ye d b y Lill y -desi g nate d la b orat or y. 
Res ults will n ot be pr o vi de d t o t he i n vesti gati ve sites.
N ot e : T he bas o p hil acti vati o n test is a n i n vitr o cell base d assa y 
t hat o nl y re q uires a ser u m s a mpl e . It is a s urr o gate assa y f or 
dr u g -s pecific I g E b ut is n ot s pecific f or I g E.
C o m ple me nt ( C 3, C 3a , a n d 
C 5a)
Assa ye d b y Lill y -desi g nate d la b orat or y. 
Res ults will n ot be pr o vi de d t o t he i n vesti gati ve sites.
C yt o ki ne pa nel
Assa ye d b y Lill y -desi g nate d la b orat or y. 
Res ults will n ot be pr o vi de d t o t he i n vesti gati ve sites.
A b bre viati o ns: A D A = a nti dr u g a nti b o d y; I g E = i m m u n o gl o b uli n E; P K = p har mac o ki netic.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
6 3
1 0. 8. A p pe n di x 8 : Me dic al De vice A d verse E ve nts, A d verse De vice Effects, 
Seri o us A d verse E ve nts , a n d De vice Deficie ncies: Defi niti o n a n d 
Pr oce d ures f or Rec or di n g, E v al u ati n g, F oll o w -u p, a n d Re p orti n g
Refer t o A p pe n di x 3 ( Sectio n 1 0. 3 ) f or defi nitio n s a n d pr oce d ures f or rec or di n g, e val uat i n g, 
f oll ow -u p, a n d re p orti n g of all e ve nts.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
6 4
1 0. 9.
A p pe n di x 9 : A b bre vi ati o ns
T er m
D efi 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
AI
a ut oi nject or
A L P
al kali ne p h os p hatase
A L T
ala ni ne a mi n otra nsferase
A S T
as partate a mi n otra nsferase
A U C
area u n der t he c o nce ntrati o n vers us ti me c ur ve
A U C( 0 -∞) 
area u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m ti me zer o t o i nfi nit y
A U C( 0 -tl a st)
area u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m ti me zer o t o ti me t, w here t is t he 
last ti me p oi nt wit h a meas ura ble c o nce ntrati o n
C D
Cr o h n’s disease
C F R
C o de of Fe deral Re g ulati o ns
CI
c o nfi de nce i nter val
C L/ F
a p pare nt t otal b o d y cleara nce of dr u g calc ulate d after e xtra -va sc ular a d mi nistrati o n
C m a x
ma xi m u m o bser ve d dr u g c o nce ntrati o n
c o m pl ai nt
A c o m plai nt is a n y writte n, electr o nic, or oral c o m m u nicati o n t hat alle ges deficie ncies 
relate d t o t he i de ntit y, q ualit y, p urit y, d ura bilit y, relia bilit y, safet y or effecti ve ness, or 
perf or ma nce of a dr u g or d r u g deli ver y s yste m.
c o m pli a n c e
A d here nce t o all st u d y -relate d, g o o d cli nical practice ( G C P), a n d a p plica ble re g ulat or y 
re q uire me nts.
C P
cli nical p har mac ol o gist
C R F
case re p ort f or m
C R P
cli nical researc h p h ysicia n: I n di vi d ual res p o nsi ble f or t he me dical c o n d uct of t he st u d y. 
Res p o nsi bilities of t he C R P ma y be perf or me d b y a p h ysicia n, cli nical researc h 
scie ntist, gl o bal safet y p h ysicia n or ot her me dical officer.
C R U
cli nical researc h u nit
C V
c oefficie nt of variati on
d e vi c e d efi ci e n ci e s
E q ui vale nt t o pr o d uct c o m plai nt.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
6 5
T er m
D efi niti o n
E C G
electr ocar di o gra m
e C R F
electr o nic case re p ort f or m
E D C
electr o nic data ca pt ure
e nr oll
T he act of assi g ni n g a partici pa nt t o a treat me nt. Partici pa nts w h o are e nr olle d i n t he 
st u d y are t h ose w h o ha ve bee n assi g ne d t o a treat me nt.
e nt er
Partici pa nts e ntere d i nt o a st u d y are t h ose w h o si g n t he i nf or me d c o nse nt f or m directl y 
or  t hr o u g h t heir le gall y acce pta ble re prese ntati ves.
G C P
g o o d cli nical practice
HI V
h u ma n i m m u n o deficie nc y vir us
I B
I n vesti gat or’s Br oc h ure
I C F
i nf or me d c o nse nt f or m
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
I E C
in de pe n de nt et hics co m mittee
I L
i nterle u ki n
inf or m e d c o n s e nt
A pr ocess b y w hic h a partici pa nt v ol u ntaril y c o nfir ms his or her willi n g ness t o 
partici pate i n a partic ular st u d y, after ha vi n g bee n i nf or me d of all as pects of t he st u d y 
t hat are rele va nt t o t he partici pa nt’s decisi o n t o partici pate. I nf or me d c o nse nt is 
d oc u me nte d b y mea ns of a writte n, si g ne d a n d date d i nf or me d c o nse nt f or m .
i n v e sti g ati o n al 
pr o d u c t
A p har mace utical f or m of a n acti ve i n gre die nt or place b o bei n g teste d or use d as a 
refere nce i n a cli nical trial, i ncl u di n g pr o d ucts alrea d y o n t he mar ket w he n use d or 
asse m ble d (f or m ulate d or pac ka ge d) i n a wa y differe nt fr o m t he a ut h orize d f or m, or 
mar kete d pr o d ucts use d f or a n u na ut h orize d i n dicati o n, or mar kete d pr o d ucts use d t o 
gai n f urt her i nf or mati o n a b o ut t he a ut h orize d f or m.
I R B
instit uti o nal re vie w b oar d
I S R
i njecti o n-site reacti o n
I V
i ntra ve n o us
L S
least s q uares
p arti ci p a nt
E q ui vale nt t o C DI S C ter m “s u bject”: a n i n di vi d ual w h o partici pates i n a cli nical trial, 
eit her as reci pie nt of a n i n vesti gati o nal me dici nal pr o d uct or as a c o ntr ol
P C
pr o d uct c o m plai nt
P F S
pr e -fille d s yri n ge
P K
p har mac o ki netics

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
6 6
T er m
D efi niti o n
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S C
su bc uta ne o us (l y)
s cr e e n
T he act of deter mi ni n g if a n i n di vi d ual meets mi ni m u m re q uire me nts t o bec o me part of 
a p o ol of p ote ntial ca n di dates f or partici pati o n i n a cli nical st u d y. 
S o A
Sc he d ule of Acti vities
t1/ 2 
half -life ass ociate d wit h t he ter mi nal rate c o nsta nt 
T B
t u berc ul osis
T B L
t otal bilir u bi n le vel
T E -A D A
treat me nt-e mer ge nt a nti dr u g a nti b o dies
T E A E
treat me nt-e mer ge nt a d verse e ve nt: A n u nt o war d me dical occ urre nce t hat e mer ges 
d uri n g a defi ne d treat me nt peri o d, ha vi n g bee n a bse nt pretreat me nt, or w orse ns relati ve 
t o t he pretreat me nt state, a n d d oes n ot necessaril y ha ve t o ha ve a ca usal relati o ns hi p 
wit h t his treat me nt.
tm a x
ti me t o ma xi m u m o bser ve d dr u g c o nce ntrati o n
U C
ulcerati ve c olitis
U L N
u p per li mit of n or mal
V A S
vis ual a nal o g scale
V z/ F
a p pare nt v ol u me of distri b uti o n d uri n g t he ter mi nal p hase after e xtra -vasc ular 
a d mi nistrati o n

C O N FI D E N TI A L
Pr ot oc ol  n u m ber I 6 T-M C -A M B X
6 7
1 1.
Refere nces
Willia ms o n A, H o g gart B. Pai n: a re vie w o f t hree c o m m onl y  use d pai n rati n g scales. J Cli n 
N urs . 2 0 0 5; 1 4( 7): 7 9 8 - 8 0 4.

L e o  D o c u m e n t  I D  =  2 4 3 b a 7 d 7 - c e 9 5 - 4 1 9 e - 8 5 7 e - 1 a e 0 e d 0 7 9 e e 2
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 1 - A u g - 2 0 2 1  0 3 : 2 5 : 4 7  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :
A p p r o v a l  D a t e  &  T i m e :  1 1 - A u g - 2 0 2 1  1 9 : 1 0 : 5 2  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D
P P D